A Novel Chemo-Based Reduced Intensity Haploidentical Two-Step Allogeneic Hematopoietic Stem Cell Transplantation, Results of a Prospective Clinical Trial
Authors: Bao Alicia , Bi Xia , Gradone Allison , Gattas Boula , Nath Arpona Dev , Grande Brenda , Mateja Gina , Filicko-O'Hara Joanne , O'Hara William , Wagner John , Grosso Dolores , Flomenberg Neal , Gergis Usama 
Published: December 2024

Background: The two-step allogeneic hematopoietic stem cell transplant (HSCT) approach was developed at Thomas Jefferson University Hospital to isolate the graft's lymphoid and myeloid components, enabling a constant T cell dosage and protecting the stem cells from cyclophosphamide's effects. Here, we present the results of our clinical trial using a chemo-based reduced-intensity conditioning (RIC) regimen for older and frail patients. Methods: All patients received fludarabine 30mg/m2 for 4 days and thiotepa 5mg/kg for 3 days (n=15, 25%) or busulfan 3.2mg/kg for 2 days (n=45, 75%). Thiotepa was substituted with busulfan due to a national shortage. The patients then received one day of TBI (2 Gy), followed by 2 x 10*8/kg donor T-lymphocyte infusion on day -6, representing step 1. On days -3 and -4, patients received two doses of cyclophosphamide (CY) 60mg/kg to tolerize reactive lymphocytes, and 24 hours later, received CD34 selected stem cell infusion (step 2). All patients received GVHD prophylaxis with MMF and tacrolimus. Results: Among the 60 patients studied, 53 (88.3%) received haploidentical (HI) stem cell grafts and 7 (11.7%) received matched related stem cell grafts. The median age was 62.5 years (range 22- 74 years), with 28 patients (46.7%) over 65 years. 43 (71%) patients identified as Caucasian and 15 (25%) as African American. Nineteen patients (31.6%) had Acute Myeloid Leukemia (AML), and 9 (15%) had Myelodysplastic Syndrome (MDS). Twelve patients (20%) had evidence of primary disease at transplant and 50% had HCT-CI of &gt;= 3. The median time to neutrophil and platelet engraftment was 11 days (range 10 - 22) and 14 days (range 12 - 26), respectively. With a median follow-up of 17.0 months (range 0.4 - 110.4 months), the 3-year overall survival (OS) was 48% (95% CI 37% - 63%), and progression-free survival (PFS) was 43% (95% CI 32%-58%). The cumulative incidence of relapse and non-relapse mortality were 25% and 32% at 3 years, respectively. At 6 months, the cumulative incidence of grade 2-4 acute graft-versus-host disease (GVHD) was 37.7%, and 20.6% for chronic GVHD at 3 years. Patients who received the thiotepa-based regimen had significantly higher non-relapse mortality (NRM) than those who received the busulfan-based regimen (53% vs. 28%, p = 0.05) at 5 years post-transplant, but rates of relapse were similar (27% vs. 24%, p = 0.84). Patients were stratified into having “Active Disease” (n=12, 20%) or in remission (n=48, 80%) at the time of transplant. The 3-year cumulative incidence of relapse was significantly lower for patients in remission at the time of transplant (19% vs 50%, p = 0.026) while NRM was similar (33% vs 42%, p = 0.66). This led to a much higher 3-year OS for patients transplanted in earlier stage disease (58% vs 8%, p = 0.00033). Patients with non-active disease who received busulfan-based conditioning at the time of transplant had significantly higher survival than patients who received thiotepa-based conditioning (58% vs 20%, p = 0.0015). Conclusion: Busulfan-based RIC HI two-step allogeneic HSCT is suitable for older and frail patients when primary disease is in remission. Rapid engraftment and low rates of GVHD despite utilizing HI stem cell grafts are encouraging.