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Introduction Use of the two commercially available anti CD19 chimeric antigen receptor T-cell (CAR T-cell) therapies in patients with relapsed and refractory (R/R) large B-cell lymphoma (LBCL) is associated with significant inpatient and outpatient resource utilization, which has not been systematically compared. We characterized institutional resources used around Tisagenlecleucel (tisa-cel) and Axicabtagene ciloleucel (axi-cel) infusion and identified factors that led to longer hospitalization during the first 100 days of therapy. Methods We reviewed medical records of consecutive adult patients with R/R LBCL treated with tisa-cel or axi-cel at our center from May 2018 to May 2020. Resource utilization data included inpatient hospital days, outpatient clinic visits, radiological studies, cardiac/neurologic studies, invasive procedures and pharmaceutical resources. "Days alive and out-of-hospital at Day 100" (DAOH100), were defined as the number of living days that a patient spent out-of-hospital, which served as a surrogate for institutional resource utilization, as it accounted for duration of index hospitalization, re-admissions and days lost due to premature death, within first 100 days of therapy. Data were collected from the day of leukapheresis through Day 100 post CAR T-cell infusion (day 0), and compared between tisa-cel and axi-cel recipients. Results Of 46 patients with R/R LBCL, axi-cel was used in 35 (76%) and tisa-cel in 11 (24%) patients. 30 (65%) patients were male, 44 (96%) were Caucasian, with median age of 61 (range, 25-77) years and 3 (range, 2-6) prior lines of therapy. Forty- one (89%) patients had stage III/IV disease, 24 (52%) had IPI 0-2, 36 (78%) had ECOG PS 0 or 1 and 29 (63%) had HCT-CI Median duration of hospitalization was 14 (range, 7-53) days, with 13 (28%) patients requiring ICU admission for a median of 3 days (range, 1-19). The median number of outpatient clinic visits, radiology studies, cardiac/neurologic evaluations and invasive diagnostic procedures through Day 100 were 5 (range, 0-11), 6 (range, 1- 31), 1 (range, 0-33) and 0 (range, 0-5), respectively. Patients required a median of 1 (range, 0-4) dose(s) of tocilizumab, 0 (range, 0-14) days of IV steroids, 7 (range, 0- 54) days of IV antibiotics and 7 (range, 0-60) blood product transfusions. When compared to patients receiving axi-cel, the tisa-cel group had significantly shorter hospital stay (P= 0.02), shorter IV steroid days (P= 0.006), fewer tocilizumab doses (P=0.04) and fewer blood product transfusions (P=0.0004) (Table 2). Cytokine release syndrome (CRS) and immune effector cell mediated neurotoxicity syndrome (ICANS) were seen in 35 (76%) and 23 (50%) patients, respectively. In comparison to axi-cel, significantly fewer patients with tisa-cel had moderate to severe (≥ Grade 2) CRS (18.18 % vs. 60%; P= 0.04), and moderate to severe (≥ Grade 2) ICANS (0% vs. 37.14%; P= 0.02) (Table 2). By Day 100, 15 (32.6%) patients had died and 4 (10.8%) had disease progression. The median DAOH100 were 86 (range, 0-93) days. Patients receiving tisa-cel experienced longer median DAOH100 compared to those receiving axi-cel (89 vs. 86; P= 0.01) (Table 2). DAOH100 were higher for patients with favorable ECOG PS (0 or 1) vs. unfavorable (≥ 2) (median of 87 vs 73 days, P=0.01). Patients with no/mild CRS, and those with no/mild ICANS, had longer DAOH100 vs. those with ≥ Grade 2 CRS and ≥ Grade 2 ICANS (median of 87 vs. 84 days; P= 0.047 & median of 87 vs. 70 days; P= 0.01), respectively. DAOH100 did not differ with respect to age, gender, stage, HCT-CI, IPI or number of prior therapies (Table 3). Conclusion Through the first 100 days of CAR T-cell therapy, R/R LBCL patients receiving tisa-cel had shorter hospital length of stay, more days alive and out-of-hospital, received fewer tocilizumab doses, steroid days and blood product transfusions, compared to those treated with axi-cel. Patients receiving tisa-cel also experienced lesser incidence of moderate/severe CRS and ICANS. Favorable ECOG PS and absence of moderate/severe CRS or ICANS significantly increased DAOH100. In light of these differences in toxicity and resource utilization, a future study is needed to compare efficacy of axi-cel vs. tisa-cel in larger patient cohorts. Disclosures Hill: Genentech: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding. Hamilton:Syndax Pharmaceuticals: Consultancy, Honoraria. Khouri:Sanofi Genzyme: Other: Advisory Board. Jagadeesh:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Debiopharm Group: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Regeneron: Research Funding; MEI Pharma: Research Funding. Anwer:Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau. Gerds:CTI Biopharma: Consultancy, Research Funding; Roche/Genentech: Research Funding; Incyte Corporation: Consultancy, Research Funding; AstraZeneca/MedImmune: Consultancy; Apexx Oncology: Consultancy; Celgene: Consultancy, Research Funding; Gilead Sciences: Research Funding; Imago Biosciences: Research Funding; Sierra Oncology: Research Funding; Pfizer: Research Funding. Majhail:Mallinckrodt: Honoraria; Anthem, Inc.: Consultancy; Nkarta Therapeutics: Honoraria; Incyte: Honoraria.

Introduction Early non-infectious pulmonary toxicity (NIPT) is a significant HCT complication and comprises diffuse alveolar hemorrhage (DAH), idiopathic pneumonia syndrome (IPS), and cryptogenic organizing pneumonia (COP) with an overall incidence ranging 1-10%. Treatment options are primarily immunosuppressive therapy and supportive care with limited efficacy. Mortality in IPS, for example, approaches 60-80% (PMID: 21531955). Therefore, to better identify potentially high-risk patients (pts) we performed a registry-based analysis of the incidence, risk factors, and outcomes of early NIPT after HCT. Methods This retrospective study included adult pts undergoing allogenic HCT for hematologic malignancies and non-malignant disorders as reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) (2008-2017). Data analyses were divided into four common disease categories (AML/ALL, CML/MDS/MPN, NHL/CLL/PCD, and non-malignant diseases) to minimize statistical interactions in the multivariate model. The primary outcome was the incidence of and risk factors for individual NIPT and a composite of the three NIPT (IPS, DAH, COP); the secondary outcome was overall survival (OS). Multivariable Cox proportional hazards regression models were developed to identify the risk factors for NIPT and OS. In addition to baseline pre-transplant covariates, post-transplant neutrophil recovery (>500/mcL x 3 consecutive days), platelet recovery (>20k/mcL x 3 consecutive days, without transfusion in 7 previous days) and grade 2-4 acute GVHD were included as time-dependent covariates in the multivariable models. Results Characteristics of 21,587 adult pts are shown in Table 1. Median age at HCT was 54 years, 59% were male, and 39% had KPS Table 2 shows the cumulative incidence of early NIPT amongst pts in the four disease categories. Multivariable analysis in the AML/ALL group identified TBI-based conditioning, grade 2-4 acute GVHD, HCT-CI score of 1-3, and prior autologous HCT were associated with increased risk of NIPT, while platelet recovery decreased the risk of NIPT. In the CML/MDS/MPN group, smoking history, grade 2-4 acute GVHD and HCT-CI scores of 2-5+ were associated with increased risk of NIPT, while non-TBI and non-myeloablative TBI conditioning and platelet recovery were associated with a lower risk. In the NHL/HD/CLL/PCD group, a higher risk of NIPT was seen with severe pulmonary comorbidity pre-HCT and chronic GVHD, while platelet recovery and non-TBI regimens were associated with a lower risk. In the non-malignant disease group, both neutrophil and platelet recovery were associated with a lower risk of NIPT. Furthermore, the multivariable analysis for OS (Table 2) showed across all disease groups, NIPT increased the risk of mortality (vs. no NIPT; HR of 4.3 in AML/ALL, 4.1 in CML/MDS/MPN, 3.5 in NHL/CLL/PCD, 6.8 in non-malignant diseases; p Conclusions This large registry-based analysis of allogeneic HCT pts highlights several risk factors for the development of early NIPT including smoking history, severe pulmonary comorbidity, myeloablative TBI conditioning, and acute and/or chronic GVHD. Identification of these risk factors can enhance appropriate selection of pts prior to HCT. We also found that post-transplant, platelet and neutrophil recovery was associated with a reduced risk of NIPT. Furthermore, early NIPT is associated with a several-fold higher mortality risk in the current era despite significant advances in supportive care. Future studies are needed to optimize risk factors such as conditioning regimen and graft source selection to reduce the risk of early NIPT. Disclosures Ustun: Kadmon: Honoraria. Hamilton:Syndax Pharmaceuticals: Consultancy, Honoraria. Majhail:Anthem, Inc.: Consultancy; Incyte: Honoraria; Nkarta Therapeutics: Honoraria; Mallinckrodt: Honoraria. Sorror:Jazz Pharmaceutical: Other: Honorarium for Advisory role. . Stadtmauer:Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Novartis, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology: Consultancy. Pasquini:Bristol Myers Squibb: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Other; Novartis: Research Funding; Kite: Research Funding.

Background: Chronic graft versus host disease (cGVHD) is a major cause of morbidity and late non-relapse mortality after allogeneic hematopoietic cell transplantation and is commonly associated with prolonged immune suppression. Patients (pts) with inadequate response to steroids have few effective therapeutic options and represent an unmet medical need. Available therapies are associated with significant toxicity, immunosuppression, and increased risk of infections. Preclinical studies demonstrate that CSF-1/CSF-1R is a key regulatory pathway involved in the expansion and infiltration of donor-derived macrophages that mediate cGVHD. Axatilimab (SNDX-6352, axa) is a humanized, full-length IgG4 antibody with high affinity to CSF-1R. Axa affects the migration, proliferation, differentiation, and survival of monocytes and macrophages by binding to CSF-1R and blocking its activation by its two known ligands, CSF-1 and IL-34. It offers a novel therapeutic option for treatment of these pts Methods: SNDX-6352-0503 is a Phase 1/2 dose-escalation and dose-expansion study evaluating safety, tolerability, pharmacokinetics (PK)/pharmacodynamics (PD), and efficacy of axa in pts >6 years of age with active symptomatic cGVHD despite ≥2 prior lines of therapy. The Phase 1 endpoints were safety, tolerability, PK and PD with the primary objective of defining optimal biologic dose; the primary endpoint of the Phase 2 study is overall response rate (CR+PR) by 6 months. Pts were dosed in 28-day cycles. The data cutoff was 22 July 2020. Results: Twelve pts have been enrolled in the Phase 1 study. Median age at enrollment was 58y (range, 29-73y), 8 pts were male. Pts had failed a median of 5 prior lines of treatment (range 4-9). Doses included 0.15 mg/kg (n=1), 0.5mg/kg (n=1), 1mg/kg (n=3), 3 mg/kg (n=6) every 2 weeks (q2w), and 3mg/kg q4w (n=1). Of these, 5 pts (42%) are still receiving axa. The median number of cycles for all pts is 5 (range 1-12). Of the 3 pts whose starting dose was 3 mg/kg q2w and remain on study, 2 dose reduced; one to 2 mg/kg q4w and one to 1 mg/kg q2w. Seven pts (58%) discontinued due to: adverse events (3 mg/kg q2w, n=2); death due to traumatic fall (1 mg/kg q2w, n=1); investigator decision (0.5 mg/kg q2w, n=1); progressive cGVHD (1 and 0.15 mg/kg q2w, n=1 each); and non-compliance (3 mg/kg q2w, n=1). Two of 6 pts (17%) at a dose of 3 mg/kg q2w reported a treatment emergent adverse event that was considered a dose limiting toxicity (DLT): 1 with CTCAE Grade 4 creatine kinase increase with symptoms of myositis after dose 1, and the 2nd with an elevation in amylase/lipase that delayed the 3rd dose for >2 weeks. The latter pt restarted therapy at 1 mg/kg q2w and remains on treatment after 5 cycles. Four pts (1 at 0.15 mg/kg and 3 at 3 mg/kg q2w, 33%) had a related treatment emergent adverse event that was ≥Grade 3: increase in aspartate aminotransferase (n=2); increase in creatine phosphokinase (n=2); and increase in gamma-glutamyl transferase (n=2). Such biochemical elevations may be a consequence of CSF-1R blockade on Kupffer cells leading to an inhibition in the clearance of these enzymes, consistent with the mechanism of action of axa and when asymptomatic have not been associated with clinical manifestations of hepatitis, pancreatitis, or rhabdomyolysis. Periorbital edema was observed in 2 pts (≤Grade 2); no additional CSF-1Ri class-effect associated TEAEs were observed Clinical responses as defined by the 2014 NIH cGVHD Consensus Criteria have been observed in 7 pts (58%) across all dose levels; median time to response was 12 weeks. Organ-specific responses have been observed in esophagus (n=1/1), eyes (n=3/10), joints/fascia (n=5/9), mouth (n=1/7), and skin (n=3/8). Prior therapies received by the responders included ibrutinib (6 pts), ruxolitinib (5 pts), and KD025 (3 pts); 3 of the responding pts had received all of these. Six pts (50%) reported at least a 7-point improvement in the Lee Symptom Score. Preliminary PK profiles and pharmacodynamic endpoints, including circulating CD14+CD16+ nonclassical and CD14++CD16+ intermediate monocyte kinetics, are consistent with those observed in healthy volunteers and pts with solid tumors see figure below. Conclusions: These data demonstrate that axatilimab is clinically active with acceptable safety profile and responses observed in heavily pretreated pts with active cGVHD. Enrollment continues in the Phase 1 study at 3 mg/kg q4w and Phase 2 study at a dose of 1 mg/kg q2w. Figure Disclosures Arora: Syndax: Research Funding; Fate Therapeutics: Consultancy; Pharmacyclics: Research Funding; Kadmon: Research Funding. Jagasia:Janssen: Research Funding; Mallinckrodt: Research Funding; Ocugen: Other. Meyers:Syndax Pharmaceuticals, Inc: Current Employment. Quaranto:Syndax Pharmaceuticals, Inc: Current Employment. Schmitt:Syndax Pharmaceuticals, Inc: Current Employment. Sankoh:Syndax Pharmaceuticals, Inc: Current Employment. Abu Zaid:Syndax: Research Funding. Hill:Roche: Research Funding; Generon: Consultancy; CSL: Research Funding; Implicit Bioscience: Research Funding; Pharmacyclics: Research Funding; Compass Pharmaceuticals: Research Funding. Weisdorf:Incyte: Research Funding; FATE Therapeutics: Consultancy. Blazar:BlueRock Therapeuetic: Consultancy; Magenta Therapeutics: Consultancy; BlueRock Therapeutics: Research Funding; Childrens' Cancer Research Fund: Research Funding; KidsFirst Fund: Research Funding; Tmunity: Other: Co-founder; Fate Therapeutics Inc.: Research Funding. Ordentlich:Syndax Pharmaceuticals, Inc: Current Employment. Lee:Takeda: Research Funding; AstraZeneca: Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Research Funding; Novartis: Research Funding; Kadmon: Research Funding; Incyte: Consultancy, Research Funding; Syndax: Research Funding. OffLabel Disclosure: The drug (Axatilimab) is a humanized antibody against CSF-1R. The study is a phase I trial testing this drug in patients with chronic graft versus host disease

BACKGROUND Autologous hematopoietic cell transplantation (AHCT) continues to be one of the most effective treatment modalities for AL amyloidosis (AL). There is a limited number of studies looking at the effect of different hematopoietic progenitor cell (HPC) mobilization regimens on HPC collection and AHCT outcomes in AL. We assessed key HPC mobilization, collection and AHCT outcomes in a cohort of AL patients. METHODS We conducted a retrospective cohort study of 50 AL patients (pts) who received AHCT and were mobilized with G-CSF alone (G) or G and Plerixafor (G+P) from March 2009 to April 2018. Per mobilization protocol, all pts received G four days prior to collection and P as rescue if peripheral blood (PB) CD34+ cell count was ≤20 on day 1. All patients received conditioning with high dose melphalan (140-200 mg/m2). The primary aim of the analysis was to evaluate the association of patient and disease variables (Revised Mayo stage, cardiac involvement, albumin, proteinuria, NT pro-BNP, thrombocytopenia) with HPC mobilization and AHCT outcomes (total CD34+ yield, day 1 CD34+ yield, PB CD34+, neutrophil and platelet engraftment, hospital length of stay, overall (OS) and progression-free survival (PFS)) using the two mobilization regimens. Variables were assessed relative to outcomes with Spearman correlation, Kruskal-Wallis test or Wilcoxon rank sum test. All variables were assessed relative to PFS and OS with Cox regression. RESULTS Fifty-four percent of pts were female, and median age was 60 years (range, 35-72). The majority of pts (64%) had single organ involvement (renal in 86%, cardiac in 18%). Median NT-pro BNP was 331 pg/ml (504); troponin was normal in all pts. A median of 1 line of therapy was given prior to HCT (range 0-5); 72% received cyclophosphamide, bortezomib and dexamethasone (CyBorD) (82% in G+P vs 66.7% in G cohort, p=0.33) with a median of 4 cycles prior to HCT (range 2-14). Lenalidomide-based therapy was used in 16% (29% in G+P vs 9% in G cohort, p=0.10). Thirty-three pts were mobilized with G and 17 with G+P. Relative to pts mobilized with G, those mobilized with G+P had a higher median bone marrow monotypic plasma cell % (BMPC) at diagnosis (15% in G+P vs 10% in G, p=0.029) and were older at the time of HPC collection. While the majority of pts in both groups had revised Mayo stage I AL at diagnosis, most pts with stage IV required rescue P (23% vs 3%). As shown in Table 1, there was no significant difference between the two mobilization groups with regard to the analyzed mobilization outcomes, AHCT outcomes or survival. Target collection goal of 5x10^6/kg CD34+ cells was reached in all patients within a median of 1 day (range, 1-5). Median total CD34+ yield was 6.04 (5.15-8.30)x10^6/kg with G and 6.84 (5.76-8.0) x10^6/kg with G+P. Pts who required P had a lower median collected total nucleated cell (TNC) dose (13.76 vs 9.36 x10^8/kg, p=0.045) and took 2 days longer to achieve platelet engraftment (13 vs 11, p=0.019). Pts with cardiac involvement had a lower median PB CD34+ on day 1 of collection (81 vs 48, p=0.048) but did not have a lower day 1 or total CD34+ yield. Adverse events at mobilization included weight gain, increased diuretic use, hypotension, or hospitalization and did not differ between groups. The mortality rate was 12% (6 deaths). No deaths occurred during mobilization. A higher 24-hour urine protein at diagnosis was associated with a higher mortality risk post HCT (HR 1.23, p=0.014). A higher serum albumin at diagnosis was associated with faster neutrophil engraftment (r=-0.315, p=0.026) and a signal towards a lower mortality risk however this did not reach statistical significance (HR 0.29, p=0.06). PFS and OS were similar in both groups. CONCLUSION In our relatively small cohort, salvage P effectively mobilized patients with low initial PB CD34 count. We found that AL patients who required rescue P (day 1 PB CD34+ cell count ≤20) had a lower TNC yield and took longer to achieve platelet engraftment speaking to suboptimal marrow reserve and possible slower engraftment kinetics. Proteinuria and potentially a low serum albumin at diagnosis may increase mortality risk post AHCT. Our study is limited by its small sample size and retrospective design. Larger cohort analyses are needed to evaluate factors associated with HPC mobilization and AHCT outcomes in AL. Disclosures Majhail: Mallinckrodt: Honoraria; Incyte: Honoraria; Nkarta Therapeutics: Honoraria; Anthem, Inc.: Consultancy. Hamilton:Syndax Pharmaceuticals: Consultancy, Honoraria. Hill:Abbvie: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding. Jagadeesh:Regeneron: Research Funding; Debiopharm Group: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Research Funding. Anwer:Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau. Chaulagain:Sanofi Genzyme: Honoraria. Khouri:Sanofi Genzyme: Other: Advisory Board.

Background: Tumor-associated macrophages (TAMs) play a key role in cutaneous T cell lymphoma (CTCL) growth and neoplastic T cells escape immune surveillance via PD1-PD-L1 axis (Querfeld, C., et al., Blood 2019; Khodadoust, M.S., et al., J Clin Oncol, 2020). There remains a lack of knowledge about how cytokines regulate the mechanisms controlling tumor-growth and polarize the tumor microenvironment (TME). Methods and Results: To investigate PD-L1 and PD1 expression on TAMs and T cells in mycosis fungoides (MF) and the leukemic variant Sézary syndrome (SS) patients, we performed multiplex immunofluorescence (IF) staining of lesional skin samples of MF patients that demonstrated co-localization of PD-L1 on CD163+ M2 macrophages and PD1 expression on CD4+ and CD8+ T cells. In addition, significant enrichment of CD14+ and CD16+/CD14dim CD163+ M2-like monocytes/macrophages with upregulated PD-L1 expression in SS patients compared to healthy donors (HDs) was found via FACS analysis. We also performed 30-plex Luminex cytokine assay on plasma samples, which showed significantly increased IL-6, IL-10, IFNγ and TNFα levels in plasma of MF/SS compared to HDs. To investigate whether polarization towards an M2-like macrophage phenotype with increased PD-L1 expression correlated with the cytokine expression from CTCL-TME, we cultured total PBMCs from HDs with conditioned media (CM) from well established CTCL cell lines MyLa and HuT78 and analyzed PD-L1 mRNA, total PD-L1 protein and PD-L1 surface expression on M2-like macrophages. Significantly increased expression of PD-L1 protein in total PBMCs, especially on CD14+ and CD16+/CD14dim M2-like macrophages was seen. To understand whether distinct cytokines are associated with PD-L1 upregulation on CD163+ M2-like populations, total PBMCs from HDs were stimulated with human recombinant IL-6, IL-10, IFNγ or TNFα. Antibody blocking studies were conducted by adding anti human IL-6, IL-10, IFNγ or TNFα to the cultures with CM. TNFα stimulation significantly increased the CD14+ M2-like subset, but did not affect CD16+/CD14dim M2-like subset. We observed increased PD-L1 expression on both M2-like populations with TNFα compared to other cytokines. In contrast, blockade of TNFα significantly decreased the CD14+ M2-like subset with reduced PD-L1 expression and increased CD16+/CD14dim M2-like cells with upregulated PD-L1 expression. To explore whether the STAT pathway regulates PD-L1 expression through cytokines from CTCL TME, we incubated total PBMCs from HDs in CM of MyLa and HuT78 cells with/without a pan-STAT inhibitor, and in media alone. Inhibition of STAT signaling decreased CD14+ M2-like macrophage population, but did not alter the CD16+/CD14dim M2-like population. In addition, pan-STAT inhibition significantly reduced surface expression of PD-L1 on both CD14+ and CD16+/CD14dim M2-like macrophages. The effects of cytokines on STAT signaling components in regulating PD-L1 expression were also investigated by FACS and immunoblots. TNFα blockade significantly downregulated PD-L1, but also pSTAT1, pSTAT3 and pNF-κB levels, illustrating the role of TNFα on STAT1, STAT3 and NF-κB pathways in conjunction with PD-L1 expression. Stimulation with TNFα increased pSTAT3 level in CD14+ M2-like macrophages, while it did not significantly change pSTAT3 in CD16+/CD14dim M2-like macrophages. Anti-TNFα reduced pSTAT3 levels in CD14+ M2-like macrophages, but profoundly increased PD-L1 in CD16+/CD14dim M2-like macrophages, which aligns with our data of increased PD-L1 expression on CD16+/CD14dim M2-like macrophages following TNFα blockade. Conclusion: We profiled immune alterations of monocyte/macrophages populations and PD-L1 expression in CTCL regulated by selected cytokines. Our results support the dominant role of TNFα in the CTCL microenvironment. Here we show that TNFα potentiates the immunosuppressive TME through macrophage polarization and STAT-mediated PD-L1 regulation. Our results identify potential targets for combination immunotherapy. Disclosures Zain: Seattle Genetics: Research Funding; Mundai Pharma: Research Funding; Kyowa Kirlin: Research Funding. Abdulla:Johnson Johnson: Research Funding; Mallinckrodt: Consultancy, Speakers Bureau. Rosen:Seattle Genetics: Consultancy; NeoGenomics: Consultancy; Aileron Therapeutics: Consultancy; Novartis: Consultancy; Pebromene: Consultancy; Celgene: Speakers Bureau; Abbvie: Speakers Bureau; paradigm Medical Communications: Speakers Bureau. Querfeld:Trillium: Consultancy; Stemline: Consultancy; Bioniz: Consultancy; Helsinn: Consultancy; Celgene: Research Funding; Kyowa Kirin: Consultancy; MiRagen: Consultancy.

BACKGROUND: In a previous study we have shown that CD19-directed chimeric antigen receptor (CAR)-T cells do not appear to be inferior to alloHCT when used as standard cellular immunotherapy (CI) for patients with multiply r/r LBCL (EBMT 2020). The purpose of the present follow-up analysis was to further compare the risk profile of the 2 cohorts by applying the EASIX score (lactate dehydrogenase (U/L) × creatinine (mg/dL)/thrombocytes (109 cells per L)), and to assess if EASIX could be used as outcome predictor in patients with r/r LBCL undergoing CAR-T and alloHCT, respectively. METHODS: Eligible were all patients referred to our institution with relapsed/refractory (R/R) DLBCL and a tumor board decision recommending treatment with CAR-T cells between 07/2018 and 02/2020 and those recommending allogeneic donor search between 2004 and 2019. Patients with DLBCL transformed from CLL were excluded. EASIX was evaluated retrospectively using uni- and multivariable analyses (with regards to age, gender and number of failed therapy lines) and mortality using Cox regression analyses. RESULTS: 41 patients intended for CAR-T cells and 60 patients intended for alloHCT were included. In both cohorts nearly all patients had active disease at indication. Cohorts were comparable for sex, time from diagnosis, ZUMA1 eligibility, and PS, but CAR-T patients tended to be older (median 56 vs 51 years, p=0.093), and had more often primary refractory and bulky disease (p=0.004 and p=0.04, respectively). Median EASIX score across both cohorts was 1.50 (0.27-70.5), with significantly higher scores in the CART group both at indication (EASIX-ind; median 1.79 and 1.22 for CAR-T and alloHCT, respectively, p=0.031) and at conditioning for CI (EASIX-pre, median 2.24 vs 1.26, p=0.005). Median OS from indication was 475d for the CAR-T cohort vs 285d for the alloHCT cohort (p=0.88). On multivariate analysis, EASIX-ind was significantly associated with adverse OS if alloHCT was intended (HR per 2fold increase 1.43, 95%CI 1.08-1.90, p=0.013), but not if CAR-T was intended (HR per 2fold increase 1.16, 95%CI 0.88-1.53, p=0.3). After CI, 12-month estimates for NRM, relapse incidence, PFS, and OS for CAR-T vs alloHCT were 3% vs 21% (p=0.04), 59% vs 44% (p=0.12), 39% vs 33% (p=0.97), and 68% vs 54% (p=0.32). EASIX-pre predicted overall survival (OS) in both CAR-T (HR per 2fold increase 2.11, 95%CI 1.21-3.7, p=0.009) and alloHCT (HR per 2fold increase 3.69, 95%CI 1.54-8.31, p=0.003) cohorts. In the alloHCT group, the EASIX effect was largely driven by higher NRM risk with increasing EASIX-pre, while in the CAR-T group poorer OS with increasing EASIX-pre was largely relapse-related. CONCLUSIONS: In patients undergoing CI for r/r LBCL, EASIX measured prior to conditioning can predict mortality after both CAR-T and alloHCT. If applied already at indication for CI, the predictive capacity of EASIX is weaker and no longer significant if CAR-T is intended. Further studies for validation of this data appear to be warrantable. Disclosures Schmitt: MSD: Membership on an entity's Board of Directors or advisory committees, Other: PI of clinical trials on letermovir; TolerogenixX Ltd: Other: Co-Founder and shareholder; Hexal: Other: Travel grants , Research Funding; Apogenix: Research Funding; Kite: Other: Travel grants, educational activities and conferences; Novartis: Other: educational activities and conferences, Research Funding. Dietrich:Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees. Schmitt:Hexal: Other: Travel grants ; TolerogenixX LtD: Other: Co-founder, Part-time employee ; Therakos/Mallinckrodt: Research Funding; Jazz Pharmaceuticals: Other: Travel grants . Dreger:Neovii: Research Funding; Roche: Consultancy, Speakers Bureau; Riemser: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Janssen: Consultancy; Gilead: Consultancy, Speakers Bureau; AstraZeneca: Consultancy; AbbVie: Consultancy, Speakers Bureau.

