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AML’s genetic complexity raises concerns about long-term prospects of single mutation-targeting agents
The targeted drug midostaurin extends survival among patients younger than aged 60 years with FLT-3 gene mutation-harboring acute myeloid leukemia (AML), results of the phase 3 RATIFY clinical study showed. Study authors announced this welcome first step toward a personalized medicine for AML Saturday, December 5 at the 57th American Society of Hematology (ASH) Annual Meeting in Orlando.
The genetic complexity and heterogeneity of AML make it unlikely that any one targeted agent will yield lasting cures, cautioned Eytan M. Stein, MD, internist and hematologic oncologist, Memorial Sloan Kettering Cancer Center, New York, N.Y, He spoke at a separate educational session at the ASH meeting.
Combinations of targeted agents might ultimately prove to be a more realistic approach than a single agent, Stein suggested.
“Physicians are rightfully enamored with the idea of a single agent curing a single disease,” said Stein. “It is intellectually satisfying to attack a fundamental abnormality leading to leukemogenesis, and many targeted agents are orally-administered; they can be given as an outpatient, and are less toxic than chemotherapy.”
The safety profile and tolerability of targeted agents is “particularly attractive to those patients who are unfit or who have a predicted poor response to induction chemotherapy,” he added.
FDA has not approved a new AML drug since 1990 and there are currently only three standard treatment options for AML, Stein noted.
“For patients aged 18 to 65 or 75, there’s intensive ‘7+3’ induction therapy [with anthracycline and cytarabine]; for patients aged 70 to 80, there are hypomethylation agents; and for patients older than 80, supportive care,” he explained. “Fifty percent of elderly people newly-diagnosed with AML don’t receive any treatment.”
AMLs frequently harbor gene aberrations like FLT-3, IDH1/2, and RAS mutations, he noted: attractive mutations for targeted-therapy agents. FLT-3 mutations occur in up to 35% of AML cases.
“The RATIFY trial is proof of concept that FLT-3 inhibition can lead to overall benefit with chemo in a multicenter, randomized, placebo-controlled study,” Dr. Stein said. The RATIFY research team announced a 5-year overall survival rate of about 51% for patients receiving midostaurin, versus 44% in the control group - a 7% difference.
Other, “second-generation” anti-FLT-3 agents are already being studied, Stein noted. But results have been mixed and these agents have tended to yield “few true complete remissions,” he said, and added that AMLs appear to evolve resistance through other, subsequent mutations.
One promising investigational agent, ASP-2215, has an “enviable” reported response rate of 55% and is accruing participants for a phase 3 clinical trial for patients with FLT-3 mutations, but “some of the remissions are less than complete,” said Stein. Monotherapy with quizartinib, a small-molecule tyrosine kinase inhibitor, is being clinically tested as well, compared against salvage chemotherapy in patients with AML harboring a particular FLT-3 mutation, and that had progressed despite standard first-line treatment.
Ultimately, “it’s unlikely that a single drug against a single molecular target will lead to clinical cure in a majority of patients - even those with the molecular alteration in question, because of disease heterogeneity,” Stein said. “AML is genetically heterogenous and inhibitors against one target will not suppress all leukemogenic clones [cell lines]."
However, he is cautiously optimistic about the prospects for combination therapies.
“It’s important that we start combining novel agents with existing drugs that we know work,” Stein said. It would be worth combining targeted therapies with chemotherapy and hypomethylating epigenetic agents, he suggested.
“There’s been recent interest in ‘going broad’ and targeting different classes” of molecular targets, agreed Roland B. Walter, MD, PhD, MS, clinical research division, Fred Hutchinson Cancer Research Center in Seattle.
Walter spotlighted targeted, antigen-specific immunotherapies under investigation for AML, as well as “conjugated” agents that load therapeutic payloads onto cancer-seeking antibodies.
“Conjugation allows use of effectors [drugs] that have unacceptable toxicities when administered systemically,” he said, because the antibodies deliver the cell-killing drugs directly to cancer cells. However, efficiently attaching cancer cell-killing drugs to antibody carriers has been a challenge, he noted.
Because AML is “exquisitely sensitive to radiation,” radioimmunotherapy agents are also being investigated, he added. Radiolabeled cancer-seeking antibodies could be used to augment conditioning therapy for AML patients preparing to undergo hematopoietic cell transplantation, he suggested. Early proof-of-concept studies have been promising, but controlled clinical trials are needed to assess the concept, he pointed out.