Shifts the the AML Treatment Landscape

Acute myeloid leukemia (AML) treatment has seen major shifts. For older and unfit patients, gentler venetoclax (Venclexta)-based regimens are replacing harsher chemotherapy-based one, with targeted therapies like FLT3 inhibitors added for specific mutations. This improves response rates, but long-term survival remains low. Researchers are exploring ways to push beyond these limitations, perhaps with deeper remissions using frontline targeted therapies or immunotherapy. Meanwhile, younger and fitter patients still receive intensive chemotherapy, but with the exciting addition of FLT3 inhibitors like quizartinib (Vanflyta), which significantly boosts survival in those with FLT3 mutations. According to Naval G. Daver, MD, associate professor in the Department of Leukemia at MD Anderson Cancer Center, quizartinib's potency and tolerability make it the go-to choice.

Here, Daver discusses more about the rapidly-evolving AML treatment landscape, including how both targeted therapies and immunotherapy hold promise for better outcomes in both older and younger patients.

Transcription:

0:09 | So in treatment of acute myeloid leukemia, the major changes have been the use of lower intensity therapies, especially [hypomethylating agents (HMA)]/venetoclax based approaches. Those have now been established and are being used commonly in patients above 70 years of age and even in some of the younger patients who may be unfit or have comorbidities, making them not suitable candidates for intensive chemo. But more and more we also have been adding other targeted therapies to the HMA/ven combination, which has led to better response rates and efficacy. And for example, we've been adding FLT3 inhibitors like gilteritinib [Xospata] and quizartinib to the HMA/venetoclax in FLT3-mutated patients. Similarly IDH inhibitors added to HMA/ven in IDH-mutated [patients]. And now there are studies looking at menin inhibitors added to the HMA/ven in those with MLL NPM1. And all of these combinations are starting to show much deeper remissions as well as more durable responses than just with HMA/ven.

1:01 | So I think the key issues now are how we can move beyond the HMA/ven, which is a good regimen, gives us good remission rates. But when you look at the long-term survival, the 3-year survival is only about 23-24%. So how do we make this better? Maybe by adding targeted therapies to the frontline combination, getting deeper remissions, and potentially that will improve the survival. And the other question that is coming is whether we can start incorporating some forms of immunotherapy, whether these are NK cell-based, T cells, in patients who will achieve remission but often have detectable low-level disease burden, what we call measurable residual disease or minimal residual disease. So those are two of the big questions in the AML field that are being looked at in ongoing clinical trials to move beyond the HMA/ven in the older unfit.

1:51 | Now in the younger patients, especially those below 60, we're still using intensive chemotherapy. In this population, the big change over the last couple of years has probably been the use of FLT3 inhibitors. So about 1/3 of patients will have a FLT3 mutation, and these patients respond better and have a more durable response and improve survival with the addition of of FLT3 inhibitors to the intensive chemo backbone. So this was now shown in 2 randomized phase 2 studies. One of them was called a RATIFY study [NCT00651261] that added midostaurin [Rydapt] to the backbone of 3+7 intensive chemo showing an improvement in survival compared to placebo with 3+7 in FLT3-mutated patients. And then the more recent study was the QuANTUM-First study [NCT02668653], which looked at quizartinib added to the backbone of induction 3+7 vs placebo [and] 3+7, again, showing a significant improvement in survival.

2:41 | We tend to use more quizartinib. And I think we will continue to use that more, especially now that it is FDA-approved, because this is a more specific potent FLT3 inhibitor also has shown better single-agent activity and seems to have better tolerability and when you look at the data in the below-60 population, which is what was allowed in the RATIFY study. We are seeing actually the survival is close to 60% as compared to about 50% 5-year survival with RATIFY, so I think quizartinib is going to be the FLT3 inhibitor use most predominantly in younger, fitter patients with FLT3 mutations who are getting intensive chemo. So these are probably the big overarching changes and directions in older and younger AML today.