Rizzieri, David A.

Summary CD19 chimeric antigen receptor T‐cell (CAR‐T) therapy is a pivotal part of the treatment algorithm for large B‐cell lymphoma (LBCL) in the second‐ and third‐line settings based on numerous clinical trials. However, these studies included very few patients with a diagnosis of high‐grade B‐cell lymphoma, not otherwise specified (HGBCL‐NOS) and it is unclear if outcomes are similar to those observed with more common LBCL histologies. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, we identified 111 HGBCL‐NOS patients who received CAR‐T therapy. The cytokine release syndrome (CRS) rate was 74% (7.7% grade 3+), median onset was 4 days (1–17) and immune effector cell‐associated neurotoxicity syndrome rate was 45.2% (22.6% grade 3+), median onset was 7 days (1–17). At 2 years post‐CAR‐T infusion, the probability of overall survival and progression‐free survival were 41.6% and 28.7% respectively. The 2‐year non‐relapse mortality and relapse/progression were 3.1% (95% confidence interval [CI]: 0.6–7.6) and 68.1% (95% CI: 57.9–77.6) respectively. Our analysis illustrates that patients with HGBCL‐NOS represent a particularly difficult group to treat, even with CAR‐T therapy. We observed that one third of patients achieved a durable response; however, the overall results were less favourable, with lower overall response rate, overall survival and progression‐free survival as compared to published reports on LBCL.

Abstract We evaluate the impact of donor types on outcomes of hematopoietic cell transplantation (HCT) in myelofibrosis, using the Center for International Blood and Marrow Transplant Research registry data for HCTs done between 2013 and 2019. In all 1597 patients, the use of haploidentical donors increased from 3% in 2013 to 19% in 2019. In study-eligible 1032 patients who received peripheral blood grafts for chronic-phase myelofibrosis, 38% of recipients of haploidentical HCT were non-White/Caucasian. Matched sibling donor (MSD)–HCTs were associated with superior overall survival (OS) in the first 3 months (haploidentical hazard ratio [HR], 5.80 [95% confidence interval (CI), 2.52-13.35]; matched unrelated (MUD) HR, 4.50 [95% CI, 2.24-9.03]; mismatched unrelated HR, 5.13 [95% CI, 1.44-18.31]; P < .001). This difference in OS aligns with lower graft failure with MSD (haploidentical HR, 6.11 [95% CI, 2.98-12.54]; matched unrelated HR, 2.33 [95% CI, 1.20-4.51]; mismatched unrelated HR, 1.82 [95% CI, 0.58-5.72]). There was no significant difference in OS among haploidentical, MUD, and mismatched unrelated donor HCTs in the first 3 months. Donor type was not associated with differences in OS beyond 3 months after HCT, relapse, disease-free survival, or OS among patients who underwent HCT within 24 months of diagnosis. Patients who experienced graft failure had more advanced disease and commonly used nonmyeloablative conditioning. Although MSD-HCTs were superior, there is no significant difference in HCT outcomes from haploidentical and MUDs. These results establish haploidentical HCT with posttransplantation cyclophosphamide as a viable option in myelofibrosis, especially for ethnic minorities underrepresented in the donor registries.

Abstract Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with a poor prognosis and considered incurable with conventional chemotherapy. Small observational studies reported allogeneic hematopoietic cell transplantation (allo-HCT) offers durable remissions in patients with BPDCN. We report an analysis of patients with BPDCN who received an allo-HCT, using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). We identified 164 patients with BPDCN from 78 centers who underwent allo-HCT between 2007 and 2018. The 5-year overall survival (OS), disease-free survival (DFS), relapse, and nonrelapse mortality (NRM) rates were 51.2% (95% confidence interval [CI], 42.5-59.8), 44.4% (95% CI, 36.2-52.8), 32.2% (95% CI, 24.7-40.3), and 23.3% (95% CI, 16.9-30.4), respectively. Disease relapse was the most common cause of death. On multivariate analyses, age of ≥60 years was predictive for inferior OS (hazard ratio [HR], 2.16; 95% CI, 1.35-3.46; P = .001), and higher NRM (HR, 2.19; 95% CI, 1.13-4.22; P = .02). Remission status at time of allo-HCT (CR2/primary induction failure/relapse vs CR1) was predictive of inferior OS (HR, 1.87; 95% CI, 1.14-3.06; P = .01) and DFS (HR, 1.75; 95% CI, 1.11-2.76; P = .02). Use of myeloablative conditioning with total body irradiation (MAC-TBI) was predictive of improved DFS and reduced relapse risk. Allo-HCT is effective in providing durable remissions and long-term survival in BPDCN. Younger age and allo-HCT in CR1 predicted for improved survival, whereas MAC-TBI predicted for less relapse and improved DFS. Novel strategies incorporating allo-HCT are needed to further improve outcomes.

