Search

Posttransplant cyclophosphamide (PTCy) platform has shown low rates of graft-versus-host disease (GVHD) and nonrelapse mortality (NRM) after haploidentical hematopoietic cell transplantation (HaploHCT). However, because of the limited disease control, relapse rate remains a major cause of treatment failure in high-risk patients. Total marrow and lymphoid irradiation (TMLI) allows for delivery of high radiation to bone marrow and other targeted structures, without increasing off-target radiation exposure and toxicity to end organs. In this phase 1 trial, 31 patients with high-risk and/or active primary refractory leukemias or myelodysplastic syndrome underwent peripheral blood stem cell HaploHCT with TMLI, fludarabine, and cyclophosphamide as the conditioning regimen. Radiation dose was escalated in increments of 200 cGy (1200-2000 cGy). GVHD prophylaxis was PTCy with tacrolimus/mycophenolate mofetil. Grade 2 toxicities by the Bearman scale were mucositis (n = 1), hepatic (n = 3), gastrointestinal (n = 5), and cardiac (n = 2). One patient (1800 cGy) experienced grade 3 pulmonary toxicity (dose-limiting toxicity). At a follow-up duration of 23.9 months for the whole cohort; 2-year NRM was 13%. Cumulative incidence of day 100 grade 2 to 4 and 3 to 4 acute GVHD was 52% and 6%, respectively. Chronic GVHD at 2 years was 35%. For patients treated with 2000 cGy, with a median follow-up duration of 12.3 months, 1-year relapse/progression, progression-free survival, and overall survival rates were 17%, 74%, and 83%, respectively. In conclusion, HaploHCT-TMLI with PTCy was safe and feasible in our high-risk patient population with promising outcomes.

Patients with acute leukemia who undergo allogenic hematopoietic cell transplantation with active disease have high rates of relapse and poor overall survival (OS) post-transplant compared to patients undergoing HCT in remission. Here, we report the long-term outcomes in 32 patients who received a high-intensity conditioning regimen comprising fractionated total body irradiation (FTBI; 1200 cGy) with pharmacokinetic (PK) dosing of intravenous Busulfan (IV BU) targeted to first dose area under curve (AUC) of 700-900 µM/min and etoposide (30 mg/kg) in a prospective phase 2 clinical trial. The median age of the patients at the time of HCT was 37 years (range: 18-50) presenting with high-risk (

Blinatumomab is a bispecific T cell-engaging antibody approved for treatment of relapsed/refractory (r/r) ALL, with 40%-50% complete response (CR)/CR with incomplete count recovery (CRi). Cytokine release syndrome (CRS) as a major adverse effect after blinatumomab therapy. Here, we evaluated the possible association between single-nucleotide polymorphisms (SNPs) in cytokine genes, disease response, and CRS in r/r ALL patients who received blinatumomab between 2012 and 2017 at our center (n = 66), using patients' archived DNA samples. With a median duration of 9.5 months (range: 1-37), 37 patients (56.1%) achieved CR/CRi, 54 (81.8%) experienced CRS (G1: n = 35, G2: n = 14, G3: n = 5), and 9 (13.6%) developed neurotoxicity. By multivariable analysis, after adjusting for high disease burden, one SNP on IL2 (rs2069762), odds ratio (OR) = 0.074 (95% CI: NE-0.43, P = .01) and one SNP on IL17A (rs4711998), OR = 0.28 (95% CI: 0.078-0.92, P = .034) were independently associated with CR/CRi. None of the analyzed SNPs were associated with CRS. To our knowledge, this is the first study demonstrating a possible association between treatment response to blinatumomab and SNPs. Our hypothesis-generated data suggest a potential role for IL-17 and IL-2 in blinatumomab response and justify a larger confirmatory study, which may lead to personalized blinatumomab immunotherapy for B-ALL.

Allogenic hematopoietic cell transplantation (alloHCT) is a well-established curative modality for acute lymphoblastic leukemia (ALL), yet large amounts of data describing alloHCT outcomes in Philadelphia (Ph)-like ALL are lacking. We retrospectively analyzed archived DNA samples from consecutive adults with B-cell Ph-negative ALL who underwent alloHCT in complete remission (CR) (n = 127) at our center between 2006 and 2020. Identification of fusions associated with Ph-like ALL was performed using cumulative results from RNA-seq, conventional cytogenetics, fluorescence in situ hybridization, and whole genome array studies. Fusions associated with Ph-like ALL were detected in 56 (44%) patients, of whom 38 were carrying CRLF2r. Compared with other non–Ph-like ALL (n = 71), patients with fusions associated with Ph-like ALL were more frequently Hispanic (P = .008), were less likely to carry high-risk cytogenetics (P < .001), and were more likely to receive blinatumomab prior to HCT (P = .019). With the median followup of 3.5 years, patients with Ph-like ALL fusions had comparable posttransplant outcomes compared with other B-cell ALL: 3-year relapse-free survival (RFS) (41% vs 44%; P = .36), overall survival (OS) (51% vs 50%; P = .59), and relapse (37% vs 31%; P = .47). In multivariable analysis, age (P = .023), disease status at the time of transplant (P < .001), and donor type (P = .015) influenced OS. RFS (primary endpoint) was significantly influenced by disease status (P < .001) and conditioning regimen intensity (P = .014). In conclusion, our data suggest that alloHCT consolidation results in similarly favorable survival outcomes in adult patients with Ph-like fusions and other high-risk B-cell ALL.

BackgroundAdoptive transfer of CD19-specific chimeric antigen receptor (CD19CAR) T cells can induce dramatic disease regression in patients with B cell malignancies. CD19CAR T cell therapy may be limited by insufficient engraftment and persistence, resulting in tumor relapse. We previously demonstrated a proof of principle that cytomegalovirus (CMV)-specific T cells can be isolated and enriched prior to CD19CAR transduction to produce CMV-CD19CAR T cells, and that these CMV-CD19CAR T cells can be expanded in vivo through CMV vaccination, resulting in better tumor control in a murine model. Here we developed a clinical platform for generating CMV-CD19CAR T cells.MethodsPeripheral blood mononuclear cells (PBMCs) collected from CMV-seropositive healthy donors were stimulated with a good manufacturing practices-grade PepTivator overlapping CMVpp65 peptide pool and enriched for CMV-responsive interferon γ (IFNγ)+T cells using IFNγ Catchmatrix, within the CliniMACS Prodigy Cytokine Capture System (Miltenyi Biotec). Resulting CMV-specific T cells were transduced with a lentiviral vector encoding a second generation CD19R:CD28:ζ/EGFRt CAR and expanded with interleukin 2 (IL-2) and IL-15 for 15 days before characterization.ResultsCMV-specific T cells were enriched from 0.8%±0.5 of input PBMC to 76.3%±11.6 in nine full-scale qualification runs (absolute yield of 4.2±3.3×106 IFNγ+T cells from an input of 1×109 PBMCs). Average CD19CAR transduction efficiency of CMV-specific T cells was 27.0%±14.2 in the final products, which underwent rapid expansion, resulting in a total cell dose of 6.2±0.9 × 106 CD19CAR-tranduced T cells with CMV specificity (ie, functionally bispecific). CMV-CD19CAR T cells were polyclonal, expressed memory markers but had low expression of exhaustion markers, responded to both CD19 and CMVpp65 stimulation with rapid proliferation and exhibited antigen-specific effector functions against both CD19-expressing tumors and CMVpp65 antigen. The final products passed release criteria for clinical use.ConclusionsWe demonstrated the feasibility of our large-scale platform for generating CMV-CD19CAR T cells for clinical application. We plan to initiate a clinical trial at City of Hope using CMV-CD19CAR T cells for patients with intermediate/high-grade B cell non-Hodgkin’s lymphoma immediately after autologous hematopoietic cell transplantation followed by vaccination with a novel CMV vaccine based on Modified Vaccinia Ankara (Triplex) 28 days and 56 days post-T cell infusion.

BACKGROUND Blinatumomab has demonstrated encouraging activity in relapsed/refractory (r/r) and minimal residual disease-positive (MRD+) acute lymphoblastic leukemia (ALL). Extramedullary disease (EMD) relapse or relapse with CD19- disease has been observed after blinatumomab therapy in patients with r/r or MRD+ ALL. However, the pathophysiology and risk factors of treatment failure are not fully understood. METHODS This study retrospectively reviewed the outcomes of adult patients with B-cell ALL treated with blinatumomab (n = 132) for either r/r (n = 103) or MRD+ disease (n = 29) at the authors' center (2013-2021) and analyzed factors associated with treatment response and EMD failure. RESULTS The overall response rate was 64%. A lower marrow blast burden before blinatumomab (P = .049) and no history of previous EMD (P = .019) were significantly associated with a higher response. Among the patients who responded to blinatumomab, 56% underwent consolidation with allogeneic transplantation. Blinatumomab failure was observed in 89 patients; 43% of these patients (n = 38) either progressed or relapsed at extramedullary sites. A history of extramedullary involvement (53% vs 24%; P = .005) and retention of CD19 expression at the time of relapse/progression (97% vs 74%; P = .012) were associated with a higher risk for extramedullary failure. Central nervous system (CNS) failure after blinatumomab was encountered in 39% of the patients with EMD. CONCLUSIONS A history of EMD predicted an inferior response to blinatumomab therapy with a higher risk for relapse/progression at extramedullary sites (particularly CNS). Consolidation with allogenic transplantation in patients who primarily responded to blinatumomab did not abrogate the risk of extramedullary relapse. The incorporation of extramedullary assessment and the intensification of CNS prophylaxis may help in addressing extramedullary failure. LAY SUMMARY Extramedullary failure is common during blinatumomab therapy for relapsed/refractory acute lymphoblastic leukemia. A history of extramedullary disease predicts an inferior response to blinatumomab therapy and a higher risk for relapse/progression at extramedullary sites. Most extramedullary failure cases retain CD19 expression.

Efficacy of PTCy after mismatched unrelated donor (MMUD) HCT is unknown. In this pilot clinical trial, we enrolled 38 patients with hematologic malignancies scheduled to undergo MMUD-HCT (≥6/8 HLA-matched donors) onto 1 of 2 conditioning strata: myeloablative using fludarabine and fractionated total body irradiation (n = 19) or reduced intensity with fludarabine/melphalan (n = 19). Graft source was peripheral blood stem cells (PBSCs), and GVHD prophylaxis was PTCy, tacrolimus, and mycophenolate mofetil. Patients’ median age was 53 years (range, 21-72 years). Median number of HLA mismatches was 2 (range, 1-4) of 12 loci. Twenty-three patients (61%) were considered racial (n = 12) or ethnic (n = 11) minorities. Median time to neutrophil engraftment was 16 days (range, 13-35 days). With a median follow-up of 18.3 months (range, 4.3-25.0 months) for surviving patients, 1-year overall survival (OS) and GVHD-free/relapse-free survival (GRFS) were 87% (95% confidence interval [CI]: 71-94) and 68% (95% CI: 51-81), respectively. Cumulative incidence of nonrelapse mortality at 100 days and 1 year were 0% and 11% (95% CI: 4-27), respectively, whereas relapse/progression was 11% (95% CI: 4-27). Cumulative incidence of 100-day acute GVHD grades 2-4 and 3-4 and 1-year chronic GVHD were 50% (95% CI: 36-69), 18% (95% CI: 9-36), and 48% (95% CI: 34-68), respectively. The rate of moderate/severe chronic GVHD was 3% in the entire cohort. We showed highly promising OS/GRFS rates with an acceptable risk profile after PBSC-MMUD-HCT with PTCy. This trial was registered at www.clinicaltrials.gov as #NCT03128359.

