Therapeutic Approach for IDH2-Mutated AML - Episode 5

Rationale for Enasidenib in AML

Courtney D. DiNardo, MD, MSCE:So, enasidenib, now called IDHIFA, was FDA approved in August of 2017, and that was based on the phase I/II clinical trial that was performed. It was a multicenter, multi-institution study treating over 200 patients. A majority of them were relapsed or refractory patients with AML. And so, these patients had had a median of 2 prior lines of therapy and, in general, were kind of older and/or unfit patients who unfortunately had minimal to no other options left. And in general, these patients did quite well with this therapy. It was well tolerated and the main safety signal, or safety adverse event, was IDH differentiation syndrome. So, differentiation syndrome was seen in about 12% of patients. It is something that the leukemia world is used to seeing in patients who have acute promyelocytic leukemia, about 25% of them will develop a differentiation syndrome responsive to steroids, and such was the case with this. So, just important to be aware of because it was a relatively unexpected but notable side effect of IDH2 inhibitor therapy. That has been important and easily managed if one is aware of it and starting steroids as needed.

The other main side effect of enasidenib is an indirect hyper bilirubinemia. So, you’ll see an elevated bilirubin level. And it’s important to know or to be aware that about one-third of patients will have some elevation of the bilirubin. But it’s actually not intrinsic liver disease. So, once you fractionate the bilirubin, you can see that it’s indirect. It’s related to the metabolism of this drug, the UGT1A1 metabolism, as an off-target effect. And so, it is not liver toxic and the drug usually does not need to be stopped, and there’s no clinically significant changes or treatments that needs to be done.

In terms of response, an overall response rate was seen in over 40% of patients on the study. So, almost half of patients derived some sort of clinical response. Over 20% of them were patients who achieved a complete remission. And about 30% of patients had a complete remission, and/or a complete remission with incomplete count recovery. And in those patients achieving a complete remission, many of them had responses going on over 8 or 9 months, which is quite notable in this relapsed population. The median overall survival was seen of over 9 months, and in patients achieving a CR that was over 18 or 19 months, I believe. So, again, just going to show that patients who were benefiting from this drug really are, and we are able to have long-lasting responses in some patients.

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