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Journal of Clinical Oncology, Vol 26, No 12 (April 20), 2008: pp. 2040-2041 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.3841
Eosinophilia With FIP1L1-PDGFRA Fusion in a Patient With Chronic Myelomonocytic LeukemiaDepartment of Pathology, University of Massachusetts Memorial Medical Center, University of Massachusetts, Worcester, MA
MDS Program, St Vincent's Comprehensive Cancer Center, New York, NY
Department of Pathology, University of Massachusetts Memorial Medical Center, University of Massachusetts, Worcester, MA A 67-year-old woman with a past medical history of alfa-thalassemia trait was referred to our medical center for evaluation of anemia, thrombocytopenia, and leukocytosis. CBC on admission revealed a WBC of 55.5 x 109/L, platelets 81 x 109/L, and hemoglobin 11.3 g/dL. The differential showed 86% neutrophils, 6% monocytes, 0.1% eosinophils, 0% basophils, 8% lymphocytes with 1% circulating blasts, and dysplastic granulocytes noted on the blood film. An enlarged spleen was discovered on physical examination, and confirmed by a computed tomography scan. The initial bone marrow (BM) examination revealed 95% cellularity with trilineage dysplasia. The BM aspirate smears showed 3% blasts, 4% monocytes, and less than 1% eosinophils. Study of 20 giemsa-trypsin-giemsa–banded metaphase cells showed a normal female karyotype. The patient was diagnosed with myelodysplastic/myeloproliferative disease, with clinicopathologic features of atypical chronic myeloid leukemia and chronic myelomonocytic leukemia 1 (CMML-1). She was started on an experimental trial with combined thalidomide, arsenic trioxide, dexamethasone, and ascorbic acid. Two months later, her peripheral monocyte proportion increased and exceeded 10%, with absolute monocytosis (up to 52.6 x 109/L). Her diagnosis met the criteria for CMML-1. Four months after the initial BM biopsy, she developed peripheral eosinophilia, with an absolute eosinophil count ranging from 1.5 to 4.2 x109/L. Her peripheral eosinophilia persisted for a period of 2 to 3 months under a close follow-up. BM biopsy now revealed a 100% cellularity with large clusters/small sheets of eosinophils (Fig 1A). The BM aspirate showed 4% blasts, 5% monocytes, and 10% eosinophils, including many eosinophilic precursors (Fig 1B). Conventional G-banding again showed a normal female karyotype. Fluorescent in situ hybridization (FISH) with a probe set containing FIP1L1 (green), CHIC2 (red) and PDGFRA (green) loci (MP Biomedicals, Solon, OH) was performed on interphase nuclei, and a hybridization pattern consistent with deletion of CHIC2 and fusion of FIP1L1-PDGFRA was observed in 16 of 100 nuclei. Figure 2 shows three nuclei containing abnormal fusion signals (arrows), with deletion of CHIC2 and a resultant FIP1L-PDGFRA (green/green) fusion. The patient was started on imatinib 400 mg orally daily, with a rapid resolution of her peripheral eosinophilia. However, her other hematologic indices showed no improvement. Imatinib was discontinued after 6 weeks. A repeated BM biopsy showed a 100% cellular marrow with only occasional eosinophils (Fig 1C). The BM aspirate revealed 11% blasts, 49% monocytes, and 1% eosinophils (Fig 1D), consistent with CMML-2. FISH performed with the same probe set showed no evidence of FIP1L1-PDGFRA fusion signals in 100 interphase nuclei. Her course was complicated by a myeloid sarcoma, which developed in abdominal lymph nodes. She was treated with experimental anti-CD33 antibody (lintuzumab) in conjunction with hydroxyurea and radiation to the spleen and abdominal lymph nodes. Despite therapy, the patient's condition deteriorated and she dies 10 months after the initial diagnosis. She had had no recurrence of peripheral eosinophilia before death. Retrospectively, FISH was performed on the initial BM specimen (before eosinophilia), which showed no evidence of FIP1L1-PDGFRA fusion signals in 100 interphase nuclei. This result indicates that a subclone of CMML cells acquired FIP1L1-PDGFRA fusion during disease evolution.
