Mismatched donor allogeneic hematopoietic cell transplantation with post‐transplant cyclophosphamide achieves comparable outcomes between racially and ethnically diverse patient populations
Authors: Teresa Caprice, Wenyi Fan, Jongphil Kim, Rawan Faramand, Asmita Mishra, Lia Perez, Farhad Khimani, Aleksandr Lazaryan, Jose L. Ochoa‐Bayona, Hien Liu, Michael D. Jain, Michael Nieder, Claudio Anasetti, Taiga Nishihori, Joseph A. Pidala, Nelli Bejanyan, Hany Elmariah
Journal: American Journal of Hematology (2024)

Allogeneic hematopoietic stem cell transplant (HCT) remains the only cure for many hematologic malignancies, but this costly and highly specialized elective procedure is prone to health disparities. Historically, underrepresented minorities (African/non-Hispanic Black, Hispanic/Latinx, Asian, Native American, Pacific Islander) have lower utilization rates of HCT.1 Among many barriers to transplant, the requirement to identify an 8/8 human leukocyte antigen (HLA) matched donor, including a matched sibling donor (MSD) or matched unrelated donor (MUD), precluded many racial and ethnic minority (REM) patients from reaching HCT as the likelihood of identifying such a donor for REM patients ranges from 16% to 52% compared to over 75% for white non-Hispanic (WNH) patients.2 For patients without an HLA-matched donor, incorporating HLA haploidentical (haplo) or HLA mismatched unrelated donors (MMUD) into donor search algorithms significantly increases the feasibility of HCT. The development of post-transplant cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis has allowed for HLA haplo and MMUD HCT with comparable outcomes to HLA-matched HCT.3, 4 By broadening the donor pool to include HLA mismatched donors, PTCy allows for almost every transplant-eligible patient, including REM patients, to have a suitable donor.3 While more REM patients can now receive an HCT, there remains a paucity of data addressing whether REM patients who receive a mismatched donor HCT with PTCy experience similar outcomes as WNH patients. The aim of this study was to address this gap in literature and compare outcomes between REM and WNH patients who received an HLA mismatched transplant with PTCy. This retrospective study included all consecutive adult patients who underwent an HLA mismatched HCT with PTCy for a hematologic malignancy at the Moffitt Cancer Center between January 2014 and June 2022. Relevant demographic and clinical information were obtained from the Moffitt Blood and Marrow Transplant Research and Analysis Information Network (BRAIN) database and additional data collection was extracted via manual chart review. All endpoints were calculated from the time of HCT and compared between four groups: WNH, white-Hispanic, Black, and Other. The patients comprised in the "Other" category included those who identified as Asian, biracial, and multiracial. Patients were categorized based on self-reported race and ethnicity. Two-sided p-values ≤ .05 were considered statistically significant. The backward elimination method with a p-stay value of .05 was applied for building multivariable models. This study was approved by the Institutional Review Board. A total of 302 patients were included of which 59% (n = 179) of patients identified as WNH, 14% (n = 41) as white-Hispanic, 16% (n = 48) as Black, 7% (n = 21) as biracial or multiracial, and 4% (n = 11) identified as Asian (Table 1). The median follow-up for survivors was 27 months (range 1.84–82.82). At 100 days post-transplant, the cumulative incidence of grade II-IV acute GVHD (aGVHD) was 37% [95% CI, 30%–44%] for WNH patients, 32% [95% CI, 18%–46%] for white-Hispanic patients, 29% [95% CI, 17%–42%] for Black patients, and 24% [95% CI, 11%–39%] for patients of Other races (p = .31; Figure 1A). In multivariate analyses (MVA, Table S1), after adjusting for patient age, conditioning intensity, and donor relation, race/ethnicity was not a risk factor for grade II-IV aGVHD (p = .30). The cumulative incidence of moderate/severe chronic GVHD (cGHVD) at 24 months was (Figure 1B): 20% [95% CI, 14%–26%] for the WNH patients, 23% [95% CI, 11%–37%] for white-Hispanic patients, 16% [95% CI, 7.1%–29%] for Black patients, and 26% [95% CI, 13%–42%] for patients of Other races. After adjusting for patient age, conditioning intensity, and donor relation, race/ethnicity was not associated with the risk of moderate/severe cGVHD (p = .87). At 24 months, the incidence of relapse was 26% [95% CI 19%–33%] for WNH patients, 26% [95% CI, 13%–42%] for white-Hispanic patients, 30% [95% CI, 17%–46%] for Black patients, and 19% [95% CI, 7.3%–34%] for patients of Other races (p = .98; Figure 1C). In MVA, after adjusting for disease risk index (DRI) and conditioning intensity, race/ethnicity was not associated with the risk of relapse (p = .85). High DRI (HR 2.32; 95% CI, 1.47–3.65; p ≤ .001) was associated with higher risks of relapse compared to low/intermediate DRI. Additionally, myeloablative conditioning (MAC, HR 0.65; 95% CI, 0.40–1.06) and reduced intensity conditioning (RIC, HR 0.41; 95% CI, 0.22–0.78) were associated with lower risk of relapse than non-myeloablative (NMA, p = .02). At 100 days post-transplant, the incidence of NRM was 8.9% [95% CI, 5.3%–14%] for WNH patients, 9.8% [95% CI, 3.1–21%] for white-Hispanic patients, 4.2% [95% CI, 0.75%–13%] for Black patients, and 15% [95% CI, 5.3%–29%] for patients of Other races (p = .77; Figure 1D). Adjusting for Karnofsky performance scale (KPS), and donor age, race/ethnicity was not associated with NRM (p = .84). Notably, donor age ≥40 years (HR 1.92; 95% CI, 1.16–3.18; p = .01) [reference group donor age <40] and KPS <90 (HR 2.03; 95% CI, 1.20–3.43) [reference group KPS ≥90] were associated with a higher risk of NRM. A total of 57 