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)
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Le résumé fourni par la source
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.
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DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- 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)
- Date Crossref
- 01/02/2025
- Éditeur
- Elsevier BV
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
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Washington University in St. Louis pays non établi dans la noticeUniversité ou école supérieure
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Washington University in St. Louis, Baptist Hospital of Miami et Baptist Health South Florida, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.