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Measurable residual disease (MRD) is a powerful prognostic factor in acute myeloid leukemia (AML). However, pre-treatment molecular predictors of immunophenotypic MRD clearance remain unclear. We analyzed a dataset of 211 patients with pre-treatment next-generation sequencing who received induction chemotherapy and had MRD assessed by serial immunophenotypic monitoring after induction, subsequent therapy, and allogeneic stem cell transplant (allo-SCT). Induction chemotherapy led to MRD- remission, MRD+ remission, and persistent disease in 35%, 27%, and 38% of patients, respectively. With subsequent therapy, 34% of patients with MRD+ and 26% of patients with persistent disease converted to MRD-. Mutations in CEBPA, NRAS, KRAS, and NPM1 predicted high rates of MRD- remission, while mutations in TP53, SF3B1, ASXL1, and RUNX1 and karyotypic abnormalities including inv (3), monosomy 5 or 7 predicted low rates of MRD- remission. Patients with fewer individual clones were more likely to achieve MRD- remission. Among 132 patients who underwent allo-SCT, outcomes were favorable whether patients achieved early MRD- after induction or later MRD- after subsequent therapy prior to allo-SCT. As MRD conversion with chemotherapy prior to allo-SCT is rarely achieved in patients with specific baseline mutational patterns and high clone numbers, upfront inclusion of these patients into clinical trials should be considered.

Cytomegalovirus infection is associated with the expansion of a mature NKG2C+FcεR1γ- NK population, which is distinct and thought to derive from the less differentiated NKG2A+ NK population. The exact mechanism underlying the emergence of NKG2C+ NK cells, however, remains unknown. Allogeneic hematopoietic cell transplantation (HCT) provides an opportunity to longitudinally study lymphocyte recovery in the setting of CMV reactivation, particularly in patients receiving T cell-depleted (TCD) allografts, in whom lymphocyte populations recover with variable rapidity. We analyzed peripheral blood lymphocytes at serial timepoints from 119 patients following infusion of their TCD allograft and compared immune recovery to samples obtained from recipients of T cell-replete (T-replete) (n=96) or double umbilical cord blood (DUCB) (n=52) allografts. NKG2C+ NK cells were detected in 92% of TCD-HCT patients who experienced CMV reactivation (n=45/49). While NKG2A+ cells were routinely identifiable early post-HCT, NKG2C+ NK cells were identified only after T cells could be detected. T cell reconstitution occurred at variable times post-HCT among patients and was comprised predominantly of CD8+ T cells. In patients with CMV reactivation, TCD-HCT patients expressed significantly higher frequencies of NKG2C+ and CD56neg NK cells compared to T-replete-HCT or DUCB transplant patients. NKG2C+ NK cells following TCD-HCT were CD57+FcεR1γ+ and degranulated significantly more in response to target cells compared to the adaptive NKG2C+CD57+FcεR1γ- NK cell population. We conclude that the presence of circulating T cells is associated with the expansion of the CMV-induced NKG2C+ NK cell population, a potentially novel example of developmental cooperation between lymphocyte populations in response to viral infection.

The post-transplant scoring system (PTSS), developed by the Francophone Society of Bone Marrow Transplantation and Cellular Therapy, is based on three independent post-transplant risk factors: grade of acute graft-versus-host disease, lack of platelet recovery before day 100, and relapse before day 100; discriminating low- (0), intermediate- (1–3), and high-risk (4–8) patients. We investigated the prognostic value of the PTSS in a cohort of patients with MDS who underwent myeloablative CD34-selected TCD transplants. From 2008 to 2018, 109 patients underwent a first TCD-HCT for MDS at our center. We used Cox proportional hazards models and different landmark analyses to evaluate the association of categorized PTSS score risk groups with overall survival (OS). Patients with an intermediate/ high risk PTSS score had decreased OS at day 180 (univariate HR 3.25 [95% CI 1.60, 6.60], p = 0.001) and at day 365 (univariate HR 5.42 [95% CI 2.21, 13.3], p

Allogeneic hematopoietic cell transplantation (alloHCT) for multiple myeloma (MM), with its underlying graft-versus-tumor capacity, is a potentially curative approach for high-risk patients. Relapse is the main cause of treatment failure, but predictors for postrelapse survival are not well characterized. We conducted a retrospective analysis to evaluate predictors for postrelapse overall survival (OS) in 60 MM patients who progressed after myeloablative T cell-depleted alloHCT. The median patient age was 56 years, and 82% had high-risk cytogenetics. Patients received a median of 4 lines of therapy pre-HCT, and 88% achieved at least a partial response (PR) before alloHCT. Of the 38% who received preemptive post-HCT therapy, 13 received donor lymphocyte infusions (DLIs) and 10 received other interventions. Relapse was defined as very early ( 24 months; 22%). At relapse, 27% presented with extramedullary disease (EMD). The median postrelapse overall survival (OS) by time to relapse was 4 months for the very early relapse group, 17 months for the early relapse group, and 72 months for the late relapse group (P = .002). Older age, relapse with EMD

Natural killer (NK) cells are potent mediators of the graft versus leukemia phenomenon critical to the success of allogeneic hematopoietic cell transplantation. Central to calibrating NK effector function via their interaction with class I human leukocyte antigens are the numerous inhibitory killer Ig-like receptors (KIR). The KIR receptors are encoded by a family of polymorphic genes, whose expression is largely stochastic and uninfluenced by human leukocyte antigens genotype. These features provide the opportunity to select hematopoietic cell donors with favorable KIR genotypes that confer enhanced protection from relapse via NK-mediated graft versus leukemia. Over the last 2 decades, a large body of work has emerged examining the use of KIR genotyping to stratify potential donors based on anticipated NK alloreactivity. Overall, these results support KIR-based donor selection for patients undergoing allogeneic hematopoietic cell transplantation for a diagnosis of acute myelogenous leukemia. Despite this, the underlying factors that control NK cell responsiveness are not completely understood, and opportunities remain to refine donor selection using NK cell receptor genotyping. In this review, we will summarize the relevant findings with respect to KIR genotyping as a selection parameter for allogeneic hematopoietic cell donors and address practical considerations with respect to KIR-based selection of donors for patients with myeloid neoplasia.

