Advances in precision epigenetic treatment for acute promyelocytic leukemia.

ABSTRACT

Introduction: Acute promyelocytic leukemia (APL) is the foremost example of a neoplasm whose outcome has been radically changed by the identification of its underlying molecular mechanism and corresponding targeting drugs, namely All-Trans Retinoic Acid (ATRA) and Arsenic Trioxide (ATO). ATRA/ATO combination is able to cure the vast majority of APL patients. Still, a significant fraction of APL patients (high-risk subgroups, elderly and frail patients) still fail to achieve disease eradication. For these patients, additional treatment is required.

Area covered: We reviewed current APL treatment and identified areas of unmet medical need. We provide an overview of the numerous preclinical studies pointing to a role for epigenetic factors in APL. Finally, we review clinical trials on epigenetic drugs in other myeloid neoplasms and the anecdotal clinical evidence in APL.

Expert opinion: Despite an integral role of epigenetic factors in the development, pathogenesis, and emergence of drug resistance in APL, their therapeutic importance has not been fully explored clinically. Ironically, many epigenetic drugs, either in combination with all-trans-retinoic acid or chemotherapy, are in clinical trials for myeloid neoplasms different from APLs. These drugs may play a role for specific APL patient populations.

KEYWORDS:

• Acute promyelocytic leukemia
• precision medicine
• epigenetic drugs
• PML-RAR
• high-risk APL patients
• ATRA/ATO combination therapy

Article highlights

• The role of ATRA/ATO combination is not completely clear in high-risk patients, where toxicity due to chemotherapy is still a problem.

• Appearance of relapse and refractory APL patient and nonresponsiveness of STAT5b-RARα and PLZF-RARα-driven APL to ATRA and/or ATO is a critical concern

• Importance of including epigenetic factors as a potential diagnostic and prognostic tool in APL

• Relevance of clinical testing of epigenetic drugs in combination with ATRA/ATO for relapse and refractory APL.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by Fondazione IEO’CCM, Ministero dell’Istruzione, dell’Universitá e della Ricerca (RBAP10XKNC_002), AIRC-Trideo Foundation (15650), Italian Ministry of Health (51/GR-2011-02350585), European Hematology Association and AIRC (IG-2017-20162).