Addition of Myeloablative Doses of Total Marrow Irradiation (TMI) to Myeloablative Fludarabine/Busulfan Conditioning for Allogeneic HSCT in Patients with High-Risk AML, CML, or Myelodysplastic Syndrome: A Phase II Clinical Trial

In allogeneic hematopoietic stem cell transplantation (HSCT) for high-risk myeloid disorders, the intensity of the conditioning regimen correlates with the risk of relapse, but its benefit may be offset by its risk of toxicity.From 2017 to 2023, 31 patients with high-risk acute myeloid leukemia (AML, n=20) or myelodysplastic syndrome (MDS, n=5), or chronic myeloid leukemia (CML, n=3) in accelerated phase or blast crisis, were enrolled into a prospective phase II clinical trial of allogeneic HSCT using myeloablative TMI at 9Gy in combination with standard myeloablative fludarabine and targeted IV busulfan (FluBu4) chemotherapy. TMI was delivered by using volumetric modulated arc therapy (VMAT) at 1.5Gy twice per day for 3 days. The primary objective of the trial was to achieve >50% Disease-Free Survival (DFS) at 1 year. Rabbit anti-thymocyte globulin (rATG) was added in transplants from unrelated donors.Here, we report the results on 28 patients who received the TMI-based transplant, whereas 3, became ineligible due to disease status. Donors were matched related (MRD, n=9), or matched unrelated (MUD, n=13) or 1-antigen mismatched unrelated (MMUD, n=6) Patients’ gender ratio was 16 female/12 male and median age was 53 years (range: 20-68). The median HCT-Comorbidity Index (HCT-CI) was 3 (range: 0-7). All 20 AML patients were at high risk of relapse because of adverse cytogenetic or molecular profile at diagnosis (n=13), or in second complete remission (CR2) (n=2), or with active disease at the time of transplant (n=5). All patients received peripheral blood stem cells (PBSC) (median CD34+ cell dose: 8.5 x 106/kg, range: 2.4-19.9). Grade 3-4 extramedullary toxicities were: mucositis in 57% (n=16), nausea/vomiting in 11% (n=3) and diarrhea in 7% (n=2) of the patients. Acute GVHD grade III-IV was seen in 3 patients (10%). Moderate/severe chronic GVHD was observed in 10 patients (36%). With a median follow-up of 1315 days (range: 158-1925 days) for patients alive, the overall 1 year and current overall survival were 73% and 64%, respectively. GVHD- Free Relapse-Free Survival (GRFS) at 1-year was 54%. Of 5 AML patients transplanted with active disease, 3 were alive and in remission at 1 year and at current date, while 2 died of relapsed disease. Of 28 patients in the study, 6 relapsed/progressed (21%) and 5 of them died of the disease (18%); whereas 5 patients (18%) died of transplant-related mortality (TRM) (2 deaths from septic shock, 1 from disseminated toxoplasmosis, 1 from idiopathic pneumonia and 1 from unknown causes). Kaplan Meyer curves for Overall Survival (OS) and DFS are shown in Figure 1 and 2, respectively.Addition of myeloablative TMI at 9Gy to standard myeloablative targeted FluBu4 was well tolerated and achieved very encouraging results in a group of patients with myeloid malignancies at high risk of relapse (clinicaltrials.gov Identifier: NCT03121014).