Introduction: Older adults with hematologic malignancies such as AML and MDS increasingly undergo allogeneic hematopoietic cell transplantation (alloHCT). The impact of the aging host environment, especially cellular senescence, remains unexplored, however. Objectives: We hypothesize that pre-transplant senescence-associated secretary phenotype (SASP) is associated with alloHCT outcomes among older patients and tested it in this biomarker correlative study. Methods: We measured ten SASP-related cytokines (IFNγ, IL1β, IL2, IL4, IL6, IL8, IL10, IL12, IL13, and TNFα, and C-reactive protein (CRP) from pre-transplant plasma samples of 155 patients (>50 years) who had undergone alloHCT at MSKCC from 2011 to 2019 for acute leukemias and other myeloid malignancies. Expression of aging biomarker p16 was measured on a subset of patients by immunohistochemistry. Results and Discussion: The median age was 64.1 years (IQR 58.3 – 67.8). Diseases included 57% acute leukemias (AML and ALL) and 43% MDS/MPN. KPS was 3 in 53% of patients. With median follow-up of 61 months for survivors, the 5-year OS and PFS is 50% and 46%, respectively. The 2-year cumulative incidence of non-relapse mortality (NRM) and relapse is 18% and 31%, respectively. At the baseline, these SASP-related cytokines have variable degree of association with KPS, chronologic age, and disease risk. IL2 trended toward significant positive association with OS (HR 1.19, 95% CI 1-1.43, p=0.052) and was significantly associated with PFS (HR 1.21, 95% CI 1.02-1.44, p=0025) in univariate analysis, but not in multivariate analysis after adjusting for clinical characteristics. No cytokine was associated with NRM. IL2 and IL4 were associated with relapse in univariate but not multivariate analysis. Several cytokines including IL12 p70, IL13, IL4, and TNFα were associated with 100d grade II-IV acute GVHD in patients who received CNI-based GVHD prophylaxis. In summary, we found potential association of SASP-related cytokines with patient characteristics and transplant outcomes. We aim to validate these findings and examine their therapeutic potential to improve alloHCT outcomes. Citation Format: Richard J Lin, Phillip Wong, Jessica R Flynn, Erika R Ritter, Caleb Ho, Josel D Ruiz, Ann A Jakubowski, Esperanza B Papadopoulos, Brian C Shaffer, Hugo R Castro-Malaspina, Christina J Cho, Doris R Ponce, Juliet N Barker, Roni Tamari, Craig S Sauter, Boglarka Gyurkocza, Marcel van den Brink, James W Young, Miguel-Angel Perales, Sean M Devlin, Sergio A Giralt. Aging-related, Senescence-associated Secretory Phenotype and Allogeneic Hematopoietic Cell Transplantation Outcomes in Older Adults [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A48.

A common method to prevent graft-versus-host disease after allogeneic hematopoietic cell transplantation (HCT) from an HLA-mismatched unrelated donor (MMUD) is tacrolimus, methotrexate, and antithymocyte globulin (ATG). The use of posttransplant cyclophosphamide (PTCy) showed promise in a prospective trial for MMUD HCT. We compared 1-year graft-versus-host disease–free, relapse-free survival (GRFS) in 128 recipients of prophylaxis based on tacrolimus/methotrexate/ATG (ATG group, n = 46) vs PTCy, mycophenolate mofetil, and tacrolimus or sirolimus (PTCy group, n = 82) after MMUD HCT. Patients receiving HCT from a MMUD mismatched at ≥1 locus among HLA-A, HLA-B, HLA-C, and HLA-DRB1 were included. The 2 groups were well matched for HCT indication, high-risk disease, and HCT comorbidity index, whereas more patients on PTCy received bone marrow (50% vs 26%; P = .01) and >1 locus HLA-mismatched (30.5% vs 2.2%; P = .001) grafts. The 1-year GRFS was 16% (95% confidence interval (CI): 8%-31%) vs 54% (95% CI: 44%-66%; P < .001) in the ATG and PTCy groups, respectively. The multivariable adjusted hazard ratio for GRFS was 0.34 (95% CI: 0.21-0.55; P < .001) with the use of PTCy. The 1-year overall survival in the ATG group was 45% (95% CI: 32%-62%) vs 75% (95% CI: 66%-85%) in the PTCy group (P < .001). Relapse incidence was similar. One-year nonrelapse mortality was greater after ATG-based prophylaxis: 38% (95% CI: 23%-52%) vs 16% (95 CI: 9%-25%), P < .001. In summary, PTCy-based prophylaxis resulted in superior GRFS and overall survival in recipients of MMUD.

The use of Post-Transplant Cyclophosphamide (PTCy) as Graft Versus Host Disease (GVHD) prophylaxis has resulted in reductions in GVHD and improved outcomes in allogeneic hematopoietic cell transplant (HCT) using HLA-mismatched related donors. We report the 3-year outcomes of the first multi-center prospective clinical trial using PTCy in the setting of mismatched unrelated donor (MMUD) bone marrow HCT. The study enrolled 80 patients (Either myeloablative (MAC) (N=40) or reduced intensity conditioning (RIC) (N=40)) with the primary endpoint of 1-year overall survival (OS). The median follow-up for this report is 34 months (range 12-46) in RIC and 36 months (range 18-49) in MAC. Three-year OS and non-relapse mortality (NRM) were 70% and 15%, and 62% and 10% in the RIC and MAC strata, respectively. No GVHD was reported after 1 year. Relapse incidence was 29% and 51% in RIC and MAC strata. OS did not differ based on HLA match grade (63% in the 7/8 strata and 71% in the 4-6/8 strata). These encouraging outcomes, sustained 3 years post-HCT, support the continued exploration of MMUD HCT using a PTCy platform. Important future areas to address include relapse reduction and furthering our understanding of optimal donor selection based on HLA and non-HLA factors.

