Ivosidenib in Patients with Mutant Isocitrate Dehydrogenase 1 (mIDH1) Relapsed/Refractory Myelodysplastic Syndromes: Update of the Phase 1 Substudy per the International Working Group 2023 Response Criteria
Authors: Madanat Yazan F , Fathi Amir T. , Garcia-Manero Guillermo , Roboz Gail J. , Watts Justin M. , Prince Gabrielle T. , Baratam Praneeth , De Botton Stephane , Stein Anthony S. , Foran James M. , Arellano Martha L. , Sallman David , Zhang Yuanye (Vickie) , Kapsalis Stephanie M. , Patel Prapti A. , DiNardo Courtney D. 
Published: December 2024

Introduction
Patients (pts) with relapsed/refractory (R/R) myelodysplastic syndromes (MDS) have a poor prognosis and, until recently, lacked therapeutic options. Ivosidenib (IVO) is an oral, targeted, small-molecule inhibitor of mIDH1. In October 2023, IVO was granted FDA approval for the treatment of adult pts with mIDH1 R/R MDS on the basis of results from the pivotal AG120-C-001 MDS substudy (NCT02074839); IVO showed an acceptable safety profile and induced durable remissions, with a high rate (38.9%) of complete remissions (CR) per International Working Group (IWG) 2006 criteria (DiNardo et al. Blood Adv 2024; bloodadvances.2023012302.).
Response criteria evolve to better reflect clinical benefit in specific pt populations and reduce interobserver variability. The updated IWG 2023 criteria for higher-risk MDS lowered the hemoglobin threshold for CR, added response categories for pts with &lt;5% blasts or limited count recovery, and eliminated the marrow CR (mCR) category. Herein we analyze responses, transfusion independence (TI), and survival outcomes of pts treated with IVO according to IWG 2023 criteria. In addition, responses assessed per IWG 2023 and IWG 2006 criteria are compared.
Methods
Pts with mIDH1 R/R MDS who had received prior SOC therapy were eligible. Oral IVO 500 mg was administered daily on days 1-28 of 28-day cycles. Responses were assessed per IWG 2023 criteria, and a composite CR (CRc) category was included in the analysis, which comprises all CR categories: CR + CR equivalent (CRe) + CR with limited count recovery (CRL) + CR with partial hematologic recovery (CRh). Overall response rate (ORR) was defined as CR + mCR + partial remission (PR) per IWG 2006 criteria, and as CRc + PR + hematologic improvement (HI) per IWG 2023 criteria. For TI analysis, non-CRc was defined as HI + PR + no response (NR)/not evaluable + progressive disease. TI was defined as requiring no transfusion for ≥56 days.
Results
In total, 19 pts were enrolled (median age: 73 yr; prior hypomethylating therapy: 78.9%) and data from 18 efficacy-evaluable pts were analyzed. CR + PR rate (primary endpoint) per IWG 2006 was 38.9%, with all 7 (38.9%) responders having CR. CRc + PR rate per IWG 2023 was 66.7% (n=12), with all responders having CRc, including 5 (27.8%) pts with CR, 3 (16.7%) with CRe, and 4 (22.2%) with CRL (CR unilineage [CRLuni], n=2 [11.1%]; CR bilineage [CRLbi], n=2 [11.1%]); no pt had CRh or PR. ORR was 83.3% per IWG 2006, with 7 (38.9%) pts having CR and 8 (44.4%) mCR; 4 (22.2%) pts with mCR had HI. Per IWG 2023 criteria, the ORR was 72.2%, with 12 (66.7%) pts having CRc and 1 (5.6%) HI with neutrophil response. The 8 mCR per IWG 2006 criteria were reclassified as 1 CR, 4 CRL (2 CRLuni and 2 CRLbi), 1 HI, and 2 NR per IWG 2023. Median time to CRc was 1.58 mo. Median duration of CRc was not reached and Kaplan-Meier (KM) estimates at 3, 6, and 12 mo were 90.9%, 81.8%, and 68.2%, respectively.
Five (CRc group n=4; non-CRc group n=1) of 7 (71.4%) and 3 (CRc, n=1; non-CRc, n=2) of 4 pts requiring red blood cell (RBC) and platelet transfusion at baseline, respectively, had TI. Median time to any (RBC/platelet) TI was 2.64 and 2.43 mo for pts with CRc and non-CRc, respectively. Moreover, 10 of 12 (83.3%) pts with CRc and 3 of 6 (50%) with non-CRc had or maintained TI during the study. Median duration of TI was not reached and KM estimates at 3 and 6 mo were 90.0% and 65.6%, respectively, for pts with CRc and 100% and 66.7% for non-CRc. Median event-free survival (EFS) was not reached for pts with CRc (n=12) or NR (n=5), and KM estimates at 1 yr were 68.2% and 53.3%, respectively. Median overall survival (OS) was not reached for pts with CRc and was 16.5 mo for pts with NR. For pts with CRc, OS KM estimates at 1, 3, and 5 yr were 90.9%, 51.1%, and 51.1%, respectively. For pts with NR, OS KM estimates were 75% at 1 yr and not estimable at 3 and 5 yr. For the pt with HI, the EFS estimate at 1 yr was 100% and OS estimates were 100% at 1, 3, and 5 yr.
Conclusions
IVO resulted in a high ORR (72.2%) according to IWG 2023 criteria, including a 66.7% CRc rate, despite the removal of the mCR category. Of 8 mCR per IWG 2006 criteria, 5 (62.5%) were reclassified as CRc per IWG 2023 criteria. By eliminating mCR and assessing response in a high-risk population with &lt;5% blasts, IWG 2023 criteria accurately capture the clinical benefit of IVO in R/R MDS. While comparison of survival outcomes between IWG 2006 and IWG 2023 is limited by the small sample size, a similar trend with response-dependent EFS and OS outcomes was observed.