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Damon Discusses Drug Development in AML

Caroline Seymour
Published: Friday, Oct 05, 2018

Lloyd Damon, MD
Lloyd Damon, MD
FLT3 and IDH1/2 mutations are two of many molecular targets that can be found in patients with acute myeloid leukemia (AML). Although there are FDA-approved agents available for those harboring such abnormalities, others are in development and quickly gaining traction, explained Lloyd Damon, MD.

“AML is rapidly advancing in terms of our knowledge of pathophysiology as well as our treatment approach,” said Damon. “Learning more about the genetics and the basic mechanisms of the formation of AML will inform us as to appropriate personalized and targeted therapies. We have had more drugs approved for AML in the last year and a half than in the last decade. Progress is around the corner.”

In August 2018, quizartinib was granted a breakthrough therapy designation by the FDA for the treatment of adult patients with relapsed/refractory FLT3-ITD–positive AML based on data from the phase III QuANTUM-R study. Compared with salvage chemotherapy, quizartinib treatment resulted in a 24% reduction in the risk of disease progression or death.

At a median follow-up of 23.5 months, the median overall survival was 6.2 months (95% CI, 5.2-7.2) and 4.7 months (95% CI, 4.0-5.5) with quizartinib and chemotherapy, respectively (HR, 0.76; 95% CI, 0.58-0.98; stratified log-rank test, 1-sided P = .0177).  

As more potent and specific FLT3 and IDH1/2 inhibitors come to market, Lloyd noted that venetoclax (Venclexta) has shown significant benefit across hematologic cancers and is likely to have an impact in AML, especially in older patients who may be unable to tolerate chemotherapy.

In an interview during the 2018 OncLive® State of the Science Summit™ on Hematologic Malignancies, Damon, director of the Adult Blood and Marrow Transplant and Hematologic Malignancies Program, and chief of the University of California, San Francisco (UCSF) Hematology Clinic, UCSF Helen Diller Family Comprehensive Cancer Center, discussed novel therapies in AML with a focus on FLT3 and IDH1/2 inhibitors.

OncLive: Could you highlight the novel FLT3 inhibitors in the landscape?

Damon: We currently know over 90% of the genetic lesions involved in the pathogenesis of AML. One's individual genetic findings may direct you to genetic-based therapies that will facilitate entering remission with chemotherapy, or ultimate cure.

FLT3-mutated AML involves 25% of AML cases. It's a great target. We now have a number of drugs, some of which are in development and one that is FDA approved for FLT3-mutated AML. Not all FLT3 inhibitors are created equal. Some of the FLT3 inhibitors are extremely potent and very specific for FLT3. Others are less potent, less specific, and have off-target effects in other tyrosine kinases, leading to excess toxicity.

Midostaurin (Rydapt) happens to be a nonpotent, nonspecific FLT3 inhibitor, which is FDA approved for patients with FLT3-positive AML in conjunction with chemotherapy. The RATIFY trial randomized patients to midostaurin or placebo with conventional chemotherapy and showed a survival advantage with midostaurin. There was a 22% reduction in death, but it's unclear if this benefit was achieved because of the agent’s FLT3 activity.

A more potent and specific drug is quizartinib. Quizartinib was part of a randomized study called QuANTUM-R that was recently presented at the 2018 European Hematology Association Congress. In that trial, patients received quizartinib at relapse or in the primary refractory setting. This was compared with conventional chemotherapy, which could either be low-dose cytarabine; mitoxantrone, etoposide, and cytarabine (MEC) chemotherapy; or fludarabine, cytarabine and GCSF with idarubicin (FLAG-IDA) chemotherapy.

There was a 24% reduction in death with quizartinib compared with chemotherapy, indicating that a potent and specific FLT3 inhibitor may have incredible activity in this disease. [There is more] to come, particularly whether it should be combined with chemotherapy.

One of the take-home points I made was that allogeneic stem cell transplant remains the standard of care for patients with FLT3-mutated AML and should be considered the pathway for an eligible patient. One of the major questions in the transplant community is whether a FLT3 inhibitor after transplant as maintenance is of value.

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