AbstractTo develop a prognostic model for patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) for myelofibrosis (MF), we examined the data of 623 patients undergoing allo-HCT between 2000 and 2016 in the United States (the Center for International Blood and Marrow Transplant Research [CIBMTR] cohort). A Cox multivariable model was used to identify factors prognostic of mortality. A weighted score using these factors was assigned to patients who received transplantation in Europe (the European Bone Marrow Transplant [EBMT] cohort; n = 623). Patient age >50 years (hazard ratio [HR], 1.39; 95% confidence interval [CI], 0.98-1.96), and HLA-matched unrelated donor (HR, 1.29; 95% CI, 0.98-1.7) were associated with an increased hazard of death and were assigned 1 point. Hemoglobin levels <100 g/L at time of transplantation (HR, 1.63; 95% CI, 1.2-2.19) and a mismatched unrelated donor (HR, 1.78; 95% CI, 1.25-2.52) were assigned 2 points. The 3-year overall survival (OS) in patients with a low (1-2 points), intermediate (3-4 points), and high score (5 points) were 69% (95% CI, 61-76), 51% (95% CI, 46-56.4), and 34% (95% CI, 21-49), respectively (P < .001). Increasing score was predictive of increased transplant-related mortality (TRM; P = .0017) but not of relapse (P = .12). The derived score was predictive of OS (P < .001) and TRM (P = .002) but not of relapse (P = .17) in the EBMT cohort as well. The proposed system was prognostic of survival in 2 large cohorts, CIBMTR and EBMT, and can easily be applied by clinicians consulting patients with MF about the transplantation outcomes.

Abstract Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with historically poor outcomes and no worldwide consensus treatment approach. Unique among most hematologic malignancies for its frequent cutaneous involvement, BPDCN can also invade other extramedullary compartments, including the central nervous system. Generally affecting older adults, many patients are unfit to receive intensive chemotherapy, and although hematopoietic stem cell transplantation is preferred for younger, fit individuals, not all are eligible. One recent therapeutic breakthrough is that all BPDCNs express CD123 (IL3Rα) and that this accessible surface marker can be pharmacologically targeted. The first-in-class agent for BPDCN, tagraxofusp, which targets CD123, was approved in December 2018 in the United States for patients with BPDCN aged ≥2 years. Despite favorable response rates in the frontline setting, many patients still relapse in the setting of monotherapy, and outcomes in patients with relapsed/refractory BPDCN remain dismal. Therefore, novel approaches targeting both CD123 and other targets are actively being investigated. To begin to formally address the state of the field, we formed a new collaborative initiative, the North American BPDCN Consortium (NABC). This group of experts, which includes a multidisciplinary panel of hematologists/oncologists, hematopoietic stem cell transplant physicians, pathologists, dermatologists, and pediatric oncologists, was tasked with defining the current standard of care in the field and identifying the most important research questions and future directions in BPDCN. The position findings of the NABC’s inaugural meetings are presented herein.

