Ivosidenib Shows Promise As Maintenance Therapy for AML After Bone Marrow Transplant
Key findings
- In this phase 1, multicenter, dose-finding study 16 patients with IDH1-mutated acute myeloid leukemia used ivosidenib as maintenance therapy beginning 37 to 109 days after hematopoietic stem cell transplantation
- Ivosidenib was well tolerated at 500 mg/day, which was deemed the recommended phase 2 dose
- The grade 3 adverse events were two cases of prolonged QTc interval and one case of paresthesia; there were no grade 4 events
- Eight patients completed all 12 protocol-assigned cycles, and only one patient stopped treatment due to adverse events judged to be at least possibly treatment-related
- Transient interruptions were required for a minority of patients (19%), who were able to resume and tolerate ivosidenib at a dose of 250 mg/day
For most patients the curative approach to acute myeloid leukemia (AML) is allogeneic hematopoietic cell transplantation (HCT), but subsequent relapse is common. For patients with FLT3-mutated AML, post-HCT maintenance therapy has been associated with improved survival.
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In Blood Advances researchers at Mass General Cancer Center previously reported on a phase 1 trial that showed the safety and potential efficacy of enasidenib as post-HCT maintenance therapy for patients with IDH2-mutated AML.
Now, the group has conducted the first trial of ivosidenib, an IDH1 inhibitor, as AML maintenance therapy after HCT. In Clinical Cancer Research they say the drug was well tolerated and showed promising activity in this setting.
The authors are Amir T. Fathi, MD, program director of the Center for Leukemia, Yi-Bin Chen, MD, director, Hematopoietic Cell Transplant & Cell Therapy Program, Zachariah DeFilipp, MD, director of clinical research in the Bone Marrow Transplant Program, Areej El-Jawahri, MD, an oncologist in the Division of Hematology and Oncology, and colleagues.
Methods
In this multi-center study,16 adults with IDH1-mutated AML started ivosidenib a median of 66 days (range, 37–109) after HCT. The median age was 62 (range, 28–76). 13 patients had newly diagnosed disease and three had AML with myelodysplasia-related changes.
Dose-Finding
Six patients were started on the first dose level specified in the protocol, 500 mg/day. The only dose-limiting toxicity was a case of grade 3 prolonged QTc interval. Dose de-escalation was therefore considered unnecessary, and per the protocol 10 more patients were enrolled to receive ivosidenib 500 mg/day, now deemed the recommended phase 2 dose.
Adverse Events
The grade 3 events were:
- Two cases of prolonged QTc interval, which did not lead to episodes of tachyarrhythmia, resolved when the drug was held and did not recur when patients were switched to ivosidenib 250 mg/day
- One case of paresthesia
Altogether, three patients required dose reduction to 250 mg and continued treatment. Three patients required transient dose interruptions on six separate occasions because of QTc prolongation (n=2 instances), skin graft-versus-host disease (n=1), pruritis (n=1), neuropathy (n=1) or azotemia (n=1).
Treatment Persistence
Eight patients received all 12 planned cycles of maintenance. Three discontinued treatment due to disease relapse, three to pursue therapies for chronic GVHD, one due to pruritis and one due to patient preference.
Outcomes
The study was not powered to evaluate efficacy, but the cumulative incidence of relapse was low (19%), no nonrelapse mortality was noted and estimated two-year survival was highly promising (overall survival, 88%; progression-free survival, 81%).
Although numbers are small and assessment of clinical activity requires larger studies, outcomes in this phase 1 study were encouraging and compared favorably to historical data.
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