First-in-human study of astatine-211 CD45 radioimmunotherapy before HCT for adults with hematologic malignancies

Relapse is the dominant cause of failure after alloHCT 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 shifting toward α-emitters, such as astatine-211 (²¹¹At), for their more potent and precise radiation delivery with minimized toxicity to surrounding tissues. A first-in-human phase 1 trial at Fred Hutchinson Cancer Center and the University of Washington (both in Seattle, WA) evaluated a single infusion of ²¹¹At-labeled anti-CD45 monoclonal antibody before nonmyeloablative conditioning with fludarabine/2-3 Gy total body irradiation (TBI) and allografting in 45 patients (38-74 years of age) at high relapse risk from myeloid malignancies or acute leukemia. In stage I, seventeen patients were treated 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 maximum tolerated dose and prompting iniation 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 GVHD rates. In stage II, six patients experienced VOD/SOS. Among 13 patients with circulating blasts at baseline, blasts cleared in 12 before initiation of fludarabine/TBI, demonstrating immediate cytotoxic activity. One-year relapse-free survival rate was 42% (95% CI 28-56) and one-year overall survival rate was 49% (34-62). The authors conclude that ²¹¹At-CD45 RIT can be incorporated into nonmyeloablative conditioning, with liver toxicity defining activity limits. Evidence of antitumor efficacy supports phase 2 evaluation.