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Background: Tisagenlecleucel, an anti-CD19 chimeric antigen receptor (CAR)-T cell therapy, has demonstrated durable responses and a manageable safety profile in adult patients (pts) with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). We report the correlation of pre- and post-infusion factors and biomarkers with efficacy in tisagenlecleucel-treated pts with r/r DLBCL. Methods: Results from JULIET, a global, single-arm, pivotal, phase 2 trial of tisagenlecleucel in adult pts with r/r DLBCL, were analyzed to identify baseline disease and pt characteristics and serum biomarkers that may correlate with efficacy. The relationships between markers such as lactate dehydrogenase (LDH), baseline tumor volume (TV, within 30 days prior to infusion) using positron emission tomography/computed tomography, pre-treatment C-reactive protein (CRP) and thrombocytopenia, as well as cytokine release syndrome (CRS; Penn scale)/neurological events (NE; CTCAE v4.03) severity, and month 3 response (complete or partial response [CR, PR]), progression-free survival (PFS), and overall survival (OS) were assessed. Results: As of December 11, 2018, 115 pts were infused with tisagenlecleucel and evaluable for efficacy. Baseline TV did not correlate with month 3 response; we then examined additional pre-treatment candidate factors. Median LDH levels at enrollment, pre-lymphodepleting chemotherapy (LDC), and pre-infusion were higher in nonresponders (NRs) compared with pts achieving CR/PR. 15/16 pts with pre-infusion grade 3/4 thrombocytopenia (2-fold above the ULN had poorer PFS and OS (Figure 1). Similar separations of PFS and OS were observed with LDH levels at enrollment and pre-LDC. Pts with pre-infusion platelet levels Post-infusion, correlations between severe (grade 3/4) CRS/NE and efficacy were examined. All 13 pts with severe NE were NRs. 9/17 pts with grade 3 CRS and all 9 pts with grade 4 CRS were also NRs. In addition, pts with severe CRS had worse PFS and OS compared with pts with grade 0-2 CRS. Similarly, pts with severe NE had worse PFS and OS compared with pts with grade 0-2 NE. High pre-infusion LDH and pre-infusion grade 3/4 thrombocytopenia and severe NE were independently associated with poorer PFS in Cox regression analyses. Severe CRS did not correlate with PFS in a multivariate Cox model. Pts with severe CRS who were also NRs had higher median baseline TV compared with other pts. Notably, the highest levels of serum biomarkers (eg, ferritin, IL4, IL8, IL10), highest LDH, and lowest platelet counts within 1 month post-infusion were observed in pts with severe CRS who were also NRs, compared with pts with severe CRS who achieved CR/PR and pts with grade 0-2 CRS. Analyses of the impact of tocilizumab and steroids usage are ongoing. Conclusions: Multivariate analyses identified that high levels of pre-infusion LDH, a known marker of tumor burden, metabolic activity, and disease aggressiveness, was associated with NRs at month 3 as well as worse PFS and OS. Grade 3/4 thrombocytopenia at pre-infusion and grade 3/4 NE were also associated with poor efficacy outcomes. Furthermore, the highest serum biomarker profiles post-infusion appeared to associate with pts with severe CRS who were also NRs. Overall, these analyses suggest that a subset of pts with aggressive disease at infusion and/or pts with severe CRS/NE had poorer outcomes in the JULIET trial. These analyses may reinforce the rationale for current and future directions of using CAR-T cell therapy in an earlier line of therapy (during less aggressive/less advanced disease), optimizing pt care, and developing interventions to prevent severe CRS and/or NE. Clinical trial information: NCT02445248. Disclosures Westin: Genentech: Other: Advisory Board, Research Funding; Novartis: Other: Advisory Board, Research Funding; Curis: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; 47 Inc: Research Funding; Juno: Other: Advisory Board; MorphoSys: Other: Advisory Board; Unum: Research Funding; Janssen: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding. Tam:Roche: Honoraria; AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BeiGene: Honoraria; Novartis: Honoraria. Jaeger:Novartis, Roche, Sandoz: Consultancy; Celgene, Roche, Janssen, Gilead, Novartis, MSD, AbbVie, Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen, AbbVie, Celgene, Eisai, Gilead, Janssen, Novartis, Roche, Takeda Millennium, MSD, BMS, Sanofi: Honoraria; AbbVie, Celgene, Gilead, Novartis, Roche, Takeda Millennium: Research Funding. McGuirk:Bellicum Pharmaceuticals: Research Funding; Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gamida Cell: Research Funding; Pluristem Ltd: Research Funding; ArticulateScience LLC: Other: Assistance with manuscript preparation; Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding; Fresenius Biotech: Research Funding; Novartis: Research Funding. Holte:Novartis: Honoraria, Other: Advisory board. Waller:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Other: Travel expenses, Research Funding; Cerus Corporation: Other: Stock, Patents & Royalties; Chimerix: Other: Stock; Cambium Oncology: Patents & Royalties: Patents, royalties or other intellectual property ; Amgen: Consultancy; Kalytera: Consultancy. Jaglowski:Juno: Consultancy, Other: advisory board; Unum Therapeutics Inc.: Research Funding; Kite: Consultancy, Other: advisory board, Research Funding; Novartis: Consultancy, Other: advisory board, Research Funding. Bishop:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees; CRISPR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Andreadis:Celgene: Research Funding; Juno: Research Funding; Novartis: Research Funding; Genentech: Consultancy, Employment; Kite: Consultancy; Gilead: Consultancy; Jazz Pharmaceuticals: Consultancy; Pharmacyclics: Research Funding; Merck: Research Funding; Roche: Equity Ownership. Foley:Janssen: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Speakers Bureau. Fleury:Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; AstraZeneca: Consultancy. Ho:Janssen: Other: Trial Investigator meeting travel costs; Celgene: Other: Trial Investigator meeting travel costs; La Jolla: Other: Trial Investigator meeting travel costs; Novartis: Other: Trial Investigator meeting travel costs. Mielke:EBMT/EHA: Other: Travel support; IACH: Other: Travel support; Celgene: Honoraria, Other: Travel support (via institution), Speakers Bureau; Kiadis Pharma: Consultancy, Honoraria, Other: Travel support (via institution), Speakers Bureau; GILEAD: Consultancy, Honoraria, Other: travel (via institution), Speakers Bureau; Miltenyi: Consultancy, Honoraria, Other: Travel and speakers fee (via institution), Speakers Bureau; Jazz Pharma: Honoraria, Other: Travel support, Speakers Bureau; DGHO: Other: Travel support; Bellicum: Consultancy, Honoraria, Other: Travel (via institution); ISCT: Other: Travel support. Teshima:Novartis: Honoraria, Research Funding. Schuster:AbbVie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Patents & Royalties: Combination CAR-T and PD-1 Inhibitors, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Loxo Oncology: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Nordic Nanovector: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Acerta: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding. Bachanova:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Incyte: Research Funding; GT Biopharma: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Gamida Cell: Research Funding; Celgene: Research Funding. Maziarz:Kite: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Incyte: Consultancy, Honoraria; Celgene/Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Van Besien:Miltenyi Biotec: Research Funding. Izutsu:Eisai, Symbio, Chugai, Zenyaku: Research Funding; Eisai, Chugai, Zenyaku: Honoraria; Chugai, Celgene, Daiichi Sankyo, Astra Zeneca, Eisai, Symbio, Ono, Bayer, Solasia, Zenyaku, Incyte, Novartis, Sanofi, HUYA Bioscience, MSD, Astellas Amgen, Abbvie, ARIAD, Takeda, Pfizer: Research Funding; Kyowa Kirin, Eisai, Takeda, MSD, Chugai, Nihon Medi-physics, Janssen, Ono, Abbvie, Dainihon Sumitomo, Bayer, Astra Zeneca, HUYA Japan, Novartis, Bristol-Byers Squibb, Mundi, Otsuka, Daiichi Sankyo, Astellas, Asahi Kasei: Honoraria; Celgene: Consultancy. Kersten:Bristol Myers Squibb: Other: Travel grants, honorarium, or advisory boards; Gilead: Other: Travel grants, honorarium, or advisory boards; Roche: Consultancy, Research Funding, Travel grants, honorarium, or advisory boards; Amgen: Other: Travel grants, honorarium, or advisory boards; Novartis: Consultancy, Other: Travel grants, honorarium, or advisory boards; Roche: Other: Travel grants, honorarium, or advisory boards; Celgene: Other: Travel grants, honorarium, or advisory boards; Kite: Consultancy, Other: Travel grants, honorarium, or advisory boards; Janssen/Cilag: Other: Travel grants, honorarium, or advisory boards; MSD: Other: Travel grants, honorarium, or advisory boards; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Wagner-Johnston:Bayer: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees. Corradini:Jazz Pharmaceutics: Honoraria; KiowaKirin: Honoraria; Kite: Honoraria; Novartis: Honoraria, Other: Travel Costs; Roche: Honoraria; Sanofi: Honoraria; Servier: Honoraria; Takeda: Honoraria, Other: Travel Costs; BMS: Other: Travel Costs; Celgene: Honoraria, Other: Travel Costs; AbbVie: Consultancy, Honoraria, Other: Travel Costs; Janssen: Honoraria, Other: Travel Costs; Gilead: Honoraria, Other: Travel Costs; Amgen: Honoraria; Daiichi Sankyo: Honoraria. Han:Novartis: Employment. Tiwari:Novartis: Employment. Agoulnik:Novartis: Employment. Eldjerou:Novartis Pharmaceuticals Corporation: Employment. Bubuteishvili Pacaud:Novartis: Employment. Salles:Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Other: Educational events; BMS: Honoraria; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Epizyme: Consultancy, Honoraria.

Introduction: 8500 adult allogeneic hematopoietic stem cell transplants (alloHSCT) are performed annually in the U.S. and 17,000 in Europe. HSCT-associated thrombotic microangiopathy (TMA), defined by thrombocytopenia, microangiopathic hemolytic anemia, and organ dysfunction in the absence of disseminated intravascular coagulation, complicates some 20% of these procedures. About half of post-alloHSCT TMAs may resolve when GvHD immunoprophylaxis is modified, but three year survival rates for those with severe HSCT-TMAs are a dismal 11%. Clinical manifestations are similar to other TMAs, but their pathophysiology may be distinct. Damage to vascular endothelium, independent of loss of ADAMTS13 activity, is thought to be critical. Fibrin-rich microthrombi, often accompanied by C4d and C5b-9 (membrane attack complex) deposition, occur in the microvasculature of multiple organs (Clin Adv Hematol Oncol 2014;12:565-573; Transplantation. 2013;96:217-223). This supports a role for complement activation in HSCT-TMA, but the importance of the various complement activation pathways is unclear. Recently, narsoplimab (OMS721), a monoclonal antibody inhibitor of MBL-associated serine protease-2 (MASP-2), a principal component of lectin-dependent complement activation, received Breakthrough Therapy Designation for HSCT-TMA, based on improved survival compared to historical controls in a phase 2 study. A phase 3 program is ongoing. Chemotherapy in association with autologous HSCT is linked to a marked increase in serum MASP-2 levels, persisting for about 4 weeks post-transplant (Front Immunol 2018;9:2153). However, TMAs are rare in autologous transplants, and circulating levels of MASP-2 following alloHSCT, and the impact of TMA development on those levels, are unknown. Methods: All individuals >18 years of age scheduled to undergo alloHSCT for hematologic malignancy at New York Presbyterian Hospital-Cornell were approached to participate in this study (NCT02604420). 100 of the first 101 subjects, age 58.3 +14 yrs, were enrolled and followed for >1.5 years post-transplant. This interval is consistent with the median time to HSCT-TMA diagnosis in adults of 90 days (range 32-733 days). Plasma was obtained at baseline (defined as between the time of consent and beginning of conditioning regimen), and at each regularly scheduled visit post-transplant-day 28 +5 days; day 100 +28 days; day 180 +28 days; and day 365 +28 days-as well as at the time of TMA diagnosis, based on the Consensus Criteria of Cho et al. (Transplantation 2010;90:918-926). A commercial ELISA (MyBioSource) was used to assess MASP-2 concentrations. Results: 20 subjects met study criteria for a HSCT-TMA diagnosis, occurring a median of 69 days (range 33-289) post-transplant. Three resolved following discontinuation of GvHD prophylaxis (mTOR or calcineurin inhibitor) and switch to mycophenolate and increased corticosteroid doses, and 7 had an intercurrent infection, 6 of whom expired with ongoing severe TMA despite a change in GvHD prophylaxis (Figure). TMAs persisted in the remaining 10 subjects. Median MASP-2 levels were significantly elevated in all subjects post-transplant, assessed at the time of TMA development or, in those not developing a TMA, at day 100 + 28 days post-transplant vs. controls (n=36, 86.2ng/ml (23.3-210.9): persistent TMA (n=9 (one plasma unavailable), 154ng/ml (range 82-209)); alloHSCT subjects who did not experience a TMA (n=40 evaluated to date, 113.5ng/ml (56-430.3)). (Figure). Lack of a significant rise in MASP-2 levels in patients with persistent TMAs vs. those who did not develop a TMA, combined with a significant decrease in variance of MASP-2 levels in the former group (p=0.005), may reflect consumption of product at sites of disease activity, i.e., the microvasculature. Conclusions: There is a significant increase in MASP-2 levels, with a wide variance, in post-alloHSCT patients evaluated at a time post-transplant typical of HSCT-TMA development. At time of development of a HSCT-TMA that persists despite withdrawal of GvHD prophylaxis, MASP-2 levels remain elevated over controls, but with a significantly lower variance vs. those not developing TMA. A study of additional samples, including longitudinal specimens, from this cohort is underway to determine if a change in MASP-2 levels correlates with HSCT-TMA development post-alloHSCT. Disclosures Van Besien: Miltenyi Biotec: Research Funding.

