Phase I/II multisite trial of optimally dosed clofarabine and low‐dose TBI for hematopoietic cell transplantation in acute myeloid leukemia

Abstract

Clofarabine is an immunosuppressive purine nucleoside analog that may have better anti‐leukemic activity than fludarabine. We performed a prospective phase I/II multisite trial of clofarabine with 2 Gy total body irradiation as non‐myeloablative conditioning for allogeneic hematopoietic cell transplantation in adults with acute myeloid leukemia who were unfit for more intense regimens. Our main objective was to improve the 6‐month relapse rate following non‐myeloablative conditioning, while maintaining historic rates of non‐relapse mortality (NRM) and engraftment. Forty‐four patients, 53 to 74 (median: 69) years, were treated with clofarabine at 150 to 250\u2009mg/m2, of whom 36 were treated at the maximum protocol‐specified dose. One patient developed multifactorial acute kidney injury and another developed multiorgan failure, but no other grade 3 to 5 non‐hematologic toxicities were observed. All patients fully engrafted. The 6‐month relapse rate was 16% (95% CI, 5%‐27%) among all patients and 14% (95% CI, 3%‐26%) among high‐risk patients treated at the maximum dose, meeting the pre‐specified primary efficacy endpoint. Overall survival was 55% (95% CI, 40%‐70%) and leukemia‐free survival was 52% (95% CI, 37%‐67%) at 2\u2009years. Compared to a historical high‐risk cohort treated with the combination of fludarabine at 90\u2009mg/m2 and 2 Gy TBI, protocol patients treated with the clofarabine‐TBI regimen had lower rates of overall mortality (HR of 0.50, 95% CI, 0.28‐0.91), disease progression or death (HR 0.48, 95% CI, 0.27‐0.85), and morphologic relapse (HR 0.30, 95% CI, 0.13‐0.69), and comparable NRM (HR 0.85, 95% CI 0.36‐2.00). The combination of clofarabine with TBI warrants further investigation in patients with high‐risk AML.