Background

Myeloablative total body irradiation (TBI) has long been a fundamental part of conditioning regimens for acute lymphoblastic leukemia (ALL), albeit with high toxicities. Total marrow and lymphoid (TMLI) irradiation is an emerging alternative that may keep the benefits of radiation but reduce toxicity to healthy tissues. Thus, our objective was to study the feasibility and safety of TMLI in the context of outpatient allogeneic hematopoietic cell transplantation (HCT).

Methods

This was a single-center phase 2 trial that included patients 16-45 years with relapsed or refractory ALL (). Patients who had received radiotherapy were excluded. The conditioning regimen was cyclophosphamide (Cy) 350 mg/m² and fludarabine25 mg/m² (day -6 to -4) followed by TMLI; 12 Gy in 6 fractions of 2 Gy every 12 hours (day -3 to -1) delivered using a tomotherapy system. For patients with a history of central nervous system (CNS) infiltration, a cranial 6 Gy boost was administered in 3 fractions. Peripheral blood stem cells were used as the graft source. Graft-versus-host disease (GVHD) prophylaxis consisted in tacrolimus or cyclosporin A started on day 0 followed by Cy 30 mg/kg for matched related and 40 mg/kg for haploidentical HSCT on day +3 and +4, and mycophenolate mofetil starting on day +5-30. Filgrastim (300 mcg/day) was started on day +5 until stable engraftment. All procedures were planned entirely on an outpatient basis. After Day 0 patients returned home and monitored in the transplant unit every 24-72 hours until engraftment and hospitalized if necessary. The primary outcome was safety defined by the incidence of adverse events (CTCAE, v5.0) and early mortality. Secondary endpoints were efficacy assessed by measurable residual disease on day +60, non-relapse mortality (NRM), relapse free survival (RFS), cumulative incidence of relapse (CIR) and overall survival (OS).

Results

Fourteen patients with B-ALL were enrolled, with a median age 20 years (range, 16-41), the median follow-up was 11 months (range, 2-17), 57% were male, 43% female. One patient was Ph-positive. The median prior therapy lines were 3 (range, 2-4), 50% blinatumomab-exposed. The HCT comorbidity index was 0 in 64.3% of patients (n=9), and ECOG was 0-1 in all. Six patients (42.9%) were in first complete remission (CR1), whereas 6 were in CR2 (42.9%) and 2 were in CR3. Thirteen (93%) patients had negative MRD before HSCT.

All TMLI sessions were performed successfully on an outpatient basis, 87% of sessions performed on schedule, with minor delays; 4 patients (28.6%) received a cranial boost. The median CD34+ cell dose was 10×10⁶/kg (range, 5.2–10.1). Most recipients underwent haploidentical HCT (71%) while 29% received a matched sibling transplant; 57% remained entirely as outpatients (n=8), while 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. Cytomegalovirus infection occurred in 35.7% (n=5) and hemorrhagic cystitis was reported in 21.4% of patients, with grade 2 in 7.1% (n=1) and grade 3 in 14.3% (n=3). Median neutrophil and platelet engraftment were 14 days (range, 11-17) and 14 days (range, 11-17) respectively. No early death was recorded ≤60 days post-HSCT.

Toxicities and adverse events on first 30 days post HSCT; nausea grade (G) 1 57.1% (n=8), G2 7.1% (n=1), anorexia G1 57.1% (n=8), G2 14.3% (n=2), diarrhea G1 14.3% (n=2), dehydration G1 42.9% (n=6), G2 7.1% (n=1), abdominal pain G1 21.4% (n=3), vomiting G1 14.3% (n=2), gastroesophageal reflux G1 28.6% (n=4). Oral mucositis was G1 in 4 patients (28.6%), G2 in 3 patients ( 21.4%). The incidence of acute GVHD was 57.1% (n=8), including G1 in 7.1% (n=1), G2 in 35.7% (n=5), and G3 in 14.3% (n=2). Chronic GVHD occurred in 35.7% of patients (n=5), moderate in 7.1% (n=1), severe in 28.6% (n=4). One patient had primary failure and died after complications of a second transplant. At evaluation on day +60 92.9% of patients were MRD-negative. Two patients have relapsed (14%), one bone marrow, the other isolated CNS. One-year OS, RFS, CIR and NRM rates were 81.3%, 80%, 24% and 7.1% respectively.

Conclusion

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.

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2025
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