IDH1/2|General AML|NPM1|FLT3

Therapeutic Mutations in AML – IDH mutations

At present there has been more and more interest in studying gene mutations and gene expression to further classify Acute Myeloid Leukemia (AML). Furthermore, molecular abnormalities have been used as a prognostic tool and to aid treatment decisions for patients with AML. Attention has been focused on driver mutations in the Isocitrate Dehydrogenase 1 (IDH1). The prevalence of IDH mutations increases with age and IDH1 mutations have been associated with lower overall survival and disease free survival in CN-AML with NPM1 mutations and wildtype FLT3. Medinger et al. published a review on prognostic and therapeutic mutations in AML. Their report was published in Cancer Genomics and Proteomics in 2016.

The therapeutic potential with respect to IDH mutations are as follows:
  • IDH1 and IDH2 mutant inhibitors are currently in phase I clinical trials (NCT02381886, NCT01915498, and NCT02074839).
  • AG-120 was a first in class potent inhibitor of IDH1 and in a phase 1 study this novel agent demonstrated an overall response rate of 35%, with a composite complete remission (CR) rate of 33%.
  • A phase I study exploring the safety of combining AG-120 and AG-221 with both induction and consolidation chemotherapy and with 5-azacitidine (NCT02632708 and NCT0267792) has commenced.1
  • Interim results of a phase I/II study of the safety and efficacy IDH2 inhibitor AG-221 in patients with relapsed/refractory (RR)-AML, were presented at the 2015 ASH Annual Meeting. The results were:
  • Objective responses were observed in 74 patients (41%), including 52 RR-AML patients (41%). 
  • There were consistent response rates observed in RR-AML patients, irrespective of number of prior treatment regimens or mIDH2 type (R140Q 36%, R172K 39%), see Fig 1.2

In conclusion, the targeting of IDH mutations may provide therapeutic benefit for RR-AML with fewer side effects. In addition, the use of IDH1 inhibitors may improve current strategies for eliminating minimal residual disease after cytotoxic therapy.

Abstract

Acute myeloid leukemia (AML) is a biologically complex and molecularly and clinically heterogeneous disease, and its incidence increases with age. Cytogenetics and mutation testing remain important prognostic tools for treatment after induction therapy. The post-induction treatment is dependent on risk stratification. Despite rapid advances in determination of gene mutations involved in the pathophysiology and biology of AML, and the rapid development of new drugs, treatment improvements changed slowly over the past 30 years, with the majority of patients eventually experiencing relapse and dying of their disease. Allogeneic hematopoietic stem cell transplantation remains the best chance of cure for patients with intermediate- or high-risk disease. This review gives an overview about advances in prognostic markers and novel treatment options for AML, focusing on new prognostic and probably therapeutic mutations, and novel drug therapies such as tyrosine kinase inhibitors.

References
  1. Medinger M.et al. Novel Prognostic and Therapeutic Mutations in Acute Myeloid Leukemia. Cancer Genomics & Proteomics. 2016 September 10; 13(5):317-29.
  2. Stein E. M. et al. Safety and Efficacy of AG-221, a Potent Inhibitor of Mutant IDH2 That Promotes Differentiation of Myeloid Cells in Patients with Advanced Hematologic Malignancies: Results of a Phase 1/2 Trial. Blood. 2015; 126: 323.