Background: Measurable residual disease (MRD) is a powerful prognostic factor in AML, including in prediction of outcomes post allogeneic stem cell transplant (alloSCT). However, genomic predictors of successful MRD eradication with chemotherapy prior to alloSCT are unclear. Objectives: Here we provide an integrated analysis of 233 patients (pts) who underwent induction chemotherapy with baseline next-generation sequencing (NGS) followed by serial immunophenotypic monitoring for MRD while patients received additional therapy and alloSCT. Methods: All pts who received anthracycline + cytarabine, +/- investigational agents at Memorial Sloan Kettering Cancer Center starting in April 2014 were retrospectively studied (A). 142 out of 233 pts subsequently underwent alloSCT after induction or additional therapy (A). Immunophenotypic MRD was identified in bone marrow aspirates (BMA) by multiparameter flow cytometry. Any level of residual disease was considered MRD+. Molecular analysis was obtained from pre-induction BMA by NGS using 28 or 49 or 400 gene panels. Results: Patient and treatment characteristics for all pts are detailed in panel (B). Induction chemotherapy resulted in an MRD-CR/CRi and MRD+CR/CRi in 29% and 23% of all pts, respectively (C). Additional therapy included consolidation (n=51), intensive re-induction/salvage (n=47) and non-intensive therapy (n=9). Of 83 AML pts with persistent AML and 58 pts with MRD+CR/CRi after induction (R1), 38/141 (27%) were able to be converted to MRD-CR/CRi. While 33/38 of pts went on to alloSCT after conversion to MRD-CR/CRi, 22 and 36 pts went to alloSCT with persistent AML and MRD+CR/CRi AML, respectively. We focused on pre-induction molecular predictors for achieving an MRD-CR/CRi response prior to transplant for the 142 pts who underwent alloSCT (D). Pts with a NPM1 (79%, Odds ratio [OR] 3.7, p=0.01), IDH1 (92%, OR 3.9, p=0.01) and KRAS (100%, OR 5.0, p=0.03) mutations achieved high rates of MRD-CR/CRi prior to alloSCT. In contrast, RUNX1 (28%, OR 0.2, p=0.01), TP53 (12%, OR 0.1, p=0.02) and SF3B1 (14%, OR 0.1, p=0.04) mutations predicted decreased odds of achieving MRD-CR/CRi prior to alloSCT despite induction and post-induction therapy. AlloSCT resulted in high rates of conversion from MRD+ and persistent disease to MRD negativity. Most pts who entered transplant with CR/CRi MRD+ (28/36, 76%) or persistent AML (14/22, 64%) cleared MRD by the first post-transplant BMA at a median of 32 days (E). Post-alloSCT follow-up indicated value in converting MRD+ to MRD- prior to alloSCT. There was no significant difference in post-transplant cumulative incidence of relapse (F) and OS (G) between early MRD-CR/CRi immediately following induction versus later conversion to MRD-CR/CRi with additional therapy prior to alloSCT. Despite initial post-transplant MRD clearance, pts who entered alloSCT with persistent AML or MRD+ had higher incidence of relapse (p=0.00037, F) and poorer post-transplant OS (p=0.013, G) compared to pts who entered alloSCT with MRD-. Pts with persistent disease prior to alloSCT had shorter duration of MRD- induced by alloSCT compared to pts with MRD-CR/CRi after induction or converted MRD-CR/CRi prior to alloSCT (p=0.0042, H). Importantly, duration of MRD negativity after alloSCT for patients who achieved MRD- prior to alloSCT was not affected by whether patients received induction +/- consolidation (I: treatment type 1-3 from B) vs. induction and salvage treatment for refractory AML (I: treatment type 4-6 from B). Conclusion: We show that transplanted AML pts with specific molecular mutations (RUNX1, SF3B1, and TP53) are unlikely to achieve MRD-CR/CRi after induction, consolidation or salvage therapy, while other mutations (NPM1, IDH1, KRAS) predict high rates of MRD- prior to alloSCT. Additional post-induction therapy may be advantageous for some MRD+ pts to achieve MRD- prior to alloSCT. Post-transplant OS is improved in pts who are MRD- at time of transplant, regardless of whether they required additional therapy beyond induction to achieve this state. AlloSCT is highly effective at eradicating MRD, but post-transplant MRD- is more durable in pts who are MRD- pre-alloSCT. Our results suggest that development of MRD-eradicating therapies has the potential to improve post-transplant outcomes and argues for innovative trials for pts with adverse molecular features currently unlikely to achieve MRD- pre alloSCT. Figure Disclosures Cai: Imago Biosciences, Inc.: Consultancy, Current equity holder in private company; DAVA Oncology: Honoraria. Geyer:Amgen: Research Funding. Glass:Gerson Lehman Group: Consultancy. Stein:Syros: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotheryx: Consultancy; Bayer: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Research Funding; Seattle Genetics: Consultancy; Abbvie: Consultancy; Amgen: Consultancy; Celgene Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Levine:Gilead: Honoraria; Isoplexis: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Qiagen: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy; Lilly: Consultancy, Honoraria; Imago: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy; Novartis: Consultancy; Prelude Therapeutics: Research Funding; Loxo: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Morphosys: Consultancy; Roche: Consultancy, Honoraria, Research Funding. Gyurkocza:Actinium: Research Funding. Perales:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Medigene: Membership on an entity's Board of Directors or advisory committees, Other; Servier: Membership on an entity's Board of Directors or advisory committees, Other; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; NexImmune: Membership on an entity's Board of Directors or advisory committees; Cidara Therapeutics: Other; Miltenyi Biotec: Research Funding; Kite/Gilead: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees. Abdel-Wahab:H3 Biomedicine Inc.: Consultancy, Research Funding; Janssen: Consultancy; Envisagenics Inc.: Current equity holder in private company; Merck: Consultancy. Papaemmanuil:Kyowa Hakko Kirin: Consultancy, Honoraria; Isabl: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; MSKCC: Patents & Royalties; Novartis: Consultancy, Honoraria; Illumina: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Prime Oncology: Consultancy, Honoraria. Giralt:KITE: Consultancy; NOVARTIS: Consultancy, Honoraria, Research Funding; OMEROS: Consultancy, Honoraria; AMGEN: Consultancy, Research Funding; TAKEDA: Research Funding; ACTINUUM: Consultancy, Research Funding; MILTENYI: Consultancy, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria. Tallman:Glycomimetics: Research Funding; Rafael: Research Funding; Amgen: Research Funding; Bioline rx: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; KAHR: Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; Rigel: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Oncolyze: Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Membership on an entity's Board of Directors or advisory committees; BioSight: Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Orsenix: Research Funding; Cellerant: Research Funding; Abbvie: Research Funding. Goldberg:AROG: Research Funding; Aprea: Research Funding; ADC Therapeutics: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy; Aptose: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dava Oncology: Honoraria; Pfizer: Research Funding; Celularity: Research Funding.

Data on whether the T cell dose of allogeneic peripheral blood stem cell (PBSC) products influences transplantation outcomes are conflicting. Using the Center for International Blood and Marrow Transplant Research database, we identified 2736 adult patients who underwent first allogeneic PBSC transplantation for acute leukemia or myelodysplastic syndrome between 2008 and 2014 using an HLA-matched sibling donor (MSD) or an 8/8-matched unrelated donor (MUD). We excluded ex vivo and in vivo T cell-depleted transplantations. Correlative analysis was performed between CD3(+) T cell dose and the risk of graft-versus-host-disease (GVHD), relapse, nonrelapse mortality (NRM), disease-free survival (DFS), and overall survival (OS). Using maximum likelihood estimation, we identified CD3(+) T cell dose cutoff that separated the risk of acute GVHD (aGVHD) grade II-IV in both the MSD and MUD groups. A CD3(+) T cell dose cutoff of 14 x 10(7) cells/kg identified MSD/low CD3(+) (n = 223) and MSD/high CD3(+) (n = 1214), and a dose of 15 x 107 cells/kg identified MUD/low (n = 197) and MUD/high CD3(+) (n = 1102). On univariate analysis, the MSD/high CD3(+) group had a higher cumulative incidence of day +100 aGVHD grade II-IV compared with the MSD/low CD3(+) group (33% versus 25%; P=.009). There were no differences between the 2 groups in engraftment rate, risk of aGVHD grade III-IV or chronic GVHD (cGVHD), NRM, relapse, DFS, or OS. The MUD/high CD3(+) group had a higher cumulative incidence of day +100 aGVHD grade II-IV compared with the MUD/low CD3(+) group (49% versus 41%; P=.04). There were no differences between the 2 groups in engraftment rate, risk of severe aGVHD or cGVHD, NRM, relapse, DFS, or OS. Multivariate analysis of the MSD and MUD groups failed to show an association between CD3(+) T cell dose and the risk of either aGVHD grade II-IV (P=.10 and .07, respectively) or cGVHD (P = .80 and .30, respectively). Subanalysis of CD4(+) T cells, CD8(+) T cells, and CD4+/CD8+ ratio failed to identify cutoff values predictive of transplantation outcomes; however, using the log-rank test, the sample size was suboptimal for identifying a difference at this cutoff cell dose. In this registry study, the CD3(+) T cell dose of PBSC products did not influence the risk of aGVHD or cGVHD or other transplantation outcomes when using an MSD or an 8/8-matched MUD. Subset analyses of CD4(+) and CD8(+) T cell doses were not possible given our small sample size. (C) 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Older patients are at increased risk for complications and death following allogeneic hematopoietic cell transplantation (allo-HCT). Traditional transplant-specific prognostic indices such as hematopoietic cell transplant comorbidity index (HCT-CI) may not capture all underlying geriatric vulnerabilities, and in-depth evaluation by a geriatrician prior to transplant may not always be available. We hypothesize that routine pre-transplant interdisciplinary clinical assessment may uncover prognostically important geriatric deficits. Using an institutional database of 457 adults aged 60 years and older who underwent first allo-HCT for hematological malignancies from 2010 to 2017, we examined the prognostic impact of pre-transplant deficits in geriatric domains of function, mobility, mood, medication, nutrition, and relevant biochemical markers. We found that impairment in instrumental activities of daily living (IADL) was associated with reduced survival through increased non-relapse mortality (NRM, HR = 1.82; 95% CI, 1.04-3.19). The combination of IADL impairment with either HCT-CI/age index or disease risk index readily stratified NRM and overall survival, respectively. In addition, we found that even mild renal dysfunction adversely impacted survival in older transplant patients. Our findings establish important geriatric vulnerabilities in older patients prior to allo-HCT and may provide an entry point for prospective, interventional trials to improve their outcomes.