Curative potential of allogeneic hematopoietic cell transplantation (aHCT) in myeloid malignancies is principally related to the graft versus leukemia (GvL) effect exerted by donor-derived immune effectors on leukemic cells. However, different pathways may drive post-transplant relapse, including perturbation/attenuation of T cell-mediated GvL responses. For example, decreased expression of HLA alleles has been described in post-aHCT relapse.1 This could be due to down-regulation of HLA or 6p HLA locus deletion. However, the occurrence of chromosome 6p uniparental disomy (UPD) along with del6p (first described by our group in the context of aplastic anemia)2 suggests that HLA loss of heterozygosity (LOH) and inherent loss of one allele (presenting immunodominant peptides) may be a significant contributor to leukemic relapse either directly, causing decreased HLA expression or as additive effect to HLA down-regulation. In relapses after haploidentical or mismatched aHCT, LOH of mismatched allele has been described.3 Here, we hypothesize that not only copy neutral LOH or haploinsufficient HLA expression but also defective function due to HLA mutations may lead to immune escape from GvL. Such a mechanism would involve the loss of an allele responsible for the presentation of an immunodominant antigenic peptide. Moreover, unlike relapse due to the acquisition of additional myeloid mutations, HLA mutant relapse would also acquire resistance to donor lymphocyte infusion (DLI) therapy. In order to dissect the immunogenomic mechanisms leading to leukemic immune-evasion, we performed a comprehensive genetic analysis of specimens sequentially collected from a cohort of patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) relapsed after aHCT. Specifically, we applied a deep-targeted NGS panel to study HLA region along with 173 genes known to have a role in leukemogenesis and cancer ontogeny. So far, 57 paired/serial biospecimens from 25 transplanted patients have been analyzed (25 samples at AML/MDS diagnosis, 25 at the moment of relapse after aHCT and 7 samples at relapse after chemotherapy) Overall, we found the acquisition of 8 disruptive HLA somatic mutations in 6 patients at post-transplant relapse (24%), 4 in class I and 4 in class II loci. None of those events were found in samples at diagnosis or at post-chemotherapy relapse, suggesting the possibility of an "immune-escape relapse". Those somatic hits accounted for 4 intronic indels, 1 frameshift insertion, one splicing site and 2 point mutations in 3′ and 5′ untranslated regions (UTRs). Median variant allele frequency (VAF) was 17% (range 2-58%). Of note is that all HLA mutant patients received a matched aHCT (4 from related and 2 from a 10/10 matched unrelated donors) suggesting that this mechanism is independent from the deletion and the loss of an immune privileged mismatched allele. Interestingly, median time to relapse was 514 (range 119-935) days for HLA-mutated patients vs 126 (62-543) for HLA wild type cases (p=.00042), consistent with the hypothesis that the establishment of immune-tolerance, and the presence of a GvL effect (less likely in early relapses) are required for the selection of those mutations. When somatic genotype of these patients prior and after transplant was studied, we found that post-aHCT relapses were associated in most cases with a new genomic configuration with either loss of previous events or acquisition of new subclonal mutations in myeloid or cancer related genes (in 17/25 cases). However no difference was seen in terms of number and patterns of new events among the HLA mutated and HLA wild type patients. Results shown here represent an important proof-of-concept for the role played by somatic mutations in HLA genes in the setting of post-aHCT AML/MDS relapses. These events, in analogy to the deletion or copy neutral LOH, may promote immune escape relapse resistant to immunologic manipulations and may coexist or be an alternative pathway to the progression/relapse characterized by acquisition of myeloid subclonal driver mutations. In that context, HLA mutations would be considered facilitator lesions. Disclosures Hsi: CytomX: Consultancy, Honoraria; Eli Lilly: Research Funding; Abbvie: Research Funding; Miltenyi: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria. Hamilton:Syndax Pharmaceuticals: Consultancy, Honoraria. Carraway:Abbvie: Other: Independent Advisory Committe (IRC); BMS: Consultancy, Other: Research support, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Stemline: Consultancy, Speakers Bureau; Takeda: Other: Independent Advisory Committe (IRC); ASTEX: Other: Independent Advisory Committe (IRC). Majhail:Incyte: Honoraria; Mallinckrodt: Honoraria; Nkarta Therapeutics: Honoraria; Anthem, Inc.: Consultancy. Maciejewski:Alexion, BMS: Speakers Bureau; Novartis, Roche: Consultancy, Honoraria.

Background: T cells in CTCL are functionally exhausted and are characterized by the expression of immune inhibitory molecules such as PD1 and PD-L1 (Cancer Immunol Res 6; 2018). These findings justify the evaluation of immune checkpoint inhibition to reverse T cell exhaustion in CTCL. We initiated a phase 1/2 clinical trial of lenalidomide and durvalumab to determine the safety and efficacy of this regimen. Durvalumab is a human monoclonal antibody with high affinity and selectivity for PD-L1, targeting exhausted T cells and distinct cells within their environment. Lenalidomide, an oral immunomodulatory drug (IMiD) and analog of thalidomide, has previously shown activity in CTCL (Blood 123; 2014). Durvalumab may restore an anti-tumor immune response, and the combination of durvalumab and lenalidomide may enhance immune checkpoint blockade-induced immune responses. Associations between immune checkpoints, gene expression profile and the clinical efficacy of durvalumab/lenalidomide combination were evaluated. The primary objectives were to determine the recommended phase 2 dose of lenalidomide in combination with durvalumab and safety with primary endpoint of toxicity (using CTCAE 4.03). Secondary end points included objective response rate (ORR) and median duration. Relationships between gene expression profile (GEP), PD-L1 expression, and antitumor activity were exploratory end points. Methods: A Phase 1 portion (NCT03011814) is ongoing to evaluate the safety and tolerability of the durvalumab and lenalidomide combination. Pts are enrolled in sequential cohorts to receive durvalumab (fixed dose at 1500 mg) and dose escalation of lenalidomide (dose level 1 = 10 mg for all cycles; dose level 2 = 10 mg for cycle 1, 15 mg for all subsequent cycles; dose level 3 =10 mg for cycle 1, 15 mg for cycle 2, and 20 mg for all subsequent cycles) to characterize safety, efficacy and antitumor activity. Serial skin samples were collected to assess the impact on the tumor microenvironment and anti-tumor activity. Results: Ten pts. were evaluable for toxicities. Nine patients were evaluable for response with three patients at each dose level. 8 males/2 females, age 29-59 y, with refractory/advanced CTCL, clinical stages IB (1), IIA (3), IIB (4), IIIA (1), and aggressive epidermotropic CD8+ CTCL (1) and a median of prior systemic treatments of 3 (range, 2-4) have been enrolled. Median follow up time was 12 (range, 3-24+) months. No serious AEs or DLTs were observed during the DLT evaluation period (cycles 1-3). The most frequently reported AEs were fatigue (n=7), skin pain (n=4), chills (n=3), anemia (n=3), and leukopenia (4). One grade 3 maculopapular rash (possibly due to lenalidomide) was observed, all other treatment-related AEs were grade 1/2 in severity. Median cycles of treatment were 7 (range, 3-20+) months. Median duration of response was 4 (range, 1- 21+) months. Six pts achieved PR, while 3 pts maintained stable disease. Three pts remain on treatment. Expression panels of several checkpoints (PD1, PD-L1 & ICOS) (Cycle1 Day1 vs Cycle 2 Day15) were analyzed. Detectable levels of PD-L1 but low levels of ICOS are observed in responding pts vs. high PD-L1 and ICOS levels in non-responders. GEP highlights downregulation of TNF-alpha signaling via NFkB, IFN-gamma, and PI3-AKT-mTOR signaling pathways among other pathways. Conclusions: Durvalumab/lenalidomide has significant clinical activity in refractory/advanced CTCL, which will be formally evaluated in the Phase 2 portion. Responses were durable and ongoing, and treatment was well tolerated. Dose escalation is up to lenalidomide 20 mg daily. Our preliminary results from pts on trial demonstrated that immune signatures on skin biopsies at baseline may be predictive of response to checkpoint blockade and yield insights into mechanisms of therapeutic resistance. Disclosures Querfeld: Bioniz: Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Soligenix: Other: Investigator; Celgene: Other: Investigator, Research Funding; City of Hope Cancer Center and Beckman Research Institute: Employment; Medivir: Consultancy; Trillium: Consultancy, Other: Investigator, Research Funding; miRagen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Kyowa: Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Eisai: Other: Investigator; Elorac: Other: Investigator, Research Funding; Helsinn: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Investigator. Palmer:Gilead Sciences: Consultancy. Zain:Spectrum: Consultancy; Seattle Genetics: Consultancy.

Introduction Intestinal graft-versus-host disease (GvHD), following allogeneic hematopoietic stem cell transplantation (allo-HSCT), has a high mortality rate and a reduced life-expectancy. In this context, failure to respond to steroid therapy is associated with limited further therapeutic options, thereby representing an unmet medical need. Aiming at restoring microbiome functions, fecal microbiota transfer (FMT) has proved to be a promising treatment modality in this challenging clinical setting, with recent studies reporting favorable results in steroid refractory-acute GVHD (SR-aGvHD) patients. Here we report on the use of a next-gen FMT product "MaaT013", a standardized, pooled-donor, high-richness microbiota biotherapeutic, used to treat 29 patients with intestinal aGvHD as part of a compassionate use/expanded access treatment program. Patients and methods Twenty-nine allo-HSCT recipients with steroid-dependent or SR intestinal GvHD (classical aGVHD n=22, late-onset aGVHD n=2; aGvHD with overlap syndrome n=5) were treated with MaaT013 biotherapeutic as part of a compassionate use/expanded access treatment program of the developer MaaT Pharma. These patients had previously received and failed 1 to 5 lines (median 3; 22/29 received ruxolitinib) of GvHD systemic treatments. Each patient received 1 to 3 doses (median: 3; total doses administered: 71) of MaaT013, a 150 mL bag, by enema (n=28) or nasogastric tube (n=1). GI-GvHD response was evaluated 7 days after each administration and 28 days after the first dose. Prepared under Good Manufacturing Practices, MaaT013 biotherapeutics are characterized by a highly consistent richness of 455 ±3% Operational Taxonomic Units and an Inverse Simpson index greater than 20. Batch release specifications are based on potency (viability), identity (diversity), and purity (microbiological safety testing and proportion of proinflammatory species), ensuring the desired consistency across batches. Results We observed a GI overall response rate of 59% (17/29) at day 28 after first dosing, including 9 complete response (CR), 6 very good partial response (VGPR), and 2 partial response (PR). Considering the best GI response achieved, 20/29 patients (69%) achieved at least a PR, with 9 CR, 8 VGPR and 3 PR. Among the 29 treated patients, 16 were still alive at last follow-up (median follow-up (FU): 131.5 days; range [28; 413]) and 6 months overall survival was 54%. Among the 9 patients achieving CR, all were still alive at last follow-up (median FU: 197 days; [49; 301]) and were able to taper or stop steroids and immunosuppressants. Among these 9 patients, three patients presented GI symptom recurrence between 2 and 3 months after dosing. In 2 patients, this recurrence occurred after heavy antibiotic treatment, one of them received an additional MaaT013 dose and achieved a second CR. Of note, among these 9 patients, mild chronic mucosal GvHD symptoms persisted in one patient, and molecular relapse of hematologic malignancy was observed in another. The safety of the MaaT013 microbiota biotherapeutic was satisfactory for all patients. One patient developed "possibly related" sepsis one day after the third dosing but no pathogen was identified in blood cultures, and the patient recovered after a course of antibiotics. Another patient developed C. difficile diarrhea 24 hours post-administration. This was not causally related to MaaT013, as C. difficile testing was negative in the MaaT013 lot. Nosocomial transmission was suspected as the cause as several patients with C. difficile infection were hospitalized in the same unit during this period. Conclusions We herein report for the first time the treatment of 29 patients with steroid-dependent or SR intestinal aGvHD using a full ecosystem, standardized, pooled-donor, high-richness biotherapeutic. The overall response rate was 59% with the off-the-shelf MaaT013 product, which was shown to be safe and effective in these heavily pre-treated and immunocompromised patients, warranting further exploration of the full ecosystem microbiota restoration approach. Disclosures Malard: Astellas: Honoraria; JAZZ pharmaceutical: Honoraria; Sanofi: Honoraria; Janssen: Honoraria; Keocyt: Honoraria; Theralos/Mallinckrodt: Honoraria; Biocodex: Honoraria. Plantamura:MaaT Pharma: Current Employment. Mohty:BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Stemline: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Background: Steroid-refractory acute graft-versus-host disease (SR-aGvHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplant in pediatric patients. Second-line therapies cause further immunosuppression, leaving patients vulnerable to life-threatening infections. Extracorporeal photopheresis (ECP) with methoxsalen (Uvadex®) sterile solution, in which apheresed leukocytes are photosensitized, exposed to ultraviolet A radiation ex vivo, and reinfused, is used to treat aGvHD because it has a low risk of infection, unlike systemic immunosuppressants. Safe use of ECP in children is not yet established. Aims: To report interim 4-week data from a 12-week phase 3 study evaluating the efficacy and safety of ECP using the photosensitizing agent methoxsalen with the Therakos® Cellex® Photopheresis System (Cellex; Mallinckrodt Pharmaceuticals, Bedminster, NJ) in pediatric/young adult patients with SR-aGvHD (NCT02524847). Methods: In this single-arm, open-label study, patients (aged 1-21 years; SR-aGvHD International Bone Marrow Transplant Registry [IBMTR] grade B-D) received ECP 3 times/wk for 4 weeks, followed by 2 times/wk for 8 weeks. Steroids were tapered according to physician discretion if SR-aGvHD responded to ECP. The primary endpoint was proportion of patients with an overall response (OR), defined using the Modified IBMTR Severity Index as complete response (CR; complete resolution of aGvHD in all evaluable organs, without next-line systemic treatment) or partial response (PR; improvement of 1 stage in ≥1 aGvHD target organ without progression in others or addition of next-line systemic treatment), after 4 weeks. The primary endpoint was considered significant if P48%. Secondary outcome measures included safety, duration of response, steroid-sparing effect, and organ-specific response. Results: Of 25 patients enrolled, 25 were evaluable for safety (patients who received ≥1 ECP treatment) and 23 were evaluable for efficacy. Patients' mean age was 9.2 years, 44% were female, mean body mass index was 18.3 kg/m2, and the majority (n=18) had Grade 3 aGvHD. Twelve patients (48%) completed all study visits; 5 withdrew early (2 deaths, 1 CR; 3 withdrew due to inadequate efficacy, 2 of whom started second-line therapy, and 3 no longer required treatment) A median of 27 ECP treatments were administered (range 3-28). OR was 61% (14/23 evaluable patients); there were 3 CRs (13%) and 11 PRs (48%; P Disclosures Kitko: Mallinckrodt: Honoraria; Novartis: Consultancy, Honoraria. Boodée:Mallinckrodt Pharmaceuticals: Employment. OffLabel Disclosure: UVADEXÃ'® (methoxsalen) Sterile Solution is indicated for extracorporeal administration with the THERAKOSÃ'® UVAR XTSÃ'® or THERAKOSÃ'® CELLEXÃ'® Photopheresis System in the palliative treatment of the skin manifestations of Cutaneous T-Cell Lymphoma (CTCL) that is unresponsive to other forms of treatment. Extracorporeal photopheresis (ECP) with methoxsalen (UvadexÃ'®) sterile solution is used to treat acute graft-versus-host disease (aGvHD), but there are few clinical trials in pediatric patients. This abstract reports on the interim results of a phase 3 clinical trial of ECP with methoxsalen used with the TherakosÃ'® CellexÃ'® Photopheresis System in pediatric/young adult patients with steroid refractory aGvHD.

Introduction: TP53 mutations have been associated with adverse outcomes in AML and MDS. While these mutations occur in less than 15-20% of pts, they are often associated with complex karyotypes and therapy-related (t)-myeloid neoplasms (MN). Previous studies showed poor outcomes with intensive chemotherapy (IC) and lower-intensity therapies [LIT] (e.g. hypomethylating agents [HMA]), and higher relapse rates after allogeneic hematopoietic stem cell transplant (alloSCT), leaving the question of optimal treatment unanswered. Methods: We conducted a retrospective review of all adult pts with MN and pathogenic TP53 mutations who were treated at Yale University from 9/1/2015 to 5/31/2019. We collected data on age, sex, ethnicity, prior malignancies and their treatments, white blood cell (WBC), hemoglobin, platelet count, disease risk, initial and subsequent lines of therapies, and use of alloSCT. Responses were recorded using modified International Working Group (IWG) criteria 2003 for AML and 2006 for MDS. Overall survival (OS) was measured using Kaplan Meier methods. Results: We identified 83 pts with TP53-mutated MN (45 AML, 31 MDS, 4 chronic myelomonocytic leukemia, and 3 JAK2-positive myeloproliferative neoplasms). Median age was 69 years (range [R], 27-88 years), 52% were male, and 88% were Caucasian [Table 1]. Prior malignancy was noted in 35 pts (42%) and 29 (17 AML, 12 MDS) pts were classified as t-MN. Median WBC on presentation was 3 x 109 /L (R, 0.2 - 74x109) with a median of 0% peripheral blasts (R, 0-43%). Complex (n=75; 90%) and monosomal karyotypes (n=54; 65%) were highly prevalent. We identified 101 unique, pathogenic or likely pathogenic mutations in the TP53 gene with 17 pts harboring more than 1 abnormal variant (16 pts with 2 mutations, 1 pt with 4 mutations). Missense variants were most commonly encountered (n=82 variants, 81%) followed by splicesite (n=9, 9%), frameshift (n=6, 6%), and nonsense variants (n=4, 4.0%). 52 pts had isolated somatic TP53 variants (63%). Among the other 31 pts DNMT3A (n=8 pts), JAK2 (n=6), and TET2 (n=5) variants were the most common somatic mutations. Of note, targetable driver mutations such as FLT3 (n=0), IDH1 (n=3), and IDH2 (n=1) were very rare. Notably, pts with complex karyotype were more likely to have isolated TP53 mutations compared to non-complex karyotype pts (complex karyotype + isolated TP53 mutations: 51 pts [68.0%] vs non-complex karyotype + isolated TP53 mutations: 2 pts [25.0%]; Fisher's exact test: p=0.024) [Table 2]. Median follow up of the cohort was 6.4 months (mos) [R: 0.2-55.3 mos]. Median OS in the entire study cohort was 7.6 mos (95% CI: 5.7-10.0 mos) with a 1-year OS rate of 30.5% (95% CI: 20.0-41.6%). Response rates and outcome for AML and MDS patients by treatment regimen are shown in Table 3. Among AML pts, IC did not appear to improve OS compared to pts receiving LIT (median OS 10.1 mos [95% CI: 6.4-15.5] vs 8.1 mos [95% CI: 1.9-13.6]; p=0.39). AML pts (median OS 6.7 mos [95% CI: 1.9-9.4]; 1-year OS: 23.2% [95% CI: 11%-38%]) had a statistically non-significant trend to poorer outcomes compared to MDS pts (median OS 10 mos [95% CI 5.7-12.9]; 1-year OS: 29.5% [95% CI 13.5-47.4%]; p=0.13). Notably, among the 10 pts who proceeded to alloSCT, only 3 pts relapsed after a median of 2.8 mos post-alloSCT. Relapse-free survival and median OS for pts who underwent alloSCT was not reached at a median follow up of 10.4 mos. Conclusions: In this case series we confirm the poor prognosis for pts with TP53-mutated MN. Median OS was only 7.6 mos, and IC did not appear to improve OS compared to LIT for AML pts. With limited follow-up, pts who underwent alloSCT appeared to benefit. Novel therapies are urgently needed to improve outcomes of this pt population. Disclosures Podoltsev: Kartos Therapeutics: Research Funding; Samus Therapeutics: Research Funding; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Research Funding; Astellas Pharma: Research Funding; Daiichi Sankyo: Research Funding; Sunesis Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; Pfizer: Research Funding; Astex Pharmaceuticals: Research Funding; CTI Biopharma: Research Funding; Celgene: Other: Grant funding, Research Funding; Genentech: Research Funding; AI Therapeutics: Research Funding; Arog Pharmaceuticals: Research Funding. Gore:Celgene Corporation: Consultancy, Research Funding. Prebet:Boehringer Ingelheim: Research Funding; Boehringer Ingelheim: Research Funding; Boehringer Ingelheim: Research Funding; pfizer: Honoraria; pfizer: Honoraria; pfizer: Honoraria; Tetraphase: Consultancy; novartis: Honoraria; novartis: Honoraria; Agios: Consultancy, Research Funding; novartis: Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; pfizer: Honoraria; Genentech: Consultancy; pfizer: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; novartis: Honoraria; novartis: Honoraria. Isufi:Celgene: Consultancy; Novartis: Consultancy; Astra Zeneca: Consultancy. Foss:Spectrum: Other: fees for non-CME/CE services ; Eisai: Consultancy; Acrotech: Consultancy; miRagen: Consultancy; Mallinckrodt: Consultancy; Seattle Genetics: Consultancy, Other: fees for non-CME/CE services . Huntington:AbbVie: Consultancy; Celgene: Consultancy, Research Funding; DTRM Biopharm: Research Funding; Pharmacyclics: Honoraria; Genentech: Consultancy; Bayer: Consultancy, Honoraria. Neparidze:Janssen Scientific Affairs, LLC: Research Funding; Eidos Therapeutics: Other: Member of Independent Diagnostic Committee; MMRF/Synteract: Membership on an entity's Board of Directors or advisory committees. Zeidan:Celgene Corporation: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Medimmune/AstraZeneca: Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Research Funding; Jazz: Honoraria; Ariad: Honoraria; Agios: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Daiichi Sankyo: Honoraria; Cardinal Health: Honoraria; Seattle Genetics: Honoraria; BeyondSpring: Honoraria; Acceleron Pharma: Consultancy, Honoraria, Research Funding.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a viable treatment option for many cancers but its clinical utility is limited due to the occurrence of graft-versus-host disease (GVHD). Understanding the impact of obesity on immune function has become increasingly important in the setting of the current obesity pandemic. We report here that obesity has a negative and selective impact on acute gut GVHD. Diet-induced obese (DIO) mice exhibited increased gut permeability, endotoxin translocation and radiation-induced gastrointestinal damage. After allo-HSCT, DIO recipients across strains and sex had markedly increased pro-inflammatory cytokines (IL-6, TNF), GVHD biomarker ST2, MHC class II expression and exhibited rapid mortality associated with severe acute gut pathology. This obesity-associated lethal acute gut GVHD was dependent on donor CD4 T cells and occurred even in minor MHC mismatch strain combination in which only a delayed skin chronic GVHD resulted in lean recipients. Pro-inflammatory cytokine blockade targeting both IL-6 and TNF ameliorated obesity-associated acute gut GVHD while maintaining graft-versus-tumor (GVT) effects. Microbiome assessment of DIO mice revealed markedly reduced microbiome diversity and decreased Clostridiaceae abundance. Additionally, DIO mice had a significant increase of GVHD-associated Akkermansia muciniphila before and after allo-HSCT compared to the controls. Extended antibiotic treatment of DIO mice protected from the endotoxin translocation, cytokine storm as well as gut GVHD pathology but did not protect later development of chronic skin GVHD. These results demonstrate that obesity alters the microbiome and imparts differential effects on GVHD following allo-HSCT with decreased survival and this inferior outcome can be pre-empted by combined pro-inflammatory cytokine blockade or antibiotic pretreatment. Disclosures Pai: Roche-Genentech: Employment. Holtan:CSL Behring: Consultancy; Incyte: Consultancy; Bristol-Myers Squibb: Consultancy; Janssen: Consultancy. Ferrara:ViraCor: Consultancy; Incyte: Consultancy; Kamada: Consultancy; Mallinckrodt: Consultancy; Enlivex: Consultancy; Xenikos: Consultancy; CSL Behring: Consultancy; National Institutes of Health: Research Funding. Levine:Novartis: Honoraria; Kamada: Research Funding; bluebird bio: Consultancy; National Cancer Institute: Research Funding; Incyte: Consultancy, Research Funding; Ironwood: Honoraria; Biogen: Other: non-financial support; Viracor: Patents & Royalties: biomarker patent. Abedi:Abbie: Speakers Bureau; Gilead: Speakers Bureau; Celgene: Speakers Bureau; BMS: Speakers Bureau; Takeda: Speakers Bureau. Blazar:Kamon Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees; Five Prime Therapeutics Inc: Co-Founder, Membership on an entity's Board of Directors or advisory committees; Regeneron Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics and BlueRock Therapeuetics: Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics, Inc.: Research Funding; RXi Pharmaceuticals: Research Funding; Alpine Immune Sciences, Inc.: Research Funding; Abbvie Inc: Research Funding; Leukemia and Lymphoma Society: Research Funding; Childrens' Cancer Research Fund: Research Funding; KidsFirst Fund: Research Funding; Tmunity: Other: Co-Founder; BlueRock Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Introduction T cells transduced with a chimeric antigen receptor (CAR) have demonstrated significant clinical efficacy in patients with lymphoid malignancies including relapsed or refractory (r/r) B-lineage acute lymphoblastic leukemia (ALL) or r/r B-cell non-Hodgkin's lymphoma (NHL). Second-generation CAR T cells comprising 4-1BB or CD28 as costimulatory domains have become commercially available for the treatment of patients with CD19+ lymphoid malignancies. However, achievement of durable clinical responses remains a challenge in CAR T cell therapy. Consequently, third-generation CARs incorporating both elements might display short-term efficacy with potent and rapid tumor elimination (CD28) as well as long-term persistence (4-1BB). So far, only two clinical trials employing third-generation CAR T cells have been reported. Both enrolled 31 patients in summary and demonstrated favorable results for third-generation CAR T cells. Here, we report on first results of our investigator-initiated trial (IIT) on third-generation CD19-directed CAR T cells: The Heidelberg CAR trial 1 (HD-CAR-1; NCT03676504; EudraCT 2016-004808-60) is a phase I/II trial initiated in September 2018 with in-house leukapheresis and CAR T cell manufacturing in full compliance with European Good Manufacturing Practice (GMP) guidelines at the University Hospital Heidelberg. Methods Adult and pediatric patients with r/r ALL and patients with r/r chronic lymphocytic leukemia (CLL) or NHL including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) or mantle cell lymphoma (MCL) are treated with autologous T lymphocytes transduced with a CD19 targeting third-generation CAR retroviral vector (RV-SFG.CD19.CD28.4-1BBzeta). The main purpose of HD-CAR-1 is to evaluate safety and feasibility of escalating third-generation CAR T cell doses (1-20×106 transduced cells/m2) after lymphodepletion with fludarabine (30 mg/m2/d on days -4 to -2) cyclophosphamide (500 mg/m2/d on days -4 to -2). Patients are monitored for cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) and/or other toxicities. In vivo function, survival and anti-tumor efficacy of CAR T cells are assessed. Results To date, 10 patients (3 adult ALL, 2 CLL, 2 MCL, 2 DLBCL, 1 transformed FL) have been enrolled and subjected to leukapheresis. Transduction efficiency of T lymphocytes ranged between 33%-66% and high numbers of transduced CAR T cells were harvested (70-123x106 CAR T cells). No production failure occurred. CAR T cell products were sterile and free from mycoplasma and endotoxins. The copy number per CAR T cell did not exceed 7. Eight patients (2 adult ALL, 2 CLL, 1 MCL, 2 DLBCL, 1 transformed FL) have received the CAR T cell product (6 patients: 106 transduced cells/m2; 2 patients 5×106 transduced cells/m2). No signs of CRS or ICANS > grade 2 have been observed. Only one patient required tocilizumab. No neurological side-effects occurred, even not in patients with involvement of the central nervous system (CNS). In quantitative real-time PCR, CAR T cells were detectable in the peripheral blood (PB) in 3 of 4 analyzed patients or the cerebrospinal fluid (CSF) of an ALL patient with CNS involvement. The CAR T cell frequency reached up to 200,000 copies/µg DNA, in some patients beyond end-of-study at day 90 after CAR T cell administration. Clinical responses to treatment were observed in 6/8 (75%) treated patients so far (2/8 patients have received CAR T cells recently and are not yet evaluable for response). Conclusion Leukapheresis and CAR T cell manufacturing were effective for all patients enrolled in the HD-CAR trial to date. Patients responded clinically to treatment despite low numbers of administered CAR T cells. CAR T cells displayed an excellent safety profile and were detectable for more than 3 months following administration. Furthermore, CAR T cells migrated into different compartments including the CSF in case of CNS involvement. For HD-CAR-1 leukapheresis, CAR T cell manufacturing, CAR T cell administration, patient monitoring and follow-up are performed in-house, providing autarky from transport or production sites outside the University Hospital Heidelberg. Altogether, HD-CAR-1 accounts to clinical evaluation of third-generation CAR T cells that might contribute to long-term CAR T cell persistence, hence improving efficient and durable responses in treated patients. Disclosures Schmitt: Therakos Mallinckrodt: Other: Financial Support . Sellner:Takeda: Employment. Müller-Tidow:MSD: Membership on an entity's Board of Directors or advisory committees. Dreger:AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Riemser, Roche: Consultancy; AbbVie, Gilead, Novartis, Riemser, Roche: Speakers Bureau; Neovii, Riemser: Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia. Schmitt:Therakos Mallinckrodt: Other: Financial Support; MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia.

