Panel of Experts Cover Clinical Scenarios in AML

Elias Jabbour, MD

In a discussion during the 4th Annual Live Medical Crossfire® in Hematologic Malignancies, a program developed by Physicians’ Education Resource® (PER®), LLC, a panel of experts in acute myeloid leukemia (AML) considered potential treatment options for patients with AML.

The session, co-chaired by Elias Jabbour, MD, a professor in the Department of Leukemia, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, consisted of 4 clinical scenarios that one might encounter in clinical practice.

Newly Diagnosed IDH2-Mutant AML

The first case consisted of a 72-year-old male showing signs of fatigue and shortness of breath. The patient has a performance status (PS) of 1 and past medical history indicates diabetes with a treatment of metformin (Glucophage). The patient doesn’t have any other comorbidities. The patient’s complete blood count indicates a hemoglobin level of 8.5 g/dL, white blood cell count of 1200/mL (0.1 absolute neutrophil count, blasts 60%), and platelet count of 40. A bone marrow examination reveals 45% myeloperoxidase-positive blasts. Regarding cytogenetics, the patient has diploid disease and mutated IDH2 and DNMT3A.

The FDA-approved option for this patient is 7 + 3 chemotherapy (cytarabine on days 1-7 and daunorubicin on days 1-3), said Richard M. Stone, MD, a professor of medicine at Harvard Medical School, and chief of staff and director of the Adult Leukemia Program, at Dana-Farber Cancer Institute. However, the combination of venetoclax (Venclexta) and a hypomethylating agent (HMA) has shown very good results in the IDH1/2-mutant setting, said Stone, who added that the BCL-2-based combination would be his preferred option for the patient. Although the combination of enasidenib (Idhifa) and an HMA could be a viable strategy, there’s no randomized data to compare its superiority to venetoclax, said Stone.

When it comes to HMA-based regimens in the IDH-mutated population, the combination of venetoclax and an HMA is preferred, said Selina M. Luger, MD, professor of medicine at Abramson Cancer Center, Perelman School of Medicine. The BCL-2-based combination has such a high response rate, that there’s no need to incorporate enasidenib up front.

Jabbour countered that enasidenib is less likely to result in myelosuppression compared with venetoclax, to which Luger responded that myelosuppression is less of a concern in a patient without significant comorbidities.

Unless the patient was not a candidate for induction chemotherapy, the standard approach would be 7 + 3, said Amir T Fathi, MD, program director of the Center for Leukemia at Massachusetts General Hospital, and an associate professor of medicine at Harvard Medical School.

“Do I believe that the combination of venetoclax and an HMA will probably produce a very similar response rate and give the patient as equal a chance of perhaps getting to transplant?” said Fathi. “Yes, but the FDA-approved approach to a patient with minimal comorbidity under the age of 75 is induction chemotherapy.”

Taking the FDA-approved option out of the equation, Naval G. Daver, MD, an associate professor in the Department of Leukemia, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, agreed that the combination of venetoclax and an HMA would be the preferred option given the high response rates and improved fitness of the patient pretransplant compared with 7 + 3.

Relapsed FLT3-Mutant AML

The second case consisted of a 68-year-old man with AML who had previously been treated with 3 + 7 chemotherapy. The patient relapsed after 1 year of remission and has a PS of 1. The patient has 65% myeloperoxidase positive blasts and diploid disease. Next-generation sequencing (NGS) reveals a FLT3-ITD mutation at an allele burden of 70% with an NRAS mutation.

The FDA-approved option for this patient is gilteritinib (Xospata), said Stone. However, the combination of an HMA and gilteritinib or an alternative FLT3 inhibitor is a viable strategy.

Luger explained that although gilteritinib monotherapy is the FDA-approved choice, the combination of gilteritinib and venetoclax has shown promise in clinical trials and could be an appropriate choice in select scenarios.

“An HMA plus gilteritinib or venetoclax plus gilteritinib both should hopefully give you a good chance to at least get a marrow complete response and get the patient to transplant,” said Daver.

Fathi called attention to the NRAS mutation, stating that the presence therein could indicate shortened response or lack of response to FLT3 inhibitors. However, he also cautioned against recommending off-label combinations. In a robust patient, Fathi stated that he would consider an HMA plus gilteritinib because the remission rate seen with gilteritinib monotherapy does not lend itself to the treatment of a patient with relapsed disease whose ultimate goal is transplant. 

MRD-Negative AML

The third case consisted of a 58-year-old male diagnosed with diploid AML. NGS reveals FLT3-ITD wild-type, NPM1 wild-type, and DNMT3A positive disease. The patient received induction therapy with FLAG-IDA and achieved minimal residual disease (MRD) negative remission, followed by 4 courses of an HDAC-based regimen. No matched related donor could be identified.

Given that the patient has ELN intermediate-risk prognosis and is in MRD-negative remission, Fathi explained that it would have to be a discussion with the patient. In the absence of a good donor source, Fathi stated that watch-and-wait would be a viable approach.

“If you look at the transplant data, those patients whose outcome is most likely to be good after transplant are patients who go into transplant looking like this,” said Luger.

Regarding the use of an HMA-based regimen in the maintenance setting, Fathi added that there is a lack of sufficient evidence to recommend its use in the post-consolidation remission setting.

However, pending FDA approval of CC-486, oral azacitidine too would become an available option worth discussing with patients, said Daver.

Newly Diagnosed IDH1-Mutant AML

The fourth case consisted of a 78-year-old female with AML who has 30% myeloperoxidase-positive blasts. Past medical history reveals diabetes with a treatment of metformin and mild chronic obstructive pulmonary disease. Cytogenetics show +8 and an IDH1 mutation.

The patient would be eligible for the combination of venetoclax and an HMA or ivosidenib (Tibsovo) alone, said Stone. However, the response rates for ivosidenib alone are not great. As such, Stone stated that he would reserve the IDH1 inhibitor for the small subset of patients who cannot receive an HMA.

“The data for the combination of venetoclax and an HMA are pretty good, so I would agree with everyone who would give that combination,” said Stone.

Assuming the patient is robust and has a good PS, Luger, Fathi, and Daver agreed that, in combination with an academic medical center, the BCL-2-based combination would be the preferred regimen for this patient.

Reference

4th Annual Live Medical Crossfire® in Hematologic Malignancies. July 11, 2020; Virtual. Accessed July 11, 2020. bit.ly/2CpbhXG.