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© 2001 American Society for Clinical Oncology
Acute Myeloblastic Leukemia as a Second Malignancy in a Patient With Hereditary RetinoblastomaHiroshima University School of Medicine, Hiroshima, Japan To the Editor:In the first August 2000 issue, Beck et al1 reported the efficacy of first-line chemotherapy in retinoblastoma (Rbl) to prevent external-beam radiotherapy (EBR) and/or enucleation. The chemotherapeutic regimen included etoposide, a topoisomerase II inhibitor. Despite the fact that prolonged use of such an inhibitor places the patient at risk of secondary leukemia, they emphasized that their chemotherapy regimen should be safe, because the cumulative dose of etoposide is moderate. Here, however, we report a patient who developed secondary acute myeloblastic leukemia (sAML) after receiving moderate-dose etoposide as first-line chemotherapy for Rbl. The patient was a 1-year-old girl with bilateral Rbl. Enucleation of the left eye and photocoagulation of the tumor in the right eye were performed. Pathologic examination of the left eye revealed no involvement of the optic nerve beyond the margin of resection, but it did show choroid involvement. To prevent metastasis, five courses of adjuvant chemotherapy were given. The schedule consisted of consecutive 5-day chemotherapy with etoposide 100 mg/m2/d and carboplatin 160 mg/m2/d. The cumulative doses of etoposide and carboplatin were 2,500 mg/m2 and 4,000 mg/m2, respectively. Twelve months after the completion of chemotherapy, the patient developed unexplained fever and diarrhea. A complete blood cell count showed hyperleukocytosis with leukemic cells and thrombocytopenia. Her bone marrow aspirate was consistent with a diagnosis of AML M5. Cytogenic and molecular analyses of leukemic cells revealed t(4;11)(q21;q23) with MLL gene involvement. Complete remission was induced by a regimen of mitoxantrone, cytarabine, and etoposide. The patient underwent an autologous bone marrow transplant, because no HLA-matched donor was available. She has been well for 10 months from the onset of AML. Characteristic findings of sAML after treatment with etoposide are a relatively short latency period, leukemic cells with 11q23 abnormalities and/or MLL gene involvement, French-American-British M4 or M5 subtype, and poor prognosis. The estimates of cumulative risk for sAML after treatment with etoposide range from 5% to 10% in patients with hematologic malignancy,2 with 0.6% incidence in patients with solid tumors.3 The data from the National Cancer Institute study suggested that for cumulative etoposide doses of 5.0 g/m2 or less, the risk of secondary leukemia was not inordinately high (0.7% at 6 years) and identical to the estimate of risk for patients with germ cell tumors who received etoposide (0.6% at 5 years).4 However, Stine et al5 reported two patients who received relatively low cumulative doses of etoposide but developed sAML, and our patient with sAML similarly received a theoretically safe dose of etoposide. The carcinogenic effect of EBR in patients with hereditary-type Rbl is evident. However, the leukemogenic effect of carcinostatics in these patients remains uncertain, because the numbers of patients studied were relatively small. It could be presumed that the estimated cumulative rate of sAML after treatment with etoposide in patients with hereditary Rbl was higher than that in patients with other solid tumors. Therefore, first-line chemotherapy with etoposide for all patients with hereditary Rbl remains controversial, since some patients may be cured with a combination of enucleation and photocoagulation without EBR. Further studies are needed to confirm the precise risk of sAML in patients with hereditary Rbl. REFERENCES
1.
Beck MN, Balmer A, Dessing C, et al: First-line chemotherapy with local treatment can prevent external-beam irradiation and enucleation in low-stage intraocular retinoblastoma. J Clin Oncol 18: 2881-2887, 2000 2. Pui CH, Ribeiro RC, Hancock ML, et al: Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphoblastic leukemia. N Engl J Med 325: 1682-1687, 1991[Abstract]
3.
Bokemeyer C, Schmoll HJ: Treatment of testicular cancer and the development of secondary malignancies. J Clin Oncol 13: 283-292, 1995
4.
Smith MA, Rubinstein L, Anderson JR, et al: Secondary leukemia or myelodysplastic syndrome after treatment with epipodophyllotoxins. J Clin Oncol 17: 569-577, 1999 5. Stine KC, Saylors RL, Sawyer JR, et al: Secondary acute myelogenous leukemia following safe exposure to etoposide. J Clin Oncol 15: 1583-1586, 1997[Abstract]
ResponseUniversity Hospital, Lausanne, Switzerland In Reply:The possibility that first-line chemotherapy in retinoblastoma (Rbl) could induce secondary acute myeloblastic leukemia due to prolonged use of topoisomerase II inhibitors is a real concern, as illustrated by Nishimura et al. Our article,1 however, did not emphasize the safety of the applied chemotherapeutic strategy but considered the risk as low with regard to the moderate cumulative doses of etoposide used.2 As the authors point out, some patients can be cured with local treatment alone or enucleation, and in fact, they were not part of the patient group included in our study.
There is some evidence that other agents, such as platinum compounds, especially carboplatin, can contribute to the development of secondary leukemia. A relative risk of 7.6 for a cumulative dose Nishimura et al’s case report shows that secondary acute myeloblastic leukemia can occur after chemotherapy in hereditary Rbl, but its precise risk still needs to be determined. REFERENCES 1. Beck MN, Balmer A, Dessing C, et al: First-line chemotherapy with local treatment can prevent external-beam irradiation and enucleation in low-stage intraocular retinoblastoma. J Clin Oncol 18: 2881-2887, 2000 2. Smith MA, Rubinstein L, Anderson JR, et al: Secondary leukemia or myelodysplastic syndrome after treatment with epipodophyllotoxins. J Clin Oncol 17: 569-577, 1999
3.
Travis LB, Holowaty EJ, Bergfeldt K, et al: Risk of leukaemia after platinum-based chemotherapy for ovarian cancer. N Engl J Med 340: 351-357, 1999
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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1,000 mg has been observed in women treated for ovarian cancer.