Antithymocyte globulin (ATG) use mitigates the risk of graft rejection and graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT), but ATG overexposure in the setting of lymphopenia negatively affects immune recovery. We hypothesized that standard empiric weight-based dosing of ATG, used to prevent graft rejection in ex vivo CD34-selected allo-HCT, may lead to serious adverse consequences on outcomes in certain patients. We evaluated 304 patients undergoing myeloablative-conditioned ex vivo CD34-selected allo-HCT with HLA-matched donors for the treatment of hematologic malignancies. Patients received rabbit ATG at a dose of 2.5 mg/kg/day i.v. on days -3 and/or -2. An ATG dosing cutoff of 450 mg was used for statistical analyses to assess the relationship between ATG and overall survival (OS). Among all patients, median total ATG dose was 360 mg (range, 130 to 510 mg); 279 (92%) received a total dose of ATG ≤450 mg, and 25 (8%) received a total dose >450 mg. On the first day of ATG administration (day -3), the median absolute lymphocyte count was .0 K/µL. For patients who received a total dose of ATG >450 mg or ≤450 mg, the incidences of acute and late-acute GVHD grade II-IV were statistically similar. At 3 years post-HCT, for patients who received a total dose of ATG >450 mg or ≤450 mg, nonrelapse mortality (NRM) rates were 35% and 18%, respectively (P = .029), disease-free survival (DFS) rates were 37% and 61%, respectively (P = .003), and OS rates were 40% and 67%, respectively (P = .001). Among all patient and HCT characteristics in multivariable analyses, receipt of a total dose of ATG >450 mg was associated with an increased risk of NRM (hazard ratio [HR], 2.9; P = .01), shorter DFS (HR, 2.0; P = .03), and inferior OS (HR, 2.1; P = .01). In summary, the use of weight-based ATG at a time of relative lymphopenia before ex vivo CD34-selected allo-HCT results in overdosing in heavier patients, leading to higher NRM and lower DFS and OS. Further pharmacokinetic investigation in this setting is critical to determining the optimal dosing strategy for ATG.

Immune-mediated cytopenias (ICs), such as immune thrombocytopenia and immune hemolytic anemia, are among the adverse events after allogeneic hematopoietic cell transplantation (allo-HCT). Previous reports suggest that in vivo T cell depletion may increase the incidence of IC after allo-HCT. We evaluated whether a strategy that reduces functional donor T cells via ex vivo CD34+-selection associates with the development of IC in a cohort of 408 patients who underwent allo-HCT for hematologic malignancy. The cumulative incidence of IC at 6, 12, and 36 months after the 30-day landmark post-HCT was 3.4%, 4.9%, and 5.8%, respectively. Among 23 patients who developed IC, 7 died of relapse-related mortality and 4 of nonrelapse mortality. A median 2 types of treatment (range, 1 to 5) was required to resolve IC, and there was considerable heterogeneity in the therapies used. In univariable analyses, a hematologic malignancy Disease Risk Index (DRI) score of 3 was significantly associated with an increased risk of IC compared with a DRI of 1 or 2 (hazard ratio [HR], 4.12; P = .003), and IC (HR, 2.4; P = .03) was associated with increased risk of relapse. In a multivariable analysis that included DRI, IC remained significantly associated with increased risk of relapse (HR, 2.4; P = .03). Our findings show that IC events occur with relatively similar frequency in patients after ex vivo CD34+-selected allo-HCT compared with unmodified allo-HCT, suggesting that reduced donor T cell immunity is not causative of IC. Moreover, we noted a possible link between its development and/or treatment and increased risk of relapse.

The role of allogeneic hematopoietic cell transplant (allo-HCT) as consolidation after initial venetoclax therapy and the efficacy of venetoclax salvage therapy for relapse after allo-HCT in patients with acute myeloid leukemia (AML) are unclear. We conducted a retrospective study of patients with AML or myelodysplastic syndrome (MDS) who received venetoclax either before or after allo-HCT at Memorial Sloan Kettering Cancer Center and Yale University from 11 August 2016 to 16 November 2020. Among 39 heavily pretreated patients who received venetoclax before allo-HCT, median OS from allo-HCT was not reached after a median follow up of 12.5 months resulting in a 12-month OS estimate of 79.0%. In 37 patients who had received venetoclax-based combinations as salvage therapy after allo-HCT, the overall response rate was 32% with a median OS of 4.7 months (12-month OS estimate: 43.4%). Four patients underwent a second allo-HCT following venetoclax-based salvage therapy suggesting it as a potential salvage treatment option.

