Arterial Versus Venous Events in Essential Thrombocythemia and Their Impact on Overall and Thrombosis Free Survival

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1611-1611
Author(s):  
A Kamel Abou Hussein ◽  
Naseema Gangat ◽  
Yoseph Elala ◽  
Curtis A. Hanson ◽  
Animesh Pardanani ◽  
...  
Keyword(s):  
Essential Thrombocythemia ◽  
Arterial Thrombosis ◽  
Leukocyte Count ◽  
Univariate Analysis ◽  
Multivariable Analysis ◽  
Jak2v617f Mutation ◽  
Prognostic Impact ◽  
Free Survival ◽  
Male Sex

Abstract Background : Current risk stratification for thrombosis in essential thrombocythemia (ET) utilizes age >60 years, history of thrombosis, JAK2V617F mutation and cardiovascular risk factors (Barbui, Blood 2012;26:5128). Thrombosis history is also predictive of inferior overall survival (OS) in ET (Passamonti, Blood 2012;6:1197). However, whether or not the prognostic impact of thrombosis in ET is contributed by arterial versus venous thrombosis is unclear. Methods: More than 45,000 patient charts with "thrombocytosis" were reviewed to identify those who met either PVSG (older patient cohort) or WHO criteria for diagnosis of ET. Details of type of thrombotic events were obtained by careful review of the medical record. A subset of patients was molecularly annotated for the JAK2, CALR and MPL mutations. OS was calculated from time of initial diagnosis to the time of last follow-up or death. Thrombosis-free survival (TFS) was calculated from the time of diagnosis of ET to the time of development of thrombosis or last follow up or death, in patients censored for thrombosis. Conventional statistics was utilized for all analyses. Results :Patient characteristics: A total of 610 patients met the above-stipulated criteria (median age 57 years; 61% females). 76 patients (12%) had thrombosis documented either prior to or at diagnosis of which 50 patients (66%) experienced arterial events. 302 patients were screened for JAK2/CALR/MPL mutations with a frequency of 53.5%, 31%, and 3% respectively, while12.5% were "triple-negative".Impact of thrombosis history on OS: At a median follow-up of 8.9 years (range: 0-43.6 years), 185 (30%) deaths were documented. Themedian OS for the entire cohort was 20 years. On univariate survival analysis, the predictors of inferior OS included: age ≥60 years (p<0.001), leukocyte count ≥11 x 10(9) (p<0.001), male sex (p=0.0002), thrombosis before or at diagnosis (p=0.01), and presence of the JAK2V617F mutation (p=0.03). All but JAK2 V617F (p=0.64) remained significant on multivariable analysis. When arterial and venous events were considered separately, in univariate analysis, only arterial (p<0.001) but not venous (p=0.387) thrombotic events retained significance. The significant prognostic contribution, to survival, of arterial thrombosis history was sustained (p=0.02) during multivariable analysis, that included age ≥ 60 years (p=<0.001), leukocyte count ≥11 x 10(9) (p=0.001), and male sex (p=0.001) on OS.Impact of thrombosis history on TFS: A total of 84 (14%) patients experienced thrombotic events during follow-up amongst which 60 (71%) experienced arterial thrombosis. On univariate analysis the predictors of inferior TFS included: age ≥ 60 years (p=0.016), leukocyte count ≥11 x 10(9) (p=0.001), thrombosis before or at diagnosis (p<0.001), and presence of the JAK2V617F mutation (p=0.002). On multivariable analysis, thrombosis before or at diagnosis (p<0.001), along with leukocyte count ≥11 x 10(9) (p=0.03), and presence of the JAK2V617F mutation (p=0.01) remained significant; the significance of age ≥60 years became borderline (p=0.07). When arterial and venous thrombosis were analyzed separately, only arterial (p<0.001), but not venous (p=0.48), thrombosis history was significantly associated with inferior TFS. The factors that predicted worse outcome with TFS included arterial thrombosis at or before diagnosis (p<0.001), leukocyte count ≥11 x 10(9) (p=0.03) and presence of the JAK2V617F mutation (p=0.01); the significance of age ≥60 years became borderline (p=0.13). Conclusions : The prognostic impact of thrombosis in ET, in terms of both overall and thrombosis-free survival, might be attributed to only arterial but not venous thrombotic events. The current study also confirms the independent prothrombotic role of JAK2V617F mutation in ET and suggests an additional role for leukocytosis. Disclosures Barbui: Novartis: Speakers Bureau.

Survival Trends in Essential Thrombocythemia in the Face of Changing Treatment Practices

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2805-2805
Author(s):  
A Kamel Abou Hussein ◽  
Naseema Gangat ◽  
Yoseph Elala ◽  
Alexandra Wolanskyj ◽  
Curtis A. Hanson ◽  
...  
Keyword(s):  
Platelet Count ◽  
Essential Thrombocythemia ◽  
Leukocyte Count ◽  
Multivariable Analysis ◽  
Controlled Study ◽  
Free Survival ◽  
Treatment Practices ◽  
Group 3 ◽  
The Impact

