A Large Proportion of Patients With a Diagnosis of Essential Thrombocythemia Do Not Have a Clonal Disorder and May Be at Lower Risk of Thrombotic Complications

Blood ◽  
1999 ◽  
Vol 93 (2) ◽  
pp. 417-424 ◽  
Author(s):  
Claire N. Harrison ◽  
Rosemary E. Gale ◽  
Samuel J. Machin ◽  
David C. Linch
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Essential Thrombocythemia ◽  
Lower Risk ◽  
Study Group ◽  
Reactive Thrombocytosis ◽  
Age Related ◽  
Hemorrhagic Complications ◽  
Thrombotic Complications

Essential thrombocythemia (ET) is traditionally considered to be a clonal disorder. No specific karyotypic abnormalities have been described, but the demonstration of clonality using X-chromosome inactivation patterns (XCIPs) has been used to differentiate ET from a non-clonal reactive thrombocytosis. However, these assays may be difficult to interpret, and contradictory results have been reported. We have studied 46 females with a diagnosis of ET according to the Polycythemia Vera Study Group (PVSG) criteria. XCIP results in 23 patients (50%) were uninterpretable due to either constitutive or possible acquired age-related skewing. Monoclonal myelopoiesis could be definitively shown in only 10 patients. Thirteen patients had polyclonal myelopoiesis, and in 8, it was possible to exclude clonal restriction to the megakaryocytic lineage. Furthermore, there was no evidence of clonal progenitors in purified CD34+CD33− and CD34+CD33+ subpopulations from bone marrow of 2 of these 13 patients. There was no difference between patients with monoclonal and polyclonal myelopoiesis with respect to age or platelet count at diagnosis, duration of follow-up, incidence of hepatosplenomegaly, or hemorrhagic complications. However, polyclonal patients were less likely to have experienced thrombotic events (P = .039). These results suggest that ET is a heterogeneous disorder, and the clinical significance of clonality status warrants investigation in a larger study.

A Large Proportion of Patients With a Diagnosis of Essential Thrombocythemia Do Not Have a Clonal Disorder and May Be at Lower Risk of Thrombotic Complications

Blood ◽  
1999 ◽  
Vol 93 (2) ◽  
pp. 417-424 ◽  
Author(s):  
Claire N. Harrison ◽  
Rosemary E. Gale ◽  
Samuel J. Machin ◽  
David C. Linch
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Essential Thrombocythemia ◽  
Lower Risk ◽  
Study Group ◽  
Reactive Thrombocytosis ◽  
Age Related ◽  
Hemorrhagic Complications ◽  
Thrombotic Complications

Abstract Essential thrombocythemia (ET) is traditionally considered to be a clonal disorder. No specific karyotypic abnormalities have been described, but the demonstration of clonality using X-chromosome inactivation patterns (XCIPs) has been used to differentiate ET from a non-clonal reactive thrombocytosis. However, these assays may be difficult to interpret, and contradictory results have been reported. We have studied 46 females with a diagnosis of ET according to the Polycythemia Vera Study Group (PVSG) criteria. XCIP results in 23 patients (50%) were uninterpretable due to either constitutive or possible acquired age-related skewing. Monoclonal myelopoiesis could be definitively shown in only 10 patients. Thirteen patients had polyclonal myelopoiesis, and in 8, it was possible to exclude clonal restriction to the megakaryocytic lineage. Furthermore, there was no evidence of clonal progenitors in purified CD34+CD33− and CD34+CD33+ subpopulations from bone marrow of 2 of these 13 patients. There was no difference between patients with monoclonal and polyclonal myelopoiesis with respect to age or platelet count at diagnosis, duration of follow-up, incidence of hepatosplenomegaly, or hemorrhagic complications. However, polyclonal patients were less likely to have experienced thrombotic events (P = .039). These results suggest that ET is a heterogeneous disorder, and the clinical significance of clonality status warrants investigation in a larger study.

scholarly journals TROMBOCYTOSIS FOLLOWING SPLENECTOMY IN PEDIATRIC PATIENTS

2016 ◽  
Vol 65 (2) ◽  
pp. 166-169
Author(s):  
Andreea Ligia Dinca ◽  
◽  
Cristina Oana Marginean ◽  
Despina Baghiu ◽  
Alina Grama ◽  
...  
Keyword(s):  
Platelet Count ◽  
Retrospective Study ◽  
Pediatric Patients ◽  
Severe Form ◽  
Study Group ◽  
Inclusion Criteria ◽  
Mild Form ◽  
Reactive Thrombocytosis ◽  
Thrombotic Complications ◽  
Post Traumatic