Background: Patients with anaplastic or poorly differentiated recurrent thyroid carcinomas have a poor prognosis, with a median survival of < 1 year. Previously, we have shown a significant correlation between ICAM-1 overexpression and malignancy in thyroid cancer and have pioneered the use of ICAM-1 targeted CAR T cells as a novel treatment modality. For clinical translation, we designed CAR T cells possessing micromolar affinity to ICAM-1 to avoid cytotoxicity in normal cells with basal levels of ICAM-1 expression. Here, we report the automated process of CAR T cell manufacturing with CliniMACS Prodigy (Miltenyi Biotec) using cryopreserved peripheral blood leukopak cells as starting material. Methods: We have chosen to use CliniMACS Prodigy system for a closed, automated, and robust CAR T cell manufacturing process. Using a cryopreserved leukopak, TCT v2.0 protocol began with rapidly thawing the leukopak while directly welded to the Prodigy. T cell lentivirus transduction was performed 2x, 24 and 48 hr post activation. CAR T cells were released after ~10 days of culture and cryopreserved in ready-to-infuse formulation (AIC100). Products were then subject to in vitro cytotoxicity, in vivo efficacy and safety in xenografted mice with ATC cells (8505C), and PET/CT imaging using 18F-NOTA-octreotide to detect T cell dynamics. Results: Prodigy manufactured CAR T cells were subjected to qualification and functional assays (n=7): cell viability, cell number, CAR expression, virus copy number (VCN), T cell subset and phenotype, and E to T assays. Consistent with reported values for Prodigy, our manufacturing protocol produced 55±9% transduction rate, 96±1.8% viability, and 2.9±0.7x10^9 final cell number. The VCN was in the range of 1.0-2.1, below the criteria of < 5 copies per cell. In NSG mice xenografted with 8505C ATC cells and treated with CAR T cells (1X= 1 million live CAR T maximum tolerable dose (MTD)= 10 million live CAR T) or non-transduced (NT) T cells, tumor burden was quantitatively evaluated by whole body luminescence imaging. Compared to cohorts with no treatment (NoT) or NT, the cohorts of AIC100 exhibited complete or near-complete tumor elimination lasting variable times before tumor relapse was seen in some subjects. Median survival time for NoT and NT groups were similar (38.5 vs. 42 days), while it was significantly longer for AIC100 1X and MTD groups (72 vs. >100 days). Conclusions: Selective anti-tumor activity in the absence of toxicity provides proof-of-concept that micromolar affinity tuned CAR T cells can be used to target tumors expressing high levels of antigen while avoiding normal tissues expressing basal levels of the same antigen. These studies support the initiation of a phase I study to examine the safety and potential efficacy of micromolar affinity tuned CAR T cells against newly diagnosed anaplastic and refractory or recurrent thyroid cancers. Citation Format: Yogindra Vedvyas, Jaclyn E. McCloskey, Yanping Yang, Irene M. Min, Thomas J. Fahey, Yen-Michael S. Hsu, Jing-Mei Hsu, Koen V. Besien, Ian Gaudet, Ping Law, Joon Kim, Eric V. Hofe, Moonsoo M. Jin. Clinical manufacturing of CAR T cells targeting ICAM-1 for a phase I study against advanced thyroid cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2329.

2532 Background: EBV is implicated in a variety of diseases. Tab-cel is an investigational off-the-shelf, allogeneic T-cell immunotherapy utilizing endogenous T cell receptors targeting EBV antigens. We hypothesized the clinical activity of tab-cel is mediated by expansion and persistence of EBV-specific T cells. Therefore, we quantified circulating EBV- CTLp after tab-cel administration and examined the correlation between expansion and clinical response. Methods: Samples from 10 patients with EBV+ post-transplant lymphoproliferative disease (PTLD) and other EBV-associated diseases enrolled in an multicenter expanded access protocol (EAP) study ( NCT02822495 ) were analyzed. To evaluate CTLp frequencies, limited dilution analysis was performed on samples taken at baseline and day 34 post first tab-cel dose (end cycle 1). The day 34 persistence of circulating EBV-CTLp from best overall response to initial tab-cel product was tested using the two-tailed Mann-Whitney test. Changes in inflammatory cytokines were also measured. Results: Responders represented in this sampling (n=6; 2 PR and 4 CR) showed a median 5.8-fold increase in circulating CTLp between baseline and day 34 (range: 0.8 to 133-fold). Five of 6 responders showed an increase in EBV-CTLp at day 34 of ≥ 3.8-fold while 1 pt showed no change in CTLp (0.8-fold change). In contrast, the 4 non-responders (3 SD; 1 PD) showed a median 0.3-fold decrease in EBV-CTLp from baseline (range: 1.2 to 0.02-fold; ns). Cumulative analyses revealed a statistically significant correlation between the fold-change of circulating CTLp at day 34 and clinical response (p=0.038) which did not appear to correlate with the type of the EBV-associated disease. Inflammatory cytokines showed no meaningful change from baseline. The safety profile remains consistent with previously reported data. Conclusions: These data support the correlation of clinical activity of tab-cel with the expansion and persistence of EBV-specific T-cells at day 34 post-treatment, as well as the use of circulating CTLp as a biomarker for response in clinical studies. Clinical trial information: NCT02822495.

Allogeneic transplantation constitutes curative treatment for acute myeloid leukemia and myelodysplastic syndrome. Its therapeutic effects are to a large extent mediated by GVL effects, but partially offset by treatment-related mortality and loss of quality of life caused by acute and chronic GVHD. Although severe acute and chronic GVHD are associated with a reduction in relapse risk, they are not associated with improved survival. Recent efforts to modulate the GVL-GVH balance include novel methods of in vitro or in vivo T-cell depletion that are associated with a minimal impact on rates of disease recurrence and a dramatically decreased risk for GVHD. Donor selection algorithms may also have a significant impact on transplantation outcomes. Low-expression HLA alleles, particularly HLA-DP, should be incorporated in selection of adult unrelated donors. Evolving data suggest that KIR typing may also be important. High-resolution HLA typing and the importance of fetal-maternal interactions in umbilical cord blood transplantation are also briefly discussed. A combination of donor selection strategies and GVHD prophylaxis methods will favorably affect long-term outcomes and create an environment suitable for effective posttransplantation interventions.

International audience; Cyclophosphamide combined with total body irradiation (Cy/TBI) or busulfan (BuCy) are the most widely used myeloablative conditioning regimens for allotransplants. Recent data regarding their comparative effectiveness are lacking. We analyzed data from the Center for International Blood and Marrow Transplant Research for 1230 subjects receiving a first hematopoietic cell transplant from a human leukocyte antigen-matched sibling or from an unrelated donor during the years 2000 to 2006 for acute myeloid leukemia (AML) in first complete remission (CR) after conditioning with Cy/TBI or oral or intravenous (IV) BuCy. Multivariate analysis showed significantly less nonrelapse mortality (relative risk [RR] = 0.58; 95% confidence interval [CI]: 0.39-0.86; P = .007), and relapse after, but not before, 1 year posttransplant (RR = 0.23; 95% CI: 0.08-0.65; P = .006), and better leukemia-free survival (RR = 0.70; 95% CI: 0.55-0.88; P = .003) and survival (RR = 0.68; 95% CI: 0.52-0.88; P = .003) in persons receiving IV, but not oral, Bu compared with TBI. In combination with Cy, IV Bu is associated with superior outcomes compared with TBI in patients with AML in first CR.

This phase I study evaluated the maximal tolerated dose of CPX-351 when administered sequentially with allogeneic hematopoietic stem cell transplantation (HSCT) in patients with refractory acute leukemia. CPX-351 is a novel liposomal formulation that combines cytosine arabinoside (ara-c) and daunorubicin in a fixed molar ratio of 5:1. Patients in cohorts of 3 were treated with CPX-351 followed by fludarabine and busulfan (Bu/Flu) conditioning at 4-week (schedule A) or 3-week (schedule B) intervals. CPX-351 doses were escalated in 20-U/m2 increments starting at 60 U/m2 for 3 doses. Of the 36 patients enrolled, 29 were able to undergo HSCT, and the other 7 (the majority on schedule A) did not proceed to HSCT because of rapid disease progression. The maximal tolerated dose of CPX-351 was not reached at the 120 U/m2 × 3 dose level. All 29 patients who proceeded to HSCT demonstrated adequate neutrophil and platelet engraftment. The median follow-up on the study for all 36 patients was 205 days (range, 20 to 996 days). The 1-year cumulative incidence of relapse for the 36 patients was 60.1% (95% confidence interval [CI], 43.4% to 77.3%), and that of nonrelapse mortality was 23.8% (95% CI, 10.9% to 47.4%). The 1-year overall survival and leukemia-free survival were 37% (95% CI, 21% to 53%) and 27% (95% CI, 13% to 43%), respectively. Our data suggest that a phase II trial should incorporate CPX-351 120 U/m2 × 3 dosing on schedule B. Patients with good performance status and those who achieve effective cytoreduction from CPX-351 derived the greatest benefit.

Bendamustine has efficacy in multiple myeloma with a toxicity profile limited to myelosuppression. We hypothesized that adding bendamustine to autologous stem cell transplant conditioning in myeloma would enhance response without significant additional toxicity. We conducted a phase 1 trial adding escalating doses of bendamustine to the current standard conditioning of melphalan 200 mg/m2. Twenty-five subjects were enrolled into 6 cohorts. A maximum tolerated dose was not encountered and the highest dose level cohort of bendamustine 225 mg/m2 + melphalan 200 mg/m2 was expanded to further evaluate safety. Overall, there was no transplant related mortality and only one grade 4 dose-limiting toxicity was observed. Median number of days to neutrophil and platelet engraftment were 11 (range, 9 to 14) and 13 (range, 10 to 21), respectively. Disease responses at day +100 posttransplantation were progression in 5 (21%), partial response in 1 (4%), very good partial response in 7 (33%), complete response in 1 (4%), and stringent complete response in 9 (38%). Six patients (24%) with pre-existing high-risk disease died from progressive myeloma during study follow-up, all at or beyond 100 days after autologous stem cell transplant. Bendamustine up to a dose of 225 mg/m2 added to autologous stem cell transplantation conditioning with high-dose melphalan in patients with multiple myeloma did not exacerbate expected toxicities.

Autologous stem cell transplantation (ASCT) conditioned with high-dose chemotherapy has long been established as the standard of care for eligible patients with newly diagnosed multiple myeloma. Despite recent therapeutic advances, high-dose melphalan (HDM) remains the chemotherapy regimen of choice in this setting. Lenalidomide (LEN) in combination with low-dose dexamethasone is recognized as a standard of care for patients with relapsed or refractory multiple myeloma (RRMM), and there is growing support for the administration of LEN as maintenance therapy post-ASCT. In view of the above, the present phase I clinical trial was designed to evaluate the safety and tolerability of high-dose LEN (HDLEN) in patients with RRMM, and to determine the maximum tolerated dose of HDLEN when added to HDM before ASCT. Despite administering HDLEN at doses of up to 350 mg/day, the maximum tolerated dose could not be determined, owing to an insufficient number of dose-limiting toxicities in the 21 patients enrolled in the trial. Conditioning with HDLEN plus HDM was associated with a favorable tolerability profile. Adverse events following ASCT were as expected with HDM. Median progression-free and overall survival were 10 months and 22 months, respectively, in this population of heavily pretreated patients. Our findings suggest that HDLEN in combination with HDM may offer significant potential as a conditioning regimen before ASCT in patients with RRMM. These preliminary findings are now being evaluated further in an ongoing phase II clinical trial.

