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<p>Patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are likely to relapse despite allogenic hematopoietic cell transplantation (HCT). Post-HCT preventative maintenance can be limited by toxicity toward the normal donor cells. Tremtelectogene empogeditemcel (trem-cel) is a CRISPR–Cas9 gene-edited allogeneic HCT product lacking CD33, designed to shield the donor graft from cytotoxicity of subsequent CD33-targeted therapies such as gemtuzumab ozogamicin (GO). In this multicenter, phase 1/2a, open-label study, adult patients with AML/MDS with high relapse risk received trem-cel after myeloablative conditioning followed by GO maintenance (0.5–2.0 mg m<sup>−</sup><sup>2</sup> day 1 per 28-day cycles). Patients receiving trem-cel were assessed for the primary safety endpoint of neutrophil engraftment by day 28 and secondary endpoints including time to neutrophil engraftment, incidence of graft-versus-host disease and graft failure, transplant-related mortality, percentage of CD33-negative myeloid cells and survival. Patients receiving trem-cel and GO were assessed for the additional secondary endpoints of safety of maintenance GO with trem-cel and pharmacokinetics of GO after trem-cel transplant. 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% confidence interval: 9–10). Nineteen patients received GO maintenance in phase 1 dose escalation (<i>n</i> = 15) and in phase 2 dose expansion (<i>n</i> = 4). The trial was stopped early, and this is the final report on the trial including the completed phase 1 portion. GO treatment was safely tolerated up to the recommended phase 2 dose of 2 mg m<sup>−</sup><sup>2</sup>, and no prolonged high-grade cytopenias were observed. The most common adverse events were cytopenias and infections. Three cases of transplant-related mortality were observed due to renal failure, sepsis and sinusoidal obstruction syndrome, respectively. In summary, trem-cel demonstrated safe, rapid, robust engraftment, and GO maintenance was administered without prolonged hematologic toxicity. ClinicalTrials.gov identifier: <a href="http://clinicaltrials.gov/study/NCT04849910">NCT04849910</a>.</p>

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CRISPR−Cas9 CD33-deleted allogeneic hematopoietic cell transplantation with gemtuzumab ozogamicin maintenance in AML: a phase 1/2 trial

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月12日

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  • John F. DiPersio,
  • Guenther Koehne,
  • Nirali N. Shah,
  • Léa Bernard,
  • Hyung C. Suh,
  • Divya Koura,
  • Roni Tamari,
  • Muhammad Umair Mushtaq,
  • Joseph Maakaron,
  • Joseph Rimando,
  • Vanessa E. Kennedy,
  • Sagar S. Patel,
  • Chad Hudson,
  • Michael R. Loken,
  • Christopher A. Slapak,
  • Deborah M. Lloyd,
  • Darren A. Stanizzi,
  • Melissa M. Lee-Sundlov,
  • Sanjana Thosar,
  • Guy Mundelboim,
  • Guangwu Guo,
  • Huanying Gary Ge,
  • Bin E. Li,
  • Juliana Xavier-Ferrucio,
  • Sharon L. Hyzy,
  • Michelle I. Lin,
  • Glen D. Raffel,
  • Brenda W. Cooper

摘要

Patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are likely to relapse despite allogenic hematopoietic cell transplantation (HCT). Post-HCT preventative maintenance can be limited by toxicity toward the normal donor cells. Tremtelectogene empogeditemcel (trem-cel) is a CRISPR–Cas9 gene-edited allogeneic HCT product lacking CD33, designed to shield the donor graft from cytotoxicity of subsequent CD33-targeted therapies such as gemtuzumab ozogamicin (GO). In this multicenter, phase 1/2a, open-label study, adult patients with AML/MDS with high relapse risk received trem-cel after myeloablative conditioning followed by GO maintenance (0.5–2.0 mg m−2 day 1 per 28-day cycles). Patients receiving trem-cel were assessed for the primary safety endpoint of neutrophil engraftment by day 28 and secondary endpoints including time to neutrophil engraftment, incidence of graft-versus-host disease and graft failure, transplant-related mortality, percentage of CD33-negative myeloid cells and survival. Patients receiving trem-cel and GO were assessed for the additional secondary endpoints of safety of maintenance GO with trem-cel and pharmacokinetics of GO after trem-cel transplant. 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% confidence interval: 9–10). Nineteen patients received GO maintenance in phase 1 dose escalation (n = 15) and in phase 2 dose expansion (n = 4). The trial was stopped early, and this is the final report on the trial including the completed phase 1 portion. GO treatment was safely tolerated up to the recommended phase 2 dose of 2 mg m−2, and no prolonged high-grade cytopenias were observed. The most common adverse events were cytopenias and infections. Three cases of transplant-related mortality were observed due to renal failure, sepsis and sinusoidal obstruction syndrome, respectively. In summary, trem-cel demonstrated safe, rapid, robust engraftment, and GO maintenance was administered without prolonged hematologic toxicity. ClinicalTrials.gov identifier: NCT04849910.