Targeted Treatment for IDH2-Mutated AML - Episode 4

Enasidenib in Relapsed/Refractory Mutant IDH2 AML

August 8, 2018

Hetty E. Carraway, MD: FDA approval for enasidenib was based on the complete response and the partial complete responses, or CRh; not only the combination of CR/CRh, but also the durability or duration of response for patients to this therapy and also the transfusion independence that patients had after being on this therapy.

The clinical responses for patients that received this therapy, there were 199 patients who were evaluated. The CRs were 20% for patients who were on enasidenib 100 mg by mouth daily. For patients that had CRh, those percentages were a little bit lower, more around 8%, I believe. Again, those are meaningful responses to patients that would otherwise not really have complete opportunities to have complete remission. So, complete remission rate in a patient population that’s tough, like the population that was studied, is pretty challenging. For example, in the study that was prescribed, the median age of patients was 68 years old. The majority of patients had intermediate- or poor-risk cytogenetics, and the performance status from the majority of patients was at least an ECOG 1. Some patients had ECOG 0, but it was ECOG 0, 1, or 2.

This particular patient that we’re now talking about is 48 years old, so he’s much younger than the median age of the patients—although there were young patients that were studied in this enasidenib study. When we talk about responses to your earlier question, the overall response rate for patients was around 40%. About half of that was CR, and some of those numbers were CRh, and the PR was closer to 6%. For some patients, they also described this morphologic leukemia-free state, and that was also in the percentages of 8% to 9%. So, all told, the overall response rate for patients was about 40% when you combine all of those pieces together. Furthermore, there has been some interest in the notion of stable disease for patients, and that has been meaningful and tallied to about 40% to 50% for some patients. So, 48% to 53% of patients had some benefit with stabilization of their disease.

This can be a little confusing in terms of a patient having anIDH2-positive acute myeloid leukemia. They go on this therapy, and what we know is thatIDH2mutation causes an accumulation of 2-hydroxyglutarate in patients. In both the cell lines, and also mouse models, we were able to see that enasidenib can cause 2-hydroxyglutarate levels to decrease. For many patients in the study, the scientists were interested in determining whether those patients that are the responders are the ones that are getting complete elimination or eradication ofIDH2. That correlation, unfortunately, did not unfold in this particular study, where even though there was persistence ofIDH2mutation, patients could still actually have responses. We are still working hard to better understand and refine what that exactly means for all of our patients, whether it’sIDH2or any of these other mutations that we evaluate using next-generation sequencing. We’re really in this wonderful era right now where we’re digging deep and trying to really understand some of the pathogenesis of these genomic alterations.

Transcript edited for clarity.


A 48-Year-Old Male With Chemo-Refractory AML

  • A healthy 48-year-old man visited his PCP for flu-like symptoms lasting more than 2 weeks. He is married, with 3 school-age children and is an avid golf and tennis player.
  • PE: mild petechiae on lower extremities; otherwise unremarkable
  • Labs:
    • WBC, 65,000 (90% blasts)
    • Hb, 8.5 g/dL
    • Platelets 65,000/mL
    • ANC 2.5/mm3
    • LDH, 392 U/L
  • Bone marrow biopsy:
    • 50% blasts
    • Cytogenetics; +8
    • NGS;IDH2(R140Q) mutation
  • Liver and cardiac workup, WNL
  • The patient received 7+3 induction chemotherapy and subsequently reinduction without achieving a remission
  • The patient was then started on enasidenib
  • He achieved stable disease after 2 cycles of therapy
  • After 3 cycles, peripheral blasts, 15%; ANC, 1.1/mm3
    • 2 weeks later, patient reports dyspnea on exertion and mild swelling
    • PE notable for rales bilaterally
    • Chest X-ray shows bilateral diffuse pulmonary infiltrates
    • Additionally, indirect bilirubin, 1.9 mg/dl
    • Patient was started on dexamethasone 10 mg bid and antibiotics; pulmonary symptoms resolved in 1 week
  • Bone marrow biopsy after 6 cycles shows morphologic CR, 2% blasts by FC; NGS shows persistence of mutantIDH2
  • Patient referred for allogeneic transplant