We report results of our prospective pilot trial evaluating safety/feasibility of peritransplantation ruxolitinib for myelofibrosis treatment. Primary objectives were to determine safety and maximum tolerated dose (MTD) of ruxolitinib. Ruxolitinib was administered at 2 dose levels (DLs) of 5 and 10 mg twice daily, with fludarabine/melphalan conditioning regimen and tacrolimus/sirolimus graft-versus-host disease (GVHD) prophylaxis. We enrolled 6 and 12 patients at DL1 and DL2, respectively. Median age at transplantation was 65 years (range, 25-73). Per Dynamic International Prognostic Scoring System, 4 patients were high and 14 intermediate risk. Peripheral blood stem cells were graft source from matched sibling (n = 5) or unrelated (n = 13) donor. At each DL, 1 patient developed dose-limiting toxicities (DLTs): grade 3 cardiac and gastrointestinal with grade 4 pulmonary DLTs in DL1, and grade 3 kidney injury in DL2. All patients achieved engraftment. Grade 2 to 4 and 3 to 4 acute GVHD cumulative incidence was 17% (95% confidence interval [CI], 6-47) and 11% (95% CI, 3-41), respectively. Cumulative incidence of 1-year chronic GVHD was 42% (95% CI, 24-74). With 22.6-month (range, 6.2-25.8) median follow-up in surviving patients, 1-year overall and progression-free survival were 77% (95% CI, 50-91) and 71% (95% CI, 44-87), respectively. Causes of death (n = 4) were cardiac arrest, GVHD, respiratory failure, and refractory GVHD of liver. Our results show peritransplantation ruxolitinib is safe and well tolerated at MTD of 10 mg twice daily and associated with dose-dependent pharmacokinetic and cytokine profile. Early efficacy data are highly promising in high-risk older patients with myelofibrosis. This trial was registered at www.clinicaltrials.gov as #NCT02917096.

A mismatch at HLA-DPB1 locus is associated with higher acute GVHD and lower relapse rate after myeloablative (MAC) allogeneic hematopoietic cell transplantation (alloHCT). Also, in MAC setting, mismatch permissiveness and expression level impact alloHCT outcomes. However, in reduced intensity conditioning (RIC), DP mismatch effect on transplant outcomes is unknown. We retrospectively evaluated DP mismatch influence (number, permissiveness, and expression) on HCT outcomes in 310 patients with high-resolution typing (HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1), who underwent RIC HCT. By multivariable analysis, 11/12 had better overall survival (OS) and relapse vs. 12/12 (HR = 1.61 and 2.02; p = 0.04 and 0.01, respectively) and better OS vs. 10/12 (HR = 1.68; p = 0.02). Within the 11/12, nonpermissive (NoPR) mismatch was associated with higher risk of grade II-IV acute GVHD (HR = 1.97; p = 0.005) and nonrelapse mortality (HR = 2.13; p = 0.02) vs. permissive (PR). Grouping 11/12 based on the DP expression conferred higher mortality (HR = 3.78; p = 0.003) when low expressers received a graft from high expressers (AG) vs. low expressers (AA). Better OS was achieved in PR 11/12, when expression was low in patient and donor (AA) vs. all other combinations. Therefore, in RIC HCT, a single-DP mismatch has a protective role, especially in permissive setting, when donor and recipient are low expressers.

Background Mutations in isocitrate dehydrogenase (IDH)1/2 genes result in nicotinamide adenine dinucleotide phosphate-dependent reduction of α-ketoglutarate and formation of 2-hydroxyglutarate, which blocks normal cellular differentiation and promotes leukemogenesis. Nearly 20% of acute myeloid leukemia (AML) patients carry IDH1/2 mutations. Although multiple investigators have described the prognostic implications of IDH mutations in AML patients receiving chemotherapy, the effect of these mutations on outcomes after allogeneic (allo) hematopoietic cell transplantation (HCT) is unknown. Patients and Methods We report on the clinical outcome of a cohort of AML patients, who were tested for IDH mutations and underwent alloHCT at City of Hope (2015-2017). Of a total of 317 screened patients, 99 (31%) underwent alloHCT, of whom 23 carried and 76 did not carry IDH mutations (control). Results No statistical significance was detected in patient’s overall survival (P = .84). With a median follow-up of 7.8 months, 1-year relapse rate of 29% and 13% was seen in the IDH-mutated and control group, respectively (P = .033). IDH1/2 mutation status remained significantly associated with relapse (hazard ratio, 2.8; P = .046) after inclusion of pre-HCT disease status in a multivariable model. Conclusion Our results, despite low patient numbers, indicate that IDH mutations are associated with higher relapse rate after alloHCT. Further prospective studies on post transplantation IDH inhibition is required to improve outcomes in AML patients who carry IDH mutations.

Although allogeneic hematopoietic cell transplantation (allo-HCT) is the only curative treatment for myelofibrosis (MF), data are limited on how molecular markers predict transplantation outcomes. We retrospectively evaluated transplantation outcomes of 110 consecutive MF patients who underwent allo-HCT with a fludarabine/melphalan (Flu/Mel) conditioning regimen at our center and assessed the impact of molecular markers on outcomes based on a 72-gene next-generation sequencing panel and Mutation-Enhanced International Prognostic Scoring System 70+ v2.0 (MIPSS70+ v2.0). With a median follow-up of 63.7 months, the 5-year overall survival (OS) rate was 65% and the nonrelapse mortality (NRM) rate was 17%. In mutational analysis, JAK2 V617F and ASXL1 mutations were the most common. By univariable analysis, higher Dynamic International Prognostic Scoring System scores, unrelated donor type, and very-high-risk cytogenetics were significantly associated with lower OS. Only CBL mutations were significantly associated with lower OS (hazard ratio [HR], 2.64; P = .032) and increased NRM (HR, 3.68; P = .004) after allo-HCT, but CALR, ASXL1, and IDH mutations did not have an impact on transplantation outcomes. Patient classification per MIPSS70 showed worse OS for high-risk (HR, 0.49; P = .039) compared with intermediate-risk patients. Classification per MIPSS70+ v2.0 demonstrated better OS when intermediate-risk patients were compared with high-risk patients (HR, 0.291) and much lower OS when very-high-risk patients were compared with high-risk patients (HR, 5.05; P ≤ .001). In summary, we present one of the largest single-center experiences of Flu/Mel-based allo-HCT, demonstrating that revised cytogenetic changes and MIPSS70+ v2.0 score predict transplantation outcomes, and thus can better inform physicians and patients in making decisions about allo-HCT.

Introduction of novel salvage therapies and expansion of the donor pool within the past decade have allowed more patients with relapsed/refractory (r/r) B cell acute lymphoblastic leukemia (B-ALL) to receive allogeneic hematopoietic cell transplantation (alloHCT). The impact of each salvage therapy on transplant outcomes have not been compared. Our primary objective was to determine post-HCT relapse-free survival (RFS) in adult patients with r/r Philadelphia-chromosome negative (Phneg) B-ALL. We retrospectively studied alloHCT outcomes in 108 adult patients with r/r Phneg B-ALL transplanted in morphological remission achieved by salvage therapy. Salvage therapies were chemotherapy-based combination (n = 45, 42%), blinatumomab (n=43, 40%), inotuzumab (n = 14, 13%), or CAR T cells (n = 6, 6%). The 2-year RFS and overall survival (OS) were 44% and 50%, respectively. In multivariable analysis, conditioning with reduced-intensity or non-myeloablative regimens (hazard ratio [HR] = 2.23, 95% confidence interval [CI], 1.31-3.80; P = .003), having received ≥3 lines of therapies prior to transplant (HR = 2.66, 95% CI, 1.56-4.54; P

The negative impact of iron overload (IO) on outcomes of allogeneic hematopoietic cell transplantation (HCT) is well recognized, but its impact on umbilical cord blood (UCB) transplant outcome is unknown. We retrospectively analyzed outcomes of 150 patients who received UCB-HCT at our institution, stratified by pre-HCT serum ferritin (SF) level of 2000 ng/mL. Two-year overall survival rate among patients with SF >2000 and ≤2000 ng/mL was 26.1% (95% CI, 10.6% to 44.7%) and 52.1% (95% CI, 40.1% to 62.8%), respectively; hazard ratio (HR) = 2.26 (95% CI, 1.28 to 4.00, P = .005). Two-year nonrelapse mortality rate was higher among patients with SF >2000 ng/mL (56.5%; 95% CI, 33.3% to 74.4%) compared to SF ≤2000 ng/mL (30.1%; 95% CI, 20.0% to 40.9%); HR = 2.18 (95% CI, 1.10 to 4.31, P = .025). Neutrophil engraftment at 42 days was 78.3% (95% CI, 53.5% to 90.8%) in patients with SF >2000 ng/mL versus 91.8% (95% CI, 82.1% to 96.4%) in patients with SF ≤2000 ng/mL; HR = 0.58 (95% CI, 0.35 to 0.96, P = .034). A significant difference in platelet engraftment at 3 months was also observed: 52.2% (95% CI, 29.4% to 70.8%) for SF >2000 ng/mL versus 80.8% (95% CI, 69.5% to 88.3%) for SF ≤2000 ng/mL; HR = 0.48 (95% CI, 0.23 to 0.98, P = .044). In conclusion, IO defined by SF of 2000 ng/mL is a strong adverse prognostic factor for UCB-HCT and should be considered when UCB is chosen as the graft source for patients without a fully matched donor.

Acute lymphoblastic leukemia (ALL) is associated with poor survival in older adults, and allogeneic hematopoietic cell transplant (HCT) with reduced-intensity conditioning (RIC) has been an increasingly used strategy in this population. At City of Hope we conducted a retrospective analysis of 72 patients who underwent allogeneic HCT with fludarabine and melphalan (FluMel) as the conditioning regimen between 2005 and 2018, from either a matched sibling or fully matched unrelated donor while in complete remission. Tacrolimus and sirolimus (T/S) were used as graft-versus-host disease (GVHD) prophylaxis. Overall survival and progression-free survival at 4 years post-HCT were 58% and 44%, respectively. The cumulative incidences of relapse/progression and nonrelapse mortality at 4 years were 34% and 22%, respectively. Patients with Philadelphia chromosome–positive (Ph+) ALL had a significantly lower cumulative incidence of relapse/progression (20% versus 48% for patients with Ph-negative status, P = .007). In conclusion, RIC HCT with FluMel conditioning and T/S GVHD prophylaxis was associated with favorable outcomes in patients with Ph+ ALL and should be considered as a viable consolidative therapy for adult patients with ALL.