Abstract Introduction: The interleukin-3 receptor alpha chain (CD123) is a cell-surface target aberrantly expressed on various myeloid neoplasms including blastic plasmacytoid dendritic cell neoplasm (BPDCN), acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML), and myelofibrosis (MF). Tagraxofusp (TAG, SL-401), a first-in-class CD123-targeted therapy, is the only treatment approved by the FDA and EMA for patients (pts) with BPDCN. It has also been investigated in phase 1/2 clinical trials for AML (including pts with minimal residual disease [MRD]), CMML, and MF. We report the aggregated safety data of TAG monotherapy from trials in BPDCN, AML, CMML, and MF. Methods: An integrated safety analysis was performed for pts who received TAG monotherapy in three phase 1/2, multicenter clinical studies: Study 0114 (NCT02113982; BPDCN/AML), Study 0214 (NCT02270463; AML with/without MRD), and Study 0314 (NCT02268253; CMML/MF; Table 1). Pts received the recommended phase 2 dose of 12 mcg/kg/day (d) IV on d1-3 (MF and CMML) or d1-5 (BPDCN and AML) and were analyzed for incidence and timing of treatment-related adverse events (TRAEs), AEs of interest, and discontinuations. Safety data for TAG monotherapy, reported as individual case study reports (ICSRs) postapproval (US) and from an early access program (EAP; EU) are also presented. Results: In total, 201 pts receiving TAG (12 mcg/kg/d) in a clinical trial setting were included: BPDCN, n=86; AML, n=36; AML with/without MRD, n=10; CMML, n=33; MF, n=36. As of Jul 2021, 11 (6%) pts discontinued TAG due to any-grade (Gr) TRAE. Most common TRAEs (any-Gr) are shown in Table 2 and included hypoalbuminemia (41%), increased alanine aminotransferase (ALT; 40%), increased aspartate aminotransferase (AST; 39%), and thrombocytopenia (26%). The most common Gr ≥3 TRAEs were thrombocytopenia (n=41; 20%), increased AST (n=40; 20%), and increased ALT (n=35; 17%). Tumor lysis syndrome occurred in 5% of pts and 1.5% had infusion-related reactions. Any-Gr and Gr ≥3 hematologic TRAEs are presented in Table 3. Most common was thrombocytopenia. All TRAEs were transient in nature; prolonged bone marrow suppression was not observed. Overall, 23% (47/201) of pts experienced ≥1 treatment-related serious AE. Onset of most TRAEs, irrespective of Gr, commonly occurred in cycle 1 and resolved by cycle 2. Although the number of pts in cycles ≥2 was lower than in cycle 1, the incidence rates of common TRAEs also substantially decreased in subsequent cycles. Capillary leak syndrome (CLS) occurred in 17% of the overall 201 pts. The majority of all CLS events were nonsevere, Gr ≤2 (n=22; 63%); also reported were Gr 3, n=10 (29%); Gr 4, n=3 (9%), and 2 pts experienced a Gr 5 event. Onset of CLS was usually within the first week of cycle 1 (median time to onset [range], d: 5.5 [1-51]) and resolved quickly (median time to resolution [range], d: 5.0 [2-69]); no pts experienced the first onset after cycle 2. Of the 15 pts who resumed treatment after an initial CLS event, only 1 pt experienced a recurrence. The most common AEs reported as ICSRs postapproval and from an EAP (December 2018 to June 2021) were CLS, blood albumin decreased, thrombocytopenia, pyrexia, and hepatic enzyme increased. No new safety signals that would alter the safety profile were observed. Conclusions: This integrated analysis represents the largest collection of safety data (N=201) following treatment with TAG monotherapy. TAG has an established and manageable safety profile, with the vast majority of AEs reported as transient and decreasing in frequency/severity with increasing cycles. CLS was reported in 17% of pts; onset was usually within cycle 1, resolved quickly (median time to resolution: 5.0 d) by early intervention measures including holding treatment, and no pts experienced first onset after cycle 2. Risk-minimization guidelines for CLS were developed and implemented during clinical trials and incorporated into prescribing information. No myelosuppression or cumulative toxicity was observed over multiple treatment cycles. The safety profile observed postapproval and in the EAP was consistent with the clinical trial data reported, reflecting successful adoption of risk-management strategies in real-world practice. These data confirm the