Thrombocytosis represents a platelet count over 500.000/mm³. Objective. The aim of this study is to evaluate the frequency and gravity of reactive thrombocytosis in pediatric patients who underwent splenectomy. Material and method. We performed a retrospective study including 20 patients (4-16 years old) who underwent splenectomy between 2006-2015. The inclusion criteria in the study were: patients with the age under 18 years, who underwent splenectomy independently by the cause, and who developed afterwards thrombocytosis. Results. In the studied group 64% of the splenectomised patients (16) developed a form of thrombocytosis. In 4 cases – severe form (Platelets > 1 million/mm3) and in 7 cases a mild form. There were not noticed any significant differences regarding the gender repartition of the patients (9 were females, and 11 were males). In 13 patients, thrombocytosis disappeared after 30 days, and only in 3 cases, the episode lasted more than 360 days. Thrombotic phenomena were noticed only in one patient from our study group. All the patients benefited from thromboprophylaxis and hydration measures, and 2 cases needed associated treatment with Hydroxyurea. Conclusions. Our study reveals an increased frequency of thrombocytosis after splenectomy (80%), with a maximum peak of incidence in 2-10 days following the intervention, thrombocytosis being generally benign and self-limited; still one of the cases experienced thrombotic complications and severe thrombocytosis was more frequent after post-traumatic splenectomy.

Essential Thrombocythemia in Patients with Platelet Counts below 600×109/L: Applicability of the 2008 World Health Organization Diagnostic Criteria Proposal

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5239-5239
Author(s):  
Mi Kwon ◽  
Santiago Osorio Prendes ◽  
Carolina Muñoz ◽  
Jose Manuel Sanchez ◽  
Monica Ballesteros ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Essential Thrombocythemia ◽  
World Health ◽  
Jak2 Mutation ◽  
Who Criteria ◽  
Platelet Counts ◽  
Bone Marrow Histology ◽  
Health Organization

Abstract WHO criteria defines platelet counts above 600×109/L as the threshold for essential thrombocythemia (ET) diagnosis. It has been argued that such threshold excludes a number of patients with ET with platelet counts below 600×109/L. Recently, a proposal for revision of the World Health Organization (WHO) diagnostic criteria for ET has been published, which includes the combination of histological bone marrow study and testing of JAK2 mutation. Design and methods: Retrospective analysis of 92 patients with ET diagnosis between 1989 and February 2008, isolating the subgroup of patients with platelet counts below 600×109/L. The aim of this study was to analyze the applicability of the 2008 WHO criteria in this subgroup. Results: Of the 92 patients, 30 patients did not fulfill the WHO criteria due to platelet counts <600×109/L and in some cases also due to the coexistence of alternative causes of thrombocytosis. There were no significant differences between the entire group and the borderline platelet count subgroup in demographics, clinical and laboratory parameters (Table 1). The median age of the borderline platelet count group was 51 years (range 19–83 years) and 20 were female (70%). At diagnosis their median platelet count was 527×109/L (range 424–597). Fifteen patients (50%) showed the presence of JAK2 mutation. Remarkably, 74% of the patients presented as high-intermediate risk at diagnosis. From the 30 patients who did not fulfill the WHO criteria due to low platelet counts, 26 (87%) satisfied the modified criteria allowing ET diagnosis. Among them, 1 patient showed an alternative cause of thrombocytosis, however JAK2 mutation was positive confirming the primary cause of the disorder. Four patients remained not fulfilling the new criteria due to insufficient bone marrow sample or incompatible histology, however one of these patients showed JAK2 mutation confirming ET. The median follow-up was 2.54 years (range 0.07–18.7). During this period, none of the 30 patients had a spontaneous decrease of platelet count to within the normal range. Furthermore, transformation from ET to IMF was observed in 2 cases supporting the diagnosis of ET. During follow-up, 27 out of 30 patients were treated with antiaggregating drugs, 3 with antithrombotic therapy, and 20 with myelosuppressive therapy. The 11 patients who did not receive myelosuppressive therapy remained with platelet counts above 400×109/L. Conclusions: In our study, patients with platelet counts below 600×109/L did not show significant differences compared with the whole ET patients group. This subgroup can be diagnosed as having ET following the 2008 WHO criteria. The detection of JAK2 mutation in this setting enables the accurate diagnosis not only in cases with borderline thrombocytosis but more importantly in cases with alternative potential causes and also in cases where bone marrow sample is not available or incompatible. This observation raises de question of the role of bone marrow histology as a subjective diagnostic tool in ET diagnosis as opposed to JAK2 mutation detection. In JAK2 negative patients, subsequent follow-up of untreated patients confirmed the diagnosis since platelet counts remained high. The modified criteria facilitates the clinician to make an early diagnosis of ET in this subgroup of patients. Furthermore, a high proportion of these patients may be at risk of vascular complications, who may beneficiate from being correctly treated. TABLE 1 Total of patients Platelet count <600×10e9/L Number 92 30 Female (number, %) 59 (64%) 20 (70%) Age (median, range) 51 (19–84) 51 (19–83) Risk Low 26 (28%) 8 (26%) Intermediate 21(22%) 6 (19%) High 45 (48%) 16 (53%) Platelets ×10e9/L 693 (424–2,777) 527 (424–597) Hb g/dL 14.5 (11–18) 14.3 (11–16.8) Leucocytes ×10e9/L 8,5 (3,6–24,2) 8,5 (5,2–13,8) LDH UI/L 380 (39–1413) 337 (39–938) Splenomegaly 16 (17%) 5 (17%) JAK2 mutation 47 (51%) 15 (50%) Bone Marrow histology Celullarity >3.5 30/88 (34%) 8/28 (29%) Fibrosis grade I 2/90 (2%) 0 Compatible histology 79/89 (86%) 21/28 (75%) Abnormal Cytogenetics 2/26 (8%) 0 Symptoms 13 (14%) 4 (13%) Thrombotic event 16 (18%) 5 (17%) Haemorrhagic event 3 (4%) 0

