Impressive thrombocytosis evolving in a patient with a BCR-ABL positive CML in major molecular response during dasatinib treatment unmasks an additional JAK2V617F

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Abstract

We present a case of a 42-year old female with the rare diagnosis of a myeloproliferative syndrome harboring both a BCR-ABL transclocation and a JAK2V617F mutation.

Initially diagnosed with a CML, the patient underwent treatment with imatinib followed by dasatinib. Despite a major molecular response, the patient developed a thrombocytosis. Molecular analyses revealed a heterozygous JAK2V617F mutation, which was detected retrospectively in the bone marrow at the time of CML diagnosis.

This case underlines the complexity of MPS pathogenesis. For the clinician, a JAK2 mutational screening should be performed in CML patients without hematological response in the absence of BCR-ABL.

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Prognostic discrimination in "good-risk" chronic granulocytic leukemia.

Joachim Braun, Elizabeth J. Robertson, E. Sokal … (1984)

The prognostic significance of disease features recorded at the time of diagnosis was examined among 813 patients with Philadelphia chromosome-positive, nonblastic chronic granulocytic leukemia (CGL) collected from six European and American series. The survival pattern for this population was typical of "good-risk" patients, and median survival was 47 mo. There were multiple interrelationships among different disease features, which led to highly significant correlations with survival for some that had no primary prognostic significance, such as hematocrit. Multivariable regression analysis indicated that spleen size and the percentage of circulating blasts were the most important prognostic indicators. These features, and age, behaved as continuous variables with progressively unfavorable import at higher values. The platelet count did not influence survival significantly at values below 700 X 10(9)/liter but was increasingly unfavorable above this level. Basophils plus eosinophils over 15%, more than 5% marrow blasts, and karyotypic abnormalities in addition to the Ph1 were also significant unfavorable signs. The Cox model, generated with four variables representing percent blasts, spleen size, platelet count, and age, provided a useful representation of risk status in this population, with good fit between predicted and observed survival over more than a twofold survival range. A hazard function derived from half of the patient population successfully segregated the remainder into three groups with significantly different survival patterns. We conclude that it should be possible to identify a lower risk group of patients with a 2-yr survival of 90%, subsequent risk averaging somewhat less than 20%/yr and median survival of 5 yr, an intermediate group, and a high-risk group with a 2-yr survival of 65%, followed by a death rate of about 35%/yr and median survival of 2.5 yr.

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A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group.

Joerg Hasford, Markus Pfirrmann, Rüdiger Hehlmann … (1998)

Interferon alfa is a conservative and widely used alternative to bone marrow transplantation in treatment of patients with early chronic myeloid leukemia (CML). A meta-analysis was conducted to develop a reliable prognostic scoring system for estimation of survival of patients with CML treated with interferon alfa. Patients treated in prospective studies, including major randomized trials, were separated into learning and validation samples. Cox regression analysis and the minimum P-value approach were used to identify prognostic factors for patient survival and to discover groups in the learning sample with the greatest differences in survival. These findings were then validated by applying the new scoring system to patients in the validation sample. We collected data on 1573 patients who were participants in 14 studies involving 12 institutions; 1303 patients (learning sample, n = 981; validation sample, n = 322) were eligible for inclusion in this analysis, and their median survival time was 69 months (range, 1-117 months). Because two previously described prognostic scoring systems failed to discriminate risk groups satisfactorily, we developed a new scoring system that utilizes the following covariates: age, spleen size, blast count, platelet count, eosinophil count, and basophil count. Among 908 patients with complete data in the learning sample, three distinct risk groups were identified (median survival times of 98 months [n = 369; 40.6%], 65 months [n = 406; 44.7%], or 42 months [n = 133;14.6%]; two-sided logrank test, P< or =.0001). The ability of the new scoring system to discriminate these risk groups was confirmed by analysis of 285 patients with complete data in the validation sample (two-sided logrank test, P = .0002). A new prognostic scoring system for estimating survival of patients with CML treated with interferon alfa has been developed and validated through use of a large dataset.

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Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study.

Jane A. Scott, Lindsay Campbell, Keith Wheatley … (2005)

An acquired V617F mutation in JAK2 occurs in most patients with polycythaemia vera, but is seen in only half those with essential thrombocythaemia and idiopathic myelofibrosis. We aimed to assess whether patients with the mutation are biologically distinct from those without, and why the same mutation is associated with different disease phenotypes. Two sensitive PCR-based methods were used to assess the JAK2 mutation status of 806 patients with essential thrombocythaemia, including 776 from the Medical Research Council's Primary Thrombocythaemia trial (MRC PT-1) and two other prospective studies. Laboratory and clinical features, response to treatment, and clinical events were compared for V617F-positive and V617F-negative patients with essential thrombocythaemia. Mutation-positive patients had multiple features resembling polycythaemia vera, with significantly increased haemoglobin (mean increase 9.6 g/L, 95% CI 7.6-11.6 g/L; p<0.0001), neutrophil counts (1.1x10(9)/L, 0.7-1.5x10(9)/L; p<0.0001), bone marrow erythropoiesis and granulopoiesis, more venous thromboses, and a higher rate of polycythaemic transformation than those without the mutation. Mutation-positive patients had lower serum erythropoietin (mean decrease 13.8 U/L; 95% CI, 10.8-16.9 U/L; p<0.0001) and ferritin (n=182; median 58 vs 91 mug/L; p=0.01) concentrations than did mutation-negative patients. Mutation-negative patients did, nonetheless, show many clinical and laboratory features that were characteristic of a myeloproliferative disorder. V617F-positive individuals were more sensitive to therapy with hydroxyurea, but not anagrelide, than those without the JAK2 mutation. Our results suggest that JAK2 V617F-positive essential thrombocythaemia and polycythaemia vera form a biological continuum, with the degree of erythrocytosis determined by physiological or genetic modifiers.

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Author and article information

Contributors

Friederike Pastore

Stephanie Schneider

Oliver Christ

Wolfgang Hiddemann

Karsten Spiekermann

Journal

Journal ID (nlm-ta): Exp Hematol Oncol

Journal ID (iso-abbrev): Exp Hematol Oncol

Title: Experimental Hematology & Oncology

Publisher: BioMed Central

ISSN (Electronic): 2162-3619

Publication date Collection: 2013

Publication date (Electronic): 5 September 2013

Volume: 2

Page: 24

Affiliations

[1 ]Laboratory for Leukemia Diagnostics, Department of Internal Medicine III, University Hospital Munich – Campus Grosshadern, Munich, Germany

[2 ]Clinical Cooperative Group, Pathogenesis of Acute Leukemia, Helmholtz Center, Munich, Germany

Article

Publisher ID: 2162-3619-2-24

DOI: 10.1186/2162-3619-2-24

PMC ID: 3847069

PubMed ID: 24007855

SO-VID: 90b7ad4c-fdba-49c1-83be-d41e250fe45e

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Impressive thrombocytosis evolving in a patient with a BCR-ABL positive CML in major molecular response during dasatinib treatment unmasks an additional JAK2V617F

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Most cited references 20

Prognostic discrimination in "good-risk" chronic granulocytic leukemia.

A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group.

Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study.

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