Allogeneic hematopoietic cell transplantation (HCT) offers a potentially curative therapy in patients with hematologic malignancies; however, nonrelapse mortality (NRM) remains a concern. Strategies to improve neutrophil recovery and immune reconstitution are needed to decrease NRM. Murine models of allogeneic HCT suggest that fractionated hematopoietic progenitor cell (HPC) infusion may improve engraftment through improved access of HPCs to a viable hematopoietic niche. The primary objective of the present study was to determine the impact of fractionated infusion versus unfractionated (bulk) infusion of HPCs on the time to achieve neutrophil engraftment. Secondary objectives included the effect of fractionated versus bulk infusion of HPCs on platelet engraftment, immune reconstitution, the incidence of acute graft-versus-host disease (GVHD) grade II-IV, NRM, and overall survival (OS). In this randomized phase 2 study, patients with hematologic malignancies undergoing allogeneic HCT were randomized to receive HPC infusion as a bulk (bulk arm) or in fractions (fractionated arm): 4 × 106 CD34+ cells/kg recipient weight infused on day 0, with the remaining HPCs CD34+ cell-selected then infused in equally distributed aliquots on days 2, 4, and 6 post-HCT. Randomization was stratified by type of transplant, unmodified (i.e. T cell-replete graft) versus CD34+ cell-selected (T cell-depleted graft). Patients whose donor failed to collect at least 7 × 106 CD34+ cells/kg of recipient weight received bulk HPC infusions regardless of randomization, for safety. These patients continued the HCT process on study but were replaced until each arm reached the prespecified accrual target. Per protocol, these patients were not included in this modified intention-to-treat analysis. A total of 116 patients were enrolled. Donors of 42 patients failed to mobilize the minimum CD34+ cell dose (7 × 106 cells/kg recipient weight) and were excluded from the analysis. The 74 evaluable patients included 38 randomized to the bulk arm and 36 randomized to the fractionated arm. All patients engrafted. The median time to an absolute neutrophil count of ≥0.5 × 109/L was 11 days on both arms. The day +180 median CD4+ cell count was 179 cells/µL in the bulk arm and 111 cells/µL in the fractionated arm (P = .779). The cumulative incidence of grade II-IV acute GVHD on post-transplant day +100 was 32% in the bulk arm and 17% in the fractionated arm (P = .131). Two patients in the bulk arm, but none in the fractionated arm, experienced grade III-IV GVHD. The 4-year OS was 60% in the bulk arm and 62% in the fractionated arm (P = .414), whereas the 4-year cumulative incidences of NRM and relapse were similar in the 2 arms. Fractionated infusion of HPCs in allogeneic HCT recipients did not impact neutrophil or CD4+ cell recovery, NRM, relapse, or OS when compared with bulk HPC infusion. We also observed that with current mobilization techniques, it was unlikely that more than 60% of healthy donors would be able to collect >7 × 106 CD34+ cells/kg recipient weight for adult recipients. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Traditional weight-based dosing results in variable rabbit antithymocyte globulin (rATG) clearance that can delay CD4+ T-cell immune reconstitution (CD4+ IR) leading to higher mortality. In a retrospective pharmacokinetic/pharmacodynamic (PK/PD) analysis of patients undergoing their first CD34+ T-cell–depleted (TCD) allogeneic hematopoietic cell transplantation (HCT) after myeloablative conditioning with rATG, we estimated post-HCT rATG exposure as area under the curve (arbitrary unit per day/milliliter [AU × day/mL]) using a validated population PK model. We related rATG exposure to nonrelapse mortality (NRM), CD4+ IR (CD4+ ≥50 cells per µL at 2 consecutive measures within 100 days after HCT), overall survival, relapse, and acute graft-versus-host disease (aGVHD) to define an optimal rATG exposure. We used Cox proportional hazard models and multistate competing risk models for analysis. In all, 554 patients were included (age range, 0.1-73 years). Median post-HCT rATG exposure was 47 AU × day/mL (range, 0-101 AU × day/mL). Low post-HCT area under the curve (

Background There are limited data on outcomes of patients with prior Coronavirus disease 2019 (COVID-19) who proceeded to autologous or allogeneic hematopoietic cell transplantation (HCT). It is unknown whether these patients are more susceptible to poor outcomes and recurrence of COVID-19. Objective We report a retrospective analysis of outcomes of 15 consecutive patients with hematologic malignancies who experienced COVID-19 and subsequently underwent autologous (n=8) or allogeneic (n=7) HCT between 6/17/20 and 2/17/21. The reported cohort included patients with asymptomatic past infections or symptomatic COVID-19 disease. Methods Data were obtained from chart review. Descriptive statistics were used to summarize patient characteristics. Results Among eight patients who underwent autologous HCT, four had a diagnosis of multiple myeloma while the rest had a diagnosis of non-Hodgkin's lymphoma. Four of the eight patients did not test positive for anti-SARS- CoV-2 IgG antibody at any point during their course. The remaining four patients had detectable anti-SARS-CoV-2 IgG antibodies prior to autologous HCT but only two of these patients remained anti-SARS-CoV-2 IgG antibody-positive at their last follow-up. One patient died from progression of disease. Seven patients with prior COVID-19 underwent allogeneic HCT for acute lymphoblastic leukemia (n=3); acute myeloid leukemia (n=1); chronic myeloid leukemia in lymphoid blast crisis (n=1); myelodysplastic syndrome (n=1); and myelofibrosis (n=1). Three of the seven patients tested positive for anti-SARS- CoV-2 IgG antibodies following the initial COVID-19 diagnosis; however, only one of these patients retained anti-SARS- CoV-2 IgG antibody following allogeneic stem cell transplantation. One patient died of infections (fungal and Pneumocystis jirovecii pneumonia) occurring in the context of ongoing treatment for GVHD. None of the 15 patients developed recurrence of COVID-19 infection. Conclusions Based on our experience, autologous and allogeneic HCT can be safely performed in select patients with previous COVID-19 infection.

Voriconazole is frequently discontinued prematurely as primary antifungal prophylaxis (AFP) in allogeneic hematopoietic cell transplant (HCT) recipients due to adverse events. Limited data exists for isavuconazole as AFP. We analyzed adult HCT recipients who received voriconazole or isavuconazole AFP to estimate rate of premature AFP discontinuation, identify risk factors for premature AFP discontinuation, and compare incidence of invasive fungal infection (IFI) and survival at day + 180 post-HCT between patients who received voriconazole/isavuconazole-AFP. This was a propensity score matched cohort analysis of 210 HCT-recipients who received voriconazole-AFP (9/1/2014-12/31/2016; voriconazole-cohort), and 95 HCT-recipients who received isavuconazole-AFP (5/1/2017-10/31/2018; isavuconazole-cohort). AFP discontinuation for any reason prior to completion was defined as “premature”. Median (interquartile range, IQR) duration of AFP was longer in the isavuconazole-cohort (94 days, 87–100) vs. the voriconazole-cohort (76 days, 23–94; P-value Lay Summary When compared to voriconazole, isavuconazole is a safer and as effective primary antifungal prophylaxis during the first 3 months after allogeneic hematopoietic cell transplant, with lower rates of hepatotoxicity, and similar rates of fungal infections and all-cause mortality.

PURPOSE Hematopoietic cell transplantation (HCT) is curative for hematologic disorders, but outcomes are historically inferior when using HLA-mismatched donors. Despite unrelated donor registries listing > 38 million volunteers, 25%-80% of US patients lack an HLA-matched unrelated donor, with significant disparity across ethnic groups. We hypothesized that HCT with a mismatched unrelated donor (MMUD) using post-transplant cyclophosphamide (PTCy), a novel strategy successful in overcoming genetic disparity using mismatched related donors, would be feasible and increase access to HCT. PATIENTS AND METHODS We performed a prospective phase II study of MMUD bone marrow HCT with PTCy for patients with hematologic malignancies. The primary end point was 1-year overall survival (OS), hypothesized to be 65% or better. 80 patients enrolled at 11 US transplant centers (December 2016-March 2019). Following myeloablative or reduced-intensity conditioning–based HCT, patients received PTCy on days +3, +4, with sirolimus and mycophenolate mofetil starting on day +5. We compared outcomes to Center for International Blood and Marrow Transplant Research contemporary controls receiving PTCy. RESULTS Notably, 48% of patients enrolled were ethnic minorities. 39% of pairs were matched for 4-6 out of 8 HLA alleles. The primary end point was met, with 1-year OS of 76% (90% CI, 67.3 to 83.3) in the entire cohort, and 72% and 79% in the myeloablative and reduced-intensity conditioning strata, respectively. Secondary end points related to engraftment and graft-versus-host-disease were reached. Multivariate analysis comparing the study group with other mismatched HCT controls found no significant differences in OS. CONCLUSION Our prospective study demonstrates the feasibility and effectiveness of HCT with an MMUD in the setting of PTCy. Remarkably, nearly half of the study participants belonged to an ethnic minority population, suggesting this approach may significantly expand access to HCT.