JAK2 V617F Mutation Identifies a Biologically Distinct Subtype of Essential Thrombocythemia Which Resembles Polycythemia Vera.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 253-253 ◽  
Author(s):  
Anthony Green ◽  
Peter Campbell ◽  
Linda Scott ◽  
Georgina Buck ◽  
Keith Wheatley ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Response To Therapy ◽  
Jak2 Mutation ◽  
Mutation Status ◽  
Cell Counts ◽  
V617f Mutation

Abstract An acquired V617F mutation in JAK2 occurs in most patients with polycythemia vera (PV) but only half of those with essential thrombocythemia (ET) and idiopathic myelofibrosis. It is not known whether mutation-bearing patients are biologically distinct from those lacking the mutation, or why the same mutation is associated with different phenotypes. Two sensitive PCR-based methods were used to assess the JAK2 mutation status of 806 patients with ET, including 776 from the MRC PT-1 trial and two other prospective studies. The combined cohort provides a unique resource for studying ET, particularly in view of its large size, centralized review of end-points and comprehensive follow-up. The involvement of a large number of secondary and tertiary centers, together with the inclusion of patients in all risk categories, suggest the results are of general relevance. JAK2 mutation status divided the cohort into two distinct subgroups. Mutation-positive patients (53.4%) displayed multiple features resembling PV, with significantly increased hemoglobin levels (p<0.0001), neutrophil counts (p<0.0001), bone marrow erythropoiesis (p=0.001) and granulopoiesis (p=0.005). They suffered more venous thromboses in the year before diagnosis (p=0.04) and during follow-up (p=0.06), together with a higher incidence of polycythemic transformation (p=0.01). To explore the resemblance between V617F-positive ET and PV further, we analysed factors that might constrain erythropoiesis. Compared to mutation-negative patients with ET, mutation-positive patients had lower serum epo (p<0.0001), lower ferritin (p=0.01), and were more likely to be microcytic (p<0.0001). V617F-positive patients were more sensitive to hydroxyurea, requiring lower doses to control platelet count than V617F-negative patients (p<0.0001), a pattern not seen with anagrelide. Despite lower doses of hydroxyurea, V617F-positive patients had greater reductions in hemoglobin, platelet and white cell counts than V617F-negative patients, with no analogous differences noted between V617F-positive and negative patients randomized to anagrelide (p=0.004, p=0.04, p=0.0003 for platelet count, Hb and WCC). Mutation-negative patients did exhibit many clinical and laboratory features characteristic of a myeloproliferative disorder, including cytogenetic abnormalities, hypercellular bone marrow, abnormal megakaryocyte morphology, PRV1 over-expression, growth of epo-independent erythroid colonies, and a risk of myelofibrotic or leukemic transformation. JAK2 mutation status defines two biologically distinct subgroups of ET with differences in presentation, outcome and response to therapy. Our results suggest a model in which V617F-positive ET and PV form a continuum, with the degree of erythrocytosis determined by physiological or genetic modifiers, including iron stores, epo homeostasis, gender and V617F-homozygosity. This concept has major implications for the classification, diagnosis and management of MPDs.

