CCR Translations

Expanding the Use of Retinoids in Acute Myeloid Leukemia: Spotlight on Bexarotene 55CommentaryonTsaietal.,p.5619

Suzan McNamara and Wilson H. Miller, Jr.

In this issue, Tsai et al. (1) report on a phase-I clinical trial of AML cells (4). These encouraging preclinical results promp- bexarotene in 27 non-M3 acute myeloid leukemia (AML). AML tedTsaietal.(1)totesttheefficacyandsafetyofbexarotene is characterized by abnormalities in the myeloid line at various in non-M3 AML patients. stages of commitment and maturation, leading to an accumu- Tsai et al. (1) report on a phase I clinical trial of bexarotene in lation of granulocyte or monocyte precursors. The French, 27 non-M3 AML patients who had relapse, had refractory AML, American, and British classification system divided the subtypes or were not eligible for chemotherapy. This study was designed of AML, M0 through M7, based on the stage of development of to evaluate bexarotene tolerability, toxicity, and activity. myeloblasts at the time of diagnosis. With the exception of M3 Bexarotene was administered daily at escalating doses of 100 AML, all AML subtypes are typically treated with intensive to 400 mg/m2. Overall, bexarotene was well tolerated, with chemotherapy induction aimed to bring the patient into only one patient reaching dose-limiting toxicity. The most complete hematologic remission. Eradication of residual common adverse effects were hypertriglyceridemia and hypo- disease to prevent AML relapse requires consolidation therapy, thyroidism, which were controlled with antihyperlipedemic which consists of intensive chemotherapy alone or in combi- agents and thyroid replacement hormone, respectively. How- nation with stem cell transplantation. Nevertheless, there is a ever, due to the occurrence of a grade 3 rash in three of six high riskof relapse, and long-term survival is less than 50%. patients who were treated at the highest dose of 400 mg/m2,the Furthermore, the low tolerance to intensive chemotherapy maximum tolerated dose was determined to be 300 mg/m2. observed in many elderly AML patients poses a treatment Response was based on changes in peripheral blood counts and challenge in a disorder that is primarily diagnosed in older bone marrow blast percentage. Five patients achieved a adults. significant clinical response, of whom four experienced a Retinoids serve as intracellular messengers or activating reduction in bone marrow blasts to V5% and one patient had ligands for the retinoic acid receptors (RAR) and retinoid X a considerable reduction in blast count from 90% to 20%. Four receptors (RXR). Because of their potential to inhibit growth patients who were thrombocytopenic at the time of study and promote differentiation, retinoids hold therapeutic initiation had platelet responses, and seven patients had promise in treating cancer, especially when used in combi- improved neutrophil counts. Medium overall survival rate nation with other chemotherapeutic agents. Most notably, in was 3.4 months, with a range of 0.1 to 18.8+ months. After 1 acute promyelocytic leukemia patients, the M3 AML subset, year of study, three patients had continued improvements in differentiation therapy induced by all-trans-retinoic acid has their blood counts. provided one of the first examples of a successful therapy Evidence of myeloid differentiation was identified in the that targets the molecular cause of an aggressive malignancy three patients with improved absolute neutrophil count and (2). Apart from acute promyelocytic leukemia, there has reduction in leukemic blasts. Fluorescence in situ hybridiza- been little evidence that other AML subtypes could respond tion analysis was done on peripheral blood granulocytes using to retinoid differentiation therapy. This has been frustrating probes for the patients’ known leukemic cytogenetic abnor- because in vitro studies have shown more promising results. mality. Indeed, between 92% and 100% of the mature For instance, the rexinoid bexarotene (Targretin) has been circulating granulocytes held the patients’ respective cytoge- shown to be effective in AML cell lines by inhibiting netic abnormality. These intriguing results suggest a leukemic proliferation and inducing differentiation (3). Moreover, origin with myeloid differentiation. Further evidence of the combination treatment of rexinoids and cyclic AMP– myeloid differentiation was observed in two patients who elevating drugs triggered differentiation and apoptosis in developed symptoms consisting of respiratory distress, dry AML patient blasts and all-trans-retinoic acid–insensitive cough, pleural and/or pericardial effusions, edema, and a rapidly increasing neutrophil count. Symptoms were resolved within 48 hours of discontinuation of bexarotene and initiation of steroids. Interestingly, these adverse effects closely mirror the differentiation syndrome observed in f25% of Authors’Affiliations: Sir Mortimer B. DavisJewish General Hospital Segal Cancer all-trans Center, and Department ofOncology, McGill University, Montreal, Quebec, Canada acute promyelocytic leukemia patients treated with - Received 5/23/08; accepted 6/2/08. retinoic acid or arsenic trioxide. Although still not complete- Requests for reprints: Wilson H. Miller, Sir Mortimer B. Davis Jewish General ly understood, it is thought that the syndrome is caused by Hospital Segal Cancer Center and Department ofOncology, McGill University, the release of cytokines from differentiating malignant 3755 Cote-Ste-Catherine, E504, Montreal, Quebec, Canada PQ H3T1E2. Phone: myelocytes. 514-340-8222-4365; Fax: 514-340-7576; E-mail: [email protected]. F 2008 American Association for Cancer Research. Bexarotene is a synthetic rexinoid compound that has doi:10.1158/1078-0432.CCR-08-1081 shown efficacy in the treatment of cutaneous T-cell lympho-