Acute lymphoblastic leukemia (ALL) is characterised by recurrent chromosomal abnormalities and genomic microdeletions. Although the incidence of adult ALL increases with age, very few studies have specifically examined the genetic aberrations in adults aged ≥60 years. The objectives of the study were to define the frequency of recurrent chromosomal abnormalities and characterise the copy number profile of ALL in older adults. All patients from UKALL14 and UKALL60+ clinical trials aged ≥60 years at diagnosis of ALL were considered in the study. Cytogenetic and fluorescence in situ hybridisation (FISH) results at diagnosis were used to classify patients in 1 of 5 genetic subgroups - BCR-ABL1, TCF3-PBX1, MLL/KMT2A rearranged (KMT2Ar), low hypodiploidy/near triploidy (HoTr) and high hyperdiploidy (HeH). T-ALL patients were considered separately. B-cell precursor (BCP) ALL patients lacking a primary chromosomal abnormality (B-other ALL - including normal, failed and complex karyotypes, and other non-recurrent chromosomal abnormalities), were selected for extended FISH screening to identify ABL-class fusions, JAK-STAT activating rearrangements and other primary translocations using dual colour break apart probes for ABL1, ABL2, PDGFRB/CSF1R, CRLF2, JAK2, IGH@, ZNF384 and MEF2D. Separately, single nucleotide polymorphism (SNP) arrays were performed to identify copy number abnormalities (CNAs). Multiplex ligation-dependent probe amplification (MLPA) was used to confirm CNAs in 9 specific genes/regions (EBF1, IKZF1, CDKN2A/B, JAK2, PAX5, ETV6, BTG1, RB1, and PAR1). 207 patients aged ≥60 years at diagnosis were identified from UKALL14 (n=91) and UKALL60+ (n=116). Median age was 64 years (range 60-83) and 50% were male. Cytogenetic data at diagnosis were available for 86% (n=178) of patients. Frequencies of individual genetic subgroups are shown in figure (A). Extended FISH screening of B-other ALL cases identified rearrangements in CRLF2 in 5% (8/146), ZNF384 in 2% (3/137) and MEF2D in SNP arrays were performed on 83 patient samples using Illumina CytoSNP 850k (n=52) or Affymetrix Cytoscan HD (n=31) arrays. Recurrent whole chromosome and whole arm abnormalities seen in >3 cases are shown in figure (B) (HeH and HoTr cases (n=10) excluded). Recurrent deletions were identified affecting IKZF1 in 52% (n=43), CDKN2A/B in 45% (n=37), PAX5 in 39% (n=32), RB1 in 22% (n=18), ETV6 in 21% (n=17), EBF1 in 19% (n=16), BTG1 in 12% (n=10), CD200/BTLA in 16% (n=13) and ATP10A in 13% (n=11). The frequency of individual deletions varied by genetic subtypes (Figure (C)). Recurrent novel and less-well described intragenic microdeletions were also seen in COL11A1 (n=11, 13%), MEF2C (n=8, 10%), MBNL1 (n=7, 8%), PTEN (n=6, 7%), NF1 (n=4, 5%), LEMD3 (n=5, 6%), and KDM6A (n=4, 5%). These deletions will need to be validated by a second technique. In this large cohort of older adults with ALL, we confirm that over a quarter of patients harbour BCR-ABL1. HoTr ALL is rare in younger patients but was the second most common specific chromosomal abnormality and good risk genetic subgroups were very uncommon. Additionally, we confirm the rarity of T-cell ALL in older adults ( Disclosures Menne: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kyowa Kirin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. McMillan:Sandoz: Honoraria; Gilead: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Speakers Bureau; BMS: Honoraria; Pfizer: Honoraria, Research Funding; MSD: Honoraria; Novartis: Honoraria; Celgene: Honoraria, Speakers Bureau. Morley:Amgen: Membership on an entity's Board of Directors or advisory committees, Other: speaker fees, conference support ; TAKEDA: Other: conference support ; Janssen Pharmaceuticals: Other: speaker fees; ROCHE: Membership on an entity's Board of Directors or advisory committees, Other: conference support; ABBVIE: Other: speaker fees. Snowden:Kiadis: Membership on an entity's Board of Directors or advisory committees; Mallinckrodt: Honoraria; Janssen: Honoraria; IDMC: Honoraria; Jazz: Honoraria; Gilead: Honoraria. Papaemmanuil:Celgene: Research Funding. Rowntree:Novartis: Consultancy. Fielding:Amgen: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Incyte: Consultancy.

Introduction: Rituximab-based high-dose therapy (HDT) is frequently prescribed to DLBCL patients (pts) undergoing auto-HCT. However data supporting the benefit of adding R to auto-HCT conditioning are not available. Herein, we report the impact of R-based conditioning on auto-HCT outcomes of DLBCL pts. Methods: Using the Center for International Blood and Marrow Transplant Research registry, 862 adult (≥18 years) DLBCL pts undergoing auto-HCT, between 2003-2017 were included. Analysis was limited to pts receiving BEAM (BCNU, etoposide, cytarabine, melphalan)-based HDT, as R was infrequently used with non-BEAM conditioning regimens. All pts received R-containing chemoimmunotherapy in the frontline setting and had chemosensitive disease prior to HCT. Early chemoimmunotherapy failure (ECitF) was defined as not achieving a complete remission (CR) after frontline chemoimmunotherapy or relapsing within 1 year of initial diagnosis. Primary outcome was overall survival (OS). Secondary outcomes included non-relapse mortality (NRM), relapse, progression-free survival (PFS) and infectious complications within 100 days post-HCT. Results: The study cohort was divided into 2 groups; BEAM (n=667) and R-BEAM (n=195). The baseline characteristics of the 2 cohorts were comparable including age at auto-HCT, disease stage, Karnofsky performance score, extranodal involvement, time from diagnosis to auto-HCT, number of prior therapies, remission status, and ECitF. However, significantly more R-BEAM cohort patients received R as part of last therapy line before auto-HCT (75% vs. 86%; P=0.001). Median follow-up of survivors was 48 (range 1-171) and 64 (range 3-142) months in the BEAM and R-BEAM cohorts, respectively. On univariate analysis, the 4 year cumulative incidence of relapse (41% vs 44%), NRM (11% vs 9%), PFS (48% vs 47%; Figure 1) and OS (58% vs 61%; Figure 2) were similar in the R-BEAM and BEAM groups, respectively (Table 1). On multivariate analysis, no significant difference was seen in OS (HR 0.81; 95% CI 0.81-1.31; P=0.83) or PFS (HR 0.94; 95% CI 0.76-1.18; P=0.61) (Table 1) between the two cohorts. Addition of R had no impact on risk of relapse (HR 0.83; 95% CI 0.65-1.07; P=0.15) or NRM (HR 1.43; 95% CI 0.909-2.26; P=0.12). Variables independently associated with lower OS included older age (HR 3.05; 95% CI 1.81-5.13; P Conclusion: In this large registry analysis of DLBCL pts undergoing auto-HCT, adding R to BEAM conditioning had no impact on transplantation outcomes. Older age, absence of CR and ECitF were associated with inferior survival. Disclosures Majhail: Mallinckrodt: Honoraria; Incyte: Consultancy; Nkarta: Consultancy; Anthem, Inc.: Consultancy; Atara Bio: Consultancy. Sureda:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Gilead: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria; BMS: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kharfan-Dabaja:Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy. Hamadani:ADC Therapeutics: Consultancy, Research Funding; Merck: Research Funding; Takeda: Research Funding; Pharmacyclics: Consultancy; Celgene: Consultancy; Medimmune: Consultancy, Research Funding; Janssen: Consultancy; Otsuka: Research Funding; Sanofi Genzyme: Research Funding, Speakers Bureau.

Introduction Although a large variety of conditioning regimens are used in autologous hematopoietic stem cell transplantation (autoSCT), including the widely used BEAM (carmustine, etoposide, cytarabine, melphalan), there is no consensus regarding a standard approach. In the context of a carmustine shortage, we replaced it with thiotepa. However, clinical data on the TEAM (thiotepa, etoposide, cytarabine, melphalan) conditioning regimen are sparse and only retrospective. Thus, we designed a multicenter prospective study (NCT02504190) to assess the efficacy and toxicity of a TEAM conditioning regimen. Patients and methods The TEAM regimen consisted of a total dose of thiotepa of 8 mg/kg on day -6; etoposide 100 mg/m2/12h and cytarabine 200 mg/m2/12h (day -5 to -2); melphalan 200 mg/m2 on day-1. Inclusion criteria were the following: age between 18 and 65 years, biopsy-proven Hodgkin or non-Hodgkin lymphoma, HIV seronegative, and first autoSCT. Results Seventy-four male and eighteen female patients with a median age of 53 years (range, 19-65) were included. Karnofsky score was Median time to neutrophil recovery was 12 days (range, 9-48) and to platelet recovery >20 G/L was 13 days (range, 7-197). The most significant regimen-related toxicities were mucositis in 100% of patients (median grade=3, range, 1-4) and diarrhea in 98% of patients (median grade=1, range, 0-3). Other non-hematologic grade 3 adverse events occurred in 17 patients (18%). Blood cultures were positive for Staphyloccocus sp. in 27% patents, other Gram- positive bacteria in 5% and Gram negative in 6%. Central line-associated bloodstream infection occurred in 22 patients (24%). Invasive fungal infection occurred in 3 patients. Four patients required transfer to the intensive care unit. The median length of stay in hospital was 27 days (range, 16-62). At day+100, 89 patients were evaluable for response and all were in CR. Deaths directly attributed to disease progression or relapse occurred in 5 patients. After a median follow-up of 31 months (range, 15-48), the non-relapse mortality (NRM) was 3.3%. Two patients died of infection during aplasia and one patient died 67 days after autoSCT of necrotizing fasciitis. At last follow-up, 17 patients (19%) relapsed, 9 died and 83 were alive. The estimated 3-year overall survival (OS) and progression-free survival (PFS) were 90.2% and 77.2%, respectively. In patients with double expressor diffuse large B-cell lymphoma (n=15), the estimated 3-year OS and PFS were 93% and 73%, respectively. None of the 31 patients with intermediate or high-risk CNS international prognostic index experienced CNS relapse. Conclusion The TEAM conditioning regimen is a safe and valid platform in autoSCT for patients with high-risk or relapsed/refractory lymphoma. Although mucositis and diarrhea were frequent, the NRM was similar to that reported for BEAM conditioning. Most notably, no CNS relapse occurred in patients at intermediate or high-risk of CNS relapse. Disclosures Duléry: Keocyt: Honoraria. Choquet:Keocyt: Honoraria. Di Blasi:Novartis: Honoraria. Malard:Therakos/Mallinckrodt: Honoraria; Janssen: Honoraria; Keocyte: Honoraria; Sanofi: Honoraria; JAZZ pharmaceutical: Honoraria; Astellas: Honoraria. Coppo:Ablynx/Sanofi: Consultancy; Shire: Consultancy; Alexion: Consultancy. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

Systemic glucocorticoids are the principal treatment for acute graft-versus-host disease (GVHD), which remains the major cause of non-relapse mortality (NRM) after allogeneic hematopoietic cell transplantation (HCT). However, there are no validated biomarkers that measure a patient's response to glucocorticoid therapy, and thus response is evaluated by the change in clinical symptom severity. A major weakness in the predictive power of clinical responses is that changes to all organs are weighted equally even though the major driver of NRM is irreversible damage to the crypts of the GI tract. Recent studies from the Mount Sinai Acute GVHD International Consortium (MAGIC) have validated an algorithm probability (MAP) that combines serum concentrations of two biomarkers of GVHD (REG3α and ST2) to generate an estimated probability of 6 month NRM for individual patients. The MAP has been considered a "liquid biopsy" that estimates the damage caused by GVHD to crypts throughout the lower GI tract (Hartwell et al., JCI Insight, 2017; Major-Monfried et al., Blood, 2018). We hypothesized that the change in MAP between start of treatment and 28 days later could serve as a response biomarker for GVHD and might compare favorably to the change in clinical symptoms that measures response to GVHD treatment, which is widely used as a surrogate for long term survival and is the primary endpoint in most GVHD treatment trials (Martin et al., BBMT, 2009; MacMillan et al., Blood, 2010). We prospectively collected serum samples and clinical staging from 368 sequential HCT patients who received systemic treatment for acute GVHD in one of 20 MAGIC centers between January 2016 and February 2018. We measured the serum concentrations of REG3α and ST2 before and after systemic therapy for acute GVHD and computed MAPs, the changes in MAPs, and clinical responses for each patient. MAPs of patients who experienced 6 month NRM showed significantly greater increases than MAPs of patients who survived (p=0.0004). In patients whose MAPs at the start of treatment were low (Ann Arbor 1, MAP < 0.141) or intermediate (Ann Arbor 2, 0.141 ≤ MAP ≤ 0.290), 6 month NRM clustered among those who had the greatest increases in MAP after 28 days (Fig 1A,B). In patients with high MAPs at the start of treatment (Ann Arbor 3, MAP > 0.290), those who survived tended to have the largest decreases in MAP (Fig 1C). These changes in MAP suggested crossing a single threshold could predict risk of mortality. We found that patients whose MAPs rose above a threshold MAP of 0.290 (5% of Ann Arbor 1, 27% of Ann Arbor 2) had significantly worse survival compared to those who remained below it, whereas the large number patients with initially high MAPs that remained above the threshold (66% of Ann Arbor 3) had a large increases in mortality (Fig 2). When measured at day 28, the MAP was significantly more accurate in predicting NRM than the gold standard of the clinical response, with areas under the receiver operating characteristic curve (AUC) of 0.86 and 0.70, respectively (p We conclude that the MAP is, to our knowledge, the first validated laboratory test to serve as response biomarker for the treatment for acute GVHD and a more accurate predictor of survival than clinical response after four weeks of treatment. The MAP may serve as a novel endpoint and an important complement to changes in clinical symptom severity in future trials of GVHD treatment. Disclosures Srinagesh: National Institutes of Health: Research Funding. Ozbek:Viracor: Patents & Royalties: Biomarker Patent. Ayuk:Novartis: Honoraria, Other: Advisory Board, Research Funding. Aziz:Doris Duke Charitable Foundation: Research Funding. Defilipp:Incyte: Research Funding. Grupp:Novartis: Consultancy, Research Funding; Roche: Consultancy; GSK: Consultancy; CBMG: Consultancy; Novartis: Research Funding; Kite: Research Funding; Servier: Research Funding; Jazz: Other: study steering committees or scientific advisory boards; Adaptimmune: Other: study steering committees or scientific advisory boards; Cure Genetics: Consultancy; Humanigen: Consultancy. Hexner:novartis: Research Funding. Kitko:Mallinckrodt: Honoraria; Novartis: Consultancy, Honoraria. Mielke:EBMT/EHA: Other: Travel support; ISCT: Other: Travel support; Miltenyi: Consultancy, Honoraria, Other: Travel and speakers fee (via institution), Speakers Bureau; Jazz Pharma: Honoraria, Other: Travel support, Speakers Bureau; IACH: Other: Travel support; Kiadis Pharma: Consultancy, Honoraria, Other: Travel support (via institution), Speakers Bureau; DGHO: Other: Travel support; Bellicum: Consultancy, Honoraria, Other: Travel (via institution); GILEAD: Consultancy, Honoraria, Other: travel (via institution), Speakers Bureau; Celgene: Honoraria, Other: Travel support (via institution), Speakers Bureau. Merli:Sobi: Consultancy; Amgen: Honoraria; Novartis: Honoraria; Bellicum: Consultancy. Pulsipher:Amgen: Other: Lecture; Miltenyi: Research Funding; Bellicum: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Other: Education for employees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Medac: Honoraria. Qayed:Bristol-Myers Squibb: Honoraria. Reshef:Pfizer: Consultancy; Magenta: Consultancy; Kite: Consultancy, Research Funding; Atara: Consultancy, Research Funding; BMS: Consultancy; Pharmacyclics: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Celgene: Research Funding; Shire: Research Funding. Levine:Incyte: Consultancy, Research Funding; Biogen: Other: non-financial support; Viracor: Patents & Royalties: biomarker patent; Ironwood: Honoraria; bluebird bio: Consultancy; National Cancer Institute: Research Funding; Novartis: Honoraria; Kamada: Research Funding. Ferrara:National Institutes of Health: Research Funding; ViraCor: Consultancy; Incyte: Consultancy; Kamada: Consultancy; Mallinckrodt: Consultancy; Enlivex: Consultancy; Xenikos: Consultancy; CSL Behring: Consultancy.

Background: Graft-versus-leukemia (GVL) responses after allogeneic hematopoietic cell transplantation (alloHCT) for AML are mediated by alloreactive donor-derived immune effector cells including T lymphocytes and natural killer (NK) cells. The function of NK cells is regulated by inhibitory and activating signals mediated through cell-surface receptors, including KIRs. Various models of NK cell alloreactivity have been associated with post-transplant outcomes, including leukemia relapse. However, these results have varied widely between different investigators employing similar models of NK cell alloreactivity. Assessment of somatic mutations in AML on post-transplant outcomes has not been investigated in the context of KIR profiles. Methods: In this single-institution retrospective cohort study, we investigated KIR haplotypes (haplotype AA vs. Bx [associated with multiple activating KIRs]; Cooley S., et al. Blood. 113:726-732. 2009) in the context of somatic mutations. We included 34 adult patients with AML who underwent alloHCT from a matched related donor from 2006 to 2013. A targeted multi-amplicon deep NGS panel of 79 commonly mutated genes in myeloid neoplasia was performed. Post-HCT outcomes were assessed based on mutational status and KIR haplotype with Kaplan-Meier method and log-rank test. Results: Median age at transplant was 54 (range 31-73). Cytogenetic risk groups were 9% favorable, 56% intermediate, and 35% poor based on 2017 ELN classification. HCT-CI scores included 26% low, 32% intermediate, and 41% high. Disease risk group defined by ASTCT included 71% low, 26% intermediate, and 3% high. Disease status at HCT included 74% CR1 and 26% CR2. Frequencies of somatic mutations prior to HCT were: 21% DNMT3A, 18% IDH2, 9% each for STAG2 and NRAS, 6% each for ASXL1, JAK2, PHF6, RUNX1, TET2, and 3% each for CBL, FLT3, NPM1, and U2AF1. Overall, 53% of patients had at least 1 mutation: 24%, 18%, 9%, and 3% of patients had 1, 2, 3, and 4 mutations, respectively. 41% were carriers of KIR haplotype AA, and 59% were haplotype Bx. Relapse (p=0.40), relapse-free (p=0.33), and overall survival (p=0.30) between haplotypes AA and Bx were not statistically different. However, when considering somatic mutations in the context of KIR haplotypes, those with any somatic mutation (n= 18) present had inferior relapse-free (p=0.002) and overall survival (p=0.002; figures A-B) as compared to those with none. Further assessment of outcomes was then considered for those who had the following poor prognostic mutations (n=12): ASXL1, DNMT3A, FLT3, NRAS, RUNX1, and TET2. KIR haplotype AA with one or more of these mutations was associated with inferior relapse-free (p=0.05) and overall survival (p=0.008). At median follow-up of 83 (range 66-137) months, 38% were alive. Non-relapse mortality rates were 21% (9-36) at 1 year and 29% (15-39) at 3 years. The most common causes of death for all patients were relapse (48%) followed by infection (33%). Conclusion: In presence of somatic mutations, carrying KIR haplotypes Bx was associated with better survival in AML post-alloHCT. The presence of multiple activating KIRs may also help mitigate the worse prognosis associated with some of the more deleterious somatic mutations in AML. These observations may have implications for improving patient risk stratification prior to transplant and optimizing donor selection. Future investigation with larger cohorts interrogating KIR haplotypes in the context of pre-transplant AML somatic mutations on post-transplant outcomes may further elucidate which patients may benefit most from transplant. Disclosures Nazha: Tolero, Karyopharma: Honoraria; Abbvie: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Speakers Bureau; Jazz Pharmacutical: Research Funding; Incyte: Speakers Bureau; MEI: Other: Data monitoring Committee. Mukherjee:Bristol-Myers Squibb: Speakers Bureau; Projects in Knowledge: Honoraria; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy; McGraw Hill Hematology Oncology Board Review: Other: Editor; Pfizer: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees. Advani:Pfizer: Honoraria, Research Funding; Macrogenics: Research Funding; Glycomimetics: Consultancy, Research Funding; Kite Pharmaceuticals: Consultancy; Amgen: Research Funding; Abbvie: Research Funding. Gerds:Sierra Oncology: Research Funding; Incyte: Consultancy, Research Funding; CTI Biopharma: Consultancy, Research Funding; Imago Biosciences: Research Funding; Celgene Corporation: Consultancy, Research Funding; Roche: Research Funding; Pfizer: Consultancy. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees. Majhail:Mallinckrodt: Honoraria; Atara Bio: Consultancy; Anthem, Inc.: Consultancy; Nkarta: Consultancy; Incyte: Consultancy. Maciejewski:Novartis: Consultancy; Alexion: Consultancy.

