Editors' ChoiceCancer

An Inferiority Complex for Chemo

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Science Translational Medicine  24 Jul 2013:
Vol. 5, Issue 195, pp. 195ec121
DOI: 10.1126/scitranslmed.3006983

Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia that is driven by an oncogenic fusion between promyelocytic leukemia protein (PML) and the retinoic acid receptor alpha (RARA). The standard of care for newly diagnosed APL includes a combination of DNA-damaging chemotherapy and the RARA-targeted compound all-trans retinoic acid (ATRA), which leads to remarkable cure rates exceeding 80%. The inclusion of chemotherapy, however, causes severe toxicities to the hematologic system, such as thrombocytopenia and neutropenia, and in some cases can lead to treatment cessation or death. Arsenic trioxide targets PML and may be an alternative to chemotherapy, without the toxic side effects. To refine the treatment for APL in a way that maximizes target specificity and reduces toxic side effects, Lo-Coco and colleagues conducted a phase 3, multicenter trial to compare the efficacy and toxicity of ATRA treatment in combination with either chemotherapy or arsenic trioxide.

Patients with PML-RARA–positive, low-to-intermediate risk APL were randomly assigned to receive ATRA with either arsenic trioxide or chemotherapy, and then monitored for 2 years for evidence of disease and toxic side effects. Strikingly, the 2-year disease-free survival rates were 97% for ATRA-arsenic trioxide and 90% for ATRA-chemotherapy, demonstrating that a drug combination that does not include chemotherapy is as effective as, and possibly superior to, one that does. Although patients receiving ATRA-arsenic trioxide had an increased level of manageable hepatic toxicity, they also experienced considerably less of the dangerous hematologic toxicities endured by patients receiving ATRA-chemotherapy. Future studies are still necessary to test whether high-risk APL patients will also benefit from this new combination.

This trial represents one of the first examples of a curative cancer regimen that eliminates the need for chemotherapy by exploiting a synergy between two drugs that target separate regions of the same oncoprotein. If results of the long-term follow-up are promising, APL patients may skip chemotherapy altogether but still have a cure and a better quality of life.

F. Lo-Coco et al., Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N. Engl. J. Med. 369, 111–121 (2013). [Abstract]

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