BACKGROUND: The management of relapsed aggressive lymphomas remains problematic. Ixabepilone (BMS-247550, epothilone B analog), a potent inhibitor of tubulin disassembly, has promising preclinical and early-phase clinical activity in drug-resistant malignancies. METHODS: This multicenter phase 2 clinical trial tested the activity and safety of ixabepilone in relapsed/refractory aggressive lymphoma patients with either chemosensitive (at least a partial response [PR] to most recent chemotherapy) or chemoresistant (less than PR to most recent chemotherapy) disease at 20 mg/m2 given intravenously weekly on days 1, 8, and 15 of a 28-day cycle. RESULTS: Fifty-one enrolled patients with a median age of 66 years received at least 1 dose of ixabepilone. Diffuse large B-cell lymphoma (n = 25; 49%), mantle cell lymphoma (n = 16; 31%), and transformed follicular lymphoma (n = 5; 10%) were the most frequent histologies. Patients were heavily pretreated, with more than one-quarter having received 4 or more prior therapies. The overall response rate was 27% (14 of 51 patients) with 12% (6 patients) experiencing complete responses and 16% (8 patients) with PRs. All responses were in patients with chemosensitive disease. The median time to response was 2 cycles with a median duration of response of 9.7 months. CONCLUSIONS: Ixabepilone was well-tolerated, with neutropenia, peripheral sensory neuropathy, fatigue, and nausea as the major toxicities. Ixabepilone has modest single-agent activity in patients with recurrent chemosensitive aggressive lymphomas. Cancer 2013. © 2013 American Cancer Society.

Analysis of the clinical characteristics of hematopoietic stem cell transplant (HSCT) donors has proven beneficial for identifying cases of heritable hematopoietic disorders. This study examines poor peripheral blood hematopoietic stem cell mobilization after granulocyte colony-stimulating factor administration among 328 donors as a potential marker for suspected familial predisposition to myeloid malignancies. Here, we present data comparing the clinical characteristics of poor-mobilizing versus nonpoor-mobilizing donors and the results of panel-based sequencing of hematopoietic genes in poor-mobilizing donors. From this analysis, we identified a novel case of a donor-derived myelodysplastic syndrome in an HSCT recipient that is consistent with clonal evolution of TET2-mutated clonal hematopoiesis of indeterminate potential (CHIP) within the donor. This study demonstrates the potential risk of using hematopoietic stem cells from a donor with CHIP and raises the question of whether there should be increased screening measures to identify such donors.

Advanced systemic mastocytosis (advanced SM), a rare disease closely associated with KIT mutations (most commonly KIT D816V), encompasses three variants: systemic mastocytosis (SM) with an associated hematologic clonal non-mast cell disorder, aggressive SM, and mast cell leukemia. All variants are associated with shortened survival. Although interferon-alpha or cladribine exhibit efficacy in selected patients, they do not result in cure. Imatinib is approved for the minority of aggressive SM patients with negative or unknown KIT D816V status. The multikinase/KIT inhibitor midostaurin is a promising agent for patients with advanced SM and is currently available on an investigational basis. We recently reported the largest retrospective study of allogeneic hematopoietic stem cell transplantation (alloHSCT) in patients with advanced SM (n=57). The evidence from this study and a few case reports indicate that it can cure some patients and lead to long-term survival. However, there is still a significant gap of knowledge regarding the use of this high-intensity therapy in advanced SM. The present paper provides a consensus opinion on methods to optimize decision-making regarding the use of alloHCT in this patient population in light of currently available data. In addition, we outline strategies that combine midostaurin in the peritransplant setting. Such protocols should generate useful outcome data regarding the safety and efficacy of KIT inhibition in conjunction with high-intensity therapy in the treatment of advanced SM.

The development of posttransplant lymphoproliferative disorder (PTLD) following solid organ transplantation (SOT) is a feared complication of chronic immunosuppressive therapy.[1] The overall incid...

Haplo-cord stem cell transplantation combines the infusion of CD34 selected hematopoietic progenitors from a haplo-identical donor with an umbilical cord blood (UCB) graft from an unrelated donor and allows faster count recovery, with low rates of disease recurrence and chronic graft-versus-host disease (GVHD). But the contribution of the umbilical cord blood graft to long-term transplant outcome remains unclear. We analyzed 39 recipients of haplo-cord transplants with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), engrafted and in remission at 2 months. Median age was 66 (18-72) and all had intermediate, high, or very-high risk disease. Less than 20% UCB chimerism in the CD33 lineage was associated with an increased rate of disease recurrence (54% versus 11% p

Haploidentical (haplo)-cord transplantation combines infusion of an umbilical cord blood (UCB) unit with CD34-selected cells usually from human leukocyte antigen (HLA) mismatched donors. Initial rapid count recovery from the haplo-hematopoietic progenitors, is gradually replaced by durable engraftment from UCB progenitors. UCB grafts used for haplo-cord are smaller, but better matched than those required for single or double UCB stem cell transplant (SCT). More than 200 patients with hematological malignancies have been transplanted. Median age was 54 years (range 17–74) and 77 were over age 60. One-year survival was 64% for patients with intermediate- and low-risk disease, with no deaths beyond 2 years. In high-risk disease, 1-year survival was 44%. In a comparison with patients undergoing double UCB SCT, haplo-cord transplant resulted in faster hematopoietic recovery, lower rates of acute and chronic graft-versus-host disease (GVHD), lower rates of disease recurrence, and improved GVHD- and relapse-free survival (GRFS). Excellent results were also reported for patients with aplastic anemia where 18 of 21 patients had sustained cord blood engraftment. Rates of GVHD and of disease recurrence after haplo-cord are encouraging. However, in the approximately 10% of patients with failure of the UCB graft disease recurrence is high, supporting the important role of UCB-mediated graft-versus-leukemia (GVL). Ongoing efforts are aimed at identifying determinants of UCB engraftment, at reducing rates of disease recurrence in high risk patients and at optimizing dose and schedule of ATG -necessary to avoid early haplo-graft rejection, but also contributing to early post-transplant immunocompromise. For those lacking haploidentical donors, unrelated donors have been successfully utilized.

After a cluster of fatal toxoplasmosis among stem cell transplant recipients at 2 hospitals, surveillance with polymerase chain reaction (PCR) (blood) was instituted. Rate of reactivation among seropositive recipients was 2.2 and 16%. Parasitemia was successfully managed with preemptive treatment. For seropositive recipients unable to take prophylaxis, toxoplasma PCR surveillance should be routinely performed.

Background The aim of this study is to describe the clinical manifestations, molecular mechanisms, and treatment outcomes of patients with echinocandin-resistant Candida tropicalis (C. tropicalis) bloodstream infections (BSI). Methods A PubMed search was conducted using the search terms related to C. tropicalis BSI and echinocandin resistance. Two previously unreported cases from our institution diagnosed with C. tropicalisBSI that developed resistance to echinocandins were also included. Demographics, comorbidities, treatment, clinical outcomes, and molecular mechanisms were analyzed. Results Seven patients with echinocandin-resistant C. tropicalis BSI were identified, including 5 previously reported cases and two from our institution. Median age was 58.7 ± 20.4 years; 3 (43%) patients were males. Three (43%) had acute myelogenous leukemia, 3 (43%) had acute lymphoblastic leukemia, and 1 (14%) had urothelial cancer. All patients were immunocompromised having received chemotherapy in the last six months and 3 (43%) were hematopoietic stem cell transplant recipients. Five (71%) had breakthrough of echinocandin resistance while receiving an echinocandin; one (14%) received caspofungin in the past 3 months and only one (14%) had no reported echinocandin exposure in the past 3 months. DNA sequencing of the FKS1 gene for mutations known to confer echinocandin resistance was performed in 4 cases, including our two index cases. Homozygous T-to-C mutations in two alleles of FKS1gene was detected in 2 cases, and a heterozygous mutation was detected in the other 2 cases, which resulted in a deduced serine-to-proline amino acid change at position 654 (S654P). Six patients (86%) survived after being treated with an antifungal agent other than an echinocandin. Treatment was changed to liposomal amphotericin B in two cases, and one each to voriconazole, fluconazole, voriconazole plus liposomal amphotericin B, and caspofungin plus voriconazole. The one patient who died received intravenous voriconazole. Conclusion Echinocandin resistance emerged in neutropenic patients with C. tropicalis fungemia through a characteristic mutational hot-spot amino acid change in the target FKS1 gene. Although alternative antifungal agents may be successfully used as salvage therapy, the outcome may still be fatal. Disclosures D. Perlin, Pfizer: Research support, honoraria and/or consulting fees and/or has served on advisory board, Research support, honoraria and/or consulting fees and/or has served on advisory board. Astrellas: Research support, honoraria and/or consulting fees and/or has served on advisory board, Research support, honoraria and/or consulting fees and/or has served on advisory board. Merck: Research support, honoraria and/or consulting fees and/or has served on advisory board, Research support, honoraria and/or consulting fees and/or has served on advisory board. Cidara: Research support, honoraria and/or consulting fees and/or has served on advisory board, Research support, honoraria and/or consulting fees and/or has served on advisory board. Synexis: Research support, honoraria and/or consulting fees and/or has served on advisory board, Research support, honoraria and/or consulting fees and/or has served on advisory board. F2G: Research support, honoraria and/or consulting fees and/or has served on advisory board, Research support, honoraria and/or consulting fees and/or has served on advisory board. Myconostica: Research support, honoraria and/or consulting fees and/or has served on advisory board, Research support, honoraria and/or consulting fees and/or has served on advisory board. Amplyx: Research support, honoraria and/or consulting fees and/or has served on advisory board, Research support, honoraria and/or consulting fees and/or has served on advisory board. Matinas: Research support, honoraria and/or consulting fees and/or has served on advisory board, Research support, honoraria and/or consulting fees and/or has served on advisory board. GAFFI: Scientific Advisor, Advisor. Bill and Melinda Gates Foundation: Scientific Advisor, Advisor

In a prior multicenter randomized controlled trial, we found that a 12-week course of extracorporeal photopheresis (ECP) plus standard immunosuppressive therapy resulted in several beneficial outcomes in patients with corticosteroid-refractory/intolerant/dependent chronic graft-versus-host disease (GVHD). Here, we report the results of an open-label crossover ECP study in 29 eligible participants randomized initially to the standard of care non-ECP (control) arm. Eligible for the crossover ECP study were control arm patients who either (1) had progression of cutaneous chronic GVHD (cGVHD), defined as >25% worsening from baseline as measured by the percent change in the total skin score (TSS) at any time, or (2) had less than 15% improvement in the TSS, or had a ≤25% reduction in corticosteroid dose at week 12 of the initial study. ECP was administered 3 times during week 1, then twice weekly until week 12, followed by 2 treatments monthly until week 24. The median age of the study cohort was 43 (20-67) years and 90% had extensive cGVHD. The median months from onset of cGVHD to start of ECP were 26 (range: 4-79). Twenty-five of 29 patients (86%) completed the 24-week course of ECP. Complete or partial skin response at week 24 was noted in 9 patients (31%). The median percent of decrease in TSS from baseline to weeks 12 and 24 was −7.9 and −25.8, respectively. In 4 (17%) and 8 (33%) patients, a ≥50% reduction in corticosteroid dose at weeks 12 and 24 was observed. Extracutaneous cGVHD response was highest in oral mucosa with 70% complete and partial resolution after week 24. In conclusion, progressive improvement in cutaneous and extracutaneous cGVHD was observed after a 24-week course of ECP in patients who previously had no clinical improvement or exhibited worsening of cGVHD while receiving standard immunosuppressive therapy alone in a randomized study. These results confirm previous findings and support the notion that prolonged ECP appears to be necessary for optimal therapeutic effects in corticosteroid-refractory cGVHD patients.

Purpose of review To provide a succinct update on the role of allogeneic stem cell transplantation (allo-SCT) in the management of patients with aggressive lymphomas. To clarify the indications for allogeneic transplantation vis-a-vis autologous transplant and to discuss the rationale and potential benefits of reduced intensity conditioning (RIC), nonmyeloablative (NMA) transplant, T-cell depletion and variations in graft vs. host disease (GVHD) prophylaxis. Recent findings Considerable effort has been spent in developing transplant regimens with reduced toxicity and reduced GVHD. The role of allogeneic transplantation has also been redefined in light of advances in lymphoma classification, diagnostic methods, particularly PET scan and advances in transplant technology. Haplo and umbilical cord blood SCT allow identification of a donor for nearly all patients. Summary In diffuse large B-cell lymphoma, the outcome of allo-SCT depends on patient characteristics and chemosensitivity. It is useful after failure of auto-SCT and in partial responses to salvage therapy. Allo-SCT may be the treatment of choice for advanced T-cell and natural killer cell lymphoma and for adult T-cell leukemia-lymphoma. Prophylactic or preemptive donor lymphocyte infusion may be useful, but requires controlled studies. RIC and NMA conditioning have reduced early toxicity but are associated with increased risk for disease recurrence. Promising data have been reported from a novel conditioning regimen combining NMA with ibritumomab tiuxetan. T-cell depletion reduces chronic GVHD but has some increase in rate of recurrence. Rapamycin may be associated with reduction in risk for disease recurrence.