Introduction Intestinal Graft-versus-Host Disease (GvHD), following allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT), comes with a high mortality rate and a reduced life-expectancy. In this context, failure to respond to steroid therapy is associated with an absence of further therapeutic options, thereby representing an unmet medical need. A marked reduction in gut microbiota diversity leading to loss of functions was strongly associated with reduced overall survival in GvHD, while a high gut microbiota diversity appears to be protective. Aiming at restoring microbiome functions, Fecal Microbiota Transfer proved to be a promising treatment modality in this challenging clinical situation, with recent studies reporting favorable results in steroid refractory-acute GVHD (SR-aGvHD) patients. Here we report on the use of "MaaT013", a standardized, pooled-donor, high-richness microbiota biotherapeutic, used to treat 8 patients with intestinal-predominant aGvHD. Patients and methods Eight allo-HSCT recipients with steroid-dependent or steroid-refractory gastrointestinal GvHD (classical aGVHD n=3, late-onset aGVHD n=2; aGvHD with overlap syndrome n=3) were treated with the MaaT013 biotherapeutic as part of a compassionate use program. These patients had previously received and failed 1 to 5 lines (median 2.5) of GvHD systemic treatments. MaaT013 microbiota biotherapeutics were provided as a pharmaceutical preparation to hospitals by the developer, "MaaT Pharma". Each patient received 1 to 3 doses (median: 3; total doses administered: 21) of MaaT013, a 150 mL bag, by enema (n=7) or nasogastric tube (n=1). GvHD response was evaluated 7 days after each administration and 28 days after the first dose. Prepared under Good Manufacturing Practices, MaaT013 biotherapeutics are characterized by a highly consistent richness of 455 +/- 3% Operational Taxonomic Units (OTUs) and an Inverse Simpson index greater than 20. Batch release specifications are based on potency (viability), identity (diversity), and purity (microbiological safety testing following regulatory guidelines and proportion of proinflammatory species), ensuring the desired consistency between batches. Results We observed 6/8 positive responses at D28 after first dosing, including 3 Complete Responses (CR), one Very Good Partial Response (VGPR), and 2 Partial Responses (PR). Considering the best GI response achieved, all (8/8) patients experienced at least a PR, with 3 CRs, 2 VGPRs and 3 PRs. The 3 patients with CR were still alive at last follow-up (60 to 192 days after last dosing; median: 115 days) and were able to taper and stop steroids and immunosuppressants without relapse of GI symptoms. Of note, among these 3 patients, mild mouth chronic GvHD symptoms persisted in one patient, and relapse of hematologic malignancy was observed in another patient. Among the 8 treated patients, 5 were still alive at last follow-up (60 to 232 days after last dosing; median: 125 days). The safety of the MaaT013 microbiota biotherapeutic was satisfactory in all patients. One patient developed a possibly related sepsis one day after the third MaaT013 administration. In the latter case, no pathogen was identified in blood cultures, and the patient recovered after a course of antibiotics. Conclusions We herein report for the first time the treatment of 8 patients with steroid-dependent or steroid-refractory intestinal aGvHD using a full ecosystem, standardized, pooled-donor, high-richness biotherapeutic. Overall, 3/8 patients attained a complete response following treatment with the off-the-shelf MaaT013 product, shown to be safe and effective in these immunocompromised patients with severe conditions, warranting further exploration of the full ecosystem microbiota restoration approach. Disclosures Malard: Sanofi: Honoraria; JAZZ pharmaceutical: Honoraria; Astellas: Honoraria; Therakos/Mallinckrodt: Honoraria; Keocyte: Honoraria; Janssen: Honoraria. Plantamura:MaaT Pharma: Employment. Carter:MaaT Pharma: Employment. Chevallier:Jazz Pharmaceuticals: Honoraria; Incyte: Consultancy, Honoraria; Daiichi Sankyo: Honoraria. Blaise:Pierre Fabre medicaments: Honoraria; Molmed: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria; Sanofi: Honoraria. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

It has been proposed that bacteria play a direct role in progression of cutaneous T cell lymphoma (CTCL), although definitive evidence is missing, and the underlying mechanism of how microbes contribute to disease progression remains unknown. The skin of CTCL patients is frequently colonized with Staphylococcus aureus (S. aureus) strains and infections with hospital and community associated strains of S. aureus are a frequent cause of morbidity and mortality among patients with advanced CTCL. Here we provide a comprehensive analysis of the association between CTCL and S. aureus colonization, and use our unique pre-clinical animal model of CTCL to determine the cause-effect relationship between skin-associated S. aureus and CTCL progression. To understand the relationship between bacterial colonization and CTCL we collected skin swabs from active lesions, unaffected skin and nares of CTCL patients to perform S. aureus cultures and 16S rRNA gene sequencing. Skin swabs of psoriasis patients and healthy donors served as controls. The frequency of S. aureus colonization determined by culture based techniques revealed that >65% of advanced stage patients had S. aureus present at lesional/tumor sites, while corresponding sites in patients with psoriasis and in healthy controls rarely had detectable S. aureus. Colonization rates correlated positively with the disease stage. Unbiased, 16s sequencing based analysis of the skin microbiome from advanced CTCL patients revealed that the overall skin microbiome of these patients is distinct from that of healthy individuals and patients with psoriasis. A lower phylogenetic diversity and significantly higher relative abundance of Staphylococcus species was found in CTCL patients. To determine the causal relationship between skin flora and progression of CTCL we used our mouse model of CTCL and assessed disease progression in both conventionally housed specific-pathogen-free (SPF) conditions and in germ free (GF) isolators using a standardized clinical score. The CD4CreSTAT3stopfl/+ mice express a hyper-active STAT3C mutant protein selectively in T lymphocytes and virtually all mutant mice develop T cell infiltration in the epidermis causing skin lesions resembling CTCL, by eight months of age. In contrast to the SPF housed animals, GF mice remained disease free or developed only a mild phenotype (clinical score 1 out of 5) after 11 months of follow-up. Notably, when GF CD4CreSTAT3stopfl/+ mice were transitioned to SPF conditions they all developed advanced disease. Finally, we examined the role of T cell antigen receptor (TCR) signaling in mediating the transformation of T lymphocytes. R26STAT3Cstopfl/+CD4Cre Rag2KO OTII mice express only OVA-specific TCRs. T cells from R26STAT3Cstopfl/+ CD4Cre Stim1fl/fl mice express a normal TCR repertoire, but exhibit defective T cell receptor signaling due to compromised calcium influx. Both strains failed to develop typical skin lesions, suggesting an essential role for TCR interaction with tumor microenvironment and microbial antigens in the pathogenesis of CTCL. In conclusion, we demonstrate a strong correlation between CTCL staging and rates of S. aureus colonization. Our study supports a cause-effect relationship between skin flora and CTCL oncogenesis. We propose that CTCL represents an antigen driven malignancy. Further studies using mono-colonization with single bacterial strains are needed to further interrogate the role of specific bacteria. Disclosures Hymes: Celgene: Consultancy. Odum:Micreos human Health B.V: Consultancy. Geskin:Merck: Other: Supported/Contracted Research; UpToDate: Patents & Royalties: Royalty, Receipt of Intellectual Property Rights / Patent Holder; Mallinckrodt: Consultancy, Honoraria, Other: Supported/Contracted Research; Helsinn: Consultancy, Honoraria, Other: Supported/Contracted Research; Stratpharma: Other: Supported/Contracted Research; Medivir: Consultancy, Honoraria; Medscape: Speakers Bureau; Actelion: Other: Supported/Contracted Research.

Background: Allogeneic transplant (alloHCT) is a curative therapy for patients with acute lymphocytic leukemia (ALL). However, the curative potential of alloHCT is hampered by relapse, which is the major cause of treatment failure. Risk factors for relapse include minimal residual disease (MRD) before or after allogeneic transplantation, patients transplanted in second complete remission or beyond, and reduced intensity conditioning (RIC) regimens. Overall, relapse rates for these patients are in the range of 30% to 50% with the majority of these relapses occurring within the first year after alloHCT. After relapse, the options for disease control are limited and overall survival rates are poor. Currently, there are no standard post-transplant therapy for patients with ALL to reduce the likelihood of relapse. Post alloHCT maintenance approaches may provide time for the graft-versus-leukemia effect to develop, while possibly treating minimal-residual disease, prolonging leukemia-free-survival and decreasing relapse rates. Inotuzumab ozogamicin (INO) is a CD22 monoclonal antibody bound to calicheamicin which has been shown to have significant activity against relapsed ALL. INO has also been used in patients with relapsed / refractory ALL in a phase 3 randomized clinical trial with an overall CR rate of 81% in the INO arm compared to 29% in the standard arm. We hypothesize that low dose post-alloHCT maintenance therapy of INO will be safe and will reduce relapse rates after alloHCT for ALL. Once the appropriate dose has been found, the study will expand to a phase II. Methods: Eligibility included patients aged 16-75 who have undergone all-HCT for CD22+ALL in complete remission, have a high risk for relapse after alloHCT, have adequate graft and organ function, are between day 40 and 100 post-transplant, do not have active grade III/IV GVHD or any active GVHD of the liver, and have no history of VOD. The primary objective of this phase I clinical trial is to define a post-alloHCT maximum tolerated dose (MTD) of INO. Secondary objectives include describing the safety profile of INO post-alloHCT, determining the rate of veno-occlusive disease in this setting, evaluating non-relapse mortality (NRM), disease free survival (DFS) and overall survival (OS) at 1 year post-alloHCT, determining the incidence of myeloid toxicity and secondary graft failure, and determining if INO at these doses are effective at eradicating MRD in this cohort of patients. Pre-treatment tests include a bone marrow biopsy and aspirate to assess disease state and MRD. The trial design is a 3+3 model. The study treatment consists of a total of four 28 day cycles of INO starting at dose level 0 (0.3mg/m2) given on day 1. The first cycle must be initiated between day 40 and 100 after alloHCT. Dose limiting toxicities (DLT) include VOD, prolonged cytopenia (more than 28 days), and death. If there are no DLTs experienced in a cohort, patients may be enrolled in the next highest dose level (Table 1). Patients will be monitored with routine blood work during each cycle. At 1 year after alloHCT, patients will be assessed by restaging bone marrow biopsy and aspirate. Results: As of July 29th, 2019, 8 patients have been treated. One patient went off treatment after 1 cycle of INO (patient choice) and two went off treatment after 3 cycles of INO (patient choice and physician choice). All continued to be followed for safety. We have completed 1 year post-transplant follow up on 4 patients. All patients are alive and in CR. No patients experienced VOD or other DLTs. Significant side effects include thrombocytopenia and neutropenia. The percentage of any aGVHD is 62.5% and the rate of grade III/IV aGVHD is 0%. The percentage of any cGVHD is 42.8%. Patient characteristics are described below (Table 2). Conclusions: In this phase 1 study, INO at doses of 0.3 and 0.4mg/m2 was well tolerated. Thrombocytopenia may be the dose limiting toxicity. The absence of disease recurrence in this small cohort of high risk ALL patients is very promising. Disclosures Metheny: Takeda: Speakers Bureau; Incyte: Speakers Bureau. Majhail:Anthem, Inc.: Consultancy; Mallinckrodt: Honoraria; Nkarta: Consultancy; Incyte: Consultancy; Atara Bio: Consultancy. Malek:Adaptive: Consultancy; Amgen: Speakers Bureau; Celgene: Consultancy; Takeda: Consultancy; Sanofi: Consultancy; Medpacto: Research Funding; Janssen: Speakers Bureau. Gerds:Roche: Research Funding; Pfizer: Consultancy; CTI Biopharma: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding; Imago Biosciences: Research Funding; Incyte: Consultancy, Research Funding; Sierra Oncology: Research Funding. OffLabel Disclosure: Low dose inotuzuamb ozogamicin in the post-allogeneic transplant setting for patients with ALL.

Background: Axicabtagene Ciloleucel (Axi-cel), the first chimeric antigen receptor T-cell therapy (CAR-T), is approved for refractory/relapsed (R/R) aggressive B-cell lymphoma with the ZUMA-1 trial reporting an objective response in 83% and complete response in 58% patients at a median duration of 27 months (Locke et al. 2019). The availability to successfully deliver CAR-T therapy may be restricted by socio-economic, technical/manufacturing challenges and comorbidities related to aggressive B-cell lymphoma and its treatment. In this intent-to treat (ITT) analysis, we compared the outcomes of patients at our center with R/R B-cell lymphoma who received Axi-cel with those for whom Axi-cel therapy was intended but not administered, in order to identify factors that may limit its use in this population. Methods: We reviewed medical records of consecutive adult patients with R/R diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (tFL) and primary mediastinal B-cell lymphoma (PMBCL) for whom letters of medical necessity (LMN) were sent to request approval for Axi-cel, from March 2018 to May 2019 at our center. Patients were grouped according to whether or not they ultimately received Axi-cel. Baseline characteristics between Axi-cel and Non-Axi-cel group were compared using Fischer's exact test for categorical and Wilcoxon rank sum test for continuous variables. Comorbidities were assessed using the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) (Sorror 2013). Time-dependent outcomes were calculated from the date of LMN. Overall survival (OS) was estimated using the Kaplan-Meier method. Results: LMNs were sent for a total of 38 patients, 27 male (71%) with a median age of 63 (range, 25-77) years. 24 patients (63%) had an ECOG PS of 0 or 1 at study entry, while median IPI at diagnosis was 2 (range, 0-5). The most common histology was DLBCL in 25 patients (66%) and 18 (47%) had a germinal center B-cell (GCB) subtype. Four patients had double/triple hit lymphoma. The median number of prior therapies was 4 (range, 2-6) and 21 patients (55%) underwent prior autologous transplant. Forty-seven percent had relapsed and 53% had refractory disease. Patient characteristics are shown in Table 1. Twenty seven (71%) patients received Axi-cel, while 11 patients (29%) were considered candidates for but could not receive Axi-cel. The median time from LMN to cell infusion was 62 (range, 33-248) days. A higher HCT-CI score was observed in the Non-Axi-cel group as compared to the Axi-cel group (median score of 4 vs 2, P=0.04). The two groups did not differ with respect to age, ECOG PS, IPI, number of prior therapies or transplant status. Median follow- up was 5 (range, 2-16) months. At the time of last follow-up, 8 out of 27 patients (30%) in the Axi-cel and 10 out of 11 (91%) in the Non-Axi-cel group had died. The median OS for the entire cohort was 10 months (95% CI, 3.7 to 13), Axi-cel group was 13 months (95% CI, 7.7 to N.R.) and Non-Axi-cel group was 1 month (95% CI, 0.4 to 3.7) (Figure 1). In the Non-Axi-cel group, 3 patients underwent leukapheresis but died prior to infusion (including 1 manufacturing failure and 2 patients with rapid systemic progression). The other 7 deaths in this group were prior to leukapheresis (3 due to sepsis, 3 due to rapid progression including 1 case of active CNS disease and 1 patient could not receive therapy due to caregiver and financial barriers). The one surviving patient in the Non-Axi-cel group had refractory CNS relapse at the time of last follow-up. Conclusions: In this retrospective ITT analysis, approximately one third of patients with R/R aggressive B-cell lymphoma for whom CAR-T therapy was intended were unable to receive it and had extremely short median OS. Patients who could not receive Axi-cel had a higher comorbidity index at the time of decision to proceed with CAR-T therapy; the majority of them died before leukapheresis from disease progression or complications of prior treatment. Improved strategies are needed to safely bridge patients with aggressive B-cell lymphoma intended to receive Axi-cel. New targeted agents such as polatuzumab vedotin and tafasitamab (formerly MOR208) may increase the proportion of patients with aggressive B-cell lymphoma who ultimately receive and benefit from CAR-T therapy. Disclosures Anwer: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; In-Cyte: Speakers Bureau. Gerds:Incyte: Consultancy, Research Funding; Imago Biosciences: Research Funding; CTI Biopharma: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pfizer: Consultancy; Roche: Research Funding. Majhail:Anthem, Inc.: Consultancy; Incyte: Consultancy; Atara Bio: Consultancy; Nkarta: Consultancy; Mallinckrodt: Honoraria. Hill:TG therapeutics: Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria; Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding; Amgen: Research Funding.

Introduction: Relapse is the most frequent cause of treatment failure after allogeneic hematopoietic cell transplantation (alloHCT). While transplant-related mortality has decreased substantially over the last few decades, little progress has been made in outcomes and no standard of care exists for patients (pts) with post-alloHCT relapse. In the recent era, several new therapies, including targeted agents, have been approved for ALL, AML, and MDS. We conducted a study to evaluate outcomes of pts with these diseases who relapse after alloHCT in the contemporary period with routine availability of these newer therapeutic agents. Methods: We performed a single-institution retrospective cohort study to review treatment strategies and outcomes of relapse post-alloHCT. We identified 420 adult pts who received their first alloHCT in 2010-2018 using any conditioning regimen or donor source. Overall, 115 (27%) pts experienced relapse (ALL=17/64 [27%], AML=67/242 [28%], MDS=31/114 [27%]) and were included in the analysis. Results: Myeloablative (54%) matched-unrelated donor grafts (50%) were the most common types of HCTs. Peripheral blood stem cell graft (49%) and bone marrow graft (48%) were used the most. Median time from alloHCT to relapse was 5 (range 1-65) months, and 83% of relapses occurred within the first year. Only 24% and 11% of pts experienced grade II-IV acute and any chronic GVHD prior to relapse, respectively. Seven of 17 pts had Philadelphia chromosome positive ALL. Mutation panel was tested in 56% of AML and MDS. Median follow-up period after relapse was 19 (range 6-80) months. The estimated survival after relapse for all diseases was 32% (95% CI 24-41%) at 6 months, 21% (14-28%) at 12 months, and 14% (8-21%) at 24 months (Fig 1). Excluding pts treated with supportive care only, the majority received a combination of different treatments; pts with ALL received median 3 (range 1-5), pts with AML received median 2 (1-4), and pts with MDS received median 1 (1-3) agent. Targeted therapies used for ALL pts included blinatumomab (n=5) and BCR-ABL targeting tyrosine kinase inhibitors with (n=2) or without (n=4) chemotherapy. Among AML pts, targeted agents were used in 15 pts (sorafenib [n=7], 2 each with enasidenib, gemtuzumab ozagamicin, and ivosidenib, and 1 each with venetoclax and SEL24 [a dual pan-PIM/FLT3 inhibitor]). One pt each was treated with enasidenib, gemtuzumab ozagamicin, and PTC299 (an inhibitor of VEGFA mRNA translation) followed by SEL24 for MDS. Second alloHCTs (n=5) were performed median 5 (range 1-16) months after first HCT and median 1 month (range 0-5 months) after relapse. Two pts received no bridging therapy, while 3 pts received chemotherapy (n=2) or donor lymphocyte infusions (DLI [n=1]) prior to the second transplant. DLI without second transplant was used in 25 pts at a median of 20 (range 3-18) months after ALL relapse, median 2 (range 0-13) months after AML relapse, and median 3 (range 1-5) months after MDS relapse. Following DLI, 53% pts developed GVHD. Targeted therapy was associated with a trend towards better survival compared to other therapies (Fig 2, HR 0.65, 95% CI 0.41-1.03, p=0.06). Based on multivariable analysis, matched unrelated (vs. matched sibling, HR 1.70, p=0.027) or haploidentical donor grafts (HR 2.69, p=0.003), presence of grade II-IV acute GVHD before relapse (HR 2.46, p12 months, HR 6.34, p12 months, HR 3.16, p=0.005) were adverse prognostic features with survival after relapse post-alloHCT (Table 1). Conclusion: Outcomes of pts with ALL, AML, and MDS who relapse following alloHCT remain poor in the contemporary era when several newer therapies, including targeted agents, are available for their treatment. Targeted agents were used only in a minority of post-alloHCT relapses likely due to the combination of pt status, absence of the target mutation, the agents' availability, and other factors. Pts who developed grade II-IV acute GVHD and had shorter "disease-free" duration from unrelated or haploidentical donor grafts had the significantly shorter survival following relapse. More innovative treatment strategies to prevent and treat relapse post-alloHCT are needed. Disclosures Hill: Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celegene: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; TG therapeutics: Research Funding; Genentech: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding. Anwer:In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Majhail:Atara Bio: Consultancy; Anthem, Inc.: Consultancy; Nkarta: Consultancy; Mallinckrodt: Honoraria; Incyte: Consultancy.

Introduction: Systemic steroids with their strong immunosuppressive and anti-inflammatory effects are the current gold standard for initial treatment of the graft-versus-host disease (GvHD). But, the effectiveness of high-dose steroids comes along with an increased susceptibility to infections and other secondary malignancies. Extracorporeal photophoresis (ECP), an immunotherapeutic therapy, is currently being used as a clinically well-established second-line treatment for GvHD. Contrary to steroid treatment, there is no clinical data showing that ECP is associated with an increased risk of infection. However, the exact mechanism of action how ECP preserves the anti-viral and anti-leukemic effects on the cellular level has not been discovered yet. Materials and methods: Thirty-four patients with steroid-refractory/resistant aGvHD ≥ II and moderate to severe cGvHD were treated with ECP at the University Hospitals in Heidelberg, Greifswald in Germany and Chaim Sheba Medical Center in Israel. A comprehensive analysis of cell subsets was performed using multi-parametric flow cytometry. Additionally, the quantity and quality of CMV-specific T cells was determined by tetramer staining and interferon-γ enzyme-linked immunospot assay. The NK activity in terms of killing functionality and cytokine release was analyzed by intracellular cytokine staining and chromium-51 release assay, respectively. The proliferative capacity of effector cells was determined by carboxyfluorescein succinimidyl ester (CFSE) staining. Results: ECP therapy was effective with an overall response rate of 75% for patients with aGvHD (x/y) and 78% (x/y) for patients with cGvHD. Of note, all patients showed neither the increased susceptibility to infections nor the reactivation of CMV nor the tumor relapse. Overall, the frequency of well-established protective cell subsets in terms of cytotoxic CD8+ T cells, CD4+CD8+ T cells, γδ T cells, NK cells and NKT cells remained constant under the ECP therapy. Specifically, no significant influence of ECP therapy on the CD56dimCD57+NKG2C+ NK cells, a specialized anti-viral/tumor population, and the CMV+CD8+ T cells could be observed. The further phenotyping of CMV+CD8+ T cells showed that CD45RA+CCR7-CMV+CD8+ TE cells and CD45RA-CCR7-CMV+CD8+ TEM cells could keep stable under the ECP therapy. Besides these, priming, differentiation and maturation of NK cells through upregulation of CD57 by ECP therapy bridged the T-cell-deficient period after HSCT in order to control the viral infections and eliminate the residual malignant cells. Moreover, ECP could reduce the CD62L expression on TE population which not only facilitates the hematopoietic engraftment and contributes to the phenotypic and functional T cell reconstitution after transplantation without causing GvHD, but also enhances the functional immune reconstitution against tumor and viral antigens. Functionally, neither IFN-g released by virus specific T cells nor production of TNF-a and IFN-g by NK cells in response to K562 cells was hampered by ECP. Of note, the functions of NK cells in terms of the MFI of cytokines and the polyfunctionality of NK cells were stable under ECP treatment. Additionally, the proliferation of NK cells, CD4+ T cells and CD8+ T cells providing an expanded pool of effector cells against the pathogens was not hampered by ECP therapy as well. Conclusions: ECP therapy constitutes an effective strategy to treat GvHD. In addition, ECP appears to be a safe therapy compared to continued steroid use. Our current results suggest that ECP allows to maintain immunity against infections and tumors. Disclosures Schönland: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Medac: Other: Travel Grant. Dreger:Neovii, Riemser: Research Funding; AbbVie, Gilead, Novartis, Riemser, Roche: Speakers Bureau; AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Riemser, Roche: Consultancy; MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia. Schmitt:MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; Therakos Mallinckrodt: Other: Financial Support. Schmitt:Therakos Mallinckrodt: Other: Financial Support .

Although alloHCT is an accepted salvage treatment in defined settings of poor-risk NHL, its potential benefit in these indications remains controversial because virtually all published studies are uncontrolled and restricted to patients who were actually able to undergo transplantation. Here, we aimed at assessing the impact of alloHCT by measuring its outcome from the time of donor search indication rather than from the time of transplant, thereby taking into account those patients who fail to proceed to allografting for any reason. Study design and patients : In a single centre retrospective analysis, course and outcome of all patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) mantle cell lymphoma (MCL) and peripheral T-cell lymphoma (PTCL) who were considered as having an alloHCT indication according to accepted guidelines between 2004 and 2018 were recorded. Primary endpoint was overall survival (OS) from start of donor search. A key secondary endpoint was comparison of OS from the 3-month landmark by donor availability. Accepted donors were matched related donors (MRD), 10/10 matched unrelated donors (MUD), 9/10 compatible unrelated donors (MMUD), and mismatched related donors (MMRD), with haplo donors being used at our institution only since 2014. Results : Altogether a donor search was initiated in 187 patients (DLBCL 32%, FL 17%, MCL 23%, PTCL 28%). Median age was 54 (19-69) years with 74% being male. Within a median time from diagnosis to search initiation of 1.1 (0.1-19) years, a median of 4 (1-9) treatment lines had been administered, including an autoHCT in 50%. 69% of the patients had active disease at the time of search initiation. Only 2 patients underwent donor search in 1st remission (for Richter transformation and hepatosplenic T cell lymphoma, respectively). With a median follow-up of 6.2 (0.6-15.9) years, OS at 5 years after search initiation for DLBCL, FL, MCL, and PTCL was 25%, 44%, 52%, and 50%, respectively (Fig 1). 171 patients (91%) were alive at the 3-month landmark. For these, an MRD (20%), MUD (44%), MMUD (25%), or MMRD (7%) could be identified in 96% of the cases. AlloHCT was performed in 72% of all 187 patients, and in 79% of the patients alive at the 3-month landmark, with a significantly lower rate in DLBCL (69%) compared to the other entities. In patients who were actually transplanted, 5-year OS from landmark for DLBCL, FL, MCL and PTCL was 32%, 63%, 62%, and 62%, respectively, whereas only 5 of the 36 patients (14%) alive at the 3-month landmark not undergoing alloHCT for any reason survived long term. Due to the low rate of unsuccessful searches, donor vs no-donor landmark survival analyses were not possible. Conclusions: Despite donor search now being successful in virtually all cases, 20-30% of those patients intended for alloHCT for NHL will never proceed to transplant. However, long-term OS by ITT does not seem substantially worse than alloHCT outcome observed in registry studies restricted to patients actually transplanted, with DLBCL appearing inferior to the other 3 entities. Patients surviving the 3-month landmark but not undergoing alloHCT for any reason have a poor outlook. These results may serve as benchmark for novel therapeutic options entering the NHL treatment landscape. Disclosures Luft: Neovii: Research Funding; JAZZ: Research Funding. Schmitt:MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; Therakos Mallinckrodt: Other: Financial Support. Dreger:Neovii, Riemser: Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; AbbVie, Gilead, Novartis, Riemser, Roche: Speakers Bureau; AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Riemser, Roche: Consultancy.

