Reduced intensity conditioning (RIC) regimens frequently provide insufficient disease control in patients with high-risk hematological malignancies undergoing allogeneic hematopoietic stem cell transplantation (HSCT).
We evaluated intensification of fludarabine/busulfan (Flu/Bu) RIC with targeted marrow irradiation (TMI) in a dose escalation with expansion phase I clinical trial. TMI doses were delivered at 1.5 Gy in twice daily fractions on days -10 through -7 (dose levels: 3 Gy, 4.5 Gy and 6 Gy), Flu (30 mg/m x 5 days) and Bu (AUC 4800 µM*minute x 2 days).
Eligible patients were ≥ 18 years with high-risk hematological malignancy and compromised organ function ineligible for myeloablative transplant (n=26). Median age was 64 years (range, 25-76). Nineteen patients (73%) had active or measurable residual disease at transplant. One-year disease free and overall survival was 55% (95% CI, 34%-76%) and 65% (95% CI, 46%-85%), respectively. Day +100 and 1-year transplant-related mortality was 4% (95% CI, 0.6%-27%) and 8.5% (95% CI, 2%-32%), respectively. One-year cumulative incidence of relapse was 43% (95% CI, 27%-69%). Grade II-IV and III-IV acute GVHD rates were 57% (95% CI, 39%-84%) and 22% (95% CI, 9%-53%), respectively. Whole blood immune profiling demonstrated enrichment of central/transitional memory-like T-cells during higher TMI dose which correlated with improved survival, when compared to control samples (from patients undergoing allogeneic HSCT).
Intensification of RIC Flu/Bu with TMI is feasible with low incidence of TRM in medically frail patients with advanced malignancies. The recommended phase 2 TMI dose is 6 Gy.

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