In the pre-tyrosine kinase (TKI) era, allogeneic stem cell transplant (allo-SCT) was the front-line treatment of choice for young patients with chronic myelogenous leukemia (CML). Today, imatinib is well established as front-line therapy for CML, with excellent long-term outcomes. This has changed the role of allo-SCT and the number of patients undergoing allo-SCT has declined dramatically. Allo-SCT is currently recommended for patients in accelerated/blast phase disease, those who have failed a second-generation TKI and those with TKI-resistant mutations such as T315I. The role of allo-SCT in the management of CML will require continual reappraisal as medical therapies continue to evolve.

Myasthenia gravis (MG) is an autoimmune disease mediated by antibodies to acetylcholine receptors (AChRs) or muscle specific tyrosine kinase (MuSK). While the frequent association of MG with thymoma in patients aged 40-60 years is well recognized, its occurrence in patients with lymphoma has not been well studied. We review the literature on the association of MG and lymphoid malignancies and report two new patients. MG can occur in a synchronous or non-synchronous fashion with lymphoma. The pathogenesis of MG in lymphoid malignancies is probably heterogeneous and likely relates to perturbations in the immune mechanisms that normally prevent the emergence of autoimmunity. These perturbations could be the result of the lymphoid malignancy per se, or its treatment.

Allogeneic transplantation is established as a curative treatment for follicular lymphoma, but with considerable short and long-term morbidity and mortality. Data and controversies regarding conditioning regimen, donor source, GVHD prophylaxis, post transplant interventions and approaches to predict and reduce morbidity and mortality are reviewed. Total body irradiation is very effective but toxic and reduced intensity conditioning is often preferred though associated with somewhat higher rates of recurrence. The risk of chronic GVHD and its late sequelae can be markedly reduced by in-vivo T-cell depletion using alemtuzumab but also leads to somewhat higher incidence of disease recurrence. When using such treatment strategies, one can consider prophylactic or preemptive donor lymphocyte infusions or low toxicity medical treatment such as rituximab. Overall the long term outcomes, particularly survival and current progression free survival of patients undergoing allogeneic transplantation for indolent lymphoma have steadily improved and transplant can now often safely be considered up to the sixth decade of life. Outcomes of unrelated donor transplantation approach those of HLA-identical sibling transplant and even mismatched umbilical cord transplant can be considered in selected patients. The assessment of risks and benefits is aided by the use of various novel tools.

Lymphoma comprises two groups of diseases: Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). Within both subsets are numerous variations with distinct biologic, molecular, and cytogenetic characteristics. The World Health Organization (WHO) classification of NHL, for example, now identifies several dozen broad entities and nearly 60 unique clinicopathologic subtypes. In addition to pathologic heterogeneity, there is clinical diversity within lymphomas, with some patients achieving cure, others having prolonged disease stabilization, and still others experiencing a rapidly fulminant decline and death. It is increasingly appreciated that both clinical and biological features strongly influence outcome. Practical implementation of a personalized approach to treatment is urgently needed, but efforts thus far have focused primarily on prognostication, with much less emphasis on determining therapeutic options. Nevertheless, better prognostic tools will facilitate the design of "risk-stratified" trials that will ultimately benefit patients. Thus far, the development of personalized treatment in lymphomas clusters into several broad approaches: refinement of clinical prognostic models for better risk stratification, use of high-throughput technology to identify biologic subtypes within pathologically similar diseases, "response-adapted" changes in therapy via imaging with [(18)F]fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET), and anti-idiotype vaccines. An important unmet need is the implementation of these tools into treatment choices for individual patients, and this is the focus of intense ongoing research.

Although autologous stem cell transplantation (ASCT) is effective for patients with multiple myeloma (MM), disease relapse remains problematic. Despite significant advances in therapeutics for MM, it remains mostly incurable. Following ASCT, a majority of MM patients are in a minimal residual disease state, at which time delivery of immunotherapy may be most effective. Regulatory T cells (Tregs) are a naturally-suppressive CD4+ T cell population (CD4+CD25+FoxP3+ T cells) that expand in MM patients, and strongly inhibit anti-tumor immune responses. In pre-clinical models Treg depletion enhanced the function of tumor antigen-specific T cells. Effective strategies to deplete Tregs in humans are being investigated. We initiated pilot study to test 2 methods of Treg depletion in MM patients undergoing ASCT. In the first approach, an anti-CD25 monoclonal antibody (basiliximab) was administered day +1 following ASCT (in vivo Treg depletion). The second method involved depleting CD4+CD25+ Tregs from autologous stem cell (ASC) grafts with clinical-grade anti-CD25 microbeads and the CliniMACS device (Miltenyi) (ex vivo Treg depletion). A control arm consisted of patients in which no Treg-depleting maneuver was performed. To date, 10 patients with symptomatic MM have been enrolled and randomly assigned to 1 of 3 study arms (arm 1 – standard ASCT; arm 2 – in vivo Treg depletion; arm 3 – ex vivo Treg depletion). Primary endpoints included: a) efficacy of ex vivo Treg depletion from ASC grafts, b) kinetics of Treg depletion and recovery in each study arm, and c) assessment of toxicity associated with Treg depletion. Secondary endpoints included time to engraftment following ASCT and disease response. The overall goal of the study was to identify a superior strategy with regard to depth and durability of Treg depletion. Ten patients (median age 59; range 46-68) have been enrolled. 4 were enrolled onto arm 1, 3 onto arm 2 and 3 onto arm 3. One patient enrolled on arm 2 was removed from study due to ASC mobilization failure. ASC were collected following neupogen and plexifor, and conditioning for ASCT consisted of melphalan (200mg/m2). Typical serious adverse events associated with ASCT were observed in all study arms, with neutropenic fever being the most common (n=2 arm 1, n=1 arm 2 and n=2 arm 3). Autoimmune complications, such as autologous graft-versus-host disease, were not observed. All patients engrafted post-ASCT with normal kinetics. Too few patients have been treated to make conclusions regarding clinical efficacy. Depletion of CD4+CD25+ Tregs from ASC grafts in arm 3 (ex vivo Treg depletion) was effective. As shown in Figure 1, 90.1% +/- 6% of CD4+25+ Tregs were depleted from 3 ASC grafts following the procedure. Baseline frequencies of peripheral blood (PB) CD4+FoxP3+ Tregs were similar between patients in all arms (p = n.s.). At least a 2-fold reduction in PB Treg frequency was observed at days +28 and + 60 following ASCT (Figure 2). At day +28, mean numbers (+/- SD) of CD4+FoxP3+ PB Tregs were 8.58% +/- 4.52%, 2.48% +/- 1.77%, and 3.28% +/- 1.12% in arms 1, 2 and 3, respectively (p = 0.08 arm 1 vs arm 2; p = 0.05 arm 1 vs arm 3; p = .57 arm 2 vs arm 3). These data suggest that both the in vivo and ex vivo Treg depletion may be effective at mediating effective and durable Treg depletion.Figure 1Treg are effectively depleted ex vivo with CD25 microbeads and the Clinimacs device. A FACS plots showing frequency of CD4 +CD25 + Tregs before (left) and after (right) ex vivo Treg depletion procedure (arm 3). B Mean CD4+CD25+ Treg frequencies before and after ex vivo Treg depletion (*p= 0.05).Figure 1. Treg are effectively depleted ex vivo with CD25 microbeads and the Clinimacs device. A FACS plots showing frequency of CD4 +CD25 + Tregs before (left) and after (right) ex vivo Treg depletion procedure (arm 3). B Mean CD4+CD25+ Treg frequencies before and after ex vivo Treg depletion (*p= 0.05).Figure 2Kinetics of Treg depletion following ASCT. Mean (+/- SD) frequency of CD4+FoxP3+ Tregs before and after ASCT in each study arm are displayed.Figure 2. Kinetics of Treg depletion following ASCT. Mean (+/- SD) frequency of CD4+FoxP3+ Tregs before and after ASCT in each study arm are displayed. In conclusion, both the in vivo or ex vivo method of Treg depletion appear to be effective based on small patient numbers. Treg depletion in MM patients undergoing ASCT is safe and does not delay engraftment. Additional patients will need to be treated to make conclusions regarding clinical efficacy. Future studies of Treg depletion in combination with other immunotherapeutic strategies are being considered. Disclosures: No relevant conflicts of interest to declare.

Introduction: Mutations at diagnosis in acute myeloid leukemia (AML) patients have prognostic implications. For AML patients undergoing allogeneic stem cell transplant (SCT), the prognostic impact of molecular mutations pre-transplant and immediately post-transplant are less well characterized. Here we examine the mutation status of AML patients at different time points in relation to allogeneic SCT and their implications in relapse and survival. Methods: AML patients who underwent allogeneic SCT after achieving complete remission with available molecular mutation testing at diagnosis, prior to transplant (within 4 weeks), and 28 days post-transplant were included in the analysis. Multivariable cox regression analysis was adjusted for age, gender, CIBMTR disease risk index (DRI), type of transplant, and genetic mutation. Backward selection method was used to select the best combination of genes that is associated with OS and relapse-free survival (RFS). Results: A total of 110 AML patients with molecular genetic data available from 2014 to2018 at Weill Cornell Medicine were included in the analysis. Clinical characteristics of the patients are summarized in Table 1. The median age was 58 years (20-77). Twenty-three molecular mutations analyzed at baseline, pre-transplant, and at 28 days are listed in Table 2. With a median follow-up time of 31.6 month, the median overall survival for the cohort was 37.1 months. Eighty-one patients had molecular testing at diagnosis. The presence of mutations in TP53 at diagnosis was associated with worse OS by both univariate (HR 3.67, p=0.0030, CI 1.56-8.68) and multivariate analysis (HR 4.75, p=0.0014, CI 1.82-12.39) with median OS reduced from 49.3 to 19.3 months (p=0.002). High CIBMTR DRI (HR 0.17, p=0.0018, CI 0.05-0.51) predicted reduced RFS, but not OS on multivariate analysis. Seventy-seven patients had molecular testing prior to transplant and 27 patients had persistent mutations (Table 2). The presence of mutations in ETV6 and FLT3-ITD were independently associated with worse RFS ((HR 49.7, p=0.001, CI 5.0-528) & (HR 36.4, p At 28 days post-transplant, only 9 of the 84 patients had persistent mutations. Persistence of FLT3-ITD conferred worse RFS and OS in both univariate ((HR 11.92, p=0.0218, CI 1.43-98.98) & (HR 25.16, p=0.0052, CI 2.62, 241.92)) and multivariate ((HR 18.13, p=0.0089, CI 2.07-158.86) & (HR 35.47, p=0.0028, CI 3.41-368.81)) analysis. Conclusions: Persistent presence of mutations in ETV6 and FLT3-ITD prior to stem cell transplant were associated with shorter RFS and OS independent of CIBMTR DRI. Persistent mutations in NRAS and CBL prior to stem cell transplant were associated with poor RFS and OS respectively. This analysis further supports association of adverse outcomes in AML patients with selected persistent mutations prior to stem cell transplant. Utility of serial mutation testing prior to transplant should be further investigated in prospective studies. Disclosures Lee: AstraZeneca: Consultancy; Clinipace: Consultancy; Karyopharm Therapeutics Inc: Consultancy; LAM Therapeutics: Research Funding; Amgen: Consultancy. Ritchie:NS Pharma: Research Funding; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; ARIAD Pharmaceuticals: Speakers Bureau; Astellas Pharma: Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer: Consultancy, Research Funding; Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau. Desai:Argenx: Consultancy; Cellerant Inc: Consultancy. Roboz:Eisai: Consultancy; Pfizer: Consultancy; AbbVie: Consultancy; Roche/Genentech: Consultancy; Aphivena Therapeutics: Consultancy; Eisai: Consultancy; AbbVie: Consultancy; Daiichi Sankyo: Consultancy; Argenx: Consultancy; Novartis: Consultancy; Janssen Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy; Orsenix: Consultancy; Celgene Corporation: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Cellectis: Research Funding; Celltrion: Consultancy; Celgene Corporation: Consultancy; Celltrion: Consultancy; Argenx: Consultancy; Astex Pharmaceuticals: Consultancy; Bayer: Consultancy; Cellectis: Research Funding; Sandoz: Consultancy; Astex Pharmaceuticals: Consultancy; Janssen Pharmaceuticals: Consultancy; Sandoz: Consultancy; Orsenix: Consultancy; Otsuka: Consultancy; Jazz Pharmaceuticals: Consultancy; Roche/Genentech: Consultancy; Otsuka: Consultancy; Bayer: Consultancy; Aphivena Therapeutics: Consultancy; Pfizer: Consultancy.

