A Phase II Study of Low Dose Melphalan with Thiotepa and Fludarabine As Preparative Regimen for Alternative Donor Transplantation

• Published in: Blood 2024-11, Vol.144, p.2131-2131
• Main Authors: Agarwal, Nikki, Fu, Pingfu, Daunov, Michael, Cooper, Brenda W, Tomlinson, Ben K., Klisovic, Rebecca B., de Lima, Marcos, Otegbeye, Folashade, Deng, Changchun, Hernandez-Collazo, Yeritza, Dalal, Jignesh, Martin, James, Margevicius, Seunghee, Ignatz-Hoover, James J., Chaekal, Ok-Kyong, Gallogly, Molly Megan, van Besien, Koen, Metheny, Leland
• Format: Article
• Language: English
• ISSN: 0006-4971
• DOI: 10.1182/blood-2024-210550

Introduction Alkylating agents such as thiotepa have shown to improve progression-free survival when added to reduced intensity conditioning (RIC) for patients with hematological malignancies undergoing allogeneic hematopoietic stem cell transplant (alloHCT). However, when combined with other conditioning agents such as high dose melphalan, it is seen to increase non-relapse mortality. In a retrospective analysis of double umbilical cord blood transplant (dUCBT) for AML, thiotepa 10mg/kg with high dose melphalan at 140mg/m2 and fludarabine 160mg/m2 showed 32% grade III gastrointestinal toxicity, 23% relapse, 28% 1-year treatment related mortality and 59%1-year overall survival1. Another retrospective study in haplo-identical transplants for AML using same doses of thiotepa, melphalan and fludarabine showed 32% non-relapse mortality and 44% relapse rate by day 72 post-transplant2. We hypothesized that reducing the dose of melphalan when combining with thiotepa and fludarabine can be a safe and effective reduced intensity conditioning regimen for alternative donor transplant in this patient population. Methods We designed an open label, single arm, non-randomized study with the primary objective of measuring leukemia-free survival (LFS). Between 2018 to 2023, we enrolled patients with high-risk hematological malignancies who did not have matched related donors. Conditioning regimen consisted of Melphalan 100mg/m2 on day -8, thiotepa 10mg/kg on day -7 (dose adjusted to 5mg/kg for age over 60 years), fludarabine 160mg/m2 in divided doses on days -6, -5, -4 and -3. Post-transplant cyclophosphamide was added as 50mg/kg given on each of days +3 and +4 for haplo-identical transplant. Graft versus host disease (GVHD) prophylaxis of tacrolimus and mycophenolate mofetil (MMF) was started on day -5 for dUCBT and T +5 for haplo-identical transplant. Patients were followed for 12 months post-transplant or until treatment failure, defined as relapse, graft failure or death. Results Forty patients were enrolled, two did not proceed to transplant. Median follow-up of transplanted patients was 11.9 months (0.5-31.8). Median age was 52.5 years (15-71 years) with 26% (10/38) older than 60 years. Eleven patients (28%) were female. Nineteen patients (50%) had AML, others had ALL, MDS, CMML, CML or T-cell lymphomas. Twenty one patients (55%) were classified as high risk disease, based on molecular/cytogenetics or clinical data. Thirty-one (81.5%) were in complete remission (CR)