Therapeutic Approach for IDH2-Mutated AML - Episode 3

AML: Significance of the IDH2 Mutation

Courtney D. DiNardo, MD, MSCE:There are 2 differentIDH2mutations. TheIDH140occurs in about 75% ofIDH2mutants, and there’s another one called theR172that’s present in the other 25%. They are a little bit different in terms of co-occurring mutations. TheIDH2 R140tends to co-occur most with splicing factor mutations,SRSF2, as well asDNMT3Amutations—RUNX1goes along with the patient’s story, who we discussed had theDMNT3and theRUNX1mutation. Both of theIDHmutations though are targeted by enasidenib, an IDH2 inhibitor. So, both of those are appropriate for treatment with an IDH2 inhibitor.

TheIDH2mutations occur overall in about 12% to 15% of patients with AML. So, it is not the majority but it certainly is a sizable percentage of AML patients. And the older a patient is, the more likely they are to have anIDH2mutation. So, especially in older patients who may not be candidates for intensive chemotherapy or who have relapsed disease after a therapeutic option, theIDHtesting is important because many of your patients may be eligible for IDH2 therapy.

The prognostic significance ofIDH2mutations in general is null. Meaning that there’s not a particularly favorable or unfavorable risk or prognosis associated with the presence of anIDH2mutation. There are a few nuances. There are patients withIDH2R172K mutations who are thought to be particularly favorable.IDH2mutations do co-occur withMPN1mutations, and when that happens, those patients are thought to be particularly favorable also. But in general, they tend to do kind of as well or as poorly as other patients with AML. The important thing aboutIDH2mutations is not the prognostic significance in and of itself, but the fact that there are now targeted therapies available for these patients, so that’s the importance of the knowledge ofIDHmutation.

Transcript edited for clarity.

Case: A 65-Year-Old Woman withIDH2-Mutated AML

November 2017

  • A 65-year-old female was diagnosed with AML, normal cytogenetics;IDH2R140,RUNX1,andDNMT3Amutations
  • 7+3 induction chemotherapy was initiated
  • Her treatment course was complicated by mucositis and febrile neutropenia
  • After resolution of her complications, she received 2 cycles of intermediate-dose cytarabine consolidation

May 2018

  • Now, 6 months after her initial diagnosis, she presents with fatigue, aches, and gum bleeding
  • Labs: leukocytosis, 20% circulating myeloblasts, ANC 450 cells/mL
  • Bone marrow biopsy: hypercellular 80% blast, normal cytogenetics
  • NGS: mutations inIDH2,RUNX1,andDNMT3A