Background: Allogeneic stem cell transplant remains the only curative modality for myelodysplastic syndrome (MDS), yet there is significant controversy and individual practice variation in offering pre-transplant therapy with the goal of reducing disease burden and/or improving marrow function. In this study, we analyze the impact of bone marrow response prior to transplant on the post-transplant overall survival and relapse. Methods: We collected data from 2007 to 2018 from patients undergoing allogeneic transplant for MDS at Weill Cornell Medicine. Patients with MDS transformed to AML were excluded. P values for survival analyses were derived from Cox models. All statistical tests were 2 sided with 0.05 alpha levels. Results: We analyzed 85 patients who underwent an allogeneic stem cell transplant for MDS and had all pertinent data available. Response to pre-transplant treatment was not a pre-requisite for proceeding to transplant. The donor source was MUD, MRD and cord blood in 40%, 37.65%, and 22.35% of patients, respectively. Median age at the time of transplant was 61 years (32.94% females). IPSS-R at diagnosis was low, intermediate, high and very high-risk in 12.94 %, 31.76 %, 24.71% and 30.59% of patients, respectively. Most (80%) patients were treated with hypomethylating agents (HMA) prior to transplant. Within 2 months of transplant, 27.06% of patients achieved CR, with 8% cytogenetic response. Hematological improvement (HI) only (without marrow CR), marrow CR and stable disease/no response were seen in 9.41%, 18.83% and 42.35% of patients, respectively. Bone marrow blasts were 0-5%, 5-10% and 11-19% in 77.5%, 18.75% and 3.75% of patients pre-transplant, respectively. Median overall survival after transplant was 28.6 months (range 14.9-48.5). 90-day transplant related mortality was 10.7 %. One-year survival after transplant was 65.7%; with a relapse rate of 30.6% at median follow up of 12 months. The incidence of grade 3 and 4 GVH of any kind was 33.33%. Using univariate models, age at transplant (HR 1.049, 95% C.I. 1.017-1.083, p value 0.002) and a high IPSS-R (p value.004) at diagnosis were associated with inferior post-transplant survival, while gender and use of HMA prior to transplant did not impact post-transplant survival. In multivariate cox regression analyses adjusting for other confounding variables, achieving a CR or HI was significantly associated with higher post-transplant survival, compared to stable disease/no response prior to transplant (HR 0.46, 95% C.I. 0.23-0.90, p value 0.02). Achievement of a marrow CR resulted in a trend toward higher post-transplant OS (HR 0.45, 95% C.I. 0.18-1.09, p value 0.07). Pre- transplant blast percentage (10%) or cytogenetic response only (without CR) did not impact survival outside the presence of a CR. In the multivariate models IPSS-R very high risk at baseline (HR 4.75, 95% C.I. 1.81-12.43, p value 0.001) was associated with reduced post-transplant OS compared to low risk. There was no association between the types of marrow response on RFS post-transplant. Of note, among 34 patients with baseline mutations in ASXL1, ETV6, EZH2, RUNX1 and TP53, mutation clearance at the time of transplant was observed in only 6/34 (17.6%) patients. The presence of a mutation in any of these 5 genes prior to transplant did not impact RFS (HR 1.12, 95% C.I. 0.38-3.26, p value 0.04) or OS (HR 3.09, 95% C.I. 0.86-11.11, p value 0.08). However, we were not able to assess the effect of individual mutations (e.g. TP53) due to small numbers. We did not see an effect of GVHD type (acute or chronic) or grade on RFS or OS. Conclusions: Achievement of CR or hematological improvement (HI) prior to allogeneic transplant was associated with superior survival post-transplant, while marrow CR and cytogenetic response did not impact post-transplant survival any different than going into allogeneic transplant with stable disease/no response. IPSS R score at diagnosis was associated with inferior post-transplant survival. The presence of mutations in ASXL1, ETV6, EZH2, RUNX1 or TP53 genes prior to transplant did not appear to impact OS or RFS post-transplant, but the total numbers were small. Although CR or HI after pre-transplant treatment improved OS post-transplant, only one third of patients achieved these responses prior to transplant. Better MDS directed treatments and conditioning regimens are needed to improve outcomes after allogeneic transplantation. Figure. Figure. Disclosures Desai: Cellerant Inc: Consultancy; Argenx: Consultancy. Lee:LAM Therapeutics: Research Funding; AstraZeneca: Consultancy; Karyopharm Therapeutics Inc: Consultancy; Amgen: Consultancy; Clinipace: Consultancy. Ritchie:Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Astellas Pharma: Research Funding; Pfizer: Consultancy, Research Funding; Incyte: Consultancy, Speakers Bureau; NS Pharma: Research Funding; ARIAD Pharmaceuticals: Speakers Bureau; Bristol-Myers Squibb: Research Funding; Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau. Roboz:Orsenix: Consultancy; AbbVie: Consultancy; Sandoz: Consultancy; Roche/Genentech: Consultancy; Celltrion: Consultancy; Aphivena Therapeutics: Consultancy; Otsuka: Consultancy; Bayer: Consultancy; Celltrion: Consultancy; Argenx: Consultancy; Sandoz: Consultancy; Argenx: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; Eisai: Consultancy; Cellectis: Research Funding; Cellectis: Research Funding; Janssen Pharmaceuticals: Consultancy; AbbVie: Consultancy; Eisai: Consultancy; Novartis: Consultancy; Bayer: Consultancy; Astex Pharmaceuticals: Consultancy; Aphivena Therapeutics: Consultancy; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; Celgene Corporation: Consultancy; Roche/Genentech: Consultancy; Otsuka: Consultancy; Jazz Pharmaceuticals: Consultancy; Astex Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; Janssen Pharmaceuticals: Consultancy; Orsenix: Consultancy; Jazz Pharmaceuticals: Consultancy.

BACKGROUND JULIET (NCT02445248) is a single-arm, open-label, multicenter, global, pivotal phase 2 trial of tisagenlecleucel, a chimeric antigen receptor (CAR)-T cell therapy targeting CD19, that has shown a high rate of durable complete responses (CR) and a manageable safety profile in adult patients with clinically active relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL). The primary objective was met at the interim analysis, with an overall response rate (ORR) of 59% (CR, 43%; partial response [PR], 16%). Here, we present an updated analysis of the JULIET trial, with a median of 19 months of follow-up, an additional 5 months since the previous report (Schuster et al. EHA 2018), demonstrating sustained activity in this patient population. METHODS Eligible patients were ≥18 years with r/r DLBCL, had received ≥2 lines of therapy, including rituximab and an anthracycline, and were ineligible for or had failed autologous stem cell transplant (ASCT). Tisagenlecleucel was centrally manufactured at 2 facilities (Morris Plains, NJ, USA [main cohort] and Leipzig, Germany [cohort A]) using cryopreserved apheresis material and provided to patients at 27 treatment sites across 10 countries on 4 continents using a global supply chain. The primary endpoint was ORR (CR + PR) per independent review committee. Efficacy results are reported for patients in the main cohort with ≥3 months of follow-up or earlier discontinuation; safety is reported for all infused patients. RESULTS At data cutoff (May 21, 2018), 167 patients were enrolled and 115 were infused (99 in the main cohort and 16 in cohort A) with a single dose of tisagenlecleucel (median, 3.0×108 [range, 0.1-6.0×108] CAR-positive viable T cells). 90% of infused patients received bridging therapy and 93% received lymphodepleting chemotherapy. Median time from infusion to data cutoff was 19.3 months. Median age was 56 years (range, 22-76 years); 23% were aged ≥65 years. At study entry, 77% of infused patients had stage III/IV disease and 17% had double/triple hit disease. 55% and 43% had germinal center and activated B-cell molecular subtypes, respectively. 51% of patients had received ≥3 prior lines of antineoplastic therapy (range, 1-6); 49% had undergone a prior ASCT. All 99 patients in the main cohort had ≥3 months of follow-up or discontinued earlier and were evaluable for efficacy. ORR was 54% (95% CI, 43%-64%), with 40% CR and 13% PR. ORR was consistent across prognostic subgroups (including prior ASCT and double/triple-hit lymphoma). Median duration of response (DOR) was not reached; the probability of being relapse free was 66% (95% CI, 51%-78%) at 6 months and 64% (95% CI, 48%-76%) at 12 and 18 months. DOR was similar by age group (≥ vs < 65 years) and by relapsed or refractory status (Figure). No relapses were observed beyond 11 months after infusion. Median OS for all infused patients was 11.1 months (95% CI, 6.6 months-NE) and not reached (95% CI, 21 months-NE) for patients in CR. OS probability was 48% (95% CI, 38%-57%) at 12 months and 43% (95%CI, 33%-53%) at 18 months (max follow-up, 29 months). No patients proceeded to allogeneic SCT or ASCT while in remission. Grade 3 or 4 adverse events (AEs) of special interest within 8 weeks of infusion included cytopenias lasting >28 days (34%), cytokine release syndrome (CRS; 23%, by the Penn scale), infections (19%), febrile neutropenia (15%), neurological events (11%; 1 case of grade 2 cerebral edema), and tumor lysis syndrome (2%). 16% of patients received tocilizumab for CRS management. 3 patients died within 30 days of infusion (all due to disease progression). No treatment-related mortality was reported. Since the previous report, no new deaths occurred due to causes other than disease progression. CONCLUSION Results from this longer-term follow-up show that tisagenlecleucel produced high response rates and durable responses in a cohort of heavily pretreated adult patients with r/r DLBCL. Efficacy was consistent in all predefined subgroups, including elderly patients, patients with r/r disease, and other clinical or biological subgroups expected to have a worse prognosis with available treatments, as demonstrated by similar and sustained DOR and OS following tisagenlecleucel treatment. Figure. Figure. Disclosures Schuster: Genentech: Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dava Oncology: Consultancy, Honoraria. Bishop:Juneau Therapeutics: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; United Healthcare: Employment; Novartis Pharmaceuticals Corporation: Speakers Bureau. Tam:AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Beigene: Honoraria. Borchmann:Novartis: Consultancy, Honoraria. Jaeger:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda-Millenium: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Takeda-Millenium: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; MSD: Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria; AOP Orphan: Membership on an entity's Board of Directors or advisory committees. Waller:Pharmacyclics: Other: Travel Expenses, EHA, Research Funding; Celldex: Research Funding; Kalytera: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cambium Medical Technologies: Consultancy, Equity Ownership. Holte:Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Roche, Norway: Research Funding. McGuirk:Novartis Pharmaceuticals Corporation: Honoraria, Other: speaker, Research Funding; Kite Pharma: Honoraria, Other: travel accommodations, expenses, speaker ; Fresenius Biotech: Research Funding; Pluristem Ltd: Research Funding; Gamida Cell: Research Funding; Bellicum Pharmaceuticals: Research Funding; Astellas Pharma: Research Funding. Jaglowski:Kite Pharma: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Juno: Consultancy. Tobinai:Abbvie: Research Funding; SERVIER: Research Funding; Takeda: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Janssen: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Chugai Pharma: Honoraria, Research Funding; HUYA Bioscience International: Consultancy, Honoraria; Zenyaku Kogyo: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Andreadis:Cellerant Therapeutics: Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Research Funding; Incyte Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Amgen: Research Funding; Genentech Inc.: Honoraria, Research Funding; Seattle Genetics: Honoraria; Gilead Sciences: Honoraria; Astellas: Honoraria. Fleury:F. Hoffmann-La Roche Ltd: Consultancy; Lundbeck: Consultancy; Gilead: Consultancy; Seattle Genetics: Consultancy; Janssen: Consultancy; Merck: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy; Celgene: Consultancy. Mielke:Celgene: Speakers Bureau; KIADIS Pharma: Speakers Bureau; Miltenyi Biotec: Speakers Bureau; DGHO: Speakers Bureau; EHA: Speakers Bureau. Westin:Apotex: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Celgen: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees. Bachanova:Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Gamida Cell: Research Funding; GT Biopharma: Research Funding. Foley:Celgene: Honoraria, Speakers Bureau; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel expenses ; Amgen: Honoraria; Janssen: Speakers Bureau; Jazz Pharma: Other: Travel expenses . Ho:Amgen: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Takeda: Honoraria, Other: travel to meeting; Celgene: Other: travel to meeting. Wagner-Johnston:JUNO: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; ASTEX: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Celgene: Research Funding. Kersten:Millennium/Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Kite/Gilead: Honoraria; Novartis Pharmaceuticals Corporation: Honoraria. Chu:Novartis Pharmaceuticals Corporation: Employment. Jary:Novartis Pharma AG: Employment. Anak:Novartis Pharma AG: Employment. Salles:Celgene: Honoraria, Other: Advisory Board, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Servier: Honoraria, Other: Advisory Board; Merck: Honoraria; Janssen: Honoraria, Other: Advisory Board; Gilead: Honoraria, Other: Advisory Board; Novartis: Consultancy, Honoraria; Acerta: Honoraria; Morphosys: Honoraria; Servier: Honoraria; BMS: Honoraria, Other: Advisory Board; Epizyme: Honoraria; Abbvie: Honoraria. Maziarz:Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Honoraria; Juno Therapeutics: Consultancy, Honoraria; Kite Therapeutics: Honoraria; Athersys, Inc.: Patents & Royalties.

