TBI-Based Myeloablative Conditioning Two-Step Haploidentical Allogeneic Hematopoietic Stem Cell Transplant Yields Excellent Outcomes in Fit Patients with High-Risk Hematologic Malignancies, Results of a Prospective Trial

Background: Since 2005, Thomas Jefferson University has developed the two-step allogeneic hematopoietic stem cell transplant (HSCT) approach that isolates the graft's lymphoid and myeloid components. The two-step platform allows for a consistent T cell dosage and shields the stem cells from the effects of cyclophosphamide. We previously reported promising outcomes and an acceptable safety profile. In this prospective study, we investigated a novel TBI-based myeloablative conditioning (MAC) prior to two-step HSCT for fit patients with high-risk hematologic malignancies. Methods: From 2017-2023, forty-six patients received 12 Gy TBI, prior to receiving 2 x 10*8 /kg DLI. Two days later, patients received cyclophosphamide 60 mg/kg/day x 2. Finally, patients received CD34- selected stem cell grafts. Patients received MMF and tacrolimus for GVHD prophylaxis. Results: The median age was 55.5 years old (range 23-65 years). Thirty-six patients (78%) identified as Caucasian and 48% female. The most common diagnosis was Acute Myeloid Leukemia, (n=25, 54%), followed by Myelodysplastic Syndromes (n=8, 17%), and Acute Lymphoblastic Leukemia (n=6, 13%). The median HCT-CI score was 3 (range, 0-7), while 10 patients (22%) had a high disease risk index. The vast majority of patients received a haploidentical (HI) stem cell graft (n=44, 96%) All patients achieved neutrophil engraftment at a median of 11 days (range 9-19) and platelet engraftment at a median of 15 days (range 12-23). After a median follow up of 23 months (range, 0-67), the Overall survival (OS) and progression-free survival (PFS) were 68% (95%CI 56% - 84%) at one year and 65% (95%CI 53% - 81%) and 60% (47% - 77%) respectively at 5 years. The cumulative incidence of non-relapse mortality (NRM) and relapse were 20% and 12% at one year and 20% and 14% at 5 years. There was a total of 15 (33%) deaths: 4 patients succumbed to toxicity, 5 to infections, and 6 to primary disease relapse. GVHD-free, relapse-free survival (GRFS) was assessed by the absence of grade III-IV acute GVHD or chronic GVHD requiring systemic treatment, with GRFS rates of 62% at one year (95% CI: 49%-78%) and 54% at 5 years (95% CI: 41%-71%). The cumulative incidence (CI) of acute grade II-IV GVHD was 27% at 100 days and 33% at 200 days, while the CI of acute grade III GVHD was 2.4% at 200 days. Chronic GVHD had a CI of 14% at both 1 year and 5 years. There were no instances of grade IV acute GVHD, severe chronic GVHD, or deaths attributable to GVHD. Patients undergoing HSCT while in remission (n=36, 78%) experienced significantly better survival rates compared to those with active disease (1-year OS 76% vs 40%, 5-year OS 76% vs 27%, p = 0.0029). Conclusion: The TBI-based myeloablative conditioning Two-Step HI HSCT yields Excellent Outcomes in Fit Patients with High-Risk Hematologic Malignancies. Despite the use of HI peripheral stem cell grafts, there were no grade IV aGVHD, severe cGVHD or GVHD related deaths.