Donor KIR and recipient HLA combinations that minimize inhibition and favor activation of the NK repertoire are associated with improved outcomes after allogeneic hematopoietic cell transplantation (HCT) in patients with myeloid neoplasia. We prospectively evaluated a weighted donor ranking algorithm designed to prioritize HLA-compatible unrelated donors (URDs) with weak inhibitory KIR3DL1/HLA-Bw4 interaction, followed by donors with nontolerized activating KIR2DS1, and finally those with KIR centromeric B haplotype. During donor evaluation, we performed KIR genotyping and ranked 2079 URDs for 527 subjects with myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML). Among all patients, 394 (75%) had at least 1 KIR-advantageous donor, and 263 (50%) underwent HCT. In patients with AML, KIR3DL1 weak inhibition provided protection from relapse. Compared with KIR3DL1-Weak Inhibiting donors, KIR3DL1-Noninteracting donors were associated with increased risk of relapse (HR, 2.97; 95% CI, 1.33-6.64; P = .008) and inferior event-free survival (EFS; HR, 2.14; 95% CI, 1.16-3.95; P = .015). KIR3DL1-Strong Inhibiting donors were associated with HR, 1.65 (95% CI, 0.66-4.08; P = .25) for AML relapse and HR, 1.6 (95% CI, 0.81-3.17; P = .1) for EFS when compared with the use of KIR3DL1-weak inhibiting donors. Donor KIR2DS1/HLA-C1 status and centromeric KIR haplotype-B content were not associated with decreased risk of AML relapse. There was no benefit to KIR-based donor selection in patients with MDS. This study demonstrates that donor KIR typing is feasible, and prioritization of donors with certain KIR3DL1 genotypes may confer a protection from relapse after HCT in patients with AML.

Individual comorbidities have distinct contributions to nonrelapse mortality (NRM) following allogeneic hematopoietic cell transplantation (allo-HCT). We studied the impact of comorbidities individually and in combination in a single-center cohort of 573 adult patients who underwent CD34-selected allo-HCT following myeloablative conditioning. Pulmonary disease, moderate to severe hepatic comorbidity, cardiac disease of any type, and renal dysfunction were associated with increased NRM in multivariable Cox regression models. A Simplified Comorbidity Index (SCI) composed of the 4 comorbidities predictive of NRM, as well as age >60 years, stratified patients into 5 groups with a stepwise increase in NRM. NRM rates ranged from 11.4% to 49.9% by stratum, with adjusted hazard ratios of 1.84, 2.59, 3.57, and 5.38. The SCI was also applicable in an external cohort of 230 patients who underwent allo-HCT with unmanipulated grafts following intermediate-intensity conditioning. The area under the receiver operating characteristic curve (AUC) of the SCI for 1-year NRM was 70.3 and 72.0 over the development and external-validation cohorts, respectively; corresponding AUCs of the Hematopoietic Cell Transplantation–specific Comorbidity Index (HCT-CI) were 61.7 and 65.7. In summary, a small set of comorbidities, aggregated into the SCI, is highly predictive of NRM. The new index stratifies patients into distinct risk groups, was validated in an external cohort, and provides higher discrimination than does the HCT-CI.

Background: Traditional weight-based dosing results in variable rabbit anti-thymocyte-globulin (rATG) clearance that can delay CD4+Tcell immune reconstitution (CD4+IR) leading to higher mortality. Methods: In a retrospective, pharmacokinetic (PK)/pharmacodynamic analysis of patients undergoing their first CD34+ T-cell depleted (TCD) Allogeneic Hematopoietic Cell Transplantation (HCT) after myeloablative conditioning with rATG, we estimated post-HCT rATG exposure as area-under-the-curve (AUC;AU*d/L) using a validated population-PK model. We related rATG exposure to non-relapse mortality (NRM), CD4+IR (CD4+≥50/µL at two consecutive measures within 100 days after HCT), overall survival, relapse, and acute-graft versus host disease (GVHD) to define an optimal rATG-exposure. Cox-proportional hazard models, and multi-state competing risk models were used. Results: 554 patients were included (age 0.1-73 years). Median post-HCT rATG exposure was 47AU*d/L (range 0–101). Low post–HCT AUC ( 55AU*d/L and 30-55AU*d/L groups, respectively, compared to

T cell depletion by CD34(+) cell selection of hematopoietic stem cell allografts ex vivo reduces the incidence and severity of GvHD, without increased risk of relapse in patients with acute leukemia in remission or MDS. The optimal candidate for CD34(+)-selected HCT remains unknown, however. OBJECTIVE: To determine outcomes based on both disease- and patient-specific factors, we evaluated a prognostic model combining the Disease Risk Index (DRI) and Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI), an approach recently shown to predicted overall survival in a broad population of allograft recipients (1). METHODS: This was a retrospective analysis of 506 adult recipients of first allogeneic HCT with CD34+ selected PBSCs from 7/8- or 8/8-matched donors for AML (n = 290), ALL (n = 72), or MDS (n = 144). The Kaplan-Meier method estimated OS and RFS. The cumulative incidence method for competing risks estimated relapse and non-relapse mortality (NRM). We evaluated the univariate association between variables of interest and OS and RFS using the log-rank test. Cox regression models assessed the adjusted effect of covariates on OS/RFS. RESULTS: Stratification of patients based on a composite of DRI (low/intermediate vs. high/very high) and HCT-CI (0–2 vs. ≥ 3) revealed differences in OS and RFS between the 4 groups. Compared with reference groups of patients with low/intermediate DRI and low or high HCT-CI, those with high DRI had a greater risk of death (HR 2.30; 95% CI 1.39, 3.81) and relapse or death (HR 2.50; 95% CI 1.55, 4.05) than patients with any HCT-CI but low/intermediate DRI (HR death 1.80; 95% CI 1.34, 2.43; HR relapse/death 1.68; 95% CI 1.26, 2.24). CONCLUSIONS AND CLINICAL IMPLICATIONS: A model combining DRI and HCT-CI predicted survival after CD34(+) cell–selected HCT. Application of this combined model to other cohorts, both in retrospective analyses and prospective trials, will enhance clinical decision making and patient selection for different transplant approaches. DATA AVAILABILITY STATEMENT: The data that support the findings of this study are available on request from the corresponding author, C Cho. In order to protect the privacy of research participants, the data are not publicly available.

Allogeneic hematopoietic cell transplantation (alloHCT) for multiple myeloma (MM), with its underlying graft-versus-tumor capacity, is a potentially curative approach for high-risk patients. Relapse is the main cause of treatment failure, but predictors for postrelapse survival are not well characterized. We conducted a retrospective analysis to evaluate predictors for postrelapse overall survival (OS) in 60 MM patients who progressed after myeloablative T cell-depleted alloHCT. The median patient age was 56 years, and 82% had high-risk cytogenetics. Patients received a median of 4 lines of therapy pre-HCT, and 88% achieved at least a partial response (PR) before alloHCT. Of the 38% who received preemptive post-HCT therapy, 13 received donor lymphocyte infusions (DLIs) and 10 received other interventions. Relapse was defined as very early (6 months; 28%), early (6 to 24 months; 50%), or late (24 months; 22%). At relapse, 27% presented with extramedullary disease (EMD). The median postrelapse overall survival (OS) by time to relapse was 4 months for the very early relapse group, 17 months for the early relapse group, and 72 months for the late relapse group (P = .002). Older age, relapse with EMD,PR before alloHCT,PR by day +100, and no maintenance were prognostic for inferior postrelapse OS on univariate analysis. On multivariate analysis adjusted for age and sex, very early relapse (hazard ratio [HR], 4.37; 95% confidence interval [CI], 1.42 to 13.5), relapse with EMD (HR, 5.20; 95% CI, 2.10 to 12.9), and DLI for relapse prevention (HR, .11; 95% CI, 2.10 to 12.9) were significant predictors for postrelapse survival. Despite their shared inherent high-risk status, patients with MM have significantly disparate post-HCT relapse courses, with some demonstrating long-term survival despite relapse.