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Fig. 1. The binding ofbexarotene to RXR activates multiple pathways through heterodimerization with several nuclear receptors to regulate the expression of genes important in differentiation, apoptosis, and cell growth.

ma (5, 6). Bexarotene selectively binds and activates all three complexity, bexarotene may elicit its effects through epige- RXR subtypes (RXR-a,RXR-h, and RXR-g), whereas it has netic modulations, as observed with the ability of all-trans- low affinity for RARs. RXRs form homodimers in vitro and retinoic acid to induce epigenetic changes associated with serve as heterodimerization partners for several nuclear transcriptional activation (12, 13). These clinical results will receptors (7). Consequently, RXR enhances the binding of encourage future studies to delineate the genes, signaling the partner receptor to its cognate response element, which is pathways, and molecular mechanisms responsible for bexar- required for proper activation function. Once activated, RXR otene activity in AML blasts. heterodimers function as transcription factors that regulate In conclusion, the trial by Tsai et al. (1) establishes gene expression. Thus, RXR serves as an integrative partner in bexarotene as safe and potentially useful for the treatment multiple signaling pathways (Fig. 1). RXR signaling com- of non-M3 AML patients. This study provides the first evidence prises two types of ligand-mediated transcriptional activation of differentiation syndrome in non-M3 AML patients and termed permissive and nonpermissive. Permissive partners suggests that bexarotene has the ability to induce the can be activated by an RXR agonist or a partner receptor maturation of AML blasts. The optimal dose of 300 mg/m2 agonist, independently or together, to induce a synergistic is now being evaluated in phase II trials, where bexarotene activation. In contrast, nonpermissive nonliganded partners monotherapy will be tested in AML patients to further explore inhibit RXR agonist activation, a phenomenon called RXR its safety, bone marrow response rates, and overall survival. subordination (8). Heterodimers formed by RAR and RXR However, it is likely that this agent will work best in are nonpermissive because they activate transcription only combination with other agents and only in certain subtypes upon RAR ligand binding. However, in the presence of both of AML patients. Additional studies will be needed to define RAR and RXR ligands, synergistic activation of transcription combination treatments and profiles of responsive versus is induced through a heterodimeric allosteric mechanism nonresponsive patients. Nonetheless, this study opens novel (9, 10). In addition, a mechanism has been described by perspectives for a differentiation therapy that may offer real which protein kinase A activation leads to corepressor release promise in the treatment of AML. from RAR that permits RXR agonists to activate the RXR/RAR heterodimer (4, 11). Whether bexarotene induces its effects in AML patients through synergy with RAR ligands or Disclosure of Potential Conflicts of Interest perhaps through a RAR-independent pathway via other heterodimer partners still remains unclear. To add further No potential conflicts of interest were disclosed.

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Suzan McNamara and Wilson H. Miller, Jr.

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