Final Phase 1 Substudy Results of Ivosidenib for Patients With Mutant IDH1 Relapsed/Refractory Myelodysplastic Syndrome

Authors

Courtney D DiNardo
Gail J Roboz
Justin M Watts
Yazan F Madanat
Gabrielle T Prince
Praneeth Baratam
Stéphane de Botton
Anthony Stein
James M Foran
Martha L Arellano
David A Sallman
Mohammad Hossain
Dylan M Marchione
Xiaofei Bai
Prapti A Patel
Stephanie M Kapsalis
Guillermo Garcia-Manero
Amir T Fathi

Publication Date

8-13-2024

Journal

Blood Advances

Abstract

Ivosidenib is a first-in-class mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor with efficacy and tolerability in patients with advanced mIDH1 hematologic malignancies, leading to approval in frontline and relapsed/refractory (R/R) mIDH1 acute myeloid leukemia. We report final data from a phase 1 single-arm substudy of once-daily ivosidenib in patients with R/R mIDH1 myelodysplastic syndrome (MDS) after failure of standard-of-care therapies. Primary objectives were to determine safety, tolerability, and clinical activity. The primary efficacy end point was the complete remission (CR) + partial remission (PR) rate. Nineteen patients were enrolled; 18 were included in the efficacy analysis. Treatment-related adverse events occurred in 8 (42.1%) patients, including a grade 1 QT interval prolongation in 1 (5.3%) patient and grade 2 differentiation syndrome in 2 (10.5%) patients. Rates of CR + PR and objective response (CR + PR + marrow CR) were 38.9% (95% confidence interval [CI], 17.3-64.3) and 83.3% (95% CI, 58.6-96.4), respectively. Kaplan-Meier estimates showed a 68.6% probability of patients in CR achieving a remission duration of ≥5 years, and a median overall survival of 35.7 months. Of note, 71.4% and 75.0% baseline red blood cell (RBC)- and platelet-transfusion-dependent patients, respectively, became transfusion independent (TI; no transfusion for ≥56 days); 81.8% and 100% of baseline RBC and platelet TI patients, respectively, remained TI. One (5.3%) patient proceeded to a hematopoietic stem cell transplant. In conclusion, ivosidenib is clinically active, with durable remissions and a manageable safety profile observed in these patients. This trial was registered at www.ClinicalTrials.gov as #NCT02074839.

Keywords

Humans, Isocitrate Dehydrogenase, Pyridines, Myelodysplastic Syndromes, Female, Male, Middle Aged, Aged, Glycine, Mutation, Treatment Outcome, Adult, Recurrence, Antineoplastic Agents, Aged, 80 and over

DOI

10.1182/bloodadvances.2023012302

PMID

38640348

PMCID

PMC11372395

PubMedCentral® Posted Date

4-23-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes