Gene-Edited Transplant Strategy May Reduce Relapse Risk in High-Risk AML

In emerging data published in JAMA Network, it was discovered that a CRISPR–Cas9 gene-edited allogeneic hematopoietic cell transplantation (alloHCT) product, tremtelectogene empogeditemcel (trem-cel/VOR33, Vor Biopharma, Inc.), demonstrated rapid engraftment and enabled post-transplant maintenance treatment with gemtuzumab ozogamicin (GO; Mylotarg, Wyeth Pharmaceuticals, Inc.) without prolonged hematologic toxicity in patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).¹

The phase 1/2 clinical trial (NCT04849910) determined whether deletion of CD33 from donor-derived hematopoietic stem cells could protect healthy transplanted cells from the toxic effects of CD33-targeted therapy while still allowing GO to target residual leukemia.¹ The data suggests the strategy may provide a novel approach to reducing relapse risk after transplant in patients with otherwise limited treatment options.¹

How Trem-cel Uses CRISPR Editing to Overcome CD33 Toxicity

Relapse following alloHCT remains one of the leading causes of mortality in patients with high-risk AML, primarily amongst those with adverse cytogenetics, measurable residual disease (MRD), secondary AML, or prior relapse before transplant.² While maintenance approaches following transplant are being explored, many are limited by severe myelosuppression and toxicity to donor-derived healthy hematopoietic cells.^2,3

Mylotarg, an anti-CD33 antibody-drug conjugate approved for select patients with AML, has been notably difficult to use in the post-transplant maintenance setting because CD33 is expressed not only on AML blasts but also on normal myeloid progenitor cells, according to prior data.⁴ Prolonged cytopenias and increased infectious complications result from this “on-target, off-tumor” toxicity.⁴

Trem-cel was formulated in order to address this limitation through using CRISPR–Cas9 gene editing to delete CD33 from donor CD34+ hematopoietic stem and progenitor cells prior to transplantation.¹ Theoretically, the edited graft permits clinicians to administer GO after transplant while sparing healthy donor-derived myeloid cells from toxicity.¹ The data notes that CD33 appears nonessential for normal hematopoiesis, supporting its viability as a gene-editing target.^1,5

Trial Design and Patient Population

The trial is a multicenter, open-label phase 1/2a that enrolled adults with CD33-positive AML or MDS considered at high risk for relapse after alloHCT.¹ Trem-cel after myeloablative conditioning was administered in 30 patients.¹ Following successful transplant recovery, eligible patients received maintenance GO administered once every 28 days at escalating doses ranging from 0.5 mg/m² to 2 mg/m² for up to 8 cycles.¹

A majority of the patients enrolled in the trial had AML (n = 29), while 1 patient had MDS.¹ More than half of patients possessed multiple adverse-risk features, including measurable residual disease at transplant, secondary AML, or adverse cytogenetics based on European LeukemiaNet criteria.¹

Key Findings

All 30 of the patients had achieved neutrophil engraftment by day 28, which met the primary endpoint.¹ The median time to neutrophil engraftment was 10 days, while median platelet recovery occurred at 16 days.¹ The research monitored 1 case of secondary graft failure, which later recovered following infusion of an unedited backup graft.¹

19 of the patients ultimately received GO maintenance therapy, completing a total of 77 treatment cycles.¹ Notably, data reports no dose-limiting toxicities and established 2 mg/m² as the recommended phase 2 dose.¹ Through O dose cohorts, neutrophil and platelet counts were largely preserved without prolonged high-grade cytopenias, supporting the hypothesis that CD33 deletion protected donor-derived hematopoietic cells from GO-associated toxicity.¹

Furthermore, peripheral blood analysis displayed near-complete enrichment of CD33-negative myeloid cells following GO initiation.¹ However, the data had emphasized that relapse events that did occur remained CD33-positive by flow cytometry, suggesting persistent target expression on leukemic cells.¹

The most common grade 3 or higher adverse events consisted of anemia, thrombocytopenia, febrile neutropenia, stomatitis, hypokalemia, and neutropenia.¹ Three transplant-related deaths were a result of renal failure, sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD), and sepsis.¹ Acute grade 2 to 4 GvHD occurred in 20% of patients, while chronic GvHD occurred in 7%.¹

Although the trial was ultimately terminated early because of fiscal reasons and longer follow-up is still needed, the researchers concluded that trem-cel demonstrated “safe, rapid, robust engraftment” and enabled GO maintenance without prolonged hematologic toxicity.¹ If validated in larger studies, this strategy could represent a meaningful advancement for patients with high-risk AML who face substantial relapse risk after transplant.

REFERENCES

1. DiPersio, J.F., Koehne, G., Shah, N.N. et al. CRISPR−Cas9 CD33-deleted allogeneic hematopoietic cell transplantation with gemtuzumab ozogamicin maintenance in AML: a phase 1/2 trial. Nat Med (2026). https://doi.org/10.1038/s41591-026-04362-1

2. Schlenk RF, Weber D, Fiedler W, et al. Midostaurin added to chemotherapy and continued single-agent maintenance therapy in acute myeloid leukemia with FLT3-ITD. Blood. 2019;133(8):840-851. doi:10.1182/blood-2018-08-869453

3. Oran B, de Lima M. Prevention and treatment of acute myeloid leukemia relapse after allogeneic stem cell transplantation. Curr Opin Hematol. 2011;18(6):388-394. doi:10.1097/MOH.0b013e32834b6158

4. Mylotarg prescribing information. Pfizer. Accessed May 14, 2026. https://www.pfizer.com/products/product-detail/mylotarg

5. Kim MY, Yu KR, Kenderian SS, et al. Genetic Inactivation of CD33 in Hematopoietic Stem Cells to Enable CAR T Cell Immunotherapy for Acute Myeloid Leukemia. Cell. 2018;173(6):1439-1453.e19. doi:10.1016/j.cell.2018.05.013