Abstract Background : Hydroxyurea has been the mainstay of cytoreductive therapy in essential thrombocythemia (ET) for over four decades. In 1988, anagrelide was first reported as an effective drug in ET (Silverstein et al. NEJM 1988;318:1292) and hundreds of patients were enrolled in clinical trials, which subsequently led to FDA approval in 1997. As a result, an increasing number of patients with ET were being treated with anagrelide until a subsequent controlled study suggested an inferior treatment outcome with anagrelide compared to hydroxyurea (Harrison et al. NEJM 2005;353:33). In the current study, we examined the impact of the corresponding practice changes on overall, myelofibrosis-free and leukemia-free survival, by comparing patients with ET diagnosed before 1988, between 1988 and 1997, and between 1998 and 2005 Methods: More than 45,000 patient charts with "thrombocytosis" were reviewed to identify those who met either PVSG (older patient cohort) or WHO criteria for diagnosis of ET. Survival was calculated from time of initial diagnosis to the time of last follow-up or death. For leukemia- or fibrosis-free survival, the time of the transformation events was considered as the uncensored variable. Conventional statistics was utilized for all analyses. Patients were divided into three groups commensurate with changes in treatment practices, corresponding to the aforementioned publications; Group 1 patients were diagnosed prior to 1988 (n =222), Group 2 1988 to 1997 (n =253), and Group 3 1998 to 2005 (n =264). Results : A total of 739 patients met the above-stipulated criteria (median age 57 years; 65% females). At a median follow-up of 12.2 years (range: 0.01-43.6 years), 368 (50%) deaths, 48 (6.5%) fibrotic transformations and 23 (3%) leukemic transformations were documented. Median overall survival (OS) was 18.6 years. On multivariable analysis, older age (P <0.001), increased leukocyte count (P <0.001), thrombosis history (P =0.04), and male sex (P<0.0001) were identified as predictors of inferior OS. Myelofibrosis-free survival (MFS) was predicted by platelet count <100 x 10(9)/L and lower hemoglobin level (multivariate P values 0.03 and <0.001, respectively). Leukemia-free survival (LFS) was predicted by increased leukocyte count, on multivariable analysis (P =0.002). Comparison of presenting features and outcome by period of diagnosis: Significant differences, in presenting features, between groups 1, 2, and 3 included age (median 55, 56, and 59 years, respectively; P =0.003), female preponderance (68, 69, and 58%, respectively; P =0.02), platelet count (1080, 995, and 890 x 10(9)/L, respectively; P <0.001), and leukocyte count (10, 9.6, and 8.4 x 10(9)/L, respectively; P <0.001). Median survival was 20.7 years, 19 years and 14.3 years, in groups 1, 2 and 3, respectively (P =0.02) (Figure 1). However, the difference in survival was no longer apparent during multivariable analysis that included age as a covariate (P=0.88). In univariate analysis, MFS was significantly shorter in group 3 patients (P=0.02; Figure 2); borderline significance was retained during multivariable analysis (p=0.13). LFS was similar among the three groups (P = 0.27). Conclusions : The results from the current retrospective study suggest increased rate of progression to myelofibrosis in ET patients diagnosed in the anagrelide era, an observation that is consistent with the results from a previous controlled study (Harrison et al. NEJM 2005;353:33). Regardless, survival in ET in the last four decades remains unchanged. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Pardanani: Stemline: Research Funding.

The impact of leukocytosis on survival, leukemic transformation, and thrombosis in polycythemia vera

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7029-7029
Author(s):  
N. Gangat ◽  
J. Strand ◽  
C. Y. Li ◽  
A. Pardanani ◽  
R. Mesa ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Polycythemia Vera ◽  
Tobacco Use ◽  
Arterial Thrombosis ◽  
Leukocyte Count ◽  
Multivariable Analysis ◽  
Advanced Age ◽  
Leukemic Transformation ◽  
The Impact

7029 Background: A leukocyte count of > 15 ×109/L has recently been associated with myocardial infarction in polycythemia vera (PV). In the current study, we examine the impact of such degree of leukocytosis on survival, leukemic transformation (LT), and thrombosis in a large cohort of PV patients from a single institution Methods: Data was abstracted from the medical records of a consecutive cohort of patients with PV defined by the World Health Organization criteria. Results: i. Patient characteristics The study cohort included 459 patients (median age, 60 years). Median follow-up was 64 months. ii. Survival In a multivariable analysis, advanced age, leukocyte count of = 15 × 109/L, and arterial thrombosis at diagnosis were significantly associated with inferior survival. A prognostic model based on age = 60 years and leukocyte count = 15 × 109/L separated low-risk, intermediate-risk, and high-risk patient groups with respective median survivals of 272, 162, and 108 months (p<0.0001). iii. Leukemic transformation In a multivariable analysis, only leukocyte count was significantly associated with LT; median leukemia-free survival for patients with leukocyte count = 15 × 109/L was 273 months vs. not reached for those with lower leukocyte count (p<0.0001). iv. Thrombosis at diagnosis In multivariable analysis, arterial thrombosis at diagnosis was significantly associated with previous history of arterial thrombosis, hypertension, and tobacco use; venous thrombosis at diagnosis was significantly associated with previous venous event and splenomegaly. v. Thrombosis during follow- up In multivariable analysis, arterial thrombosis during follow-up was significantly associated with previous arterial event, hypertension, and tobacco use; venous thrombosis during follow-up was significantly associated with previous venous event, diabetes mellitus, advanced age, and leukocyte count = 1,500 × 109/L. Conclusions: The current study for the first time identifies leukocytosis as a risk factor for inferior survival, LT risk, and venous thrombosis in PV. No significant financial relationships to disclose.

