Haploidentical Vs. Matched Unrelated Donor Transplants Using Post-Transplant Cyclophosphamide for Lymphoma: A Joint CIBMTR/EBMT Study

Introduction: Post-transplant cyclophosphamide (PTCy) is a standard GVHD prophylactic approach for haploidentical hematopoietic cell transplantation (haploHCT). Retrospective studies in patients with lymphoma showed lower chronic GVHD in haploHCT with PTCy-based GVHD prophylaxis compared to matched unrelated donor (MUD) HCT with calcineurin-based GVHD prophylaxis (+/- ATG). Recent retrospective studies showed that using MUD donors was better than haplo donors when PTCy and reduced-intensity conditioning are used for ALL, AML or MDS. However, no studies to date have compared haploHCT and MUD HCT when PTCy is used in the setting of lymphomas. Methods: 2155 adults (730 CIBMTR, 1425 EBMT) aged =/>18 years who received their first haploHCT or MUD HCT (8/8 match at HLA-loci A, B, C and DRB1) using PTCy from 2010-2019 for lymphoma were included. The majority of both MUD (n=312; 14%) and haplo (n=1843; 86%) HCTs received reduced intensity/non-myeloablative conditioning (n=1655; 77%) using a peripheral blood stem cell graft (n=1379; 64%) and a three-drug GVHD prophylaxis (PTCy + calcineurin inhibitor + MMF, n=1805; 84%). Hodgkin's lymphoma was the most common indication (n=899; 42%) followed by diffuse large B-cell lymphoma (n=525; 24%), T-cell lymphomas (n=328; 15%), mantle cell lymphoma (n=234; 11%) and follicular lymphoma (n=169; 8%). Most had chemosensitive disease at transplant (n=1781; 83%). Some main characteristics of the two cohorts are shown in Figure 1. Median follow-up among survivors was longer for haplo-HCT (36 and 31 months for the CIBMTR and EBMT cohort, respectively) than MUD-HCT (24 and 17 months, respectively). Cox proportional hazards models were built using stepwise forward and backward selection with a selection/retention threshold of 0.05. Any clinical variables that did not meet the proportional hazard assumption were adjusted for by stratification, and regression models were built to compare outcomes between donor types. Center effect was adjusted in all the models. Results: Figures 2 and 3 show the multivariate analysis results. Overall survival was 73% (71-75%) at 1 year and 65% (63-67%) at 2 years. Relapse was 21% (20-23%) at 1 year and 26% (24-28%) at 2 years. All outcomes favored MUD over haplo donors with the use of PTCy-based GVHD prophylaxis for both. Conclusions: Patients with lymphoma receiving PTCy HCT from MUDs demonstrated better outcomes than those with haplo donors in this retrospective study of CIBMTR and EBMT data Future prospective studies are needed to confirm and clarify the reasons for these differences. Figure 1 Figure 1. Disclosures Mussetti: GILEAD: Other: Clinical trials participation, Research Funding; TAKEDA: Honoraria; NOVARTIS: Honoraria, Other: Clinical trials participation. Hamadani: Janssen, Incyte, ADC Therapeutics, Omeros, Morphosys, Kite: Consultancy; Sanofi, Genzyme, AstraZeneca, BeiGene: Speakers Bureau; Takeda, Spectrum Pharmaceuticals and Astellas Pharma: Research Funding. Glass: Novartis: Consultancy; Riemser: Research Funding; Helios Klinik Berlin-Buch: Current Employment; Kite: Consultancy; Roche: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy. Blaise: Jazz Pharmaceuticals: Honoraria. Paczesny: Medical University of South Carolina: Patents & Royalties: inventor on the ST2 bispecific antibody patent application. Dreger: Novartis: Consultancy, Speakers Bureau; Riemser: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy; Bluebird Bio: Consultancy; AstraZeneca: Consultancy, Speakers Bureau; Gilead Sciences: Consultancy, Speakers Bureau; Janssen: Consultancy; AbbVie: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau. Lee: AstraZeneca: Research Funding; Incyte: Research Funding; Janssen: Other; Kadmon: Research Funding; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Syndax: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Amgen: Research Funding. Sureda: BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau; Bluebird: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Mundipharma: Consultancy; Roche: Other: Support for attending meetings and/or travel; GSK: Consultancy, Honoraria, Speakers Bureau.

