Improved Hematologic Recovery with Ivosidenib in Patients with mIDH1 Relapsed or Refractory MDS: Results from a Phase 1 Substudy
Authors: Prince Gabrielle T. , Baratam Praneeth , Garcia-Manero Guillermo , Angiolillo Anne , Bhagnani Tarun , Vestin Assaf , Fathi Amir T. 
Published: December 2024

Introduction:
Somatic mutations in the isocitrate dehydrogenase 1 (IDH1) gene have been reported in approximately 3% of patients with myelodysplastic syndromes (MDSs). IDH1 mutations (mIDH1) in MDS are commonly associated with high-risk disease and typically have a worse prognosis, including a higher risk of progression to acute myeloid leukemia, compared with patients with wild-type IDH1. Ivosidenib (IVO) is an oral, potent, mIDH1 targeted inhibitor approved for patients with mIDH1 refractory/relapsed (R/R) MDS based on a phase 1 study (NCT02074839) that reported improvement in several hematologic parameters in these patients. Here we report additional results from the phase 1 study in terms of blood count recovery for all patients, as well as hematologic improvement (HI) and transfusion status for patients, including for those who did not achieve complete remission (CR) with IVO.
Methods:
IVO was evaluated in a phase 1 substudy in patients with mIDH1 R/R MDS. Eligible patients with R/R mIDH1 MDS received oral IVO at a starting dose of 500 mg daily in 28-day cycles. Here we report additional outcomes from the study, including kinetics of blood count recovery; HIs for neutrophil (HI-N), erythroid (HI-E), and platelet (HI-P) lineages; and transfusion independence (TI) in terms of red blood cell (RBC) and platelet independence.
Results:
The phase 1 study included 18 patients with mIDH1 R/R MDS who were treated with IVO for a median duration of 9.3 months (range, 3.3-78.8 months). Seven patients (38.9%) achieved CR, and there were no partial remissions. Eight patients achieved marrow CR (mCR). Mean (standard deviation [SD]) absolute neutrophil count (ANC) for all patients at baseline was 0.8 × 109/L (1.13). At cycle 1, day 15, mean (SD) ANC was 3.7 × 109/L (6.23). Mean ANC levels were sustained above 2.0 × 109/L until cycle 82, with 1 exception at cycle 67 (1.8 × 109/L). Mean (SD) baseline hemoglobin (Hb) was 93.1 (15.06) g/L, which gradually rose to 101.8 (14.59) by cycle 1, day 22. Mean Hb levels remained consistently above 100 g/L from cycle 4, day 1 until end of treatment. Mean (SD) baseline platelet count was 136.6 × 109/L and rose to 145.8 × 109/L by cycle 1, day 15. Platelet levels fluctuated between 87.0 × 109/L and 163.5 × 109/L until end of treatment. The blood count dynamics were similar between the subgroups of patients who achieved CR and mCR. Among the 11 patients who did not achieve CR, 4 (36.4%) patients achieved HI-N within 0.9-1.9 months, 2 (18.2%) patients achieved HI-E within 3.7-13.9 months, and 2 (18.2%) patients achieved HI-P within 1.0-3.0 months. Durations of HI-N, HI-E, and HI-P ranged from 1.9-70.9, 1.9-58.0, and 2.8-70.9 months, respectively. Most patients with mCR (n=8) achieved platelet independence (n=7, 87.5%) or RBC independence (n=6, 75%), and 62.5% (n=5) achieved both. The 2 patients with stable disease achieved platelet TI, and 1 also achieved RBC TI. Among mCR patients, duration of TI of any lineage and RBC TI ranged from 1.9-72.5 months, and duration of platelet transfusion ranged from 3.3-72.5 months.
Conclusions:
The study findings confirm that IVO leads to rapid and sustained ANC recovery in patients with mIDH1 R/R MDS, regardless of the treatment response status. Furthermore, most patients who did not achieve CR also experienced a sustained HI and TI. Together with the previously reported outcomes from this study, these additional data demonstrate that IVO can lead to clinical benefit in the rare population of patients with mIDH1 R/R MDS.