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 posttransplant maintenance treatment with gemtuzumab ozogamicin (GO; Mylotarg, Wyeth Pharmaceuticals, Inc) without prolonged hematologic toxicity in patients with high-risk acute myeloid leukemia (AML) or 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 suggest 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 among those with adverse cytogenetics, measurable residual disease (MRD), secondary AML, or prior relapse before transplant.² Although 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 posttransplant 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 to address this limitation by 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 note 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), and 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 patients had achieved neutrophil engraftment by day 28, meeting the primary end point.¹ The median time to neutrophil engraftment was 10 days, whereas median platelet recovery occurred at 16 days.¹ The research monitored 1 case of secondary graft failure; the patient later recovered following infusion of an unedited backup graft.¹

Nineteen of the patients ultimately received GO maintenance therapy, completing a total of 77 treatment cycles.¹ Notably, there were no dose-limiting toxicities, and 2 mg/m² was established 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, and sepsis.¹ Acute grade 2 to 4 graft-vs-host disease (GVHD) occurred in 20% of patients, and chronic GVHD occurred in 7%.¹

Although the trial was ultimately terminated early due to fiscal constraints 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 JF, Koehne G, Shah NN, et al. CRISPR−Cas9 CD33-deleted allogeneic hematopoietic cell transplantation with gemtuzumab ozogamicin maintenance in AML: a phase 1/2 trial. Nat Med (2026). doi:10.1038/s41591-026-04362-1

2. Schlenk RF, Weber D, Fiedler W, et al; German-Austrian AML Study Group. 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