Historically, outcomes of adult patients with relapsed acute lymphoblastic leukemia (ALL) who fail to enter remission with conventional chemotherapy are very poor. Blinatumomab, a bispecific CD3/CD19 antibody, has shown remarkable activity in relapsed/refractory (r/r) ALL. Although allogeneic hematopoietic cell transplant (HCT) is the recommended consolidation therapy for patients with r/r ALL who respond to salvage therapy, HCT and toxicity outcomes for those who received blinatumomab salvage and HCT remain largely unknown. We treated 89 patients with r/r ALL with blinatumomab, of whom 43 patients (48%) achieved remission. Here we describe our single-center experience in the subset of patients who responded to blinatumomab salvage therapy for eradication of either gross (n = 24) or minimal residual disease (n = 11) before HCT. Overall survival at 1 and 2 years after allogeneic HCT was 77% and 52%, respectively. Leukemia-free survival at 1 and 2 years were 65% and 40%, respectively. Additionally, with blinatumomab administration pre-HCT, no unusual toxicities such as delayed neutrophil/platelet engraftment or graft failure were observed. Acute grades II to IV graft-versus-host disease (GVHD) at day +100 post-HCT was at 43% and 2-year chronic GVHD was 36%, both comparable with historic control subjects. Finally, results of our subset analysis based on pre-HCT minimal residual disease (MRD) status indicated no significant difference in survival outcomes among patients undergoing transplant in MRD-negative status and the entire cohort. In conclusion, based on results of this study, blinatumomab may be considered as a safe and effective agent for r/r ALL patients before HCT.

We compared outcomes of 1461 adult patients with acute lymphoblastic leukemia (ALL) receiving hematopoietic cell transplantation (HCT) from a haploidentical (n = 487) or matched unrelated donor (MUD; n = 974) between January 2005 and June 2018. Graft-versus-host disease (GVHD) prophylaxis was posttransplant cyclophosphamide (PTCy), calcineurin inhibitor (CNI), and mycophenolate mofetil (MMF) for haploidentical, and CNI with MMF or methotrexate with/without antithymoglobulin for MUDs. Haploidentical recipients were matched (1:2 ratio) with MUD controls for sex, conditioning intensity, disease stage, Philadelphia-chromosome status, and cytogenetic risk. In the myeloablative setting, day +28 neutrophil recovery was similar between haploidentical (87%) and MUD (88%) (P = .11). Corresponding rates after reduced-intensity conditioning (RIC) were 84% and 88% (P = .47). The 3-month incidence of grade II-IV acute GVHD (aGVHD) and 3-year chronic GVHD (cGVHD) was similar after haploidentical compared with MUD: myeloablative conditioning, 33% vs 34% (P = .46) for aGVHD and 29% vs 31% for cGVHD (P = .58); RIC, 31% vs 30% (P = .06) for aGVHD and 24% vs 29% for cGVHD (P = .86). Among patients receiving myeloablative regimens, 3-year probabilities of overall survival were 44% and 51% with haploidentical and MUD (P = .56). Corresponding rates after RIC were 43% and 42% (P = .6). In this large multicenter case-matched retrospective analysis, despite the limitations of a registry-based study (ie, unavailability of key elements such as minimal residual disease testing), our analysis indicated that outcomes of patients with ALL undergoing HCT from a haploidentical donor were comparable with 8 of 8 MUD transplantations.

Allogeneic hematopoietic stem cell transplantation (alloHCT) is offered increasingly to elderly patients with hematologic malignancies. However, outcome data in those who are 70 years or older are limited, and no standard conditioning regimen has been established for this population. In this retrospective study we evaluated the outcome of 53 consecutive patients aged 70 years and older who underwent alloHCT with melphalan-based reduced-intensity conditioning (RIC) at City of Hope. Engraftment was prompt, with median time to neutrophil engraftment of 15 days. More than 95% of patients achieved complete donor chimerism within 6 weeks from HCT, consistent with the "semiablative" nature of this regimen. With a median follow-up of 31.1 months, the 2-year overall survival (OS), progression-free survival (PFS), and nonrelapse mortality (NRM) were 68.9%, 63.8%, and 17.0%, respectively. Cumulative incidence of relapse at 1 and 2 years was 17.0% and 19.3%, respectively. One hundred–day cumulative incidence of grades II to IV acute graft-versus-host disease was 37.7% (grades III to IV, 18.9%), and 2-year cumulative incidence of chronic graft-versus-host disease was 61.9% (extensive, 45.9%). The only significant predictor for poor OS was high/very high disease risk index. Transplant-related complications and morbidities observed here did not differ from the commonly expected in younger patients treated with RIC. In conclusion, alloHCT with a melphalan-based conditioning regimen is associated with acceptable toxicities and NRM, lower incidence of relapse, and favorable OS and PFS in patients aged 70 years or older.

The gut microbiota plays an important role in maintaining intestinal homeostasis by regulating the maturation of the mucosal immune system, which constitutes an immune barrier for the integrity of the intestinal tract. In recent years, the role of the human GI microbiota in graft-versus-host disease (GVHD) and other outcomes after allogeneic hematopoietic cell transplantation (HCT) has been increasingly evaluated in observational studies. However, there have been limited interventional trials specifically designed to alter the microbiota of HCT recipients. CBM588 (clostridium butyricum MIYAIRI 588) is a novel Live Biotherapeutic Product (LBP) that produces short chain organic acids, mainly butyric acid, which plays a key role in the maintenance of colonic homeostasis by regulating fluid and electrolyte uptake, epithelial cell growth, and inflammatory responses. In this pilot trial (NCT03922035) we sought to determine the safety, feasibility, biologic activities, and preliminary efficacy of CBM588 in HCT recipients. Patients age ≥18 years, scheduled to undergo HCT from an 8/8 or 7/8 matched related/unrelated donor with reduced intensity conditioning (RIC) were eligible. Following the patient safety lead-in (SLI; n=6), 30 patients were randomized (1:1 ratio) to receive either standard peri-transplant supportive care alone (control arm) or with CBM588 (treatment arm, open label) at the fixed dose of 160 mg orally (2x/day) from day -8 or hospital admission until day +28 or discharge (figure 1). Patients received prophylactic antibiotics per intuitional SOPs. Study objectives were to evaluate the safety/feasibility of CBM588 (Primary), and to compare the incidence and severity of adverse events (AE), HCT outcomes including GVHD, and gut microbiome diversity between the Treatment and Control arms. Feasibility was defined as the ability to consume CDM588 for 14 days during the SLI phase. For microbiome analysis, we isolated DNA from weekly collected stool samples, and amplified the V4 region of the bacterial 16S rRNA gene from each total DNA sample. Between April, 2018 and January, 2020, we enrolled 36 patients (20 were female) at the median age of 66 years (range: 34-77). The indication for HCT was Leukemias (n=22), MDS (n=5), lymphoma (n=3), myeloma (n=3), or other (n=3). All but one patient received fludarabine/melphalan-based RIC and tacrolimus/sirolimus-based GVHD prophylaxis. Graft source was peripheral blood stem cell from a matched related (n=13) or unrelated (n=23) donor (Table 1). One patient assigned to the Treatment arm declined to receive CBM588 before the first dose; but remained on the study with clinical data/biospecimen collections and safety/feasibility/biologic endpoints were analyzed as treated for this patient. All the other patients who were assigned to the treatment arm (n=21, including the patients in SLI segment) were able to take the prescribed study drug; with the median 52 doses (range: 0-55), and 19 of 21 subjects (90.5%) consumed at least 14 days of the study drug. There were no serious adverse events (SAE) related to CBM588. The overall AEs and infection- or GI-specific AEs were similar between the Treatment and Control arms. All but one patient (who died of sepsis in the Control arm - on day 8) engrafted with a median of 15 days for neutrophils. The 100-day non-relapse mortality (NRM) was 0% in the Treatment and 6.7% in the Control arm. According to the intent-to-treat principle, acute GVHD (grade 2-4) was observed in 4 of 15 patients in the Treatment arm and 5 of 15 in the Control arm. The lower GI GVHD was seen in 2 patients in the Treatment and 4 in the control arm. As treated analyses showed the overall grade 2-4 GVHD in 3 of 14 (21.4%) with the use of CBM588 and 6 of 16 (37.5%) without CBM588 (one case of lower GI GVHD with CBM, 5 cases without; (Table 2). The Shannon Diversity Index was similar between the two groups at each time point tested. (Figure 1). However, had favorable microbial profile was detected as the pathogens Enterobacteriaceae, Clostridium baratii, and Clostridiodes difficile were reduced in the treatment group. (Figure 2) In summary, our data demonstrate the feasibility and safety of CBM588 administration during the peri-transplant period, which was associated with an intended biologic impact on the gut microbiome, and an early favorable sign of GI-GVHD incidence and HCT outcomes in this older population who underwent RIC HCT. Figure 1 Figure 1. Disclosures Dadwal: Astellas: Speakers Bureau; Aseptiscope: Consultancy; Shire/Takeda: Research Funding; AlloVir: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Other: Investigator; Karius: Other: Investigator. Pullarkat: AbbVie, Amgen, Genentech, Jazz Pharmaceuticals, Novartis, Pfizer, and Servier: Membership on an entity's Board of Directors or advisory committees; Amgen, Dova, and Novartis: Consultancy, Honoraria. Al Malki: CareDx: Consultancy; Neximmune: Consultancy; Hansa Biopharma: Consultancy; Rigel Pharma: Consultancy; Jazz Pharmaceuticals, Inc.: Consultancy. Ali: Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees. Artz: Radiology Partners: Other: Spouse has equity interest in Radiology Partners, a private radiology physician practice. Stein: Amgen: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; Stemline: Speakers Bureau. Budde: Roche: Consultancy; BeiGene: Consultancy; IGM Biosciences: Research Funding; Merck, Inc: Research Funding; Gilead: Consultancy; AstraZeneca: Research Funding; Mustang Bio, Inc: Research Funding; Novartis: Consultancy; Amgen: Research Funding. Popplewell: Hoffman La Roche: Other: Food; Pfizer: Other: Travel; Novartis: Other: Travel. Marcucci: Novartis: Other: Speaker and advisory scientific board meetings; Agios: Other: Speaker and advisory scientific board meetings; Abbvie: Other: Speaker and advisory scientific board meetings. Forman: Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company; Allogene: Consultancy.