favorable benefit-risk profile of TAG monotherapy has been maintained in the 3 years following US approval. Figure 1 Figure 1. Disclosures Pemmaraju: ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Sager Strong Foundation: Other; Blueprint Medicines: Consultancy; Incyte: Consultancy; Bristol-Myers Squibb Co.: Consultancy; Pacylex Pharmaceuticals: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Aptitude Health: Consultancy; Celgene Corporation: Consultancy; CareDx, Inc.: Consultancy; Springer Science + Business Media: Other; Daiichi Sankyo, Inc.: Other, Research Funding; Samus: Other, Research Funding; Clearview Healthcare Partners: Consultancy; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; MustangBio: Consultancy, Other; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; LFB Biotechnologies: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Affymetrix: Consultancy, Research Funding; DAVA Oncology: Consultancy; Plexxicon: Other, Research Funding; Roche Diagnostics: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; ImmunoGen, Inc: Consultancy. Kantarjian: NOVA Research: Honoraria; Aptitude Health: Honoraria; Immunogen: Research Funding; BMS: Research Funding; Precision Biosciences: Honoraria; Novartis: Honoraria, Research Funding; Ascentage: Research Funding; Pfizer: Honoraria, Research Funding; Astra Zeneca: Honoraria; Astellas Health: Honoraria; Jazz: Research Funding; Ipsen Pharmaceuticals: Honoraria; Amgen: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; KAHR Medical Ltd: Honoraria; AbbVie: Honoraria, Research Funding; Taiho Pharmaceutical Canada: Honoraria. Sweet: Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wang: Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; DAVA Oncology: Consultancy, Speakers Bureau; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; Takeda: Consultancy, Honoraria, Other: Advisory board; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Advisory Board; Mana Therapeutics: Consultancy, Honoraria; Rafael Pharmaceuticals: Other: Data safety monitoring committee; Gilead: Consultancy, Honoraria, Other: Advisory board; Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory board; PTC Therapeutics: Consultancy, Honoraria, Other: Advisory board; Genentech: Consultancy; MacroGenics: Consultancy. Lane: N-of-One: Consultancy, Honoraria; Stemline Therapeutics: Research Funding; Qiagen: Consultancy, Honoraria; AbbVie: Research Funding. 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. Stein: Amgen: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; Stemline: Speakers Bureau. Yacoub: Agios: Membership on an entity's Board of Directors or advisory committees; Acceleron Pharma: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau. Rizzieri: Celltron/Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: presentation to FDA for biosimilar review ; AROG: Other; Amgen: Other: personal fee; Bayer: Consultancy, Honoraria; Kite: Other: personal fee; Mustang: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Other: personal fee; Gilead: Other: personal fee; Jazz: Other: personal fee; Pharmacyclics: Other. Vasu: Seattle Genetics: Other: travel support; Boehringer Ingelheim: Other: Travel support; Kiadis, Inc.: Research Funding; Omeros, Inc.: Membership on an entity's Board of Directors or advisory committees. Gupta: AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy; Constellation Pharma: Consultancy, Honoraria; Pfizer: Consultancy; BMS-Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Research Funding. Lee: BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pin Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Innate: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees. Schiller: Sangamo: Research Funding; Actinium Pharmaceuticals, Inc: Research Funding; FujiFilm: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Abbvie: Research Funding; Karyopharm: Research Funding; Onconova: Research Funding; Celator: Research Funding; Actuate: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Trovagene: Research Funding; Deciphera: Research Funding; Gamida Cell Ltd.: Research Funding; Forma: Research Funding; Ono-UK: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Arog: Research Funding; Takeda: Research Funding; Geron: Research