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February 25, 2019
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Will targeted therapies become the mainstay of AML treatment?

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Click here to read the Cover Story, “Targeted treatments for acute myeloid leukemia yield modest improvements, great hope.”

POINT

Yes.

After a long drought, the past 2 years have seen a flurry of drug approvals in AML, including three highly specific agents that target discrete mutations — ivosidenib for IDH1 mutations, enasidenib for IDH2 mutations and gilteritinib for FLT3 mutations. IDH mutations occur in approximately 20% of patients with AML and FLT3 mutations occur in approximately 30%, with perhaps 5% having both mutations. In other words, approximately 45% of patients realistically could receive at least one targeted agent.

Alexander E. Perl, MD, MS
Alexander E. Perl

Although these drugs have each been approved as single-agent therapies for relapsed/refractory patients based upon response and toxicity data, — rather than proven effects upon survival from randomized studies, data for which are forthcoming — monotherapy of advanced leukemia likely only provides a glimpse of their full potential.

Relapsed/refractory AML is highly polyclonal, occurs in response to multiple genetic and epigenetic events, and is uniformly lethal in the absence of HSCT. Because molecularly targeted drugs attack the functional consequences of a single mutation, their clinical activity merely has a disease-stabilizing effect in patients not subsequently transplanted. Ultimately, clonal selection and/or evolution breeds drug resistance and targeted therapy loses its effectiveness. This has led some to downplay the potential benefits of targeted agents.

Instead, two obvious strategies emerge as major priorities for the field.

First, targeted agents should be used earlier in therapy to enhance frontline results and prevent, rather than treat, relapse.

Second, targeted agents should be combined with other effective antileukemic agents. Although IDH and FLT3 inhibitors are active as single agents, they have limited ability to clear cells from the marrow because they exert antileukemic effects through the induction of terminal differentiation. Thus, cytotoxic or novel agents that induce apoptosis (eg, venetoclax) emerge as obvious choices to pair with molecularly targeted drugs; these studies are underway. If successful, targeted agents realistically could be moved to the frontline setting to benefit a larger group of patients.

This approach has already proven successful with FLT3 inhibitors. The RATIFY study demonstrated that adding the multikinase inhibitor midostaurin to cytarabine/daunorubicin-based intensive chemotherapy in newly diagnosed FLT3-mutated patients improved survival. These results led to the approval of midostaurin in 2017, establishing a new standard of care. If midostaurin’s success is indeed due to FLT3 inhibition rather than nonselective kinase inhibition, then more potent and selective FLT3 inhibitors — such as gilteritinib or the investigational drugs crenolanib (Arog Pharmaceuticals) or quizartinib — potentially could yield transformative results. Given a proven benefit, physicians should seek out patients with FLT3 mutations to add agents shown to improve therapeutic outcomes.

A final strategy under study is maintenance therapy with targeted drugs. Large single-arm and smaller randomized studies of sorafenib (Nexavar, Bayer) or midostaurin given after transplant for up to 2 years suggest substantially lower rates of relapse and relapse-related death with FLT3 inhibitor maintenance, particularly among patients not treated with frontline midostaurin.

Randomized phase 3 studies testing gilteritinib vs. placebo given after consolidation or transplant are underway and have incorporated measurable residual disease assessment to better characterize what population would benefit. Frontline and maintenance studies with IDH inhibitors are ongoing and no doubt will clarify in what treatment contexts these drugs offer maximal benefits. Preliminary data show intensive chemotherapy combined with IDH inhibitors is feasible, and we await long-term efficacy data.

Overall, randomized data to support the recently approved targeted agents within their label indication are limited, but available data nonetheless suggest that a substantial number of patients could benefit from targeted agents outside of the relapsed/refractory context and, thus, their use is likely to expand significantly.

Reference:

Stone RM, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1614359.

