February 2019 Edition Vol.11, Issue 2

Molecular Testing Becoming Essential in AML Treatment

By Ted Bosworth

Introduction

Precision medicine in acute myeloid leukemia (AML) has arrived, and the definition of adequate molecular profiling is rapidly evolving. This summary, based in part on an education program at the 2018 American Society of Hematology annual meeting called AML: Moving Beyond 7 + 3, updates the issues and the potential for AML subtyping to guide therapy.

In 2010, guidelines from the European LeukemiaNet (ENL) recommended molecular profiling for patients with AML by screening for NPM1, CEBPA, FLT-3ITD, and TP53 mutations.1 In a 2017 update, RUNX1, ASXL1, and BCR-ABL1 were added.2 Although the purpose of surveying these mutations was risk stratification, two of these mutations have now become targets of an approved therapy.

Additional mutations not listed in the ENL 2018 guidelines have also become therapeutic targets either with newly approved agents or novel therapies that have reached clinical trials. The result is a fundamental change and evolving approach to treating AML.

Practical Molecular Characterization of AML

The characterization of AML by cytogenetics rather than morphology was made possible by studies that isolated several somatic mutations associated with risk of disease and disease progression.3 Ongoing classification of AML subsets by molecular profiling is providing new insight into disease biology, prognosis, and treatment. However, profiling is not simple. Despite the fact that about 50% of AML patients have a normal karyotype, the average number of somatic AML-related mutations is three.4

Although personalized therapy may become available for most patients with AML, its role should not be overstated. By themselves, targeted therapies are not now or likely soon to fully replace cytotoxic chemotherapy regimens, which remain a backbone of AML therapies with curative intent.

Emphasizing this point Laura C. Michaelis, MD, Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, characterized tension between targeted agents and cytotoxic therapy as “likely a false choice.” Dr. Michaelis iterated that chemotherapy is a standard or part of a standard for most AML patients. For those eligible, the classic 7+3 (cytarabine plus an anthracycline) induction regimen, whether or not it is modified with additional agents, has so far offered the greatest potential for cure or long-term remission.5

Yet, targeted therapies have an important and growing role in AML. In patients eligible for front-line chemotherapy, the addition of an FMT3 inhibitor is now a standard when that target is present. On the basis of other recent approvals, two other targeted therapies can now be considered in the front-line setting. Both the BCL-2 inhibitor, venetoclax, and the hedgehog pathway inhibitor, glasdegib, are reserved for those who are ineligible for intensive chemotherapy. However, based on the studies that led to approval, neither requires first establishing the presence of the target.

In the relapsed and refractory setting, three targeted therapies can now be considered on the basis of a molecular profile with the expectation that this list will soon grow.

According to Elizabeth A. Griffiths, MD, an associate professor of oncology at Roswell Park Cancer Institute, Buffalo, New York, molecular profiling for therapeutic decisions—not just risk stratification—has come to standard AML management.

Dr. Griffiths explained that it is reasonable to extend routine molecular profiling beyond those in the 2017 ELN guidelines to include “a broad net” of potentially druggable mutations with the expectation that profiling will be even more extensive as the cost of next generation sequencing (NGS) declines and more is understood about the prognostic significance and druggable potential AML-associated mutations.

Due to the evolving mutational burden in AML and its impact on treatment decisions during progressive AML, Dr. Griffiths advised that it is appropriate to consider molecular profiling at the time of diagnosis, at the time of complete remission, and at the time of relapse. Each offers potential opportunities for individualizing therapy. Although she acknowledged that the definition of optimal mutational profiling is a moving target, she indicated that profiling is no longer optional.

In the Case of FLT3 Mutations…

Approximately 30% of patients with AML have a fms-related tyrosine kinase 3 gene (FLT3) mutation, of which the most common is a tandem duplication (FLT3-ITD).6 Mutations in FLT3, which has a role in cell proliferation, are associated with a poor prognosis in AML and an increased risk of relapse. The FLT3 mutation was proven druggable in the landmark RATIFY trial in which the addition of the FLT inhibitor, midostaurin, improved overall survival (HR 0.78; P=0.009) relative to 7+3 alone in the first-line setting.7 The study enrolled 717 patients less than 60 years of age positive for FLT-ITD.

On the basis of RATIFY, midostaurin became the first AML therapy approved for a mutational profile subset. Subsequently, the FLT3 inhibitor gilteritinib received FDA approval for relapsed or refractory FLT3-ITD or FLT3-TKD mutation-positive AML on the basis of interim analysis in the ADMIRAL trial.8

Other inhibitors with varying specificity for FLT3 have reached late stages of clinical testing and are likely to expand the list of drugs in the class.