Funding; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; PrECOG: Research Funding; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Mateon: Research Funding; Constellation Pharmaceuticals: Research Funding; Daiichi-Sankyo: Research Funding; Tolero: Research Funding; Stemline Therapeutics, Inc.: Honoraria, Research Funding, Speakers Bureau; Samus: Research Funding; Astellas: Honoraria, Research Funding, Speakers Bureau; Regimmune: Research Funding; BMS/Celgene: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Agios: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Research Funding, Speakers Bureau; Bio: Research Funding; Elevate: Research Funding; Delta-Fly: Research Funding; Genentech-Roche: Research Funding; Ariad: Research Funding; Sanofi: Honoraria, Research Funding, Speakers Bureau; Pharma: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company; Biomed Valley Discoveries: Research Funding; Eli Lilly: Research Funding; ASH foundation: Other: Chair-unpaid; Sellas: Research Funding; Ono: Consultancy; Incyte: Consultancy; AstraZeneca: Consultancy; Kaiser Permanente: Consultancy; Cyclacel: Research Funding; MedImmune: Research Funding; Ambit: Research Funding; Leukemia & Lymphoma Society: Research Funding; Bluebird Bio: Research Funding; Boehringer-Ingleheim: Research Funding; Cellerant: Research Funding; CTI Biopharma: Research Funding; Janssen: Research Funding; Kura Oncology: Research Funding; Pharmacyclics: Honoraria, Speakers Bureau; Millennium: Research Funding; National Marrow Donor Program: Research Funding; NIH: Research Funding; Onyx: Research Funding; Pharmamar: Research Funding; UC Davis: Research Funding; UCSD: Research Funding; Evidera: Consultancy; NCI: Consultancy; Novartis: Speakers Bureau. Foran: trillium: Research Funding; actinium: Research Funding; aptose: Research Funding; novartis: Honoraria; OncLive: Honoraria; servier: Honoraria; gamida: Honoraria; takeda: Research Funding; boehringer ingelheim: Research Funding; abbvie: Research Funding; certara: Honoraria; bms: Honoraria; pfizer: Honoraria; sanofi aventis: Honoraria; revolution medicine: Honoraria; taiho: Honoraria; syros: Honoraria; kura: Research Funding; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Walter: Macrogenics: Consultancy, Research Funding; Jazz: Research Funding; Pfizer: Consultancy, Research Funding; Selvita: Research Funding; Amphivena: Consultancy, Other: ownership interests; Agios: Consultancy; Astellas: Consultancy; BMS: Consultancy; Genentech: Consultancy; Janssen: Consultancy; Kite: Consultancy; Immunogen: Research Funding; Celgene: Consultancy, Research Funding; Aptevo: Consultancy, Research Funding; Amgen: Research Funding. Sieminski: Stemline Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Patnaik: Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees. Mughal: Oxford University Press, Informa: Other: financial benefit and/or patents ; Stemline: Current Employment, Current holder of stock options in a privately-held company. Konopleva: Calithera: Other: grant support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Ascentage: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Stemline Therapeutics: Research Funding; KisoJi: Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Cellectis: Other: grant support; Sanofi: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding.

Abstract Background: CD19 CAR T cell therapies have demonstrated high initial complete remission (CR) rates of 70-80% in relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) with durable remissions observed in a subset of patients. Despite the remarkable initial CR rate, relapses occur in 20-45% of patients and with increasing use of CD19 CAR T cell therapies in ALL, a key remaining clinical question is the role of post-CAR HCT. Methods: Patients up to 26 years treated with the commercial (i.e., tisagenlecleucel) or investigational CD19 CAR T cell products from 2014 to 2019 in the United States were included. The objectives were to examine the impact of post-CAR HCT on mortality, disease-free survival (DFS), leukemia relapse, GVHD and transplant related mortality among HCT recipients. The intent of HCT was analyzed as consolidation when there was no evidence of post-CAR T cell relapse prior to HCT. Cox regression multivariable analysis used HCT