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Expert Recaps Advances in AML

Caroline Seymour
Published: Wednesday, Sep 26, 2018

Dr. Rami S. Komrokji
Rami S. Komrokji, MD
Now that physicians have access to novel therapies for patients with acute myeloid leukemia (AML) following a 30-year gap in therapeutic development, physicians must now aim to understand their optimal placement in treatment, explained Rami S. Komrokji, MD.

“The landscape is changing; it’s an exciting time,” said Komrokji. “We have midostaurin (Rydapt), gemtuzumab ozogamicin (Mylotarg), and CPX-351 (Vyxeos) as new upfront therapies. We have IDH1/2 inhibitors, and gemtuzumab ozogamicin in the relapsed setting. Hopefully, we’ll soon have 2 FLT3 inhibitors—quizartinib and gilteritinib approved for patients with relapsed/refractory AML with a FLT3 mutation.”

Most recently, the FDA approved ivosidenib (Tibsovo) for the treatment of adult patients with relapsed/refractory IDH1-mutant AML in July 2018. The approval was announced following the results of a single-arm, phase I study of patients with IDH1-positive relapsed/refractory AML. The complete remission (CR) rate was 24.7% (95% CI, 18.5%-31.8%). The rate of CR with partial hematologic improvement was 8% (95% CI, 4.5%-13.1%).

In an interview during the 2018 OncLive® State of the Science Summit™ on Hematologic Malignancies, Komrokji, principal investigator, MDS Research Consortium, Aplastic Anemia and MDS International Foundation, clinical director, Hematologic Malignancies, Moffitt Cancer Center, reflected on the diverse AML treatment landscape and touched on the prognostic importance of biomarkers.

OncLive: How has the treatment landscape of AML changed in recent years?

Komrokji: It’s been an exciting time for researchers and patients. Now, we have more options that we can offer patients than we had in the past 30 years. In the last 2 years, we’ve witnessed the approval of several drugs in AML. I started the presentation by discussing the current risk stratification for AML, which is all based on cytogenetics and molecular data. I then went through all of the new drugs and where they are to be positioned in the management of patients.

We discussed treatment for younger patients with good-risk disease who have core binding factor abnormalities, which include t(8;21) or inv(16). Those patients seem to derive a favorable outcome and significant survival advantage from the incorporation of gemtuzumab ozogamicin into induction and consolidation. This is a lower dose of gemtuzumab ozogamicin than we’ve traditionally used in the past. Now, incorporating gemtuzumab ozogamicin is becoming standard of care for patients who are known to have good- or favorable-risk disease.

We also discussed patients who have FLT3 mutations. The incorporation of midostaurin with a chemotherapy backbone has become the standard of care for patients and has demonstrated an overall survival (OS) benefit.

Challenges sometimes include getting this information on time for patients. Now, the academic centers and the labs that perform those tests have a rapid turnaround time of a few days, and [we can get] those results and make decisions based on the molecular status and cytogenetics.

The other drug we discussed that has now been approved and become one of the standards for therapy is CPX-351. This is approved for patients with therapy-related AML, AML from myelodysplastic syndrome (MDS), AML with a carrier type similar to MDS, or AML with MDS-related dysplastic changes. CPX-351 is a fixed molar ratio of cytarabine and daunorubicin, which is packaged in a better way to ensure delivery of the 5:1 ratio. It has a better [ability to] kill the leukemia cells and has a slower release. In phase III trials comparing it with traditional cytarabine and daunorubicin (7+3), it demonstrated higher response rates, less mortality at day 30 or 60, and improved OS. That led to its approval. [We expect to see] a little bit more delay in the recovery of the blood count as the duration of myelosuppression is longer by 1 or 2 weeks than with the 7+3.

Then, there are promising data coming down the pipeline with venetoclax (Venclexta) plus hypomethylating agents. There is a study that randomized patients to low-dose cytarabine or low-dose cytarabine and venetoclax. If the study is positive, that may lead to venetoclax’s upfront approval in patients with AML who are not candidates for intensive chemotherapy.

In the relapsed/refractory setting, there are 2 drugs approved for patients who have IDH mutations. For IDH2 mutations, enasidenib (Idhifa) was approved by the FDA. It’s an orally administered drug that led to a complete response rate of nearly 20%, a 40% overall response rate, and a median duration of response around 9 months. In terms of adverse events (AEs), we watch for hyperbilirubinemia and differentiation syndrome.

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