Targeted agents have greatly improved outcomes for patients (pts) with chronic lymphocytic leukemia (CLL) and other B cell lymphomas; however, single agents have been limited by intolerance, resistance and depth/durability of responses. Current novel targeted agent combinations may improve depth of response, but such "full dose" strategies have been associated with significant AEs, dose reductions/interruptions and discontinuations. Our in vitro & in vivo screening/optimization studies identified that concurrent inhibition of BTK & mTOR targets plus IMiD at low doses of each inhibitor can synergistically kill B-cell malignancies and may address drug-resistance. DTRM-555 is an optimized oral triplet combination of a novel BTK inhibitor DTRMWXHS-12 (DTRM-12) with everolimus (EV) & pomalidomide (POM). This once daily therapy was tested in a stepwise, phase I, US multicenter study in patients with highest unmet medical needs including r/r CLL, Richter's transformation (RT) of CLL, DLBCL, transformed B-cell lymphomas. We conducted a 3+3 design phase I, first human trial exploring DTRM-555 in pts ≥18 years, ECOG PS ≤1 with CLL, B-cell NHL, or Hodgkin lymphoma (HL) with no available standard therapy (NCT02900716). Our goal was to determine optimal doses for triplet combination therapy through 3 escalating phases of study: DTRM-12 in escalating doses (50, 100, 200, & 300 mg/day) in Part Ia, DTRM-12 at 200 mg or 300 mg & EV at 5 mg (doublet or DTRM-505) in Part Ib Arm A while DTRM-12 at 200 mg or 300 mg, EV at 5 mg & POM at 2 mg in Part Ib Arm B. For all arms, treatment was administered for 21 consecutive days of a 28-day cycle, until disease progression or unacceptable toxicity. Safety was the primary endpoint, and the dose-limiting toxicity (DLT) period was cycle 1. Secondary endpoints included response (iwCLL 2018 or Cheson 2014), progression free survival, duration of response and pharmacokinetics. Intra-patient migration between arms (Mono to doublet to triplet) was permitted if subsequent doses were tolerated. The trial commenced 9/27/2016 and completed enrollment 7/25/2019. Thirty-three pts were enrolled, including 2 screen failures and 4 intra-cohort migrations, with r/r DLBCL (n=8), CLL/SLL (n=5), RT (n=6), FL (n=5), MCL (n=4), MZL/LPL (n=3), HL (n=2). 30 of 31 treated pts were evaluated: 8 pts participated in phase Ia (DTRM-12) while 23 pts were treated on phase Ib combinations (DTRM-505 & DTRM-555). Baseline characteristics: 70% male (n=23), median age 70 years (range 46-94) and 94% white. Median prior therapies were 3 (range 1-10), 53% had been treated with ≥1 prior targeted agent (i.e., CD19/CD3 bispecific antibody, obtinutuzumab, pembrolizumab, nivolumab, ibrutinib, venetoclax, PI3k-i), CAR-T or HSCT. 35% pts were previously treated with ibrutinib. Table 1 describes Grade (Gr) 3 and 4 AEs (all causality, stratified by treatment arm). Regarding safety, AEs were manageable, with a total of 5 DLTs were observed: 2 (Gr 3 febrile neutropenia, URI) in part Ib arm A, 3 (Gr 4 thrombocytopenia, Gr 3 diarrhea, G3 febrile neutropenia) in Part Ib arm B. No MTD was reached for the mono & doublet arms, with the MTD of the triplet determined to be DTRM-12 200 mg, EV 5 mg, & POM 2 mg. Spider plot (Figure 1a) shows the clinical response for individual CLL and lymphoma pts treated with mono, doublet and triplet therapies. Depth and durability of response improved with combination therapies (vs. mono). Of note, 48% of all patients had a ≥50% reduction in sum of the products of lymph node diameters. Representative PET-CT scans are in Figure 1b-c. Responses in multi-refractory pts are ongoing (including 15+ mos in a pt with r/r DLBCL and 5+ mos PR in a pt aged > 90 yrs with r/r DLBCL; 4+ & 13+ mos PRs in two pts with RT). DTRM-12 plasma concentrations were unaffected by EV & POM (Once Daily Oral Therapies) in Figure 1d. The clinical trial met its primary endpoint as the triple combination DTRM-555 had an acceptable safety profile. Dose dependent drug levels with minimal inter-pt variations were observed in all arms, supporting once daily oral administration of this low-dose combination therapy. Encouraging clinical activity was observed in several high-risk, multi-refractory CLL and lymphoma pts, including those previously treated with ibrutinib. Thus synthetic lethality is a viable treatment approach. A phase II US expansion study is underway targeting pts with transformed lymphomas (follicular or prior CLL) and r/r DLBCL cohorts. Table 1. Disclosures Mato: AbbVie: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Research Funding; Celgene: Consultancy; AstraZeneca: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Gilead: Research Funding; Acerta: Consultancy; Janssen: Consultancy; TG Therapeutics: Consultancy, Other: DSMB member , Research Funding; LOXO: Consultancy, Research Funding; DTRM Biopharma: Research Funding. Schuster:DTRM Biopharma: Research Funding. Foss:Mallinckrodt: Consultancy; Acrotech: Consultancy; miRagen: Consultancy; Seattle Genetics: Consultancy, Other: fees for non-CME/CE services ; Eisai: Consultancy; Spectrum: Other: fees for non-CME/CE services . Isufi:Novartis: Consultancy; Astra Zeneca: Consultancy; Celgene: Consultancy. Ding:Merck: Research Funding; DTRM Biopharma: Research Funding. Brander:Novartis: Consultancy; MEI: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy; BeiGene: Research Funding; AstraZeneca: Consultancy, Research Funding; Acerta: Research Funding; Tolero: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria, Research Funding; DTRM Biopharma: Research Funding. Tun:Mundi-pharma: Research Funding; TG Therapeutics: Research Funding; Curis: Research Funding; DTRM Biopharma: Research Funding; Celgene: Research Funding; BMS: Research Funding. He:DTRM Biopharma: Employment, Equity Ownership. Kearney:DTRM Biopharma: Employment, Equity Ownership. Gui:DTRM Biopharma: Employment, Equity Ownership. Anderson:Theradex: Employment. Roeker:AbbVie: Equity Ownership; Abbott Laboratories: Equity Ownership. Huntington:Bayer: Consultancy, Honoraria; AbbVie: Consultancy; Celgene: Consultancy, Research Funding; Genentech: Consultancy; Pharmacyclics: Honoraria; DTRM Biopharm: Research Funding. OffLabel Disclosure: Everolimus in B cell lymphomas and CLL Pomalidomide in B cell lymphomas and CLL

Background: There is a large unmet need for relapsed/refractory T cell lymphoma. For patients (pts) with recurrent disease, the efficacy of salvage and autologous stem cell transplant (if feasible) is moderate and the 3-year overall survival is less than 30%. Romidepsin is a histone deacetylase inhibitor (HDACi) that is FDA approved for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma. Immune checkpoint blockade (CPB) of PD1/PDL-1 has been successful in many malignancies. In a recent report, PDL1 expression was observed 5-17% of tumor cells and 43%-57% in stromal histiocytes in PTCL-NOS or AITL. A phase II single agent study of the PD1 monoclonal antibody (mAB) pembrolizumab in PTCL demonstrated modest responses (Barta et.al). In addition, PTCL often carries multiple gene mutations in epigenetic modifier genes (TET2, IDH2, DNMT3A) and others (RHOA, FYN) that may impair immunogenicity and promote immune escape. This was the rationale for combining HDACi and CPB. We report this single center, single arm, nonrandomized trial of pembrolizumab in combination with romidepsin in subjects with relapsed or refractory PTCL that have failed to achieve a complete response or progressed after at least one systemic treatment regimen (NCT03278782). METHODS: This is a phase I/II study to examine the safety and efficacy of pembrolizumab 200 mg fixed dose administered every 3 weeks (Q3W) in combination with romidepsin. The safety of the combination was tested in the lead-in phase I study with a strategy of dose de-escalation, keeping the starting dose of romidepsin 14 mg/m2 on days 1 and 8. This eventually became the dosing for the phase II study. Adverse events were monitored throughout the trial and graded in severity according to the guidelines outlined in the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The primary objectives of the trial are to determine safety, tolerability, and overall response rate (ORR) of the combination. Secondary objectives include further analysis of various efficacy parameters [complete remission rate (CRR), progression free survival (PFS), overall survival(OS) and duration of response (DOR)]. Response assessment was performed utilizing Lugano Revised Response Criteria, and PD-L1 expression assessed by immunohistochemistry and exploratory analysis of targeted Next Generation Sequencing in the primary lymphoma tissue. Changes in peripheral blood T-cell repertoire were assessed primarily by flow cytometry. RESULTS: 15 pts were evaluable for the primary endpoint (demographics in figure 1). The phase I part was expanded from 3 to 6 pts, because of a dose limiting toxicity (DLT) of hypotension and renal insufficiency which resolved. The phase II is ongoing with 9 pts enrolled. The overall response rate was 44%; 3 pts. achieved a complete response and 2 achieved PR. The median follow-up was 6 months (3 weeks- 12 months). The 3 complete responders remain in remission > 10 months. One patient with refractory ALCL who achieved CR after 3 cycles is now 6 months post Haplo-identical transplant. Nausea and vomiting was the most common adverse event (Grade 1/2-). The most common ≥ grade 3 treatment-emergent adverse events were Nausea/vomiting and fatigue ( n =1 and n= 2). Two patients experienced hyperprogression within the first 10 days after the treatment. Correlative studies including NGS, expression of PD-L1, CD4+ T lymphocytes counts are in progress. CONCLUSIONS: The combination of Romidepsin and Pembrolizumab has demonstrated acceptable safety and early encouraging results. Table. Disclosures Iyer: Spectrum: Research Funding; Seattle Genetics: Research Funding; Merck: Research Funding; Trillium Therapeutics: Research Funding; Rhizen: Research Funding. Neelapu:BMS: Research Funding; Allogene: Consultancy; Acerta: Research Funding; Incyte: Consultancy; Cell Medica: Consultancy; Pfizer: Consultancy; Unum Therapeutics: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Precision Biosciences: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Karus: Research Funding; Cellectis: Research Funding; Poseida: Research Funding. Nieto:Affimed: Research Funding; Novartis: Research Funding; Astra-Zeneca: Research Funding; Affimed: Consultancy. Westin:Genentech: Other: Advisory Board, Research Funding; Novartis: Other: Advisory Board, Research Funding; MorphoSys: Other: Advisory Board; Juno: Other: Advisory Board; Janssen: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; Unum: Research Funding; 47 Inc: Research Funding; Kite: Other: Advisory Board, Research Funding; Curis: Other: Advisory Board, Research Funding. Parmar:Cellenkos Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Fowler:TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nastoupil:Bayer: Honoraria; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Spectrum: Honoraria; Novartis: Honoraria; TG Therapeutics: Honoraria, Research Funding. Duvic:Janssen Pharmaceuticals (div of Johnson & Johnson): Speakers Bureau; PleXus Communications: Speakers Bureau; Therakos: Speakers Bureau; Eisai: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Jonathan Wood & Assoc.: Speakers Bureau; Mallinckrodt Pharmaceuticals (formeraly Therakos, Inc): Research Funding; Soligenetics: Research Funding; Evidera, Inc.: Consultancy; Guidepoint Global: Consultancy; Cell Medica Inc.: Consultancy; UT MD Anderson Cancer Center: Employment; Shape: Research Funding; USCLC Registry: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Secretary/treasurer of Item h; Hawaiian Dermatology Society: Speakers Bureau; Hemedicus: Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Spatz Foundation: Research Funding; Oncoceuticals: Research Funding; Millennium (formerly Takeda): Research Funding; Allos: Research Funding; Rhizen Pharma: Research Funding; Cutaneous Lymphoma Foundation: Membership on an entity's Board of Directors or advisory committees; Cell Medica Ltd.: Honoraria; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees; Tetralogic: Research Funding. Huen:Galderma Inc: Research Funding; Glaxo Smith Kline Inc: Research Funding; Rhizen Pharmaceuticals: Research Funding; Innate Pharmaceuticals: Research Funding. OffLabel Disclosure: Pembrolizumab in T cell lymphoma

Background Tipifarnib is a potent and selective inhibitor of the enzyme farnesyltransferase (FT). FT catalyzes post-translational attachment of farnesyl groups required for localization of signaling molecules to the inner cell membrane. CXCL12 is a chemokine that is essential for T cell homing to lymphoid organs and the bone marrow, and for the maintenance of immune cell progenitors. Herein we report preliminary efficacy, safety and biomarker data from a Phase 2 study of tipifarnib in angioimmunoblastic T-cell lymphoma (AITL) and CXCL12+ peripheral T-cell lymphoma (PTCL) patients (pts). Methods This Phase 2 study is a multi-institutional, single-arm, open-label trial initially designed as a two-stage (11+7 pts) cohort to determine the efficacy, safety and biomarkers of tipifarnib in pts with relapsed/refractory (R/R) PTCL, age >/=18 years and a performance status of 0-2. Based on initial findings, the study was amended to include a cohort of AITL (n=12) and PTCL (n=12) pts with the CXCL12 rs2839695 A/A genotype (CXCL12+ cohort). Pts received tipifarnib 300 mg administered orally twice daily on days 1-21 of 28-day treatment cycles until progression of disease (PD) or unacceptable toxicity. The primary endpoint of the study is overall response rate (ORR). Ancillary studies are also ongoing to investigate the prognostic value of CXCL12 expression in patients who received standard of care treatment. Results As of 25 July 2018, 34 PTCL pts (13 AITL, 1 ALK- ALCL, 20 PTCL-NOS) have been treated with tipifarnib, 19 pts in stages 1 and 2, and 15 pts in the ongoing AITL histology and CXCL12 cohorts. Median number of prior treatment regimens was 3. The most common treatment-related adverse events (AE) (grade ≥ 3) are hematological, including neutropenia (50%), thrombocytopenia (43%), leukopenia (33%), febrile neutropenia (27%), and anemia (20%). Skin and subcutaneous tissue disorders were reported in 9 pts, 6 of them with AITL histology. One pt with AITL experienced an episode of possible Stevens Johnson Syndrome that resolved with dose discontinuation and did not recur upon re-challenge at one dose level reduction. Of 18 evaluable patients enrolled in Stages 1 and 2 of the trial, 3 partial responses (PR), 2 of them in pts with AITL histology, and 4 best responses of stable disease (SD) were observed. Pre-treatment tumor tissue CXCL12 expression correlated with favorable pt outcomes. In the AITL cohort (10 evaluable pts), 1 PR and 1 SD have been observed so far, with 5 pts pending cycle 2 response evaluation. In the CXCL12+ cohort (n=3 evaluable pts), 1 SD has been observed, with 2 pts pending cycle 2 response evaluation. Plasma levels of CXCL12 decreased over time with tipifarnib treatment. Expression of CXCL12 mRNA and other biomarkers in pre-treatment biopsies of pts in the AITL and CXCL12+ cohorts are being evaluated using RT-PCR assays. In addition, the prognostic value of CXCL12 is being investigated in approximately 100 diagnostic specimens of PTCL pts who received standard therapy. Preliminary data suggest that CXCL12 overexpression is observed in approximately 25% of PTCL and negatively affects pt survival. Conclusion Preliminary activity of tipifarnib was observed in PTCL pts, particularly in those with tumors of AITL histology and high CXCL12 expression and enrollment continues. Disclosures Witzig: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sokol:Mallinckrodt Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Spectrum Pharmaceuticals: Consultancy. Jacobsen:Merck: Consultancy; Seattle Genetics: Consultancy. Kim:Takeda: Research Funding; J&J: Research Funding; Mundipharma: Research Funding; Roche: Research Funding; Novartis: Research Funding; Kyowa-Kirin: Research Funding; Celltrion: Research Funding. Foss:Miragen: Consultancy, Speakers Bureau; Spectrum: Consultancy; Seattle genetics: Consultancy; Mallinkrodt: Consultancy. Advani:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kura: Research Funding; Merck: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Regeneron: Research Funding; Janssen: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Cell Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Autolus: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Gilead/Kite: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millenium: Research Funding; Agensys: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Infinity: Research Funding. Marin Niebla:Amgen: Other: Medical education of Staff, Speakers Bureau; Roche: Consultancy, Other: Medical education of Staff, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Other: Medical education of Staff, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Medical education of Staff, Speakers Bureau. Piris:Kura: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Gilead: Honoraria. Curry:Kura Oncology: Employment, Equity Ownership. Gualberto:Kura Oncology: Employment, Equity Ownership.

Background: Current treatment of advanced stage Mycosis fungoides (MF) and Sézary syndrome (SS) remains unsatisfactory. Complete responses (CR) are typically Methods: This single-arm, multicenter study by the Cancer Immunotherapy Trials Network (CITN) enrolled 24 patients with MF/SS stages IB-IV, with at least one prior systemic therapy. Pembrolizumab was administered at 2 mg/kg every 3 weeks for up to two years. The primary endpoint was overall response rate (ORR) using global response criteria according to the ISCL/EORTC consensus guidelines. Skin responses were measured by mSWAT. Secondary endpoints were safety/tolerability, time to response (TTR), duration of response (DOR) and progression-free survival (PFS). Correlative studies included immunohistochemistry (IHC), mass cytometry, whole exome sequencing, gene expression profiling, and serum cytokine analysis. Results: Patients had advanced stage disease (23/24 with stage IIB-IV MF/SS), and were heavily pretreated (median of 4 prior systemic therapies). The ORR was 38% with 2 CR and 7 PR. Of the 9 responding patients, 6 had ≥90% improvement in skin disease by mSWAT. The median TTR was 11 weeks. Responses were durable, with 8 of 9 responses ongoing at last follow up (median DOR 64 weeks, range 32-153 weeks). One responding patient progressed 2 months after discontinuing treatment due to an adverse event (AE). The median PFS was not reached. Overall, the toxicity profile was similar to prior studies of pembrolizumab. Four patients discontinued treatment due to treatment related serious AEs of duodenitis, pneumonitis, hepatitis, and corneal ulcer. Skin flare reactions were observed early in the treatment course in 40% of patients with SS, but none with MF. The skin flare reactions did not result in any treatment discontinuation, and did not correlate with subsequent response to treatment. There was no significant association between response and clinical characteristics including stage, disease type (MF vs. SS), or number of prior therapies. IHC assessment of PD-1, PD-L1, and PD-L2 did not predict response. Treatment resulted in an increase of PD-L1 expression by both IHC and nanoString analysis. A nanoString18 gene signature of tumor inflammation that is predictive of response to pembrolizumab in other tumor types was not predictive in this cohort. High dimensional mass cytometry enabled precise identification and phenotyping of malignant T cells. There was a positive correlation between PD-1 expression on the malignant T cells and development of the skin flare reaction. Whole exome sequencing revealed genomic disruptions of PD-1 signaling including copy loss of PD-1. No associations were found between outcomes and genomic events involving the PD1/PD-L1 axis, total mutation number, or neoantigen numbers. Conclusions: The 38% ORR rate in this heavily pretreated population was 38% with a highly encouraging DOR of 64 weeks. No predictive biomarkers have emerged thus far, but additional studies are ongoing. Additional combination studies with pembrolizumab are warranted to improve response rates. Figure. Figure. Disclosures Khodadoust: Innate Pharma: Research Funding. Porcu:Innate Pharma: Consultancy. Foss:Miragen: Consultancy, Speakers Bureau; Seattle genetics: Consultancy; Spectrum: Consultancy; Mallinkrodt: Consultancy. Moskowitz:Bristol Myers-Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Merck: Research Funding; Takeda: Honoraria; ADC Therapeutics: Research Funding. Shustov:Seattle Genetics: Research Funding. Sokol:Seattle Genetics: Consultancy; Mallinckrodt Pharmaceuticals: Consultancy; Spectrum Pharmaceuticals: Consultancy. Yearley:Merck: Employment. Horwitz:Mundipharma: Consultancy; Celgene: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Kyowa-Hakka-Kirin: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Aileron Therapeutics: Consultancy, Research Funding; Portola: Consultancy; Trillium: Consultancy; Innate Pharma: Consultancy; Spectrum: Research Funding; Corvus: Consultancy. Kim:miRagen: Research Funding; Horizon Pharma: Consultancy, Research Funding; Neumedicine: Consultancy, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Galderma: Research Funding; Soligenix: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetralogic: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Portola: Research Funding; Merck: Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees; Kyowa-Kirin-Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Research Funding.

BACKGROUND: ABVD with or without radiation is standard therapy for limited stage HL, but carries risks of bleomycin-lung injury and radiation toxicity. Brentuximab vedotin (BV) is an anti-CD30 antibody drug conjugate which is highly active in relapsed classical HL. We previously combined BV with AVD in limited stage non-bulky classical HL which resulted in a high CR rate, but at the cost of increased neutropenia, neutropenic fever, and neuropathy, likely related to the overlapping toxicity profile with vinblastine. Similar toxicity findings were also observed with BV-AVD in advanced stage classical Hodgkin lymphoma. We therefore evaluated BV plus AD (BV-AD) without radiation therapy for non-bulky stage I-II classical HL with the goal of reducing toxicity and maintaining high rates of inducing CR. METHODS: This is a multicenter single arm open label phase 2 study. Patients received BV 1.2 mg/kg plus standard dose adriamycin and dacarbazine on days 1 and 15 of each 28 day cycle. GCSF prophylaxis was not included. Patients received 4 or 6 cycles of BV-AD based on the results of an interim PETCT scan performed following cycle 2. PET negativity was defined as Deauville scores 1-3. Patients in CR on interim PETCT received 4 total cycles of therapy; patients in PR completed 6 cycles. The primary endpoint is complete response rate (CRR) at end of treatment. A sample size of 34 was required to detect an end of treatment CRR of 95% with 91% power and alpha error of 0.09. RESULTS: 34 patients were enrolled. Median age is 36 (range 18-63). Stage is IA (3), IB (1), IIA (29) and IIB (1). Risk is classified per the GHSG criteria as early unfavorable in 47%, and favorable in 53%. The interim CR rate is 94%. Accordingly, 32 interim PET negative patients (94%) received 4 total cycles of therapy, and 2 interim PET positive patients (6%) received 6 total cycles of therapy. No patients received consolidative radiation therapy, per protocol. The primary endpoint of end of treatment CR rate is 100%. At a median follow-up of 15 months, the FFS, PFS and OS are all 100%. The most common adverse events of any grade are nausea (79%), peripheral sensory neuropathy (56%), fatigue (50%), constipation (38%), alopecia (35%) and neutropenia (24%). Most toxicities were low grade, with only 15% of subjects experiencing any grade 3 toxicity, and there were no grade 4 or 5 toxicities. Specifically, 2 patients had grade 3 neutropenia, and 1 patient each had grade 3 nausea/vomiting, pneumonia and thromboembolic event. Peripheral sensory neuropathy was grade 1 in 17 patients, and grade 2 in 2 patients. There were no cases of neutropenic fever. CONCLUSIONS: BV-AD for 4-6 cycles induces high interim and end of treatment CR rates of 94% and 100%, respectively, allowing 4 total cycles of therapy in most patients. The PFS, FFS and OS are all 100% at last follow up. Toxicity appears mild and notable for a low incidence of neutropenia, alopecia, and moderate peripheral neuropathy. This promising regimen avoids bleomycin, vinblastine, radiation and primary GCSF prophylaxis with resultant low toxicity and preserved high efficacy rates in patients with early favorable and early unfavorable non-bulky limited stage classical Hodgkin lymphoma. Follow up for this trial is ongoing. Figure. Figure. Disclosures Abramson: Merck: Consultancy; Seattle Genetics: Consultancy; Karyopharm: Consultancy; Verastem: Consultancy; Amgen: Consultancy; Humanigen: Consultancy; Juno Therapeutics: Consultancy; Gilead: Consultancy; Novartis: Consultancy; Bayer: Consultancy; Celgene: Consultancy. Sokol:Mallinckrodt Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Spectrum Pharmaceuticals: Consultancy. Jacobsen:Merck: Consultancy; Seattle Genetics: Consultancy. LaCasce:Seattle Genetics: Consultancy, Honoraria; Research to Practice: Speakers Bureau; Humanigen: Consultancy, Honoraria; Bristol-Myers Squibb: Other: Data safety and monitoring board.

Relapse of malignancy and lethal graft versus host disease (GVHD) are the principal causes of failure of allogeneic hematopoietic cell transplant (HCT). Recently we have shown that at seven days after HCT an algorithm using two serum biomarkers (ST2 and REG3α) can predict severe GVHD (Hartwell et al. JCI Insight 2017). We determined whether serial testing (in the first month following HCT) of patients with low probability biomarkers would improve the predictive accuracy of the algorithm and identify patients with different risks of relapse and lethal GVHD. Patients who received an HCT at 18 centers in the Mount Sinai Acute GVHD International Consortium (MAGIC) for hematologic malignancy and who supplied three blood samples were divided into a training set and validation set with equal numbers of lethal GVHD events, which was defined as death from GVHD or infection during treatment for GVHD. Patients in the training set (n=702) underwent HCT from January 1, 2006 until June 30, 2015, whereas patients in the validation set (n=906) underwent HCT from July 1, 2015 to May 1, 2017. Serum samples were analyzed using the previously published algorithm of two biomarkers up to three times (day 7, day 14, day 28 or GVHD onset, if onset occurred within the first 28 days). The algorithm generates a predicted probability of lethal GVHD between 0 and 1 for each patient. Patients were categorized as either low probability (LP) or high probability (HP) for lethal GVHD. HP thresholds of 0.20 and 0.16 were used to classify patients with and without GVHD symptoms, respectively (once categorized as HP, patients remained in that category and were not retested). All results were similar between training and validation sets, and we present here the validation set results. Serial testing identified 28% of patients as HP with a three-fold greater cumulative incidence of lethal GVHD at one year (13% vs 4%, p Early development of GVHD (by day 28) is a risk factor for lethal GVHD. Therefore, we next plotted RFS (dashed line), relapse (solid line), and lethal GVHD (dotted line) rates in patients who developed GVHD by day 28. 25% of patients with GVHD were categorized as HP and had a cumulative incidence of lethal GVHD more than four times higher (28%) than that of relapse (6%); however the risks were reversed for the 75% of patients who were LP, where relapse (15%) occurred twice as often as lethal GVHD (7%) (Figure 3B). In patients who did not develop GVHD in the first month, this reversal of risks was even more dramatic. Approximately half (53%) of the entire validation cohort did not develop GVHD by day 28 and was LP at all three evaluations. These patients had an exceptionally low risk of lethal GVHD and thus they relapsed (25%) much more often than they died from GVHD (3%). When malignancies were classified according to risk for relapse by the disease risk index (DRI) (Figure 3C), the probability of relapse was three fold higher than lethal GVHD in malignancies with a low DRI (12%), six fold higher for intermediate DRI (20%), and eleven fold higher for high/very high DRI (33%). We conclude that a serial monitoring strategy using GVHD biomarkers for one month after HCT is able to identify two groups of patients with very different risks of lethal GVHD and relapse. For these patients, the intensity of immunosuppression after day 28 could be tailored according to the probabilities of developing lethal GVHD and relapse in the context of clinical trials. Disclosures Aziz: Doris Duke Charitable Foundation: Research Funding. Ayuk:Therakos (Mallinckrodt): Honoraria; Novartis: Honoraria; Celgene: Consultancy; Gilead: Consultancy. Chen:REGiMMUNE: Consultancy; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy. Merli:Neovii Biotech: Honoraria; AMGEN: Honoraria. Roesler:Sanofi: Other: Travel, Accommodations, Expenses; Amgen: Equity Ownership; Jazz Pharmaceuticals: Other: Travel, Accommodations, Expenses; Immunomedics: Equity Ownership; Biogen: Equity Ownership; Merck: Consultancy; Pfizer: Consultancy. Kitko:Novartis: Consultancy, Honoraria; Mallinckrodt: Honoraria, Other: Travel, Accommodations, Expenses. Qayed:Novartis: Consultancy. Wölfl:Bristol-myers Squibb: Equity Ownership; Novartis: Equity Ownership; Taheda: Equity Ownership; Juno: Equity Ownership; Neovii: Other: Travel, Accommodations, Expenses. Mielke:Celgene: Speakers Bureau; DGHO: Speakers Bureau; EHA: Speakers Bureau; Kiadis Pharma: Speakers Bureau; Miltenyi: Speakers Bureau. Wudhikarn:Takeda Oncology: Other: Travel, Accommodations, Expenses. Nakamura:Celgene: Honoraria; Molmed: Honoraria; Merck: Consultancy; Pharmacyclics: Consultancy; Atara: Consultancy; Jazz Pharmaceuticals: Consultancy. Pulsipher:CSL Behring: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; Adaptive Biotech: Consultancy, Research Funding; Amgen: Honoraria. Reshef:Pfizer: Consultancy; Atara Biotherapeutics: Consultancy; Kite Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy; Incyte: Consultancy. Levine:Therakos: Consultancy; Novartis: Consultancy; Bluebird: Consultancy; Incyte: Consultancy; Kamada: Research Funding; Viracor: Patents & Royalties. Ferrara:Incyte: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Xenikos: Consultancy, Other: Travel, Accommodations, Expenses; Kamada: Consultancy, Research Funding; Viracor: Consultancy, Patents & Royalties.

