Blood, 15 August 2002, Vol. 100, No. 4, pp. 1514-1515
CORRESPONDENCE
To the editor:
Second malignancy after treatment of acute promyelocytic
leukemia: experience of GIMEMA trials
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.1
The 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.2-4
All 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.7
In 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.
Livio Pagano and Alessandro Pulsoni, on behalf of GIMEMA
(Gruppo Italiano Malattie Ematologiche dell'Adulto)
Correspondence: Livio Pagano, Istituto di Ematologia,
Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, I-00168 Roma, Italy; e-mail: lpagano{at}rm.unicatt.it.
References
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Latagliata R, Petti MC, Fenu S, et al.
Therapy-related myelodysplastic syndrome - acute myelogenous leukemia in patients treated for acute promyelocytic leukemia: an emerging problem.
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