Targeted Treatment for IDH2-Mutated AML - Episode 3

Treatment of Patients With Chemo-Refractory AML

August 8, 2018

Hetty E. Carraway, MD: This patient, given his age of 48, was treated pretty quickly. These are patients that we want to get in to the hospital and start chemotherapy as soon as we know and have the diagnosis. This patient was found to have an acute myeloid leukemia. Again, it was not a core-binding factor leukemia. It had trisomy 8, and the mutation panel was anIDH2-positive status. So, this patient underwent induction chemotherapy with 7 and 3, or 7 days of cytarabine and 3 days of daunorubicin. Unfortunately, he did not respond to this therapy and had primary refractory disease.

At this point, when a patient like this has not responded to induction chemotherapy, their prognosis is not good, as everybody is aware of. In this scenario, because he had theIDH2mutation being positive—options for patients we’ll talk about in the next number of questions—this patient went on to receive enasidenib 100 mg by mouth once a day. He tolerated that therapy very well, was able to resume therapy as an outpatient, was able to do better in terms of his physical activities once discharged from the hospital, and also had improved appetite. He was able to improve his performance status, just getting out of the hospital and recovering from the intensive chemotherapy.

We want to talk a little bit more about how he did on this enasidenib. After about 2 months on therapy, he eventually showed evidence of stable disease. He had improvement of his neutrophil count, up to 1000. In addition, he became transfusion-independent. After about another 3 months of therapy, this patient then went on to have even more response to this therapy and had a decrease in his blast count, as evidenced by a bone marrow biopsy. This bone marrow biopsy demonstrated that he had 15% blasts in the bone marrow and again stabilization of his disease.

Shortly thereafter, this patient went on to have symptoms of hypoxia and shortness of breath, and he was then evaluated with a chest X-ray that showed diffuse pulmonary infiltrates. He also manifested other symptoms, such as a fever, during that time. These symptoms are consistent with differentiation syndrome, and as a result of that, he was started on dexamethasone 10 mg twice a day by mouth, with resolution of his symptoms after about 1 week of time. He remained on enasidenib without difficulty. Notably though, he had an elevation in his total bilirubin at 1.9 mg/dL, and we’ll talk a little bit more about how that was managed.

Subsequently, at 6 months of therapy, he ended up having a repeat bone marrow biopsy and at that time, he was in complete remission with 2% blasts and had normalization of his neutrophil count, his hemoglobin, and his platelet count. At that time, reevaluation of the status of hisIDH2was also performed by next-generation sequencing, and it was found that the presence ofIDH2was still there.

Touching base about his total bilirubin, now that we’ve talked a little about his resolution and complete remission, this was managed just by monitoring. The bilirubin can be elevated because of inhibition of the UGT1A1 enzyme and enasidenib, and because his total bilirubin remained less than 2 or 3 times normal, he was able to continue on enasidenib and had no other abnormalities with AST or ALT that were concurrent with that. Thus, it was safe to continue him on that therapy, and he had no adverse events from that.

This is a young patient, 48 years old, that had primary refractory disease to standard induction chemotherapy. For patients in this age range, we typically would start with a clinical trial in the primary refractory disease setting. For some patients that have controlled disease, we would even consider a bone marrow transplant in that setting and not even use other therapy. In the past or even now, if patients don’t have anIDH2mutation in that setting, you might consider going straight to a bone marrow transplant in a primary refractory disease setting, especially if there has been some response, but not complete remission, for those patients.

Alternatively, we can often use induction chemotherapy for those patients, or induction therapy combined with other novel therapies. So, yes, clinical trials are an option for patients that are this young, that have primary refractory disease, primarily because their performance status is usually excellent, and they can tolerate novel therapies. For this particular patient, enasidenib was used as a single agent, given the data that we know about for patients that have relapsed/refractory AML. It was mostly relapsed/refractory patients that were evaluated that we can speak to, but, in this particular scenario, he benefitted from being on this medication and had complete remission from this therapy. We didn’t talk about this, but he ended up going forth to a bone marrow transplant after he obtained a complete remission.

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