To our knowledge, PDGFRA rearrangements have never been reported in CMML with or without eosinophilia. To date, FIP1L1-PDGFRA fusion has been demonstrated only in patients with clinical phenotypes of chronic eosinophilic leukemia/hypereosinophilic syndrome (CEL/HES)1,2 or systemic mastocytosis.3 It has been shown that CEL/HES with FIP1L1-PDGFRA fusion and systemic mastocytosis exhibit striking overlapping histologic features; therefore, such marrow neoplasms might be well fit into one entity as CEL/HES-systemic mastocytosis.4 In CMML with eosinophilia, the rearrangement involving PDGFRB has been reported, of which, a t(5;12)(q33;p13) translocation associated with an ETV6-PDGFRB fusion gene is most common.5-8 PDGFRA and PDGFRB genetic alternations in these diseases are considered important in leukemogenesis. It is notable that women were rarely affected by these specific genetic alternations. Nevertheless, in patients with FIP1L1-PDGFRA fusion or PDGFRB rearrangement, imatinib 400 mg/d has shown to be therapeutically effective and the response is durable.1,2,5,7-9 In the recent review article by Tefferi and Vardiman10 on the 2008 WHO classification of myeloproliferative neoplasms (MPNs), the authors have incorporated the new molecular/genetic findings in MPNs and emphasized their role in disease pathogenesis and therapeutic application. MPNs associated with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1 are separated from Philadelphia-negative chronic myeloproliferative disease to form a distinct entity. Our case illustrates that FIP1L1-PDGFRA fusion can occur in an otherwise typical CMML as a secondary event during disease evolution. Imatinib was effective in eradicating/suppressing the emerging clone that harbored the FIP1L1-PDGFRA fusion, but had no effect on the underlying marrow disease. The 2008 revision of WHO classification with emphases on molecular genetic alternations would allow a more precise categorization, compared with the traditional morphology-based classification. This approach would be generally appreciated by treating hematologists and diagnostic pathologists if some rare exceptions/variants are well recognized and documented. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
REFERENCES
1. Cools J, DeAngelo DJ, Gotlib J, et al: A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med 348:1201-1214, 2003 2. Pardanani A, Brockman SR, Paternoster SF, et al: FIP1L1-PDGFRA fusion: Prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosinophilia. Blood 104:3038-3045, 2004 3. Vandenberghe P, Wlodarska I, Michaux L, et al: Clinical and molecular features of FIP1L1-PDFGRA (+) chronic eosinophilic leukemias. Leukemia 18:734-742, 2004[CrossRef][Medline] 4. Tefferi A, Elliott MA, Pardanani A: Atypical myeloproliferative disorders: Diagnosis and management. Mayo Clin Proc 81:553-563, 2006 5. Apperley JF, Gardembas M, Melo JV, et al: Response to imatinib mesylate in patients with chronic myeloproliferative diseases with rearrangements of the platelet-derived growth factor receptor beta. N Engl J Med 347:481-487, 2002 6. David M, Cross NC, Burgstaller S, et al: Durable responses to imatinib in patients with PDGFRB fusion gene-positive and BCR-ABL-negative chronic myeloproliferative disorders. Blood 109:61-64, 2007 7. Drechsler M, Hildebrandt B, Kundgen A, et al: Fusion of H4/D10S170 to PDGFRbeta in a patient with chronic myelomonocytic leukemia and long-term responsiveness to imatinib. Ann Hematol 86:353-354, 2007[CrossRef][Medline] 8. La Starza R, Rosati R, Roti G, et al: A new NDE1/PDGFRB fusion transcript underlying chronic myelomonocytic leukaemia in Noonan syndrome. Leukemia 21:830-833, 2007[Medline] 9. Klion AD, Robyn J, Akin C, et al: Molecular remission and reversal of myelofibrosis in response to imatinib mesylate treatment in patients with the myeloproliferative variant of hypereosinophilic syndrome. Blood 103:473-478, 2004 10. Tefferi A, Vardiman JW: Classification and diagnosis of myeloproliferative neoplasms: The 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia 22:14-22, 2008[CrossRef][Medline]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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