scholarly journals Mutation-Enhanced International Prognostic Systems for Essential Thrombocythemia (MIPSS-ET) and Polycythemia Vera (MIPSS-PV)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 578-578 ◽  
Author(s):  
Ayalew Tefferi ◽  
Paola Guglielmelli ◽  
Terra L. Lasho ◽  
Giacomo Coltro ◽  
Christy Finke ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Leukocyte Count ◽  
Multivariable Analysis ◽  
Survival Prediction ◽  
Leukemic Transformation ◽  
Abnormal Karyotype ◽  
Tp53 Mutations ◽  
Male Sex ◽  
Mutation Information

Abstract Background : Survival prediction in essential thrombocythemia (ET) and polycythemia vera (PV) is currently based on clinically-derived risk variables, including age, thrombosis history and leukocyte count (Blood. 2012;120:1197; Leukemia. 2013;27:1874). We have previously reported on the prognostic contribution of mutations, in both ET and PV (Blood Adv. 2016;1:21). The current study examines the possibility of integrating genetic and clinical information for predicting overall (OS), leukemia-free (LFS) and myelofibrosis-free (MFFS) survival in ET and PV. Methods : Study patients were recruited from the Mayo Clinic, Rochester, MN, USA and the University of Florence, Florence, Italy, based on availability of next-generation sequencing (NGS)-derived mutation information. Diagnoses were according to the 2016 World Health Organization criteria (Blood. 2016;127:2391). NGS-detected coding region variants were filtered through the Exome Aggregation Consortium (ExAC) database and annotated by the Catalogue of Somatic Mutations in Cancer (COSMIC) database as mutants or variants of uncertain significance (VUS). Conventional statistics was employed for outcome analysis and assessment of model performance. Results: 906 molecularly-annotated patients (416 from Mayo and 490 from Florence), including 502 ET and 404 PV cases, were included in the current study. The Mayo/Florence cohorts included 270/232 ET (median age 57/54 years, 60%/59% females) and 146/258 PV (median age 63/58 years, 52%/44% females) patients; median follow-up was 9.9/12.9 years for ET and 10.7/12.4 years for PV; during this time 39%/38% deaths and 4.4%/6.5% leukemic and 16%/33% fibrotic progressions were documented for ET, with the corresponding figures for PV being 50%/26%, 4.8%/3% and 13%/36%. Cytogenetic information was available in 84%/63% ET and 80%/49% PV cases in the Mayo/Florence cohorts. In both Mayo and Florence cohorts, multivariable analysis of mutations identified primarily spliceosome mutations to adversely affect OS (SF3B1 and SRSF2 in ET and SRSF2 in PV) and MFFS (U2AF1 and SF3B1 in ET); in addition, TP53 mutations was associated with leukemic transformation in ET, in both patient cohorts. Other mutations with independently significant contribution, validated in one but not both cohorts, included EZH2 (OS and LFS in ET), IDH2 (OS and LFS in PV) and RUNX1 (LFS in PV and ET). For the purposes of the current study, mutations considered "adverse" for subsequent analysis and development of prognostic models required validation in both Mayo and Florence cohorts. Age-adjusted, all-inclusive multivariable analysis of genetic and clinical variables identified the following as independent risk factors for OS, in both Mayo and Florence cohorts: ET ─ SRSF2/SF3B1 mutations, age >60 years and male sex; PV ─ SRSF2 mutations, age >67 years and leukocyte count ≥11 x 109/l. In addition, multivariable analysis flagged leukocytosis in ET (Florence cohort only) and abnormal karyotype in PV (Mayo cohort only) as additional factors. Development of mutation-enhanced international prognostic systems for ET and PV In order to optimize the number of informative cases, the two Mayo and Florence databases were subsequently combined and subjected to multivariable analysis that confirmed the independent survival effect, in ET, of SRSF2/SF3B1 mutations (HR 2.8, 95% CI 1.8-4.3), age >60 years (HR 6.7, 95% CI 4.8-9.4) and male sex (HR 1.8, 95% CI 1.4-2.4) and, in PV, of SRSF2 mutations (HR 7.0, 95% CI 2.3-17.4), age >60 years (HR 5.7, 95% CI 3.3-10.1), and leukocyte count ≥11 x 109/l (HR 2.4, 95% CI 1.5-3.9); the combined analysis also flagged independent prognostic contribution from abnormal karyotype in PV (HR 2.1, 95% CI 1.1-3.6). HR-weighted risk point allocation resulted in new, mutation-enhanced 4-tiered risk models for ET (MIPSS-ET based on mutations, age and sex; figure 1a) and PV (MIPSS-PV based on mutations, karyotype, leukocyte count and age; figure 1b). Both models displayed high predictive accuracy and were internally validated by bootstrapping. The combined analysis also confirmed the impact of TP53 mutations on LFS (figure 1c) and U2AF1/SF3B1 mutations on MFFS (figure 1d), in ET. Conclusions: Spliceosome mutation information enhances survival prediction in ET and PV and identifies those at risk for fibrotic progression. TP53 mutations predict leukemic transformation in ET. Disclosures No relevant conflicts of interest to declare.

