Phase I Dose Escalation Trial of 3-Day Total Marrow and Lymphoid Irradiation for Leukemia as Part of Myeloablative Conditioning in Unrelated Bone Marrow Transplantation

Abstract

<h3>Purpose/Objective(s)</h3> Increasing the total body irradiation (TBI) dose during allogeneic hematopoietic stem cell transplantation (HSCT) has the potential to decrease relapse rates. However, higher doses of TBI increase toxicity and long-term morbidity. Total marrow and lymphoid irradiation (TMLI) allow for increased treatment intensity while avoiding dose escalation for at-risk organs. TMLI is expected to improve long-term survival outcomes of HSCT for hematologic malignancies. This prospective phase I trial aimed to determine the recommended dose of 3-day TMLI for a myeloablative conditioning regimen, by increasing the dose per fraction. <h3>Materials/Methods</h3> The eligibility criteria for this study were as follows, 1) diagnosed with hematologic malignancy, 2) planned HSCT with a myeloablative regimen, 3) with clinical remission status at pre-transplantation, and 4) with no evidence of extramedullary disease. The primary endpoint of this single-institution dose escalation study was the recommended TMLI dose, based on the frequency of dose-limiting toxicity (DLT) within 100 days after HSCT; a 3 + 3 design was used to evaluate the safety of TMLI. Three dose levels of TMLI (14/16/18 Gy in 6 fractions over 3 days) were set, and the treatment protocol began at 14 Gy. DLTs were defined as grade 3 or 4 non-hematological toxicities including those of cardiac, bladder, renal, pulmonary, hepatic, and central nervous system tissues, oral mucositis, gastrointestinal toxicities according to Bearman's criteria, and other grade 3 or higher non-hematological toxicities according to the Common Terminology Criteria for Adverse Events version 4.0. Grade 4 neutropenia (as per the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0) associated with fever or infection lasting beyond 3 weeks, or grade 4 neutropenia persisting for at least 28 days were also considered DLTs. <h3>Results</h3> The median follow-up period after HSCT was 453 (range, 131–915) days. Three patients were enrolled for each dose level. None of the patients exhibited DLT within 100 days of HSCT. Three patients experienced relapse, and no non-relapse mortality was documented during the observation period. One patient died 306 days after HSCT due to disease relapse. <h3>Conclusion</h3> The recommended dose of 3-day TMLI for a myeloablative conditioning regimen was 18 Gy in 6 fractions. The efficacy of this regimen is currently being planned in a phase II study.