Therapeutic Approach for IDH2-Mutated AML - Episode 6

Clinical Implication of AML Treatment

July 23, 2018

Courtney D. DiNardo, MD, MSCE:The mechanism of action is a bit interesting. It’s not standard cytotoxic therapy that we’re used to seeing. So, in our patients who we’re treating with an IDH2 inhibitor, when you do that day 14 marrow, you don’t see any sort of bone marrow aplasia or ablation. You see an actual differentiation process in many patients where you have that atypical myeloid blast population that is maturing into its normal counterpart. In many cases, let’s say your patient had a cytogenetic abnormality like a trisomy 8, that clone is present in the mature neutrophils, and so you haven’t lost the leukemia clone. It has just evolved into its normal granular site counterparts. So, that is an important distinction and why we see differentiation syndrome, because these patients are having, in some cases, a dramatic and robust maturation of their myeloid lineage. And so, that is something that we see.

In terms of the difference between IDH1 and IDH2, they are 2 different enzymes that are part of the same metabolic pathways. And so, they are mutually exclusive for the most part. So, a patient will have either an IDH1 or an IDH2. It’s quite rare for a patient at diagnosis to have both. And overall, about 20% of patients will have anIDHmutation.

My experience with enasidenib has been very positive. I have treated many patients with enasidenib, and in general, I find it to be a very well tolerated therapy. Patients have minimal side effects or trouble tolerating it. And a lot of my patients have responded incredibly favorably, and a lot of them have gone on to have nice responses. Some have been able to transition to a stem cell transplant that wasn’t an option for them before. Unfortunately, it’s not perfect. I have some patients who respond and then relapse or some patients who don’t respond. And so, certainly combination strategies—as we talked about earlier—adding the IDH2 inhibitor to combination therapy upfront, I think it’s hopefully going to lead to even more favorable and improved responses.

But I think these therapies are a fantastic new addition to the arsenal of treating leukemia patients and really speaks to the future of individualized therapy. You know, personalizing your therapy for your patients, especially in this case with a therapy that is so well tolerated and not that traditional cytotoxic therapy.

I think the future of AML has changed quite a bit. So, I have been practicing for about 5 to 10 years now, and therapy has changed. It’s not the same one-size-fits-all approach for each and every leukemia patient who walks in my door. I think that the IDH inhibitors are a fantastic example of the addition of targeted therapy for our patients. And I hope that more and more in the future there will be additional small molecule inhibitors for different patients based on their genomic profile, such that we’re able to treat patients with well tolerated, often oral outpatient, therapy, which is as effective, hopefully even more so, as that standard cytotoxic therapy.

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