Introduction: Umbilical cord blood (UCB) transplant supported by third party CD34-selected cells results in rapid count recovery, UCB mediated GVL effects and low rates of chronic GvHD. For patients lacking haplo-identical relatives, other sources of CD34 progenitors are needed. Methods: We identified partially matched unrelated donors for patients lacking suitable haplo-identical donors -including second-degree relatives - and who otherwise were candidates for haplo-cord transplant. Most were treated on prospective studies (clinicaltrials.gov 00943800 and 01810588). For 5 patients, UCB were obtained through NCT01351545. Results: Between 12/2014 to 7/2018 of 126 candidates for haplo-cord transplant, 26 (21%) had no suitable related donor. Most common reasons were: no first or second degree partially matched donors, ill or unavailable relative, high titers of HLA-antibodies against all relatives, or evidence of hematological familial hereditary syndrome. Diagnoses were: 16 AML/MDS, 5 ALL, 2 MPN, 1 NHL, 1 plasma cell leukemia and 1 SAA. Median age was 57 (24-75). 50% were women. 42% non-Hispanic white (NHW), 19% non-Hispanic blacks (NHB), 19% Hispanic, 8% other minorities. CIBMTR Disease Risk Index (DRI): 46% intermediate, 38% high and 8% very high. Median HCT-CI was 3.5 (25%-75% IQR 2-6). Conditioning: 16 Flu/Mel/TBI (94% 400cGray), 8 Flu/Mel,1 Flu/Cy, 1 Etoposide/TBI. All except 1 received ATG 4.5 mg/kg and all received post-transplant Tacrolimus and MMF. UCB matching was 4/8, 5/8, 6/8 or 7/8 HLA in 12%, 27%, 23%, and 38%, respectively. HLA matching for unrelated haplos was 5-6/12, 7-8/12, >9/ 12 HLA in 15%, 54% and 19%, respectively. For UCB, median cells collected were 2.1 (range1.1-4.0) ×107 TNC/kg. CD34 cell dose of unrelated donor graft was 3-5 ×106 CD34/kg. Median time to ANC engraftment was 11 days (range 9-35) and platelet engraftment was 18 days (range11-124). Chimerism on day 56 are shown in figure 1. There were three patients with graft failures: Pt #5 with complete graft rejection, autologous reconstitution, but ongoing clinical remission that persists to date (Day+ 1223); Pt #13 with graft failure and subsequent relapse, rescued with second UCB HSCT but died of progression of disease; and pt #18 who died from infectious complications after graft failure. Acute GvHD occurred in 35% of patients (4 Grade I-II, 4 Grade III, and 1 Grade IV). cGvHD was rare: One patient with mild severity and a second with severe lung involvement. After a median follow up of 209 days, 6 months cumulative incidence of relapse (CIR) was 16% and non-relapse mortality (NRM) was 20%. Median OS was 14 months (95%CI 7-27). Conclusion: 20% of adults without matched related or unrelated donors, also lack suitable first or second degree haplo-identical donors. UCB transplant with partially matched unrelated donor accessory cells provides an alternative for transplantation. Engraftment is rapid, rates of acute GVHD are acceptable and incidence of chronic GVHD is very low. Prolonged survival is encouraging in this patient cohort with adverse characteristics and who would not be candidate for haplo-identical HSCT. Disclosures No relevant conflicts of interest to declare.

Background: The myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF) can be characterized by heterogeneous symptoms, disease features, and prognosis. Timely monitoring of blood counts and if needed, referral for discussion of stem cell transplant (SCT), are critical to optimizing survival and quality of life. In connection with the MPN SCT Transplantation Timing Taskforce's (MS3T's) work in developing the DIPPS-based Stem Cell Spectrum Timing Tool, the survey was deployed to explore factors contributing to delayed entry to SCT. National Comprehensive Cancer Network (NCCN) guidelines for MPNs strongly recommend referral to specialized centers with expertise in the management of MPNs (Mesa et. al. 2017). To date, efforts to assess the timing and quality of MPN patient care from the patient's perspective have been minimal. Methods: Patients were recruited from MPN-related Facebook pages, subscribers of MPNforum Magazine and E-mail support groups including the MPN-NET, MPDchat, and the MPN Research Foundation. Hematologists, MPN patients, and advocates constructed the 11-item survey questions and content. The survey was available for patient response between July 4-11th2018. Patients were queried on MPN type, time of diagnosis, and details regarding knowledge of their MPN disease features and care. Data: Demographics.Overall 2382 MPN patients responded to the online survey. Of these, 901 (38%) patients had ET, 865 (36%) had PV, 561 (24%) had MF, 41 (2%) had MPN-unclassifiable or MPN/MDS overlap and 15 (1%) did not respond. Among MF patients, 56% reported having primary MF, 42% secondary MF, 1% prefibrotic MF, and 1% reported having already undergone SCT (1% did not specify type of MF or transplant). The majority of patients were diagnosed with their MPN by a hematology/oncology (77.8%) or family practice (15 %) physician. MPN Care provider and monitoring: Out of all respondents, 35% reported being cared for by an MPN specialist, 36% were not cared for by an MPN specialist and 27% were unsure if their provider was an MPN specialist. Overall less than half (42%) of patients reported having sought a second opinion from an MPN specialist. The majority (87%) of participants knew their mutational status relating to the highly publicized and widely tested JAK2 V617F mutation (73.8%) and CALR (10.2%). However, a statistically insignificant number of patients had any idea of other driving and secondary mutations including MPL, EZH2, SRSF2, IDH1/2 or ASLX-1. Blood counts were reviewed by a hematologist for the majority of patients (93% responded "yes", 4% responded "sometimes", 3% responded "no"). SCT Referral: Among ET and PV, Conclusions: MPN patients often report receiving care outside of the care of an MPN specialist. Additionally, despite the poor outcomes and higher likelihood of progression to AML, less than a third of patients with secondary MF report being referred for SCT discussion. Independent validation of patient responses, particularly in regards to MPN specialized care and timing of transplant discussion should be investigated further. However, these patient responses suggest many patients may be receiving less than optimal MPN care. These results demonstrate the importance of community hematology/oncology physician and patient education regarding optimal MPN care. Disclosures Mesa: UT Health San Antonio - Mays Cancer Center: Employment; Celgene: Research Funding; Novartis: Consultancy; Incyte Corporation: Research Funding; Pfizer: Research Funding; CTI Biopharma: Research Funding; Genentech: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; Gilead: Research Funding. Palmer:Novartis: Research Funding. Harrison:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; CTI BioPharma: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Speakers Bureau. Verstovsek:Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Scherber:Gilead: Honoraria.

Background Conventional salvage chemotherapy has limited efficacy in relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL). In the last decade, several novel agents, including pralatrexate, an antifolate, brentuximab vedotin (BV), a CD30-directed antibody-drug conjugate, and romidepsin, a histone deacetylase inhibitor, have been introduced into clinical practice based on phase 2 data demonstrating efficacy in relapsed/refractory (R/R) diseases. Their impact on real world survival remains to be defined. In this single-center retrospective cohort study we assessed survival including outcomes after hematopoietic stem cell transplant (HSCT) with respect to novel agent exposure. Methods Patients diagnosed with PTCL from 2012-2017 who consented for inclusion in the Weill Cornell lymphoma and bone marrow transplant databases with adequate treatment records were included. Medical records were reviewed for baseline characteristics, treatment course, and outcomes including overall survival and HSCT. Median follow-up time was estimated on overall survival by reverse Kaplan-Meier method. Overall Survival (OS) time was calculated from date of diagnosis to date of death or last follow-up. Kaplan-Meier estimator was used to estimate survival probability. Survival difference between groups was tested by log-rank test and Cox regression analysis for statistical significance. Results A total of 123 cases were reviewed with median follow-up of 34 months. The major PTCL subtypes were PTCL NOS (N=34, 27.6%), angioimmunoblastic T-cell lymphoma (N=21, 17%), adult T-cell leukemia/lymphoma (N=19, 15.4%), and anaplastic large cell lymphoma (N=14, 11.4%). The most common 1st line chemotherapy regimens were CHOP (N=34, 31.5%), EPOCH (N=21, 19.4%), or CHOEP (N=10, 9.3%). Ninety-two patients had relapsed or refractory disease, and the most common 2nd line therapies were DICE/ICE (N=17, 18.4%), gemcitabine-based regimens (N=6, 7.5%), bendamustine (N=5, 5.4%), hyperCVAD (N=5, 5.4%), or combinations of novel agents. Thirty-three R/R patients received a novel agent, including pralatrexate alone (N=3), BV (N=13), or romidepsin (N=17). Thirty-six R/R patients underwent HSCT, including 26 allogeneic and 10 autologous. Baseline characteristics at diagnosis including age, gender, Ann Arbor stage, ECOG status, and IPI were similar between R/R patients who received a novel agent and those who did not. Although no differences in OS were seen with novel agent use among patients with R/R disease, there was a significant difference in OS among patients who received HSCT and those who did not (p=0.012 by log-rank test). Compared to no HSCT, significantly improved survival was observed in patients receiving allogeneic HSCT (HR = 0.47, p = 0.03) as well as autologous HSCT (HR = 0.27, p= 0.03) by Cox regression survival analysis, both univariate and multivariate when adjusting for interaction with novel agents. Conclusion Data from this single-center retrospective cohort study suggest that hematopoietic stem cell transplant, both autologous and allogeneic, was associated with overall survival benefit in R/R diseases in the novel agent era. The real world impact of novel agents use in PTCL subtypes warrants further study, preferably in a prospectively designed multicenter population study with larger sample size where disease subtypes, therapeutic targets of novel agents, and line of therapies can be sufficiently delineated for response and survival analysis. Disclosures Martin: AstraZeneca: Consultancy; Gilead: Consultancy; Bayer: Consultancy; Janssen: Consultancy; Seattle Genetics: Consultancy; Kite: Consultancy. Allan:Acerta: Consultancy; Sunesis: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees. Furman:TG Therapeutics: Consultancy; Sunesis: Consultancy; Loxo Oncology: Consultancy; Incyte: Consultancy, Other: DSMB; Gilead: Consultancy; Genentech: Consultancy; Acerta: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy; Verastem: Consultancy; Janssen: Consultancy; AbbVie: Consultancy.

Background: Although current antiretroviral therapies have effectively changed the course of HIV-1 infection, it remains an incurable illness. The C-C chemokine receptor type 5 (CCR5) is the key co-receptor for HIV entry into CD4+ T cells. Homozygous 32 deletion (delta32) in CCR5 genes leads to resistance to HIV-1 infection 1. Allogeneic stem cell transplant from a donor with CCR5 delta32/32 mutation was curative for HIV in an HIV-1-infected man (Berlin Patient) with AML 2. It has been challenging to replicate this experience. We present our experience with a single case of successful engraftment of CD34-selected, related haploidentical peripheral blood and CCR5delta32 cord blood stem cell transplant (haplo-cord) in an HIV-1-infected woman who, like the Berlin patient, developed AML and is now doing well at almost one-year post transplantation. Clinical case: A 60-year-old African-American woman was diagnosed with HIV-1- infection in June 2013 and was started on an antiretroviral treatment (ART) regimen consisting of tenofovir, emtricitabine and raltegravir. Her pre-ART viral load and CD4 counts were 1,000,000 copies/ml and 1003 cells/mm3, respectively. In Nov, 2013 she had viral load < 20 copies/ml with CD4 counts of 980 cells/mm3 and her HIV-1 infection was relatively asymptomatic. In March 2017, she was diagnosed with AML with monosomy 7. Her HIV therapy after the AML diagnosis was changed to abacavir- lamivudine -dolutegravir- combination. She achieved morphologic and cytogenetic remission after 1 cycle of standard idarubicin/cytarabine induction chemotherapy. In addition, she received 1 cycle of HiDAC consolidation and was referred for allogeneic stem cell transplant. We identified a CCR5 delta32/32 mutated cord blood unit (CBU) which was 5/8 HLA matched and contained 1.3 x 107 nucleated cells/kg and 3.2 x 104 CD34+ cells/kg. She underwent a combined CD34-selected, haploidentical peripheral blood and CCR5delta32 cord blood stem cell transplant (haplo-cord) in August 2017. Her conditioning regimen was with fludarabine/melphalan/and TBI400 and she also received ATG/MMF/tacrolimus for GVHD prophylaxis. Her neutrophils and platelets engrafted on day 10 and 16, respectively and she was discharged on day +16 post-transplant. Her post-discharge hospital course was complicated by CMV reactivation (no organ involvement) 2 months post-transplant with peak viral level of 1374 copies/ml. She did not have evidence for EBV re-activation or graft-vs-host disease. Her plasma HIV viral load remained undetectable post- transplant while remaining on abacavir/lamivudine and dolutegravir-based ART. Her day+180 bone marrow showed continued AML remission and she remains in clinical remission near one year post-transplant. CD3 chimerism showed 82% haploidentical donor and 8% CBU and 10% recipient on day +15 post-transplant (Figure 1). The chimerism composition switched to 96% CBU by day+34, and became and remained 100% CBU since day+55. CD33 chimerism showed 98% haploidentical donor and 2% cord donor on day+15 post-transplant. It was 81% haploidentical donor and 19% cord on day+55 and became 100% cord by day+100. She has continued CD4, CD8, NK and CD19 cell recovery, with normal T cell subsets currently (Figure 2). Her CD4 count dropped to 27 cells/mm3 at one-month post-transplant and currently is at 673cells/mm3. She is currently 11 months post-transplant and is back to her normal daily activities Conclusion: Haplo-cord transplantation with CCR5 delta 32/32 CBU resulted in rapid engraftment and immune replacement with dominance of the CCR5 delta 32/32 CBU graft in an HIV-1-infected woman. Successful suppression of HIV-1-replication to clinically undetectable levels was maintained throughout the transplant period for up to one year. . Correlative viral and immunological studies are ongoing, along with effects on the latent reservoir, which was detectable pre-transplant. It is possible to identify appropriate CCR5 delta 32/32 CBU units for haplo-cord transplantation in HIV-1- infected patients with implications for HIV-1 cure. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

