A Risk Adaptive Approach at Reduced Intensity Conditioning (RIC) and Transplantation of HLA-Haploidentical Hematopoietic Cells Using Fludarabine, Melphalan, Cyclophosphamide, and Total Body Irradiation (Flu/Mel/Cy/TBI) for Elderly or Infirm.

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Introduction In older patients (pts) undergoing allogeneic stem cell transplantation , reduced intensity conditioning (RIC) offers potential cure. However, in pts without HLA-matched related (MRD) or unrelated (MUD) donors, haploidentical (haplo) grafts have historically higher rates of transplant-related mortality (TRM) and graft-versus-host disease (GVHD). Adding melphalan (Mel) 140mg/m2 to conditioning improved disease-free survival (DFS) with high TRM and GVHD risk. Decreasing Mel dose through risk-adaption may improve DFS and reduce TRM. Methods This Phase II clinical trial used HLA-haplo bone marrow (BM) grafts with pts stratified to four arms based on age & HCT-CI score. • Arm A (Mel 100mg/m2; age <55, HCT-CI <3) • Arm B (Mel 70mg/m2; age>55 or <55 with HCT >2) • Arm C (Mel 70mg/m2; age >55 and <65, HCT-CI <3) • Arm D (no Mel; age 65-75, or HCT-CI >3). Each arm received RIC standard of care (SOC) conditioning: Fludarabine 30mg/m2 on D-6 to D-2, Cyclophosphamide at 30mg/kg on D-6, Total Body Irradiation (TBI) 2Gy/day on D-2 and D-1. All pts received GVHD prophylaxis with post-transplant Cyclophosphamide (50mg/kg on D+3 and D+4) and Tacrolimus with Mycophenolate Mofetil from D+5. The primary objective was DFS at 1 year (yr) and secondary objectives were incidence of grade 2-4 aGVHD at D+100, Overall Survival (OS), TRM, Infectious Mortality (IDM), and GVHD-Relapse Free Survival (GRFS) at 1 yr post-transplantation. Results Seventy-eight patients were enrolled between 2018-2023 with patient and disease characteristics in Table 1. There was no difference in 1yr DFS between arms, but OS decreased in arm B (Table 2) due to higher 1yr TRM (Fig. 1). Compared to SOC arm D, arm B had higher TRM due to CMV/EBV infections (Fig. 2). When Mel100 (arm A) was compared to Mel70 (arm C) in fit pts, no difference in DFS, TRM or OS exists (Fig. 3). Conclusion Adding Mel to Flu/Cy/TBI RIC in haplo-BM graft recipients did not improve DFS, but was associated with higher TRM driven by infections. For patients with low HCT-CI, adding Mel 100mg/m2 over 70mg/m2 had no impact on DFS

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