Subnormal Lymphocyte Count Predicts Inferior Survival in Myelodysplastic Syndromes: A Single Center Experience in 889 Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5534-5534
Author(s):  
Lyla Saeed ◽  
Mrinal M Patnaik ◽  
Kebede H. Begna ◽  
Aref Al-Kali ◽  
Curtis A. Hanson ◽  
...  
Keyword(s):  
Adverse Effect ◽  
Bone Marrow ◽  
Platelet Count ◽  
Risk Stratification ◽  
Lower Risk ◽  
Research Funding ◽  
Leukocyte Count ◽  
Monocyte Count ◽  
Free Survival

Abstract Background In myelodysplastic syndromes (MDS), we have previously shown the adverse prognostic effect of ALC <1.2 x 10(9)/L (Nisha et al. Am J Hematol 2010;85:160). In the current larger study of 889 patients with MDS, we sought to validate and expand on our previous observations and also examine the effect of lymphocyte-to-monocyte ratio (LMR). Methods We retrospectively recruited 889 consecutive patients with primary MDS who were untreated at the time of referral to our institution, and in whom ALC and absolute monocyte count (AMC) at time of referral was documented. The diagnosis of MDS and leukemic transformation (LT) was according to WHO criteria (Blood. 2009;114:937). Complete follow-up information was updated in January 2015. Comparison of laboratory and clinical features was made between patients with subnormal and normal ALC; patients with above normal ALC were considered separately. Overall and leukemia-free survivals of patients with normal ALC was compared to those with either subnormal ALC or, in order to validate our previous observation, with ALC <1.2 x 10(9)/L. Results Patient characteristics: Median (range) values for the 889 study patients (69% males) included: age 72 (18-98), hemoglobin 9.6 g/dL (5.4-15.7), leukocyte count 3.4 x 10(9)/L (0.4-35), AMC 0.2 x 10(9)/L (0-1.7), platelet count 106 x 10(9)/L (2-1804), circulating blasts 0% (0-18) and bone marrow blasts 3% (0-19). Transfusion need was documented in 33% of patients and abnormal karyotype in 49%. Risk stratification by the revised international prognostic scoring system (IPSS-R) was very high in 10%, high in 16%, intermediate in 20%, low in 36% and very low in 16%. The median (range) ALC for the entire study population of 889 patients was 1.16 x 10(9)/L (0.02-8.9). The normal range of ALC at our institution was 0.9-2.9 x 10(9)/L; the number of patients with subnormal, normal and above normal ALC was 261 (29%), 598 (67%) and 30 (4%), respectively. In addition, 442 (50%) and 417 (47%) patients had ALC below 1.2 x 10(9)/L and ALC between 1.2 and the upper limit of normal, respectively. After a median follow-up of 27 months, 712 (80%) deaths and 116 (13%) leukemic transformations were documented. Comparison of patients stratified by absolute lymphocyte count Compared to patients with normal ALC, patients with subnormal ALC displayed lower hemoglobin (p=0.002), higher red blood cell transfusion need (p=0.0003), lower leukocyte count (p<0.0001), lower monocyte count (p=0.002) and lower platelet count (p<0.0001), whereas borderline association was also apparent for older age (p=0.06). In univariate analysis, survival was adversely affected by lower ALC, treated as a continuous variable (p=0.01). Similarly, when compared to patients with normal ALC, patients with subnormal ALC (p=0.001; HR 1.3, 95% CI 1.1-1.5) and those with ALC <1.2 x 10(9)/L (p=0.0002; HR 1.3, 95% CI 1.2-1.6) experienced significantly shortened survival. There was no difference in survival between patients with above normal ALC and those with either subnormal (p=0.58) or normal (p=0.41) ALC; accordingly, patients with above normal ALC were excluded from subsequent analysis. In multivariable analysis, the adverse effect of subnormal ALC was shown to be independent of age, gender, anemia, thrombocytopenia, neutropenia , circulating blast percentage, bone marrow blast percentage or cytogenetic risk stratification by and IPSS; the same held true for ALC <1.2 x 10(9)/L. The association with IPSS-R was of borderline significance for both ALC <1.2 x 10(9)/L (p=0.06) and subnormal ALC (p=0.1). The adverse effect of ALC was most apparent in patients with very low or low risk disease per IPSS-R (p=0.0007 for subnormal ALC and 0.0003 for ALC <1.2 x 10(9)/L), compared to those with higher risk status (p=0.67 and 0.7, respectively). Neither subnormal ALC (p=0.4) nor ALC <1.2 x 10(9)/L (p=0.1) affected leukemia free survival. Analysis using LMR in place of ALC showed similar but not necessarily superior results. Conclusions Compared to those with normal ALC, MDS patients with either subnormal ALC or with ALC below 1.2 x 10(9)/L experienced shorter overall, but not leukemia-free, survival; this adverse effect was most apparent in lower risk patients and was independent of most of the currently established risk factors for survival in MDS. The observations from the current study suggest the possible therapeutic value of augmenting host immunity in lower risk MDS. Disclosures Al-Kali: Onconova Therapeutics, Inc.: Research Funding; Celgene: Research Funding.

