First-In-Human Study of 211 At-CD45 Radioimmunotherapy With Nonmyeloablative Conditioning Hematopoietic Cell Transplantation for Adults With Hematologic Malignancies

Purpose Relapse is the dominant cause of failure after allogeneic hematopoietic cell transplantation (HCT) for aggressive hematologic malignancies. CD45-directed radioimmunotherapy (RIT) has been investigated to intensify conditioning and augment antitumor efficacy. After gaining clinical experience with β-emitting radionuclides, attention is now shifting toward α-emitters, such as astatine-211 ( 211 At), for their more potent and precise radiation delivery with minimized toxicity to surrounding tissues. Patients and Methods To our knowledge, in this first-in-human, two-stage dose-finding study, we administered a single infusion of 211 At-labeled anti-CD45 monoclonal antibody before nonmyeloablative conditioning with fludarabine/2-3 Gy total body irradiation and allografting from HLA-matched or single-allele–mismatched donors in 45 adults (38-74 years of age) at a high relapse risk from myeloid malignancies or acute leukemia. Results Seventeen patients were treated in stage I with 85-591 μCi/kg of 211 At. The patient receiving 591 μCi/kg developed veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), thereby establishing 500 μCi/kg as the protocol-defined maximum tolerated dose and prompting initiation of stage II at that dose in 28 patients. Infusion reactions were mild. 211 At-CD45 RIT did not delay hematopoietic recovery, impair donor chimerism, or increase graft-versus-host disease (GVHD) rates. In stage II, six patients (all receiving sirolimus as part of GVHD prophylaxis for unrelated donor HCT) experienced VOD/SOS. Among the 13 patients with circulating blasts at baseline, blasts cleared in 12 before initiation of fludarabine/total body irradiation, demonstrating immediate cytotoxic activity. Estimated 1-year relapse-free and overall survival were 42% (95% CI, 28%-56%) and 49% (34%-62%), respectively. Conclusion 211 At-CD45 RIT can be incorporated into nonmyeloablative conditioning, with liver toxicity defining activity limits. Evidence of antitumor efficacy supports phase II evaluation.