Analysis of hematologic improvement (HI) by time to response in Relapsed/Refractory Acute Myeloid Leukemia (AML) patients treated with olutasidenib

Abstract Background: Olutasidenib is a potent, selective, oral inhibitor of mutated IDH1 (mIDH1) approved for the treatment of relapsed or refractory (R/R) mIDH1 AML. The phase 2 pivotal cohort (NCT02719574) demonstrated efficacy and tolerability of olutasidenib, with a complete remission (CR)/CR with partial hematologic recovery (CRh) rate of 35% and a median duration of CR/CRh of 25.3 months. This analysis evaluated baseline characteristics and changes in platelet count, hemoglobin levels, and blast percentages by time to response (TTR) among patients in the pivotal cohort. Methods: Adult patients with R/R mIDH1 AML were treated with olutasidenib 150 mg BID. Patients were stratified by best overall response and TTR: <2 months, 2 to 4 months, and >4 months. Hematologic characteristics, including platelet counts, hemoglobin levels, and blast burden were evaluated over the course of olutasidenib treatment. Results Among 147 efficacy-evaluable patients, the median age was 71.0 years (range 32.0, 87.0) and 50% were female. Mean baseline hemoglobin levels, platelet counts, and blast percentages were 9.7 g/dL, 87.2×109/L, and 45.2%, respectively. In the overall cohort (N=147), increases in hemoglobin were seen early in the course of treatment and levels continued to increase over 12 cycles; a mean of 11.0 g/dL was seen at cycle 6. Similarly, platelet counts increased and blast percentages decreased over the course of treatment, with a mean platelet count of 136.3×109/L and blast percentage of 14.2% at cycle 6. A total of 71 patients (48%) achieved overall response criteria; 47 patients (32%) achieved CR and 51 (35%) achieved CR/CRh. Among CR/CRh responders, 28 (55%) achieved a response in <2 months, 17 (33%) from 2 to 4 months, and 6 (11.7%) at >4 months. Patients with TTR >4 months had lower baseline platelet counts and hemoglobin levels and higher blast percentages compared with earlier responders. Mean hemoglobin level of 12 g/dL was achieved by cycle 4, 6, and 8 in <2, 2-4, and >4 month TTR groups, respectively. Mean blast count below 5% was achieved by cycle 2 in the <2 month TTR group, by cycle 4 in the 2-4 month TTR group, and by cycle 6 in the >4 month TTR group. Additionally, in 37 patients (25%) who had a best response of stable disease (SD), several showed improvement in platelets and hemoglobin levels by end of treatment, including 7 of 21 (33%) who were previously transfusion-dependent for platelets became independent and 7 of 23 (30%) who were previously transfusion-dependent for red blood cells became independent. Conclusions Later responders tended to have lower baseline platelet counts and higher bone marrow blast percentages, suggesting lower hematopoietic reserve and greater disease burden. Some patients with best overall response of SD experienced modest improvements in hematologic parameters, including platelets, hemoglobin, and transfusion independence. These findings suggest that continuing olutasidenib treatment beyond 2 cycles may offer hematologic benefits, even in the absence of an early clinical response.