A CD33-Deleted Allograft (Trem-cel) Enables Post-Hematopoietic Cell Transplant (HCT) Maintenance Dosing of Gemtuzumab Ozogamicin (GO) with Therapeutic Levels of Drug Exposure and Low Hematologic and Hepatic Toxicity in Patients with High-Risk Acute Myeloid Leukemia (AML)

Background Maintenance therapy post-HCT is a strategy to reduce AML relapse , however use of GO (Mylotarg TM ), an anti-CD33 antibody-drug conjugate, for this purpose is limited by hepato- and hematologic toxicity. Tremtelectogene empogeditemcel (trem-cel, formerly VOR33) is a hematopoietic stem and progenitor cell product produced by CRISPR/Cas9 gene-editing to delete CD33 from CD34+ cells allowing CD33-directed targeting of leukemia while sparing the donor graft. Methods VBP101 (NCT04849910) is a Phase 1/2 trial testing safety of trem-cel followed by GO maintenance for patients with CD33+ AML or MDS with high-risk features for relapse post-HCT. Patients must have an 8/8 HLA-matched donor. Donor CD34+ cells are isolated from G-CSF/plerixafor-mobilized peripheral blood. After ∼60 days post-myeloablative HCT with trem-cel, patients begin maintenance therapy with GO in a 3+3 dose escalation with 0.5, 1 and 2 mg/m 2 doses given every 28 days for 4-8 cycles. Results 18 patients received trem-cel with a median dose of 8.71 × 10 6 CD34+ cells/kg (2.62-12.44) and CD33 editing efficiency median 89% (71-94%). All patients achieved primary neutrophil engraftment , with a median of 9 days (8-12d). Platelet recovery occurred at a median of 16 days (13-22d) (Fig 1). D28 assessment showed full donor myeloid chimerism in all evaluable patients and a mean of 93.1% (73-99%) of myeloid cells lacked CD33 expression by flow cytometry. Pharmacokinetic analysis demonstrated dose proportional AUC exposures in trem-cel patients in all cohorts, with the 2 mg/m 2 doses of GO similar to 9 mg/m 2 therapeutic doses in relapsed/refractory (R/R) AML patients. C max , after 2 mg/m 2 doses in trem-cel patients, was comparable to R/R AML patients receiving 4-5 mg/m 2 doses, suggesting a reduced risk of hepatotoxicity .(Fig 2) No Gr 4 neutropenia was observed and only a single episode of Gr 4 thrombocytopenia was reported in 40 GO cycles administered (Fig 3). No elevation of transaminases beyond transient Gr 1 was observed during GO cycles. CD33 negative myeloid cells increased from a mean 93.2% (76-99%) to 98.2% (95-99.9%) after the first GO cycle suggesting enrichment for CD33-edited cells which was increased and sustained through subsequent cycles. With a median follow-up of ∼6 months, 4 patients relapsed (2 prior to GO dosing) and the median RFS has not been reached. Enrollment is ongoing at the 2 mg/m 2 dose. Conclusions Preliminary results from VBP101 show trem-cel rapidly engrafts, sustains hematopoiesis with persistent myeloid absence of CD33 and protects from prolonged deep GO-associated cytopenias . GO exposures correlate with higher doses seen in R/R AML patients, likely due to reduction CD33-mediated clearance and supports an increased therapeutic window . These data support safe and effective administration of GO after trem-cel HCT, enabling repeated maintenance dosing intended to reduce risk of relapse.