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) represents 20% of newly diagnosed adults with B cell ALL (B-ALL), with increased frequency in adults with Hispanic ethnicity. Ph-like ALL harbors a diverse range of genetic alterations with CRLF2-rearrangement/overexpression (CRLF2r) being the most common one. When treated with chemotherapy, Ph-like ALL is associated with inferior response, high relapse rate, and low overall survival (OS). Allogenic hematopoietic cell transplantation (alloHCT) is a well-established curative modality for adults with high-risk ALL. Considering that Ph-like ALL is a high-risk leukemia subtype, it is appealing to recommend alloHCT consolidation routinely for this entity in adults. However, large datasets describing alloHCT outcomes in patients with Ph-like ALL is lacking. In this study, we retrospectively analyzed archived DNA samples from 125 consecutive adult patients with Ph-negative ALL who underwent alloHCT in complete remission (CR) at our center between 2006 and 2020. Classification of Ph-like versus non-Ph-like was performed according to WHO 2017 classification using accumulative results from RNAseq, conventional cytogenetics, FISH, and whole genome array studies. A proprietary RNA sequencing assay covering 1,188 genomic regions from 235 genes was designed to detect all the clinically significant fusions and expressions for Ph-like ALLs. In addition, an algorithm employing the RNAseq data was developed to further aid in classification of Ph-like ALL. Boruta feature selection (R package "Boruta" version 7.0.0) was used to identify the most informative genes for prediction with an out-of-bag error of 9.62%. The following 24 genes were identified: CCND2, SOX11, PAX5, DENND3, RARA, MME, ID4, SH3BP5, HOXA9, CA6, MUC4, CYB5R2, CD97, EPOR, IL2RA, RAB29, PDGFRA, MLLT4, RHOA, JAK2, DNM2, ASXL1, BCL2A1, and KDR. The results were used to predict Ph-like status by a Random Forest model (R package "randomForest" version 4.6-14) that generates a probability/similarity score of Ph gene expression profile (Ph score). The testing samples with Ph score over 50% and without other subtype-defining lesions are defined as Ph-like. We identified Ph-like genetic alterations in 66 (53%) patients, of whom 42 (66%) were carrying CRLF2r and 24 (36%) were non-CRLF2r. Compared to non-Ph-like ALL (n=59), Ph-like ALL patients were younger (42 vs 36 years old, p=0.022), more frequently Hispanic (56% vs 83%, p=0.003), less frequently carried high-risk cytogenetics (39% vs 9%, p1 regimen to achieve their first complete remission (CR1; 30% vs 55%, p=0.025). However, we did not detect any significant difference between the two groups in disease status (CR1 vs. CD2/3; p=0.81) or minimal residual disease clearance at the time of HCT (negative vs. positive; p=0.17), donor type (match related/unrelated vs mismatch vs haplo vs cord blood; p=0.88), conditioning regimen intensity (myeloablative vs non-myeloablative/ reduced intensity; p=0.59), GVHD prophylaxis (tacrolimus/sirolimus-based vs PTCy-based; p=0.84), Karnofsky Performance Status (KPS; p=0.24) or HCT comorbidity index (0 vs 1-2 vs >2; p=0.42). With the median follow-up of 3.2 years, we observed similar 3-years leukemia-free survival (LFS) (40% vs 47%; p=0.95), OS (44% vs 54%; p=0.96), relapse rate (33% vs 34%; p=0.96) and non-relapse mortality (NRM) (27% vs 19%; p=0.92) between non-Ph-like and Ph-like ALL patients, respectively. (Figure) In multivariable analysis, disease status at the time of HCT (HR=2.63, 95% CI: 1.57-4.41; p In conclusion, our data suggest that alloHCT consolidation results in favorable outcomes in adult patients with Ph-like ALL with comparable outcomes to non-Ph-like ALL. Our data support utilization of alloHCT for adults with Ph-like ALL in CR. Figure 1 Figure 1. Disclosures Al Malki: Neximmune: Consultancy; Rigel Pharma: Consultancy; Jazz Pharmaceuticals, Inc.: Consultancy; Hansa Biopharma: Consultancy; CareDx: Consultancy. Khaled: Omeros: Honoraria; Alexion: Honoraria, Speakers Bureau; Janssen: Current Employment; Astellas: Honoraria; Jazz: Honoraria. Ali: Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees. Aribi: Seagen: Consultancy. Mei: BMS: Research Funding; Epizyme: Research Funding; TG Therapeutics: Research Funding; EUSA: Honoraria; Janssen: Honoraria; Morphosys: Research Funding; Beigene: Research Funding. Koller: Novartis: Consultancy. Artz: Radiology Partners: Other: Spouse has equity interest in Radiology Partners, a private radiology physician practice. Stein: Amgen: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; Stemline: Speakers Bureau. Marcucci: Abbvie: Other: Speaker and advisory scientific board meetings; Novartis: Other: Speaker and advisory scientific board meetings; Agios: Other: Speaker and advisory scientific board meetings. Forman: Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company; Allogene: Consultancy. Pullarkat: AbbVie, Amgen, Genentech, Jazz Pharmaceuticals, Novartis, Pfizer, and Servier: Membership on an entity's Board of Directors or advisory committees; Amgen, Dova, and Novartis: Consultancy, Honoraria.

Graft-versus-host disease (GVHD) remains a major cause of treatment failure after allogeneic hematopoietic cell transplantation (alloHCT). In HLA-mismatched donor setting, indirect presentation of allogeneic peptides from recipient's mismatched HLA class I or II proteins by donor or recipient antigen presenting cells can be an immunogenic driver of GVHD. However, the potential diversity of such antigens is large, and predicting them in a systematic manner has proven challenging. Using a novel, highly-multiplexed peptide-MHC binding assay (MHC-PepSeq) we sought to 1) identify allogeneic peptides derived from mismatched HLA protein that can be efficiently presented by HLA-DR, and 2) explore the possibility that the frequency of these HLA-DRB1 binding allopeptides may be predictive of clinical GVHD in HLA-DPB1 mismatched donor/recipient pairs. Using publicly-available population allele frequency data (allelefrequencies.net), we identified a set of class I and II sequences that cover >95% of alleles at each of 9 human HLA-loci (-A, -B, -C, -DRA1,-DRB1, -DQA1, -DQB1, -DPA1, -DPB1) in 3 major US populations (European Caucasian, African American, Mexican Chicano). When represented in the form of densely overlapping tiled 15-mer peptides, 7,744 unique 15mers were identified. We encoded these peptides into DNA oligonucleotides and used the PepSeq parallel synthesis protocol to generate a library of the corresponding DNA-barcoded peptides. The library was incubated with recombinantly-expressed full-length HLA proteins, washed, eluted, amplified, and sequenced to identify the various HLA-derived peptides that bind to the assayed HLA proteins (Figure 1). In the current study, DPB1-derived allopeptides in the setting of HLA-A, B, C, DRB1, and DQB1 (10/10) matched unrelated (MUD) HCT donors with a mismatch in DPB1 were investigated. The peptide library was assayed for binding to the DRB1*07:01 protein, selected since it was the common allele in this cohort. We identified 327 patients who were transplanted at our center and met these criteria. For each case, we used comprehensive in silico tiling to identify HLA-DPA and DPB-derived peptides present in the recipient but absent in the donor. This set was intersected with the peptides identified as binders to HLA-DRB1*07:01 in the 7,744-plex MHC-PepSeq assay, to arrive at a donor-recipient pair-specific set of 'allopeptides' Overall, we identified such allopeptide at the median of 0 (range: 0-8) across the 327 cases. Next, we examined an association between the number of allopeptides and acute GVHD in the cohort of 94 patients with positive HLA-DRB1*07:01. Median age at alloHCT was 60 years (range: 19-78), 53% males, 1.% bone marrow graft and only 7% female to male donors. Ablative (TBI) conditioning was delivered to 34%) pts. 83% received Tacrolimus/Sirolimus-based, and 9% received post-transplant cyclophosphamide-based GVHD prophylaxis. Patient/HCT characteristics are summarized in Table 1. In this cohort, 18% had no DPB1 mismatch, 54% had a single and 28% had double mismatches, with 21% pts carrying non-permissive DPB1 mismatches. Allopeptide score was 0 in 75% of pts. Non-permissive mismatch 9 (39%) vs. 11 (16%) were more likely to have allopeptide score ≥1 and similarly double mismatches 11 (48%) vs. 15 (21%) were more likely to have allopeptide score of ≥1. Among pts with ≥1 allopeptide score 14 (61%) had DPB1 matched or permissive mismatch. The cumulative incidence of grade 2-4 acute GVHD was 40.8% (range: 29-52) in pts with no allopeptides from DPB1 compared with 56% (range: 34-74) in those with ≥1 allopeptides (p=0.259) (Figure 2). The cumulative incidence of grade 3-4 acute GVHD and chronic GVHD were similar between allopeptide 0 vs. ≥1. Together, we show that the "MHC-PepSeq" assay can identify novel candidate HLA-derived allopeptides in 10/10 MUD HCTs. The number of such peptides are relatively low - with a majority having no allopeptide. In an exploratory analysis in a selected cohort of patients with HLA-DRB1*0701 in the setting of 10/10 MUD HCT, the number of allopeptides in our assay may be predictive of GVHD. The expanded analyses on other HLA-DRB1 restriction elements are underway. Figure 1 Figure 1. Disclosures Al Malki: CareDx: Consultancy; Hansa Biopharma: Consultancy; Neximmune: Consultancy; Jazz Pharmaceuticals, Inc.: Consultancy; Rigel Pharma: Consultancy. Ali: BMS: Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees. Forman: Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company; Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Allogene: Consultancy.

