Intensified conditioning with high-dose total marrow irradiation and myeloablative chemotherapy reduces risk of relapse without increasing toxicity in allogeneic hematopoietic stem cell transplant for high-risk myeloid malignancies: a phase II study.

The intensity of the conditioning regimen in hematopoietic stem cell transplantation (HSCT) correlates with the risk of relapse, however its potential benefit may be outweighed by the associated risk of toxicity. The addition of total marrow irradiation (TMI) to myeloablative conditioning provides an opportunity to increase intensity with minimal additional toxicity. In this phase 2 clinical trial, 30 patients with high-risk myeloid malignancies received an allogeneic HSCT using myeloablative TMI at 9Gy in combination with standard myeloablative fludarabine/intravenous busulfan (FluBu4) chemotherapy. The study included patients with matched-related donors (n=10) receiving TMI/FluBu4 and patients with matched unrelated (n=14) or 1-antigen mismatched unrelated (n=6) donors receiving TMI/FluBu4 and rabbit antithymocyte globulin. All patients achieved sustained engraftment. Grade 3-4 extramedullary toxicities were: mucositis in 59% (n=17), nausea/vomiting in 10% (n=3) and diarrhea in 7% (n=2) of the patients. Acute graft-versus-host disease (GVHD) grade III-IV was seen in 4 patients (13.3%). Moderate/severe chronic GVHD was observed in 11 patients (36.7%). With a median follow-up of 1483 days (range: 63-2260 days) for patients alive, the overall survival and disease-free survival at 1 year were 72.4% and 65.5%, respectively. GVHD-Free Relapse-Free Survival at 1-year was 41.4%. Of 30 patients in the study, 6 relapsed/progressed (20%) and 5 of them died of the disease (16.7%); whereas 6 patients (20%) died of transplant-related mortality. We conclude that a myeloablative regimen with TMI at 9Gy and FluBu4 was well tolerated and achieved encouraging results in patients with myeloid malignancies at high risk of relapse (clinicaltrials.gov Identifier: NCT03121014).