Extramedullary Hematopoiesis and Splenic Vein Thrombosis, a Unique Presentation Of Pre-Clinical Essential Thrombocythemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5257-5257 ◽  
Author(s):  
Abdulraheem Yacoub ◽  
Abigail Brockman
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Liver Biopsy ◽  
Essential Thrombocythemia ◽  
Extramedullary Hematopoiesis ◽  
Common Finding ◽  
Thrombotic Risk ◽  
Vein Thrombosis ◽  
Life Threatening

Abstract Essential thrombocythemia (ET) is of the BCR-ABL-Negative myeloproliferative neoplasms (MPN). The incidence of ET is approximately 2.5 in every 100,000 person per year. However, given the good prognosis, associated long life expectancy, and increasing detection in younger populations,ET is associated with a higher prevalence rate estimated to be 24 in every 100,000 person per year. ET is characterized by thrombocytosis, vasomotor symptoms, and a variable but increased risk of thrombosis and bleeding. Half of all ET patients will have a positive JAK2 and/or MPL mutation(s). Extramedullary hematopoiesis (EMH) is not a common finding in ET. Nonetheless, ET and other MPNs are associated with the mobilization of CD34+ cells into the peripheral blood. This process can ultimately lead to the seeding of extramedullary sites with primitive hematopoietic capacity, resulting in EMH within the spleen and liver, as well as a variety of other organs. Herein we describe a case that presented with life-threatening thrombosis and was found to have hepatic EMH several months prior to a clinical and pathologic diagnosis of ET. Case description A 22 year-old woman presented 10 days post Cesarean section with abdominal pain and hematemesis. Abdominal imaging showed hepatomegaly, splenomegaly, along with splenic and portal vein thrombosis. The patient underwent an emergency surgical splenectomy due to severe portal hypertension and endoscopic evidence of gastric variceal bleeding. A random liver biopsy was also performed intra-operatively. The splenectomy resulted in resolution of the GI bleeding and the varices normalized on follow up. Her platelet count was normal at the time of operation, but post-splenectomy her platelet count peaked at 1,217 K/ µL. Extensive testing did not unravel any identifiable inherited and/or acquired hypercoaguable factors. Subsequently anticoagulation therapy was recommended for 6 months. On pathology review, the spleen histology showed congestion, but otherwise no diagnostic abnormalities were noted. The liver biopsy showed evidence of EMH but did not identify any liver parenchymal disease. On subsequent follow up, the patient had persistent and marked thrombocytosis for over a year. A bone marrow biopsy was performed which showed a hypercellular bone marrow and megakaryocytic hyperplasia with a few large forms. There was no dysplasia or significant reticulin fibrosis. JAK2 mutation and BCR-ABL translocation were negative. Hydroxyurea and aspirin were started due to high risk of thrombosis. Discussion We report this unique case in which there was evidence of extramedullary hematopoiesis, along with pathologic and life threatening visceral thrombosis several months before the patient met criteria for diagnosis of ET. This supports the notion that neoplastic cells can mobilize and seed other organs early in the course of MPNs, including ET. Thrombotic risk in MPNs can also occur in the preclinical phase of MPNs as has been suggested in other reports. We also conclude that the demonstration of EMH in individuals with no preexisting hematologic neoplasm should warrant close follow up and assessment. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Correlation of blood counts with vascular complications in essential thrombocythemia: analysis of the prospective PT1 cohort