CMV recipient seropositivity (R+) and CMVi are independent risk factors for increased mortality after alloHCT. Preemptive therapy (PET) was standard of care until LTV approval by the FDA in November 2017 for CMVi prevention in CMV R+ alloHCT patients (pts). In a registration trial, LTV led to a significant reduction in clinically significant CMVi (CS-CMVi) defined as CMVi requiring PET in both high-risk (HR) or low-risk (LR) recipients. In the HR-group, defined as mismatched related / unrelated donor with at least one mismatch in one of the four HLA-gene loci of HLA-A, -B, -C or -DRB1, haploidentical donor, umbilical cord source or grade ≥2 acute graft-versus-host disease (aGVHD) at randomization, the impact of LTV on CS-CMVi was more robust. Small studies have confirmed the positive impact of LTV on CS-CMVi. Here, we compared the natural history of CMVi and CS-CMVi between the pre-LTV and LTV era in the first 100 days after HR-alloHCT. We also explored the impact on non-relapse mortality (NRM), overall survival (OS), disease free survival (DFS), and incidence of aGVHD between the two eras. In this IRB approved retrospective study, we identified 450 consecutive HR-alloHCT pts who underwent their first HCT from 1/1/2016 to 12/31/2020 at our center. Pre-LTV era was from 1/1/2016 to 2/28/2018 and LTV era was from 3/1/2018 onwards when prophylaxis became standard of care (SOC) for all R+ alloHCT at our institution. In the HR-alloHCT, the uptake of the new SOC was consistent in all HR-R+ pts beginning LTV prophylaxis on day +7 post-HCT. We defined R+ HR-alloHCT pts at high-risk for CMVi or CS-CMVi as described above except for aGVHD (not recorded at time of institution of LTV). CMVi was defined as first time viral load (VL) of >500 genomic copies/ml (gc/ml). CS-CMVi was defined as a VL >500 gc/ml (910 IU/ml) on two consecutive tests done atleast 48 hours apart, that triggered PET (ganciclovir, valganciclovir, foscarnet, cidofovir), or had identification of CMV end organ disease . The incidence of CMVi and CS-CMVi in R+ allo-HCT was compared by LTV era using Gray test. Kaplan-Meier curves and log-rank tests were used for OS and DFS by LTV era. NRM, relapse, acute and chronic GVHD were compared using cumulative incidence curves and Gray test. All tests were 2-sided at 0.05 level. Of the 450 HR-alloHCT pts, 146 were R+ in pre-LTV vs. 246 R+ in LTV era. R+ patient, their eligible underlying disease, and HCT characteristics are shown in Table 1. There was a significant reduction in both CMVi and CS-CMVi in LTV era vs pre-LTV era (24.1% vs 45.2%, and 22.3% vs 44.5% respectively; p Although there were no significant differences in OS, DFS, NRM, relapse, and chronic GVHD between the two eras at 6, 12, and 18 months post-HCT in R+ pts, a trend towards improved OS and DFS in LTV era was noted (p=0.06 and p=0.07) in this patient population. There was a significantly lower rate of grade III-IV acute GVHD in the LTV era (9.2% vs 17.8% at day 100, p=0.012 with HR = 0.49). No case of CMV disease was identified in the first 100 days. LTV has substantially reduced CS-CMVi in the first 100 days post-HCT in HR-R+ pts and resultant burden from PET. We identified a significant reduction in grade III - IV aGVHD in LTV era suggesting that with reduced CMVi, LTV may have a salutary impact on development of aGVHD; this is in agreement with studies showing bidirectional relationship between CMVi and onset of aGVHD. We did not observe a significant difference in OS, DFS, NRM amongst the two eras but there was trend towards higher OS and DFS in LTV era that requires further assessment in a larger multicenter cohort. Lastly, significant burden persists from CS-CMVi in this patient population during the first 100 days of alloHCT that underscores the need of efforts to identify other novel methods to mitigate it. One of the limitations in the LTV era is identifying the clinical scenarios surrounding the CMVi and CS-CMVi that may relate to compliance, absorption from gastrointestinal tract, and affordability or coverage of LTV after discharge from hospital. Figure 1 Figure 1. Disclosures Dadwal: Astellas: Speakers Bureau; Aseptiscope: Consultancy; AlloVir: Research Funding; Shire/Takeda: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Other: Investigator; Karius: Other: Investigator. Marcucci: Novartis: Other: Speaker and advisory scientific board meetings; Agios: Other: Speaker and advisory scientific board meetings; Abbvie: Other: Speaker and advisory scientific board meetings. Taplitz: Merck: Membership on an entity's Board of Directors or advisory committees. Artz: Radiology Partners: Other: Spouse has equity interest in Radiology Partners, a private radiology physician practice. Stein: Amgen: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; Stemline: Speakers Bureau. Forman: Allogene: Consultancy; Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company. Al Malki: Neximmune: Consultancy; Jazz Pharmaceuticals, Inc.: Consultancy; CareDx: Consultancy; Rigel Pharma: Consultancy; Hansa Biopharma: Consultancy.

Cytomegalovirus reactivation commonly referred to as CMV infection (CMVi) is a frequent event after allogeneic hematopoietic cell transplantation (HCT), with studies associating CMVi within the first 100 days post-HCT with higher risk of non-relapse mortality (NRM) and decreased overall survival (OS). In addition, understanding the impact of CMVi on resource utilization during the primary HCT admission is critical. Together, this knowledge of epidemiology and resource utilization may be used to inform preventive strategies to minimize CMVi, e.g., use of antiviral agent letermovir. After receiving IRB approval, we retrospectively reviewed institutional electronic medical records and CMVi database from 824 patients who underwent their first allogeneic HCT between 2011 and 2016 at City of Hope (pre-letermovir era). Patients were censored at death, disease relapse or lost to follow up. Data collected: demographics, HCT indication, conditioning regimen, CMV serostatus of the donor and recipient (D/R), length of stay (LOS) for primary HCT admission (all allo HCT were performed as inpatient), readmission rates in first 100 days, and use of supportive care. CMV viral load of >250 genomic copies/ml constituted a diagnosis of CMVi. CMV viral load surveillance in MUD recipients began at engraftment or day +21 post-HCT, whichever occurred earlier. For Haplo and cord blood (CB) HCT, CMV viral load surveillance started on day +14. The primary endpoint of the study was LOS for HCT admission. Supportive care use, transfusions, growth factors and antiviral usage were secondary endpoints. The differences in resource utilization between different groups were examined by CMVi during the primary HCT admission period, using Wilcoxon test or chi-square test whenever appropriate. Median age of patients at the time of HCT was 52 years (range: 1-78), with 57% of patients being male. The most common diagnoses included: AML (39%), ALL (21%) and MDS/MPN (17%). Patients underwent MUD (n=627, 76%), Haplo (n=102, 12%), or CB-HCT (n=95, 12%), and 44% of patients received myeloablative conditioning regimen. Majority of the patients were CMV seropositive (83.7%). Graft source was peripheral blood stem cells in 75% of the recipients. Most commonly used graft-versus-host disease prophylaxis consisted of post-transplant cyclophosphamide (100%), Tacrolimus/sirolimus (83%), and cyclosporine/cellcept (78%) in Haplo, MUD, and CB-HCT recipients, respectively. During the primary HCT admission, rate of CMVi was 7%, 36% and 28% in all of MUD, Haplo, and CB-HCT, respectively (compared to 25%, 71.6%, and 50.5% in MUD, Haplo and CB-HCT respectively in the first 100 days after HCT). Rate of CMVi in CMV+ recipients was 8.2% in MUD, 41.6% Haplo and 34.2% in CB-HCT (Table 1). Majority of patients with CMVi received antiviral therapy (85.8%), with Haplo and CB-HCT more likely to be treated than MUD (p=0.023). LOS was longer among CMVi patients compared to no CMVi patients in each donor type, median of 59 vs. 36 days for the overall cohort (p0.2). Transfusion of packed red blood cells (PRBC) and platelet units were significantly higher among CMVi recipients of MUD and Haplo (p0.82). There was no significant difference in hospital readmission by CMVi across donor type in the first 100 days (p>0.5). In conclusion, the rate of CMVi during primary HCT admission was high, particularly in the Haplo and Cord HCT (>50% of the CMVi occurring within 100 days of HCT). Given the relatively high CMV viral load cut-off values and later CMV surveillance initiation, the rate could, in fact, have been underestimated in our cohort. CMVi during primary HCT admission was associated with significantly higher health care resource utilization; longer hospital LOS and supportive care utilization (CMV specific antiviral usage, transfusion and growth factors use). Prophylactic strategies to prevent early CMVi in alloHCT should be considered to decrease NRM and improve value based care delivery. Disclosures Dadwal: Shire/ Takeda: Research Funding; Karius: Research Funding; Astellas: Speakers Bureau; Janssen: Other: Advisory board meeting; Ansun Biopharma: Research Funding; Chimerix: Research Funding; Gilead: Research Funding; Merck: Consultancy, Honoraria, Other: Advisory board meeting, Research Funding, Speakers Bureau. Pullarkat:Dova: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genetech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Stein:Stemline: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Taplitz:Merck: Other: Immunocompromised Advisory Group. Al Malki:Neximmune: Consultancy; Rigel Pharma: Consultancy; Jazz Pharmacuticals, Inc: Consultancy. Nakamura:NapaJen Pharma: Consultancy; Magenta Therapeutics: Other: Advisory board meeting; Alexion: Other: Support on a meeting presentation; Kyowa-Kirin: Other: Support on a meeting presentation; Celgene: Other: Support on seminar; Viracor: Consultancy; Merck: Other: advisory board meeting; Kadmon Corporation: Other: Advisory board meeting.

Peripheral blood stem cell (PBSC) as a graft source compared to bone marrow has been reported to result in lower risk of relapse after haploidentical hematopoietic cell transplantation (haplo-HCT) with use of post-transplant cyclophosphamide (PTCy) as a graft-versus-host-disease (GvHD) prophylaxis. However, cytokine release syndrome (CRS) is a common complication of this platform that can affect the outcomes of patients after PBSC haplo-HCT. CRS occurs due to rapid activation and proliferation of alloreactive donor T cells resulting in the elevated secretion of inflammatory cytokines. In this study, we sought to examine the risk factors for CRS and the effect of CRS severity on outcomes of PBSC haplo-HCT. We identified total of 271 consecutive patients with hematological malignancies who received their first PBSC haplo-HCT with PTCy-based GVHD prophylaxis at City of Hope (n=157) or Moffitt (n=114) Cancer Centers between 2014 and 2019. The median patient age at HCT was 54 years (INQ range, 37-64) for the entire cohort and 48% of the patients had HCT-CI ³3. Close to 70% of the study cohort had acute leukemia and 33% of all patients had high/very high-risk disease risk index. Myeloablative conditioning was used in 52% of the cases and 81% of all HCT recipients were CMV seropositive. The median donor age at HCT was 33 years (INQ range, 26-43). The HLA -A, -B, -C, -DRB1, -DQB1, or -DPB1 mismatch between the recipient and the donor in the GVH direction was 5/10 in 51%, 4/10 in 29% and £3/10 in 20% of cases. Offspring donors were used in 54% of the patients, sibling donors in 35%, and parent/other relative donors in 11%. Female donors to male recipients were used in only 22% of patients. The median infused CD34 dose was 5.25 x106 cells/kg (range, 2.3-22.4x106) and the CD3 dose was 2.48x108 cells/kg (range, 0.002-8.88 x108). CRS of any grade by ASTCT criteria was observed in 92% of study patients within first 7 days of HCT: 54% had grade 1, 39% grade 2, and 5.2% grade 3-4. Infused cell doses of CD34 >5x106 cells/kg and of CD3 >2.5x108 cells/kg had no significant effect on grade 3-4 CRS. On multivariable analysis, the use of reduced-intensity conditioning (RIC) was associated with increased grade 2-4 CRS (HR = 1.6, 95% CI: 1.11.-2.33, p=0.01) and grade 3-4 CRS (HR = 14.7, 95% CI: 1.97-109.5, p=0.009) compared with the myeloablative conditioning. Donor 5/10 HLA-mismatch was also associated with increased grade 2-4 CRS (HR = 1.5, 95% CI: 1.05-2.18; p=0.03) and grade 3-4 CRS (HR = 3.50, 95% CI: 1.00-12.32; p=0.05) compared with £4/10 HLA-mismatch. Non-relapse mortality (NRM) at day 100, and 1-year overall survival (OS) by CRS severity is shown in Figure. Comparing with the grade 0-1 CRS in multivariable analysis (Table), increase in CRS severity was associated with lower probability of neutrophil engraftment (HR = 0.9 for grade 2 and HR = 0.4 for grade 3-4; p=0.03). Increased CRS severity as compared to the grade 0-1 was also predictive of higher risks of NRM (HR = 1.6, 95% CI: 0.95-2.79 for grade 2 and HR = 6.6, 95% CI: 3.12-13.78 for grade 3-4; p We conclude that CRS is a common complication after PB haplo-HCT/PTCy. CRS severity is associated with post-HCT outcomes with grade 3-4 CRS associated with the highest risk of NRM and overall mortality after HCT. Infused CD34 or CD3 cell doses effect on CRS is unclear. RIC and higher degree of HLA-mismatch are predictive of higher-grade CRS. Identification of modifiable risk factors can help to mitigate the risk for serious CRS and subsequent mortality after PB haplo-HCT/PTCy. Figure 1 Disclosures Nishihori: Karyopharm: Other: Research support to institution; Novartis: Other: Research support to institution. Pidala:CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Takeda: Research Funding; Janssen: Research Funding; Johnson and Johnson: Research Funding; Pharmacyclics: Research Funding; Abbvie: Research Funding; BMS: Research Funding; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees. Nakamura:Merck: Other: advisory board meeting; Alexion: Other: Support on a meeting presentation; Kyowa-Kirin: Other: Support on a meeting presentation; Celgene: Other: Support on seminar; Magenta Therapeutics: Other: Advisory board meeting; Viracor: Consultancy; Kadmon Corporation: Other: Advisory board meeting; NapaJen Pharma: Consultancy. Al Malki:Rigel Pharma: Consultancy; Jazz Pharmacuticals, Inc: Consultancy; Neximmune: Consultancy. Bejanyan:Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees.