Introduction Acute graft-versus-host disease (aGVHD) is a significant cause of mortality post allogeneic stem cell transplantation (SCT). First line therapy is corticosteroid based for patients with aGVHD ≥grade (Gd) II. Steroid refractory (SR) aGVHD is associated with a dismal prognosis. Although experimental therapeutics is an unmet need, there is no recent prospective real world data to establish a benchmark for outcomes of best available therapy. We undertook a prospective observational multi-centre international clinical trial of outcomes of second line therapy of steroid refractory aGVHD. The aim was to measure recently defined endpoints including Day 28 (D28) overall response rate (ORR), and 6 month freedom from treatment failure (6mFFTF; defined as a patient (pt) being alive, without relapse of underlying disease or addition of new systemic therapy for aGVHD, prior to the development of chronic(c) GVHD. Methods Data was collected prospectively in a longitudinal observational study in patients starting second line therapy for SR aGVHD. Twelve UK and 2 US sites participated. Adult pts with Gd II-IV aGVHD refractory to corticosteroids were enrolled within 5 days of starting second line therapy. Modified Glucksberg criteria were used to grade aGVHD. Expert panel consensus recommendations (Martin et al 2009) were used for complete response (CR), very good partial response (VGPR), partial response (PR), stable disease (SD) and progressive disease (PD). Kaplan-Meier survival curves and log rank tests for comparison were done on Prism7. Results Between 2014-2018, 64pts were enrolled; 4pts were excluded due to incomplete data. Baseline characteristics of the cohort are outlined in Table 1. GVHD prophylaxis varied according to centre. Forty-seven percent had T depletion; 32% ATG and 25% Alemtuzumab. GVHD was donor lymphocyte infusion (DLI) induced in 7%. At start of second line therapy,5% had Gd I, 27% Gd II and 68% Gd III-IV aGVHD. All patients had received corticosteroids at a minimum dose of 1mg/kg. Second line therapies varied, 60% received ECP and 40% non-ECP therapy including anti-TNF-alpha antibodies (20%), mycophenolate mofetil (MMF) (8%), mesenchymal stem cells (4%) and 'other' (8%). The cumulative incidence of 6mFFTF was 32% (n=19), with 68% (n=41) failing to meet the 6mFFTF endpoint. The causes of failure were, addition of third line therapy in 40% (n=24), relapse 8%(n=5), cGVHD 7% (n=4) and death 13% (n=8). The 6m incidence of death was 45% (n=27); death due to GVHD 30%, infection 8% and relapse 7%. D28 responses were: 56% ORR (8% CR, 28% VGPR, 20% PR), 13% SD, 18% PD and 13% died before D28. Using Kaplan-Meier analysis, median OS was 7.3m with a median follow up of 1 year. The overall cumulative incidence of death was 63% (n=38); GVHD was the leading cause of death 40%, infection 8% and relapse 8%. D28 ORR was associated with a significantly improved median OS not reached versus (vs) 5.2m (p=0.03) in pts who had SD or PD at D28. In pts that achieved 6mFFTF, median survival beyond 6m was not yet reached vs median survival of 3.9m in those that did not achieve 6mFFTF (p=0.0004). The trend was for a longer median OS of 8.2m in the ECP arm vs 5.3m in non ECP (p=0.79). GVHD Gd at start of second line therapy was associated with a longer median survival, not reached in Gd II cohort vs 5.7m in Gd III-IV cohort (p=0.25). Discussion Our multi-centre prospective study illustrates 'real-life' data of clinical outcomes in pts starting second line therapy for SR aGVHD. Median survival from start of second line therapy was 7.3m with a high mortality rate of 63%. D28 ORR was 56% but only 32% met the composite 6mFFTF endpoint, although both outcomes predicted survival. The leading cause for failure of 6mFFTF was starting third line therapy which may be subject to clinician bias, however the 6m mortality was 45%, thus pts went on to die after failing for another cause. This data can be used as a contemporary data while planning studies of experimental intervention vs. best available therapy. Disclosures Radia: Mallinckrodt: Research Funding. Alfred:Mallinckrodt: Speakers Bureau. Dignan:Mallinckrodt: Research Funding, Speakers Bureau. Jagasia:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees.

Background: Myelodysplastic Syndromes (MDS) are genetically and hematologically diverse stem cell malignancies pathogenetically linked to constitutive innate immune activation. Other than rare germline mutations and age, the only known predispositions to adult MDS include prior cytotoxic therapy, clonal hematopoiesis, and autoimmune or chronic inflammatory disorders. Few studies investigating the genetic susceptibility to MDS have been performed owing to the limitations of SNP-array sample size. Here, we report the results from the first unbiased genome wide analysis of germline polymorphisms associated with non-del(5q) MDS using a multinational curated data set. Methods: Association analyses were performed on 2 sample sets (set 1: 555 cases, 2,964 controls; set 2: 352 cases, 2,640 controls) and combined by meta-analysis. Standard SNP- and sample-level QC was applied. Haplotype reference consortium (HRC) imputation was done by the Michigan imputation server (Rsq>0.4) providing 23,278,269 markers for analysis. Gene expression sequencing was performed on an independent sample set from the National Taiwan University Hospital (213 MDS cases, 20 healthy donors; HumanHT-12 v4 Expression BeadChip; Chuang et al. Leukemia 2015). Functional analyses were performed as described. Results: Eight MDS associated loci were identified with lead variants, rs6683416, rs34539210, rs341274, rs1634783, rs7099032, rs2947170, rs4404050, and rs1206818, at 1q31.1 (PLA2G4A), 3p14.1 (FAM19A4), 5q21.3 (EFNA5), 6p21.33, 10q23.1 (GRID1), 12q24.32, 15q26.1, and 20q13.12 (EYA2), respctively. Odds ratio (OR) and p-values of each are listed in Table 1. Using gene expression profiling in an independent MDS sample set, we found expression of these five candidate genes was significantly increased in MDS vs controls (p Conclusion: We describe here the first MDS susceptibility loci ever identified the majority of which have a direct relationship to innate immune activation, a driver of MDS pathogenesis. Expression of genes housing these loci is increased in MDS with demonstrable prognostic and biological relevance. Further, functional studies implicate EYA2 as a novel, biologically rational target for MDS treatment. The direct functions of each polymorphism as well as the potential relationship between these predisposition loci to age-related clonal hematopoiesis merits further investigation. Disclosures Cluzeau: Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Menarini: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Speakers Bureau. Sallman:Celgene: Research Funding, Speakers Bureau. Sokol:Spectrum Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Mallinckrodt Pharmaceuticals: Consultancy. Maciejewski:Ra Pharmaceuticals, Inc: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Apellis Pharmaceuticals: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. List:Celgene: Research Funding.

Background: Allo HCT candidates undergo comprehensive evaluations including psychosocial assessment, although there are no validated tools to objectively assess psychosocial status prior to transplant. PACT, originally developed to address psychosocial risks in solid organ transplant recipients, has been evaluated by our group in allo HCT patients (Foster et al, BMT, 2009). It consists of 8 subscales which are scored from 1 to 5 (support stability, support availability, psychopathology, risk for psychopathology, health lifestyle, drug and alcohol use, compliance, and relevant knowledge). A final PACT score (range 0-4) provides an overall impression of a patient's suitability for transplantation. Patients and Methods: This retrospective cohort study reviewed 404 adult allo HCT cases between 2003 and 2014 at Cleveland Clinic to identify predictors of adverse psychosocial status prior to allo HCT as determined by PACT. We then studied the association of PACT scores with allo HCT outcomes. Social workers generated a PACT score based on a comprehensive assessment of the patient. Median age of the study population was 50 (range 18-73) years, patients were 46% female, 11% non-White, 20% rural residents, and had mainly AML (41%) or MDS (18%). Majority of patients received HLA matched (84%) unrelated donor (55%) bone marrow grafts (55%) using myeloablative conditioning (78%). Results: Final PACT rating was poor/borderline (score 0/1) in 5% (n= 21), acceptable (score 2) in 22% (87), good (score 3) in 44% (177), and excellent (score 4) in 29% (119) of recipients. In multivariable ordinal logistic regression, higher PACT score at pre-HCT assessment was associated with White race (OR 2.95, [95% CI 1.56-5.58], p Conclusion: Non-White race, lack of a related donor, and lower QOL are associated with adverse psychosocial risk as measured by PACT prior to allo HCT. Low "relevant knowledge" and "final PACT" ratings were associated with NRM and suggest vulnerable populations. PACT can be effectively used as part of a comprehensive psychosocial assessment for identifying patients who may require additional psychological and social resources to help them navigate the transplant process. Disclosures Lee: Kadmon: Research Funding; Onyx: Research Funding; Amgen: Consultancy, Research Funding; Mallinckrodt: Honoraria; Pfizer: Consultancy; Takeda: Research Funding; Incyte: Consultancy. Majhail:Atara: Honoraria; Anthem, Inc.: Consultancy; Incyte: Honoraria.

Introduction: cGVHD remains a leading cause of post-transplant morbidity / mortality, exhibiting features of both autoimmune and fibrotic diseases across multiple organ systems. cGVHD is characterized by an imbalance between effector and regulatory arms of the immune system that results in over production of inflammatory cytokines including IL-17 and IL-21. Moreover, a persistent reduction in the number of regulatory T (Treg) cells limits the ability of the immune system to re-calibrate this pro-inflammatory environment. KD025 is an orally available Rho-associated coiled-coil kinase 2 (ROCK2) selective inhibitor. In vitro data have demonstrated that KD025 (1) attenuates IL-21 and IL-17 secretion in human CD4+ T cells via STAT3, IRF4 and RORγt regulation, and (2) leads to increased percentages of Foxp3+ CD4+ T cells via a STAT5-dependent mechanism and upregulates the suppressive function of human Tregs. These MOA suggest that KD025 modulates immune homeostasis by shifting the Th17/Treg balance towards a Treg phenotype. No studies have examined KD025 effects in patients with dysregulation associated with high Th17 and low Tregs. Methods: KD025-208 enrolled 3 cohorts (C1: 200 mg QD, C2: 200 mg BID, and C3: 400 mg QD) of patients (pts) with cGVHD after 1-3 prior lines of systemic therapy. Treatment is in 28-Day cycles until disease progression or unacceptable toxicity. The primary endpoint is the overall response rate (ORR) (% pts achieving partial response (PR) or complete response (CR)) as per 2014 NIH response criteria. Secondary endpoints include duration of response (DOR) and corticosteroid (CS) dose reductions. Exploratory endpoints include Lee Symptom Scale (LSS) score and pharmacodynamics (PD). Peripheral blood samples were collected from all pts at Cycle 1 Day 1 (C1D1), C2D1, C4D1 and C6D25, and shipped at ambient temperature. PBMC were isolated and kept frozen until analysis. The intracellular expression of IL-17A and FOXP3 on viable CD3+ CD4+ cells was determined by using multicolor flow cytometry. Results: Data as of 6-June-2018 for C1 and C2 are included; C3 data will be available 4Q18. 17 and 16 pts were enrolled in C1 and C2 with median age 52 years, median time from cGVHD diagnosis to KD025 treatment of 19 months, and a median of 3 prior treatment regimens. Median duration of treatment was 37 (C1) and 33 (C2) weeks (wks). KD025 demonstrated an ORR of 65% in C1 and 63% in C2. ORR in key subgroups is shown below. Responses were rapid (76% achieved at first assessment at 8 wks) and durable with 82% (C1) and 50% (C2) of responders sustaining response for ≥20 wks. Responses including CRs were observed across all affected organ systems except lung (mouth, eyes, joints/ fascia, skin, upper GI, lower GI, esophagus, liver). A previously reported lung PR was deemed on review to be IPF with no cGVHD involvement. During treatment with KD025, median CS dose was reduced by 44% (C1) and 26% (C2). 76% and 56% of pts achieved CS dose reductions. 5/33 (15%) pts discontinued CS. 65% (C1) and 50% (C2) achieved a meaningful improvement (≥7 point reduction) in the LSS score, including both responders (67%) and non-responders (42%). KD025 has been well tolerated. AEs reported were generally consistent with those expected in pts with advanced cGVHD treated with CS. Common AEs were increased LFTs (42%), URI (33%), anemia (27%), nausea (24%), diarrhea (24%) and fatigue (21%). Increased LFTs did not lead to treatment discontinuation, commonly occurred prior to KD025 dosing and were often considered attributable to cGVHD. Grade 3+ LFT increases were reported for 6 (18%) pts. 2 pts discontinued treatment due to AEs possibly related to KD025 (headache, diarrhea). SAEs were reported for 11/33 (33%) pts, none considered related to KD025 treatment. There was no apparent increased risk of infection. Exploratory PD analyses of PBMCs across C1 and C2 revealed an early increase in the percentage of CD4+ Treg cells by C2D1 of KD025 treatment with a simultaneous decrease in Th17 cells. The percentage of CD4+ Tregs continued to increase, and the Th17 cells continued to decrease through C4D1 and C6D25. Conclusion: Treatment with KD025 has demonstrated encouraging clinical responses in cGVHD pts with little toxicity. Responses have been clinically meaningful as evidenced by durability, reductions in CS doses and improvement in LSS score. Exploratory PD data indicate treatment with KD025 may modulate immune homeostasis by restoring the Th17/Treg balance. Figure. Figure. Disclosures Jagasia: Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Salhotra:Kadmon Corporation, LLC: Consultancy. Bachier:Sanofi: Speakers Bureau; Seattle Genetics: Speakers Bureau. Weisdorf:Seattle Genetics: Consultancy; Pharmacyclics: Consultancy; Equillium: Consultancy; SL Behring: Consultancy; FATE: Consultancy. Green:Kadmon Corporation, LLC: Employment. Schueller:Kadmon Corporation, LLC: Employment. Zanin-Zhorov:Kadmon Corporation, LLC: Employment. Weiss:Kadmon Corporation, LLC: Employment. Eiznhamer:Kadmon Corporation, LLC: Employment. Aggarwal:Kadmon Corporation, LLC: Employment. Blazar:Kadmon Corporation, LLC: Consultancy, Research Funding. Lee:Takeda: Research Funding; Kadmon: Research Funding; Amgen: Consultancy, Research Funding; Mallinckrodt: Honoraria; Incyte: Consultancy; Pfizer: Consultancy; Onyx: Research Funding.

In patients with acute leukemia, relapse remains one of the most frequent causes of treatment failure after allogeneic transplantation (allo-HCT). Early after transplant, natural killer (NK) cells predominate and thus, they have been implicated in graft vs. leukemia (GVL) reactions after allo-HCT. Killer Ig Receptors (KIR) are a family of 15 distinct genes that both positively and negatively regulate NK cell function. Individuals vary in the number of genes that they possess within their genome and thus, may vary in their GVL capacity. Accordingly, numerous studies have investigated the association of donor KIR gene content (B/x vs. A/A), KIR B gene score (neutral, better, best), KIR composite score (taking into account CenB/x and TelA/A gene status) and KIR ligand mismatching in the setting of allo-HCT. These studies have largely focused on adult transplant recipients, yielding variable outcomes. However, pediatric patients may differ from adult transplant recipients in a variety of ways including differential sensitivity of leukemic blasts to NK cytotoxicity, distinct cytogenetic changes, the higher propensity to receive myeloablative conditioning and an earlier adoption of minimal residual disease-driven timing of transplantation. The purpose of this analysis was to investigate the impact of KIR gene content and KIR ligand mismatching on outcomes of children transplanted with acute lymphoblastic and acute myeloid leukemia (ALL and AML, respectively), reported to CIBMTR. The study cohort included pediatric patients (0- Disclosures Fleischhauer: GENDX: Research Funding. Fleischhauer:GENDX: Research Funding. Lee:Merck, Sharp, and Dohme: Consultancy; Courier Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; CytoSen Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Paczesny:Viracor IBT Laboratories: Patents & Royalties. Lee:Kadmon: Research Funding; Amgen: Consultancy, Research Funding; Incyte: Consultancy; Mallinckrodt: Honoraria; Pfizer: Consultancy; Takeda: Research Funding; Onyx: Research Funding.

Background: Peripheral T-cell lymphomas (PTCL) are a rare and heterogeneous group of NHL with poor prognosis. Frontline therapy yields a 50-70% overall response rate, but the majority of pts will relapse, which translates to poor overall survival. ALRN-6924, the first-in-class clinical stage stapled peptide, has been structurally stabilized ("stapled") in an α-helical configuration, to mimic the inhibitor-binding region of the tumor suppressor protein, p53. By mimicking this region, ALRN-6924 binds the two most important endogenous inhibitors of p53, murine double minute-X (MDMX) and -2 (MDM2), thereby restoring p53's ability to induce cell cycle arrest and apoptosis in TP53 wild-type (WT) cancer cells. ALRN-6924 is the first known synthetic agent to simultaneously target both of these important p53 inhibitors. A durable CR has been reported in a pt with an angioimmunoblastic subtype of PTCL who is part of the first-in-human study of ALRN-6924 (Meric-Bernstam et al., 2017), providing the rationale for two PTCL expansion cohorts. The PTCL QW cohort is receiving treatment at the recommended Phase 2 dose (QWx3 every 28 days). Preclinical data suggest that more frequent dosing may enhance efficacy (Carvajal et al., 2018; Ng et al., 2018) and this hypothesis is being evaluated in a second PTCL cohort, treated TIWx1 every 21 days. Methods: Pts with relapsed or refractory PTCL are receiving treatment with 3.1 mg/kg of ALRN-6924 IV over 1 hour, on Days 1, 8, and 15 of a 28-day cycle (QW) or Days 1, 3, and 5 of a 21-day cycle (TIW). Treatment continues until symptomatic progressive disease (PD), unacceptable toxicity, or other indication for treatment withdrawal. Due to documented cases of pseudoprogression, continuation beyond radiographic PD is permitted at the investigator's discretion. Response is evaluated by investigators according to IWG 2014. Additionally, an independent radiologist reviews response using IWG 2014 and modified Cheson 2007. Adverse events (AEs) are assessed per CTCAE V4.03. Results: As of 13 July 2018, 26 PTCL pts have been treated (16 QW, including one from Phase 1, 10 TIW) with a median age of 63 years (31-82). Here, we report safety from the QW and TIW cohorts as well as efficacy from the QW cohort. Accrual to TIW continues; its efficacy data as well as updated safety data will be presented at the meeting. Median number of prior systemic therapies is 3 (1-10). Pts have received 1-34 cycles. Of the 16 QW-pts and 10 TIW-pts, 2 and 6 pts remain on therapy, respectively. Treatment-related AEs have been reported in 76.9% of 26 PTCL pts dosed QW or TIW. Fatigue (50.0%), nausea (42.3%), anemia (19.2%), diarrhea (15.4%), headache (15.4%), vomiting (15.4%), and hyperbilirubinemia (11.5%) are most frequent. 46.2% have experienced grade 3 AEs, most commonly fatigue (7.7%), anemia (7.7%), and hyperbilirubinemia (7.7%). No related grade 4 or 5 AEs have been reported. SAEs have been reported in 10 pts, including 3 treatment-related SAEs: a grade 3 lung infection, a grade 3 nausea/vomiting, and a grade 3 hyperbilirubinemia, which is a known transient effect of ALRN-6924 and has not been associated with liver injury. Treatment has been discontinued due to related AEs in 2 pts, for a grade 1 infusion-related reaction and a grade 3 lung infection (pneumonia). Main reasons for treatment discontinuation include disease progression (46.1%; objective PD 19.2%, clinical PD 26.9%) and AE (7.7%). Pts receiving QW treatment who received at least one dose of ALRN-6924, had TP53 WT, and a post-baseline assessment or evidence of clinical disease progression were evaluated for efficacy. Table 1 shows responses determined by IWG 2014 (investigator-reported) and modified-Cheson 2007 (independent radiologist-determined) for the evaluable QW patients. One pt was not evaluable per IWG 2014. Cases of pseudoprogression during treatment of PTCL pts with ALRN-6924 have been documented. Several pts with new FDG-avid lesions and/or transient lymph node enlargement on CT have benefitted from treatment continuation, including pts who went on to achieve a subsequent response. Conclusion: ALRN-6924 has shown activity against PTCL and has an acceptable safety profile across QW and TIW dosing. The potential for pseudoprogression was not initially recognized, hence raising the possibility that the true response rate for QW may be higher. These early data support continued development of ALRN-6924 for the treatment of PTCL. Disclosures Shustov: Seattle Genetics: Research Funding. Horwitz:Celgene: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Mundipharma: Consultancy; Kyowa-Hakka-Kirin: Consultancy, Research Funding; Spectrum: Research Funding; Millennium/Takeda: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Portola: Consultancy; Aileron Therapeutics: Consultancy, Research Funding; Innate Pharma: Consultancy; Trillium: Consultancy; Corvus: Consultancy. Sokol:Seattle Genetics: Consultancy; Mallinckrodt Pharmaceuticals: Consultancy; Spectrum Pharmaceuticals: Consultancy. Meric-Bernstam:Genentech: Consultancy; Inflection Biosciences: Consultancy; Pieris Pharmaceuticals: Consultancy; Clearlight Diagnostics: Consultancy; Darwin Health: Consultancy; Bioepis: Consultancy; Novartis: Research Funding; AstraZeneca: Research Funding; Taiho Pharmaceuticals: Research Funding; Genentech: Research Funding; Calithera Biosciences: Research Funding; Debiopharm: Research Funding; Bayer: Research Funding; Aileron Therapeutics: Research Funding; PUMA Biotechnology: Research Funding; CytomX Therapeutics: Research Funding; Zymeworks: Research Funding; Curis: Research Funding; Pfizer: Research Funding; eFFECTOR Therapeutics: Research Funding; Abbvie: Research Funding; Sumitomo Group: Honoraria; Dialecta: Honoraria. Shapiro:Roche: Membership on an entity's Board of Directors or advisory committees; Merck/EMD Serono: Research Funding; G1 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Merck/EMD Serono: Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Lilly: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Research Funding; Lilly: Research Funding. Dwivedy Nasta:Roche: Research Funding; Takeda/Millenium: Research Funding; Aileron: Research Funding; Rafael/WF: Research Funding; Merck: Other: DSMC; Debiopharm: Research Funding; Pharmacyclics: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding. Janakiram:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Weinstock:Novartis, Astra Zeneca, Abbvie, Aileron, Surface Oncology, Daiichi Sankyo: Research Funding; Novartis: Consultancy, Research Funding; Genentech/Roche, Monsanto: Consultancy; Novartis, Dragonfly, Travera, DxTerity, Travera: Consultancy; Travera: Equity Ownership; Astra Zeneca, JAX, Samumed, Regeneron, Sun Pharma, Prescient: Patents & Royalties. Korn:Imaging Endpoints: Employment, Equity Ownership; Aileron Therapeutics Inc.: Other: Client. Payton:Aileron Therapeutics: Employment, Equity Ownership. Annis:Aileron Therapeutics Inc.: Employment, Equity Ownership, Patents & Royalties. Pinchasik:Aileron Therapeutics Inc.: Employment, Equity Ownership. Aivado:Aileron Therapeutics Inc.: Employment, Equity Ownership, Patents & Royalties. Mehta:Kite: Consultancy, Speakers Bureau; Celgene: Consultancy; Spectrum: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Incyte: Research Funding; Merck: Research Funding; Gilead: Consultancy, Speakers Bureau; Epizyme: Research Funding; Seattle Genetics: Research Funding; AstraZeneca: Consultancy, Speakers Bureau; Carevive: Other: Patient engagement; Medpage: Other: Medical website.

Introduction Mesenchymal stem cells (MSCs) isolated from donated tissue have been widely investigated as a treatment for acute graft versus host disease (GvHD), but with mixed results. Factors including MSC donor variability and the effects of prolonged MSC culture expansion may have contributed to inadequate outcomes. Induced pluripotent stem cells (iPSCs) can proliferate indefinitely without loss of pluripotency. The novel Cymerus™ manufacturing process facilitates a virtually limitless supply of well-defined and consistent MSCs from a single donation. Production is achieved by differentiating iPSCs into MSCs using proprietary clonogenic progenitor-based technology. This avoids both donor to donor variability and the need for excessive culture expansion once MSCs are formed. We are undertaking a Phase I clinical trial of Cymerus iPSC-derived MSCs (CYP-001) in steroid-resistant acute GvHD (NCT02923375). We believe this will be the first completed clinical trial involving iPSC-derived cells. Methods This is a multi-center, open label, dose escalation study to assess the safety, tolerability and efficacy of CYP-001 in adults with grade II-IV steroid-resistant acute GvHD, following allogeneic hematopoietic stem cell transplantation. All subjects had failed to respond to at least three days of steroid treatment (≥1 mg/kg/day), administered in accordance with standard management at each center. The first eight subjects enrolled in Cohort A received two intravenous (IV) infusions of CYP-001 one week apart, at a dose of 1 x 106 cells/kg, in addition to standard of care medications. After an independent data and safety monitoring board review, the next eight subjects entered Cohort B, in which the MSC cell dose was doubled. Primary evaluation was performed over eight study visits to day 100. Subjects then entered a follow-up phase of up to two years. Data for subjects in Cohort A with a minimum of six months follow-up are presented here. GvHD was staged and graded according to the 1994 Consensus Conference on Acute GvHD Grading. A Partial Response (PR) was defined as improvement in the severity of GvHD by at least one grade compared to baseline, while a Complete Response (CR) was defined as the absence of any GvHD signs or symptoms. The Overall Response (OR) rate was defined as the proportion of subjects showing either a PR or CR. The primary objective was assessment of the safety and tolerability of two infusions of CYP-001. The secondary objective was efficacy, assessed by best response to treatment, by Day 28 and Day 100 and overall survival at Day 28 and Day 100. Results Four males and four females, with an average age of 57 years (range: 45-66) were enrolled in Cohort A during 2017. At baseline, subjects had Grade II (n=3) or Grade III (n=5) steroid-resistant acute GvHD. One subject had skin, gastrointestinal (GI) and liver involvement; four subjects had skin and GI involvement; two subjects had GI involvement only; and one subject had skin involvement only. The treatment was well tolerated in all cases, and there were no treatment-related Serious Adverse Events (SAEs) reported. Three subjects experienced SAEs that were not considered to be study drug related: (i) febrile neutropenia, hypokalemia and parainfluenza, each of which resolved; (ii) a lower respiratory tract infection, which resolved; (iii) pneumonia, which was fatal. All eight subjects showed at least a PR. Four subjects achieved a CR by Day 100. In all four cases where a CR was achieved, it was then sustained until Day 100. The median GvHD grade at Day 100 was 0 (range: 0-II), compared to a median grade of III (range: II-III) at baseline. Disease progression (an increase in the severity of GvHD by at least one grade compared to baseline) was not observed in any subject at any study visit. Overall survival was 7/8 (87.5%) six months after the first infusion of CYP-001. The best response rates by Day 28 and Day 100 are summarized in Table 1, while the maximal response by individual subject is illustrated in Figure 1. Conclusion Infusion of CYP-001 at 1 x 106 iPSC-derived MSCs/kg was safe and well tolerated in this patient cohort. Treatment response and overall survival rates are encouraging compared to previously published outcomes. The Cohort B primary evaluation period is expected to be completed by September 2018, and progression to a Phase II trial in this clinically challenging disease will then be considered. Disclosures Bloor: AbbVie: Research Funding; Janssen: Research Funding. Radia:Mallinckrodt: Research Funding. Yeung:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria; Amgen: Honoraria; Specialised Therapeutics Australia: Honoraria. Slukvin:Cynata Therapeutics Limited: Consultancy, Equity Ownership. Kelly:Cynata Therapeutics Limited: Employment, Equity Ownership. Rasko:Gilead: Honoraria; Abbvie: Speakers Bureau; Takeda: Speakers Bureau; International Society for Cellular Therapy: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Speakers Bureau; Cynata: Consultancy, Honoraria; bluebird bio: Honoraria, Other: Clinical trials ; Spark: Consultancy; FSHD Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Current Cure The Future Foundation: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Pfizer: Honoraria; GSK: Honoraria; Genea: Equity Ownership; IMAGO Biosciences: Consultancy; Rarecyte: Consultancy, Equity Ownership; Gene Technology Technical Advisory, OGTR, Australian Government: Other: Chair; Advisory Committee on Biologics, Therapeutics Goods Administration, Australian Government: Other: Past Chair.