Multifactorial geriatric syndromes are highly prevalent in older patients with cancer. Because an increasing number of older patients undergo allogeneic hematopoietic stem cell transplantation (allo-HCT), we examined the incidence and impact of transplant-related geriatric syndromes using our institutional database and electronic medical records. We identified 527 patients age 60 years or older who had undergone first allo-HCT from 2001 to 2016 for hematologic malignancies. From the initiation of conditioning to 100 days posttransplant, new geriatric syndromes were predominantly delirium with a cumulative incidence of 21% (95% confidence interval [CI], 18%-25%) at day 100 followed by fall at 7% (95% CI, 5%-9%). In multivariable analyses of available pretransplant variables, fall within the last year, potentially inappropriate use of medication, thrombocytopenia, and reduced creatinine clearance were significantly associated with delirium; age older than 70 years and impaired activities of daily living were significantly associated with fall. In the 100-day landmark analysis, both delirium (hazard ratio [HR], 1.66; 95% CI, 1.09-2.52; P = .023) and fall (HR, 2.14; 95% CI, 1.16-3.95; P = .026) were significantly associated with increased nonrelapse mortality; moreover, fall (HR, 1.93; 95% CI, 1.18-3.14; P = .016), but not delirium, was significantly associated with reduced overall survival. Here, we establish baseline incidences and risk factors of common transplant-related geriatric syndromes. Importantly, we demonstrate significant associations of delirium and fall with inferior transplant outcomes. The burden and impact of transplant-related geriatric syndromes warrant the institution of patient-centered, preemptive, longitudinal, and multidisciplinary interventions to improve outcomes for older allo-HCT patients.

HLA-B allotypes exhibiting the Bw4 epitope trigger variable inhibitory signaling of KIR3DL1 receptor types, where strong inhibitory HLA-B and KIR3DL1 allele combinations are associated with increased risk for relapse of acute myelogenous leukemia (AML) following allogeneic hematopoietic cell transplantation (HCT). Several HLA-A allotypes also exhibit the Bw4 epitope. Studies with natural killer (NK) cell clones have demonstrated NK inhibition via KIR3DL1 by HLA-A Bw4+ allotypes, but did not delineate strengths of inhibition or hierarchies of NK education. Using primary NK cells from healthy donors, we demonstrate that HLA-A*23, HLA-A*24, and HLA-A*32 proteins are expressed at different densities and exhibit different capacities to educate and inhibit KIR3DL1-expressing NK cells in vitro. Among the HLA-A Bw4+ allotypes, HLA-A*24 and HLA-A*32 demonstrate the strongest inhibitory capacity. To determine if HLA-A allotypes with strong inhibitory capacity have similar negative impact in allogeneic HCT as HLA-B Bw4+ allotypes, we performed a retrospective analysis of 1729 patients with AML who received an allogeneic HCT from a 9/10 or 10/10 HLA allele-matched unrelated donor. Examination of the donor-recipient pairs whose Bw4 epitope was exclusively contributed from HLA-A*24 and A*32 allotypes revealed that patients with HLA-A*24 who received an allograft from a KIR3DL1+ donor experienced a higher risk of disease relapse (hazard ratio, 1.65; 95% confidence interval, 1.17-2.32; P = .004) when compared with patients without a Bw4 epitope. These findings indicate that despite weak affinity interactions with KIR3DL1, common HLA-A allotypes with the Bw4 epitope can interact with KIR3DL1+ donor NK cells with clinically meaningful impact and provide additional insight to donor NK alloreactivity in HLA-matched HCT.

6523 Background: Whether patient (pt) ancestry impacts the time to BMT is not established. Methods: We hypothesized that non-European (non-EURO) ancestry AML pts are at increased risk of delayed time to transplant. Thus, we analyzed time to allograft (Allo) by ancestry defining delayed (late) times as: Allo Indication to BMT Consult (Ind. – Consult) > 90 days, Consult – BMT > 120 days & Allo Indication to BMT (Ind. - BMT) > 180 days. We studied pts < 70 yrs transplanted 1/2016-7/2021. Results: In 279 AML pts (median 56 yrs, range 19-69), BMT indication was date of diagnosis if ELN 2017 intermediate/ high risk &/or high risk mutations &/or sAML in 261 (94%) pts, or date of refractory/ relapsed disease in 18 (6%) pts. European (EURO) pts (n = 195, 70%; median 60 yrs) were older than non-EURO pts (n = 84, 30%; median 49 yrs), p

Although the 5-year survival rate of chronic lymphocytic leukemia (CLL) patients has risen to >80%, the only potentially curative treatment is allogeneic hematopoietic stem cell transplantation (alloHSCT). To identify possible new monoclonal antibody (mAb) drugs and targets for CLL, we previously developed a phage display–based human mAb platform to mine the antibody repertoire of patients who responded to alloHSCT. We had selected a group of highly homologous post-alloHSCT mAbs that bound to an unknown CLL cell surface antigen. Here, we show through next-generation sequencing of cDNAs encoding variable heavy-chain domains that these mAbs had a relative abundance of ∼0.1% in the post-alloHSCT antibody repertoire and were enriched ∼1,000-fold after three rounds of selection on primary CLL cells. Based on differential RNA-seq and a cell microarray screening technology for discovering human cell surface antigens, we now identify their antigen as Siglec-6. We verified this finding by flow cytometry, ELISA, siRNA knockdown, and surface plasmon resonance. Siglec-6 was broadly expressed in CLL and could be a potential target for antibody-based therapeutic interventions. Our study reaffirms the utility of post-alloHSCT antibody drug and target discovery. Cancer Immunol Res; 6(9); 1008–13. ©2018 AACR.

