 This select AML [acute myeloid leukemia] study is a randomized study looking at newly diagnosed patients with AML who overexpress RARA. Ultimately, patients will be randomly assigned to receive either venetoclax plus azacitidine plus a placebo, or venetoclax plus azacitidine plus tamibarotene. This is a promising study design because monocytic AML is often resistant to venetoclax, and we also know that monocytic AML often overexpresses RARA. There seems to be some overlap in the diagrams that would allow us to hypothesize that patients who overexpress RARA are also less likely to respond to venetoclax in HMA [hypomethylating agent] onload. The idea behind this study is to try to select from those patients who are going to be less likely to respond to venetoclax and add tamibarotene to their treatment. That’s what the study is doing, and it’s looking at response rates, survival, and the toxicity profile. It’s a promising strategy as a way to potentially have a triplet therapy for a newly diagnosed unfit patient with AML.

If a patient is resistant to venetoclax combinations because of a mechanism that overlaps with increased RARA expression, which we think is possible, then adding tamibarotene could allow a patient to have their response to a venetoclax-based regimen restored. The idea is that if you find a population of patients less likely to respond to venetoclax, and they have some other weakness or target, if you can exploit that target as well, you might be able to overcome the resistance. That’s 1 of the fundamental hopes of this randomized clinical trial.

We’re all really excited, based on our recent history in this field of AML and drug development, that we can continue the momentum we’ve had. New investigational therapies in our field may come in the form of immunotherapies or new targeted therapies against particular gene mutations and chromosome abnormalities. I’m especially thinking of the Menin inhibitors, which are showing so much promise for patients with MLL [mixed lineage leukemia] gene rearrangements and 

 mutations. Those are really promising, and we should all be very enthusiastic about watching how things unfold.

There are many new, exciting biomarkers that have potential. We might be able to inhibit MCL1 in some patients with therapeutic effect. There’s a monocytic target called LILRB4 that might be an appealing target for patients with AML with monocytic differentiation who have a lessened response to venetoclax regimens. Then there are more traditional targets, perhaps a new FLT3 inhibitor, based on some data that we’ve seen on quizartinib. There’s a lot of exciting stuff here and right around the corner.

Videos

Daniel Pollyea, MD, MS, reviews the ongoing SELECT-AML-1 trial and comments on novel therapies and biomarkers in patients with newly diagnosed unfit AML.

Review of the SELECT-AML-1 Trial and the Future of Newly Diagnosed AML

 The use of venetoclax plus an HMA [hypomethylating agent] in AML [acute myeloid leukemia] has been revolutionary. This is the standard of care for a patient who’s newly diagnosed and so-called unfit-for-intensive-chemotherapy. This is increasingly being in other areas as well. For younger fit patients who have disease biology that would be associated with a worse response to standard conventional treatment, or in the relapsed/refractory setting, this is often used off-label. This regimen has really expanded. In just a few years, it’s become a mainstay of the treatment for AML.

Even though we’re very optimistic about the outcomes with venetoclax plus HMA in patients with AML, not everyone responds or has a good outcome. A percentage of patients are refractory, and the majority of responders will ultimately relapse. The community is working really hard to ascertain which factors might be associated with a poor or worsening response to a venetoclax-based regimen. Our group, as well as some others, recently showed that the leukemia cells that arrest at a more mature stage of maturation, the monocytic stage or phase, are more resistant to venetoclax-based regimens. It’s been an observation. It’s also possible that upregulation of MCL1 can overcome resistance to venetoclax, which is a BCL2 inhibitor. We’ve also seen that mutations in 

, are associated with suboptimal outcomes with this regimen. Those are all potential predictors of suboptimal outcomes to this regimen. We also think 

 mutations could go into that category; a lot of work is being done in this area. We’re learning a lot, but we all need to learn more.

Dr Daniel Pollyea discusses the role of venetoclax plus an HMA agent in patients with AML and talks about some possible mechanisms of resistance to the venetoclax-HMA combination.

Venetoclax and HMA Resistance in Patients with AML

 Tamibarotene is a really interesting drug. About 30% of patients with non–APL [acute promyelocytic leukemia] AML [acute myeloid leukemia] overexpress RARA, which is a type of transcription factor. When we add an agonist against that, tamibarotene, it could be an effective tool to induce maturation or differentiation of the leukemia cells. This is very much in question and the subject of clinical trials that are ongoing, but it looks to be a potentially promising therapy. In APL, a type of AML in which RARA overexpression is universal, using a drug like tamibarotene, and tamibarotene itself, has been a really effective strategy for those patients. We’re hopeful that in non-APL AML situations with RARA overexpression, we may also be able to have an effective target with tamibarotene.

