Intensive Conditioning with Fludarabine Plus Melphalan Versus Total Body Irradiation Prior to Haploidentical Transplant and Post-Transplant Cyclophosphamide
Authors: Solomon Scott R. , Sanacore Melissa , Bashey Asad , Jackson Katelin C , Bachier Rodriguez Lizamarie , Morris Lawrence E , Holland H. Kent , Solh Melhem M. 
Published: December 2024

Total Body Irradiation (TBI) is often included in conditioning regimens prior to haploidentical donor transplantation (HIDT) in order to improve engraftment and reduce graft failure, however the technique is resource intensive, expensive, and not universally available globally. Therefore, chemotherapy-only preparative regimens that can provide sufficient immune- and myelo-ablation to eliminate the need for TBI are clearly desirable. Starting in 2015, we introduced an intensive conditioning regimen of fludarabine 150mg/m2 and Mel 140mg/m2 (FM), which allowed sustained engraftment for haploidentical transplant recipients without the need of TBI (Solh et al., Adv Hematol 2021). In this analysis, we compared contemporaneous recipients of FM (n=25) with those receiving fludarabine and TBI 1200 cGy (FTBI, n=124) from 2015-2023. Eligible patients were 18-64 years with acute leukemia or MDS/CML receiving a first HIDT. Compared with FTBI, FM recipients were older (median 55 vs. 43 yrs) with more comorbidity (HCT-CI ≥3 80% vs. 47%). DRI was low, intermediate and high/v.high in 8%, 67% and 25% and comparable between groups. Compared with FTBI, FM recipients had similar ANC recovery (16 vs. 16 days), slower PLT recovery (33 vs. 27 days) and more graft failure (12% vs. 0%). Grade ≥1 cytokine release syndrome (CRS) was similar in FM vs FTBI recipients (93.6% vs. 92.0%), whereas grade ≥2 CRS was significantly higher in FM patients (16% vs. 0.8%, p=0.003). HLA-DR matching in the GVH direction was associated with significantly less CRS (73% vs. 98%, p&lt;0.001), however the percentage of HLA-DRB1 GVH matching was similar in FM vs. FTBI recipients (16% vs. 21%). FM recipients required longer inpatient hospitalization in the first 30 days (median 17 vs. 13.5 days, p=0.014). Acute GVHD grade 2-4 was significantly less in FM recipients (28% vs. 56%, p=0.005, whereas grade 3-4 acute GVHD and chronic GVHD were statistically similar. In FM recipients, there was a trend for inferior 3-yr OS (63% vs. 75%, p=0.09) and DFS (50% vs. 68%, p=0.09) in univariate analysis, but this did not reach statistical significance in multivariable analysis when controlled for HCT-CI and DRI (OS HR 1.70, p=0.14; DFS HR 1.61, p=0.16). The 3-yr cumulative incidence of relapse (34% vs. 23%) and non-relapse mortality (16% vs. 9%)) were not statistically different in FM vs. FTBI recipients, respectively. In summary, within the statistical limitations of this analysis, TBI-free conditioning with FM provided transplant outcomes not statistically different from FTBI in younger HIDT recipients needing intensive conditioning, at the expense of more frequent high-grade CRS, graft failure and requirement for inpatient hospitalization. Acute GVHD was less frequent in FM patients. Thus, FM is a reasonable alternative to FTBI for patients requiring intensive conditioning, where TBI is unavailable or impractical.