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Journal of Clinical Oncology, Vol 25, No 28 (October 1), 2007: pp. 4493-4494 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.12.9338
Long-Term Survival and Secondary Acute Leukemia After Fotemustine Therapy for Metastatic MelanomaDepartment of Oncology, Cabrini Medical Centre, Malvern, Australia
Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Australia, and University of Melbourne, Parkville, Melbourne, Australia
Department of Oncology, Cabrini Medical Centre, Malvern, Australia, and University of Melbourne, Parkville, Melbourne, Australia Prolonged survival after metastatic melanoma is relatively uncommon, and less than 5% of patients survive for longer than 5 years.1 We report a case of metastatic melanoma achieving a complete and durable response to single-agent fotemustine and complicated by treatment-related acute myeloid leukemia. A 59-year-old man presented in April 2002 with headaches and personality change. Six prior cutaneous melanomas had been treated with wide local excisions over the preceding 3 years. He was found to have a 5-cm right frontal cerebral tumor and a 5-cm left adrenal mass. These were both resected with clear margins and found to be consistent with metastatic melanoma. There was no disease elsewhere on baseline and upon follow-up with [18F]fluorodeoxyglucose positron emission tomography and computed tomography (CT) scanning. Three months later, a follow-up CT scan demonstrated several rounded pulmonary lesions (Fig 1A). These were not biopsied. He was then treated with fotemustine 100 mg/m2/wk for 3 weeks followed by 100 mg/m2 every 3 to 4 weeks for 6 months. The chemotherapy was well-tolerated with no significant hematologic toxicity except for neutropenia with a nadir of 0.5 x 109/L during cycle one, not requiring granulocyte colony-stimulating factor support. Repeat CT imaging after two cycles confirmed a complete response with disappearance of the previously noted pulmonary nodules (Fig 1B). Follow-up since has revealed no evidence of recurrent visceral disease although he required further excision of cutaneous melanomas, and in mid-2006, a new deposit within the right trapezius muscle was found on imaging and excised with clear margins; staging investigation after this procedure showed no further evidence of melanoma. Approximately 3.5 years after receiving fotemustine, he developed cytopenias with full blood examination demonstrating a hemoglobin of 134 g/L, mean cell volume of 95 fL (80 to 100), neutrophils of 1.2 x 109/L (2.0 to 7.5), and platelets of 128 x 109/L (150 to 450). Bone marrow aspirate and biopsy was diagnostic of myelodysplastic syndrome (MDS), with the WHO subtype refractory cytopenias with multilineage dysplasia. Cytogenetic analysis demonstrated a clone of cells with deletion of the long arm of chromosome 20. There was no evidence of melanoma involvement of the marrow. Vitamin B12, red cell folate, and liver function tests were normal. A repeat bone marrow aspirate 8 months later, 4.3 years after the commencement of fotemustine therapy, was stained with May-Grunewald-Giemsa and demonstrated an increased number of blasts as well as dyserythropoiesis (Fig 2A). The bone marrow biopsy was stained with hematoxylin and eosin and showed an interstitial infiltrate of immature precursors and mild megakaryocytic clustering and dysplasia (Fig 2B). These findings were consistent with progression to acute myeloid leukemia with 27% myeloblasts and multilineage dysplasia. Cytogenetic analysis demonstrated no mitoses.
This case is notable for two reasons. It illustrates a rare prolonged complete response of metastatic melanoma to single-agent fotemustine, with prolonged survival after initial diagnosis. Moreover, this is the first convincing report of secondary myelodysplasia and acute leukemia after single-agent fotemustine therapy. Chemotherapy benefits a minority of patients with advanced metastatic melanoma and single agent dacarbazine, temozolomide, or fotemustine produce responses of 10% to 15% that are usually partial and of short duration, with median survival remaining well under 12 months. However, durable complete responses of 1% to 2% have been reported for dacarbazine monotherapy.2 In a phase III trial comparing fotemustine with dacarbazine, approximately 10% of patients randomly assigned to fotemustine were alive at a median follow-up of 35 months, however it was not clear whether these patients achieved or indeed remained in complete response. That study also demonstrated that fotemustine achieved higher response rates, but no significant differences in progression-free or median overall survival.3 Clearly, prolonged complete remissions like the one reported here are rare. Indeed, in a phase II trial of fotemustine for the treatment of metastatic melanoma, five of 153 patients were in complete remission 7 years after therapy and all of those patients had required surgical excision of recurrent or persistent disease.4 Fotemustine is an alkylating agent from the nitrosourea family. It has been noted to cause delayed reversible neutropenia or thrombocytopenia in up to 40% of patients and prolonged hematologic toxicity after discontinuation of this drug has been reported.5 There have been two prior reported cases of myelodysplasia with fotemustine but both had been after combination therapy with dacarbazine and occurred 2 and 9 months after therapy, an unusually short interval for the development of secondary myelodysplasia with alkylator agent-induced MDS expected to be much longer. No information on morphologic changes or cytogenetic abnormalities were contained in the report.6 The 20q deletion occurs in a variety of myeloid malignancies and in de novo MDS it has been reported to be associated with a high rate of transformation to AML and a poor prognosis.7 This abnormality has been previously described in a case of secondary myelodysplasia.8 In conclusion, we report what is to our knowledge a previously unrecognised risk of prolonged survival with fotemustine, secondary acute leukemia. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
REFERENCES
1. Tsao H, Atkins MB, Sober AJ: Management of cutaneous melanoma. N Engl J Med 351:998-1012, 2004 2. Hill GJ, Krementz ET, Hill HZ: Dimethyl triazeno imidazole carboxamide and combination therapy for melanoma. IV. Late results after complete response to chemotherapy (Central Oncology protocols 7130, 7131, and 7131A). Cancer 53:1299-1305, 1984[CrossRef][Medline] 3. Avril MF, Aamdal S, Grob JJ, et al: Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: A phase III study. J Clin Oncol 22:1118-1125, 2004 4. Petit T, Borel C, Rixe O, et al: Complete remission seven years after treatment for metastatic malignant melanoma. Cancer 77:900-902, 1996[CrossRef][Medline] 5. Turrisi G, Sozzi P, Marinozzi C, et al: Persistent thrombocytopenia during melanoma treatment with fotemustine. Melanoma Res: 16:543-544, 2006[CrossRef][Medline] 6. Perrot JL, Lanthier K, Benoit F, et al: Acquired myelodysplastic syndromes after treatment of melanoma with fotemustine and dacarbazine. Ann Dermatol Venereol 122:663-666, 1995[Medline] 7. Campbell LJ, Garson OM: The prognostic significance of deletion of the long arm of chromosome 20 in myeloid disorders. Leukemia 8:67-71, 1994[Medline] 8. Redei I, Mangan KF, Ming PL, et al: Detection of a dormant 20q- leukemia clone in bone marrow cultures with hematopoietic growth factors: Implications for secondary leukemia post-transplant. Bone Marrow Transplant 19:521-523, 1997[CrossRef][Medline]
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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