Low JAK2V617F Allele Burden in Primary Myelofibrosis, Compared to Either a Higher Allele Burden or Unmutated Status, Predicts Inferior Overall and Leukemia-Free Survival.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 676-676
Author(s):  
Ayalew Tefferi ◽  
Terra L. Lasho ◽  
Jocelin Huang ◽  
Christy Finke ◽  
Curtis A. Hanson ◽  
...  
Keyword(s):  
Leukocyte Count ◽  
Univariate Analysis ◽  
Multivariable Analysis ◽  
Primary Myelofibrosis ◽  
Older Age ◽  
World Health ◽  
Lower Quartile ◽  
Free Survival ◽  
Allele Burden ◽  
Mutational Status

Abstract Background : Two previous studies have reported significant but inconsistent associations between the presence of JAK2V617F in primary myelofibrosis (PMF) and older age at diagnosis, risk of thrombosis, higher leukocyte count, and inferior survival (Tefferi, et al. BJH2005;131:320, Campbell, et al. Blood2006;107:2098). The clinical relevance of V617F allele burden in PMF has not been previously studied. Methods : Diagnosis of PMF was based on the World Health Organization criteria and study eligibility included the availability of bone marrow-derived DNA that was collected either at time of diagnosis or within one year of diagnosis. Quantitative allele specific PCR was utilized to meaure V617F allele burden. Results I. V617F-positive vs. V617F-negative comparisons: A total of 199 patients (60% males; median age 61 years) were suitable for analysis of comparisons between mutation-positive and mutation-negative disease. The Dupriez prognostic scoring system (PSS) risk distributions were 61% low-risk, 31% intermediate-risk, and 8% high-risk. Hypercatabolic symptoms were present in 27% of the patients and ≥1% peripheral blood (PB) blasts in 37%. At a median follow-up of 23 months (range 0–266), 57 patients (29%) had died, 17 (9%) developed leukemic transformation (LT) and 10 (5%) experienced major thrombosis. V617F mutational frequency was 58%. Univariate analysis identified older age (p=0.0007), platelet count ≥ 100 x 109/L (p=0.05), and PB blast percentage < 3% (p=0.001) as being associated with a positive mutational status; all three variables sustained their significance during multivariable analysis. The presence of the mutation did not affect the incidence of thrombosis (p=0.78), overall survival (p=0.22) or leukemia-free survival (p=0.5). Results II. Clinical correlates of V617F allele burden: Quantitative measurement of V617F allele burden was performed in 129 patients that were divided into four groups: V617F-negative (n=53) and V617F-positive with mutant allele burden in the lower quartile (n=19), middle quartiles (n=38), or upper quartile (n=19) range (median and range of V617F allele burden ratio was 29% and 1% to 74%). Kaplan-Meier plots revealed significantly shortened overall (Figure; p = 0.0008) and leukemia-free (p = 0.01) survival for the lower quartile allele burden group; survival significance was sustained in a multivariable analysis that included the Dupriez PSS. Lower quartile allele burden was also associated with lower leukocyte count (p = 0.003) and presence of hypercatabolic symptoms (p=0.05). Thrombosis incidence was not affected by allele burden. Conclusions: In PMF, patients with a low V617F allele burden, compared to those with either undetectable (i.e. wild-type) or higher allele burden, display significantly shorter overall and leukemia-free survival. In contrast, the presence or absence of the mutation, by itself, does not result in distinct groups that differ significantly in terms of survival, LT, or incidence of thrombosis. These data suggest that a low V617F allele burden in PMF is a surrogate for the development of dominant V617F-negative subclones that are more likely to undergo LT. Figure Figure

scholarly journals Deciphering the Individual Contribution of Absolute Neutrophil, Lymphocyte and Monocyte Counts to Thrombosis Risk in Patients with Myeloproliferative Neoplasms

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3651-3651
Author(s):  
Faiqa Farrukh ◽  
Paola Guglielmelli ◽  
Giuseppe Gaetano Loscocco ◽  
Animesh D. Pardanani ◽  
Curtis A. Hanson ◽  
...  
Keyword(s):  
Risk Factors ◽  
Venous Thrombosis ◽  
Board Of Directors ◽  
Arterial Thrombosis ◽  
Leukocyte Count ◽  
Myeloproliferative Neoplasms ◽  
Advisory Committees ◽  
Free Survival ◽  
The Individual

