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Novel Therapies Likely to Transform AML Landscape

Gina Columbus and Elizabeth Leick
Published: Wednesday, Jan 04, 2017

Martin S. Tallman, MD

Martin S. Tallman, MD

A combination regimen of the BCL-2 inhibitor venetoclax (Venclexta) plus low-dose cytarabine (Depocyt) demonstrated an acceptable safety and pharmacokinetic profile in elderly patients with treatment-naïve acute myeloid leukemia (AML), according to findings of a phase I dose-expansion study presented at the 2016 ASH Annual Meeting.1

Results showed that the overall response rate was 75%, with an estimated 12-month overall survival (OS) rate of 74.7%. The majority of patients, all of whom (n = 20) were ineligible for intensive anthracycline-containing chemotherapy, experienced clinical remissions. The median OS had not been reached.

Further clinical trials exploring this early, yet encouraging regimen, add to a growing list of promising therapies for patients with AML, including midostaurin (PKC412) for patients with newly diagnosed FLT3-mutated disease. The FDA granted a priority review to midostaurin for this indication in November 2016.

Additionally, venetoclax received a breakthrough therapy designation by the FDA in January 2016 for use in combination with hypomethylating agents in treatment-naïve patients ineligible for standard high-dose induction treatment.

Pracinostat, an HDAC inhibitor, was also granted a breakthrough therapy designation for use in combination with azacitidine (Vidaza) for newly diagnosed patients who are aged more than 75 years or are ineligible for intensive chemotherapy.

“I want people to know it is an exciting time,” says Martin S. Tallman, MD, hematologic oncologist, chief of Leukemia Service, Memorial Sloan Kettering Cancer Center. “We have many new exciting agents—novel agents—that are going to be rapidly incorporated into the treatment of patients with AML. Finally, we are going to make significant progress in the field.”

Tallman, who lectured on the changing AML landscape during the 2016 OncLive® State of the Science Summit on Hematologic Malignancies, sat down for an interview to discuss these novel therapies and the future role of transplantation in more detail.

OncLive: Can you provide an overview of your presentation?

Tallman: The presentation has to do with the state of the art in the treatment of AML in 2017. The state of the art rests on a number of principles. First, the disease is really defined today by cytogenetic and molecular or genomic abnormalities. Second, induction chemotherapy can be intensified for the benefit of patients. Third, consolidation might be able to be deintensified. Fourth, the benefit of allogeneic transplantation has only increased, and there has been an expanded pool of patients who may benefit from transplantation.

Fifth, there is an increasing awareness of the importance of minimal residual disease studies, both following intensive chemotherapy and before allogeneic transplantation. Finally, and perhaps the most exciting, is the development of new agents that are very promising in the treatment of AML today.

What role will transplant continue to have as more agents are developed and improved going forward?

More patients are able to undergo transplantation. First of all, we’re able to transplant older adults more safely. We have been able to expand the pool of patients who are potential candidates because of increasing graph sources such as umbilical cord, haploidentical transplant, and combinations of umbilical cord and haploidentical transplant.

A very important principle that has emerged is that patients who have minimal residual disease before transplantation have less favorable outcomes after transplantation. Now, there are major efforts to try to eradicate all evidence of disease before undergoing transplantation.

Are there any characteristics that patients might have in which you don’t recommend they undergo transplant?

Patients who have favorable-risk disease, have core binding factor AML, or have acute promyelocytic leukemia, are patients who have a sufficiently favorable outcome without transplantation. Then, they are not going to benefit from transplantation.

What are some of the novel agents that are moving down the pipeline?

One of them is the drug called venetoclax. Venetoclax is a BCL-2 inhibitor. It’s actually been approved for patients with chronic lymphocytic leukemia, but it’s been used very successfully now by patients with myeloid leukemia, particularly in combination with hypomethylating agents such as decitabine (Dacogen) or azacitidine. There have been several studies that have combined it with azacitidine or decitabine, suggesting that the drug in combination is very effective in AML.

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