International Journal of
HEMATOLOGY Case Report
Chronic Eosinophilic Leukemia with the FIP1L1-PDGFR Fusion Gene in a Patient with a History of Combination Chemotherapy Yasuhiro Tanaka,a Masayuki Kurata,a Katsuhiro Togami,a Haruyuki Fujita,a Naoko Watanabe,a Akiko Matsushita,a Akinori Maeda,a Kenichi Nagai,a Akiko Sada,b Toshimitsu Matsui,b Takayuki Takahashia a
Department of Hematology and Clinical Immunology, Kobe City General Hospital; b Division of Endocrinology/Metabolism, Neurology, and Hematology/Oncology, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan Received April 5, 2005; received in revised form October 18, 2005; accepted October 24, 2005
Abstract Hypereosinophilic syndrome (HES) was diagnosed in December 2000 in a 43-year-old man on the basis of persistent eosinophilia (11.7 109/L) and a normal karyotype of the bone marrow cells. He had developed intra-abdominal non-Hodgkin’s lymphoma and in 1992 had received 3 courses of combination chemotherapy with doxorubicin (Adriamycin), cyclophosphamide, vincristine, methotrexate, bleomycin, and prednisolone. The patient was orally given prednisolone (10 mg/day) and cyclophosphamide (50 mg/day) as HES treatment without a subsequent improvement of the eosinophilia. In May 2003, anemia (hemoglobin, 7.9 g/dL) and thrombocytopenia (65 109/L) manifested with progressive eosinophilia (21.0 109/L) and a small number of blasts. The patient became febrile and was admitted in July 2003. Cytogenetic reexamination of the bone marrow cells disclosed the deletion of 4q12, indicating the presence of a fusion of the Fip1-like 1 (FIP1L1) gene to the plateletderived growth factor receptor (PDGFR) gene and consequently the clonal nature of his hematopoietic cells. DNA sequence analysis demonstrated that the breakpoints of the FIP1L1 and PDGFR genes were present in exon 9 and exon 12, respectively. Treatment with imatinib mesylate (300 mg/day) promptly brought about complete remission. Although a number of similar eosinophilic cases have been reported, our patient may be the first such patient with a history of chemotherapy. Int J Hematol. 2006;83:152-155. doi: 10.1532/IJH97.05048 ©2006 The Japanese Society of Hematology Key words: Chronic eosinophilic leukemia; Hypereosinophilic syndrome; Secondary leukemia; Imatinib mesylate; FIP1L1-PDGFR fusion gene by chromosomal examination and so on, the diagnosis should be changed from HES to leukemia or myeloproliferative disorder (MPD) [2,3].The response of HES to treatment, including bolus corticosteroids, is generally poor. However, Schaller et al reported in 2003 that imatinib mesylate, a tyrosine kinase inhibitor, exhibits an excellent effect in some patients with HES without chromosomal abnormality [4]. The mechanism of the efficacy of imatinib mesylate is unclear, although additional HES patients who responded to the agent have been reported [5-11]. In the same year, Cools et al demonstrated a fusion of the FIP1-like 1 (FIP1L1) gene to the plateletderived growth factor receptor (PDGFR) gene as a result of chromosome 4q12 interstitial deletion in HES with normal karyotype and reported that imatinib mesylate is effective in treating such HES cases [12]. Since then, a number of similar HES patients have been described [13-18]. However, all of these reported cases appear to be of primary clonal disorder/ chronic eosinophilic leukemia, because no history of chemotherapy or radiotherapy was described in these studies. We
1. Introduction Hypereosinophilic syndrome (HES) is characterized by persistent eosinophilia (more than 6 months) of unknown cause with an eosinophil count >1.5 109/L, eosinophil infiltration of organs (eg, in the lungs, gastrointestinal tract, or heart), and organ injury caused by the infiltrating eosinophils [1].Although the etiology of eosinophilia in HES is unknown, when a patient’s eosinophils are proved to be of clonal origin
N.W. is currently at the Institute of Medical Science, The University of Tokyo, Tokyo, Japan. Correspondence and reprint requests: Takayuki Takahashi, Department of Hematology and Clinical Immunology, Kobe City General Hospital, 4-6 Minatojima-Nakamachi, Chuo-ku, Kobe 650-0046, Japan; 81-78-302-4321; fax: 81-78-302-7537 (e-mail:
[email protected]).
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encountered a chronic eosinophilic leukemia patient with the FIP1L1-PDGFR fusion gene. The patient had a history of 3 courses of combination chemotherapy for malignant lymphoma 8 years prior to the onset of the eosinophilia. Here we report this case as a possible therapy-related leukemia with the FIP1L1-PDGFR fusion gene.
2. Case Report A 43-year-old man was admitted to our hospital in July 2003 because of fever and dizziness. He had had a history of intra-abdominal non-Hodgkin’s lymphoma (the subtype was unclear) and had received 3 courses of combination chemotherapy with doxorubicin (Adriamycin), cyclophosphamide, vincristine, methotrexate, bleomycin, and prednisolone (MACOP-B regimen) in 1992. In December 2000, a hematologic examination showed leukocytosis (16.2 109/L) with 72% eosinophils. A bone marrow aspirate revealed normoplastic cells with 51.6% eosinophils and 0% blasts. A chromosomal analysis of the marrow cells with the conventional G-banding method showed a normal 46,XY karyotype, and thus a diagnosis of HES was made in January 2001. The patient orally received 10 mg/day prednisolone in February 2001 and additionally received 50 mg/day cyclophosphamide in June 2001. However, these agents did not improve the eosinophilia. He developed anemia and thrombocytopenia in May 2003, and a hematologic examination showed a white blood cell (WBC) count of 21.0 109/L with 82.0% eosinophils, a hemoglobin concentration of 7.9 g/dL, and a platelet count of 65.0 109/L. In June 2003, the WBC count was 15.8 109/L with 2% blasts and 74% eosinophils; therefore, the patient was admitted. A physical examination of the patient revealed a fever of 38.1C, a blood pressure of 124/76 mm Hg, and a heart rate of 85 beats/min. Oxygen saturation measured by pulse oximetry was 99% in room air. The palpebral conjunctivae were anemic. Superficial lymph node swelling was not observed. A midsystolic cardiac murmur (Levine II/VI) was heard. The liver and spleen were palpable 2 cm and 8 cm, respectively, below the costal margin. No neurologic abnormalities were noted. An abdominal ultrasonography examination revealed marked hepatosplenomegaly but not lymphoadenopathy. A hematologic examination showed a WBC count of 17.2 109/L with 5% blasts, 1% promyelocytes, 1% myelocytes, 1% metamyelocytes, 19% neutrophils, 60% eosinophils, 3% monocytes, and 12% lymphocytes; a hemoglobin concentration of 6.9 g/dL; and a platelet count of 51.0 109/L. Serum lactate dehydrogenase, C-reactive protein, and vitamin B12 levels were elevated to 673 IU/L (normal range,
