Sharma, Akshay

Abstract Background: Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). While many factors influence the outcomes of allo-HCT in these leukemias, the independent impact of ABO mismatching between the patient and donor remains unclear. Methods: Using the CIBMTR database, we identified adults aged ≥18 years with AML or ALL who underwent allo-HCT from HLA-matched sibling donor (MSD) or 8/8 matched unrelated donor (MUD) between 2008-2018. We excluded patients who underwent transplant from a mismatched donor source or who received an ex-vivo T-cell depleted graft. Patients were stratified into cohorts based on ABO status (match, minor mismatch, major mismatch, bidirectional mismatch). Outcomes such as overall survival (OS), disease free survival (DFS), non-relapse mortality (NRM), relapse, incidence of acute graft versus host disease (GVHD), chronic GVHD, neutrophil engraftment, platelet engraftment and graft failure were evaluated. Survival analysis was done using Kaplan-Meier method and significant predictors were evaluated using Cox-proportional hazard regression method. Multivariate regression model included main effect (ABO status) and covariates (patient age, gender match, disease type, disease status, HCT-CI, Karnofsky performance status, donor type, conditioning intensity/use of TBI, stem cell source, GVHD prophylaxis, ATG/alemtuzumab use, transplant year). Results: Of 4946 patients who met the study criteria, 2741 patients (55.4%) were ABO matched, 1030 patients (20.8%) had minor ABO mismatch, 899 patients (18.1%) had major ABO mismatch and 276 patients (5.6%) had bidirectional ABO mismatch. Graft manipulation for ABO incompatibility was performed in 900 patients (minor ABO mismatch=532; major ABO mismatch=226; bidirectional mismatch=142), however, the information on individual graft manipulation techniques was limited. In multivariable analysis (table 1), major ABO mismatch significantly affected the OS, platelet engraftment and primary graft failure. Compared to ABO matched allo-HCT, major ABO mismatched allo-HCT was associated with worse OS (major mismatch - HR 1.16, 95% CI 1.05-1.29; p=0.005), inferior platelet engraftment (HR 0.83, 95% CI 0.77-0.90; p=<0.001), and higher risk of primary graft failure [4.5% (major mismatch) vs. 3.2% (ABO matched) - HR 1.60, 95% CI 1.12-2.30, p=0.01]. There was a significant interaction between the ABO status and graft type (peripheral blood vs. bone marrow) for the acute GVHD grades 2-4 model, and they are presented separately (table 1). Bidirectional ABO mismatch also significantly impacted the outcomes such as acute GVHD grades 2-4 (in bone marrow stem cell subgroup, HR 0.50, 95%CI 0.27-0.93, p=0.02) in addition to a trend towards inferior survival and NRM (p-value not significant). Other outcomes such as relapse (p=0.41), acute GVHD grades 3-4 (p=0.13), and chronic GVHD (p=0.30) were not significantly influenced by the ABO status. Conclusions: Our study demonstrates that pre-transplant ABO status is an independent predictor of survival and other post-transplant outcomes in a large cohort of patients with AML and ALL undergoing allo-HCT in the recent era. This demonstrates the importance of considering ABO status in the donor selection algorithms and potential strategies to mitigate its adverse impact. Due to the limited information available on graft manipulation strategies, the impact of graft manipulation techniques on the outcomes could not be evaluated and needs to be investigated in future studies. Figure 1 Figure 1. Disclosures Guru Murthy: Techspert: Consultancy; Guidepoint: Consultancy; Cancerexpertnow: Honoraria; Qessential: Consultancy; TG therapeutics: Other: Advisory board; Cardinal Health Inc.: Honoraria. Devine: Magenta Therapeutics: Current Employment, Research Funding; Tmunity: Current Employment, Research Funding; Sanofi: Consultancy, Research Funding; Johnsonand Johnson: Consultancy, Research Funding; Orca Bio: Consultancy, Research Funding; Be the Match: Current Employment; Vor Bio: Research Funding; Kiadis: Consultancy, Research Funding. Farhadfar: Incyte: Consultancy. Sharma: Vertex Pharmaceuticals/CRISPR Therapeutics: Other: Salary support paid to institution; Novartis: Other: Salary support paid to institution; Spotlight Therapeutics: Consultancy; Medexus Inc: Consultancy; CRISPR Therapeutics: Other, Research Funding; Vindico Medical Education: Honoraria. Stefanski: Novartis: Honoraria. Pulsipher: Equillium: Membership on an entity's Board of Directors or advisory committees; Adaptive: Research Funding; Jasper Therapeutics: Honoraria. Shaw: mallinkrodt: Other: payments; Orca bio: Consultancy.

Abstract Little is known about whether risk classification at diagnosis predicts post-hematopoietic cell transplantation (HCT) outcomes in patients with acute myeloid leukemia (AML). We evaluated 8709 patients with AML from the CIBMTR database, and after selection and manual curation of the cytogenetics data, 3779 patients in first complete remission were included in the final analysis: 2384 with intermediate-risk, 969 with adverse-risk, and 426 with KMT2A-rearranged disease. An adjusted multivariable analysis detected an increased risk of relapse for patients with KMT2A-rearranged or adverse-risk AML as compared to those with intermediate-risk disease (hazards ratio [HR], 1.27; P = .01; HR, 1.71; P < .001, respectively). Leukemia-free survival was similar for patients with KMT2A rearrangement or adverse risk (HR, 1.26; P = .002, and HR, 1.47; P < .001), as was overall survival (HR, 1.32; P < .001, and HR, 1.45; P < .001). No differences in outcome were detected when patients were stratified by KMT2A fusion partner. This study is the largest conducted to date on post-HCT outcomes in AML, with manually curated cytogenetics used for risk stratification. Our work demonstrates that risk classification at diagnosis remains predictive of post-HCT outcomes in AML. It also highlights the critical need to develop novel treatment strategies for patients with KMT2A-rearranged and adverse-risk disease.

