Every Friday before the annual American Society of Hematology (ASH) meeting features a variety of symposia that feature current treatment practices for every type of hematological disease and malignancy. Today we kicked off the 2021 ASH annual conference in Atlanta, Georgia by attending a satellite symposium hosted by PeerView that featured AML experts Dr. Daver, Dr. DiNardo, Dr. Borate and Dr. Stein.
CPX351, otherwise known as Vyxeos, is an FDA-approved drug for AML that arises due to prior cancer treatment or a type of AML that has myelodysplasia-related changes (AML-MRC). A diagnosis of AML-MRC requires the presence of at least 20% blasts in the peripheral blood and/or bone marrow, an absence of any of the AML-associated recurrent genetic abnormalities seen in AML (such as inv(3), t(6;9), or NPM1 mutation), and the absence of a history of chemotherapy or radiation therapy for a different cancer or disease. More recently, Vyxeos has been FDA approved for children with therapy-related AML or AML-MRC as well. Researchers are making strides in determining additional ways to use Vyxeos in various combinations. The V-FAST trial is an ongoing investigation looking at the use of Vyxeos in combination with other medications such as venetoclax and midostaurin, and the results we have so far suggest that these drugs can be safely combined with Vyxeos with manageable side effects.
Vyxeos in newly diagnosed AML is attractive as it has been shown to produce fewer gastrointestinal side effects, it has a lower 30 and 60 day mortality rate compared to the 7+3 treatment and patients experience minimal hair loss.
In an abstract that will be presented tomorrow at ASH, researchers will reveal that Vyxeos used in patients with newly diagnosed, adverse risk AML had better overall survival than those treated with hypomethylating agents + venetoclax, especially in patients with TP53 mutated AML. More of the Vyxeos treated patients went on to have a stem cell transplant, however, there was no difference in overall survival between the Vyxeos group and the hypomethylating + venetoclax group for the patients that did not go on to have a transplant.
Studying AML mutations and developing drugs that target these specific mutations is how AML treatment becomes personalized from person to person and much more effective. Currently, we have targeted drugs that are FDA approved for FLT3 mutations, IDH1 mutations and IDH2 mutations.
The 2017 RATIFY study showed that adding a FLT3 inhibitor called midostaurin to intensive chemotherapy in newly diagnosed AML improved survival. Midostaurin is considered a first generation FLT3 inhibitor. Gilteritinib is a newer FLT3 inhibitor that is considered second generation, and there are many more FLT3 inhibitors in development that are hoped to be even more potent and effective at treating FLT3 mutated AML.
Dr. DiNardo mentioned news from a very recent press release about the randomized phase 3 QuANTUM-First trial that included 539 patients with FLT-ITD AML looking at the use of 7+3 chemotherapy with and without quizartinib (a selective FLT3 inhibitor in development) in patients ages18-75. According to the press release, there was a statistically significant and clinically meaningful improvement in overall survival in the patients that received quizartinib in combination with 7+3.
The panel then discusses the use of hypomethylating agents with venetoclax in FLT3 mutated AML and states that these patients respond really well with this combination and mostly go into remission. They mention that FLT-TKD AML typically has a significant benefit from this therapy while those with FLT3-ITD see a smaller, but still impactful benefit.
They also report that a triplet combination of azacitidine, venetoclax and gilteritinib has shown promising activity among 26 newly diagnosed patients but note that in order to manage this triplet, dosing for these medications must be much different than if they were given alone. The panel believes that triplet use is the future for AML treatment for many patients, but figuring out how to best optimize triplet therapy should be a big area of research over the next few years.
For patients not going to transplant, the 2020 QUAZAR study suggests that oral azacitidine (Onureg) has an improved overall survival of 24.7 months vs 14.8 months with no treatment. From the QUAZAR study, experts learned that Onureg is a well-tolerated drug but only delivers 30-40% of the therapy that IV azacitidine does so that’s likely why it’s not used in newly diagnosed patients. It works well as a maintenance drug because it delivers a small amount of medication over time. The panel's main point is that there need to be additional steps taken to further improve the overall survival from 24.7 months to a length of time that is much more significant. The panel states that patients with NPM1 mutations are likely the ones to benefit most from oral azacitidine maintenance therapy.
The patients to benefit from hypomethylating agent + venetoclax in the relapsed setting are likely the same as those that benefit when newly diagnosed. These are typically the patients with NPM1, IDH, RUNX1 or spliceosome mutations. Intermediate cytogenetics are most sensitive to this combination.
There is exciting preclinical data on small molecule inhibitors that are being used for patients with MLL rearrangements (MLLr) or NPM1 mutations which make up about 40% of AML patients. These therapies block the protein-protein interaction between menin and MLL fusion proteins which play a role in the development of AML. The Phase 1/2 AUGMENT-101 trial found a 48% overall response rate in patients with MLLr or NPM1 and 67% of responders achieved minimal residual disease-negative status with the use of a menin inhibitor called SNDX-5613.
Dr. Stein claims menin inhibitors are a major breakthrough in AML treatment. Researchers are now working on figuring out the differences between the various menin inhibitors and learning how to combine them with other therapies.
about the author
Katie joined HealthTree as the Community Director for AML in 2021. She is a registered dietitian who previously worked at the VA hospital in Dallas, Texas where she coached veterans with blood cancer on how to use nutrition to improve their treatment outcomes and minimize cancer-related side effects. Katie is passionate about health education and patient empowerment. In her spare time, she loves to experiment with new recipes in the kitchen, spend time running outdoors and travel to new places.