A phase I trial of bexarotene, a retinoid X receptor agonist, in relapsed or refractory non-M3 acute myeloid leukemia (AML)

Abstract

6567 Background: In vitro, bexarotene inhibits the proliferation of non-M3 AML cell lines and induces differentiation of leukemic blasts. This phase I study was designed to evaluate the safety of escalating doses of bexarotene in patients with relapsed or refractory non-M3 AML. Methods: Bexarotene was administered orally daily until disease progression occurred. Five dose levels ranging from 100 to 300 mg/m2 were planned. Dose escalation occurred in cohorts of 3–6 patients based on dose-limiting toxicity. Results: Fourteen patients have been enrolled in 4 dose cohorts (100–250 mg/m2) with enrollment demographics: 8M/6F, median age 63 (range 51–76), 6 prior MDS, 6 primary refractory, median number of induction attempts 2, prior autologous stem cell transplant 4, 14 blood transfusion dependent, 12 platelet transfusion dependent, and 12 neutropenic. Two patients developed hypothyroidism. Despite prophylactic use of antihyperlipidemic agents, 4 patients developed grade 2 or 3 hypertriglyceridemia. Two patients developed a syndrome reminiscent of retinoic acid syndrome, consisting of dyspnea/hypoxia, pleural/pericardial effusions, weight gain/edema and dry cough in the setting of a rapidly rising neutrophil count. This syndrome resolved within 48 hours of stopping bexarotene and initiating steroids. One patient had a WBC rise from 1.7×103/μL (ANC 1,037/μL, 18% blasts) pre-bexarotene to 23.9×103/μL (ANC 19,368/μL, 3% blasts) during this syndrome. Flow cell sorted peripheral blood neutrophils all contained this patient’s original t(8;21) by FISH, suggesting differentiation of the leukemic blasts. Bone marrow blasts decreased to ≤5% in two patients. Three platelet transfusion dependent patients had increases in their platelet counts to a peak count of 40–292×103/μL on bexarotene. Conclusion: Daily oral bexarotene is well tolerated at the dose levels studied to date. Early evidence for activity has been seen as exemplified by improvement in platelet counts, decreased bone marrow blast counts, blast differentiation and possible retinoic acid syndrome. Patient enrollment is ongoing. [Table: see text]