Blast transformation and fibrotic progression in polycythemia vera and essential thrombocythemia: a literature review of incidence and risk factors

Thrombosis is the major cause of morbidity and mortality in polycythemia vera (PV) and essential thrombocythemia (ET). Age ≥60 years (y) and/or history of thrombosis labels patients (pts) as high-risk for thrombosis. Yet, thrombosis frequently occurs prior to the diagnosis of PV/ET. In a multicenter study of the East German Study Group (HINC-207; OSHO #091), the interaction between age and time occurrence of the first thrombosis as risk factors for thrombosis after diagnosis was studied. Methods After IRB approvals, JAK2 mutated adults with PV or ET were prospectively enrolled in 9 centers and centrally stratified in a one to two ratio (group A: pts with a history of thrombosis; group B: pts without thrombosis) with a pre-planned minimum of 60:120 pts. Based on a longitudinal and cross-sectional design, clinical and laboratory data at diagnosis, last follow-up, and thrombosis (for group A) were collected. Thrombosis prior to diagnosis was labeled as A1 and thrombosis after diagnosis as A2. Thrombosis risk factors were grouped into age-, previous thrombosis-, thrombosis prior to PV/ET-, cardiovascular (CV)-, thrombophilia-, and disease- (JAK2 allele burden, Hct, and WBC) related. Additionally, therapies [aspirin (ASS), anticoagulation, phlebotomy, and cytoreduction] and data from a study-own patient questionnaire were included. All pts signed informed consent. The primary endpoint was the phenotypic diversity in JAK2-mutated ET and PV pts with or without thrombosis. Results From April to Dec, 2019, 246 pts were recruited. Data on 237 pts (median age 62y; 59% females, 58% PV) are available. At diagnosis, pts in group A (n=71, median age 59.5y) tended to be younger than those in group B (n=166, median age 63y) (p=0.07). Yet, 70.4% thrombotic events (venous: median age 46.5y; arterial: median age 57y) occurred in A1 and correlated with younger age (p=0.03). Only 3 pts developed a second event after diagnosis. These were counted in A2 (n=24, median age at thrombosis: 61y). Overall, thrombosis occurred either prior to or within the first 3y after diagnosis in 63/71 (89%) pts. Age>60y could not be identified as a risk factor for thrombosis or type of thrombosis at any time point. The 5 y probability of no thrombotic event after diagnosis in pts >60y was 90.4% vs. 89.2% for pts <60y (p=0.8) and that of a thrombotic event >3y after diagnosis in pts >60y was 3.7% vs. 4.9% for pts <60y (p=0.7). Similarly, A1 did not correlate with A2 (p=0.3). With 1691 patient-years for the entire cohort, the incidence of thrombosis after PV/ET diagnosis was 0.7 for arterial and 0.6 for venous events per 100 patient-years. Smoking was more prevalent in pts >60y (p=0.003) and was not associated with thrombosis. Irrespective of age, hypertension (65%, p=0.03), hyperlipidemia (19%, p=0.008), and diabetes (16.4%, p=0.05) were frequent and correlated with A2 while atrial fibrillation (p=0.03) and inherited thrombophilia risk factors (p<0.00) with A1. JAK2 allele burden (median 19%) and Hct >45% (median 45%) at diagnosis correlated strongly with age >60y (p=0.005) but not with A, A1, or A2, although Hct >45% at diagnosis correlated with A2 in PV (p=0.001). Surprisingly, a Hct >45% at thrombosis was more frequently present in A1 (55%) vs A2 (30%) (p<0.00). Median WBC at diagnosis was higher in B compared to A (p=0.004), strongly associated with age >60y (p<0.00) but not with A2. WBC >15% at thrombosis did not correlate with A. Age rather than thrombosis was the trigger for cytoreduction [82% hydroxyurea (HU) in B pts >60y vs 53% in A pts <60y] (p<0.00). In PV, ASS did not correlate with thrombosis (25% of pts in B did not receive ASS). Cytoreduction, interval between diagnosis and cytoreduction, nor the duration of exposure correlated with thrombosis. Conclusions: The majority of thrombotic events occurred prior to or within the first 3 years after the diagnosis of JAK2 mutated PV/ET and were associated with CV-risk factors rather than older age. Phenotypic features such as Hct >45%, high WBC, and JAK2 allele burden were associated with age >60y and less with thrombosis. Their value as surrogate markers for therapeutic interventions to reduce thrombosis needs to be critically evaluated in larger series. Whether adequate PV/ET- or CV-risk- treatments account for the low rate of CV events after diagnosis (despite a higher incidence of CV-risk factors) compared to the general population could not be answered due to study design and needs to be addressed prospectively. Disclosures Al-Ali: Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

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Thrombotic and Hemorrhagic Complications after Surgery in Patients with Essential Thrombocythemia and Polycythemia Vera.

