Clinical and molecular characteristics of patients with AML with an exceptional response to ivosidenib

7036 Background: Ivosidenib (IVO) twas approved based on a CR/CRh rate of 31.8% in IDH1 mutant (IDH1m) R/R AML; median duration of CR/CRh (DOR) was 8.2 months (mo). The purpose of this study is to elucidate the clinical and molecular characteristics of exceptional responders to single agent IVO. Methods: We analyzed all patients (pts) with IDH1m R/R AML who received IVO 500mg QD on the phase 1 dose escalation/expansion study and had a DOR of >12 mo. Results: Of 179 pts who received IVO 500 mg QD, 57 (31.8%) achieved a CR/CRh. Of these, 20 (35.1%) had a DOR >12 mo. After excluding 7 pts who went to HSCT, 13 (22.8% of responders, 7.3% of cohort) had DOR >12 mo (exceptional response) and 8 (14% of responders, 4.5% of cohort) had DOR >24 mo. The 13 exceptional responders all achieved CR as best response, and median DOR was 42.6 mo. Median OS was not reached; estimated OS at 48 mo was 67.1%. Median EFS was 44.4 mo. Reasons for discontinuing treatment included relapse (n=4), adverse event unrelated to IVO (n=3), and patient (pt) decision (n=3). Three pts remain on treatment. All pts who relapsed had DOR between 1-2 years; none of the 8 pts with DOR >2 years relapsed. Baseline characteristics are in the table. The most common co-mutations were DNMT3A, ASXL1, SRSF2, and JAK2 (3 each, 23%). Five pts (39%) had a splicing factor mutation. No pts had FLT3 or RTK pathway mutations other than JAK2. Only 1 pt with NPM1 had an exceptional response, and 1 pt had TP53 (VAF 3.6%). Six pts (46%) had an abnormal karyotype, 6 normal (46%), and 1 missing (8%). Most pts had intermediate-risk cytogenetics (10 pts, 77%), 2 poor-risk, and 1 missing. The median IDH1 VAF was 25% (range 10-50%). The median number of co-mutations was 1 (range 0-6). Having 0-1 co-mutations was associated with a longer response. Eleven pts (85%) had an IDH1 R132C mutation; 1 each (7.7%) had R132H and R132L mutations. Mutation clearance of IDH1 was noted in 8 pts (61.5%). Conclusions: A subset of pts with IDH1m R/R AML have prolonged CR on single agent IVO without HSCT (22.8% of CR/CRh responders) and no pts in CR for >2 years (14% of CR/CRh responders) relapsed. A low mutational burden, lack of RTK pathway mutations and canonical AML drivers, and co-occurrence of mutations associated with clonal hematopoiesis appear to be associated with exceptional response. Clinical trial information: NCT02074839 . [Table: see text]