The epichaperome is a new cancer target defined, in part, by changes in the interaction strength between chaperone and co-chaperone proteins to form stable hyperconnected networks that support oncoprotein stability and are vital for tumor survival (Nature 2016, Nature Rev Cancer 2018 and Nature Med 2018). Cancers with this altered chaperone configuration may become susceptible to drugs that target the epichaperome, such as the inhibitor PU-H71. We have developed a novel flow cytometry-based test, the PU-FITC binding assay, to evaluate epichaperome levels at the single cell level and identify patients who are most likely to respond to PU-H71 treatment. A 61-year-old woman was diagnosed with an accelerated phase myeloproliferative neoplasm in 2013 after years of leukocytosis, arthritis, urticaria, and vasculitis. Cytogenetic analysis revealed t(9;15) involving the PML gene. Molecular studies were negative for BCR-ABL, PDGFRA/B and FGFR1 rearrangements as well as JAK2 mutation. Mutations in ETV6 and multiple ASXL1 subclones were present. She was treated with hydroxyurea and in Aug 2013 underwent matched unrelated donor allogeneic stem cell transplantation conditioned with Fludarabine/Melphalan, followed by 3 cycles of vidaza in 2014 for early recurrence. In Jan 2016, she relapsed and was treated with hydroxyurea. She also had painful ulcerations of toes, thought to be an atypical presentation of graft versus host disease complicated by her underlying Raynaud's disease and treated successfully with ruxolitinib. During 2017, she had bone marrow (BM) evidence of recurrent disease, skin lesions consistent with recurrent disease, and significant splenomegaly, but since neutrophils and platelets were preserved, she did not require transfusions and she had no bleeding or infections, she was maintained on hydrea, prednisone and ruxolitinib. In 2017, BM biopsy showed progression to AML with fibrosis. She developed progressive splenomegaly and weight loss and was treated with 2 cycles of decitabine without response. The patient was sent for precision medicine evaluation. Whole-exome sequencing and RNA-seq was performed with a control buccal swab. No somatic alterations in clinically relevant genes were found. However, a novel fusion protein, PML-SYK, was detected and validated by FISH and PCR. We found constitutive Syk, Stat5, Erk and ribosomal S6 kinase phosphorylation. Elevated epichaperome levels were found in the cell populations bearing the translocation, suggesting sensitivity to PU-H71. Also, invitro treatment of patient's cells with PU-H71 resulted in cell death and decreased colony formation. These findings confirm preclinical data in AML in which a relationship between a hyperactive signalosome and epichaperome expression was observed (Cell Reports 2015). Based on the poor prognosis, lack of effective therapies, and laboratory data suggesting sensitivity to PU-H71, the patient was granted compassionate access to this medication by the FDA. After 16 doses of PU-H71 at 300 mg/m2 over 3 months, the patient has attained complete remission, with normalization of peripheral blood counts and In summary, a novel flow cytometry-based PU-FITC binding assay to evaluate epichaperome levels at the single cell level successfully identified a patient predicted to respond to treatment with PU-H71. This poor prognosis AML patient who had relapsed after allogeneic stem cell transplantation is presently in remission and the assay is being used to screen other potential patients. Figure. Figure. Disclosures Roboz: Sandoz: Consultancy; Janssen Pharmaceuticals: Consultancy; AbbVie: Consultancy; Eisai: Consultancy; Celgene Corporation: Consultancy; Sandoz: Consultancy; Celgene Corporation: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Orsenix: Consultancy; Aphivena Therapeutics: Consultancy; Novartis: Consultancy; Orsenix: Consultancy; Roche/Genentech: Consultancy; AbbVie: Consultancy; Argenx: Consultancy; Bayer: Consultancy; Roche/Genentech: Consultancy; Otsuka: Consultancy; Astex Pharmaceuticals: Consultancy; Otsuka: Consultancy; Argenx: Consultancy; Cellectis: Research Funding; Janssen Pharmaceuticals: Consultancy; Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy; Cellectis: Research Funding; Astex Pharmaceuticals: Consultancy; Celltrion: Consultancy; Aphivena Therapeutics: Consultancy; Celltrion: Consultancy; Daiichi Sankyo: Consultancy; Bayer: Consultancy; Eisai: Consultancy; Daiichi Sankyo: Consultancy. Morgan:Samus Therapeutics, Inc: Employment, Equity Ownership. Chiosis:Samus Therapeutics, Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Guzman:Cellectis: Research Funding.

Background Fluoroquinolone (FQ) prophylaxis is widely used to prevent bloodstream infections (BSIs) in neutropenic patients undergoing hematopoietic stem cell transplantation (HCT). In order to assess whether increasing FQ resistance threatens the effectiveness of FQ prophylaxis, we screened HCT recipients for colonization with FQ-resistant Enterobacteriaceae (FQRE) and assessed the impact of colonization on the risk of BSI. Methods We collected stool samples on admission for HCT and weekly until neutrophil engraftment from patients at NewYork-Presbyterian Hospital/Weill Cornell Medical Center from November 2016 to March 2018. Patients received FQ prophylaxis during neutropenia. Perianal swabs were used when stool was unavailable. Stool and swab samples were plated onto MacConkey agar with 1 μg/mL ciprofloxacin, and colonies were identified and underwent antimicrobial susceptibility testing. We determined the prevalence of colonization with FQRE on admission for HCT, the risk of acquiring FQRE, and compared the risk of BSI during the transplant admission in colonized and noncolonized patients. Results We evaluated 178 HCT recipients and found that 35 (20%) had pre-transplant FQRE colonization (allogeneic: 20/89, 22%; autologous: 15/89, 17%). Thirty FQRE (86%) were Escherichia coli, 5 (14%) were Klebsiella pneumoniae, and 13 (37%) were extended-spectrum β-lactamase producers. Five (14%) of the 35 patients with pre-transplant FQRE colonization developed BSI due to an Enterobacteriaceae, and all bloodstream isolates had identical susceptibility profiles to the colonizing FQRE. In contrast, only one (1%) of 143 patients without pre-transplant FQRE colonization developed Enterobacteriaceae BSI (P = 0.001). Patients with pre-transplant FQRE colonization also had higher rates of any Gram-negative BSI (20% vs. 1%, P < 0.001), but did not have increased risk of Gram-positive BSI (6% vs. 11%, P = 0.5). Of 123 patients without initial FQRE colonization who had follow-up samples collected, 10 (8%) acquired FQRE during post-HCT neutropenia. Conclusion FQRE colonization is common on admission for HCT and is associated with decreased effectiveness of levofloxacin prophylaxis in preventing Gram-negative BSI during post-transplant neutropenia. Disclosures M. J. Satlin, Hardy Diagnostics: Grant Investigator, Research support; Allergan: Grant Investigator, Grant recipient; Merck: Grant Investigator, Grant recipient; Biomerieux: Grant Investigator, Grant recipient; Achaogen: Consultant, Consulting fee. R. Malherbe, Hardy Diagnostics: Employee, Salary. S. G. Jenkins, Merck: Grant Investigator, Grant recipient. L. F. Westblade, Accelerate Diagnostics: Grant Investigator, Grant recipient; Biomerieux: Grant Investigator, Grant recipient; Allergan: Grant Investigator, Grant recipient; Merck: Grant Investigator, Grant recipient. T. J. Walsh, Merck: Grant Investigator, Research grant; Atellas: Consultant, Grant Investigator and Scientific Advisor, Consulting fee and Research grant; Gilead: Scientific Advisor, Consulting fee; Allergan: Grant Investigator and Scientific Advisor, Consulting fee and Research grant; Scynexis: Grant Investigator, Research grant; Amplyx: Grant Investigator, Research grant; Shionogi: Scientific Advisor, Consulting fee.

Background Seasonal influenza causes significant morbidity and mortality on HSCT recipient. The 2017–2018 influenza has been characterized in the United States by prolonged high rates of both influenza A (IAV) and B (IBV) and low vaccine effectiveness. The aim of this study was to assess the impact of both IAV and IBV during 2017–2018 influenza season on a cohort of stem cell transplant (SCT) recipients at Weill Cornell- NYP. Methods We reviewed charts of HSCT recipients that were diagnosed with influenza by PCR on nasopharyngeal swabs. Demographics, clinical and microbiological data, and outcomes were collected. The study was approved by Weill Cornell Institutional review board. Results From September 2017 to March 2018, 30 stem cell transplant recipient at NYP were diagnosed with influenza. IAV cases peaked in January (11 cases) while IBV infected-patients were equally distributed from December to March. Infected subject were more likely to be male (n = 20, 66.6%) with mean age of 57 ± 12 (IAV) vs. 59 + 11 (IBV). Nine patients had received auto SCT and 21 patient allo SCT. Most commons symptoms were cough (present in all patients), fever (28/30), nausea, dyspnea. Patient received oseltamivir (for 5 or 10 days) in 28/30 cases, with one patient developing resistance under treatment. Interestingly both IAV and IBV caused lower respiratory tract infection (LRTI, 7 cases) with severe pneumonia (IAV 1 cases, IBV 2 cases) and intubation. In two severe cases IV was detected in the BAL. 13 subjects (56%) with a URTI and 4 (43%) subjects with LRTI had not received the influenza vaccine for the season. Prolonged shedding of influenza on oseltamivir treatment was documented in 7 patients. Conclusion Both IAV and IBV are serious threat in SCT population. Vaccination and oseltamivir are useful tools. Resistance testing should be considered in subjects with prolonged disease. Disclosures S. G. Jenkins, Merck: Grant Investigator, Grant recipient. M. J. Satlin, Hardy Diagnostics: Grant Investigator, Research support. Allergan: Grant Investigator, Grant recipient. Merck: Grant Investigator, Grant recipient. Biomerieux: Grant Investigator, Grant recipient. Achaogen: Consultant, Consulting fee. L. F. Westblade, Accelerate Diagnostics: Grant Investigator, Grant recipient. Biomerieux: Grant Investigator, Grant recipient. Allergan: Grant Investigator, Grant recipient. Merck: Grant Investigator, Grant recipient.

Purpose Despite high initial remission rates, most lymphomas relapse and require further therapy. The mammalian target of rapamycin (mTOR) pathway is a validated target in mantle cell lymphoma, but has not been extensively evaluated in other lymphomas. Patients and Methods We performed a phase II trial of single-agent temsirolimus 25-mg weekly in patients with relapsed aggressive and indolent lymphomas. The primary objective was overall and complete response rate. Patients were stratified by histology: group A (diffuse large B-cell lymphoma, transformed follicular lymphoma), group B (follicular lymphoma), and group C (chronic lymphocytic leukemia/small lymphocytic lymphoma, and other indolent lymphomas). Results Eighty-nine patients were treated, with outcome strongly dependent on histology. Group A had an overall and complete response rate of 28.1% and 12.5%, respectively, and median progression-free survival (PFS) of 2.6 months and median overall survival (OS) of 7.2 months. Group B had overall and complete response rates of 53.8% and 25.6%, respectively, and median PFS of 12.7 months; median OS has not yet been reached. Group C had a partial response rate of 11% with no complete responders. Toxicity was mainly mild and/or reversible myelosuppression and mucositis; however, four patients developed pneumonitis. Conclusions Single-agent temsirolimus has significant activity in both diffuse large B-cell lymphoma and follicular lymphoma, although the durability of responses and PFS are longer for patients with follicular lymphoma. This is the first report of substantial activity of temsirolimus in lymphomas other than mantle cell lymphoma, and supports further evaluation of mTOR as a target in these diseases.