Abstract Background In addition to its influence on survival, leukocytosis in myeloproliferative neoplasms (MPN) has also been implicated as a risk factor for thrombosis, including venous thrombosis in PV (Blood Cancer J, 2017;7:662) and arterial thrombosis in ET (Blood. 2011;117:5857). In the current study, we sought to clarify the individual prognostic contribution of absolute neutrophil (ANC), lymphocyte (ALC) and monocyte (AMC) counts, for arterial and venous thrombotic events in essential thrombocythemia (ET) and polycythemia vera (PV). Methods The current study included 487 patients with ET (n=349) or PV (n=138), recruited from the Mayo Clinic MPN database, based on availability of information on ANC, ALC and AMC. Conventional criteria were used for diagnosis (Blood 2016;127:2391) and definitions of major vascular events (Blood Cancer J. 2018;8:25). Conventional statistical models were applied using JMP Pro 14.0.0 software package, SAS Institute, Cary, NC. Multivariable analyses included previously established risk factors for arterial or venous thrombosis. Results Essential thrombocythemia patients: 349 patients (median age 57 years, range 18-89; females 61%) with ET were included in the study: 46% JAK2, 34% CALR, 16% triple-negative and 4% MPL mutated; IPSET risk category high 24%, intermediate 41%, and low 35%; presenting median (range) values were 13.8 g/dL (11.1-16.4) for hemoglobin, 8.2 x 10(9)/L (3.2-52) for leukocyte count, and 859 x 10(9)/L (451-3460) for platelet count; palpable splenomegaly was present in 48 (14%) patients and cardiovascular risk factors in 56%; median follow-up was 10 years (range 0-47). There were 38 (11%) documented venous events at diagnosis and 31 (9%) after diagnosis and 42 (12%) arterial events at diagnosis and 64 (18%) after diagnosis. Polycythemia vera patients: 138 patients (median age 62 years, range 20-94; females 50%) with PV were included in the study; presenting median (range) values were 17.9 g/dL (16.1-24) for hemoglobin, 11.8 x 10(9)/L (2.7-65.8) for leukocyte count, and 434 x 10(9)/L (44-1679) for platelet count; 57% of patients presented with leukocytosis &gt;11 x 10(9)/L; palpable splenomegaly was present in 37 (27%) patients; abnormal karyotype was documented in 17% of patients. Median follow-up was 11 years (range 0.03-36.7). There were 22 (16%) documented venous events at diagnosis and 21 (16%) after diagnosis and 28 (20%) arterial events at diagnosis and 15 (11%) after diagnosis. ANC/ALC/AMC associations with thrombosis in ET and PV: In both ET and PV, ANC/ALC/AMC did not correlate with arterial thrombosis at/prior to diagnosis (p&gt;0.1 in all instances). By contrast, in both ET and PV, higher ANC (p=0.05 and 0.04, respectively) and higher AMC (p=0.005 and 0.07), but not ALC (p=0.6 and 0.7), were correlated with venous thrombosis at/prior to diagnosis. Arterial thrombosis-free survival was not affected by ANC/ALC/AMC in either ET or PV (p&gt;0.1 in all instances). By contrast, venous thrombosis-free survival in both ET and PV was compromised by higher ANC (p=0.05 and 0.003, respectively), but not ALC or AMC. The significant association between higher ANC and inferior venous thrombosis-free survival in both ET (p=0.01) and PV (p=0.007) was sustained during multivariable analysis that included history of venous thrombosis, age and sex; the only other variable of significance was older age in ET (p&lt;0.001). The significant association between ANC and venous thrombosis-free survival was also noted in an external cohort of PV patients from the University of Florence (n=576). Conclusions: The current study identifies ANC as having a direct correlation with venous thrombosis in both ET and PV, independent of currently known risk factors. An additional risk contribution from AMC was apparent for events occuring at or prior to but not after diagnosis. Taken together, these observations flag both neutrophils and monocytes as potential contributors to venous but not arterial thrombosis in MPN, at least not by themselves. Additional collaborative studies are ongoing in order to integrate and reconcile our observations in the context of neutrophil/lymphocyte ratio (Carobbio et al) and JAK2V617F allele burden (Loscocco et al), on venous thrombosis-free survival in PV, reported in concomitantly submitted ASH 2021 abstracts, especially in light of the relatively small number of events in the current study. Disclosures Barbui: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding. Vannucchi: AbbVie: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Platelet Antiaggregant Therapy Prevents Venous Thrombosis in Patients with JAK2 V617F Positive Essential Thrombocythemia without Indication of Cytoreductive Treatment.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3906-3906
Author(s):  
Alberto Alvarez-Larrán ◽  
Francisco Cervantes ◽  
Eduardo Arellano-Rodrigo ◽  
Virginia Pérez-Andreu ◽  
Juan-Carlos Hernández-Boluda ◽  
...  
Keyword(s):  
Risk Factors ◽  
Venous Thrombosis ◽  
Essential Thrombocythemia ◽  
Arterial Thrombosis ◽  
Univariate Analysis ◽  
Elevated Serum ◽  
Jak2v617f Mutation ◽  
Probability Of Survival ◽  
Increased Risk ◽  
Antiaggregant Therapy

Abstract Abstract 3906 Poster Board III-842 Essential thrombocythemia (ET) patients under the age of 60 years without history of thrombosis are not considered candidates for cytoreductive therapy. In these patients, risk factors for thrombosis as well as the benefit of platelet antiaggregants are not well established. The aim of the present study was to determine the risk factors for thrombosis in ET patients without indication of cytoreductive therapy and to assess the effect of platelet antiaggregation in thrombosis prevention. For such purpose 300 patients (101 M, 199F) diagnosed with ET at a median age of 39 years (range 5-59) were included in a multicenter retrospective study. Initial treatment consisted of platelet antiaggregants (n=196) or observation (n=104). During a median follow up of 8.6 years (range: 0.2-25), 137 patients initiated cytoreductive therapy being the indication for cytoreduction age > 60 years (n=18), thrombosis (n=25), bleeding (n=13), microvascular symptoms not responding to platelet antiaggregants (n=37), extreme thrombocytosis (n=37) and other (n=7). Median time free of cytoreductive therapy was 4.4 years (Range: 0.1-25). Thrombosis-free survival restricted to the time of cytoreductive therapy abstention was calculated using the Kaplan-Meier method. Variables attaining a significant level at the univariate analysis were included in a Cox proportional hazard model. A total of 32 thromboses (arterial thrombosis: n=21, vein thrombosis: n= 11) were registered during the period of cytoreduction abstention. The probability of survival free of arterial thrombosis was 94% at five years. Elevated serum LDH levels at ET diagnosis and smoking were associated with an increased risk of arterial thrombosis, hazard ratio: 3.1 (CI95%: 1.1-8.3) and 2.9 (CI95%: 1.1-7.9) for LDH and smoking respectively. Age, gender, hypertension, diabetes mellitus, hypercholesterolemia, leukocytosis, thrombocytosis and JAK2 mutational status were not associated with an increased risk of arterial thrombosis. Platelet antiaggregant therapy did not reduce the incidence of arterial thrombosis. The probability of survival free of venous thrombosis was 96% at five years. Patients with JAK2V617F mutation showed and increased risk of venous thrombosis: HR 4.6 (IC95%: 1.1-18.3) whereas platelet antiaggregant therapy resulted in a low risk of venous thrombosis: HR 0.12 (CI95%: 0.03-0.5). When analysis was restricted to patients with the JAK2V617F mutation, the probability of venous thrombosis at 5 years was 96% in those patients receiving platelet antiaggregants and 58% in those patients managed with observation alone (p=0.0006). Platelet antiaggregant therapy was not associated with an increased risk of severe/major bleeding. In conclusion, JAK2V617F-positive ET patients without indication of cytoreductive therapy have an increased risk of venous thrombosis that could be reverted with platelet antiaggregant therapy. Disclosures: No relevant conflicts of interest to declare.

