Subscribe

Subscribe Today!

To sign up for our newsletter or print publications, please enter your contact information below.

I'd like to receive:

MBG453 in Combination with Hypomethylating Agents in Patients with High-Risk Myelodysplastic Syndrome or Acute Myeloid Leukemia

2020 Year in Review - AML - Leukemia

T-cell immunoglobulin and mucin domain-3 (TIM-3) is an immune checkpoint that is expressed on multiple cell types, including leukemic stem cells (LSCs) and blasts. However, it is not expressed on normal hematopoietic stem cells, which makes it a potential target for treating myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML). MBG453 (sabatolimab), a high-affinity, humanized, anti–TIM-3 IgG4, boosts immune cell–mediated killing of AML cells in vitro. It may also target TIM-3 on immune cells and LSCs. This multicenter, open-label, phase 1b, dose-escalation study was designed to evaluate MBG453 combined with the hypomethylating agents (HMAs) decitabine or azacitidine in patients with high-risk MDS or AML.

Patients were eligible if they were HMA-naïve and not candidates for intensive chemotherapy. Decitabine (20 mg/m2 intravenously on days 1-5) or azacitidine (75 mg/m2 subcutaneously or intravenously on days 1-7) were administered every 28 days. Patients also received escalating doses of MBG453 intravenously at 240 mg or 400 mg every 2 weeks (day 8, day 22) or 800 mg every 4 weeks (day 8). Safety and tolerability were primary objectives. Key secondary objectives were pharmacokinetics and preliminary efficacy.

Of the 69 patients to receive MBG453 + decitabine, 19 had high-risk MDS (per Revised International Prognostic Scoring System) and 50 had AML. Of the 29 patients who received MBG453 + azacitidine, 13 had high-risk MDS and 16 had AML. Half (50%) of the patients in the combined AML cohort (N = 63) had adverse cytogenetic risk per the European LeukemiaNet 2017 classification. Median age was 71 and 74 years for the MBG453 + decitabine and MBG453 + azacitidine arms, respectively. Maximum tolerated dose was not reached for either combination. In the MBG453 + decitabine arm, there was 1 dose-limiting toxicity (a corticosteroid-responsive grade 3 abnormal alanine aminotransferase elevation). Median exposure duration was 4.9 months (range, 0.7-26.7 months) with 15 patients ongoing for MBG453 + decitabine and 3.0 months (range, 0.1-9.2 months) with 19 patients ongoing for MBG453 + azacitidine.

The most common grade 3/4 treatment-emergent adverse events were thrombocytopenia (41%, 52%), febrile neutropenia (46%, 21%), neutropenia (42%, 38%), and anemia (25%, 28%) for MBG453 + decitabine and MBG453 + azacitidine, respectively. Potentially treatment-related grade ≥3 immune-related adverse events occurred in 4 patients (3 AML, 1 MDS) in the MBG453 + decitabine arm. There were no potentially treatment-related grade ≥3 immune-related adverse events in the MBG453 + azacitidine arm. No treatment-related grade 4 immune-related adverse events or deaths occurred. Most patients on either combination were able to complete 8 cycles of therapy.

In the MBG453 + decitabine arm, overall response rate (ORR) among evaluable patients was 58% (11/19), 41% (7/17), and 24% (6/25) for high-risk MDS, newly diagnosed AML, and relapsed/refractory AML, respectively. Among responders, median exposure was 8.6 months (range, 2.0-26.7 months). In the MBG453 + azacitidine arm (median exposure duration 3.0 months), ORR among evaluable patients was 70% (7/10) for high-risk MDS and 27% (3/11) for newly diagnosed AML. In both arms, responses were seen with all 3 MBG453 doses. Doses of MBG453 400 mg every 2 weeks and 800 mg every 4 weeks were predicted to have similar average steady-state pharmacokinetic concentrations and similarly high receptor (TIM-3) occupancy rates (>95% occupancy in 95% of patients).

This study indicates that MBG453 combined with decitabine or azacitidine was safe and well-tolerated by these patient populations. Both combinations showed encouraging response rates and emerging durability.