De-Escalation of Ptcy Dosing in Matched Allogenic Transplants: A Single Institution Retrospective Study

Introduction The role of post-transplant cyclophosphamide (PTCy) in preventing acute GVHD (aGVHD) and chronic GVHD (cGVHD) has been well established in the haploidentical setting (Al-Homsi AS et al., Post-transplant high-dose cyclophosphamide for the prevention of graft-versus-host disease. Biol Blood Marrow Transplant. 2015;21(4):604-611). More recently, several studies are also supporting its use in matched related and unrelated donors (Williams L et al., Post-transplantation Cyclophosphamide: From HLA-Haploidentical to Matched-Related and Matched-Unrelated Donor Blood and Marrow Transplantation. Front Immunol. 2020;11(April):1-7). But as new emerging data are starting to show some toxicities from that regimen, a reevaluation of the optimal PTCy dose is highly valuable (Duléry R et al., Early Cardiac Toxicity Associated with Post-Transplant Cyclophosphamide in Allogeneic Stem Cell Transplantation. JACC CardioOncology. 2021;3(2):250-259; Goldsmith et al., Posttransplant cyclophosphamide is associated with increased cytomegalovirus infection: a CIBMTR analysis. Blood. 2021;137(23):3291-3305). PTCy dose de-escalation in preventing GvHD was also evaluated in a phase I/II study (NCT03983850) with initial results indicating that de-escalation of PTCy (DL2, 25 mg/kg/day given in Days 3−4) may provide a feasible and effective approach in preventing severe aGvHD(McAdams MJ et al., Phase I Study De-Intensifying Exposure of Post-Transplantation Cyclophosphamide (PTCy) after HLA-Haploidentical Hematopoietic Cell Transplantation (HCT) for Hematologic Malignancies. Transplant Cell Ther Off Publ Am Soc Transplant Cell Ther. 2021;27(3): S9-S11). However, this was in the setting of haplo-identical transplants. Currently there are no studies that investigate the safety and efficacy of a lower dose of PTCy in matched allogenic transplants. Methods We retrospectively selected 37 consecutive patients who underwent transplant at our center from January 2017 to April 2021. Patients who received a mismatched or haploidentical transplants were excluded. 26 matched sibling or matched unrelated donor transplants were further analyzed. These were divided into 3 cohorts according to GVHD prophylaxis: cohort 1 (No-PTCy) received standard calcineurin inhibitor-methotrexate based GVHD prophylaxis (n=16), cohort 2 (PTCy-50) received PTCy at 50 mg/kg (D+3 and D+4) in combination other immunosuppressive drugs (ISD) (n=6), and cohort 3 (PTCy-25) received PTCy at 25 mg/kg (D+3 and D+4) in combination with other ISD (n=4). The reduced PTCy dosing was based on physician discretion due to various reasons (2 cardiac risk, 1 heavy pre-treatment, 1 unknown). Results Baseline characteristics are summarized in table 1. Median follow up for all survivors was 523 days (range, 97-1463) while it was shorter for PTCy cohorts at 152 days (97-534). There were zero grade 3 aGVHD in PTCy groups compared to 12.5% (2/16) in No-PTCy cohort (p=0.30). cGVHD was significantly lower in PTCy-50 and PTCy-25 as compared to No-PTCy (0/6, 0/4, 5/16 respectively, p=0.04). The 100-day treatment-related mortality (TRM) was significantly lower in PTCy-25 as compared to PTCy-50 and No-PTCy (0/4, 2/6, 2/16 respectively, p<0.001). There was no viral reactivation (EBV/CMV) in PTCy-25 as compared to 1/6 in PTCy-50 and 5/16 in No-PTCy (p=0.54). The length of hospital stay (LOS) for transplant and the median days for neutrophil recovery (NR) were shorter in PTCy-25 as compared to PTCy-50 and No-PTCy (25.5 days, 31 days and 28.5 days respectively for LOS, p=0.60; 15.5 days, 22 days and 17.5 days for NR, p=0.87). Although the overall survival (OS) seems to favor PTCy-25 (Figure 1), it is limited by short follow up. Conclusion De-escalating the dose of PTCy to 25mg/kg x 2 in GVHD prophylaxis regimens appears to be efficacious and safe in patients receiving matched allogenic transplant. Further prospective studies including a larger patient sample and longer follow-up is warranted to investigate lower PTCy dosing in matched transplants over the current standard dosing. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Posttransplant Cyclophosphamide-Based Haploidentical Vs Matched Unrelated Donor Peripheral Blood Hematopoietic Stem Cell Transplantation Using Myeloablative Targeted Busulfan-Based Conditioning for Pediatric Acute Leukemia