as time-dependent variable along with age, performance status and time from diagnosis to CAR-T cell infusion to evaluate its impact on outcomes. Results: We identified 347 patients who received CD19 CAR T cells from 86 centers. Median age was 13 (range, 0.4-26 years) with 39% of patients from Hispanic or Latino ethnic origin. Patients were high risk and heavily pretreated; 56% had poor cytogenetics, 51% had ≥3 line of prior therapies and 34% had prior HCT. Most of the patients (74%) received tisagenlecleucel. Disease burden at the time of CAR T cell infusion included morphologic disease (≥5% bone marrow blasts) (65%), measurable residual disease (MRD) positive (16%) and negative CR (18%). CRS of all grades was observed in 57.6% and grade 3-4 CRS in 13%; neurotoxicity of all grades was observed in 25% and grade 3-4 in 8%. With a median follow-up of 12.7 months (range, 2.2-60.3), DFS at 3, 6 and 12 months following CAR T cell infusion was 80.9% % (95% CI: 76.6%-84.9%), 71.2% (95% CI: 66.1%-76.0%) and 57.6% (95% CI: 51.8%-63.3%), respectively. OS at 3, 6 and 12 months was 93.6% (95% CI: 90.8%-96.0%), 89.8% (95% CI: 86.4%-92.8%) and 79.4% (95% CI: 74.7%-83.6%), respectively. Incidences of relapse without censoring at subsequent HCT at month 3, 6 and 12 were 18.5% (95% CI: 14.5%-22.8%), 28.2% (95% CI: 23.5%-33.3%), and 40.6% (95% CI: 35.0%-46.3%), respectively. Of the 347 patients who received CD19 CAR therapy, 62 patients (18%) had subsequent HCT in CR as a consolidation post-CAR with a median time from CAR T to HCT of 4.7 months (range, 1.1-18.6). 36% had a prior HCT (i.e., pre-CAR), 87% received myeloablative regimen and among the 57 patients with MRD evaluation 56 were negative (98%). Frequencies of post-CAR HCT did not change during the 5-year study period. Overall, transplant related mortality (TRM) at month 6 was 8.9% (95% CI: 3.6-16.1), and grade 2-4 acute GvHD was observed in 38.0% (95% CI: 28.4-48.2) of patients at month 6. Post-CAR HCT used as a consolidation was associated with lower relapse (hazard ratio (HR) 0.37; p=0.037) but no significant impact on mortality (HR 0.75, p=0.51) or DFS (HR=0.46, p=0.057). When accounting for any HCT performed after CAR T cell, HCT was associated with higher mortality (Figure). Conclusions: This is the largest clinical series to date examining the impact of post-CAR HCT on clinical outcome of R/R B-ALL patients. We found that 18% of the patients had post-CAR HCT as a consolidation therapy with a favorable safety profile of 8.9% TRM rate despite a prior transplant rate of 36%. Consolidation HCT after CAR T cell resulted in significant reduction in leukemia relapse with a trend towards better DFS. Consolidation HCT seem safe and incurred a benefit by reducing disease relapse. Further studies in understanding the role of consolidation HCT as planned, or post-CAR T cell response-based strategy or treatment for early B-cell recovery are needed to further define the best candidates for HCT after tisagenlecleucel . Figure 1 Figure 1. Disclosures Park: BMS: Consultancy; Affyimmune: Consultancy; Kite Pharma: Consultancy; Curocel: Consultancy; Novartis: Consultancy; Minerva: Consultancy; Innate Pharma: Consultancy; PrecisionBio: Consultancy; Intellia: Consultancy; Amgen: Consultancy; Autolus: Consultancy; Servier: Consultancy; Artiva: Consultancy; Kura Oncology: Consultancy. Nikiforow: Kite/Gilead: Other: ad HOC Advisory Boards; Novartis: Other: ad Hoc Advisory Boards; Iovance: Other: ad Hoc Advisory Boards; Glaxo Smith Kline (GSK): Other: ad Hoc Advisory Boards. Hu: Kite/Gilead: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Ahmed: Merck: Research Funding; Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seagen: Research Funding; Xencor: Research Funding. Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Cairo: Servier: Speakers Bureau; Sanofi: Speakers Bureau; Amgen: Speakers Bureau; Jazz Pharmaceutical: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sobi: Speakers Bureau; Omeros: Membership on an entity's Board of Directors or advisory committees; Nektar: Membership on an entity's Board of Directors or advisory committees. Dholaria: Janssen: Research Funding; Takeda: Research Funding; Jazz: Speakers Bureau; MEI: Research Funding; Pfizer: Research Funding; Angiocrine: Research Funding; Poseida: Research Funding; Celgene: Speakers Bureau. Grover: Kite: Other: Advisory Board; Genentech: Research Funding; ADC: Other: Advisory Board; Tessa: Consultancy; Novartis: Consultancy. Locke: Gerson Lehrman Group: Consultancy; Emerging Therapy Solutions: Consultancy; Moffitt Cancer Center: Patents & Royalties: field of cellular immunotherapy; Calibr: Consultancy, Other: Scientific Advisory Role; BMS/Celgene: Consultancy, Other: Scientific Advisory Role; Wugen: Consultancy, Other; Legend Biotech: Consultancy, Other; Janssen: Consultancy, Other: Scientific Advisory Role; Iovance Biotherapeutics: Consultancy, Other: Scientific Advisory Role; Novartis: Consultancy, Other, Research Funding; GammaDelta Therapeutics: Consultancy, Other: Scientific Advisory Role; Takeda: Consultancy, Other; EcoR1: Consultancy; Cowen: Consultancy; Umoja: Consultancy, Other; Kite, a Gilead Company: Consultancy, Other: Scientific Advisory Role, Research Funding; Cellular Biomedicine Group: Consultancy, Other: Scientific Advisory Role; Bluebird Bio: Consultancy, Other: Scientific Advisory Role; Amgen: Consultancy, Other: Scientific Advisory Role; Allogene Therapeutics: Consultancy, Other: Scientific Advisory Role, Research Funding. Murthy: CRISPR Therapeutics: Research Funding. Mussetti: GILEAD: Other: Clinical trials participation, Research Funding; TAKEDA: Honoraria; NOVARTIS: Honoraria, Other: Clinical trials participation. Pulsipher: Jasper Therapeutics: Honoraria; Adaptive: Research Funding; Equillium: Membership on an entity's Board of Directors or advisory committees. Qayed: Novartis: Membership on an entity's Board of Directors or advisory committees; Medexus: Membership on an entity's Board of Directors or advisory committees; Mesoblast: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; BMS: Other. Reshef: Gilead, BMS, Precision, Immatics, Atara, Takeda, Shire, Pharmacyclics, Incyte: Research Funding; Gilead and Novartis: Honoraria; Bayer, BMS, Regeneron, TScan, Synthekine, Atara, Jasper: Consultancy. Rizzieri: Kite: Honoraria, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Acrotech: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees; Mustang: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria; Pharmacyclics: Honoraria. Sharma: Vertex Pharmaceuticals/CRISPR Therapeutics: Other: Salary support paid to institution; Medexus Inc: Consultancy; CRISPR Therapeutics: Other, Research Funding; Vindico Medical Education: Honoraria; Spotlight Therapeutics: Consultancy; Novartis: Other: Salary support paid to institution. Schultz: BMS DSMB: Other: payment; Sobi: Membership on an entity's Board of Directors or advisory committees. Turtle: Century Therapeutics Ad hoc advisory boards (last 12 months): Nektar Therapeutics, Allogene, PACT Pharma, Astra Zeneca, Amgen: Membership on an entity's Board of Directors or advisory committees; Precision Biosciences: Membership on an entity's Board of Directors or advisory committees; Eureka Therapeutics: Membership on an entity's Board of Directors or advisory committees; Caribou Biosciences: Membership on an entity's Board of Directors or advisory committees; T-CURX: Membership on an entity's Board of Directors or advisory committees; Myeloid Therapeutics: Membership on an entity's Board of Directors or advisory committees; ArsenalBio: Membership on an entity's Board of Directors or advisory committees; Minerva: Other; Nektar Therapeutics: Other; Juno Therapeutics/BMS: Other: Payments, Patents & Royalties: Patent licensed to Juno Therapeutics.; Precision Biosciences, Eureka Therapeutics, Caribou Biosciences, Myeloid Therapeutics, ArsenalBio: Current holder of stock options in a privately-held company. Pasquini: Kite Pharma: Research Funding; Novartis: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; GlaxoSmithKline: Research Funding. Perales: MorphoSys: Honoraria; Cidara: Honoraria; Bristol-Myers Squibb: Honoraria; Miltenyi Biotec: Honoraria, Other; Sellas Life Sciences: Honoraria; Takeda: Honoraria; Karyopharm: Honoraria; Celgene: Honoraria; Omeros: Honoraria; Nektar Therapeutics: Honoraria, Other; Equilium: Honoraria; Novartis: Honoraria, Other; NexImmune: Honoraria; Incyte: Honoraria, Other; Kite/Gilead: Honoraria, Other; Merck: Honoraria; Servier: Honoraria; Medigene: Honoraria.

