CCR New Strategies New Strategies in Acute Promyelocytic Leukemia: Moving to an Entirely Oral, Chemotherapy-Free Upfront Management Approach

Incorporation of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) into themanagement paradigms of acute promyelocytic leukemia (APL) has markedly improved outcomes. Significant progress occurred in understanding the molecular pathogenesis of APL. ATO, in contrast with ATRA, is capable of eradicating the APL-initiating cells and can result in cure. Preclinical and clinical data confirmed the synergy of ATO and ATRA, and the ATRA–ATO combination was proved noninferior to a standard ATRA–chemotherapy regimen in patients with non–high-risk APL. Oral formulations of arsenic exhibited excellent activity in advanced clinical testing and their combinations with ATRA offer an opportunity for a completely oral, chemotherapyfree regimen for curing APL. Nonetheless, significant challenges remain. Reducing early death due to bleeding complications is an important area of unmet need. Data suggest that delays in initiation of ATRA upon suspectingAPL continue tooccur in the community and contribute to earlymortality.Questions remain about the optimal place and schedule of arsenic in the therapeutic sequence and the role of the oral formulations. Refining the role of minimal residual disease in directing treatment decisions is important. Development of novel targeted agents to treat relapsed disease requires deeper understanding of the secondary resistance mechanisms to ATRA and ATO. Clin Cancer Res; 20(19); 4985–93. 2014 AACR. Disclosure of Potential Conflicts of Interest No potential conflicts of interest were disclosed. CME Staff Planners' Disclosures The members of the planning committee have no real or apparent conflicts of interest to disclose. Learning Objectives Upon completion of this activity, the reader should have a better understanding of the biologic rationale and clinical evidence of combining arsenic with all-trans retinoic acid (ATRA) in the treatment of acute promyelocytic leukemia and how would the ongoing research of oral formulations of arsenic lead to an entirely oral, chemotherapy-free management approaches for the disease. Acknowledgment of Financial or Other Support This activity does not receive commercial support. Background At one time a highly lethal malignancy, significant progress has transformed acute promyelocytic leukemia (APL) into the most curable form of acute myelogenous leukemia (1). APL was one of the first leukemias linked to a recurrent mechanistically important genetic translocation, and remains the only type of leukemia in which oncoproteintargeting therapy cures patients (2, 3). Approximately 98% of patients have a reciprocal translocation, involving the retinoic acid receptor-alpha gene (RARA) on chromosome 17 with the promyelocytic leukemia gene (PML) on chromosome 15 resulting in creation of the chimeric oncogene t (15;17)(q24.1;q21.1) PML–RARA (2, 4). A few patients have translocations involving RARA with other partner genes, the most common of which are t(11;17)(q23; q21.1)PLZF/RARA, t(5;17)(q35;q21.1)NPM/RARA, and t(11;17)(q13;q21.1)NuMA/RARA (5–7). RARA is a nuclear hormone receptor that heterodimerizes with retinoid X receptor to recruit transcription corepressor complexes (CoC) and induces gene transcription repression, except when bound to ligand Department of Oncology, Johns Hopkins University, Baltimore, Maryland. Section of Hematology, Department of Internal Medicine, Yale University, New Haven, Connecticut. Corresponding Author: Amer M. Zeidan. Current address: Department of Medicine, Yale University, 333 Cedar Street, PO Box 208028, New Haven, CT 06520-8028. Phone: 203-737-7103; Fax: 203-785-7232; E-mail: [email protected] doi: 10.1158/1078-0432.CCR-13-2725 2014 American Association for Cancer Research. Clinical Cancer Research www.aacrjournals.org 4985 on May 2, 2017. © 2014 American Association for Cancer Research. clincancerres.aacrjournals.org Downloaded from (4, 8). In APL, PML–RARA proteins recruit CoCs, leading to sustained transcriptional inhibition, blocking myeloid differentiation in a negative dominant fashion, and increasing self-renewal of leukemic progenitor cells (Fig. 1; refs. 8, 9). PML–RARA also exerts negative dominant effects on PML, which also contribute to the pathogenesis of APL (10). At pharmacologic doses, alltrans retinoic acid (ATRA) binds to the RARA moiety of PML–RARA, leading to dissociation of the CoCs and recruitment of transcription coactivators (8, 9). This results in epigenetic reprogramming with transcriptional derepression and eventually into terminal myeloid differentiation (11). A high index of suspicion for APL is essentially based on morphologic (promyelocytic blasts in the peripheral blood smear) and clinical features (e.g., coagulopathy and pancytopenia). Suspected APL is a medical emergency, and prompt initiation of ATRA and aggressive transfusion support should be implementedwithoutwaiting for pathologic and/or genetic conformation (12). The microgranular variant of APL presents a particular challenge for early diagnosis and treatment (13). These monoblast-like cells often have few or no granules visible byWright–Giemsa staining; a high index of suspicion is required when evaluating patients with apparent monoblastic leukemia and coagulopathy (14). Unlikemostmonoblastic leukemias, themicrogranular variant often has bilobed nuclei ("wasp-waisted"; ref. 14). Flow cytometric analysis can support the diagnosis of APL; definitive diagnosis requires documentation of a pathognomic translocation using reverse transcriptase PCR COCs COAs COCs dissociate upon binding of ATRA to RARA moiety