Alternative treatment for acute promyelocytic leukemia promising

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1. Patients with newly-diagnosed low-to-intermediate risk acute promyelocytic leukemia (APL) treated with all-trans retinoic acid (ATRA) plus arsenic trioxide experienced similar outcomes to patients treated with conventional ATRA plus anthracycline-based chemotherapy. 

2. Patients with APL treated with ATRA plus arsenic trioxide experienced significantly lower rates of hematologic side effects (neutropenia, thrombocytopenia, fever of unknown origin, infectious episodes) but significantly higher rates of hepatic toxic effects and prolongation of the QTc interval. 

Evidence Rating Level: 1 (Excellent) 

Study Rundown: This randomized control study showed that in newly diagnosed patients with low-to-intermediate risk APL, combination induction and consolidation therapy with ATRA and arsenic trioxide was non-inferior to the current standard-of-care treatment with ATRA-anthracycline chemotherapy. Benefits of combination therapy with arsenic trioxide were measured in terms of event-free survival at 2 years after diagnosis and appear to derive from reduced incidence of severe cytopenias, mucositis, and infections, which were more commonly associated with chemotherapy.  However, these benefits were counterbalanced by a significantly increased rate of toxic hepatic effects and prolonged QTc intervals in patients treated with ATRA-arsenic trioxide, warranting close monitoring of serum electrolytes, liver transaminases, and cardiac arrhythmias. The median follow-up period of 34.4 months suggests that future studies, potentially with larger treatment groups, will be required to investigate the longer term usage of this drug combination.

Click to read the study, published today in NEJM

Relevant Reading: Management of acute promyelocytic leukemia

In-Depth [randomized control trial]: This study compared the efficacy and adverse effect profiles of ATRA-arsenic trioxide versus standard-of-care ATRA-chemotherapy for the treatment of newly diagnosed APL classified as low-to-intermediate risk (WBC count at diagnosis ≤ 10×10⁹ per liter).  162 patients were randomized into either treatment arm from multiple centers across three countries.

The primary end point was event-free survival at 2 years after diagnosis, with treatment failure defined as lack of complete hematologic or molecular remission after induction therapy or three consolidation courses respectively, molecular relapse, hematologic collapse, or death. The median follow-up period was 34.4 months.

97% of patients in the ATRA-arsenic trioxide group were alive and event-free at 2 years as compared with 86% in the ATRA-chemotherapy group (95% CI 2 to 22 percentage points, P<0.001 for noninferiority and P=0.02 for superiority).  Severe neutropenia and severe thrombocytopenia lasting more than 15 days were significantly more frequent in the ATRA-chemotherapy group than the ATRA-arsenic trioxide group. There were 59 episodes of fever of unknown origin and infections in the ATRA-chemotherapy group versus 26 episodes in the ATRA-chemotherapy group (P<0.001). However, 63% of patients in the ATRA-arsenic trioxide group versus 6% in the ATRA-chemotherapy group experienced severe hepatic toxicity (P<0.001).

By Matthew Growdon and Mitalee Patil

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