Abstract Background: Relapsed Acute Lymphoblastic Leukemia (ALL) is not curable with standard therapies. Effective outpatient treatment, allowing patients to maintain a good quality of life, while offering a meaningful chance of remission, is an appealing alternative to prolonged admission required for currently available multi-agent regimens. Vincristine sulfate liposomal injection (Marqibo) was approved in 2012 for treatment Ph-ALL in second or greater relapse, originally developed to overcome pharmacokinetic and pharmacodynamic limitations of vincristine. Approved dosing is 2.25 mg/m 2 without a dose cap. Pre-clinical studies showed it increases plasma circulation time, increases tumor tissue delivery, accumulates in tumor tissue, and slowly releases vincristine in tumor tissues rather than into systemic circulation. In a phase 2 trial, as a weekly administered single agent, CR/CRi rate was 20%, with median duration of 23 weeks and overall response rate of 35%. Blinatumomab is a murine recombinant single-chain antibody construct belonging to a class of bispecific T-cell engager (BITE) immuno-oncology. BITE molecules are designed to direct T-effector memory cells towards target cells, triggering cell-specific cytotoxicity. Blinatumomab specifically targets cells that express CD19 and the presence of both, CD19+ target cells and T cells are required for its cytotoxic activity. In previous phase 2 trials, responses to single agent blinatumomab in the relapsed setting were near 60%, although only 34% (44%, including partial and incomplete hematologic recovery) in the pivotal phase 3. Median duration of remission was only 7.3 months and half were very heavily pretreated. Here, we describe a trial designed to target ALL cells with Marquibo as a microtubule inhibitor and blinatumomab as a BiTE immuno-oncology therapy and evaluate whether this combination results in an effective and safe therapeutic option for relapsed/refractory ALL patients. We anticipate additive benefits of the regimen and define a clinically meaningful outcome as >75% (CR/CRi) rate and median progression-free survival (PFS) of ≥1 year. This higher rate of response is expected as many patients are using blinatumomab at first relapse, and therefore we anticipate less prior therapy than overall in the pivotal phase 3 study. Further, we hypothesize that the combination will result in a high rate of response, allowing enhanced immunologic recovery. Study Design/Methods: This is a phase 2, single arm, trial to evaluate the efficacy of blinatumomab and vincristine sulfate liposomal injection. The study will include up to 35 participants who are ≥18years of age, with Ph-, CD19+ ALL, and are either relapse or refractory to ≥2 prior regimens, have ≥5% blasts in the bone marrow or peripheral blood or persistent extranodal/marrow site or have an Eastern Cooperative Oncology Group (ECOG) performance status ≤2. The active study period includes a 3-week screening phase, followed by a treatment period (induction phase and consolidation phase) of up to 58 weeks (6 cycles), a safety follow-up 30 days later and a long-term follow-up period of up to 18 months. The induction phase includes two cycles of blinatumomab and liposomal vincristine. A single cycle is defined as 6 weeks in duration, which includes 4 weeks of continuous intravenous infusion (CIVI) of blinatumomab (initial dose 9 μg/day for first 7 days, then escalated to 28 μg/day starting on day 8 (week 2) through day 29 (week 4), followed by a 2-week treatment-free interval and 3 weekly doses of liposomal vincristine, administered intravenously at 2.25 mg/m 2, with no dose cap (per label),in the outpatient setting over 1 hour. Subjects who achieve at least stable disease within 2 induction cycles may continue to the consolidation phase to receive up to a maximum of 6 cycles under the same treatment schedule. The primary objectives are to evaluate whether the combination will result in a median PFS of ≥1 year, and if the CR/CRi rate is ≥75% following 2 cycles and duration of remission. Secondary outcomes will include evaluation of the rate of Minimal Residual Disease (MRD) and duration, the proportion of patients who are able to progress to allogeneic transplantation, the safety of blinatumomab and liposomal vincristine sulfate in combination and the effect of the combination and response on measures of immune reconstitution. Figure 1 Figure 1. Disclosures Rizzieri: Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Acrotech: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees; Mustang: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria; Pharmacyclics: Honoraria. Leonard: Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Shah: Bristol-Myers Squibb/Celgene: Consultancy, Other: Expenses; Adaptive Biotechnologies: Consultancy; Novartis: Consultancy, Other: Expenses; Incyte: Research Funding; Jazz Pharmaceuticals: Research Funding; Servier Genetics: Other; Kite, a Gilead Company: Consultancy, Honoraria, Other: Expenses, Research Funding; Precision Biosciences: Consultancy; Pharmacyclics/Janssen: Honoraria, Other: Expenses; Acrotech/Spectrum: Honoraria; BeiGene: Consultancy, Honoraria; Pfizer: Consultancy, Other: Expenses; Amgen: Consultancy.