Prognostic Impact of JAK2V617F Mutation In MDS: a Matched Case Control Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 440-440
Author(s):  
Benoit de Renzis ◽  
Eric Wattel ◽  
Odile Beyne-Rauzy ◽  
Laurent Knoops ◽  
Françoise Boyer ◽  
...  
Keyword(s):  
Survival Analysis ◽  
Cox Model ◽  
Univariate Analysis ◽  
Patient Characteristics ◽  
Jak2v617f Mutation ◽  
Prognostic Impact ◽  
Jak2 Mutation ◽  
Platelet Counts ◽  
A Prospective Study

Abstract Abstract 440 Background: The JAK2V617F mutation is found in a small proportion of MDS, especially in RARS-T and occasionally in other MDS subtypes, but the overall impact of JAK2V617F on MDS characteristics and outcome remains unclear. Method: Diagnostic and follow up data on MDS patients (pts) with known JAK2V617F mutation status were collected from 19 centers of the Groupe Francophone des Myélodysplasies (GFM) and the French Intergroup of MPN (FIM). MDS post MPN and CMML were excluded. Patient characteristics and outcome according to JAK2V617F status were analyzed by univariate analysis. Survival analysis with Cox model matched on age, IPSS score and sex according to JAK2 status was also made. Analysis was performed using STATA 10.0 software. Result: 161 cases were collected, including 65 JAK2V617F mutated (JAK2 pos) and 96 unmutated (JAK2 neg) cases. Median age was 75 years and M/F ratio 1.2 in JAK2 pos vs 71 years (p=NS) and 1 (p=NS) in JAK2 neg pts, respectively (resp). WHO 2008 distribution was RA (8%), RARS (12%), RARS-T (41%), CRDM (15%), RAEB-1 (11%), RAEB-2 (5%), 5q- (3%), unclassified (5%) in JAK2 pos pts and RA (25%), RARS (9%), RARS-T (1%), CRDM (14%), RAEB-1 (28%), RAEB-2 (19%), 5q- (1%), unclassified (3%) in JAK2 neg pts, resp (p&lt;0.001). Hb (median 103 vs 98 g/L, p=NS) and MCV (98 vs 98 fL, p=NS) were similar in JAK2 pos and JAK2 neg pts resp but WBC (median 7.3 vs 4.4 G/L, p&lt;0.001), ANC (4.85 vs 2.1 G/L, p&lt;0.001) and platelets counts (541 vs 160 G/L p&lt;0.001) were higher in JAK2 pos than in JAK2 neg pts. Conversely, marrow blasts % was significantly lower in JAK2 pos than in JAK2 neg pts (median 2% vs 4%, p&lt;0.001). Karyotype was abnormal in 40% JAK2 pos pts (10% +8, 17% del5q, 7% −7/del7q, 3% del20q) and in 35% JAK2 neg pts (3% +8, 5% del5q, 2% −7/del 7q, 3% del20q) (p=NS). Unfavorable karyotypes (complex and −7/del7q) were seen in 9% JAK2 pos and 13% JAK2 neg pts (p=NS). IPSS was low or int-1 in 93% JAK2 pos and in 82% JAK2 neg pts (p=0.056). Median follow up was 44 months [8-350] in JAK2 pos and 62 months [25-182] in JAK2 neg pts. Progression to AML occurred in 6% JAK2 pos and in 20% JAK2 neg pts (p&lt;0.001). 5-year OS was 88% in JAK2 pos and 57.8% in JAK2 neg pts (p&lt;0.001). When the analysis was performed after exclusion of RARS-T (n=133) median age was 74 years and M/F 1.1 in JAK2 pos vs 70 years (p=NS) and 0.7 (p=NS) in JAK2 neg pts resp. Hb (median 103 vs 98 g/L, p=NS) and MCV (102.5 vs 98 fL, p=NS) remained similar in JAK2 pos and JAK2 neg pts, resp. WBC (median 6.4 vs 4.4 G/L, p&lt;0.001), ANC (3.88 versus 2.1 G/L, p=0.001) and platelet counts (268 versus 156 G/L p&lt;0.001) were still higher in JAK2 pos than in JAK2 neg pts. Marrow blasts % was still significantly lower in JAK2 pos than in JAK2 neg pts (median 2% vs 4%, p=0.016). IPSS was low and int-1 in 88% JAK2 pos and in 82% JAK2 neg pts (p=NS). Progression to AML occurred in 9.7% JAK2 pos and in 20% JAK2 neg pts (p=NS). 5 year OS was 92.2% in JAK2 pos and 57.6% in JAK2 neg pts (p=0.0052). When survival analysis was matched on age, IPSS and sex, JAK2 mutation was associated with better OS both in the whole population (p=0.011) and after excluding RARS-T (p=0.028). Finally, in JAK2 pos RARS-T pts (n=27) no AML progression was seen, and 5-year OS was 84.9%. Conclusion: We found JAK2V617F mutation in MDS to be associated with higher WBC, ANC and platelet counts, lower % marrow blasts, less progression to AML and better survival than JAK2V617F neg MDS. This positive prognostic impact persisted after exclusion of RARS-T. However, our results will require confirmation in a prospective study. Disclosures: Fenaux: CELGENE, JANSSEN CILAG, AMGEN, ROCHE, GSK, NOVARTIS, MERCK, CEPHALON: Honoraria, Research Funding.