patients had NRM events. The most common cause of NRM death was infection (n = 24), followed by organ failure (n = 22), and GVHD (n = 11). Cause of death was similarly distributed across race (p = .46) and ethnicity (p = .61). The RFS probability at 24 months was 54% [95% CI 47%–63%] for WNH patients, 59% [95% CI, 44%–78%] for white-Hispanic patients, 49% [95% CI, 36%–68%] for Black patients, and 57% [95% CI, 42%–77%] for patients of Other races (p = .87, Figure 1E). In MVA, after adjusting for Karnofsky performance scale (KPS), DRI, type of insurance, and donor age, race/ethnicity was not associated with RFS (p = .65). KPS <90 (HR 1.54; 95% CI, 1.05–2.24; p = .03) [reference group KPS ≥90], High DRI (HR 2.15; 95% CI, 1.50–3.09; p ≤ .001) [reference group: low/intermediate DRI], Tricare insurance (HR 2.14; 95% CI, 1.10–4.19; p = .01) [reference group: commercial/employer based], and a donor age ≥40 (HR 1.53; 95% CI, 1.07–2.17; p = .02) [reference group donor age <40] were associated with worse RFS outcomes. OS at 24 months was 63% [95% CI, 55%–71%] for WNH patients, 71% [95% CI, 58%–87%] for white-Hispanic patients, 51% [95% CI, 37%–71%] for Black patients, and 62% [95% CI, 47%–82%] for patients of Other races (p = .89, Figure 1F). After adjusting for DRI and donor age, MVA again showed that race/ethnicity was not a prognostic factor for OS (p = .55). High DRI (HR 2.46; 95% CI, 1.69–3.59; p ≤ .001) [reference group: low/intermediate DRI] and a donor age ≥40 (HR 1.63; 95% CI, 1.13–2.35; p = .01) [reference group donor age <40] were associated with significantly worse OS outcomes. PTCy was developed as GVHD prophylaxis to safely transplant patients with HLA haploidentical donors, thus addressing the lack of donor availability that has been one of the main causes of disparities for racial and ethnic minorities requiring HCT.1-4 Despite its utility as a solution to HCT disparities related to donor availability, there is limited data evaluating outcomes of allogeneic HCT specifically in REM patients who have received PTCy. This study shows that REM patients who receive an HLA mismatched HCT with PTCy have similar outcomes to WNH patients. Previous studies with traditional calcineurin inhibitor (CNI)-based GVHD prophylaxis have shown that even the subset of REM patients who reached transplant still experienced inferior transplant-related outcomes compared to WNH patients.1 In contrast to CNI-based GVHD prophylaxis, our results suggest that PTCy may be a critical factor in balancing disparities in outcomes across racial and ethnic groups receiving allogeneic HCT. Beyond expanding the pool of donors available for HCT, other factors inherent to the PTCy platform may be contributors to the favorable outcomes in REM patients. Previous studies have shown that racial and ethnic minorities, especially Black patients, are more genetically diverse, resulting in a greater degree of donor/recipient genetic disparity such as minor antigen mismatches, even in the setting of an HLA-matched donor.2 As PTCy is known to successfully mitigate the risks of alloreactivity related to genetic disparity, it is likely that PTCy decreases the significance of such untested mismatches that are more prevalent in genetically heterogeneous populations.5 Rather than race/ethnicity, other known risk factors such as high DRI and older donor age are better predictors of poor prognosis. However, in contrast to prior literature showing inferior HCT outcomes in beneficiaries of government-sponsored insurance, our data showed patients with Medicaid had an improved probability of RFS in comparison to patients with commercial insurance.6 This may reflect the effects of PTCy to lower the risks of GVHD and decrease the need for prolonged, expensive treatments that would be burdensome for most Medicaid patients. Conversely, our data showed patients with military Tricare insurance had worse RFS, which may reflect the anecdotal experience that these patients continue to experience delays in insurance authorization related to transplant consultation and treatment. However, due to small sample sizes of these groups, additional investigation would be necessary to confirm the significance of these findings. Based on our results, PTCy mitigates the effect of HCT health disparities by equalizing outcomes between WNH and REM patients in the setting of HLA mismatched allogeneic HCT. Our data provides further evidence to support the increased use of HLA mismatched donor or haploidentical donors HCT with PTCy to expand utilization and access to curative therapy for REM patients. Rawan Faramand receives research funding from Gilead. Aleksandr Lazaryan provides consultancy, receives Honoria, and is a member of the scientific advisory board for Sanofi. Hien Liu has a membership on the board of directors of the advisory committee at BioLineRx. Michael Jain receives research funding from Incyte; provides consultancy and receives honoraria from Myeloid Therapeutics; receives research funding from Loxo@Lilly; provides consultancy and receives honoraria and research funding from Gilead. Taiga Nishihori is on the Speakers Bureau at Medexus Pharmaceuticals and receives personal fees from Karyopharm and Novartis outside the submitted work. Nelli Bejanyan provides consultancy and receives research funding from Orca Bio, CareDx Pharma, CRISPR, Sanofi, CTI BioPharma, Medexus Pharmaceuticals, and Magenta. Hany Elmariah receives research funding from Bristol Myers Squibb and serves on the advisory board for Shoreline Biosciences. The remainder of the authors have no conflicts of interest to disclose. Informed patient consent was not necessary for this work. Table S1. Multivariate analysis of transplant outcomes. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.