In 2020, Eytan Stein and colleagues presented an abstract on the use of tamibarotene plus azacitidine for patients with relapsed/refractory AML who overexpressed RARA. This was presented at the annual meeting for ASH [American Society of Hematology], and a population of patients responded, about 20%. These are relapsed/refractory patients who’ve had multiple other therapies. Historically, the bar is pretty low for them, and we don’t have any good therapies to use. In this very small study, there’s reason to be optimistic about this combination for this population of patients, and the toxicity profile was not overly concerning. Given the tolerability of the therapy and some efficacy responses in a relatively small population, there’s reason to be hopeful that this could be an effective treatment for the percentage of patients who overexpress RARA.

Daniel Pollyea, MD, MS, reviews the initial results from the biomarker-directed phase 2 tamibarotene trial that were presented at ASH 2020.  

Potential Role of Tamibarotene in AML

 When a patient is diagnosed, it’s crucial to test for particular biomarkers. Here, we’re talking about different cytogenetic abnormalities or gene mutation status, what we call molecular tests. Those are crucial for us to be able to effectively treat, and in some cases cure these patients. It’s really important to get that biomarker testing, and we do recommend cytogenetic testing and a comprehensive profile of gene mutations to be tested at diagnosis, because that changes the way we treat these patients. We don’t test for 

 expression in any cases in the newly diagnosed setting. With tamibarotene, which is a 

 agonist, there’s a clinical trial looking at patients who overexpress this gene to see if they may benefit from the addition of tamibarotene. But outside of the clinical trial, it is not standard to do any sort of testing for 

As for barriers to the routine testing, cytogenetic and molecular testing, there are many; the main one is probably cost. This varies from place to place and location to location, but it’s cost, and then it’s remembering to do the testing. I think these are the main barriers.

Dr Daniel Pollyea comments on biomarker testing in acute myeloid leukemia and the potential role for RARA testing.

Biomarker Testing in AML

 Hi everybody. I’m Dan Pollyea from the University of Colorado, Division of Hematology, where I direct the clinical leukemia program. We are talking today about tamibarotene in patients with newly diagnosed AML [acute myeloid leukemia].

A patient with newly diagnosed AML now has a variety of different treatment options. If a patient is a suitable candidate for intensive induction chemotherapy, then that is what they receive. That can be the standard 7-plus-3 regimen, with in some cases gemtuzumab, or in other cases, 7-plus-3 with the FLT3 inhibitor midostaurin. Other patients receive the 7-plus-3 regimen alone. Patients with this disease, however, are frequently older and poor candidates for intensive induction chemotherapy because of their age or comorbidities. For them, the standard of care is usually a venetoclax-based regimen, usually venetoclax plus azacitidine. There are a few other caveats to this, but those are the main treatment approaches for a patient with newly diagnosed AML.

Patients are assessed at diagnosis with AML for their suitability for intensive chemotherapy; that’s the way we’ve regarded newly diagnosed patients for a very long time. In the past, if they were a candidate for intensive induction chemotherapy, they got that treatment, and if they weren’t, there weren’t any really good options for that patient. Things have really changed, but not so much with the landscape for the intensive chemotherapy; the backbone of that treatment has stayed safe for a very long time. Things have changed more in the treatment options we have for a so-called unfit patient. But fitness comes down to subjective types of calls. This includes how a patient looks, their performance status, and sometimes more objective things like organ function. But it’s definitely not always a scientific decision as to whether a patient is fit or unfit for intensive chemotherapy.

For a newly diagnosed unfit patient, I think that in the United States, the main treatment approach for these patients is venetoclax plus azacitidine. That therapy was superior to azacitidine alone, and is the new standard of care. We have other options, including the Hedgehog inhibitor glasdegib with low-dose cytarabine, and if a patient has an 

 mutation, we also have the option of using ivosidenib. There are a few other options, but I would say they are not preferred options compared to venetoclax plus usually azacitidine.

A review of treatment options for patients with newly diagnosed acute myeloid leukemia and differences between patients who are fit vs unfit for chemotherapy.

Daniel Pollyea, MD, MS

Articles

Review of the SELECT-AML-1 Trial and the Future of Newly Diagnosed AML

Venetoclax and HMA Resistance in Patients with AML

Potential Role of Tamibarotene in AML

Biomarker Testing in AML

Treatment Options for Patients with Newly Diagnosed Acute Myeloid Leukemia (AML)