Remission induction in older or less fit adults with acute myeloid leukemia (AML) has historically been problematic.
“The average age at diagnosis is between 60 and 65,” said Laura Michaelis, MD, of Medical College of Wisconsin in Milwaukee. “And the great majority of those patients have not had optimal treatment with cytotoxic treatment, which has been designed for younger people.”
“It has been in the last 10 years or so that new ways of treating leukemic cells have been developed, and that has led to the development of novel agents that have marked the last 4 or 5 years, and changed the safety profile for chemotherapy for AML, and the ways we treat it,” she told MedPage Today.
This includes the introduction of agents that target FLT3, a mutation that is present in about a third of patients and, according to Michaelis, “portends a much more difficult prognosis.”
The first drug in this space was midostaurin, which was approved for newly diagnosed AML patients in 2017 based on results from the RATIFY trial.
“Since that time we’ve had second-generation FLT3 inhibitors and those are now being discussed in combination with cytotoxic chemotherapy,” said Michaelis. For example, the phase I study of once-daily oral gilteritinib plus intravenous chemotherapy in patients with newly diagnosed AML, presented at this year’s American Society of Hematology (ASH) virtual meeting, found that the combination was well tolerated and that favorable anti-leukemic responses were observed in FLT3-positive patients, with a mutational clearance rate of 70.0%.
“In addition, we are seeing agents like gilteritinib combined with hypomethylating agents like azacitidine and decitabine, and safety data is accumulating on that, not only in the upfront population, but in relapse and refractory FLT3-positive disease,” noted Michaelis.
Other new agents target IDH1 and IDH2 mutations, which occur in about 20% of AML patients. Ivosidenib and enasidenib have been approved as single agents, and there are trials ongoing, such as the phase III AGILE study, evaluating ivosidenib in combination with azacitidine in adults with newly diagnosed AML and an IDH1 mutation.
Another new agent under investigation is the menin-mixed lineage leukemia (menin-MLL) inhibitor KO-539. “This was designed to target NPM1-mutated AML, but it could also be targeted at those who are not just NPM1-mutated patients, but with other mutations in AML,” said Michaelis.
In a session at ASH, Eunice Wang, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, New York, presented results from the first-in-human phase I/IIA KOMET-001 study that showed that KO-539 demonstrated activity in patients with relapsed/refractory AML.
“So these small-molecule inhibitors mean that if we can precisely describe the clones that are causing disease, we may be able to attack them in a much more specific way,” noted Michaelis. “This means we can increase the potency of the treatment without increasing the toxicity of the treatment in people with these mutations.”
She pointed out that venetoclax (Venclexta), a BCL-2 inhibitor first designed to treat chronic lymphocytic leukemia, “is now carving out a really important role in AML as well.”
Venetoclax has been approved by the FDA in combination with azacitidine, decitabine, or low-dose cytarabine for adults 75 years or older with newly diagnosed AML, or in those who have comorbidities precluding intensive induction chemotherapy. The FDA first granted accelerated approval for this indication in 2018.
VIALE-A showed that median overall survival was 14.7 months in patients treated with venetoclax and azacitidine compared with 9.6 months for patients treated with placebo and azacitidine. In addition, patients treated with venetoclax plus azacitidine achieved a composite complete remission rate of 66% compared with 28% for azacitidine plus placebo.
“For someone with AML and normally not considered fit, and then treated with azacitidine monotherapy, we could anticipate complete remission about 15% of the time at best,” said Michaelis. “We could control the disease, but this would be considered palliative chemotherapy. When Vidaza [azacitidine] is combined with venetoclax you can see complete remission 60% to 70% of the time, so that is a huge increase of people getting complete remissions, or complete remission with incomplete platelet or red cell recovery. That really changes the whole landscape and why this combination has become the standard of care for older, less fit patients with AML.”
“In addition, the safety data is very good,” she added. “The early mortality is less than 5%, which is very good for this older patient population. It is harder to take than taking Vidaza alone, but with the benefits — including some patients who become MRD [minimal residual disease] negative — these are really remarkable findings.”
“What we are doing now, is looking at what this means if a patient is taken to transplant,” she noted. “Does that MRD negativity translate into more effective transplant outcomes? And second, are there certain forms of AML where even if you are fit and young, it is better to undergo this combination rather than a cytotoxic chemotherapy? And the third trajectory of investigation is how we can combine venetoclax and azacitidine and other targeted agents. There are no phase III data on triplets, but [we] did see some early data at ASH this year.”
Michaelis served as a consultant to Novartis, Celgene, and Incyte; previously held stock in Pfizer; and receives research funding from Jazz Pharmaceuticals.