First-In-Human Study of 211At-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 (211At), 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 211At-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 211At. 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. 211At-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

211At-CD45 RIT can be incorporated into nonmyeloablative conditioning, with liver toxicity defining activity limits. Evidence of antitumor efficacy supports phase II evaluation.