CXCR4-directed endoradiotherapy with [177Lu]Pentixather added to total body irradiation for myeloablative conditioning in patients with relapsed/refractory acute myeloid leukemia.

Rationale: Despite recent advances in the targeted therapy of AML, the disease continues to have a poor prognosis. Allogeneic hematopoietic stem cell transplantation (alloSCT) remains to be the curative therapy option for fit patients with high-risk disease. Especially patients with relapsed or refractory (r/r) AML continue to have poor outcomes. Myeloablative total body irradiation (TBI) based conditioning can be used in AML patients refractory to multiple lines of standard therapy, but the optimal conditioning regimen remains unclear for patients considered to be chemotherapy- refractory. Feasibility of C-X-C-motif chemokine receptor 4 (CXCR4)-directed endoradiotherapy (ERT) has previously been demonstrated in AML patients with CXCR4 expression on leukemic blasts. Methods: Here, we report on a small cohort of seven AML patients refractory to multiple lines (range 3-7) of therapy, who received CXCR4-directed ERT with [¹⁷⁷Lu]Pentixather in combination with TBI and chemotherapy prior to alloSCT. We report outcomes with a focus on toxicity, engraftment, the impact on the bone marrow (BM) niche and efficacy. Results: In this intensively pre-treated group of patients, promising response (6 out of 7 patients) and engraftment (6 out of 7 patients) rates were observed. Histopathological analysis showed that niche compartments are spared and allow for engraftment to occur despite the combined ERT and TBI conditioning. Conclusion: To the best of our knowledge, we report on the first seven patients who received CXCR4-directed ERT in sequential combination with TBI and chemotherapy, providing an effective, individualized conditioning regimen for intensively pre-treated r/r AML patients.