ExpandingtheUseofRetinoidsinAcuteMyeloidLeukemia: SpotlightonBexarotene 55Commentary on Tsai et al., p. 5619 Suzan McNamara and Wilson H. Miller, Jr. In this issue, Tsai et al. (1) report on a phase-I clinical trial of bexarotene in 27 non-M 3 acute myeloid leukemia (AML). AML is characterized by abnormalities in the myeloid line at various stages of commitment and maturation, leading to an accumu- lation of granulocyte or monocyte precursors. The French, American, and British classification system divided the subtypes of AML, M 0 through M 7 , based on the stage of development of myeloblasts at the time of diagnosis. With the exception of M 3 AML, all AML subtypes are typically treated with intensive chemotherapy induction aimed to bring the patient into complete hematologic remission. Eradication of residual disease to prevent AML relapse requires consolidation therapy, which consists of intensive chemotherapy alone or in combi- nation with stem cell transplantation. Nevertheless, there is a high risk of relapse, and long-term survival is less than 50%. Furthermore, the low tolerance to intensive chemotherapy observed in many elderly AML patients poses a treatment challenge in a disorder that is primarily diagnosed in older adults. Retinoids serve as intracellular messengers or activating ligands for the retinoic acid receptors (RAR) and retinoid X receptors (RXR). Because of their potential to inhibit growth and promote differentiation, retinoids hold therapeutic promise in treating cancer, especially when used in combi- nation with other chemotherapeutic agents. Most notably, in acute promyelocytic leukemia patients, the M 3 AML subset, differentiation therapy induced by all-trans -retinoic acid has provided one of the first examples of a successful therapy that targets the molecular cause of an aggressive malignancy (2). Apart from acute promyelocytic leukemia, there has been little evidence that other AML subtypes could respond to retinoid differentiation therapy. This has been frustrating because in vitro studies have shown more promising results. For instance, the rexinoid bexarotene (Targretin) has been shown to be effective in AML cell lines by inhibiting proliferation and inducing differentiation (3). Moreover, the combination treatment of rexinoids and cyclic AMP– elevating drugs triggered differentiation and apoptosis in AML patient blasts and all-trans -retinoic acid–insensitive AML cells (4). These encouraging preclinical results promp- ted Tsai et al. (1) to test the efficacy and safety of bexarotene in non-M 3 AML patients. Tsai et al. (1) report on a phase I clinical trial of bexarotene in 27 non-M 3 AML patients who had relapse, had refractory AML, or were not eligible for chemotherapy. This study was designed to evaluate bexarotene tolerability, toxicity, and activity. Bexarotene was administered daily at escalating doses of 100 to 400 mg/m 2 . Overall, bexarotene was well tolerated, with only one patient reaching dose-limiting toxicity. The most common adverse effects were hypertriglyceridemia and hypo- thyroidism, which were controlled with antihyperlipedemic agents and thyroid replacement hormone, respectively. How- ever, due to the occurrence of a grade 3 rash in three of six patients who were treated at the highest dose of 400 mg/m 2 , the maximum tolerated dose was determined to be 300 mg/m 2 . Response was based on changes in peripheral blood counts and bone marrow blast percentage. Five patients achieved a significant clinical response, of whom four experienced a reduction in bone marrow blasts to V5% and one patient had a considerable reduction in blast count from 90% to 20%. Four patients who were thrombocytopenic at the time of study initiation had platelet responses, and seven patients had improved neutrophil counts. Medium overall survival rate was 3.4 months, with a range of 0.1 to 18.8+ months. After 1 year of study, three patients had continued improvements in their blood counts. Evidence of myeloid differentiation was identified in the three patients with improved absolute neutrophil count and reduction in leukemic blasts. Fluorescence in situ hybridiza- tion analysis was done on peripheral blood granulocytes using probes for the patients’ known leukemic cytogenetic abnor- mality. Indeed, between 92% and 100% of the mature circulating granulocytes held the patients’ respective cytoge- netic abnormality. These intriguing results suggest a leukemic origin with myeloid differentiation. Further evidence of myeloid differentiation was observed in two patients who developed symptoms consisting of respiratory distress, dry 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 acute promyelocytic leukemia patients treated with all-trans - retinoic acid or arsenic trioxide. Although still not complete- ly understood, it is thought that the syndrome is caused by the release of cytokines from differentiating malignant myelocytes. Bexarotene is a synthetic rexinoid compound that has shown efficacy in the treatment of cutaneous T-cell lympho- CCR Translations Authors’Affiliations: Sir Mortimer B. Davis Jewish General Hospital Segal Cancer Center, and Department of Oncology, McGill University, Montreal, Quebec, Canada Received 5/23/08; accepted 6/2/08. Requestsforreprints: Wilson H. Miller, Sir Mortimer B. Davis Jewish General Hospital Segal Cancer Center and Department of Oncology, McGill University, 3755 Cote-Ste-Catherine, E504, Montreal, Quebec, Canada PQ H3T1E2. Phone: 514-340-8222-4365; Fax: 514-340-7576; E-mail: wmiller@ldi.jgh.mcgill.ca. F 2008 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-08-1081 www.aacrjournals.org ClinCancerRes2008;14(17)September1,2008 5311 Research. on June 1, 2020. © 2008 American Association for Cancer clincancerres.aacrjournals.org Downloaded from