Introduction: Thrombotic microangiopathy (TMA) is a known complication of allogeneic hematopoietic cell transplantation (HCT). An ongoing debate is whether TMA is caused by acute graft-versus-host disease (GVHD) or calcineurin inhibitor (CNI)/sirolimus. Previous studies have not examined the impact of CNI/sirolimus average trough levels while accounting for the confounding effect of GVHD. In the current study, we examined the association between time-varying levels of CNI/sirolimus and the onset of TMA among 2105 adult allogeneic HCT recipients. Methods: We performed a retrospective cohort analysis of allogeneic HCT recipients during 2006-2015 at Fred Hutchinson Cancer Research Center who received CNI/sirolimus for GVHD prophylaxis. TMA (outcome) was ascertained and validated as previously described (Blood 130;Suppl:666). Acute GVHD (confounder) was defined and graded according to established criteria. Consecutive CNI/sirolimus trough levels (exposure) were obtained and interval values between checks were imputed via linear interpolation. We followed patients from the time of hematopoietic cell infusion until the onset of TMA and censored patients at day 100 or >1 week of missing drug levels. To examine the association between the "type" of immunosuppressant and TMA, CNI/sirolimus exposure over time was characterized as a discrete categorical variable (tacrolimus alone, cyclosporine alone, or sirolimus + CNI). To examine the impact of the "level" of immunosuppressant on TMA, CNI/sirolimus exposure was both defined as an average of the previous 7-day trough levels (continuous variable) as well as a discrete time-above-peak variable (binary variable for tacrolimus >15 ng/mL, cyclosporine >450 ng/mL, or sirolimus >10 ng/mL). Extended Cox regression models were built to examine the time-varying association between CNI/sirolimus exposures and TMA after adjusting for GVHD. Results: In the current study, 2105 adult allogeneic HCT recipients contributed 173,171 person-days and 150 cases of TMA. The median follow-up time was 94 days and trough blood levels were checked on average 3x per week. Initial GVHD prophylaxis regimen for patients included 54% on tacrolimus (n=1135), 40% on cyclosporine (n=837), and 6% on a combination of sirolimus + CNI (n=133). Nearly no one received sirolimus alone without CNI. Eight percent of patients (n=162) had at least one switch in the immunosuppression regimen within 100 days. The median (IQR) trough levels for tacrolimus, cyclosporine, and sirolimus were 9 ng/mL (7-12), 283 ng/mL (206-372), and 5 ng/mL (4-7), respectively. Acute GVHD developed in 64% of patients including 53% grade 2 (n=1115), 9% grade 3 (n=185), 2% grade 4 (n=52). In the analysis adjusted for both discrete time-varying CNI/sirolimus exposure and GVHD, higher grades of GVHD had strong associations with TMA (Table 1: grade 2 HR 2.24, P=0.001; grade 3 HR 12.38, P In the analyses of individual drug levels adjusted by GVHD, higher trough levels of tacrolimus and cyclosporine (either as a linear average level or binary time-above-peak) were not associated with an increased risk of TMA (Table 2). However, higher sirolimus trough levels were associated with an appreciable risk of TMA (HR 1.44, P=0.001 for every 1 ng/mL increase in sirolimus average trough level; HR 3.23, P=0.164 for time above 10 ng/mL). Conclusion: In allogeneic HCT patients, acute GVHD was strongly associated with the onset of TMA independent of ongoing exposures of CNI/sirolimus. We did not find an association between CNI recipients (tacrolimus versus cyclosporine) or CNI levels and the risk of TMA. However, when combined with CNI, higher sirolimus trough levels were linearly associated with a higher risk for TMA. Limitations in this observational study include the inability to adjust for concomitant medications and conditions that might have altered drug levels and inability to adjust for target drug levels since recognized risk factors might have led clinicians to target higher drug levels due to higher risks of GVHD. These findings suggest that prevention and treatment of GVHD and avoidance of high sirolimus levels will decrease the risk of TMA. Disclosures Lee: Amgen: Consultancy, Research Funding; Mallinckrodt: Honoraria; Incyte: Consultancy; Pfizer: Consultancy; Onyx: Research Funding; Kadmon: Research Funding; Takeda: Research Funding. Garcia:Pfizer: Consultancy; Portola: Research Funding; Shingoi: Consultancy; Retham Technologies LLC: Consultancy; Janssen: Consultancy, Research Funding; Bristol Meyers Squibb: Consultancy; Daiichi Sankyo: Research Funding; Incyte: Research Funding; Boehringer Ingelheim: Consultancy.

The last two authors contributed equally Elevated soluble Stimulation-2 (sST2), the decoy IL-33 receptor, in plasma/serum post-HSCT is a biomarker for death due to GvHD. ST2 is the product of IL1RL1 (2q12.1) and this ~.5Mb region contains >300 single nucleotide polymorphisms (SNPs) significantly associated (P We measured plasma/serum sST2 levels in pre-HCT samples in a subset of AML and MDS patients (n=759) and their donors (n=757) from DISCOVeRY-BMT, a GWAS of >3,000 recipient-unrelated donor pairs reported to the CIBMTR between 2000-2011. After quality control (info>.8, MAF>.005), 3613 SNPs in the IL1RL1 region were tested for association with sST2 levels; 1541 donor SNPs associated with sST2 levels (P AIC multivariable models for GvHD-death included AML diagnosis, recipient obesity (>30 mg/kg2), peripheral blood cell source, donor age, rs1558645 (Pmeta=.001), and rs2310241(Pmeta=.0003), for which the risk alleles at each SNP increased risk of GvHD death ~1.5 fold. The model for infection-death included advanced disease at HCT, recipient/donor CMV status, peripheral blood cell source, rs13019803 (Pmeta=1.1 x 10-6), rs13015714 (Pmeta=5 x 10-4) and rs4851601 (Pmeta=2 x 10-6), with risk alleles at each SNP increasing risk of infection-death ~2-fold. To capture the total contribution of these donor variants to each outcome we created multi-allele models for GvHD-death (0-4 alleles) and infection-death (0-6 alleles).The multi-allele GvHD models showed a 1.5 fold increased risk of GvHD-death with each additional allele (Pmeta=3.4 x 10-6 ) (Figure 2). Individuals whose donors are homozygous for both risk alleles at each SNP have a ~3 fold, and ~2 fold higher risk of dying of GvHD versus those with zero, and 1-2 risk allele(s), respectively. The multi-allele infection models (0-6 alleles) show a ~2 fold increased risk of infection-death (Pmeta= 1.22 x 10-10) with each risk allele (Figure 2). sST2 is one of the most reproducible GvHD biomarkers to date. As hypothesized, specific alleles correlated with high sST2 levels in donors and with GvHD-death. Our novel finding is that some ST2 alleles associated with low sST2 levels correlated with infection-death. These results are not without precedent, for example the low-sST2 associated allele in rs13019803 (T) associates with higher mortality in the CHARGE consortium. The risk allele in rs13015714 (T) is significantly associated with lower IL1RL1 and IL18R1 (P= 5 x 10-10) gene expression in lung tissue, indicating biochemical functions for these SNPs. Importantly the non-risk allele in all 5 variants are common (>20%) across races and ethnicities, which means there is an opportunity to select donors without combinations of these variants and perhaps without the requirement of measuring the protein level pre-transplant. Disclosures McCarthy: Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Lee:Kadmon: Research Funding; Amgen: Consultancy, Research Funding; Mallinckrodt: Honoraria; Incyte: Consultancy; Pfizer: Consultancy; Onyx: Research Funding; Takeda: Research Funding. Paczesny:Viracor IBT Laboratories: Patents & Royalties.

Background: ALRN-6924, an α-helical stapled p53 peptide, is the first-in-class and only dual inhibitor of MDMX and MDM2 currently in clinical trials for both, solid and hematologic malignancies. In tumors with wild-type (WT) TP53, ALRN-6924 can induce p53-dependent cell cycle arrest and apoptosis and separately can invoke p53-mediated immunomodulatory effects, including but not limited to lymphocyte chemotaxis and diminution of PD-L1 expression on tumor cells. This report begins to describe the biologic underpinnings of PsP in selected PTCL patients (pts) treated with ALRN-6924. Despite imaging-based progressive disease (PD), careful monitoring for clinical benefit in light of conflicting imaging (PsP) results led to the decision to treat beyond radiologic progression and the observation of subsequent, delayed radiologic responses. Methods: Pts with relapsed or refractory PTCL received either 3.1 mg/kg ALRN-6924 on days 1, 8, and 15 of a 28-day cycle (QW) or Days 1, 3, and 5 of a 21-day cycle (TIW). Responses were assessed locally using IWG 2014 criteria as well as through independent radiology assessment. Treatment continued until symptomatic PD, unacceptable toxicity, or other indication for withdrawal. Continuation beyond radiologic PD was permitted for perceived clinical benefit. RNA-based immune profiles from pre- and post-treatment tumor biopsies from pts who were treated with ALRN-6924 were evaluated by gene expression panels. Clinical findings were correlated with CT26 and MC38 murine syngeneic tumor models, where immune cell infiltration after ALRN-6924 dosing was measured by flow cytometry. Results: PsP was observed in 3 PTCL pts who eventually achieved a PR. A pattern of transient tumor flare and new lesion formation was noted in one pt (pt 13-196) while the other 2 PsP pts (pt 3-159 and 11-155) had atypical PsP patterns, including tumor shrinkage by CT, but transient new and/or increased 18Fluorodeoxyglucose (FDG)-PET uptake. In one pt, there was rapid clinical improvement of malignant hypercalcemia and B symptoms despite formal IWG 2014 progression after 2 cycles of ALRN-6924 QW treatment plus an additional transient episode of PsP due to new FDG-avid lesions at cycle 8. Another pt had a similar PsP pattern with decrease in lesion size on CT but increased FDG-avidity of target lesions following 2, 4, and 6 cycles of QW-therapy with ALRN-6924, with new FDG-avid lesions that appeared, and then resolved in different anatomical locations at each imaging assessment. Local pathology reported findings consistent with PTCL upon post-baseline biopsy of one of these lesions. Pre- and post-baseline biopsies were analyzed for differences in RNA-expression of immune-related genes, and showed changes consistent with p53-mediated immunomodulatory effects. Despite formal progression due to transient PET-avid lesions, both pts remained on therapy, subsequently achieving a confirmed PR. A pt treated with TIW ALRN-6924 (pt 13-196) exhibited worsening abdominal pain by Day 5 of ALRN-6924, with CT scans on days 6, 11, and 22 showing transient enlargement and increased number of nodes, splenomegaly, and ascites, consistent with progression. The pt continued therapy with resolution of clinical symptoms, and an efficacy assessment after 3 cycles showed dramatic reduction in lesion sizes and FDG-avidity, assessed as a PR (unconfirmed). Preclinically, in mice treated with ALRN-6924, a significant increase in tumor-infiltrating CD8+ T cells and M1-polarized macrophages was found in murine TRP53-WT CT26 tumors as well as in TRP53-mutant MC38 tumors. Conclusion: Treatment of PTCL with ALRN-6924 can be associated with PsP. Pts have benefitted from treatment beyond radiologic progression, with new FDG-avid lesions resolving over time. Murine tumor models plus changes in immune-related gene expression in pre- and post-baseline tumor samples from pts suggest that p53-mediated immune-activation may account for these findings. Transient tumor flare observed in pts, was consistent with increased immune cell infiltration that was detected after p53-activation in the tumor microenvironment of TRP53-mutant syngeneic models. ALRN-6924 is a promising anticancer agent that warrants further investigation and consideration should be given to possible pseudoprogression prior to discontinuing pts from treatment with ALRN-6924. Disclosures Shustov: Seattle Genetics: Research Funding. Mehta:Spectrum: Consultancy; Gilead: Consultancy, Speakers Bureau; Incyte: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Kite: Consultancy, Speakers Bureau; Celgene: Consultancy; F. Hoffmann-La Roche Ltd: Research Funding; Merck: Research Funding; Epizyme: Research Funding; Seattle Genetics: Research Funding; AstraZeneca: Consultancy, Speakers Bureau; Carevive: Other: Patient engagement; Medpage: Other: Medical website. Sokol:Mallinckrodt Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Spectrum Pharmaceuticals: Consultancy. Carvajal:Aileron Therapeutics Inc.: Employment, Equity Ownership. Guerlavais:Aileron Therapeutics Inc.: Employment, Equity Ownership, Patents & Royalties. Samant:Aileron Therapeutics Inc.: Employment, Equity Ownership, Patents & Royalties. Narasimhan:Aileron Therapeutics Inc.: Employment, Equity Ownership. Sutton:Aileron Therapeutics Inc.: Consultancy. Annis:Aileron Therapeutics Inc.: Employment, Equity Ownership, Patents & Royalties. Pinchasik:Aileron Therapeutics Inc.: Employment, Equity Ownership. Aivado:Aileron Therapeutics Inc.: Employment, Equity Ownership, Patents & Royalties. Korn:Aileron Therapeutics Inc.: Other: Client; Imaging Endpoints: Employment, Equity Ownership.

BACKGROUND: While there is increasing interest in measuring quality of life (QOL) in patients with acute myeloid leukemia (AML), few published studies have done so. Among those that have, there is considerable heterogeneity in instrument used, and interpretability is often limited by low survey compliance. Furthermore, our group has recently highlighted important limitations of non-disease-specific instruments in this population: (a) patients who face temporary logistical restrictions that have low impact on QOL cannot be easily distinguished from those who face more long-term functional restrictions that result in larger QOL impact, and (b) questionnaires may fail to ask about important concepts and (c) may instead ask about concepts that are less impactful. We therefore developed a new disease-specific quality of life instrument (the AML-QOL) based on cognitive interviews with 82 patients with AML and other aggressive myeloid neoplasms (Buckley SA et al. Cancer 2018). Here, we describe further development and validation of the AML-QOL. METHODS: This study consists of three phases. In the first phase, iterative revisions of the AML-QOL were performed based on feedback from 16 patients, 8 medical providers, and 2 psychometricians. In the second phase, factor analysis and convergent / divergent validity testing was performed based on responses from 202 patients who completed the AML-QOL along with the PROMIS Global 10. The third phase, a prospective validation study to assess sensitivity to change and test-retest reliability, is currently underway. RESULTS: The AML-QOL prototype underwent 4 iterative revisions followed by factor analysis, resulting in a final version containing 27 items categorized into 5 domains (physical, social, cognitive, anxiety, depression), 7 symptom questions scored individually and collectively as a symptom index, one global QOL item, and a summary score. The AML-QOL domains show high internal consistency (mean alpha: 0.82, range: 0.72-0.86). All domains demonstrated convergent validity with analogous items from the PROMIS Global 10 (Figure 1). Prospective validation testing is currently underway. CONCLUSION: The AML-QOL measures quality of life in patients with acute myeloid leukemia and analogous aggressive myeloid neoplasms. Once fully validated, this instrument can be used for clinical and research purposes. Figure 1. Figure 1. Disclosures Buckley: CTI Biopharma: Employment; TwinStrand Biosciences: Consultancy. Walter:Amphivena Therapeutics: Consultancy, Equity Ownership, Other: Clinical trial support, Research Funding; Aptevo Therapeutic: Consultancy, Other: Clinical trial support, Research Funding; Covagen AG: Consultancy, Other: Clinical trial support, Research Funding; Seattle Genetics, Inc.: Consultancy, Other: Clinical trial support, Research Funding; Boehringer Ingelheim Pharma GmbH & Co. KG: Consultancy; Pfizer: Consultancy; Amgen Inc.: Other: Clinical trial support, Research Funding; Actinium Pharmaceuticals, Inc.: Other: Clinical trial support, Research Funding. Lee:Takeda: Research Funding; Amgen: Consultancy, Research Funding; Mallinckrodt: Honoraria; Pfizer: Consultancy; Kadmon: Research Funding; Onyx: Research Funding; Incyte: Consultancy.

Background: CTCL represents a rare group of non-Hodgkin lymphomas with substantial negative impact on patient (pt) quality of life and mortality in advanced-stage disease. Mycosis fungoides (MF), the most common subtype of CTCL, and the rarer leukemic variant Sézary syndrome (SS) are distinct subtypes of CTCL. Mogamulizumab is a first-in-class, defucosylated monoclonal antibody directed against C-C chemokine receptor 4 (CCR4), which is highly expressed on malignant T-cells in CTCL. Primary results from the MAVORIC study (data cut-off December 2016), a phase 3 trial comparing mogamulizumab to FDA-approved vorinostat in adults with relapsed/refractory MF/SS, showed mogamulizumab significantly prolonged median progression-free survival compared with vorinostat (7.7 vs 3.1 months, P Methods: This was an open-label, randomized, international, phase 3 study (NCT01728805). Pts with MF/SS who were treated with ≥1 prior systemic therapy were randomized 1:1 to receive mogamulizumab (1.0 mg/kg, administered once weekly for the first 28-day cycle, then on Days 1 and 15 of subsequent cycles) or oral vorinostat (400 mg daily). In this follow-up analysis (data cut-off September 2017), exposure quartiles were determined, and baseline demographics, confirmed global response rate, and safety were analyzed by exposure group. To detect linear trends across exposure quartiles, frequencies were analyzed using Chi-square test and continuous data were assessed by analysis of variance. Results: A total of 184 pts randomized to mogamulizumab were included in this analysis. Mean time of mogamulizumab exposure was 275 days (d; standard deviation [SD]: 292 d; range: 1-1617). Based on quartile assessment, >351 d was defined as cut-off for long-term exposure. Baseline characteristics across exposure groups are shown in the Table. Significant trends were observed for baseline Eastern Cooperative Oncology Group performance status (ECOG PS; P=0.04), disease type (P=0.03), and blood involvement (defined as ≥B1 per Olsen et al J Clin Oncol 2011; P351 d, 76% had a confirmed global response (ie, either complete or partial response). The percentage of pts reporting a treatment-emergent adverse event (AE) or serious AE did not vary with increasing exposure to mogamulizumab (351 d: 21% and 4%, respectively). The most common treatment-related AEs reported by pts after >351 d of exposure to mogamulizumab were drug eruption (9/45 [20%]), thrombocytopenia (5/45 [11%]), stomatitis (4/45 [9%]), and anemia (4/45 [9%]). Conclusions: This follow-up analysis of the phase 3 MAVORIC study demonstrated mogamulizumab treatment of pts with MF/SS for approximately 1 year was not associated with an increased safety risk. Significant long-term clinical benefit was observed in pts with blood involvement at baseline, regardless of CCR4 expression status. A higher proportion of pts who had long-term (>351 days) exposure attained confirmed global response versus those who had less exposure. Disclosures Bagot: Takeda: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees; Actelion: Membership on an entity's Board of Directors or advisory committees. Dalle:Kyowa Hakko Kirin Pharmaceutical: Research Funding. Sokol:Mallinckrodt Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Spectrum Pharmaceuticals: Consultancy. Tsianakas:Kyowa Kirin: Research Funding. Musiek:Seattle Genetics: Honoraria; Kyowa Kirin: Honoraria; Actelion: Other: Scientific Advisory Committee . Ortiz-Romero:Innate Pharma: Consultancy; Takeda: Consultancy; MEDA: Research Funding; Actelion: Consultancy; 4SC: Consultancy. Poligone:Johnson and Johnson: Research Funding; Kyowa Hakko Kirin: Research Funding; Soligenix: Research Funding; Mallinckrodt: Speakers Bureau; Stemline Therapeutics: Honoraria; Seattle Genetics: Honoraria. Duvic:Clinical Care Options: Consultancy; Soligenix, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Mallinckrddt Pharmaceuticals (formerly Therakos): Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Huron Consulting Group: Consultancy; Taiwan Liposome Company LTD: Consultancy; Rhizen Pharma: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin, Co: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Oncology, LLC: Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; UT MD Anderson Cancer Center: Employment; Dr. Reddy's Laboratories (A.K.A. Promius Pharma): Consultancy; Defined Health: Consultancy; Medivir AB: Membership on an entity's Board of Directors or advisory committees; Medscape: Other: Speaker/Preceptor; Guidepoint Global: Consultancy; Jonathan Wood & Associates: Other: Speaker; Celgene Corp: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Evidera, Inc.: Consultancy; Kiniksa Pharmaceuticals: Consultancy; MEDACorp: Consultancy; The Lynx Group: Consultancy; Spatz Foundation: Research Funding; Forty Seven, Inc.: Membership on an entity's Board of Directors or advisory committees; Shape: Research Funding; Aclaris Therapeutics Int'l Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cell Medica Inc.: Consultancy, Honoraria; Allos: Research Funding; American Council on Extracorporeal Photopheresis (ACE): Membership on an entity's Board of Directors or advisory committees; Concert Pharmaceuticals, Inc.: Consultancy; Millennium Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MiRagen Therapeutics: Consultancy; Huya Bioscience Int'l: Consultancy; Array Biopharma: Consultancy, Honoraria; Oncoceuticals: Research Funding; Tetralogics: Research Funding. Elmets:NCI: Research Funding; Veterans Administration: Research Funding; California Wine Grape Association: Research Funding; Soligenix: Research Funding; Elorac: Research Funding; Leo Pharma: Other: Data and Safety Monitoring Board. Leoni:Kyowa Kirin: Employment. Dwyer:Kyowa Kirin: Employment. Sun:Kyowa Kirin: Employment. Nikonova:Kyowa Kirin: Employment. Kim:miRagen: Research Funding; Forty Seven Inc: Research Funding; Kyowa-Kirin-Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon Pharma: Consultancy, Research Funding; Merck: Research Funding; Soligenix: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees; Neumedicine: Consultancy, Research Funding; Portola: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Galderma: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetralogic: Research Funding.

Introduction: Thrombotic microangiopathy (TMA) is a clinical syndrome that can develop after hematopoietic cell transplantation (HCT). Previous studies have been limited to small case series with conflicting results. In this large, single-center longitudinal TA-TMA database, we describe the incidence, etiology, treatment, and outcome of this rare but challenging clinical presentation. Methods: We performed a retrospective cohort analysis of consecutive allogeneic HCT recipient during 2006-2015 at Fred Hutchinson Cancer Research Center. TA-TMA was defined as persistent microangiopathic hemolytic anemia (MAHA) composed of red cell fragmentation, elevated lactate dehydrogenase (LDH), thrombocytopenia, anemia, and lack of coagulopathy (Table 1). We performed a primary search algorithm using "consecutive MAHA" followed by a secondary search algorithm using "suspected hemolysis" to identify all cases from date of transplant until date of death or last follow-up (Table 1). For each suspected case, we further reviewed available patient records to confirm the diagnosis, determine the etiology, treatment, and complication. The most likely etiology was determined by reviewing the clinical events in the 2-week window before the TMA onset. Since 96% of patients were receiving calcineurin inhibitor (CNI), we chose idiopathic/drug as a diagnosis of exclusion if all other causes were excluded. TMA resolution was defined as LDH Results: Among 2241 consecutive adult allogeneic HCT recipients, 209 patients (9%) met the laboratory criteria of TA-TMA (Table 2) with a median onset time of 62d (35d-93d). One hundred and nine patients (52%) had end-organ damage with either acute kidney injury (AKI) or neurologic deficit. The median follow-up was 181d (92d-478d) and 53 patients (25%) achieved hematologic resolution. Diagnostically, acute GVHD (n=96) represented the largest category and those with GVHD refractory to high dose steroid (n=61) had poor prognosis. Diffuse alveolar hemorrhage (DAH) and idiopathic pneumonia syndrome (IPS) (n=30) also frequently preceded the TMA onset. Finally, despite excluding patients with coagulopathy, non-specific causes of TMA such as disease recurrence (n=20) and systemic infection (n=33) were frequently evident. Overall survival, separated by TMA etiology is shown in Figure 1. Whereas the idiopathic/drug and non-refractory acute GVHD categories approached the survival of non-TMA post-HCT recipients, the other groups had worse prognosis. Regardless of cause, the most common treatment (32%) was CNI cessation or CNI switch (in no particular pattern). We did not observe an association between changes to CNI therapy and TMA resolution (24% vs. 26%, Fisher P 0.80) or overall survival at 6 months (37% vs. 34%, Wald P 0.75). This remained true when each diagnostic category and each CNI drug was separately analyzed. Plasma exchange was rarely performed at our center. Finally, TMA resolution often correlated with improvement of the underlying disorder. The achievement of TMA resolution was associated with significantly improved survival (HR 0.35, P Conclusion: Despite meeting the same laboratory definition for persistent MAHA, clinical review revealed heterogeneous disease groups with dissimilar prognostic implications. Our data suggest that TA-TMA is not one disease entity but rather a "final common pathway" for several disorders that likely have different pathophysiologic mechanisms. Instead of empiric treatment with CNI adjustment, we need to identify and understand the underlying causal pathway towards TA-TMA, and to determine if earlier recognition and successful treatment improves patient outcomes. Disclosures Lee: Kadmon: Other: One-time advisory board member; Amgen: Other: One-time advisory board member; Bristol-Myers-Squibb: Other: One-time advisory board member; Mallinckrodt: Honoraria. Gopal: Seattle Genetics: Consultancy, Research Funding.

