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Clinical use of cyclophosphamide (CYC) improves the prognosis of Wegener's granulomatosis (WG),1 2 though treatment related malignancies have been recorded.3-5 Among treatment related malignancies, the development of erythroleukaemia has been rarely reported.6 In addition, there have been no reports of erythroleukaemia arising in patients with WG.
A 59 year old woman presented with nasal bleeding, nasal obstruction, and fever in December 1994. A biopsy specimen from nasal mucosa was compatible with WG, and cytoplasmic antineutrophil cytoplasmic antibodies (cANCA) were 13 EU (normally undetectable). A chestx ray examination on admission showed the presence of a cavity in the right lung field. She received 30 mg/day of prednisolone, with limited improvements. CYC (100 mg/day) was therefore given orally from 19 December. As a result, her complaints ameliorated and her nasal cavity cleared up in February 1995.
Her clinical condition was well controlled until July 1996 when her platelet count fell to 13.8×1010/l. Because CYC was effective against WG, and no further thrombocytopenia was verified, CYC was continued (50 mg/day), with stringent monitoring of the complete blood cell count. In November 1997 anaemia developed, and bone marrow specimens showed dysplasia of the trilineages accompanied by pseudo-Pelger-Huët anomaly indicating myelodysplastic syndrome (MDS), though we could not verify abnormal chromosomal changes in the specimen at that time. Despite stopping CYC (a cumulative dose of 9.7 g), she finally became febrile and exhausted in November 1998. The bone marrow specimens showed a marked proliferation of erythroblasts (92.5% of nucleated cells), indicating erythroleukaemia (fig 1). An analysis of chromosomes in the bone marrow specimens showed the complex heterogeneous karyotypic abnormalities: 46, XX, +1, +8, del (10) (q22), −21, −22. Because of the rapid progress of anaemia and thrombocytopenia, we initiated intensive chemotherapy. Despite such chemotherapy, she eventually died of disseminated intravascular coagulation in December 1998. A necropsy was not permitted.
Recently, the use of CYC has been reported to improve the prognosis of WG,1 2 though we should be aware of its possible carcinogenicity. Among neoplastic disorders, treatment related malignancy can develop after the use of such cytotoxic agents as CYC, azathioprine, etc.7 CYC is a highly carcinogenic agent and induces renal cancer, bladder cancer, MDS, and myelogenous leukaemia.3-11 CYC related second malignancies in WG have also been reported,3-7 11 though no erythroleukaemia was recorded.
The patient did not exhibit karyotypic abnormalities at the diagnosis of MDS, but did show such abnormalities after the development of erythroleukaemia. Alkylating agent related leukaemia is likely to manifest unique karyotypic disorders including −5/5q−, −7/7q−,10 whereas our case did not have such abnormalities. Although the chromosomal changes may not be consistent with CYC induced leukaemia, we cannot rule out the possibility of treatment induced malignancy. We chronologically observed the developing process of CYC related erythroleukaemia: it began with thrombocytopenia, followed by MDS, and finally ended with erythroleukaemia with chromosomal abnormalities. Thrombocytopenia developed 20 months after the initiation of CYC, and then changed into MDS 36 months later. Despite the discontinuance of CYC, the patient developed erythroleukaemia 12 months later.
Although the findings of chromosomal changes failed to support CYC induced leukaemia, we should be aware of treatment related malignancy in patients receiving this drug, especially when a cumulative dose of more than 10 g is given.11 When rheumatologists prescribe CYC for the treatment of patients with rheumatic diseases, stringent monitoring of the haematological parameters should be required, even after the discontinuance of CYC. All possible efforts should be made to discontinue CYC to minimise the risk of developing treatment related malignancies after remission. Lastly, when myelosuppression develops, we should discontinue CYC as soon as possible to avoid the development of treatment related leukaemia.
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