Blood ◽  
2012 ◽  
Vol 120 (7) ◽  
pp. 1409-1411 ◽  
Author(s):  
Peter J. Campbell ◽  
Cathy MacLean ◽  
Philip A. Beer ◽  
Georgina Buck ◽  
Keith Wheatley ◽  
...  
Keyword(s):  
Platelet Count ◽  
Essential Thrombocythemia ◽  
Myeloproliferative Neoplasm ◽  
Vascular Complications ◽  
Complication Rates ◽  
Normal Range ◽  
Major Hemorrhage ◽  
Confounding Variables ◽  
Wbc Count

Abstract Essential thrombocythemia, a myeloproliferative neoplasm, is associated with increased platelet count and risk of thrombosis or hemorrhage. Cytoreductive therapy aims to normalize platelet counts despite there being only a minimal association between platelet count and complication rates. Evidence is increasing for a correlation between WBC count and thrombosis, but prospective data are lacking. In the present study, we investigated the relationship between vascular complications and 21 887 longitudinal blood counts in a prospective, multicenter cohort of 776 essential thrombocythemia patients. After correction for confounding variables, no association was seen between blood counts at diagnosis and future complications. However, platelet count outside of the normal range during follow-up was associated with an immediate risk of major hemorrhage (P = .0005) but not thrombosis (P = .7). Elevated WBC count during follow-up was correlated with thrombosis (P = .05) and major hemorrhage (P = .01). These data imply that the aim of cytoreduction in essential thrombocythemia should be to keep the platelet count, and arguably the WBC count, within the normal range. This study is registered at the International Standard Randomized Controlled Trials Number Registry (www.isrctn.org) as number 72251782.

scholarly journals BCR-ABL Transcripts in Bone Marrow Aspirates of Philadelphia-Negative Essential Thrombocythemia Patients: Clinical Presentation

Blood ◽  
1997 ◽  
Vol 90 (7) ◽  
pp. 2768-2771 ◽  
Author(s):  
Dorit Blickstein ◽  
Adina Aviram ◽  
Jacob Luboshitz ◽  
Miron Prokocimer ◽  
Pinhas Stark ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Essential Thrombocythemia ◽  
Clinical Presentation ◽  
Molecular Level ◽  
Philadelphia Chromosome ◽  
Nested Polymerase Chain Reaction ◽  
History Of ◽  
Polymerase Chain ◽  
Positive Groups

Abstract One of the diagnostic criteria of essential thrombocythemia (ET) is the absence of the Philadelphia chromosome (Ph-neg). On the molecular level, Ph-neg ET patients may carry BCR-ABL transcript. The natural history of BCR-ABL positive Ph-neg ET patients is undetermined. We examined the BCR-ABL status by reverse transcriptase two-step nested polymerase chain reaction in bone marrow aspirates of 25 Ph-neg ET patients. We found 12 BCR-ABL positive and 13 BCR-ABL negative patients in the study group. The comparison showed that the two groups had similar clinical and laboratory characteristics, except for a significant increased patients' age and decreased polymorphonuclear cell count in the BCR-ABL positive group. During a median follow-up of 20 and 22.5 months for the BCR-ABL negative and positive groups, respectively, there was neither blastic transformation nor unrelated death in both groups. We conclude that it is important to look for BCR-ABL transcript in Ph-neg ET patients and to follow them closely to investigate the nature of this translocation in this group of patients.