Abstract The role of haploidentical hematopoietic cell transplantation (HCT) using posttransplant cyclophosphamide (PTCy) for acute lymphoblastic leukemia (ALL) is being defined. We performed a retrospective, multivariable analysis comparing outcomes of HCT approaches by donor for adults with ALL in remission. The primary objective was to compare overall survival (OS) among haploidentical HCTs using PTCy and HLA-matched sibling donor (MSD), 8/8 HLA-matched unrelated donor (MUD), 7 /8 HLA-MUD, or umbilical cord blood (UCB) HCT. Comparing haploidentical HCT to MSD HCT, we found that OS, leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and acute graft-versus-host disease (aGVHD) were not different but chronic GVHD (cGVHD) was higher in MSD HCT. Compared with MUD HCT, OS, LFS, and relapse were not different, but MUD HCT had increased NRM (hazard ratio [HR], 1.42; P = .02), grade 3 to 4 aGVHD (HR, 1.59; P = .005), and cGVHD. Compared with 7/8 UD HCT, LFS and relapse were not different, but 7/8 UD HCT had worse OS (HR, 1.38; P = .01) and increased NRM (HR, 2.13; P ≤ .001), grade 3 to 4 aGVHD (HR, 1.86; P = .003), and cGVHD (HR, 1.72; P ≤ .001). Compared with UCB HCT, late OS, late LFS, relapse, and cGVHD were not different but UCB HCT had worse early OS (≤18 months; HR, 1.93; P < .001), worse early LFS (HR, 1.40; P = .007) and increased incidences of NRM (HR, 2.08; P < .001) and grade 3 to 4 aGVHD (HR, 1.97; P < .001). Haploidentical HCT using PTCy showed no difference in survival but less GVHD compared with traditional MSD and MUD HCT and is the preferred alternative donor HCT option for adults with ALL in complete remission.

Abstract Social determinants of health, including poverty, contribute significantly to health outcomes in the United States; however, their impact on pediatric hematopoietic cell transplantation (HCT) outcomes is poorly understood. We aimed to identify the association between neighborhood poverty and HCT outcomes for pediatric allogeneic HCT recipients in the Center for International Blood and Marrow Transplant Research database. We assembled 2 pediatric cohorts undergoing first allogeneic HCT from 2006 to 2015 at age ≤18 years, including 2053 children with malignant disease and 1696 children with nonmalignant disease. Neighborhood poverty exposure was defined a priori per the US Census definition as living in a high-poverty ZIP code (≥20% of persons below 100% federal poverty level) and used as the primary predictor in all analyses. Our primary outcome was overall survival (OS), defined as the time from HCT until death resulting from any cause. Secondary outcomes included relapse and transplantation-related mortality (TRM) in malignant disease, acute and chronic graft-versus-host disease, and infection in the first 100 days post-HCT. Among children undergoing transplantation for nonmalignant disease, neighborhood poverty was not associated with any HCT outcome. Among children undergoing transplantation for malignant disease, neighborhood poverty conferred an increased risk of TRM but was not associated with inferior OS or any other transplantation outcome. Among children with malignant disease, a key secondary finding was that children with Medicaid insurance experienced inferior OS and increased TRM compared with those with private insurance. These data suggest opportunities for future investigation of the effects of household-level poverty exposure on HCT outcomes in pediatric malignant disease to inform care delivery interventions.

BackgroundThe association of community factors and outcomes after hematopoietic cell transplantation (HCT) has not been comprehensively described. Using the County Health Rankings and Roadmaps (CHRR) and the Center for International Blood and Marrow Transplant Research (CIBMTR), this study evaluated the impact of community health status on allogeneic HCT outcomes.MethodsThis study included 18,544 adult allogeneic HCT recipients reported to the CIBMTR by 170 US centers in 2014‐2016. Sociodemographic, environmental, and community indicators were derived from the CHRR, an aggregate community risk score was created, and scores were assigned to each patient (patient community risk score [PCS]) and transplant center (center community risk score [CCS]). Higher scores indicated less healthy communities. The impact of PCS and CCS on patient outcomes after allogeneic HCT was studied.ResultsThe median age was 55 years (range, 18‐83 years). The median PCS was –0.21 (range, –1.37 to 2.10; standard deviation [SD], 0.42), and the median CCS was –0.13 (range, –1.04 to 0.96; SD, 0.40). In multivariable analyses, a higher PCS was associated with inferior survival (hazard ratio [HR] per 1 SD increase, 1.04; 99% CI, 1.00‐1.08; P = .0089). Among hematologic malignancies, a tendency toward inferior survival was observed with a higher PCS (HR, 1.04; 99% CI, 1.00‐1.08; P = .0102); a higher PCS was associated with higher nonrelapse mortality (NRM; HR, 1.08; 99% CI, 1.02‐1.15; P = .0004). CCS was not significantly associated with survival, relapse, or NRM.ConclusionsPatients residing in counties with a worse community health status have inferior survival as a result of an increased risk of NRM after allogeneic HCT. There was no association between the community health status of the transplant center location and allogeneic HCT outcomes.