Tremtelectogene empogeditemcel (trem-cel, formerly VOR33), evaluated in the VBP101 trial (NCT04849910), is a gene-edited hematopoietic stem and progenitor cell therapy designed to improve post-transplant outcomes in patients with CD33-positive AML or high-risk myelodysplastic syndromes. VBP101 is a Phase I/II study testing trem-cel in combination with post-HCT maintenance therapy using MYLOTARG. Trem-cel is created by CRISPR/Cas9-mediated deletion of CD33 in donor-derived CD34+ cells, allowing selective targeting of residual leukemia by MYLOTARG while sparing the donor graft from off-target toxicity. Eligible patients underwent myeloablative conditioning followed by trem-cel transplant from 8/8 HLA-matched donors, with MYLOTARG in maintenance initiated ~60 days later at escalating doses (0.5, 1, or 2 mg/m² every 28 days for 4–8 cycles). The trial also provides access to donor-derived CD33 CAR-T therapy (VBP301) for relapsed patients.

Among 25 treated patients, trem-cel demonstrated high CD33 editing efficiency (median 90%) and consistent engraftment, with median neutrophil and platelet recovery achieved by days 9.5 and 16, respectively. All evaluable patients showed full donor myeloid chimerism by Day 28, and over 93% of myeloid cells lacked CD33 expression. MYLOTARG pharmacokinetics were dose-proportional, and the 2 mg/m² dose in trem-cel patients reached exposure levels similar to 4–9 mg/m² in R/R AML, suggesting effective therapeutic exposure with reduced hepatotoxicity risk. Safety results were favorable, with no Grade 4 neutropenia and only one case of Grade 4 thrombocytopenia across 64 MYLOTARG cycles. Post-MYLOTARG treatment, the proportion of CD33-negative myeloid cells increased to 98.3%, indicating selective enrichment and persistence of edited cells. 

With a median follow-up of 7.4 months, four patients relapsed (two prior to MYLOTARG), and median relapse-free survival has not yet been reached. These findings support trem-cel with MYLOTARG maintenance as a novel, well-tolerated strategy to reduce relapse post-HCT in high-risk AML.

KOL insights

“The unmet medical need for AML is significant and hematopoietic cell transplant (HCT) is the best hope for these patients. Early treatment data in the first patient show that trem-cel can engraft normally and maintain normal hematopoiesis following MYLOTARG dosing, which typically causes severe cytopenias. These data support the promise of this approach.” – Expert Opinion

“These early engraftment data represent the first time genome engineering has been used to genetically alter donor cells by removing an antigen present on blood cells, thereby allowing treatment using a CD33 targeted therapy while protecting normal blood cells. These encouraging data represent the first clinical validation of our platform to potentially enable next-generation transplants for patients with blood cancers.” – Expert Opinion

Conclusion

Adding MYLOTARG (gemtuzumab ozogamicin) to standard chemotherapy for newly diagnosed pediatric acute myeloid leukemia may improve event-free survival (EFS) and reduce relapse risk, but does not appear to enhance overall survival. Biomarkers such as CD33 expression, related single nucleotide polymorphisms (SNPs), PgP-1, and Annexin A5 may help identify which pediatric patients are most likely to benefit from gemtuzumab ozogamicin. Future research should aim to reduce toxicity from gemtuzumab ozogamicin, which may ultimately lead to improved OS outcomes.

Preliminary data from the VBP101 trial indicate that trem-cel enables rapid engraftment and durable hematopoietic recovery, while maintaining long-term myeloid CD33-negativity. This selective CD33 deletion appears to mitigate prolonged cytopenias commonly associated with gemtuzumab ozogamicin therapy. Notably, gemtuzumab ozogamicin exposure levels were higher than typically observed in R/R AML patients, likely due to reduced CD33-mediated drug clearance, suggesting an expanded therapeutic window. These findings collectively support the feasibility of sustained post-transplant gemtuzumab ozogamicin maintenance following trem-cel HCT, with potential to lower relapse risk without compromising hematologic safety.