scholarly journals Prospective analysis of TEL/AML1-positive patients treated on Dana-Farber Cancer Institute Consortium Protocol 95-01

Blood ◽  
2006 ◽  
Vol 107 (11) ◽  
pp. 4508-4513 ◽  
Author(s):  
Mignon L. Loh ◽  
Meredith A. Goldwasser ◽  
Lewis B. Silverman ◽  
Wing-Man Poon ◽  
Shashaank Vattikuti ◽  
...  
Keyword(s):  
Leukocyte Count ◽  
Lymphoblastic Leukemia ◽  
Multivariable Analysis ◽  
Predictors Of Outcome ◽  
Event Free Survival ◽  
Free Survival ◽  
Dana Farber Cancer Institute ◽  
Aml1 Gene ◽  
A Prospective Study

Abstract In a retrospective analysis, we previously reported that children whose leukemia cells harbored the TEL/AML1 gene rearrangement have excellent outcomes. From 1996 to 2000, we conducted a prospective study to determine the incidence and outcomes of children with TEL/AML1-positive acute lymphoblastic leukemia (ALL). Children with newly diagnosed ALL were treated on DFCI ALL Consortium Protocol 95-01. Patients were risk stratified primarily by current National Cancer Institute (NCI)–Rome risk criteria. With a median follow-up of 5.2 years, the 5-year event-free survival for TEL/AML1-positive patients was 89% compared with 80% for TEL/AML1-negative B-precursor patients (P = .05). The 5-year overall survival rate was 97% among TEL/AML-positive patients compared with 89% among TEL/AML1-negative patients (P = .03). However, in a multivariable analysis, risk group (age and leukocyte count at diagnosis) and asparaginase treatment group, but not TEL/AML1 status, were found to be independent predictors of outcome. We conclude that TEL/AML1-positive patients have excellent outcomes, confirming our previous findings. However, factors such as age at diagnosis and presenting leukocyte count should be taken into consideration when treating this group of patients.

Leukocytosis at Diagnosis and the Risk of Subsequent Thrombosis in Low-Risk Essential Thrombocythemia and Polycythemia Vera.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1751-1751 ◽  
Author(s):  
Naseema Gangat ◽  
Alexandra Wolanskyj ◽  
Susan Schwager ◽  
Curtis A. Hanson ◽  
Ayalew Tefferi
Keyword(s):  
Venous Thrombosis ◽  
Arterial Thrombosis ◽  
Leukocyte Count ◽  
Univariate Analysis ◽  
Hemoglobin Level ◽  
Low Risk ◽  
Advanced Age ◽  
Risk Patients ◽  
The Impact

Abstract Background: Leukocytosis has recently been implicated as an adverse prognostic feature for thrombosis in both ET and PV. Such an association would be therapeutically most relevant in the context of “low-risk” disease. In the current study, we sought to clarify the relationship between leukocytosis at diagnosis and the subsequent occurrence of either arterial or venous thrombosis, in “low-risk” patients with ET or PV. Methods: Data was abstracted from the medical records of a consecutive cohort of patients with WHO-defined ET or PV seen at the Mayo Clinic. Low-risk disease was defined by the absence of both thrombosis history and age 3 60 years. Cox proportional hazards model was utilized to determine the impact of clinical and laboratory variables on thrombosis-free survival (TFS). Arterial- or venous-specific TFS curves were constructed by Kaplan-Meier method. Results: i) Patient characteristics and outcome A total of 407 “low-risk” patients were studied; 153 had PV (median age 48 years; females 43%) and 254 ET (median age 42 years; females 71%). A total of 46 thrombotic events (22 arterial and 24 venous) were recorded in 41 (27%) patients with PV during a median follow up of 130 months (range 2–562 months). The corresponding figures in ET were 54 total thrombotic events (41 arterial and 14 venous) in 47 (19%) patients at a median follow up of 104 months (range 0.25–424 months). Cytoreductive therapy was avoided in the presence of &lt; 1000 x 109/L platelet count but, at the discretion of the treating physician, some patients with higher platelet counts received prophylactic cytoreductive therapy. ii) Correlation between leukocytosis and thrombosis A leukocyte count of 3 15 x 109/L at diagnosis was documented in 42 (27%) patients with PV and 21 (8%) patients with ET; 102 patients (40%) with ET had &gt; 9.4 x 109/L leukocyte count. Leukocyte count considered as either a continuous or categorical variable (using cutoff levels of 15 x 109/L for PV and either 15 x 109/L or 9.4 x 109/L for ET) was not significantly associated with either arterial or venous thrombosis (Figure 1). iii) Correlation between other risk factors and thrombosis In univariate analysis, presence of the JAK2V617F was significantly associated with arterial thrombosis in ET (p=0.049) but significance was lost during multivariable analysis that included age as a covariate. Only advanced age was found to be significantly associated with arterial thrombosis in PV (p=0.04) and higher hemoglobin level with venous thrombosis in ET (p&lt;0.0001). Conclusion: The current study does not identify leukocyte count at diagnosis as a marker of increased thrombosis risk in low-risk patients with either ET or PV. Instead, the study found an association between arterial thrombosis and advanced age in PV and venous thrombosis and higher hemoglobin level in ET. Figure Figure