Haploidentical related donor (HRD) is a common alternative donor strategy used when matched sibling or unrelated donors are not available for hematopoietic stem cell transplantation (HSCT). Post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis is an attractive option when performing a HRD HSCT because of its promising outcomes and easy application. However, there have been no studies comparing HRD HSCT with PTCy and MUD HSCT with antithymocyte globulin, using similar busulfan-based myeloablative conditioning regimen in pediatric acute leukemia. Herein, we compared the outcomes in children and adolescents with acute leukemia after HRD HSCT with PTCy (n=35) and matched unrelated donor (MUD) HSCT (n=45) after targeted busulfan-based myeloablative conditioning using intensive pharmacokinetic monitoring. The median follow-up times of the HRD and MUD groups were 3.7 and 4.6 years. No engraftment failure was observed. The cumulative incidence of GVHD grades II-IV (34.3% versus 48.9%, p=0.142), grades III-IV (2.9% vs. 8.9%, p=0.272), extensive chronic GVHD (11.4% vs. 18.3%, p=0.417), relapse (25.6% vs. 28.0%, p=0.832), and non-relapse mortality (0% vs. 2.2%, p=0.420) were not significantly different. The 3-year severe chronic GVHD-free/relapse-free, leukemia-free and overall survival rates in the HRD and MUD groups were 62.9±8.7% versus 49.8±7.6% (p=0.318), 74.4±8.0% versus 67.5±7.2% (p=0.585), and 88.6±5.4% versus 83.7±5.7% (p=0.968), respectively. In subgroup analyses of patients with acute lymphoblastic leukemia and acute myeloid leukemia, there were no significant differences in outcomes between the groups. Our results demonstrated that HRD HSCT with PTCy using a targeted busulfan-based myeloablative conditioning shows outcomes similar to those of MUD HSCT. HRD HSCT with PTCy could be considered for pediatric acute leukemia patients who lack an HLA-matched donor. Disclosures Kang: Cartexell: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Korea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen Korea: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Low-dose antithymocyte globulin plus low-dose posttransplant cyclophosphamide combined with cyclosporine and mycophenolate mofetil for prevention of graft-versus-host disease after HLA-matched unrelated donor peripheral blood stem cell transplantation

The standard regimens for graft-versus-host disease (GvHD) prophylaxis in matched unrelated donor (MUD) transplantation were based on antithymocyte globulin (ATG) in combination with calcineurin inhibitors (CNIs). To improve the efficiency of GvHD prophylaxis in MUD peripheral blood stem cell transplantation (MUD-PBSCT), 51 patients with hematological malignancies received a novel regimen for GvHD prophylaxis, which is composed of low dose of ATG (5 mg/kg) plus low-dose posttransplant cyclophosphamide (PTCy, 50 mg/kg) (low-dose ATG/PTCy) combined with cyclosporine A (CsA) and mycophenolate mofetil (MMF). The cumulative incidences (CIs) of grades I–IV and II–IV acute GvHD (aGvHD) were 14.5% (95% CI, 9.4–19.6%) and 6.2% (95% CI, 2.8–9.6%) within 100 days after transplantation, respectively. The CI of mild-to-moderate chronic GvHD (cGvHD) within 1 year was 11.5% (95% CI, 6.6–16.4%). The 1-year probabilities of GvHD and relapse-free survival, relapse-free survival, and over survival were 70.6% (95% CI, 64.2–77.0%), 76.5% (95% CI, 70.6–82.4%), and 82.0% (95% CI, 76.5–87.5%), respectively. The CIs of CMV and EBV reactivation by day 180 were 10.4% (95% CI, 1.5–19.4%) and 8.3% (95% CI, 0.2–16.4%), respectively. The results suggested that low-dose ATG/PTCy combined with CsA/MMF as GvHD prophylaxis in MUD-PBSCT had promising activity.