Chronic graft-versus-host disease (cGVHD) is a late-occurring inflammatory condition post- allogeneic hematopoietic cell transplantation (HCT), which involves multiple distinct interactions among alloreactive dysregulated T and B cells. Prior studies have shown that autoantibodies to platelet-derived growth factor receptor (PDGFR) induce tyrosine phosphorylation and accumulation of Reactive Oxygen Species (ROS), causing expression of collagen type-1 gene through the Ha-Ras-Erk1/2–ROS signaling pathway. We hypothesize that antioxidant markers of inflammation (8-OHdG, total antioxidant levels, CXCL4 and pH2Ax) will be elevated in patients with scleroderma cGVHD compared to patients who do not develop cGVHD or have non-scleroderma cGVHD. Patients (n=36) were consented on an IRB-approved protocol for a cross-sectional single time point biospecimen collection. Patients with established cGVHD (n=29) or ≥2 years post-HCT without clinical manifestations of cGVHD (n=7) were included. Patients with cGVHD were divided into Scleroderma cGVHD (n=14) and Non-scleroderma cGVHD (n=15). Median age was 49 (range: 21-69) and 56 years (range: 18-72) for patients with scleroderma (group 1) and without scleroderma or no GVHD (group 2), respectively. Median prior lines of therapy was 3.2 (range: 2-5) for patients in group 1. All patients is group 1 and 77% of patients in group 2 received PBCSs as the graft source. Transplant was from a matched unrelated (group 1: 75%, group 2: 73%) or a matched sibling donor (group 1: 25%, group 2: 23%). Tacrolimus/sirolimus was the most commonly used GVHD prophylactic regimen in both groups (group 1: 83% and group 2: 64%). Peripheral blood samples were drawn at a single time point post-HCT, and serum samples were used for ELISA assays for levels of total antioxidants, 8-OHdG, and CXCL4. Flow cytometric analysis was performed to investigate percentage of Tregs and pH2AX+ cells. There were no differences in the total antioxidant levels, CXCL4 and Tregs between groups 1 and 2. Using a cutoff threshold of 10 ng/ml of 8-OHdG, 11 patients (78%) in group 1 and 9 patients (40.9%) in groups 2 had elevated levels of 8-OHdG (p=0.029, Fisher's exact). Percentage of pH2AX expressing cells was lower in group 2. At the cutoff threshold of 37%, only one patient (7%) in group 1 and 13 patients (59%) in group 2 had more than 37% pH2AX-expressing CD45+ cells in their peripheral blood (p=0.002, Fisher's exact). In conclusion, our pilot cross-sectional study showed that scleroderma cGVHD is associated with increased ROS levels (8-OHdG) without elevation of pH2AX cells in peripheral blood T cells. Our results indicate that ROS elevation in scleroderma patients may be a stress response to inflammatory milieu and is independent of DNA damage. Our data justify further prospective cohort studies to define the role of ROS markers in scleroderma cGVHD and to develop novel strategies to treat/prevent cGVHD.

Transplant outcomes for patients with acute lymphoblastic leukemia (ALL) after haploidentical hematopoietic cell transplantation (haploHCT) with post-transplant cyclophosphamide (PTCy) compared to an HLA matched unrelated donors (MUD) transplantation are unknown. We, therefore retrospectively compared outcomes of 487 patients with ALL who underwent haploHCT with PTCy, reported from the participating centers (TCT-RC and EBMT) from 01/2005 to 06/2018, with a matched cohort of 974 patients (1:2 ratio) who underwent MUD-HCT and were reported to the EBMT. Patients were matched for sex, disease stage (CR1, CR2, other), disease risk (high or others), Philadelphia chromosome status (positive or negative), and conditioning regimen (MAC or RIC). Other significant differences in patient/transplant characteristics were adjusted for. Median age at HCT was 33 years (range: 18-73) for haplo and 36 years (range: 18-76) for MUD; (p=0.024). Median time from diagnosis to transplant was significantly longer in haploHCT (at 6 months: 23% vs. 29%; p=0.024). More patients in the haplo group received a female-to-male transplantation (27% vs. 13%; p With a median follow up of 2 and 3 years in haplo and MUD, respectively, there was no statistical differences in overall survival (OS), (p=0.82); GvHD- and relapse- free survival (GRFS), (p=0.78); relapse rate, (p=0.88); or non-relapse mortality (NRM), (p=0.86) between haplo- and MUD-HCT recipients after adjusting for all covariates. (Fig 1) GvHD rates and severity were not different in patients undergoing haplo compared to those undergoing MUD HCT, possibly due to the use of ATG in 2/3 of patients with MUD HCT. However, mortality related to GVHD was significantly lower in patients undergoing haploHCT (HR= 0.45, p=0.003). We next did subgroup analysis based on conditioning intensity, disease status in first remission, Philadelphia chromosome status, and stem cell source. OS, disease-free survival (DFS), relapse rate and NRM were comparable between patients undergoing haplo and MUD HCT. Engraftment was faster in MUD if RIC was used (HR=0.75, p=0.05), grade 2-4 acute GvHD was lower in haplo if BM was the graft source (HR =0.57, p=0.04). Severe chronic GvHD was lower in haplo if transplant was done in CR1 (HR 0.52, p=0.05) and if BM was the graft source (HR 0.45 p=0.07). In conclusion, in this large retrospective analysis, outcomes of patients with ALL undergoing transplant from a haplo donor with PTCy is comparable with those undergoing an 8/8 MUD transplantations in subgroups analysis and regardless of the disease and Philadelphia chromosome status.

BACKGROUND While tacrolimus and sirolimus (T/S)-based graft-versus-host disease (GvHD) prophylaxis has been effective in preventing acute GvHD post hematopoietic cell transplantation (HCT), its efficacy and long-term outcome in matched (MUD) and mismatched unrelated donor (mMUD) setting is not well defined. METHODS Herein, we evaluated a consecutive case-series of 482 patients who underwent unrelated donor HCT (2005-2013) with T/S-based GvHD prophylaxis. RESULTS With a median follow-up of 6.2 years (range = 2.4-11.3), the 5-year overall survival (OS) and relapse/progression-free survival were 47.5% (95% confidence interval [CI]: 43.0-52.0) and 43.6% (95% CI: 39.1-48.1), respectively; and the 5-year cumulative incidence of nonrelapse mortality (NRM) and relapse were 24.9%, and 31.5%, respectively. In this cohort, mMUD was associated with worse OS (39.0% versus 50.7% at 5 y; P = 0.034), primarily due to greater risk of NRM (33.5% versus 21.7%; P = 0.038). While rates of relapse, acute (II-IV or III-IV) or chronic GvHD (limited or extensive) were not different, death caused by chronic GvHD (20.8% versus 12.8%; P = 0.022) and infection (33.0% versus 18.1%; P < 0.01) were significantly greater in mMUD. In multivariable analysis, high-risk disease (hazard ratio [HR] = 2.21, 95% CI: 1.16-4.23; P < 0.01) and mMUD (HR = 1.55, 95% CI: 1.15-2.08; P = 0.004) were independent predictive factors for OS. CONCLUSIONS T/S-based GvHD prophylaxis is an effective and acceptable GvHD prophylactic regimen. However, survival after mMUD remained poor, possibly related to the severity of chronic GvHD.

BACKGROUND: Ganciclovir (GCV) and foscarnet (FOS) are the most commonly used antivirals for preemptive treatment of cytomegalovirus (CMV) viremia in recipients of allogeneic hematopoietic cell transplantation (alloHCT). The current literature indicates similar efficacy between these agents. Thus, the primary consideration for choice of initial anti-CMV treatment is the safety profile, time period after alloHCT and concern of myelosuppression or renal dysfuction. METHODS: Herein, we retrospectively reviewed medical records of 124 alloHCT recipients who received GCV or FOS between April 27, 2014 and December 31, 2015 during the first year post-transplant. Health care resource use included drug, hospitalization, home health, dialysis, and growth factor costs. RESULTS: Total duration of therapy was longer in the GCV group (37 days vs. 28 days, p=0.21) but hospitalization days were similar (9 days) in both groups. The total treatment cost was significantly lower in the GCV group ($38,100 vs. $59,400, p

