Safety and Feasibility of Outpatient Myeloablative Total Marrow and Lymphoid Irradiation-Based Allogeneic Transplantation in Adults with High Risk Acute Lymphoblastic Leukemia: Results of a Phase I/II Trial

Total marrow and lymphoid (TMLI) irradiation may keep the benefits of total body radiation but reduce toxicity to healthy tissues in patients with high risk acute lymphoblastic leukemia (ALL). Thus, our objective was to study the feasibility and safety of TMLI in the context of outpatient allogeneic hematopoietic cell transplantation (HCT). Primary outcome was safety defined adverse events (CTCAE, v5.0) & early mortality. Secondary endpoints were D60 measurable residual disease, non-relapse mortality (NRM), relapse free survival (RFS), cumulative incidence of relapse (CIR) & overall survival (OS). This was a phase I/II trial that included patients 16-45 years with relapsed or refractory ALL (NCT06209190). The conditioning was cyclophosphamide (Cy) 350 mg/m² and fludarabine 25 mg/m² (-6 to -4) followed by TMLI; 12 Gy in 6 fractions of 2 Gy BID (-3 to -1) using tomotherapy. For patients with prior central nervous system (CNS) infiltration, a cranial 6 Gy boost was administered. Peripheral blood cells were used. Graft-versus-host disease (GVHD) prophylaxis was post-transplant cyclophosphamide, calcineurin inhibitor and mycophenolate. All procedures were planned entirely on an outpatient basis with hospitalization only if clinically necessary. Fourteen patients with B-ALL were enrolled, with median age 20 years (16-41), 57% male, with 3 lines of prior therapy (2-4). Thirteen (93%) MRD negative before HCT. All TMLI sessions were performed successfully on an outpatient basis, 87% of sessions performed on schedule, with minor delays. Median CD34+ dose was 10 × 10⁶/kg (5.2–10.1). Recipients underwent haploidentical HCT (71%); 57% remained entirely as outpatients (n=8), 42.9% required hospitalization: 21.4% (n=3) for social support, 7.1% (n=1) due to oral intolerance, and 14.3% (n=2) for febrile neutropenia. G2-3 AE included hemorrhagic cystitis (n=3), without cases of severe mucositis or organ damage. G1-2 AE in >10% were all gastrointestinal. Cytomegalovirus infection occurred in n=5. Median neutrophil and platelet engraftment were 14 days (11-17) and 14 days (11-17) respectively. No early death was recorded ≤60 days post-HCT. Acute GVHD was 57.1% (n=8), including G1 in n=1, G2 in n=5, and G3 in n=2. Chronic GVHD was 35.7%, moderate in n=1, severe in n=4. One patient transplanted with active disease had primary failure and died after relapse and complications of a second transplant. At evaluation on D+60 100% were MRD-negative. Two patients relapsed (14%), one bone marrow, the other isolated CNS. 1-year OS, RFS, CIR and NRM rates were 81.3%, 80%, 24% and 7.1% respectively. The median follow-up was 11 months (2-17). TMLI-based conditioning in adolescents and young adults with ALL was feasible and safe, allowing for a full-outpatient conduct in 57% of patients, supporting further studies assessing its efficacy and the safety of larger doses.