Leukemia & Lymphoma, A p ril 2015; 56(4): 1143-1144

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© 2014 In fo rm a UK, Ltd. ISSN: 1042-8194 p r in t /1 0 2 9 -2 4 0 3 o n lin e

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DOI: 10.3109/10428194.2014.941831

LETTER TO THE EDITOR

Development of myelodysplastic syndrome in a patient with chronic myelogenous leukemia treated with imatinib Nabhajit Mallik1, Anita Chopra1, Akash Jha2, Ajay Gogia2 & Rajive Kumar1 1Department o f Laboratory Oncology and 2Department o f Medical Oncology, Dr. B. R. A., Institute Rotary Cancer Hospital, A ll India Institute o f Medical Sciences, New Delhi, India

Chronic myelogenous leukemia (CML) is a myeloprolifera­ tive neoplasm that is constantly associated with the BCRABL1 fusion gene [1], This fusion gene encodes a chimeric protein with increased tyrosine kinase activity that plays a central role in the pathogenesis of CML [2], Imatinib mesy­ late is a potent and selective competitive inhibitor of the BCR-ABL protein tyrosine kinase. It is used as a front-line therapy for CML, and induces complete hematological and cytogenetic response in most patients with chronic phase CML [3], During treatm ent for CML, a subset of patients develop chromosomal abnormalities in the Philadelphia chromosome (Ph) negative cells that emerge as they respond to therapy [4], However, the incidence and signifi­ cance of these abnormalities are poorly understood. Some of these abnormalities are associated with myelodysplastic syndrome (MDS). However, only a few cases that harbor these cytogenetic abnormalities along with MDS are reported [5], We report a case of MDS arising in a patient who was being treated for CML with imatinib. A 60-year-old male presented with a history of weak­ ness, fever and splenomegaly in August 2005 at our center, and was diagnosed as having Ph positive chronic phase CML. He was started on imatinib at a dose of 400 mg/day. The treatm ent was interrupted many times initially due to low platelet counts. The dosage of imatinib was reduced to 300 mg/day, and he achieved complete hematological response in June 2007. The patient continued on the drug and was asymptomatic until September 2012, when he presented with bleeding, and was found to have low hem o­ globin and platelets. He developed pancytopenia, with progressively decreasing counts, and required multiple blood transfusions. Imatinib was stopped in April 2013. Bone marrow examination showed dysmegakaryopoiesis and dyserythropoiesis, along with 4% blasts. Cytogenetics study by fluorescence in situ hybridization (FISH) showed that 100% cells were Ph negative. However, new clonal cytogenetic abnormalities were noted, with del 7q being observed in 86% of cells, monosomy 7 in 6% of cells and

del 20q in 32% of cells. The patient was diagnosed as hav­ ing MDS, high risk (according to the revised International Prognostic Scoring System [IPSS-R]). He was started on decitabine injection, 20 m g/m 2 (day 1 to day 5), every 28 days. The patient has to date received four cycles of decit­ abine. Bone marrow examination after four cycles showed progression to refractory anemia with excess blasts-2 (RAEB-2), with 12% blasts. There have been no episodes of febrile neutropenia or bleeding. The patient is now on close hematological follow-up. The development of cytogenetic abnormalities in Ph neg­ ative metaphases in patients with CML treated with imatinib has been reported, but its clinical implications are poorly understood. Most cytogenetic abnormalities encountered in Ph negative cells of patients treated with imatinib are not related to myelodysplasia, and some seem to be transient [6,7], In a study of 272 patients treated with imatinib, this phenom enon was seen in 21 (8%) cases [6], Trisomy 8 has been found to be the most frequent cytogenetic abnormality in such cases [5]. Development of MDS in patients with Ph negative m eta­ phases after treatment with imatinib, however, is rare [8-11]. Interestingly, in such patients, chromosome 7 abnormalities have been found to be particularly common [12], especially monosomy 7, which was also seen in our patient. This abnor­ mality is common in secondary MDS or acute myelogenous leukemia (AML), evolving after exposure to alkylating agents, and patients with MDS or AML with this abnormality have poor outcomes. The etiology of imatinib induced MDS is yet to be com ­ pletely understood. Two mechanisms have been proposed. First, imatinib may provide an advantage to abnormal clones that were already present in the patient at low levels. Second, these changes could be directly due to imatinib toxicity [5]. To conclude, MDS developing in patients with CML treated with imatinib is a rare entity. Further studies with long-term follow-up are required to understand the etiology

