All-trans retinoic acid and arsenic rescue patients with acute promyelocytic leukemia from a potential ‘perfect storm’

The outcome of patients with therapy-related acute myeloid leukemia (t-AML) is generally poor, and allogeneic hematopoietic cell transplant may provide the only curative treatment [1]. In striking contrast, the outcome for patients with therapy-related acute promyelocytic leukemia (t-APL) appears to be as favorable as that of patients with de novo APL when treated with all-trans retinoic acid (ATRA) plus anthracycline-based chemotherapy [2,3].

Information describing therapeutic approaches for patients with t-APL is important, since the incidence may be increasing, and efforts to minimize cytotoxic chemotherapy are a major focus of current clinical research in the field [2,4]. This particular subtype of AML generally occurs less than 3 years after treatment of the primary malignancy, and may occur after exposure to chemotherapy (usually the epipodophyllotoxins, anthracyclines, or anthracenediones), radiation therapy, or both. These agents induce cleavage of DNA by topoisomerase II at the translocation breakpoints in APL [5–7]. In one recent small series, dyserythropoiesis or dysmegakaryopoiesis was identified in 11 of 12 patients [8]. Two-thirds of the patients had a cytogenetic abnormality in addition to the characteristic t(15;17) (q22;q21). Interestingly, mutations of the FLT3 (FMS-like tyrosine kinase 3) gene, known to be relatively common in APL in general, were identified in 42% of cases. This observation provides the rationale for combining ATRA with a FLT3 inhibitor in such patients [9].

Recent studies have suggested that treatment of patients with de novo APL with ATRA plus arsenic trioxide (ATO) is a very effective therapeutic strategy [10]. Furthermore, conventional cytotoxic chemotherapy can be minimized and even potentially eliminated. It stands to reason that such treatment of patients with t-APL would be equally effective as that of patients with de novo APL. However, few data are available which address this issue.

Malhotra and colleagues from India report excellent outcomes of three patients with t-APL treated with the combination of ATRA and ATO [11]. While the first patient's history is complicated, all three patients received three cycles of consolidation once in complete remission with ATRA and ATO, and all three patients received maintenance therapy, two with ATRA, 6-mercaptopurine, and methotrexate, and one with these agents plus ATO. Two of the three patients described in the letter by Malhotra and colleagues presented with high-risk disease (white blood cell count ≥10 000/μL), a subset of patients with a generally less favorable outcome when treated with standard ATRA plus anthracyclines.

The follow-up is short for all three patients, but the results are impressive enough to take notice. The optimal number of cycles of ATRA plus ATO to cure as many patients as possible is not known. Furthermore, it is not known if maintenance therapy is definitely required after induction and consolidation with ATRA plus ATO. Nevertheless, such an approach is particularly attractive in this setting. Patients with t-APL constitute a population for whom the avoidance of additional anthracycline-based chemotherapy is particularly important, since anthracyclines may have contributed to the development of the disease, potentially creating a ‘perfect storm.’ In addition, some patients may have reached their cumulative maximal dose of anthracyclines. The information reported by Dr. Malhotra and colleagues contributes to mounting evidence that ATRA plus ATO is emerging as a useful therapy for many patients with APL, and that the efficacy of this combination is not limited to patients with de novo disease. Further studies will need to be carried out to confirm these results in a larger population of patients. However, to avoid exposure to anthracyclines, so important in the current standard treatment of most patients with APL, or because some patients have reached their maximal cumulative dose, treatment of patients with t-APL with ATRA plus ATO is an appealing strategy to rescue patients from the potentially rough waters in the midst of a ‘perfect storm’ generated by exposure to additional toxic chemotherapy.