Fludarabine-Melphalan with Total Body Irradiation or with Thiotepa Conditioning for Adult Patients with Acute Lymphoblastic Leukemia Receiving Allogeneic Stem Cell Transplantation
Authors: Chumnumsiriwath Piyatida , Vittayawacharin Pongthep , Jeyakumar Deepa , Naqvi Kiran , Lee Benjamin , Doh Jean , Griffin Shawn P. , Kuo Jeffrey , Harris Jeremy , Kongtim Piyanuch , Ciurea Stefan O. 
Published: December 2024

Background:Total body irradiation (TBI) - based conditioning regimens have preferentially been used for adult patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (AHSCT). Our group developed a conditioning regimen consisting of fludarabine, melphalan (FM) and low-dose TBI (FMT) or low-dose thiotepa (FMTT) for patients with hematologic malignancies (Gaballa S et al. Cancer. 2016).This study aims to retrospectively evaluate transplant outcomes of patients with ALL who received conditioning with FMT or FMTT and post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis at our institution.

Methods:All adult patients (&gt;18-year-old) with ALL who underwent AHSCT between 05/2020-05/2024 were included. Conditioning consisted of fludarabine 40 mg/m2/d on days -5 to -2, melphalan 100-140 mg/m2 on day -5 and TBI 2-4 Gy on day -1 for patients without central nervous system (CNS) involvement, or thiotepa 5 mg/kg on day -6 for patients with CNS involvement. Patients with CNS involvement also received craniospinal irradiation (CSI) prior to transplant (18 Gy in 10 daily fractions) and monthly intrathecal methotrexate after transplant for a total of 6 doses. GVHD prophylaxis comprised of PTCy 50 mg/kg on days +3 and +4, tacrolimus (target trough level 6-10 ng/mL) which was continued for at least 6 months as well as mycophenolate mofetil (MMF) 15 mg/kg (capped at 1,000 mg) TID, and budesonide 3 mg TID starting on day +5 which was continued until day +90, if no symptoms of acute GVHD.

Results:A total of 29 patients with a median age of 44 years (range, 22-72) were included. Twenty-four (83%) patients had B-cell ALL including 20 patients (70%) with either Ph+ or Ph-like ALL. Donor types were haploidentical (N=17, 59%), HLA match-sibling (N=11, 38%), and match-unrelated (N=1, 3%). Nine patients (31%) had CNS involvement, and received CSI, FMTT conditioning followed by 6 monthly IT chemotherapy post-transplant after blood count recovery. Nineteen (66%) patients received melphalan 100 mg/m2. Twenty-four patients (83%) were in complete remission (CR1) and 19 patients (66%) had MRD-negative CR1 before transplant. Median HCT-CI was 2 (range, 0-6). The median follow-up of survivors was 443 days. All patients engrafted with neutrophils (100%) and platelets (100%) with median time to neutrophil and platelet engraftment of 15 and 19 days, respectively. All patients achieved full donor chimerisms from days 30 to 365 post-transplant. Two-year overall survival (OS) and progression-free survival (PFS) were 83% (95%CI: 59.9-93.1) and 83% (95%CI: 59.9-93.1), respectively. The cumulative incidence of non-relapse mortality (NRM) and relapse at 2 years were 17.4% (95%CI: 5.4-35.0) and 0%, respectively. Cumulative incidence of grade II-IV acute GVHD was 3.9% (95%CI: 5.4-35.0) at 100 days, and chronic GVHD was 4.2% (95%CI: 0.3-17.6) at 1 year. All 9 patients who received FMTT conditioning were alive and disease-free at 1-year post-transplant. Eleven patients (38%) with high-risk features received maintenance blinatumomab every 3 months x 4 and 5 patients (17%) with Ph+ B-cell ALL received both blinatumomab and tyrosine kinase inhibitor (ponatinib). All 11 patients were alive and disease-free at 1-year post-transplant. Four patients died of NRM including 2 patients from severe COVID-19 infection, 1 from transplant-associated thrombotic microangiopathy (TA-TMA), and 1 from intracerebral hemorrhage.

Conclusion: An intensified FM-based conditioning regimen with low-dose TBI or thiotepa is effective in adult patients with ALL with very low relapse rate, regardless of donor type. Patients with history of CNS disease who achieved disease control prior to transplant have excellent outcomes with FMTT conditioning, CSI pre- and 6 doses of monthly IT chemotherapy post-transplant. Outcomes with Blinatumomab +/- TKI maintenance were highly encouraging in high-risk B-cell ALL patients and may be considered for those with high-risk features.