In a recent issue Latagliata et al reported 5 cases of therapy-related myelodysplastic syndrome-acute myelogenous leukemia (tMDS-AML) following acute promyelocytic leukemia (APL) in a cohort of 77 patients who achieved a complete remission (CR) after chemotherapy according to GIMEMA 0389 and AIDA trials.1The authors, on the basis of these data, concluded that the observation of tMDS-AML is an emerging problem that could increase in the future. The responsibility of this phenomenon was attributed to chemotherapy, which in some cases included topoisomerase II inhibitors or alkylating agents; furthermore, APL patients presented a high percentage of curability with a consequently large number of long-term survivors.
Between 1982 and 1997 in the GIMEMA APL trials (LAP 0383, 0389, and 0493), 1145 patients were recruited (261 patients in the 0389 trial, 113 patients in the 8303 trial, and 771 patients in the 0493 trial). Details on treatment schedule were previously reported.2-4All trials included anthracycline administration (daunorubicin or idarubicin) during the induction and consolidation phases. Maintenance therapy was randomly administered only in the 8303 trial (no therapy vs methotrexate plus 6-mercaptopurine for 2 years) and in the 0493 trial (no therapy vs ATRA vs methotrexate plus 6-mercaptopurine vs 2 + 3 for 2 years). Among these patients, only 4 males (0.3%) aged 36, 38, 61, and 76 years, respectively, developed a second primary malignancy (SPM) (kidney, bowel, melanoma, and thyroid, respectively). All these patients were treated according to the 0493 trial. The median latency between APL diagnosis and SPM was 6.6 months (range, 3.8-7.6 months). The median follow-up was 2.2 years (range, 0-13.8 years). None of them received methotrexate plus 6-mercaptopurine as maintenance therapy. Two patients died from progression of secondary malignancy (bowel and melanoma), without signs of APL relapse, after 3 and 12 months, respectively. The other 2 patients are still alive without signs of relapse of either of the malignancies after 46 months (kidney) and 97 months (thyroid).
Based on the incidence rate data produced by the combined Italian Cancer Registries in the general population,5 among the APL population the expected number of patients with a second cancer was estimated in 11.98 cases; conversely, in our series only 4 cases were observed (standardized incidence ratio 0.33; 95% CI 0.09-0.86). The estimated cumulative incidence of a second malignancy at 5 years was 0.43 (95% CI 016-1.15) and was unchanged at 10 years.
Our data allow some interesting considerations. The probability of developing an acute leukemia in patients who received chemotherapy or radiotherapy for a previous malignancy (PM), including acute leukemia, is a well-known occurrence: secondary forms constitute approximately 8% to 10% of all acute leukemias and are usually myeloid.6
The main reason for this event is that several drugs employed in the treatment of the PM, particularly topoisomerase II inhibitors (epipodophyllotoxins and anthracyclines), and combined chemotherapy including alkylating agents, are considered potentially mutagenic. As suggested by Latagliata et al,1 the use of intensive chemotherapy to cure APL, with the inclusion of topoisomerase II inhibitors, has a potential role in inducing a tMDS-AML.7In our cohort of patients, the number of secondary malignancies is lower than expected in the normal population. The estimated cumulative incidence at 5 and 10 years is also lower than that expected. Furthermore, the brief latency between the onset of the 2 malignancies leads to the hypothesis that the second malignancy is probably not related to the carcinogenic action of the drugs employed for the treatment of APL, but perhaps to a chance association only.
These considerations suggest that APL treatment is not relevant in inducing the onset of secondary nonhematological malignancies. On the contrary, the action of topoisomerase II inhibitors, which represent one of the main anticancer drugs used in APL, could favor the development of a tMDS-AML with a leukemogenic action on blood stem cells.