JAK2V617F-Positive Patients with Essential Thrombocythemia or Early Primary Myelofibrosis: The Impact of Histological Diagnosis on Outcome

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1614-1614
Author(s):  
Nicola Polverelli ◽  
Roberto Latagliata ◽  
Giuseppe A. Palumbo ◽  
Alessia Tieghi ◽  
Margherita Perricone ◽  
...  
Keyword(s):  
Essential Thrombocythemia ◽  
Primary Myelofibrosis ◽  
Jak2v617f Mutation ◽  
Event Free Survival ◽  
Disease Evolution ◽  
Free Survival ◽  
Mutational Status ◽  
Early Primary ◽  
The Impact

Abstract Introduction It is acknowledged that an accurate histological diagnosis may distinguish Essential Thrombocythemia (ET) from early Primary Myelofibrosis (early-PMF), which is projected to worse outcome in terms of survival and disease evolution into acute leukemia (AL) or overt myelofibrosis (MF). It is also accepted that the outcome of ET is related to the mutational status, with JAK2V617F mutation having a negative impact. In previous analyses, outcome data derived from the admixture of the two variables, histology and mutational status. Here, we present a large cohort of ET/early-PMF patients positive for the JAK2V617F mutation, with the aim to evaluate the impact on outcome of the sole histological definition. Methods A clinic-pathologic database of ET patients followed in four Italian Hematology Centers was created and a total of 475 WHO-diagnosed ET or early-PMF JAK2V617F-positive patients was collected. Bone marrow specimens were performed or reviewed at local institution. Baseline clinical/molecular characteristics and outcome measures (vascular complications, disease transformation/progression, overall and event-free survival) were evaluated. In all patients, JAK2V617F allele-burden was assessed in granulocyte DNA by using ipsogen JAK2 MutaQuant Kit (qPCR). The study was approved by the Ethic Committee of each participating Centers. Results Overall, 329 WHO-defined ET and 146 early-PMF patients positive for the JAK2V617F mutation were included in the study. Median follow-up was 6.6 years (range: 0.5-32.4). Compared to ET patients, early-PMF patients presented with older age (median, 57 versus 53.5yr, p=0.02), lower hemoglobin levels (median, 14.2 versus 14.5 g/dl, p=0.01), higher leukocyte count (median, 10.4 versus 9.5x109/l, p=0.01), and higher incidence of spleen enlargement (35.9% versus 13.9%, p<0.001). JAK2V617F mutation was heterozygous in 90% and 87% of ET and early-PMF patients, respectively (p=0.34). Use of antiplatelet and cytoreductive therapies was also comparable in the two groups. During follow-up, 32 (9.7%) ET and 18 (12.3%) early-PMF patients experienced a total of 59 thrombotic events (arterial: 49%), with an incidence rate of 1,3% patients/yr. The cumulative incidence of thrombosis was 8% and 14% at 5 and 10 years, respectively. Overall, 27 patients (5,6%) and 6 (1.2%) patients evolved to MF and AL, respectively. The cumulative incidence of disease progression into MF/AL was 2% and 5% at 5 and 10 years, respectively. At last contact, 28 (5.8%) patients had died, at a median age of 77.5 years (20-88), for an overall survival of 93.8% at 10 years. In early-PMF compared to ET, the 10-year survival rates (91.6% and 95%, respectively, p=0.75), leukemic transformation rates (6% and 1.2%, respectively, p=0.45) and rates of thrombosis (6.7% and 2.2%, p=0.12) were comparable. However, progression to overt MF at 5 years (4.4% and 0.9%, respectively) and 10 years (11.5% and 1.5%) was significantly worse (p=0.004). Multivariable analysis confirmed this finding and also identified homozygosity for the JAK2V617F mutation (p=0.008) as additional risk factor for disease evolution into secondary MF. The rate of composite outcomes (thrombosis, evolution into overt MF or AL and death) was significantly higher in early-PMF (3.1% vs 2,3% pts/yr) with a combined event-free survival of 69% versus 82% in ET patients at 10 yrs (figure 1). Conclusions. This study eliminates the confounding factor of different molecular status on outcome by focusing on a large cohort of WHO-defined ET/early-PMF patients, all carrying the JAK2V617F mutation. Overall, the study validates the clinical relevance of strict adherence to WHO criteria on prognosis, and particularly on disease progression into secondary MF. Figure 1. Combined event-free survival according to histology Figure 1. Combined event-free survival according to histology Disclosures Palumbo: Novartis: Honoraria, Other: Advisory Board. Martinelli:MSD: Consultancy; BMS: Speakers Bureau; Roche: Consultancy; ARIAD: Consultancy; Novartis: Speakers Bureau; Pfizer: Consultancy.

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