Ex vivo CD 34+ selection prior to allogeneic hematopoietic stem Cell transplantation (allo-HCT) reduces GVHD without increasing relapse, but usually requires myeloablative conditioning. We aimed to identify toxicity patterns in older patients & the association with overall survival (OS) & non-relapse mortality (NRM). We conducted a retrospective analysis of 200 pts who underwent CD34+ selection allo-HCT using the ClinicMACS® system between 2006-2012. All grade 3-5 toxicities by CTCAE v4.0 were collected. Eighty patients ≥ 60yrs with a median age of 64 (range 60-73) were compared to 120 pts

The late adverse events in long-term survivors after myeloablative-conditioned allogeneic hematopoietic cell transplantation (HCT) with ex vivo CD34+ cell selection are not well characterized. Using the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.0, we assessed all grade ≥3 toxicities from the start of conditioning to the date of death, relapse, or last contact in 131 patients who survived >1 year post-HCT, identifying 285 individual toxicities among 17 organ-based toxicity groups. Pretransplantation absolute lymphocyte count >.5 K/µL and serum albumin >4.0 g/dL were associated with a reduced risk of toxicities, death, and nonrelapse mortality (NRM), whereas serum ferritin >1000 ng/mL was associated with an increased risk of toxicities and NRM after 1 year. An HCT Comorbidity Index (HCT-CI) score ≥3 was associated with an increased risk of all-cause death and NRM, but was not associated with a specific increased toxicity risk after 1 year. Patients who incurred more than the median number of toxicities (n = 7) among all patients within the first year subsequently had an increased risk of hematologic, infectious, and metabolic toxicities, as well as an increased risk of NRM and inferior 4-year overall survival (OS) (67% versus 86%; P = .003) after the 1-year landmark. The development of grade II-IV acute graft-versus-host disease (GVHD) within the first year was associated with incurring >7 toxicities within the first year (P = .016), and also with an increased risk of all-cause death and NRM after 1 year. In multivariate models, cardiovascular, hematologic, hepatic, infectious, metabolic, neurologic, and pulmonary toxicities incurred after 1 year were independently associated with increased risk of death and NRM when adjusting for both HCT-CI and grade II-IV acute GVHD within the first year. One-year survivors of ex vivo CD34+ selection had a favorable 4-year OS of 77%, although the development of grade ≥3 toxicities after the first year was associated with poorer outcomes, emphasizing the fundamental importance of improving survivorship efforts that may improve long-term toxicity burden and outcome.

The current standard of care to prevent graft versus host disease (GVHD) after HLA mismatched unrelated donor (URD) allogeneic hematopoietic cell transplantation (HCT) is tacrolimus, methotrexate (MTX) and anti-thymocyte globulin (ATG). Recently, an approach based on administration of post-transplant cyclophosphamide (PT-Cy) demonstrated promise in a prospective trial for HLA mismatched URD HCT. Here, we compared tacrolimus/MTX/ATG (ATG group) treatment, with that of PT-Cy, mycophenolate mofetil, and tacrolimus or sirolimus (PT-Cy group) after HLA mismatched URD HCT, at two academic centers with similar peri-transplant supportive care practices. Subjects that underwent HCT from a URD mismatched at one or more loci among HLA-A, -B, -C, and -DRB1 from 2010-2020 were included. The primary endpoint of our study was one-year GVHD-free, relapse-free survival (GRFS). Of 128 total subjects included (ATG: 46; PT-Cy: 82), the median age was 54.7 (range: 21.0 - 72.0) in the ATG group and 60.3 (21.0 - 75.2) in the PT-Cy group. Notably, 74 subjects (57.8%) belonged to a racial/ethnic minority, while 53 (41.4%) received a bone marrow (BM) graft, and 26 (20.3%) received a highly mismatched (i.e., The rate of primary neutrophil engraftment at day 28 post HCT was similar between the two groups: 91% (83%-99%), in the ATG group, and 90% (84%-97%), in the PT-Cy group. The median day of neutrophil engraftment was +17 in the ATG, and +20 in the PT-Cy groups. Platelet engraftment at day 100 was 84.8% (74.4% - 95.2%) and 86.6% (79.2% - 94%) in the ATG and PT-Cy groups, respectively. Among subjects that survived 3-months post HCT and had donor chimerism testing, full donor chimerism (≥95% donor) was achieved in 24/26 (92.3%) patients in the ATG group, and 61/68 (89.7%) subjects in the PT-Cy group. Overall, the one-year GRFS was 16% (95% confidence interval: 8% - 31%) vs. 54% (44% - 66%, p < 0.001) in the ATG and PT-Cy groups, respectively. The adjusted, multivariate hazard ratio (HR) for GRFS was 0.34 (0.21 - 0.55, p < 0.001), in association with the use of PT-Cy. The one-year overall survival (OS) in the ATG group was 45% (32% - 62%) vs. 75% (66% - 85%, p < 0.001) in the PT-Cy group. There was no difference in 2-year relapse incidence (27%, 14-39% vs. 19%, 10% - 28%, p = 0.2), whereas 1-year non-relapse mortality (NRM) was increased with ATG-based prophylaxis: (38%, 23% - 52% vs. 16%, 9% - 25%, p = The use of PT-Cy, compared to ATG, was associated with lower rates of grade 3-4 acute GVHD in the entire cohort (ATG: 22%, 18% - 45% vs. PT-Cy: 15%, 8% - 23%; p = 0.03), and in the sub-cohorts of patients transplanted with PB (ATG: 33%, 17% - 49% vs. PT-Cy: 20%, 9% - 33%) and BM grafts (ATG: 25%, 1% - 50% vs. PT-Cy: 10%, 1% - 19%). Chronic GVHD requiring systemic immune suppression was more frequent in the ATG/PB group (26%, 13% - 42%) than in the ATG/BM (8%, 0% - 24%), the PT-Cy/PB (8%, 2% - 19%), and the PT-Cy/BM (10%, 1% - 19%) groups. Despite greater HLA-mismatching, PT-Cy following mismatched URD HCT resulted in superior GRFS, OS and lower NRM and GVHD rates compared to ATG-based GVHD prophylaxis. These results indicate that PT-Cy is the preferred method to prevent GVHD after mismatched URD HCT and confers a benefit in patients treated with either PB or BM-derived allografts. Combinatorial approaches, using the T-cell co-stimulatory blockading agent abatacept, in addition to tacrolimus/methotrexate, may also prevent GVHD in this population, and can be compared to a PT-Cy-based approach in a prospective clinical trial. Figure 1 Figure 1. Disclosures Jimenez: AbbVie: Research Funding; Takeda: Research Funding. Perales: MorphoSys: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Karyopharm: Honoraria; Merck: Honoraria; Equilium: Honoraria; Miltenyi Biotec: Honoraria, Other; Medigene: Honoraria; Kite/Gilead: Honoraria, Other; Incyte: Honoraria, Other; Cidara: Honoraria; Takeda: Honoraria; Nektar Therapeutics: Honoraria, Other; Servier: Honoraria; Sellas Life Sciences: Honoraria; Omeros: Honoraria; NexImmune: Honoraria; Novartis: Honoraria, Other. Sauter: Precision Biosciences: Consultancy; Genmab: Consultancy; Celgene: Consultancy, Research Funding; Kite/Gilead: Consultancy; Bristol-Myers Squibb: Research Funding; GSK: Consultancy; Gamida Cell: Consultancy; Novartis: Consultancy; Spectrum Pharmaceuticals: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding. Beitinjaneh: Kite/Gilead: Other: Ad Board Event Attendee. Ponce: CareDx: Consultancy, Honoraria; Ceramedix: Consultancy, Honoraria; Seres Therapeutics: Consultancy, Research Funding; Kadmon pharmaceuticals: Consultancy, Honoraria; Takeda Pharmaceuticals: Research Funding; Generon Pharmaceuticals: Consultancy. OffLabel Disclosure: Off-label use of Cyclophosphamide for Graft-versus-Host Disease prevention will be discussed in the abstract.