Reference

Borate U, Esteve J, Porkka K, et al. Anti-TIM-3 Antibody MBG453 in Combination with Hypomethylating Agents (HMAs) in Patients (Pts) with High-Risk Myelodysplastic Syndrome (HR-MDS) and Acute Myeloid Leukemia (AML): A Phase 1 Study. Presented at: 25th European Hematology Association Congress Virtual; June 11-21, 2020. Abstract S185.

Related Items
Tibsovo Received a New Indication, in Combination with Azacitidine, for Newly Diagnosed Patients with AML and IDH1 Mutation
JHOP - June 2022 Vol 12, No 3 published on June 16, 2022 in FDA Oncology Update, Leukemia
Vidaza Received New Indication for Patients with Newly Diagnosed Juvenile Myelomonocytic Leukemia
JHOP - June 2022 Vol 12, No 3 published on June 16, 2022 in FDA Oncology Update, Leukemia, Pediatric Cancer
Arsenic Trioxide–Induced QTc Interval Prolongation and the Potential Benefit of Beta-Blockers in Patients with Acute Promyelocytic Leukemia: Case Series
JHOP - April 2022 Vol 12, No 2 published on May 3, 2022 in Case Reports, Leukemia, Adverse Events
Effect of Concomitant Azole Antifungals on Duration of Myelosuppression in Newly Diagnosed Patients with AML Receiving Venetoclax in Combination with Cladribine and Low-Dose Cytarabine
JHOP - March 2022 Vol 12 Special Feature published on March 22, 2022 in HOPA Abstracts, Leukemia
Dasatinib-Induced Gynecomastia in 2 Patients with Chronic Myeloid Leukemia: Case Reports and Review of the Literature
Jessie Signorelli, PharmD, BCOP, Amir T. Fathi, MD, Gabriela Hobbs, MD
JHOP - February 2022 Vol 12, No 1 published on March 1, 2022 in Case Reports, Leukemia, Adverse Events
Lidocaine plus Tetracaine–Medicated Patch Used for Propofol Sedation During Lumbar Punctures in Pediatric Patients with Blood Cancer
Lisa R. Garavaglia, PharmD , Frank Casey, MD, Lesley Cottrell, PhD, Claudiu Faraon-Pogaceanu, MD, Stephan Paul, MD, Melvin Lee Wright, DO
JHOP - February 2022 Vol 12, No 1 published on March 1, 2022 in Original Article, Pediatric Cancer, Leukemia, Lymphoma
Myeloablative and Reduced-Intensity Preparative Regimens for Allogeneic Transplant in the Outpatient versus Inpatient Setting in Patients with Acute Myeloid Leukemia or Myelodysplastic Syndromes
Gretchen Pardo, PharmD, Beth Eddy, PharmD, BCOP, Zahra Mahmoudjafari, PharmD, BCOP, Dennis Grauer, PhD, MS, Joseph McGuirk, DO
JHOP - August 2021 Vol 11, No 4 published on August 17, 2021 in Original Article, Transplant, Leukemia, Myelodysplastic Syndromes, Conditioning Regimen
Pharmacy Resident–Led Medication Reconciliation and Patient Education Service in Adults with Leukemia Receiving Anticancer Oral Agents: A Pilot Study
Lily Y. Jia, PharmD, BCOP, Jessie Signorelli, PharmD, BCOP, Samantha O. Luk, PharmD, BCOP, E. Bridget Kim, PharmD, BCPS, BCOP, Gayle C. Blouin, PharmD, BCOP
JHOP - June 2021 Vol 11, No 3 published on June 16, 2021 in Original Article, Leukemia, Oncology Pharmacy Programs
Pegaspargase-Induced Diabetic Ketoacidosis in a Patient with Acute Lymphoblastic Leukemia
Ellen Madarang, PharmD, BCOP, Leslie Gallardo, PharmD, BCPS, Terrence Bradley, MD
JHOP - June 2021 Vol 11, No 3 published on June 16, 2021 in Case Reports, Acute Lymphoblastic Leukemia, Leukemia, Adverse Events
Oral Azacitidine Prolongs Survival in Patients with Acute Myeloid Leukemia
Robert J. Ignoffo, PharmD, FASHP, FCSHP, FHOPA
JHOP - April 2021 Vol 11, No 2 published on April 27, 2021 in From the Literature, Leukemia
Copyright © The Lynx Group, LLC. All rights reserved.