Title: The Philadelphia translocation and pre‐existing myeloproliferative disorders
Abstract: British Journal of HaematologyVolume 128, Issue 5 p. 734-736 Free Access The Philadelphia translocation and pre-existing myeloproliferative disorders First published: 21 February 2005 https://doi.org/10.1111/j.1365-2141.2005.05396.xCitations: 23AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat There has been increasing interest in the development of Ph-negative clones in patients with chronic myeloid leukaemia (CML). We present a case that provides new insights into this phenomenon. A 73-year-old man presented in April 2003 with an isolated thrombocytosis since 1991. Investigations revealed: haemoglobin, 15·3 g/dl; platelets, 790 × 109/l; leucocytes, 10·8 × 109/l with a normal differential. Erythrocyte sedimentation rate, C-reactive protein and serum ferritin were normal; an ultrasound showed mild splenomegaly (13·3 cm); serum erythropoietin was reduced (<2·5 U/L), erythropoietin-independent erythroid burst-forming units were grown from peripheral blood; bone marrow aspirate was mildly hypercellular with increased megakaryopoiesis and a normal megakaryocyte:erythrocyte (M:E) ratio; trephine biopsy was hypercellular with increased numbers of large megakaryocytes in clusters but no fibrosis; cytogenetic analysis showed a normal karyotype in 20 metaphases; fluorescence in situ hybridization (FISH) studies of interphase bone marrow cells identified normal BCR and ABL signal patterns in 100 cells. A diagnosis of essential thrombocythaemia (ET) was made and he was commenced on aspirin (75 mg/d). By August 2003, his platelet count had spontaneously normalised (365 × 109/l) but his white cell count had climbed to 40·6 × 109/l. A repeat bone marrow biopsy showed marked hypercellularity with a high M:E ratio and increased megakaryocytes with some micromegakaryocytes. Cytogenetic analysis of bone marrow revealed a Ph chromosome in seven of 10 cells with BCR/ABL co-localization by interphase FISH in 67 of 100 cells. Re-analysis of the original sample from April 2003 demonstrated that two of 125 metaphases carried the Ph translocation. Hydroxyurea was commenced and the leucocyte count fell from 70·5 × 109 to 10·3 × 109/l over 3 weeks (Fig. 1). The platelet count remained within the normal range. Imatinib mesylate was commenced and the hydroxyurea was stopped. The leucocyte count remained well controlled but the platelet count increased from 310 × 109 to 1043 × 109/l over the subsequent 4 weeks. Interphase FISH studies of bone marrow cells at 3 and 6 months after commencing imatinib showed a major cytogenetic response. Despite this response, the patient has continued to require 0·5–1·0 g/d of hydroxyurea to control his thrombocytosis. Figure 1Open in figure viewerPowerPoint Relationship of white cell count (WCC) and platelet count to therapy with hydroxyurea and imatinib mesylate. Development of a Ph chromosome is rarely reported in patients with a myeloproliferative disorder (Haq, 1990). We are aware of one previous report of a patient with ET who developed CML after 18 years of therapy with hydroxyurea (Wahlin & Golovleva, 2003). By contrast, the patient described here had not received chemotherapy and so the Ph translocation was not therapy-related, as suggested in other cases (Haq, 1990; Wahlin & Golovleva, 2003). We have considered three possible explanations for this atypical presentation and response to treatment. (1) The patient has CML as a single diagnosis, with the thrombocytosis at presentation reflecting preferential megakaryocytic differentiation of the, initially small, clone of Ph positive cells. This model is difficult to reconcile with the long history of thrombocytosis and does not explain the failure of imatinib to control the platelet count. (2) The patient had longstanding ET with the separate development of CML, representing independent transformation of a normal stem cell. (3) The patient had longstanding ET with the Ph translocation occurring in a stem cell that was part of the ET clone. We favour model 2 or 3 in this case. The spontaneous normalization of the platelet count presumably reflected the expansion of the more dominant Ph positive clone, with imatinib reversing the process and resulting in recurrent thrombocytosis. The bone marrow of such patients is likely to contain a mixture of normal and 'transformed' stem cells; model 2 may therefore apply in some patients and model 3 in others. Therapy of CML with imatinib reveals Ph negative clonal disorders in more than 10% of patients (Bumm et al, 2003). This relatively high figure would be difficult to explain by chance alone (given the low incidence of each disorder) and may indicate genetic and/or environmental predisposition. References N. J. Curtin 1 , P. J. Campbell 1,2 , A. R. Green 1,2 1 Haematology Department, Addenbrooke's NHS Trust, Hills Road, Cambridge, UK , 2 University Department of Haematology, Cambridge Institute for Medical Research, Hills Road, Cambridge, UK. E-mail: [email protected] References Bumm, T., Muller, C., Al-Ali, H.K., Krohn, K., Shepherd, P., Schmidt, E., Leiblein, S., Franke, C., Hennig, E., Friedrich, T., Krahl, R., Niederwieser, D & Deininger, MW. (2003) 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, 101, 1941– 1949.CrossrefCASPubMedWeb of Science®Google Scholar Haq, A. (1990) Transformation of polycythaemia vera to Ph-positive chronic myelogenous leukemia. American Journal of Haematology, 35, 110– 113. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar Wahlin, A. & Golovleva, I. (2003) Emergence of Philadelphia positive chronic myeloid leukaemia during treatment with hydroxyurea for Philadelphia negative essential thrombocytosis. European Journal of Haematology, 70, 240– 241.Wiley Online LibraryCASPubMedWeb of Science®Google Scholar Citing Literature Volume128, Issue5March 2005Pages 734-736 FiguresReferencesRelatedInformation
Publication Year: 2005
Publication Date: 2005-02-21
Language: en
Type: letter
Indexed In: ['crossref', 'pubmed']
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Cited By Count: 38
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