Targeted Therapies Continue to Show Promise Against FLT3, IDH1/2 Mutations in AML

Danielle Ternyila
Published: Friday, Mar 01, 2019

Jorge E. Cortes, MD

Jorge E. Cortes, MD

Anthracyclines and cytarabine have remained the standard of care for most patients with acute myeloid leukemia (AML) over the last 50 years. However, over time, investigators have learned more about the molecular heterogeneity of the disease and are now able to target specific mutations in effort to improve outcomes in these patients.

For patients who harbor FLT3 or IDH1/2 mutations, novel targeted agents have become available for use, explained Jorge E. Cortes, MD, who mentioned FLT3-targeted therapies such as midostaurin (Rydapt), gilteritinib (Xospata), and IDH1/2-targeted agents such as ivosidenib (Tibsovo) and enasidenib (Idhifa).

FLT3 mutations are important because they are common,” said Cortes. “It’s one of the most common mutations in AML.”

Moreover, quizartinib is an agent moving through the pipeline for patients with FLT3-mutant AML. An update of the phase III QuANTUM-R trial, which evaluated quizartinib in patients with relapsed/refractory AML, was presented at the 2018 ASH Annual Meeting. Results showed that, at a median follow-up of 23.5 months, the median OS was 6.2 months (95% CI, 5.3-7.2) with quizartinib compared with 4.7 months (95% CI, 4.0-5.5) with salvage chemotherapy (HR, 0.76; 95% CI, 0.58-0.98; stratified log-rank test, 1-sided P = .0177).

A new drug application (NDA) for quizartinib was granted a priority review designation in November 2018 for the treatment of adult patients with relapsed/refractory FLT3-ITD–positive AML. Under the Prescription Drug User Fee Act, the FDA will decide on the NDA by May 25, 2019.

In an interview with OncLive during the 23rd Annual International Congress on Hematologic Malignancies: Focus on Leukemias, Lymphomas, and Myeloma®, Cortes, deputy chair of the Department of Leukemia in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discussed the current treatment options for patients with AML, including the use of quizartinib in patients with FLT3 mutations, as well as data from the QuANTUM-R trial.

OncLive: Could you discuss the current treatment landscape for AML?

Cortes: For the longest time, since around 1970, the treatment with anthracycline and cytarabine was introduced. For nearly 50 years, that standard did not change. Still today, that is the standard for the majority of patients. However, what has happened in recent years is that we started discovering the molecular heterogeneity of the disease, and understanding all of these molecular mutations and changes that happen. Very importantly, [we are] able to translate that into development of new therapeutic strategies.

That led to the discovery of FLT3 mutations, the prognostic implications, and then the development of drugs. Now, we have 3 FLT3 inhibitors approved by the FDA. First, midostaurin [is approved] in combination with chemotherapy for the frontline treatment of patients with FLT3-mutated disease. More recently, gilteritinib [was approved] as a single agent for patients with relapsed/refractory FLT3-mutant AML. Quizartinib is now being reviewed by the FDA, hopefully, to be approved soon.

IDH1/2 mutations are not as common, but each of them still occur in about 8% to 12% of patients. Prognostically, they are not as adverse as the FLT3 mutations. However, they do represent a target, and we have been able to develop both IDH1 and IDH2 inhibitors that are both approved by the FDA. We know patients respond very well, even as single agents, and durable responses are seen with these very well-tolerated drugs.

Those are the 2 main advances in the last few months. Another important drug that has been approved includes venetoclax (Venclexta) in combination with hypomethylating agents. It gives outstanding responses in older and unfit patients in the range of 70%. These responses can be durable. The study was not randomized compared with historical [data], but the median survival in these studies were about 15 months. It’s much better than we expect in that patient population and, again, is very well tolerated. With venetoclax, you need to know how to use it. If you know how to use it properly to minimize the risk of tumor lysis syndrome, it’s a very safe drug.

The other drug was glasdegib (Daurismo), which is a hedgehog inhibitor. These drugs have been used in squamous cell carcinomas of the skin, but in combination with low-dose cytarabine, again in patients [who are older] and with comorbidities, it gave a significant prolongation of survival. This is an additional drug for AML treatment today.

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