Identification of Homozygous JAK2V617F Mutation in Unfractioned Blood Samples in a Substantial Proportion of Myeloproliferative Disorders: Long Term Follow-Up Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4644-4644
Author(s):  
Irina Panovska ◽  
Nadica Matevska ◽  
Martin Ivanovski ◽  
Sanja Trajkova ◽  
Aleksandar Stojanovik ◽  
...  
Keyword(s):  
Jak2 V617f ◽  
Jak2v617f Mutation ◽  
Study Group ◽  
Hematopoietic Progenitors ◽  
Blood Samples ◽  
Allele Burden ◽  
Long Term Follow Up ◽  
Thrombotic Complications

Abstract The discovery of the activating V617F mutation in the JAK2 tyrosine kinase gene in patients with myloproliferative disorders (MPD) provides a major breakthrough in the understanding of the pathogenesis, proving clonality and securing diagnosis of these diseases. The JAK2 V617F allele is an acquired somatic disease allele that arises in hematopoietic progenitors and confers a selective growth advantage. The mutation has been traced to a primitive stem cell that is capable of erythroid and myeloid differentiation. The data for the potential involvement of the B and T lymphocytes with the JAK2V617F mutation are still inconsistent. We present the results from the study designed the evaluate the prevalence of the JAK2V617F mutation in MPDs patients in our population and to investigate whether MPD patients that carry the JAK2V617F mutation differ in clinical course and outcome from JAK2V617F negative MPD patients. The study group consisted of 64 living MPD patients diagnosed according to standard WHO criteria for diagnosis of MPD (26 patients were diagnosed as polycythemia vera (PV), 34 as essential thrombocythemia (ET), 6 as idiopatic myelofibrosis (MF) and 8 were classified as atypical MPD) with the median follow-up of 7,4 years. DNA samples were obtained from unfractionated blood samples and the frequency of V617F JAK2 mutation was analyzed by allele-specific PCR assay. The mutant allele burden in mutation positive samples was analyzed by DNA sequencing. Our results showed that the JAK2 V617F mutation was present in 79% of patients with PV (36% were homozygous for the mutation), 58% with ET (11% homozygous), 69% with MF (28% homozygous) and in 33% of patients with atypical MPD. The mutant JAK2V617F allele burden was greater than 95% in two PV patients, which in the presence of 27% lymphocytes in the peripheral blood of the patients indicate lymphocytes involvement with the mutation. The high frequency of observed homozygosity for JAK2V617F in our study group was probably due to the long disease duration (median follow-up 11,4 years) and favors the theory of a time dependent increase in clonal dominance. Correlations of clinical and laboratory features at diagnosis and subsequent follow-up, including incidence of thrombo-hemorrhagic events, disease transformation and survival of JAK2V617F-positive and JAK2V617F-negative patients did not reveal significant differences except for the incidence of thrombotic complications. The JAK2V617F positive group had a higher incidence of thrombotic complications (30%) compared with the JAK2-V617F-negative group (14%, P< 0.05). Although we observed a disparity in the incidence of the JAK2V617F mutation in different MPD entities in our population with respect to the expected frequency of JAK2V617F from the literature, our results confirm the diagnostic significance of the JAK2V617F mutation in MPDs and support the notion that patients with this mutation should be classified in a new entity of MPDs. Identification of homozygous JAK2V617F mutation in unfractionated blood samples in a substantial proportion of long term follow-up MPD patients, together with the identification of the mutant JAK2V617F allele burden greater than 95% in two PV patients, suggests that acquisition of the JAK2V617F mutation arises in early multilineage hematopoietic progenitors and warrants further investigation.

Cytoreductive Therapeutic Approach in the Essential Thrombocythemia (ET) Patients of the Registro Italiano Trombocitemia (RIT): Preliminary Data

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5248-5248
Author(s):  
Luigi Gugliotta ◽  
Alessia Tieghi ◽  
Anna Candoni ◽  
Monia Lunghi ◽  
Gianluca Gaidano ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Essential Thrombocythemia ◽  
Therapeutic Approach ◽  
Jak2 V617f ◽  
Bone Marrow Biopsies ◽  
Thrombotic Risk ◽  
Significant Difference ◽  
Cytoreductive Treatment ◽  
Wbc Count

