Fractionated Total Body Irradiation and Fludarabine Based Conditioning Regimen with Post-Transplant Cyclophosphamide (PTCy) for Mismatched Related and Unrelated Donors HCT for Acute Leukemia and MDS
Authors: Arslan Shukaib , Desai Amrita , Yang Dongyun , Mokhtari Sally , Blackmon Amanda , Agrawal Vaibhav , Pourhassan Hoda , Ball Brian J. , Amanam Idoroenyi , Otoukesh Salman , Koller Paul B. , Sandhu Karamjeet S. , Aldoss Ibrahim , Ali Haris , Salhotra Amandeep , Othman Tamer , Aribi Ahmed , Artz Andrew , Becker Pamela S. , Pullarkat Vinod , Stewart Forest Marc , Smith Eileen Patricia , Stein Anthony , Marcucci Guido , Forman Stephen J. , Nakamura Ryotaro , Al Malki Monzr M. 
Published: December 2023

Background: Allogeneic hematopoietic cell transplantation (alloHCT) remains the only curable treatment option for several hematological malignancies. Preparative and graft-versus-host disease (GVHD) prophylactic regimens combined with graft-versus-leukemia effect (GVL) are important in preventing graft rejection, disease relapse and GVHD; and subsequently impact the success of this life saving procedure. Choice of regimen depends on patient, donor/graft source and disease characteristics.

Objectives: Assess the outcomes of patients who underwent haploidentical (haplo) or mismatched unrelated donor (MMUD) HCT with myeloablative conditioning (MAC) regimen using radiation in combination with fludarabine (FLU) with PTCy as higher intensity GVHD prophylaxis and evaluate the feasibility of a fludarabine and fractionated total body irradiation (FLU/FTBI)-based regimen in both donors.

Study Design: Retrospective analysis to study the outcomes of patients receiving FLU/FTBI as myeloablative conditioning for mismatched (related or unrelated) donor HCT combined with post-transplant cyclophosphamide (PTCy) as GVHD prophylaxis.

Results: One hundred and fifty-five consecutive patients undergoing HCT at City of Hope (COH) from January 2015 to December 2021 were included. Median age was 38 years (range 9-60) and 56.8% of patients were male and 97.5% had a Karnofsky performance status (KPS) ≥ 80. HCT comorbidity index was ≥ 3 in 36.1% cases and 29% with a disease risk index (DRI) of high/very high. Disease diagnosis included acute lymphoblastic leukemia (ALL) (46.5% of cases) and acute myeloid leukemia (AML) (36.1% of cases). The median donor age was 31-years with 67.1% haplo donors and 32.9% mismatched unrelated donors (MMUD). MMUD HCT led to faster neutrophil recovery (15 vs 16 days, p= 0.01) and platelet count recovery (18 vs 23 days, p= 0.029). Day 100 cumulative incidence of grade II-IV and III-IV acute GVHD had no statistical difference between the two cohorts. With a median follow-up of 24 months (range 3 to 81), 100-day and 1-year NRM was 1.9% and 8.5%, respectively. There was no difference in the NRM between MMUD and haplo (HR 0.92, CI (0.35,2.39), p=0.86). Two-year relapse rate and DFS were 11.8% and 76.9%, respectively. In this study, 7 out of 51 patients in the MMUD group and 17 out of 104 patients in the haplo group relapsed with no statistically significant difference between the groups (HR 0.82, CI: (0.35,1.97), p=0.67). At a median follow-up of 2 years, GRFS was 60% (95% CI 0.51- 0.67). There was no statistically significant difference in GRFS between the MMUD and haplo groups (HR 0.76, CI (0.44,1.32), p=0.33). Two-year OS was 80.1%. There were no DFS or OS differences between the MMUD and haplo groups. On multivariate analysis, age less than 40 and low to intermediate DRI showed a DFS benefit (p = 0.004 and 0.029 respectively). None of the demographic factors affected OS or GRFS. Disease risk index was the only factor on multivariate analysis affecting relapse rates with higher risk of relapse with higher DRI (p= 0.017) and extensive chronic GVHD risk (p= 0.014) with no impact on acute GVHD.

Conclusions: FLU/FTBI followed by PTCy for GVHD prophylaxis is a well-tolerated myeloablative regimen in mismatched donors with acute leukemia or myelodysplastic syndrome (MDS) with low transplant related morbidity and mortality and has produced promising HCT outcomes.