Single Agent Tamibarotene Has Activity in Acute Promyelocytic Leukemia Patients Previously Treated with ATRA and Arsenic Trioxide, but Does Not Produce Durable Responses

Background:

Treatment of acute promyelocytic leukemia (APL) with arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) is highly effective as first-line therapy, although approximately 10% of patients relapse after treatment. Several mechanisms of ATRA resistance have been proposed including accelerated clearance of ATRA and increased levels of cellular retinoic acid-binding protein (CRABP), which induces retinoic acid metabolism. Tamibarotene is a synthetic retinoid that does not significantly bind CRABP, suggesting that it might be effective in APL patients with ATRA resistance. Tamibarotene has shown efficacy in APL patients with relapse after chemotherapy and ATRA, but has not been studied in relapse after treatment with ATO and ATRA

Methods:

We conducted a multicenter phase II clinical trial of tamibarotene in adult patients with relapsed or refractory APL after treatment with ATRA and ATO (concomitant or sequential). Participants were treated with single agent tamibarotene at a daily dose of 6 mg/m² for up to 56 days during induction. Patients achieving a complete response were eligible to continue on consolidation treatment with tamibarotene at the same dose for a maximum of six 28 day cycles. The primary outcome for this trial was to determine the rate of durable complete response (CR) using tamibarotene as a single agent. Secondary outcomes included the rate of morphologic complete remission, partial response, cytogenetic complete response, molecular complete response as well as the safety profile and tolerability of this medication.

Results:

We enrolled 14 patients from March 2008 to October 2011 at 8 centers. The median age of the participants was 56 years (range 20-76). Twelve patients had relapsed APL and 2 had primary refractory disease. Patients had a median of 2 remissions (range 1-5) prior to enrollment with a median time from the most recent remission to study screening of 23 months (range 2-102). Twelve patients (86%) had received other treatments including stem cell transplant (n=4) in addition to ATO and ATRA prior to enrollment. Eight patients achieved a morphologic remission during treatment with tamibarotene and 2 had a partial response (>50% reduction in BM blasts). Three (21%) patients with complete morphologic remission had a CR, whereas 5 (36%) had a complete remission with incomplete hematologic recovery (CRi), without meeting pre-specified recovery of neutrophil (>1,000/μL) and platelet counts (>100,000/μL). Seven out of 8 patients who achieved CR or CRi relapsed after treatment. The median duration of response for patients achieving CR was 203 days (range 183-212). The median overall survival for the entire group was 233 days (95% CI 196-526 days). Thirteen patients reported treatment-emergent adverse events, although the majority were mild (Grade 1-2). The most frequently reported adverse events included rash (n=6, grade 1-3), headache (n=4, grade 1) and neutropenia (n=3, grade 3-4). Two patients experienced APL differentiation syndrome (grade 2). Two patients discontinued the study due to adverse events: one patient developed progressive multifocal leukoencephalopathy and the other developed pneumonia, although neither of these events was thought to be related to tamibarotene.

Discussion:

These results suggest that tamibarotene has activity in patients with relapsed APL after treatment with ATO and ATRA. Although the CR rate of 21% is lower than that reported in a previous trial using tamibarotene (58%; Tobita, 1997), the 24 patients in that study had received ATRA alone or in combination with chemotherapy, but not ATO. Thus, tamibarotene has significant clinical activity in this heavily pre-treated population with acceptable toxicity. Further studies using tamibarotene as initial therapy and in combination with ATO are warranted.