Correspondence: Dr. Anita Chopra, Room No 423, 4th Floor, Dr. BRAIRCH, AIIMS, Ansari Nagar, New Delhi-110029, India. Tel: 91-11-29575415. Fax: 91-1126588663. E-mail: [email protected] Received 11 February 2014; revised 17 June 2014; accepted 29 June 2014 1143

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and prognosis of this condition. Moreover, periodic monitor­ ing of patients with CML by metaphase karyotyping might be warranted to recognize this disease entity.

Potential conflict o f interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal. References

HI Vardiman JW, Melo JV, Baccarani M, et al. Chronic myelogenous leukemia, BCR-ABL1 positive. In: Swerdlow SH, Campo E, Harris NL, et al., editors. WHO classification of tumors of hematopoietic and lymphoid tissues. Lyon: IARC Press; 2008. pp. 32-37. [2] Shtivelman E, Lifshitz B, Gale RP, et al. Fused transcript of ABL and BCR genes in chronic myelogenous leukemia. Nature 1985;315: 550-554. [3] Kantarjian H, Sawyers C, Hochlaus A, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 2002;346:645-652. [41 Cortes J, O’Dwyer ME. Clonal evolution in chronic myelogenous leukemia. Hematol Oncol Clin North Am. 2004;18:671-684. [5] Navarro JT, Feliu E, Grau J, et al. Monosomy 7 with severe myelodysplasia developing during imatinib treatm ent of Philadelphia­ positive chronic myeloid leukemia: two cases with a different outcome. Am J Hematol 2007;82:849-851.

[6] Medina J, Kantarjian H, TalpazM, etal. Chromosomal abnormalities in Philadelphia chromosome-negative metaphases appearing during imatinib mesylate therapy in patients with Philadelphia chromosome­ positive chronic myelogenous leukemia in chronic phase. Cancer 2003;98:1905-1911. [7] Terre C, Eclache V, Rousselor P, et al. Report of 34 patients with clonal chromosomal abnormalities in Philadelphia-negative cells during imatinib treatm ent of Philadelphia-positive chronic myeloid leukemia. Leukemia 2004;18:1340-1346. [8] Bumm T, Muller C, Al-Ali HK, et al. Emergence of clonal cytogenetic abnormalities in Ph- cells in some CML patients in cytogenetic remission to imatinib but restoration of polyclonal hematopoiesis in the majority. Blood 2003;101:1941-1949. [9] Mozziconacci MJ, Cailleres S, Maurice C, et al. Myelodysplastic features developing in Philadephia-negative cells during imatinib mesylate therapy for CML: report of a new case. Leukemia 2003; 17: 1901-1902. [10] O'Dwyer ME, Gatter KM, Loriaux M, et al. D em onstration of Philadelphia chrom osom e negative abnorm al clones in patients with chronic myelogenous leukem ia during major cytogenetic responses induced by im atinib mesylate. Leukemia 2003;17: 481-487. HU Alimena G, Breccia M, Mancini M, et al. Clonal evolution in Philadelphia chromosome negative cells following successful treatment with imatinib of a CML patient: clinical and biological features of a myelodysplastic syndrome. Leukemia 2004;18:361-362. [12] Kovitz C, Kantarjian H, Garcia-Manero G, et al. Myelodysplastic syndromes and acute leukemia developing after im adnib mesylate therapy for chronic myeloid leukemia. Blood 2006;108:2811-2813.

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Development of myelodysplastic syndrome in a patient with chronic myelogenous leukemia treated with imatinib.

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