Clinical Outcomes for Patients with Myeloid Malignancies Harboring IDH1/2mutations after Intensive Chemotherapy
Authors: Thota Swapna , Patel Bhumika J. , Carraway Hetty E. , Griffiths Elizabeth A. , Przespolewski Amanda , Thompson James E. , Kuzmanovic Teodora , Nazha Aziz , Barot Shimoli Vipul , Hirsch Cassandra M. , Przychodzen Bartlomiej P. , Mukherjee Sudipto , Scully Meghan , Gerds Aaron T. , Advani Anjali S. , Sekeres Mikkael A. , Meggendorfer Manja , Wang Eunice S. , Maciejewski Jaroslaw P. 
Published: October 2019

Abstract
Background: AML and MDS are heterogeneous myeloid neoplasias (MN) characterized by varied pathogenic mechanisms and associated with mixed clinical outcome. Five-year overall survival rates for younger AML patients (pts) are between 40-50% and for elderly pts, a dismal 10%. Until recently, molecular information has informed risk stratification for MN patients, but targeted therapies were limited (i.e ckit, flt3 inhibitors). Clinical characterization of IDH1/2mutant MN is of particular interest since the recent availability of specific IDH1/2inhibitors (i.e., enasidenib and ivosidenib). Datasets describing the outcome for patients with MN harboring IDH1/2mutations are critical to inform the potential utility of these novel IDH inhibitors as single agents or in combination with standard of care. Ongoing clinical trials are investigating the addition of IDH inhibition for upfront AML therapy. In this retrospective study, we combined cohorts from three institutions to enable reporting of the largest cohort (N=425) of IDH mutated MN pts in order to establish a baseline for therapeutic outcomes in an era which pre-dates the availability/addition of IDH inhibitors.
Methods:We identified 425 patients from three large academic centers with a confirmed diagnosis of IDH1/2mutant AML (n=387), MDS (n=29) or MPN (n=9). Blood and bone marrow samples were analyzed for the presence of recurrent somatic mutations using NGS based multi-gene targeted sequencing panels. Demographic and disease related variables were annotated for initial treatment, response to therapy (IWG criteria) and subsequent survival details (overall survival, progression free survival). Time to first relapse and duration of remission was collected for 107 patients to date. Comprehensive response assessment details were available for 234 patients.
Results: Of the 425 patients, 165 had a mutation inIDH1and 264 had a mutation in IDH2(82% IDH2R140, 18% R172K). Four cases had co-occurring mutations in IDH1 & IDH2. IDH1mutant cases were younger than IDH2mutant cases (62 vs. 65 years, p=0.05), predominantly male (50% vs.38%, p=0.01) and more likely to have intermediate risk AML (68% of IDH1/IDH2mutant cases had normal karyotype). A majority of these patients were treated with cytarabine-based intensive chemotherapy (n=362). Hypomethylating agents (n=29) or other less intensive therapies (n= 27) were also used. The overall response rate (ORR) to initial therapy was 65%. Response rates were similar for patients with both IDH1and IDH2mutation (i.e, 66% to any therapy). Response to intensive chemotherapy was 68% and 64% in IDH1and IDH2mutant cases respectively. As expected IDH1/2 mutant younger pts (<60 years) had a higher response rate to intensive chemotherapy (81% and 80 % respectively). The ORR for HMA therapy was 73% (64% IDH1, 80% IDH2mutants). 34% of IDH1mutants and 30%IDH2mutant patients underwent allogeneic stem cell transplantation. We have analyzed the impact of co-occurring somatic mutations on response to intensive chemotherapy. Non-responders to intensive therapy were enriched for RUNX1(26% vs.7%, p=0.002), SRSF2(34% vs.19%, p=0.045), and ASXL1 (18% vs.9%, p=0.11) mutations and were less likely to have NPM1 (24% vs. 51%, p=0.001) mutation. The median overall survival for IDH1 and IDH2 mutant MN caseswas 16.6 and 19.1 months, respectively.
Conclusions: IDH1/2 mutated young AML patients appear to have chemo-sensitive disease. Despite excellent initial responses to intensive and non-intensive chemotherapy, the overall survival for IDH mutated pts was poor with shorter than expected remissions. Co-occurring mutations in RUNX1 and SRSF2 appeared to confer therapeutic resistance. Ongoing combination and maintenance strategies with targeted IDH1/2 inhibitors in conjunction with traditional therapies offer the potential to improve upon these outcomes in IDH1/2mutant MN. Future studies exploring the impact of early transplantation on overall survival for IDH1/2mutated MN are needed

Disclosures
Thota: Incyte: Speakers Bureau. Carraway:Novartis: Speakers Bureau; Jazz: Speakers Bureau; Agios: Consultancy, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; FibroGen: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Balaxa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Griffiths:Pfizer, Inc.: Research Funding; Novartis, Inc.: Research Funding; Celgene, Inc: Honoraria, Research Funding; Astex/Otsuka Pharmaceuticals: Honoraria, Research Funding; Alexion Inc.: Honoraria, Research Funding. Nazha:MEI: Consultancy. Gerds:CTI Biopharma: Consultancy; Apexx Oncology: Consultancy; Celgene: Consultancy; Incyte: Consultancy. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Wang:Amgen: Consultancy; Jazz: Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Novartis: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Amgen: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Maciejewski:Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Apellis Pharmaceuticals: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharmaceuticals, Inc: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.