Background: Delayed or failed engraftment after adult UCBT is a major contributor to the morbidity, mortality and resource utilization associated with this procedure. Increasing the number of hematopoietic stem and progenitor cells within the cord blood graft may overcome this limitation. NiCord, developed and manufactured by Gamida Cell, is an ex vivo-expanded, cryopreserved graft derived from an entire cord blood unit (CBU). In a pilot study, NiCord transplanted with a second, unmanipulated CBU was shown to shorten time to neutrophil engraftment and provide long-term hematopoiesis (Horwitz M, JCI 2014). In another study, NiCord UCBT demonstrated clinical benefit by reducing the incidence of severe infections as well as the duration of hospitalization during the first 100 days following transplantation (Anand S BBMT 2017). With confirmation that NiCord expands both hematopoietic stem and progenitor cells, we conducted a multicenter study using NiCord as a single stem cell graft. Methods: The study objective was to assess safety and efficacy of NiCord as a single, ex vivo expanded stem cell graft. The primary endpoint was to assess the cumulative incidence of NiCord-derived neutrophil engraftment. Thirty-five evaluable patients, median age 44 (13-63) with ALL (n=9), AML (n=16), MDS (n=7), CML (n=2) or Hodgkin lymphoma (n=1) were transplanted at 10 sites in the USA, EU, and Singapore. 79% had intermediate-high risk disease by Disease Risk Index. All patients received myeloablative conditioning with a TBI-based (n=14) or chemotherapy-only (n=21) regimen. Graft vs. host disease (GvHD) prophylaxis consisted of MMF for a minimum of 60 days and tacrolimus or cyclosporine for a minimum of 180 days. HLA matching was 4/6 (n=25), 5/6 (n=8) or 6/6 (n=2). Results: NiCord processing resulted in a median 32-fold (20-52 fold) increase in CD34+ cells relative to that reported by the cord blood bank prior to cryopreservation. This translated to a median CD34+ cell dose of 6.3 x 106/kg (1.4-14.9 x 106/kg). The cumulative incidence of engraftment at day 42 was 94%. Two patients experienced secondary graft failure; one at day 40 due to HHV6 infection, and another at day 260 due to an overwhelming, lethal adenovirus infection. Neutrophil engraftment occurred at a median of 11 days (95% CI: 9-13 days)(Figure 1). Platelet engraftment occurred at a median 34 days (95% CI:32-42 days)(Figure 2). Full donor whole blood chimerism (≥ 95%) was observed in 100% of engrafted patients by day 100 following transplantation. The incidence of grade II-IV and grade III/IV acute GvHD was 48.6% and 12.2%, respectively. Cumulative incidence of all chronic GvHD was 45%, and moderate/severe cGvHD 11.5% at 1 year following transplantation. Median CD3+, CD4+, and CD19+ lymphocyte counts were 286/µl, 183/µl, and 147/µl at day 100, and 479/µl, 290/µl, and 446/µl at 6 months, respectively. The incidence of grade 2-3 bacterial (n=9) or grade 3 fungal (n=0) infections was 23.9% by day 100. With a median follow-up of 13 months (range 1-35 months), the 6-month and 2-year non-relapse mortality was 12.8% and 20.3%, respectively. The cumulative incidence of relapse was 27% at 2 years. The Kaplan-Meier estimate of overall survival at 6 months and 2 years was 80.5% and 50.8%, respectively. Conclusions: The rapid engraftment kinetic coupled with a low graft failure rate and durable hematopoiesis suggests a favorable safety profile of NiCord as a single umbilical cord blood graft. Ex vivo expansion of the CBU resulted in a CD34+ cell dose comparable to adult mobilized peripheral blood stem cell grafts. Compared to a recently reported multi-center phase II study of adult, unmanipulated myeloablative double UCBT (Barker J, Br. J. Haem 2014), NiCord markedly reduced the median time to neutrophil recovery (11 days vs. 22 days) and platelet recovery (34 days vs. 49 days). Transplantation of NiCord appears not to adversely affect cellular immune recovery. Quantitative assessment of neutrophil, T-cell, and B-cell recovery is comparable to that observed following adult matched unrelated donor transplantation. We conclude that UCBT using NiCord has the potential to broaden accessibility to stem cell transplantation and to become a graft of choice for patients without a matched donor. A global randomized phase III study of NiCord vs. standard UCBT is ongoing (NCT02730299). Figure 1 Figure 1. Disclosures Jagasia: Therakos: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Mallinckrodt: Consultancy. Wagner: Magenta Therapeutics: Research Funding; Novartis: Research Funding. Kuball: Gadeta (www.gadeta.nl): Consultancy, Equity Ownership, Patents & Royalties: on gdT cells and receptors and isolation strategies , Research Funding; Miltenyi: Research Funding. Majhail: Anthem, Inc.: Consultancy; Sanofi: Honoraria. Montesinos: Celgene Corporation: Honoraria, Research Funding. Kurtzberg: Gamida Cell: Research Funding. Sanz: Gamida Cell: Research Funding.

Introduction & Objectives: MRG-106 is an oligonucleotide inhibitor of miR-155, a microRNA with a strong mechanistic link to CTCL. The goals of this first-in-human study are to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of MRG-106 in patients with mycosis fungoides (MF). Methods: This Ph 1 trial employs a dose-escalation design to evaluate the administration of MRG-106 via subcutaneous (SC) injection, 2-hour intravenous (IV) infusion, or IV rapid bolus injection (≤ 900 mg/dose). An additional cohort received intralesional injections (75 mg/dose) to evaluate tolerability and efficacy with local delivery. Subjects were required to have biopsy-proven MF stage I-III with plaque and/or tumor lesions. Subjects were permitted to remain on concurrent stable CTCL therapy. Subjects received 6 doses (SC/IV) in the first 26 days of the study followed by weekly or bi-weekly doses in patients who continued beyond the first cycle. Safety was monitored by physical exams, clinical laboratory tests, and assessment of adverse events (AEs). Immunophenotyping of peripheral blood was performed to measure the impact of MRG-106 on normal immune cell subsets. The PK properties of MRG-106 were compared between different routes of administration. The effect of MRG-106 on individual skin lesions or total skin disease was assessed by the Composite Assessment of Index Lesion Severity (CAILS) score or the modified Severity Weighted Assessment Tool (mSWAT), respectively. Biopsies were collected from all subjects treated by intralesional injection and from a subset of subjects in the SC/IV cohorts to assess molecular and cellular responses to MRG-106. Baseline miR-155 expression and changes in gene expression and T cell repertoire (T cell receptor sequencing) in response to MRG-106 treatment were assessed. Results: 24 subjects (18M/6F, median age 62 yrs) have been in the study for up to 10 months (as of 7/31/2017). 4 subjects received only intralesional doses; 2 subjects were enrolled into both the intralesional and SC cohorts. 18 subjects received only SC injections or IV infusions/bolus injections of MRG-106. 22/26 subjects completed the first treatment cycle per protocol; 2 subjects are on-going. 2 subjects discontinued: one due to progressive disease found shortly after enrollment, and one due to an AE of worsening pruritus (Grade 3), judged as a dose-limiting toxicity at 900 mg SC. The drug was otherwise well-tolerated: of the other 48 drug-related AEs, all were Grade 1 or 2. The MTD has not been reached. 23/24 subjects (95%) showed improvement in either the individually treated lesion (intralesional cohort) or total skin disease (SC/IV cohorts) as measured by maximal change in CAILS or mSWAT. In the SC/IV-infusion cohorts, 17/18 subjects had an improvement in mSWAT score; 9/18 subjects (50%) reached a PR defined as ≥ 50% reduction in mSWAT score. Of the 9 subjects who received MRG-106 for > 1 cycle, 78% reached a PR, suggesting that longer treatment may provide greater benefit. Improvements in mSWAT scores were observed as early as Study Day 19 (the 1st post-treatment assessment), and for all but one subject, improvements from baseline were maintained through the treatment period. Based on immunophenotyping of peripheral blood, absolute numbers and proportions of subjects' leukocyte subpopulations were not significantly altered with MRG-106 treatment, with the exception of transient increases in NK and NK T cells observed only at the highest dose. TCR sequencing of pre- and post-treatment biopsies showed that T cell clonality decreased with intralesional injection of MRG-106. miR-155 was elevated in the lesions of most subjects, drug accumulation was observed with all routes of administration, and gene expression changes were associated with inactivation of the STAT, NFκB, and PI3K/AKT pathways. Conclusions: These preliminary results suggest that MRG-106 is well-tolerated and has clinical activity as indicated by meaningful reductions in CAILS and mSWAT assessments. Exploratory analyses of lesion biopsies support the clinical activity of MRG-106 with reductions in T cell clonality and gene expression changes consistent with the known mechanism of miR-155. These encouraging data support the continued investigation of MRG-106 in MF patients and expansion of the study to include additional hematological malignancies in which miR-155 is known to be elevated and relevant. Disclosures Querfeld: Medivir: Honoraria; Actelion: Honoraria, Research Funding; MiRagen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Elorac: Research Funding; Soligenix: Research Funding; Kyowa: Research Funding; Trillium Therapeutics: Research Funding; City of Hope: Employment; Mallinckrodt: Honoraria; Mindera: Consultancy. Foss: seattle genetics: Speakers Bureau; Eisai: Honoraria; spectrum: Honoraria, Speakers Bureau; immune design: Research Funding; celgene: Honoraria. Porcu: Tetralogic: Research Funding; Celgene: Research Funding; Cell Medica: Research Funding; Galderma: Research Funding; Kura: Research Funding; Innate Pharma: Research Funding; Miragen: Research Funding; Kiowa: Research Funding. Kim: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; miRagen: Research Funding; Merck: Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees; Soligenix: Research Funding; Portola: Consultancy, Research Funding; Neumedicine: Research Funding; Kyowa-Kirin-Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Consultancy, Research Funding; Horizon Pharma: Consultancy, Research Funding; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding; Tetralogic: Research Funding; Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Halwani: Kyowa Hikko Kirin: Research Funding; Bristol Myers Squib: Research Funding; Seattle Genetics: Research Funding; Roche/Genentech Inc.: Research Funding; Genetech Inc.: Research Funding; Takeda: Research Funding; Pharmacyclics: Research Funding; Amgen: Research Funding; AbbVie: Research Funding; Immune Design: Research Funding; Miragen: Research Funding. Seto: miRagen Therapeutics: Employment, Equity Ownership, Patents & Royalties: Inventor on patents. Pestano: Sanofi: Equity Ownership; Cascadian Therapeutics: Equity Ownership; miRagen Therapeutics: Employment, Equity Ownership. Jackson: miRagen Therapeutics: Employment, Equity Ownership. Williams: miRagen Therapeutics: Employment, Equity Ownership. Dickinson: miRagen Therapeutics: Employment, Equity Ownership. Ruckman: miRagen Therapeutics: Employment, Equity Ownership. Gordon: Syndax: Consultancy; Taiho: Consultancy; Pre-cell: Consultancy; Bayer: Consultancy; ElevenP15: Consultancy; Clinipace: Consultancy; Ruesch Center for the Cure of Gastrointestinal Cancer: Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy; Heron Therapeutics: Consultancy; Themis: Consultancy; Caring for Colorado Foundation: Membership on an entity's Board of Directors or advisory committees; TEQ laboratories: Membership on an entity's Board of Directors or advisory committees; GLPI: Consultancy, Equity Ownership; Industrial Laboratories: Membership on an entity's Board of Directors or advisory committees; Axion: Membership on an entity's Board of Directors or advisory committees; Globavir: Consultancy; miRagen Therapeutics: Consultancy; IGM: Consultancy; Cleave Pharmaceuticals: Consultancy; Flugen: Consultancy; Inovio: Consultancy. Rubin: miRagen Therapeutics: Employment, Equity Ownership. Marshall: Colorado BioScience Association: Membership on an entity's Board of Directors or advisory committees; Atlas Venture: Consultancy; AmideBio: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Fluorofinder: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; miRagen Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Inventor on various patents.

Background: The predominant source of hematopoietic progenitor cells (HPCs) for hematopoietic stem cell transplantation (HSCT) is peripheral blood (PB). HPCs are collected for HSCT using large volume leukapheresis (LVL) that typically involves processing >4 blood volumes to ensure adequate yield of HPCs. LVL is time-intensive, causes volume overload and hypocalcemia, and in small children, requires prolonged sedation. The purpose of this quality improvement project was to assess whether a collection efficiency-based, data-driven prediction algorithm for HPC collection can meaningfully decease the volume of blood processed in well-mobilized patients. Methods We evaluated the CD34+ cellular collection efficiency 2 (CE2; see below) in 240 consecutive adult autologous (A-auto), 59 adult allogeneic (A-allo), and 23 pediatric autologous (P-auto) collections ("training set"). In the training set, mean (1SD) CD34+ CE2s in A-auto, A-allo and P-auto collections were 47% (16%), 51% (14%), and 59% (32%), respectively (Fig. 1). CD34 Collection Efficiency 2 (CE2) was calculated as below: CD34+ CE2= CD34+ yield/[BVP x Precollection PB CD34 count] Blood Volume to be processed (BVP) was calculated as below: BVP= CD34+ cell target/ [CD34+ CE2 x Precollection PB CD34+ count] In order to have a high level of confidence that the targeted dose of CD34+ cells will be collected with implementation of the prediction formula, the CD34+ CE2 was set at the 3rd percentile (30%) in the A-auto group, and lowest attained CD34+ CE2 in the A-allo (30%) and P-auto groups (25%) for the A-auto, A-allo and P-auto prediction formulae, respectively. These CD34+ CE2s were used to calculate the BVP in a large cohort of consecutive patients from Froedtert Memorial Lutheran Hospital and the Children's Hospital Wisconsin which included 461 A-Auto, 90 A-Allo and 16 P-Auto collections over a period of 16 months (2/2015- 5/2016). Data was collected from both prediction-driven truncated and standard non-truncated LVLs and comparisons were made with regards to blood volume processed, duration of LVL, financial impact and time to neutrophil and platelet engraftment. Results After implementation of the BVP prediction formula, 91 truncations were performed in 42 (9%), 41 (46%) and 8 (50%) of 461 A-auto, 90 A-allo and 16 P-auto collections, respectively, representing an overall truncation rate of 16% (Fig. 2). Of the 91 total procedures truncated, 4 procedures (all A-Auto) failed to reach the CD34+ collection target, however, cell yields were extremely close to targets and were not deemed to be prediction failures (Table 1). In truncated LVL procedures, reduction in volume of blood processed was 34% overall, with average decreased processing of 31%, 36% and 46% (of 4 blood volumes) in A-auto, A-allo and P-auto collections, respectively (Fig. 3). The average time for a randomly selected group of 20 standard 4BV collections was 4 hr 49 mins. A 34% truncation in BVP would result in the procedure concluding 1 hr 38 mins earlier and this prediction formula based intervention is predicted to save on average $132 per patient ($35/hr Nursing time; $25/hr Cell Processing technologist time, and 35% overhead) and total savings of $12,039 over 91 truncated procedures during the 16 month period assessed. Median neutrophil and platelet engraftment were not significantly different in autologous HSCT patients with truncated vs. non-truncated procedures (10 days each for neutrophil engraftment, and 20 days vs. 19 days in truncated vs. non-truncated procedures for platelet engraftment). Conclusion The use of a data-driven HPC prediction algorithm resulted in the truncation of 16% of all LVL procedures. The volume of truncation was significant in most cases and did not adversely impact the ability to collect the desired number of stem cells and resulted in comparable neutrophil and platelet engraftment time. This approach may be particularly important in mitigating risks of LVL in populations with higher concern for adverse events such as children, and patients with poor tolerance for LVL-induced volume overload. Finally, in our experience, this approach has resulted in enhancing patient satisfaction associated with shorter procedures and promotes optimal use of healthcare resources by limiting costs. Table 1. Truncated procedures resulting in "undercollection" Table 1. Truncated procedures resulting in "undercollection" Disclosures Padmanabhan: Bloodcenter of Wisconsin: Patents & Royalties: A patent application has been filed on a Method of detecting platelet activating antibodies that cause heparin-induced thrombocytopenia/thrombosis; PCT/US14/62591; Terumo BCT: Consultancy, Honoraria; Schlesinger & Associates: Consultancy, Honoraria; LEK Consulting: Consultancy, Honoraria; Mallinckrodt Pharmaceuticals: Consultancy, Honoraria; Fenwal (Fresenius Kabi): Research Funding.

Heparin-induced thrombocytopenia (HIT) is characterized by antibodies (abs) directed to complexes of PF4 and heparin that are an important cause of morbidity and mortality in heparin-treated patients. Direct Thrombin inhibitors (DTIs) and fondaparinux (off-label) are the mainstays of therapy, but despite their use, thrombosis is common. Thus there is a need for additional treatment regimens, especially in severely affected patients. We recently encountered two patients with severe thrombotic HIT and persistent thrombocytopenia who responded dramatically to intravenous immunoglobulin G (IVIg) and performed studies to examine the basis for this effect. Patient 1, a 47-year-old man, presented with severe thrombocytopenia (TP, 13,000/ul), lower extremity thromboses and pulmonary embolism 13 days after being treated with heparin during cardiac surgery. PF4 ELISA (2.7 OD) and serotonin release assay (SRA) (100%) were strongly positive. Argatroban and then bivalirudin were given, but TP persisted for 17 days (Fig 1A). On Days 18 and 19 1gm/Kg of IVIg was administered. Platelet counts rose dramatically and he was discharged four days later (Fig 1A). Surprisingly, despite platelet recovery, two "platelet-activating" HIT tests, the SRA and newly described PEA (Padmanabhan et al, Chest 2016, epub) remained strongly positive (data not shown). The standard PEA is performed using platelets "primed" by pre-incubation with 30 ug/ml platelet factor 4 (PF4) and no heparin. However strong platelet-activating HIT abs, like those seen in this patient with "delayed HIT" may require only a small amount of PF4 to prime platelets for activation. When testing was repeated using platelets primed with only 1 ug/ml PF4 (Low PF4 PEA, LP-PEA), an inverse correlation between the PEA signal and platelet counts was observed (Fig 1A). Patient 2, a 73-year-old man, presented with severe TP (25,000/ul) and pulmonary embolism 9 days after receiving heparin during cardiac surgery. PF4 ELISA (2.3 OD) and SRA (100%) were strongly positive. He was treated with bivalirudin but remained thrombocytopenic with positive HIT test results (not shown) for 3 weeks (Fig 1B). Therapeutic plasma exchange (TPE) was performed on Day 22 with no effect on platelet counts. On Days 23 and 24, 1gm/Kg of IVIg was administered. Platelet counts rose sharply and he was discharged one week later. As with Patient 1, the LP-PEA but not the PEA test results became negative after IVIg treatment, coinciding with improvement in platelet counts (Fig 1B). To understand the beneficial effect of IVIg in these patients, we added IVIg to patient serum in amounts sufficient to produce IgG levels comparable to those achieved in vivo and examined the effects in the PEA/LP-PEA assay. At the 2gm/Kg dose, IVIg reduced the LP-PEA signal significantly in both patients (Fig 1C). Similar results were obtained with sera from 5 other patients with HIT, indicating that the IVIg effect is not restricted to HIT sera with unique characteristics (Fig 1D). Purified IgG Fc fragments are both necessary and sufficient to achieve this effect, while Fab fragments demonstrated no inhibitory activity (Fig 1E). IgG2 comprises approximately 25% of IVIg and it is known that IgG2 binds poorly to the RR131 isotype of the platelet Fc receptor, FcGammaRIIa. Thus, RR131 platelets should be less susceptible to IVIg-based inhibition than HH131 platelets. Consistent with this, activation was more effectively inhibited with HH131 platelets than with RR131 (Fig 1F). These results were confirmed using a second HIT ab (data not shown). Experience with these patients shows that IVIg can be highly effective for treating patients with HIT unresponsive to standard therapies. The constant domain (Fc) of IgG plays a critical role in mediating this effect. Patients homozygous for the RR131 FcGammaRIIa polymorphism may be less responsive to IVIg treatment and may require higher doses or more prolonged therapy. IVIg has been used only rarely to treat HIT. Additional studies are needed to define its role in treating this dangerous condition. Figure 1 LP-PEA results shown are the means of duplicate determinations. Fig 1C, D and F. Results shown are means and SDs of triplicate determinations. Fig 1E. Results shown are representative of duplicate determinations. Fig 1F. IVIg doses at 2, 1, 0.5 and 0.25gm/Kg correspond to IVIg at a final concentration of 46, 23, 12 and 6mg/ml in the HIT sample, respectively. Figure 1. LP-PEA results shown are the means of duplicate determinations. Fig 1C, D and F. Results shown are means and SDs of triplicate determinations. Fig 1E. Results shown are representative of duplicate determinations. Fig 1F. IVIg doses at 2, 1, 0.5 and 0.25gm/Kg correspond to IVIg at a final concentration of 46, 23, 12 and 6mg/ml in the HIT sample, respectively. Disclosures Padmanabhan: Bloodcenter of Wisconsin: Patents & Royalties: A patent application has been filed on a Method of detecting platelet activating antibodies that cause heparin-induced thrombocytopenia/thrombosis; PCT/US14/62591; Fenwal (Fresenius Kabi): Research Funding; Schlesinger & Associates: Consultancy, Honoraria; LEK Consulting: Consultancy, Honoraria; Mallinckrodt Pharmaceuticals: Consultancy, Honoraria; Terumo BCT: Consultancy, Honoraria. Jones:Bloodcenter of Wisconsin: Patents & Royalties: A patent application has been filed on a Method of detecting platelet activating antibodies that cause heparin-induced thrombocytopenia/thrombosis; PCT/US14/62591. Bougie:Bloodcenter of Wisconsin: Patents & Royalties: A patent application has been filed on a Method of detecting platelet activating antibodies that cause heparin-induced thrombocytopenia/thrombosis; PCT/US14/62591. Aster:Bloodcenter of Wisconsin: Patents & Royalties: A patent application has been filed on a Method of detecting platelet activating antibodies that cause heparin-induced thrombocytopenia/thrombosis; PCT/US14/62591.

Cold agglutinin disease (CAD) is an autoimmune hemolytic anemia characterized by the presence of autoantibodies (cold agglutinins) that bind to red blood cells (RBC) at low temperatures. Cold agglutinin binding to RBCs results in antibody-mediated classical complement activation with deposition of complement C4 and C3 fragments onto the RBC surface. Complement-opsonized RBCs are removed from the circulation by macrophage-driven phagocytosis in the liver or spleen and via intravascular hemolysis following assembly of the terminal lytic complex (C5b - C9), together resulting in clinical anemia. C1q is the initiating molecule for cold agglutinin-mediated complement activation on the surface of human RBCs. We hypothesized that directly blocking C1q recruitment onto cold agglutinin-sensitized RBCs will prevent complement activation and opsonization and reduce hemolysis. To this end, we have developed a humanized monoclonal antibody (ANX005) that binds with high-affinity (~10 pM) to C1q and blocks classical complement activation & hemolysis in an in vitro sheep RBC assay. We evaluated the impact of ANX005 on hemolysis and complement deposition on human RBCs that were pre-sensitized with sera from CAD subjects. ANX005 showed a dose-dependent reduction in hemolysis using both individual and pooled CAD sera as the source of cold agglutinin. We further demonstrated that C1q blockade led to a robust reduction in C4 and C3 fragment deposition onto human RBCs. These results demonstrate that C1q inhibition is an effective way to impede C4 and C3 activation and downstream assembly of the lytic complex in sera from CAD patients, and support the clinical development of ANX005 in CAD and other antibody-mediated diseases. Disclosures Gertz: Prothena Therapeutics: Research Funding; Sandoz Inc: Honoraria; NCI Frederick: Honoraria; Celgene: Honoraria; Med Learning Group: Honoraria, Speakers Bureau; Research to Practice: Honoraria, Speakers Bureau; Alnylam Pharmaceuticals: Research Funding; Novartis: Research Funding; Ionis: Research Funding; Annexon Biosciences: Research Funding; GSK: Honoraria. Qiu:Annexon Biosciences: Employment, Equity Ownership. Kendall:Annexon Biosciences: Employment, Equity Ownership. Saltarelli:Mallinckrodt: Equity Ownership; Abbvie: Equity Ownership; Annexon Biosciences: Employment, Equity Ownership, Patents & Royalties. Yednock:Annexon, Inc: Employment, Equity Ownership. Sankaranarayanan:Annexon Biosciences: Employment, Equity Ownership.

Background: HIT is a life-threatening complication that occurs in a subset of heparin-treated patients. To our knowledge, a large population-based estimate of HIT disease burden, complication rates and economic cost has not been reported previously. Based on small studies, wide variations in the incidence of HIT has been observed in some patient populations. For example, among patients undergoing knee and hip arthroplasties, rates of HIT were reported to be less than 0.5% in some studies, but others, including a recent study suggest a much higher risk (Blood. 2016 25;127(8):1036-43). Similarly, rates of HIT reported in patients undergoing hemodialysis are highly variable, with some reporting an incidence as high as 3.9% (AJKD 1996; 28(1):82-5). To better address these discrepant findings and to benchmark disease burden and complication rates, we performed an analysis of the Nationwide Inpatient Sample (NIS). Methods: The NIS is a large inpatient healthcare database in the US. Unweighted, it contains data from >7 million hospital stays each year and weighted, it estimates >35 million hospitalizations. Full-year HIT data was available for 2009-2013, and this study period was queried to identify patients >18 years of age with a discharge diagnosis of HIT. Survey weighted domain analysis was conducted to estimate the incidence of HIT. HIT rates were also estimated in patients who underwent specific procedures (coronary artery bypass grafting [CABG, a known "high" risk setting for HIT development], hip and knee replacement, and dialysis. Incidence of thrombosis, bleeding, in-hospital mortality, and length and cost of hospitalization were also calculated. Outcomes in HIT patients were compared to those without HIT using ANOVA and Chi-squared test for continuous and categorical variables, respectively. Results: The annual HIT burden averaged ~22,000 annually over the study period with no change over that time frame (Fig 1A, p=0.1). The incidence of HIT was highest in patients undergoing CABG at 0.51%, followed closely by dialysis at 0.43% (Fig 1B). HIT rates were low in knee and hip arthroplasty at 0.02% each, even lower than the 0.07% overall rate of HIT for all patients (Fig 1B). The incidence of thrombosis was high in HIT (Fig 1B) with venous thrombosis being the most common type (17.9%), followed by pulmonary embolism (8.3%) and arterial thrombosis (2.3%) (Fig 1C), consistent with the relative incidence reported in the published literature. Rates of major bleeding in HIT is estimated to be 10-20% with direct thrombin inhibitor therapy. Our analysis yielded much lower major bleeding rates of 2.5% and 0.7% for gastrointestinal and intracranial bleeding, respectively (Fig 1D). In-hospital mortality in HIT was 9.5%, almost five times higher than in patients without HIT (Fig 1E). Notably, the length of hospitalization and cost of care were approximately 3x higher in patients with HIT compared to those without (Fig 1E & 1F). Conclusions: Surprisingly, HIT disease burden was large and unchanged during the study period averaging >20,000 cases annually. A recent study suggests that an "avoid unfractionated heparin" protocol can significantly decrease the incidence of HIT (Blood. 2016; 127(16):1954-9). Large scale interventions of this type may be needed to tackle this common disorder. Our data also suggests that rate of HIT in knee and hip arthroplasty are low, while in patients undergoing dialysis it is more common than generally believed. We found that thrombosis, a serious complication of HIT is a very common finding, but major bleeding rates were low. HIT also resulted in a disproportionate utilization of resources with costs per patient of ~ $150,000. There are important limitations with use of data from the NIS, where missing/miscoded information are concerns. Additionally, the NIS has no information on drug use. For example, HIT incidence in CABG includes all patients who underwent the procedure whether or not heparin exposure occurred (both off- and on-pump). In addition, rates of thrombosis may be overestimates as heparin may have been used to treat thrombosis in some patients and caused HIT with isolated thrombocytopenia. Despite these shortcomings, in addition to disease benchmarking, this information may aid healthcare providers and public health professionals plan and implement broad preventative and therapeutic interventions to tackle this dangerous yet common disease. Figure 1 Figure 1. Disclosures Padmanabhan: Bloodcenter of Wisconsin: Patents & Royalties: A patent application has been filed on a Method of detecting platelet activating antibodies that cause heparin-induced thrombocytopenia/thrombosis; PCT/US14/62591; Fenwal (Fresenius Kabi): Research Funding; Terumo BCT: Consultancy, Honoraria; Mallinckrodt Pharmaceuticals: Consultancy, Honoraria; LEK Consulting: Consultancy, Honoraria; Schlesinger & Associates: Consultancy, Honoraria.