Abstract Background: the Registro Italiano Trombocitemia, that is a GIMEMA project, has been activated to registry Italian Essential Thrombocythemia (ET) patients, to improve the diagnosis appropriateness (WHO criteria), to verify the prognostic value of the clinical and biological parameters, to evaluate the compliance to the therapeutical Italian guidelines (1), and to create a network for activation of new studies. Objective: this analysis is mainly devoted to describe the ET patients registered in the RIT and to evaluate the therapeutic approach adopted in the 102 participating hematological centers. Material and methods: two thousand and fifteen ET patients have been registered after the written informed consent was obtained, and data validation by various expert panels is in progress. This preliminary report considers 1785 patients, diagnosed mainly (1078, 60.4%) since the publication in the year 2004 of the ET therapy Italian guidelines (1). Results: the patients, 678 (38%) males and 1107 (62%) females, showed at diagnosis: age 60.3 ± 16.8 years with higher values in males than in females (61.7 ± 15.3 vs. 59.4 ± 17.7, p&lt;0.05), being the patients below 40 years 14% and those over 70 years 33% of cases; PLT count (109/L) 846 ± 309 with lower values in males than in females (813 ± 261 vs. 866 ± 334, p&lt;0.002), and with values 1001–1500 and over 1500 in 16% and 4% of cases, respectively; WBC count (109/L) 9.1 ± 2.9, without difference by sex, and with values 12–15 in 10% and over 15 in 3% of cases; Hgb (g/dL) 14.2 ± 1.6 with higher values in males than in females (14.8 ± 1.5 vs. 13.8 ± 1.5, p&lt;0.001), and with values over 16.5 in 8.5% of males and 2.7% of females, respectively; splenomegaly in 488 (27%), echo-documented in 324 cases (18%); history of hemorrhage and thrombosis in 90 (5%) and 325 (19%) of cases, respectively; disease-related symptoms in 41% and general thrombotic risk factors in 93% of cases, respectively. The WHO 2001 diagnostic criteria were reported for 33% of cases observed before the year 2004 and for 53 % of cases observed since the year 2004. Detailed data at diagnosis were reported as follows: bone marrow biopsy in 1087 cases (61%) with a frequency of 51% and 68% before and since the year 2004, respectively; bcr-abl study in 1045 cases (59%); cytogenetics in 828 cases (46%) with karyotype abnormalities in 27 patients (3%). The JAK2 V617F mutation, searched in 574 cases (32%), was observed in 320 of them (56%). The patient follow-up was 4.5 ± 4.5 years with a total of 5245 pt-yrs. During the follow-up the hemorrhagic events were 5.7% (1.3/100 pt-yrs), being the major events 1.9% (0.4/100 pt-yrs); the thrombotic complications were 14.9 % (3.3/100 pt-yrs), resulting the major arterial 9.4% (2.1/100 pt-yrs), the major venous 3.5% (0.8/100 pt-yrs) and the minor thrombosis 2% (0.4/100 pt-yrs). An antiplatelet treatment, almost always with low dose aspirin, was performed in 75% of the patients, without significant difference in the cases diagnosed before and since the 2004. A cytoreductive treatment was done with use of Hydroxyurea (HU, 64%), Interferon alpha (IFN, 16%), Anagrelide (ANA, 15%), Busulfan (BUS, 4%), and Pipobroman (PIPO, 2 %). In the ET patients diagnosed since the year 2004 respect those diagnosed before, it was observed a decrease in the use of all the cytoreductive drugs, particularly BUS (−62%), IFN ((−62%), and ANA ((−68%). The use of the cytoreductive drugs was related to the patient mean age (years): BUS (76), PIPO (72), HU (67), ANA (53), IFN (48). In the patients diagnosed since the 2004 as compared with those before 2004, the mean age of the treated patients increased for BUS (from 69 to 81 yrs, p&lt;0.001) and for HU (from 64 to 69 yrs, p&lt;0.001) while it decreased for IFN (from 49 to 46 yrs, p&lt;0.05). Conclusion: in the analyzed patients of the ET Italian registry the diagnosis appropriateness resulted improved in the cases observed since the year 2004 respect those observed before, with an increase of bone marrow biopsies from 51% to 68% of patients. Moreover, in accord with the ET therapy Italian guidelines, the use of the cytoreductive drugs was less frequent in the patients diagnosed since the year 2004 than before (particularly for BUS, IFN, and ANA) and the more safe molecules IFN and ANA were preferentially deserved to the younger patients.

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