High-dose chemotherapy followed by autologous stem cell transplant (ASCT) leads to durable remissions in approximately half of patients with chemosensitive relapsed or refractory aggressive lymphomas; however, many will relapse despite ASCT secondary to persistent minimal residual disease (MRD) or malignant graft contamination. Post-transplant rituximab may eradicate MRD. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-2 (IL-2) might enhance the efficacy of rituximab by augmenting antibody-dependent cellular cytotoxicity (ADCC). We hypothesized that given together, rituximab, GM-CSF, and IL-2 might eradicate MRD and improve event-free survival following ASCT. Forty-six patients with relapsed non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma (HL) were enrolled. Stem cells were mobilized with G-CSF and GM-CSF following chemotherapy. Following BEAM conditioning, patients received GM-CSF until neutrophil engraftment. Between days + 30 and + 120, patients received one dose of rituximab 375 mg/m(2) (cycle 1), followed by three cycles of GM-CSF 250 microg/m(2)/day SQ days 1-5, IL-2 1.5 x 10(6) IU/m(2)/day SQ days 6-12, and rituximab 375 mg/m(2) IV day 9, repeated every 21 days. Thirty-eight patients were eligible for post-ASCT immunotherapy. Nine patients completed 1-2 cycles and 21 completed 3-4 cycles; eight patients did not receive post-ASCT immunotherapy. Grade 3-4 neutropenia and grade 3 thrombocytopenia were observed. With a median follow-up of 30 months, the estimated 5-year OS and EFS for all patients eligible for immunotherapy are 65% and 45%, respectively. Post-ASCT immunomodulation with rituximab, IL-2, and GM-CSF was feasible and safe, but not all patients were able to continue on to post-ASCT immunotherapy.

Clinical research examining the role of hematopoietic stem cell transplantation (SCT) in the therapy of follicular non-Hodgkin lymphoma in adults is presented and critically evaluated in this systematic evidence-based review. Specific criteria were used for searching the published literature and for grading the quality and strength of the evidence and the strength of the treatment recommendations. Treatment recommendations reached unanimously by a panel of follicular lymphoma experts are: (1) autologous SCT is recommended as salvage therapy based on pre-rituximab data, with a significant improvement in overall survival (OS) and progression-free (PFS) survival; (2) autologous SCT is not recommended as first-line treatment for most patients because of no significant improvement in OS; (3) autologous SCT is recommended for transformed follicular lymphoma patients; (4) reduced intensity conditioning before allogeneic SCT appears to be an acceptable alternative to myeloablative regimens; (5) an HLA-matched unrelated donor appears to be as effective an HLA-matched related donor for reduced intensity conditioning allogeneic SCT. There are insufficient data to make a recommendation on the use of autologous SCT after rituximab-based salvage therapy. Eleven areas of needed research in the treatment of follicular lymphoma with SCT were identified and are presented in the review.

We compared outcomes of 916 diffuse large B cell lymphoma (DLBCL) patients aged >or=18 years undergoing first autologous (n = 837) or myeloablative (MA) allogeneic hematopoietic cell transplant (HCT) (n = 79) between 1995 and 2003 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Median follow-up was 81 months for allogeneic HCT versus 60 months for autologous HCT. Allogeneic HCT recipients were more likely to have high-risk disease features including higher stage, more prior chemotherapy regimens, and resistant disease. Allogeneic HCT was associated with a higher 1 year treatment-related mortality (TRM) (relative risk [RR] 4.88, 95% confidence interval [CI], 3.21-7.40, P 50 years), lower performance score, chemoresistance, and earlier year of transplant. In a cohort of mainly high-risk DLBCL patients, upfront MA allogeneic HCT, although associated with increased early mortality, was associated with a similar risk of disease progression compared to lower risk patients receiving autologous HCT. American Society for Blood and Marrow Transplantation. All rights reserved.

Incorporation of the anti-CD20 monoclonal antibody rituximab into front-line regimens for diffuse large B-cell lymphoma (DLBCL) has resulted in improved survival. Despite this progress, many patients develop refractory or recurrent DLBCL and then receive autologous hematopoietic stem cell transplantation (AuHCT). It is unclear to what extent pre-transplant exposure to rituximab affects outcomes following AuHCT. Outcomes of 994 patients receiving AuHCT for DLBCL between 1996 and 2003 were analyzed according to whether rituximab was (n=176, “+R” group) or was not (n=818, “ −R” group) administered with front-line or salvage therapy prior to AuHCT. The +R group had superior progression-free survival (50% versus 38%, p=0.008) and overall survival (57% versus 45%, p=0.006) at 3 years. Platelet and neutrophil engraftment were not affected by exposure to rituximab. Non-relapse mortality (NRM) did not differ significantly between the +R and −R groups. In multivariate analysis, the +R group had improved progression-free survival (relative risk of relapse/progression or death 0.64, p

We evaluated stem cell mobilization in 195 consecutive sibling donors who underwent a uniform mobilization regimen of granulocyte colony-stimulating factor (G-CSF) at 10 microg/kg/day divided into twice daily dosing. On day 5, peripheral blood (PB) CD34 cells/microL were measured immediately prior to peripheral blood stem cell (PBSC) apheresis. Failed mobilization was defined as20 CD34 cells/microL on day 5. The median age was 52 years and 73 (37%) were 55 years or greater. Comorbid conditions by the Charlson Comorbidity Index (CCI) occurred in 13%, but only 3% had Karnofsky performance status (PS)100%. Eight (4%) failed mobilization, defined as20 CD34 cells/microL on day 5. Older age was associated with fewer CD34 cells/microL (P=.002). In addition, 6/73 (8.2%) older donors failed mobilization compared to 2/122 (1.6%) younger donors (P=.054). Comorbidity, sex, race, and donor weight did not influence mobilization. Although low PS was very uncommon, it was associated with reduced mobilization (P=.021), but not mobilization failure. A small fraction of older donors mobilize poorly, and this is not explained by standard measures of comorbidity or PS.

Outcome disparity associated with race or ethnicity in the United States has been observed in hematopoietic cell transplantation (HCT). The underlying reasons for such disparity are not known. In the United States, an optimal study of healthcare disparity by race or ethnicity involves consideration of both biological and psychosocial determinants which requires an adequately powered, prospective cohort study design. In order to better characterize the nature and quantify the magnitude of the many impediments relevant to conducting a successful prospective study involving racial or ethnic minorities in HCT, we conducted a feasibility study to help guide planning of a larger scale, outcome and disparity study in HCT. The primary questions to be addressed in the study were: 1) can we establish a racially or ethnically diverse patient sample who will respond to a survey focused on socio-demographic, economic, health insurance, cultural, spiritual and religious well-being, and social support information?; 2) what is the retention rate in the study over time?; and 3) what is the quality of the data collected from the patients over time? The challenges we faced in conducting this multicenter feasibility study are summarized in this report. Despite the difficulty in conducting disparity studies in racial and ethnic minorities, such studies are essential to ensure that people of all ethnic and racial backgrounds have the best chance possible of benefiting from HCT.

The purpose of this study was to determine the effect of alemtuzumab on treatment-related mortality (TRM), relapse, overall survival (OS), and disease-free survival (DSF) in patients with acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS) undergoing reduced intensity conditioning (RIC). We compared the outcome of 95 patients treated at the University of Chicago with fludarabine melphalan (Flu + Mel) + alemtuzumab conditioning and 59 patients treated at the M.D. Anderson Cancer Center with Flu + Mel conditioning. Both groups had similar patient and donor characteristics. There were no significant differences in TRM, relapse, survival, and DFS between the 2 groups. The incidence of acute graft-versus-host disease (aGVHD) grade II-IV (relative risk [RR] 5.5, P < .01) and chronic GVHD (cGVHD) (RR 6.6, P < .01) were significantly lower in patients receiving alemtuzumab. The addition of alemtuzumab to an RIC regimen dramatically reduces the incidence of aGVHD and cGVHD in patients with AML and MDS undergoing allogeneic transplantation. TRM, relapse risk, OS and DFS are not affected.

We analyzed the outcomes of 283 patients receiving unrelated donor allogeneic hematopoietic cell transplantation for non-Hodgkin lymphoma (NHL) facilitated by the Center for International Blood and Marrow Transplant Research/National Marrow Donor Program (CIBMTR/NMDP) between 1991 and 2004. All patients received myeloablative conditioning regimens. The median follow-up of survivors is 5 years. Seventy-three (26%) patients are alive. The day 100 probability of death from all causes is estimated at 39%. The cumulative incidence of developing grade III-IV acute graft-versus-host disease (aGVHD) at day 100 is 25%. The estimated 5-year survival and failure free survival are 24% (95% confidence interval [CI]: 19-30) and 22% (95% CI: 17-28), respectively. Factors adversely associated with overall survival (OS) included increasing age, decreased performance status, and refractory disease. Follicular lymphoma (FL) and peripheral T cell lymphoma had improved survival compared to aggressive B cell lymphomas. Factors adversely associated with progression-free survival (PFS) included performance status, histology, and disease status at transplant. Long-term failure-free survival is possible following unrelated donor transplantation for NHL, although early mortality was high in this large cohort.

3 patients with pregnancy-associated aplastic anemia are reported. Management throughout most of the pregnancy consisted of supportive care. In 2 patients an improvement in blood counts occurred after delivery and, in 1 of these, the pancytopenia recurred during a subsequent pregnancy. In 1 case no improvement occurred after delivery and the patient ultimately required an allogeneic bone marrow transplantation. The outcome of these 3 cases demonstrates that pregnancy-associated aplastic anemia can be managed successfully. The improvement that often occurs after delivery suggests a pathogenetic role for pregnancy in the development of this disease.

Primary mediastinal large B-cell lymphoma (PMBCL) is a subtype of lymphoma that shares similarities with diffuse large B-cell lymphoma and with classic Hodgkin's lymphoma. The current study evaluates the use of autologous stem cell transplant (ASCT) as part of initial therapy in a cohort of patients with PMBCL treated between 1985 and 2006. The study demonstrates excellent survival and progression-free survival for patients in complete remission (CR) at ASCT, and for those achieving CR after ASCT. It also shows a benefit to administration of involved-field radiation therapy. However, front-line therapy has evolved considerably since these patients were treated. Dose-dense chemotherapy regimens show excellent results without transplant and the incorporation of rituximab in the treatment may have further improved outcomes. Given these excellent results, ASCT should not currently be used in patients in first CR, but ASCT remains the treatment of choice in relapsed and refractory PMBCL. Similarly, radiotherapy is unnecessary in patients in first CR but is probably useful in patients with residual active mass.

Myeloablative allogeneic hematopoietic cell transplantation (HCT) may cure patients with relapsed or refractory Hodgkin lymphoma (HL), but is associated with a high treatment-related mortality (TRM). Reduced-intensity and nonmyeloablative (RIC/NST) conditioning regimens aim to lower TRM. We analyzed the outcomes of 143 patients undergoing unrelated donor RIC/NST HCT for relapsed and refractory HL between 1999 and 2004 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Patients were heavily pretreated, including autologous HCT in 89%. With a median follow-up of 25 months, the probability of TRM at day 100 and 2 years was 15% (95% confidence interval [CI] 10%-21%) and 33% (95% CI 25%-41%), respectively. The probabilities of progression free survival (PFS) and overall survival (OS) were 30% and 56% at 1 year and 20% and 37% at 2 years. The presence of extranodal disease and the Karnofsky Performance Scale (KPS)

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the treatment of choice for patients with chronic myelogenous leukemia (CML) who have failed or are intolerant to tyrosine kinase inhibitors (TKI). Myeloablative conditioning regimens have been associated with high treatment-related mortality (TRM) rate in such patients, and reduced-intensity conditioning (RIC) regimens are often preferred but have high rates of disease recurrence and graft-versus-host-disease (GVHD). We report our experience with nine CML patients (four chronic phase and five with accelerated phase or blast crisis) who failed TKI and underwent allo-HSCT using an alemtuzumab-based RIC regimen. The conditioning regimen was well tolerated and induced engraftment in all patients, and complete cytogenetic remission (CCyR) in eight of nine. Four patients, all with a history of accelerated phase or blast crisis, died. Four of the five remaining patients had a cytogenetic relapse a median of 10 months after transplantation. Donor lymphocyte infusion (DLI), TKI or both induced a CCyR in all cases. With a median follow-up of 47 months, five patients, including all those transplanted in first or second chronic phase, are alive and in remission. Allo-HSCT with an alemtuzumab-based conditioning regimen induces remission in patients with CML that have failed TKI therapy and has a low incidence of GVHD. Disease recurrence is frequent but responds to DLI. In some cases, restoration of susceptibility to TKI was observed. Outcomes may improve with the routine administration of post-transplant TKI.

To compare the clinical outcomes of older (age ≥55 years) non-Hodgkin lymphoma (NHL) patients with younger NHL patients (