A Phase II Trial of Melphalan Based Reduced Intensity Conditioning and Transplantation of Partially HLA-Mismatched Peripheral Blood Stem Cells for Patients with Hematologic Malignancies

HLA-haploidentical (haplo) stem cell transplantation is now widely used for patients lacking a suitably matched related or unrelated donor (MUD). Conventionally, T-replete Haplo transplantation has been performed using non-myeloablative conditioning and a bone marrow graft. Subsequently, our group has developed the use of myeloablative conditioning and PBSC grafts for Haplo (Solomon et al BBMT 2015, 2019). However, some patients with hematologic malignancies who are unable to tolerate a fully myeloablative regimen may benefit from intermediate intensity conditioning. We conducted a prospective phase II trial utilizing melphalan based preparative regimen ( fludarabine 30mg/m² days -6 to -2, melphalan 140 mg/m² day -1) followed by infusion of unmanipulated peripheral blood stem cells (PBSCs) ,capped at 5x10 ⁶ CD34+/kg,from a haploidentical first degree family donor. Graft-versus-host disease (GVHD) prophylaxis consisted of Cy 50mg/kg on days 3 and 4, MMF through day 35, and tacrolimus through day 180. The primary endpoint was to estimate the incidence of graft rejection following Fludarabine/Melphalan conditioning. For the graft failure endpoint we tested the hypotheses H0: p=10% versus Ha: p<10% using a one-sided exact Binomial test. Assume that none of patients undergoing the proposed regimen will have graft failure, the power for confirming p less than 15% is always 100% if the null hypothesis is rejected. The population enrolled was needed to achieve rejection of the null hypothesis at the 5% significance level. Twenty-five patients had their first allogeneic transplant on this study, and their characteristics were as follows: median age 57 years (range 35-68), male sex 44%, transplant diagnosis included AML [11], ALL [3], MDS/MPN [7], NHL [3], and multiple myeloma [1]. Using disease risk index (DRI), patients were classified as low [1], intermediate [13], or high/very high [11]. Twenty patients (80%) had a comorbidity index (HCT-CI) of ≥ 3. Median follow up for survivors was 28.3 (range 8.7-43.9) months. Post infusion fevers that subsided after receiving Cytoxan were seen in 93% and two patients had grade 2 cytokine release syndrome. Median time to ANC and platelet engraftment was 18 days (13-32) and 36 days (21-224), respectively. Three patients failed to engraft with spontaneous count recovery in one of them. Two of the three graft failures ended up engrafting after a second transplant. All engrafting patients had sustained complete donor myeloid and T cell chimerism by day 30. Acute GVHD grade II-IV and III-IV was seen in 20% and 8% respectively. The cumulative incidence of chronic GVHD was 16% (moderate-severe 12%). The estimated 2-year overall survival (OS) was 56%, disease-free survival (DFS) 44%, non-relapse mortality (NRM) 20%, relapse rate 36% and GVHD-, relapse-free survival (GRFS) 41%. For patients with high/very high DRI, the 2 year OS was 53%. For patients with HCT-CI 0-2, 2 year OS and DFS were at 75%. When compared to a contemporaneous cohort of patients receiving haplo transplant using fludarabine, Cytoxan and low dose TBI (Baltimore regimen), outcomes were not significantly different for OS, DFS, NRM and relapse. Patients receiving Flu/Mel had lower incidence of acute II-IV GVHD at 100 days (16% vs 44%). A matched pairs comparison (n=18) using matching at age range, DRI and HCT-CI between Flu/Mel and patients receiving Flu/Cy/TBI at our center, showed significant difference in OS, DFS, NRM and relapse (graph 1) between Flu/Mel and flu/Cy/TBI. All patients with primary MPD (n=4) had successful engraftment on this protocol which historically had a high graft failure rate on the non-ablative flu/Cy/TBI.

Haplo transplant using fludarabine/melphalan with PBSCs is a valid option for some patients lacking a timely access to a matched donor. It is well tolerated and provides full and rapid donor myeloid and T-cell chimerism.

Figure 1:Overall Survival and Disease Free Survival In Matched Cohorts of Flu/Mel versus Flu/Cy/TBI

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