With IDH 1/2 Mutations…

Up to 20% of patients with AML have somatic mutations in isocitrate dehydrogenase 1 (IDH1) or 2 (IDH2) genes.9 Both genes play a role in cellular metabolism, including control of oxidative stress.10 The IDH1 inhibitor ivosidenib was approved in 2018 for relapsed or refractory AML patients positive for IDH1 mutation. Within weeks of that approval, the IDH2 inhibitor enasidenib was approved for relapsed or refractory IDH2 mutation-positive AML. In both cases, respectively, these targeted drugs achieved substantial rates of response in patients with diminishing therapeutic options.11,12

For BCL-2 Overexpression…

As in other hematologic malignancies, BCL-2, which mediates apoptosis, is frequently overexpressed in AML.13 Venetoclax, a BCL-2 inhibitor, was approved in late 2018, in combination with the hypomethylating agents azacitidine or decitabine or with low dose cytarabine for the treatment of newly diagnosed AML in adults who are not candidates for intensive chemotherapy. In this case, the use of venetoclax does not require first establishing BCL-2 overexpression, which was not required in the study on which the approval was based.14

Hedgehog Pathway Signaling…

Activation of hedgehog pathway signaling has been implicated in the pathogenesis of AML and in increased drug resistance among AML patients specifically.15 The hedgehog pathway inhibitor glasdegib, approved November 21, 2018, is one of the newest treatment options for AML. It is indicated in combination with cytarabine as a first-line therapy for adult AML patients who are not candidates for intensive chemotherapy. Hedgehog pathway activation was not required for enrolment in the phase 2 study on which approval was based and is not a prerequisite for glasdegib treatment in the labeling.16

Proof of Principle: the BEAT AML Umbrella Study

By establishing a survival benefit with an FLT3 inhibitor, the RATIFY trial was the first to establish that treatments selected on the basis of upfront molecular profiling improves outcomes. The concept is being further explored in the BEAT AML Umbrella study, presented at the 2018 ASH meeting (abstract 559). The ongoing proof of principle study, led by Amy Burd, PhD, an investigator from the Leukemia and Lymphoma Society, began enrolling previously untreated AML patients 60 years of age or older more than two years ago.

In the BEAT phase I/II trial, treatment assignment is based on a cytogenetics profile achieved with NGS. In an early feasibility stage, it was confirmed that cytogenetic results could be reliably obtained within seven days in most patients. Once the AML subtype is established, an appropriate targeted agent is assigned. At the ASH meeting, initial results were presented.

Of the 273 patients assigned to treatment within seven days of enrollment, 146 (53.5%) were treated based on their subtype. There were varied reasons for those who did not receive a subtype-based treatment, but the most common was selection of an alternative not based on the protocol. Consistent with recent approvals, those positive for an FLT3 mutation were assigned gilteritinib with or without decitabine, those positive for an IDH1 mutation were assigned ivosidenib with azacitidine, and those positive for an IDH2 mutation were assigned enasidenib.

Novel agents were assigned to those with AML subtypes for which there is no approved therapy. For example, the Syk inhibitor entospletinib was employed in those with the TP53 positive AML subtype. The experimental anti-CD33 monoclonal antibody BI 836858, administered with decitabine, was assigned to those with Tet2-positive subtype.

Other examples of novel therapies assigned include the Nedd8 inhibitor pevonedistat, which along with a hypomethylating agent was also an option for the TP53-positive subtype, and samalizumab, an anti-CD200 monoclonal antibody that was combined with an induction regimen, in those with the core binding factor (CBF) AML subtype.

Results, although incomplete, have been encouraging. At the time of the ASH 2018 meeting, the substudy of patients with AML who were IDH2 positive and treated with enasidenib had completed enrollment, providing data on immediate drug activity. In this group, there was a 43% rate of complete remission (CR) when including CR with incomplete hematologic recovery (Cri), Dr. Burd reported.

By testing the concept of personalized medicine in AML subtypes, this trial serves “as a model for dynamic, mechanism-based clinical trials in blood cancers where genomic analysis may inform, accelerate, and improve drug treatment,” said Dr. Burd.

Promise and Reality

High-level sequencing in newly diagnosed patients with AML can be considered a standard of care, according to Daniel A. Pollyea, MD, Division of Hematology, University of Colorado, Aurora, but he also called for a “management of expectations” to avoid excess enthusiasm. Dr. Pollyea identified several important limitations not likely to be soon resolved.

Among these, establishing a molecular AML subset does not guarantee response from the appropriate targeted therapy. In addition, responses to targeted therapies used alone are generally brief. Although combination strategies, particularly targeted therapies with cytotoxic agents, offer an increased potential for durable remission through deeper response, Dr. Pollyea cautioned that strategies “to fully realize the potential for genomically derived targeted therapies has yet to be realized.”

He called molecular profiling “a huge leap forward” but indicated that treatments based on single mutations appear unlikely to ultimately fulfill the promise of personalized therapy. Rather, a more detailed understanding of clonal evolution in the individual patient and a broader selection of therapies available for addressing driver mutations appear to be needed to further the role of genomically determined AML management.

References

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