Alexander E. Perl, MD, MS, is associate professor in the division of hematology-oncology, leukemia program at Penn Medicine’s Abramson Cancer Center. He can be reached at alexander.perl@uphs.upenn.edu. Disclosure: Perl reports consultant/advisory roles with AbbVie, Agios, Arog, Astellas, Daiichi Sankyo, Jazz Pharmaceuticals, NewLink Genetics, Novartis, Pfizer and Takeda; and research support to his institution from Astellas, Bayer, Daiichi Sankyo, FujiFilm and Novartis.

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COUNTER

No.

It is very logical that personalized, genomically defined therapies are foremost in our minds for treating AML today. Over the past 10 years, our field has taken genomic sequencing from a research-only effort to a standard-of-care test performed at diagnosis. The results yield powerful insights into the biology of each patient’s specific disease, and it follows that this should allow us to break down AML into its elemental parts and pick off each mutation with laser-focused, highly personalized therapies. Given our emphasis on genomics, and access to this information, it makes sense that we’ve come to this point where it seems like this is the way forward. But I don’t think this is the way things are going to go.

Daniel A. Pollyea, MD
Daniel A. Pollyea

Don’t get me wrong. I think targeted, genomically defined therapies have an important role, but that role is still not clearly defined and it won’t be the panacea we all hoped it would be. I think there are several reasons why this is true.

First, there are probably a limited number of targetable genes. Several drugs targeting these genes are already FDA approved and others are in the queue, but the number of genes we now regard as druggable is very small compared with the total number of genes we know can be mutated in this disease. If we pick away at this disease one gene at a time, the cupboard looks a bit bare and the pipelines look a bit dry. Barring major changes in the way we target mutated genes (and in our field, I admit this could change overnight), we just don’t have the weapons in the arsenal for our heterogenous disease.

Let’s assume that by the time you read this I’m already wrong, and a major breakthrough that allows for the targeting of currently undruggable genes has rendered my above argument obsolete. We now have a targeted therapy for every gene our patients can acquire. We’ll diagnose a patient, find they have mutations in ASXL1, SRSF2 and RUNX1 and prescribe them an ASXL1, SRSF2 and RUNX1 inhibitor, just like we’ve always envisioned. I would be concerned about the tolerability of this approach. Patients have plenty of toxicity with just one targeted therapy; what would the side effect profile of this regimen look like? Overlapping toxicity is going to be a problem, and a limitation.

Flash forward to the hopeful future and let’s assume I’m wrong again (usually a safe bet). It turns out all of these targeted therapies are actually very well-tolerated by our elderly, comorbid patients. We still have a major obstacle: AML is a clonally evolving monster that will not rest just because we picked off the mutations we could detect. Any AML facing this bottleneck will simply adapt, and the selective pressure we applied will result in a new clone or disease with resistant mutations. The best-case scenario of this strategy is a temporary pause in the disease. This is a game of whac-a-mole we will never win.

So, is it all hopeless? I don’t think so. Instead of spending so much time and energy trying to ascertain what makes each patient’s disease different, perhaps we should start focusing on what this disease has in common. For example, the leukemia stem cell compartment has some common weaknesses in the way they metabolize energy that appear to be consistent between patients, agnostic of features like genomic signatures and cytogenetic profiles. Exploiting these weaknesses may free us from depending on strategies that will impact small slivers of the population and bring us shallow and short-term responses. Genomically defined personalized therapies are here to stay and have made and will continue to make their mark on AML. But, if this strategy turns out to be the mainstay of therapy, we will continue to struggle mightily with this disease.

Daniel A. Pollyea, MD, is associate professor of medicine and clinical director of leukemia services at University of Colorado School of Medicine in the division of hematology. He can be reached at daniel.pollyea@ucdenver.edu. Disclosure: Pollyea reports research funding from AbbVie and consultant roles with AbbVie, Agios, Astellas, Celgene, Daiichi Sankyo, Gilead and Pfizer.