The combination of ivosidenib and CPX-351 has demonstrated promising efficacy and safety in treating patients with IDH1-mutated acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS), according to interim results from a phase 2 trial presented at the 2024 ASH Annual Meeting.
Early efficacy data showed remarkable results in newly diagnosed patients, with all four participants achieving an overall response rate (ORR) of 100% and reaching undetectable measurable residual disease (uMRD) levels. In the relapsed/refractory group, three out of seven patients (43%) responded to treatment, with all responders achieving uMRD.
Clinical Outcomes and Survival Data
The newly diagnosed patient group demonstrated impressive survival metrics, with a median duration of response of 16.3 months, median event-free survival of 17.5 months, and median overall survival of 29.3 months. The relapsed/refractory group showed median event-free survival of 4.2 months and overall survival of 12.0 months.
Notably, 89% of evaluated patients showed a decrease in IDH1 variant allele frequency, with 67% achieving undetectable levels at 2% sensitivity. Four responding patients proceeded to hematopoietic stem cell transplantation, with three maintaining remission and one experiencing relapse at 17.5 months post-transplant.
Treatment Protocol and Patient Characteristics
The study enrolled patients aged 18 and older with IDH1-mutated disease. The treatment regimen combined CPX-351 (daunorubicin 44 mg/m² and cytarabine 100 mg/m²) administered on specific days during 28-day cycles, with daily oral ivosidenib at 500 mg.
The newly diagnosed group had a median age of 56 years, while the relapsed/refractory group's median age was 63 years. The latter group had received a median of three prior therapies, including exposure to venetoclax and hypomethylating agents.
Safety and Tolerability Profile
The combination therapy demonstrated a manageable safety profile. In newly diagnosed patients, the most common treatment-related adverse effects included rash (50% any-grade, 25% grade ≥3) and ECG changes (25% any-grade). The relapsed/refractory group experienced similar adverse effects, with rash and thrombocytopenia each occurring in 29% of patients.
Two cases of grade 4 prolonged thrombocytopenia were reported as dose-limiting toxicities, both resolving without requiring dose interruption. Importantly, no differentiation syndrome cases or treatment-related deaths were observed. The median count recovery after induction was 39 days.
Expert Perspective
"Interim results suggest the acceptable safety and promising efficacy of CPX-351 combined with ivosidenib in newly diagnosed or relapsed/refractory, IDH1-mutated AML," stated Dr. Jennifer Croden, lead study author and clinical fellow at The University of Texas MD Anderson Cancer Center.
This combination builds on ivosidenib's established role in AML treatment, following its FDA approval in combination with azacitidine for newly diagnosed AML in May 2022 and as monotherapy for relapsed/refractory MDS with IDH1 mutations in October 2023.