Despite of the continuous increase in the number of volunteer donors available through the registry, many patients who require an allogeneic hematopoietic cell transplantation (HCT) cannot find a fully-matched donor. While a mismatched unrelated donor (MMUD) is frequently available, it is associated with inferior outcomes and increased risk of graft-versus-host disease (GvHD). Post-transplant cyclophosphamide (PTCy) has been effective in haploidentical HCT, and increasingly used in matched donor HCTs. However, limited data exist in MMUD setting. We conducted a prospective single center trial (NCT 03128359) of PTCy for MMUD HCT with the primary objective of estimating 1-year GvHD-free relapse/progression-free survival (GRFS). As of October 2019, all planned 39 patients have been enrolled with a median follow up of 11 months (range: 1-23). Here we present the preliminary estimate of 1-year GRFS and other HCT outcomes in two strata; myeloablative conditioning (n=19) using Fludarabine (90 mg/m2) and FTBI (1200 cGy) or reduced intensity conditioning (n=19) using Fludarabine (100 mg/m2) and Melphalan (140 mg/m2 or 100 mg/m2 if >60 years old). Patients between 0 to 75 years of age and KPS of ≥70% with hematologic malignancies undergoing HCT from a 7/8 HLA-matched (A-, B-, C-, and DR-) donor were eligible. Patients with donor specific antibodies to the mismatched HLA-locus were excluded. All patient received PBMCs (3-5 × 106/kg) followed by GVHD prophylaxis consisting of PTCy (50 mg/kg for 2 days), Tacrolimus (1 mg), and mycophenolate mofetil (1 gr 3 × a day). Median age at the time of HCT was 53 years (range: 21-72), and 50% of patients were male. Disease risk was low in 47% (n=18), intermediate in 37% (n=14), and high in 16% of the patients (n=6). At transplant, 29 patients were in complete remission, and 9 had active disease. HCT-CI was 0 in six (16%) and 1-2 in 15 (39%) and >2 in 17 (45%) patients. Donors' median age was 32 years (range: 19-53) and donors were mismatched at HLA-A (n=14), -B (n=12), -C (n=8), or DR-loci (n=5). Median number of mismatches was 2 of 12 (range: 1-4). Female to male donor HCT was in 11% of recipients. Neutrophil engraftment occurred in all patients (median time to engraft: 16 days; range 13-35). One-year overall survival (OS) and GRFS were 92% (95% CI: 70-98) and 70% (95% CI: 51-83), respectively. Non-relapse mortality and relapse rate at 1 year were at 8% (95% CI: 2-29) and 13% (95% CI: 5-34), respectively. Cumulative incidence of day 100 acute GvHD grade 2-4 was 50% (95% CI: 35-71) and 1-year chronic GvHD was 56% (95% CI: 39-81). No severe chronic GvHD by the NIH criteria was observed. In conclusion, the data from our phase II trial of PTCy showed highly promising OS/GRFS in patients receiving 7/8 MMUD HCT, and that PTCy in MMUD setting offers an alternative and effective HCT approach for patients who do not have an available matched donor.

We have successfully established a clinical platform for CD19 chimeric antigen receptor (CAR) T cells and evaluated its safety and efficacy in a series of pilot clinical trials following autologous hematopoietic cell transplantation (HCT) for treatment of high-risk non-Hodgkin lymphoma (NHL) and acute lymphoblastic leukemia (ALL). However, the full potential of this therapy has been limited by the lack of engraftment and persistence of CAR T cells in patients, most likely due to the inadequate antigen drive to stimulate robust expansion and long-term persistence of the infused CAR T cells. Additionally, CD19+ NHL seems less responsive to current CAR T cell technology than does CD19+ ALL that might be explained by lower engraftment and persistence of CAR T cells in NHL. To improve the efficacy and durability of CAR T cells in these disease settings, we sought to examine a novel approach based on properties of cytomegalovirus (CMV)-specific T cells. Specifically, we select CMV pp65-specific T cells for ex vivo modification with a CAR targeting CD19. After in vitro expansion, CMV-CD19 bi-specific T cells will be infused into the patient. A second round of expansion will be done in vivo, using a CMV vaccine (Triplex), developed and clinically evaluated multiple clinical sites including City of Hope. Triplex is a multi-antigen recombinant modified vaccinia Ankara (MVA) virus vaccine expressing pp65, IE1 and IE2, that has proven safe and immunogenic in Phase I trials in healthy volunteers and transplant patients and was highly tolerable and efficacious in a completed Phase II vaccine trial in allogeneic HCT recipients. We hypothesis that shorter ex vivo expansion time will prevent CAR T cell exhaustion that results in better in vivo expansion, especially after Triplex vaccination. Thus far, we have performed six large-scale manufacturing process development (PD) runs of CMV-CD19 CAR T cells using T cells from healthy donors. Briefly, peripheral blood mononuclear cells (PBMCs) were collected and processed in the CliniMACS Prodigy® system, in which PBMCs were first stimulated with a GMP-grade PepTivator® overlapping CMV pp65 peptide pool, then enriched for CMV-responsive IFNɣ+ T cells using the IFNγ Catchmatrix reagent (Miltenyi Biotec Inc.). CMV-responsive IFNɣ+ T cells were next transduced with a lentiviral vector encoding EGFRt/CAR, and finally expanded for approximately 15 days in vitro. As summarized in Table 1, we consistently recovered 4.8%+/-1.4 ×106 CMV specific T cells with 78.3%±2.9 purity from 1×109 PBMC input, which is the maximum input number suggested by the CCS program associated with the Prodigy system (Miltenyi Biotec Inc.). During the early stage PD runs, we noticed that red blood cell contamination in the PBMC layer after ficoll separation could negatively impact the yield of CMV-specific T cells. Thus, we optimized the separation process by performing a second ficoll whenever a red buffy coat was observed, and increased the yield of CMV-specific T cells from 2.8 ×106 to 9.25×106 (Table 1, HD 187.2 PBMCs underwent 2 subsequent ficolls). Phenotypic analysis demonstrated that freshly isolated CMV-specific T cells consisted of four different memory subsets (TEMRA, Tscm, Tcm and effector memory T cells). After in vitro expansion for 15 days, CMV-CAR bi-specific T cell expansion was significantly improved from 60×106 cells in the early stage runs to 200×106 in the late stage optimized runs (Figure 1). The CMV-CD19CAR T cells expressed CD62L, though not exhaustion markers such as PD1. Bispecific T cells exhibited bi-functionality upon stimulation with CD19+ tumor cells or CMVpp65 antigen, as indicated by secretion of IFNγ. Interestingly, we detected stronger effector function against CD19+ tumor cells from CMV-CD19CAR T cells compared to conventional CD19CAR T cells that were derived from the same donor (Figure 2). To validate our manufacturing process, we are currently conducting IND-enabling studies using patient-derived PBMC as the starting population and will initiate our first clinical trial in early 2020 for patients with intermediate/advanced-grade B cell NHL post lymphodepletion or autologous/allogeneic HCT followed by Triplex vaccination 28 days after T cell infusion for in vivo expansion of bi-specific CAR T cells. The primary objectives of these two trials are to examine safety and persistence/expansion of CMV-CD19CAR T cell before and after Triplex vaccine boost. Disclosures Nakamura: Merck: Membership on an entity's Board of Directors or advisory committees; Celgene: Other: support for an academic seminar in a university in Japan; Alexion: Other: support to a lecture at a Japan Society of Transfusion/Cellular Therapy meeting ; Kirin Kyowa: Other: support for an academic seminar in a university in Japan.

The current standard of care for patients with Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) is high-dose conditioning followed by autologous stem cell transplantation (ASCT). For some patients (ie, those with highest-risk disease, insufficient stem cell numbers after mobilization, or bone marrow involvement) allogeneic hematopoietic cell transplantation (alloHCT) offers the potential for cure. However, the majority of patients undergoing alloHCT receive reduced-intensity conditioning as a preparative regimen, and studies assessing outcomes of patients after alloHCT with myeloablative conditioning are limited. In this retrospective study, we reviewed outcomes of 22 patients with recurrent and refractory NHL who underwent alloHCT with myeloablative BEAM conditioning and received tacrolimus/sirolimus as graft-versus-host disease (GVHD) prophylaxis at City of Hope between 2005 and 2018. With a median follow-up of 2.6 years (range, 1.0 to 11.2 years), the probabilities of 2-year overall survival and event-free survival were 58.3% (95% confidence interval [CI], 35.0% to 75.8%) and 45.5% (95% CI, 24.4% to 64.3%), respectively. The cumulative incidence of grade II to IV acute GVHD was 45.5% (95% CI, 23.8% to 64.9%), with only 1 patient developing grade IV acute GVHD. However, chronic GVHD was seen in 55% of the patients (n = 12). Of the 22 eligible patients, 2 had undergone previous ASCT and 2 had undergone previous alloHCT. Both patients with previous ASCT developed severe regimen-related toxicity. Patients who underwent alloHCT with chemorefractory disease had lower survival rates, with 1-year OS and EFS of 44.4% and 33.0%, respectively. In conclusion, alloHCT with a BEAM preparative regimen and tacrolimus/sirolimus-based GVHD should be considered as an alternative option for patients with highest-risk lymphoma whose outcomes are expectedly poor after ASCT.

Chronic graft-versus-host disease (cGVHD) continues to be a major complication after allogeneic hematopoietic cell transplantation, significantly affecting patients' quality of life. A regimen of systemic corticosteroids is considered first-line therapy but is often associated with inadequate responses and multiple side effects. In patients with refractory disease, an evidenced-based consensus is lacking as to the single best approach to managing symptoms. Ruxolitinib, a selective JAK1/2 inhibitor, has recently gained favor as a second-line approach in patients with steroid-refractory cGVHD. In this retrospective study, we evaluated the outcomes of 46 patients who received ruxolitinib for cGVHD between March 2016 and December 2017 at our institution, and evaluated ruxolitinib's impact at 6 and 12 months, based on the National Institutes of Health Severity Scale, including organ-specific responses, and mean prednisone dose. Furthermore, we present the first reported probability of ruxolitinib's treatment failure-free survival (FFS) in patients with cGVHD. After 12 months of ruxolitinib therapy, complete response, partial response, and stable disease was observed in 13% (n = 6), 30.4% (n = 14), and 10.9% (n = 5) of patients, respectively. The 1-year probability of FFS was 54.2% (95% confidence interval, .388 to .673), and ruxolitinib use was associated with a reduction in prednisone dose. In conclusion, our data, which represent the largest cohort of patients with cGVHD reported to date, support the use of ruxolitinib for cGVHD refractory to steroids and currently available salvage therapies, discontinued due to lack of response and high cost.

Chronic GVHD remains as the major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation. Systemic corticosteroids are the first line of therapy, but outcomes are poor in steroid refractory (SR) patients. Previous reports show that in SR patients, IL-2 therapy results in partial response (PR) associated with increase in regulatory T cells (Tregs). ECP has been used for cGVHD with skin response rates of 40-100%. Based on non-overlapping toxicities and, we prospectively studied a combination of low dose IL-2 + ECP to treat SR-cGVHD. Patients with SR-cGVHD, were treated with low dose IL-2 (1 × 106 U/m2, daily) + ECP for 12 weeks. IL-2 was provided by Prometheus Laboratories. ECP was administered 2 times/week for 4 weeks followed by 2 treatments every 2 weeks for the next 8 weeks. The NIH consensus criteria was used to assess cGVHD severity. PBMC and plasma samples were banked at baseline and on 3-week intervals to assess regulatory T cell (Tregs) and reactive oxygen species (ROS). Of the 12 consented patients, 9 completed the study (2 were not treated due to rapid disease progression before enrollment and 1 died from sepsis at week 11). All enrolled patients (n=10) had scleroderma as the predominant cGVHD manifestation. Median age was 45.6 years (range: 23-66). Median prior lines of therapy were 4.2(range 3-6), 5 patients had prior exposure to ruxolitinib and 4 were on ECP at the enrollment. Donors were fully matched unrelated (n=8), matched sibling (n=1) or mismatched unrelated (n=1). Conditioning regimen was myeloablative (n=5) or reduced intensity (n=4). GVHD prophylaxis was tacrolimus/Sirolimus (tac/sir) (n=6), tac/methotrexate (MTX) (n=2), or Tac/sir/MTX (n=1). Of the 10 enrolled patients, 9 responded to IL-2 + ECP combination (all classified as PR). A 37% dose reduction in steroid dose was noted among 7 patients. The remaining 3 patients were on stable steroid dose at end of study. Only 1 patient had progressive cGVHD in form of scleroderma. ECP+IL-2 therapy was well tolerated with no drug related serious adverse events (SAE). Grade 3-4 AEs included grade 3 metabolic and nutrition (n=8), grade 3 anemia (n=3), and grade 4 atrial flutter (n=1). Infectious complications were noted in 3 patients (one grade 4 [sepsis]). There was a robust increase in Tregs from the baseline mean of 0.755% (range 0.08-1.88) to end of treatment 6.999% (range 0.78-17.13) [p=0.02] Fig 1. Increment in Tregs was seen in patients who were on ECP therapy prior to enrollment (n=4) and in one patient who progressed while on therapy. No correlation was found between the treatment response and ROS levels. In conclusion, the combination of ECP +IL-2 is well tolerated in patients with SR-cGVHD with no apparent increase in infectious complications or other toxicities. Clinical response correlates with a robust increase in Tregs, but no correlation was found with ROS levels.

Historically, outcomes of adult patients (pts) with ALL who fail to enter remission with standard induction chemotherapy are very poor. Blinatumomab, a bispecific CD3/CD19 antibody, has shown remarkable activity in relapsed/refractory (r/r) ALL. While allogeneic HCT is the recommended consolidation therapy for r/r ALL pts who respond to salvage therapy, HCT and toxicity outcomes for those who received blinatumomab salvage and HCT remains largely unknown. A retrospective review of r/r ALL pts medical records, who received blinatumomab salvage therapy from 2012 to 2018 at our institution was obtained. Only pts who responded to blinatumomab and underwent HCT were included (n=29). Kaplan-Meier curves and the log-rank test were used to evaluate the overall survival (OS) and progression-free survival (PFS). Cumulative incidence (CI) curves and the Gray test were used to examine the differences in relapse rates and non-relapse mortality (NRM). The median age at the time of HCT was 29 years (range: 19-65), and 8 pts (28%) were over 50 years old. HCT was done in complete remission- (CR)-1 (n=14, 48%) or ≥CR-2, with 2pts receiving blinatumomab salvage after relapse from a prior HCT. Pts received transplant from a matched sibling (n=11), matched unrelated (n= 12), haploidentical donor (n=5) or double umbilical cord blood (n=1) after myeloablative (n=20, including TBI+VP16, n=15) or reduced intensity (n=9) conditioning. The graft source was PBSCs in 25 pts (86.2%). Graft-versus-host disease (GVHD) prophylaxis was tacrolimus/sirolimus-based (n=19, 66%), and post-HCT cyclophosphamide (n=5, 17%) for haploidentical transplants. At the time of salvage therapy initiation, pts had either gross residual (n=22) or minimal residual disease (MRD+) (n=7). Negative MRD remission status was achieved prior to HCT in 15 pts, including those who were MRD+ before blinatumomab salvage. With a median follow up of 21.7 months (mo) (range: 1.1-55.7) for all pts and 6.4 mo for surviving pts, the 1-year OS and PFS were 72.8% (95% CI: 48.5-87.0) and 63.0% (95% CI: 38.8-79.8), respectively (Fig 1). Causes of death post-HCT were GVHD (n=3); NRM (n=4; 3 sepsis and 1 regimen related toxicity) and relapse (n=3). The CI of relapse at 1 and 2 years were 24.9% (95% CI: 8.6-45.3) and 45.9%, (95% CI: 20.3-68.3), respectively. NRM at 100 days was 6.9% (95% CI: 1.2-20.0) and at 12 mo was 12.1% (95% CI: 2.7-29.0). The incidence of grades 3-4 acute GVHD and extensive chronic GVHD at 24 mo were 25.0% (95% CI: 8.7-45.5) and 38.8% (95% CI: 14.2-63.1), respectively. No cases of veno-occlusive disease post-HCT were reported. We present here, for the 1st time, detailed data showing the tolerability and efficacy of HCT following salvage therapy with blinatumomab. No unexpected toxicities were noted post-HCT and the study showed encouraging 1-year OS and PFS with. Longer-term follow-up is ongoing for these patients.

Identification of anti-apoptotic properties of the Bcl2 protein has offered novel treatment options in many malignancies including AML. Venetoclax, a Bcl2 inhibitor, has shown promising results as upfront therapy in elderly patients (pts) and relapse/refractory (R/R) AML, when combined with hypomethylating agents (HMA). Yet, due to the high relapse risk, allogenic HCT remains as the only curative option for these high risk populations. To date, outcomes of HCT after prior therapy with Venetoclax + HMA have not been described. Also, as Venetoclax induces aplasia of antigen presenting cells expressing Bcl2, we hypothesized that pre-HCT treatment with venetoclax may be associated with a lower risk for GvHD. We retrospectively analyzed 26 consecutive AML pts who underwent HCT at our institution from 2016 to 2018 with final line of systemic therapy of venetoclax + HMA. Pts were not eligible for upfront standard induction chemotherapy (n=8) or had R/R disease (n=18). Fifteen pts received ≥2 lines of therapy and 3 had previous HCT. CR/CRi was achieved in 62% (n=16), of which 3 pts had minimal residual disease and the rest (n=10) had persistent disease prior to HCT. Donors were matched related (n=8), matched unrelated (n=16), or haploidentical (n=2). Conditioning regimen was myeloablative (38.5%) or reduced intensity (61.5%). Most pts (n=24, 92.3%) received PBMCs as the graft source. Tacrolimus/Sirolimus (Tac/Sir) was administered in most pts (n=20, 77%) for GvHD prophylaxis. Descriptive statistics were used for baseline characteristics. Kaplan-Meier and cumulative incidence curves were constructed for overall survival (OS), progression-free survival (PFS), relapse, none-relapse mortality (NRM), and aGvHD. Median age at the time of HCT was 59 years (range: 18-73). Median time to neutrophil and platelet engraftment were 17 days (range: 14-20) and 20 days (range: 16-61), respectively. With a median follow up of 4.5 months (range: 1.4-18.6), 6 months relapse rate was 12% (95% CI: 0.16-0.54) and 100 day NRM was 4% (95% CI: 0.02-0.34). Grade II-IV aGvHD at 100 days was noted in 34% (95% CI: 0.15-0.51). One-year OS and PFS for all pts were 72% (95% CI: 0.43-0.88) and 40% (95% CI: 0.16-0.63), respectively. For patients in CR at the time of HCT, 1-year OS was 80% (95%CI: 37-95) and PFS was 38% (95%CI: 0.08-0.69) (Fig 1). Only one patient who had been treated with three lines of systemic therapy prior to HCT experienced veno-occlusive disease. Thus, administration of Venetoclax-based salvage regimen as a bridge to HCT is safe with no added immediate toxicities post-HCT. Our early outcome data are promising for this otherwise high-risk population. Our data also justify further studies on the role and impact of Venetoclax and its anti-Bcl2 properties as a component of the conditioning regimen or as post-HCT maintenance.

CMVi leads to significant morbidity in R+ HCT and preemptive therapy (PET) has been the standard of care. LTV was FDA-approved in Nov. 2017 for CMVi prevention in R+ HCT. Besides the clinical trials, there is are real world data on LTV. Upon IRB approval, we retrospectively studied consecutive R+ HCT pts with their first HCT between 1/1/2017 and 6/30/2018. LTV group included pts with HCT between 2/20/18 and 6/30/2018, who had LTV Px started within 28 days of HCT (n=59), and R+ HCT between 1/1/2017 and 2/19/2018 (n=307) served as control (ctrl). We compared CMVi rates in first 100 days of HCT, and time to engraftment between the 2 groups. Risk stratification: high risk - haplo/cord HCT & ATG use, low risk - all others. CMVi was defined as viral load (VL) of 625 IU/ml to 1250 IU/ml or higher (CMV assay conversion factor of 1 genomic copy/ml = 2.5 IU/ml). CMV VL less than 625 IU/ml is reported negative, VL between 625 and 1250 IU/ml is qualitative positive but numeric value is provided only for VL ≥ 1250 IU/ml. PET was recommended for VL >1250 IU/ml (500 copies/ml) in high risk and > 3750 IU/ml (1500 copies/ml) in low risk HCT (including those on LTV requiring PET). Descriptive statistics was done for baseline characteristics. Cumulative incidence curves were generated for CMVi within 100 days post-HCT and Gray's test was used to compare the difference between the 2 groups. In both groups, median age was 54 years and HCT indications were similar. Donor type in LTV/ Ctrl groups: MRD (27 vs 36%), MUD (44 vs 47%), haplo (27 vs 15%), cord (1.7 vs 1.6%). PBMC was graft source in 90% of both groups. Myeloablative conditioning: 40.7% in LTV and 35% in Ctrl. GVHD Px: Cellcept (32 vs 25%), methotrexate (7 vs 9%), tacro/siro (58 vs 65), and others (3.4 vs 0.3%) in LTV & Ctrl respectively. A majority (n=36) received both intravenous & oral LTV formulation while 23 received oral only. Median time from HCT to LTV start was 13 days (range: 4-26). LTV group had significant reduction in CMVi rate (22.4% [95%CI: 12.7-34.0]) compared with ctrl group (41.1% [95%CI: 35.4-46.7], p=0.008, Fig 1). In a subgroup of high-risk HCT LTV was significantly reduced CMVi rate (22.2%) compared with ctrl (62.8%, p=0.004, Fig 2) while statistical difference was not reached in low-risk HCT pts (22.8% vs. 35.6%, p=0.11). In the LTV Px, clinically significant (CS)-CMVi requiring PET occurred in 8.4% (n=5) and on excluding 2 pts who were not on LTV at the time of CMVi, the rate was 5% (Fig 1). CMVi cleared without PET in 8/13 LTV pts and LTV was continued; all pts had VL LTV use in a real world setting is associated with significant reduction of CMVi and CS-CMVi without any discernible myelosuppression. The low level CMVi resolved spontaneously in majority with continued LTV Px and PET was not necessary. The high-risk HCT had most benefit with LTV Px.