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How We Treat Patients with Relapsed/Refractory AML

Dinardo, Courtney D. MD, MSCE; Ravandi, Farhad MD

doi: 10.1097/01.COT.0000476189.00210.32
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AML Overview

Figure. C

Figure. C

Standard intensive therapy for newly diagnosed patients with acute myeloid leukemia (AML) consists of the nucleoside analogue cytarabine in combination with an anthracycline as induction chemotherapy, followed by consolidation therapy with repeated cycles of high-dose cytarabine and/or stem cell transplant to maintain complete remission (CR). With such intensive chemotherapy approaches, remissions are common, but unfortunately durable long-term cures occur only in a minority of adult patients with AML. This is especially true in older patients—typically those older than 60 or 65 years of age at diagnosis—which constitute the majority of patients diagnosed with AML.

There are currently no FDA-approved therapies for patients with relapsed/refractory AML. The only drug historically approved in this setting, the anti-CD33 monoclonal antibody gemtuzumab ozogamicin (GO), was withdrawn from the market in 2010 due to concerns for treatment-related toxicity. Thus, there is a clear and unmet need for effective treatment options for patients with relapsed/refractory AML.

In the past decade, extraordinary progress has been made in understanding cancer biology and the mechanisms of leukemogenesis. With the advent and streamlining of modern techniques such as next-generation sequencing, recurrent genomic alterations including cytogenetic abnormalities and somatic mutations can be routinely identified in over 95 percent of AML cases.

Increased knowledge of genomic abnormalities has already led to improved prognostic classification of patients with AML at diagnosis—i.e., the updated European Leukemia Net (ELN) classification system. In addition to improved AML risk-stratification, improved understanding of clonal AML architecture is leading to rationally designed treatment strategies to improve upon both the initial and salvage treatment regimens.

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Treatment Options for Relapsed/Refractory AML

Relapsed/refractory AML can be (rather simplistically) divided into two groups: (1) AML that is sensitive to the conventional chemotherapeutic agents—i.e., cytarabine and anthracyclines; and (2) AML that is intrinsically resistant to or has developed secondary resistance to standard intensive chemotherapy.

Notably, there are certain AML subgroups, such as the core-binding factor leukemias (inv(16) or t(8;21)) and perhaps the newly defined ELN favorable subgroups that are exceptionally sensitive to high-dose cytarabine-based regimens; dose intensification may benefit these patients.

Additionally, if a long time has elapsed between initial complete response from a conventional intensive chemotherapy regimen before relapse (often considered to be 12 or more months) re-challenging the patient with intensive chemotherapy is a warranted and often successful strategy.

For patients with relapsed or refractory AML who fall into the second category, several investigational treatment approaches exist. Detailed AML characterization at the time of relapse is essential, in terms of immunohistochemistry and cytogenetic and molecular annotation, to fully consider all novel agents available on the existing clinical trials.

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Avenues of Salvage Therapy/Clinical Trials

Molecularly Targeted Therapy

Identification of recurrent somatic mutations in AML has improved our understanding of AML pathophysiology, and our awareness of functional AML subsets can now be used to inform rational treatment strategies. Clinical trials with tyrosine kinase inhibitors (e.g., sorafenib, quizartinib, midostaurin, and crenolanib) for patients with activating FLT3 mutations are well underway, with demonstrable activity both as monotherapy and in combination regimens in the front-line and relapsed setting.

IDH1 or IDH2 mutations are recurrently identified in about 20 percent of AML patients, with an increased incidence with increasing patient age, and targeted small molecule IDH1 and IDH2 inhibitors are now available in clinical trials with promising early efficacy as monotherapy in relapsed patients.

Somatic mutations in NRAS or KRAS are also frequent in AML patients, and combination strategies of PI3K/AKT-signaling inhibition and RAS/RAF/MEK/ERK pathway inhibition are ongoing strategies for RAS-mutated AML.

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Antibody-based Therapy

Monoclonal antibodies against commonly expressed myeloid antigens are currently under development, and can be regarded as akin to the anti-CD19, -CD20, and -CD22 antibodies available for patients with lymphoid malignancies.

While the initial anti-CD33 immunotoxin GO is no longer clinically available, novel anti-CD33 compounds including innovative bispecific T-cell engaging (BITE) therapies are now available within clinical trials. Monoclonal antibodies directed against the IL-3R (anti-CD123) are also under clinical development.

As in lymphoid neoplasms, where the addition of monoclonal antibodies to the standard cytotoxic regimens have improved outcomes significantly, it is hoped that the addition of effective antibody-based therapies to AML-specific regimens will improve the outcomes for the majority of patients with AML who express these surface antigens.

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Epigenetic Therapy

The frequency of genomic alterations leading to aberrant epigenetic regulation (i.e., mutations in IDH1/2, DNMT3A, TET2, EZH2, ASXL1, MLL, and others) supports the dysregulation of epigenetic machinery as a fundamental component of leukemogenesis. Treatment with the hypomethylating agents azacitidine and decitabine, provides an important approach in both the front-line and relapsed settings (particularly in the elderly population due to the better tolerability of these agents), with responses seen regardless of the identification of epigenetic mutations.

Second-generation hypomethylating agents (SGI-110) are also under clinical development, with a randomized Phase III study ongoing.

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Additional Salvage Treatment Options

An exhaustive list of currently available and promising clinical trials for patients with relapsed/refractory AML is outside the scope of this brief review, as the speed of scientific discovery in the past decade has led to the development of numerous exciting compounds with unique mechanisms of action and improved safety profiles.

Some notable compounds include the small molecule BCL2 inhibitor (venetoclax), MDM2 inhibitors, the selective inhibitor of nuclear export (SINE) compound selinexor (KPT-330), and the Polo-like kinase-1 inhibitor volasertib. Referral of patients with AML and relapsed/refractory disease to academic leukemia centers of excellence for consideration of appropriate investigational clinical trials is paramount.

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Conclusion

We expect that the future of AML therapy will incorporate well-designed and target-specific molecules into current treatment strategies in an individualized manner, founded upon a detailed understanding of the specific genomic aberrations and aberrant signaling pathways unique to each individual patient.

With improved identification of patient-specific leukemia-promoting pathogenic processes as well as the expanding armamentarium of effective therapeutic options, we will likely witness continued progress in the management of patients with relapsed/refractory AML.

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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