Outcomes of Patients with IDH1-Mutated Myeloid Neoplasms Treated with Olutasidenib
Authors: Chien Kelly S. , Sasaki Koji , McCue Deborah , Daver Naval , Kadia Tapan M. , Short Nicholas J. , Issa Ghayas C. , Montalban-Bravo Guillermo , Haddad Fadi G. , Hammond Danielle , Swaminathan Mahesh , Bazinet Alexandre , Ravandi Farhad , Garcia-Manero Guillermo , Pierce Sherry , Kantarjian Hagop M. , DiNardo Courtney D. 
Published: December 2024

Background: IDH1 mutations occur in 7-14% of patients with acute myeloid leukemia (AML) and are associated with shortened leukemia-free and overall survival and increased rates of transformation to AML in patients with myelodysplastic syndromes (MDS). Olutasidenib (previously FT-2102) is an oral, selective potent inhibitor of the IDH1 mutant protein with no significant off-target activity that received FDA approval as monotherapy in relapsed/refractory (RR) IDH1-mutated AML.
Methods: We retrospectively evaluated all patients with IDH1-mutated myeloid neoplasms who were treated with olutasidenib monotherapy or in various therapeutic combinations at a tertiary cancer center. Clinical patient characteristics and bone marrow (BM) data, including morphology, cytogenetics, and mutations, were assessed at diagnosis and the time of olutasidenib initiation. Overall survival was analyzed using the Kaplan-Meier method, and survival data was updated in July 2024.
Results: A total of 19 AML patients and 5 MDS patients received olutasidenib, including 2 previously-untreated patients in both the AML and MDS groups. The 17 RR AML patients received a median of 3 (range: 1-9) prior therapies; 8 had received prior ivosidenib and 10 venetoclax, with 7 patients having received both. Most of the patients were treated on clinical trials with olutasidenib +/- azacitidine, but 8 of the RR AML received standard-of-care olutasidenib. Median age at diagnosis was 75 (range: 40-85) with 15 (62%) male patients. Patients were generally high risk, with 15 (79%) and 16 (84%) patients having adverse-risk AML by European Leukemia Network (ELN) 2017 and 2022 guidelines, respectively, and all MDS patients had higher-risk disease with Revised International Prognostic Scoring System (IPSS-R) scores &gt;3.5 and Molecular International Prognostic Scoring System (IPSS-M) risk categories of moderate high, high, or very high. Of the 19 AML patients, 9 (47%) had secondary AML and 1 (5%) had extramedullary leukemia involvement of their central nervous system. Olutasidenib was administered as monotherapy in 8 patients (6 RR AML and 2 RR MDS) and in combination with various agents, including hypomethylating agents in 13 (all 4 frontline AML/MDS, 8 RR AML, 1 RR MDS), chemotherapy in 2 (both RR AML), and lenalidomide in 1 RR AML patient with concomitant del(5q).
In the AML cohort, both (100%) frontline patients responded (1 complete remission [CR], 1 CR with incomplete count recovery [CRi]). Of the 17 RR AML patients, 6 (35%) responded with 1 CR, 4 CRi, and 1 partial remission (PR). Both the frontline and RR AML patient who achieved CR remain in durable long-term remissions and remain on olutasidenib for 5-7 years at approximately cycle 61 and 86. Two AML patients underwent allogeneic stem cell transplantation after receiving olutasidenib: the frontline AML patient remains in remission, and the RR patient relapsed and attained CR2 on venetoclax + ivosidenib. In the MDS cohort, both (100%) frontline patients achieved CR, and 1 (33%) RR MDS patient responded with marrow CR (mCR). The median duration of response was for frontline AML, 4.1 months for RR AML, 13.8 months for frontline MDS, and 6.1 months for RR MDS.
With a median follow-up time of 67.2 months, the median overall survival from the time of olutasidenib initiation was not reached (95% confidence interval [CI]: not estimable [NE], NE) in frontline AML, 3.3 months (95% CI: 2.1, NE) in RR AML, 26.8 months (95% CI: 26.7, NE) in frontline MDS, and 14.0 months (95% CI: 0.9, NE) in RR MDS. When analyzing particular subgroups in the RR AML cohort, no significant differences in overall survival were observed by secondary AML status (3.32 vs 3.43 months, p=0.877), prior ivosidenib administration (2.69 vs 4.17 months, p=0.146), or previous venetoclax exposure (2.69 vs 4.17 months, p=0.492). One (50%) frontline and 2 (67%) RR MDS patients eventually progressed to AML with a median time to transformation of 17.3 months (95% CI: 7.6, NE).
Conclusions: In this group of high-risk patients with IDH1-mutated AML or MDS treated with olutasidenib-based therapy, response rates were 100% in frontline patients and 33-35% in heavily-pretreated RR patients. Durable long-term remissions were achieved in those who achieved CR or underwent allogeneic stem cell transplantation. Further investigation into olutasidenib-based treatment as first-line therapy in IDH1-mutated AML or MDS is warranted.