Removing the Target From Blood-Forming Cells First: CRISPR Transplant Trial Opens a New Path for Blood Cancer Treatment, but Also Raises Safety Concerns

One challenge in treating acute myeloid leukemia is that cancer cells and normal bone marrow cells share several surface markers: when drugs pursue tumors, they may also severely damage the healthy hematopoietic system. An early multicenter clinical trial sought to change this situation—first using CRISPR to remove CD33 from donor hematopoietic stem cells, then administering a CD33-targeted drug after transplantation so that, in theory, treatment could attack residual cancer cells more selectively.

The Phase I/II trial, named VBP101 and registered as NCT04849910, enrolled 30 adults with high-risk acute myeloid leukemia or myelodysplastic syndrome at 15 sites in the United States and Canada. Patients received gene-edited, CD33-deleted, HLA-matched donor CD34-positive cells. This cell product, called trem-cel, was intended not to directly modify patients’ cancer cells, but to establish a new hematopoietic system better able to withstand subsequent CD33-targeted treatment.

The clearest result came from the transplantation itself: all 30 participants achieved neutrophil engraftment by day 28, with a median time of 10 days, meeting the study’s primary safety endpoint. This shows that CRISPR-treated donor cells can still take hold, proliferate, and rebuild blood cell production in the human body—the first hurdle in determining whether this strategy can work.

After engraftment, 19 participants received the CD33-targeted antibody-drug conjugate gemtuzumab ozogamicin (brand name Mylotarg) as maintenance therapy. The study report stated that these patients did not develop persistent high-grade cytopenias, providing preliminary support for the possibility that deleting CD33 may protect newly formed hematopoietic cells. However, the trial was small, had no randomized control group, and only some participants entered the maintenance-treatment stage, so it was not sufficient to prove that this combination can prolong survival or reduce relapse.

The safety signals also cannot be obscured by the successful engraftment. Seven participants died during the study: four from disease progression and three in transplant-related deaths caused, respectively, by renal failure, sepsis, and hepatic sinusoidal obstruction syndrome. The trial was subsequently stopped early. These events were not necessarily caused directly by gene editing, but they prevented the study from fully answering its planned questions about dosage and clinical benefit, while also highlighting the substantial risks that patients with high-risk blood cancers already face when undergoing allogeneic transplantation.

At this stage, the study primarily provides proof of feasibility in humans: rather than modifying only the weapons used to attack cancer, healthy tissue can first be modified so that it avoids the same target. trem-cel is manufactured by Vor Biopharma, which also funded the trial, and some of the paper’s authors are company employees. Determining whether the technology can change the standard of care will require larger studies with comparison groups and longer follow-up to clarify relapse, survival, late adverse effects, and the long-term stability of gene-edited cells.