Abatacept and Post Transplant Cyclophosphamide Based Regimen for Graft Versus Host Disease Prevention in High-Risk Stem Cell Transplantation from Unrelated Donor Is Safe and Feasible, with Low Non- Relapse Mortality

Introduction

The combination of Abatacept (ABA) with tacrolimus and methotrexate is FDA-approved for the prevention of acute graft versus host disease in patients undergoing allogeneic hematopoietic stem cell transplantation (HCT) from matched unrelated donors (MUD) or one allele mismatched unrelated donors (MMUD). Additionally, recently published data demonstrated improved outcomes with ABA combined with post- transplant cyclophosphamide (PTCY) when used as GVHD prophylaxis following T cell replete peripheral blood haplo-identical stem cell transplants. However, there is very limited data regarding the use of the combination of ABA and PTCY for GVHD prophylaxis in MUD and MMUD HSCT.

Here, we report retrospective review of the outcomes of 25 consecutive patients who underwent mobilized peripheral blood MUD/MMUD HSCT for high-risk hematological malignancy and received ABA and PTCY for GVHD prevention.

Method:

There was 16 MUD (8/8 match) and 9 MMUD (7/8 match) patients. The median age of the patients was 53.8 (range 23-73). The median age of the donors was 26.5 (range 18-43). There was only 1 pair donor- recipient CMV negative. All other patients either the donor or recipient were CMV positive. There was 17 males and 8 Females. Comorbidity score was 5 or higher in 13 patients (52%) and 3-4 in 5 patients (20%). There was 15 AML, 3 ALL, 6 MDS and 1 myelofibrosis patients. Status at transplant was primary induction failure or relapsed disease in 6 patients (24%), persistent /stable disease in 7 (28%), CR1 in 9 (36%) and CR2 or beyond in 3 (12%). High risk mutations were identified in 14 out of 25 patients (56%). Molecular studies at diagnosis identified TP53, ASXL1, FLT-3 and KRAS in 5, 5, 3 and 1 patients respectively. Conditioning regimens were Busulfan based (Flu-Bu) in12 patients, Melphalan based (Flu-Mel) in 9 patients and Fludarabine/Cyclophosphamide/Total Body Irradiation in 4 patients. All the regimens used were reduced intensity except for 4 patients who received myeloablative dosing. ALL patients received GVHD prophylaxis with ABA at day -1, +5, +14 and +28 at dose of 10 mg/Kg. Tacrolimus started at day +5 with target goal level of 5-12. PTCY was given at dose of 25 mg/Kg for MUD and 50 mg/Kg for MMUD recipients on Day +3 and +4. Patients received institutional antimicrobial prophylaxis with Acyclovir, Levofloxacin, Posaconazole, letermovir and Bactrim. Immune reconstitution studies were available for 11 patients at day 30 and 12 patients at day 100.

Results: All the patients engrafted with median absolute neutrophilic count and platelets recovery of 13.6 and 21 days respectively. All Patients achieved full Chimerism by day 30 with no primary or secondary graft failure. The median time of follow up was 290 days (9.3 Month) as of July 31, 2024 (range 68-573). The overall survival (OS) by log rank test at day 100 and 1 year was 100% and 91% respectively. The cumulative incidence of relapse was 8.7% and 36% at day 100 and 1 year respectively. One patient with TP53 AML and one patient with relapsed ALL (Ph negative) died at day 135 and 139 from relapsed disease respectively. There was no non-relapse mortality (0%) at day 100 and 1 year. The cumulative incidence of acute GVHD at day 180 was 36%; all grade 2 with no grade 3 or 4 acute GVHD. Two patients were excluded from chronic GVHD assessment because of short follow up less than 100 days. Chronic GVHD developed in 11of 23 patients with cumulative incidence of 62.8% at 1 year. Chronic GVHD was extensive in 9 patients (7 moderate and 2 severe) and mild limited in 2 patients. It has resolved in 7 of the 11 patients as of the last follow up. Viral reactivation occurred in 14 patients (56%); CMV in 12 and HHV6 in 2 patients. Median CD3, CD4, CD8, CD 16/56, CD19 and absolute lymphocytic count were 424, 76, 67, 280, 1and 466 per cubic mm at day 30 and 366, 163, 190, 138, 127 and 641 per cubic mm at day 100 respectively.

Conclusion:

The combination of ABA and PTCY for GVHD prevention in MUD/MMUD recipients was feasible with low non- relapse mortality and no increase in relapse rates in this cohort of patients with significant comorbidity and high-risk disease. We observed early accentuated NK cell proliferation and near absence of B cells recovery at day 30. However, there was a gradual recovery of T and B cell by day 100. This is a single institution, limited patient cohort, and prospective studies are undergoing to further evaluate and optimize the proposed regimen for GVHD prevention in MUD/MMUD recipients.