Abstract
Of two new FDA-approved therapies for acute myeloid leukemia (AML), hematologists expect that the FLT3/AXL inhibitor gilteritinib will likely become an integral part of treatment. However, they think glasdegib, which targets the Sonic hedgehog pathway, may have limited utility, because it must be prescribed alongside cytarabine, an uncommon AML treatment option in the United States.
Of two new targeted therapies recently approved by the FDA for acute myeloid leukemia (AML), physicians predict that one, gilteritinib (Xospata; Astellas Pharma), will be widely used, whereas the other, glasdegib (Daurismo; Pfizer), probably won't.
The FDA greenlighted gilteritinib, which blocks the tyrosine kinases FLT3 and AXL, for the 25% to 30% of adults with relapsed or refractory AML who carry a mutation in FLT3. The phase III trial that led to gilteritinib's approval showed that it provides some benefit in this population. Complete remissions or complete remissions with partial hematologic recovery—less than 5% of bone marrow blasts remaining, but no evidence of disease—occurred in 21% of the study's 138 patients. Gilteritinib is the second FLT3-targeted agent indicated for AML, with midostaurin (Rydapt; Novartis) receiving approval in 2017.
Many patients with AML relapse after intensive chemotherapy and aren't immediately eligible for a hematopoietic stem cell transplant (HSCT), says Geoffrey Uy, MD, of Washington University School of Medicine in St. Louis, MO. “This drug will be very useful for patients in that setting,” he says.
“The importance [of gilteritinib's approval] is that we should now have a few more patients achieve remission and become eligible for a transplant, and some who see improvements in symptomology,” adds Carlos Vigil, MD, of the University of Iowa Carver College of Medicine in Iowa City. He notes, however, that gilteritinib alone is unlikely to be as effective as in combination with chemotherapy.
The drug may be useful in another situation as well. AML often recurs in FLT3-mutant patients who have undergone HSCT. If such post-transplant relapses occur, gilteritinib “would be an excellent option,” says Laura Michaelis, MD, of the Medical College of Wisconsin in Milwaukee.
Gilteritinib does cause side effects that doctors need to watch for, including a prolonged QT interval, pancreatitis, and posterior reversible encephalopathy syndrome, a neurologic condition that can lead to seizures and vision loss if not treated. Even so, all three physicians agree that doctors will likely prescribe gilteritinib for FLT3-mutant patients. “It's an important drug,” says Uy.
They were less enthusiastic about glasdegib, an inhibitor of the Sonic hedgehog pathway. The FDA approved this drug in combination with low-dose cytarabine for patients who are 75 years or older or who have health problems that preclude them from receiving intensive chemotherapy. Given that the average age at diagnosis for patients with AML is 68, “there's a significant number of patients who could benefit,” says Vigil. A phase III clinical trial found that the glasdegib–cytarabine combination increased overall survival by 4 months compared with cytarabine alone. Another plus for the drug, says Michaelis, is that a broad range of patients can receive it, not just those with specific mutations.
However, Uy says, low-dose cytarabine is not a common treatment for AML in the United States, thereby limiting glasdegib's usefulness. And Michaelis notes that results from a phase I/II trial suggest that the combination of cytarabine and the BCL2 inhibitor venetoclax (Venclexta; AbbVie) would also be an attractive option for this patient population. “I don't anticipate that glasdegib will change the landscape” of AML treatment, she says. –Mitch Leslie
