Multicenter phase 1-2 trial of CRISPR-Cas9 CD33-deleted alloHCT with gemtuzumab ozogamicin maitenance in high-risk AML
Patients with high-risk AML and MDS are likely to relapse despite allogeneic hematopoietic transplantation (alloHCT). Post-HCT preventative maintenance can be limited by toxicity toward the normal donor cells. Tremtelectogene empogeditemcel (trem-cel) is a CRISPR-Cas9 gene-edited alloHCT product lacking CD33, designed to shield the donor graft from cytotoxicity of subsequent CD33-targeted therapies such as gemtuzumab ozogamicin (GO). In a multicenter phase 1-2 trial, adult patients with high relapse risk AML or MDS received trem-cel after myeloablative conditioning followed by GO maintenance. All 30 patients receiving trem-cel achieved the primary safety endpoint of neutrophil engraftment by day 28 with a median engraftment time of 10 days (95% CI 9-10). Nineteen patients received GO maintenance in phase 1 dose escalation (n=15) and in phase 2 dose expansion (n=4). GO treatment was safely tolerated up to the recommended phase 2 dose of 2 mg/m2, and no prolonged high-grade cytopenias were observed. Three cases of transplant-related mortality were observed (renal failure, sepsis, and sinusoidal obstruction syndrome). The authors conclude that trem-cel demonstrated safe, rapid, and robust engraftment, and GO maintenance was administered without prolonged hematological toxicity.