Blood ◽

10.1182/blood.v108.11.2693.2693 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2693-2693 ◽

Cited By ~ 1

Author(s):

Marco Ruggeri ◽

Francesco Rodeghiero ◽

Alberto Tosetto ◽

Giancarlo Castaman ◽

Francesca Scognamiglio ◽

...

Keyword(s):

Risk Factors ◽

Risk Factor ◽

Polycythemia Vera ◽

Surgical Procedures ◽

Essential Thrombocythemia ◽

Arterial Thrombosis ◽

Surgical Interventions ◽

Antithrombotic Prophylaxis ◽

Unfractioned Heparin ◽

Hemorrhagic Complications

Abstract Essential Thrombocythemia (ET) and Polycythemia Vera (PV) are chronic myeloproliferative diseases characterized by frequent episodes of deep venous thrombosis (DVT), arterial thromboembolism (AT) and by hemorrhagic complications. Surgical procedures could represent a risk factor for thrombosis and bleeding, but no data on the real frequency of these complications are available. To estimate the frequency of thrombosis and haemorrhages after surgical procedures and their outcomes, a multicenters retrospective analysis was performed. Data from 105 PV and 150 ET patients (128 males, 127 females, median age at diagnosis 60, were analyzed, for a total of 311 surgical interventions. At least one risk factor for arterial thrombosis (diabetes mellitus, hypercholesterolemia, arterial hypertension, previous AT, smoke) was present in 128/255 (50.1%), more frequently in PV than in ET patients (58.5 vs. 46.8%, p=0.02). An excess of male and older patients in PV than in ET explained this finding (multivariate analysis). Previous DVT was present in 9/255 patients (3.5%). After diagnosis, antiplatelet drugs were given to 211/255 patients (82.7%); cytoreductive treatments to 188/255 (74%), warfarin to 16/255 (6.2%); all PV patients were phlebotomized. In 25/311 surgeries (8.0%), an emergency procedure was performed; 195 surgeries were done under general anaesthesia; 21/91 abdominal interventions (23%) were performed under laparoscopy. Major surgeries were 160/311 (51.4%). Data about antithrombotic prophylaxis were available for 292/311 surgeries: in 126 (43.2%) low molecular heparin, in 38 (13%) unfractioned heparin, in 5 (1.7%) warfarin and in 123 no anticoagulant therapy was administered. In 45/123 (36.6%) patients without antithrombotic prophylaxis, antiplatelet therapy was administered before surgery. 189/255 (74%) were on cytoreductive therapy before surgery; for 9 surgical procedures, a short cycle of chemotherapy was administered before surgery. Clinical outcomes after surgery were recorded with a 3 months follow-up. No event was observed in 259/311 procedures (83.2%); there were 12 arterial and 12 venous thrombotic events, 23 major and 7 minor hemorrhages and 5 deaths. AT were more frequent in ET patients (5.3 vs. 1.5%, p=0.08) while venous events were more frequent in PV patients (7.7 vs. 1.1%, p=0.002). There was a strong risk gradient for AT associated with the presence of one or more arterial risk factors (OR for 4 or more risk factors: 40.9, p=0.003). Platelet count and hematocrit at surgery (median 477 x 109 /l and 42.6%, respectively) were not associated with either venous or arterial thrombosis. There was no correlation between bleeding episodes and type of diagnosis, use of antithrombotic prophylaxis and type of surgery. In conclusion, despite an active approach (cytoreduction and antithrombotic prophylaxis in the majority of the cases) a high proportion of PV and ET surgeries was complicated by DVT and AT (7.7%) but also by major hemorrhages (7.3%), requiring more investigation on the optimal prophylaxis in these patients.

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Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis

Blood ◽

10.1182/blood-2014-05-579136 ◽

2014 ◽

Vol 124 (16) ◽

pp. 2507-2513 ◽

Cited By ~ 311

Author(s):

Ayalew Tefferi ◽

Paola Guglielmelli ◽

Dirk R. Larson ◽

Christy Finke ◽

Emnet A. Wassie ◽

...

Keyword(s):

Polycythemia Vera ◽

Essential Thrombocythemia ◽

Blast Transformation ◽

Term Survival ◽

Free Survival ◽

Long Term Survival ◽

Mutational Status ◽

Key Points

Key Points Survival in ET is superior to that of PV, regardless of mutational status, but remains inferior to the sex- and age-matched US population. JAK2/CALR/MPL mutational status is prognostically informative in PMF, regarding overall and leukemia-free survival.

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CARDIOVASCULAR RISK IN ESSENTIAL THROMBOCYTHEMIA AND POLYCYTHEMIA VERA: THROMBOTIC RISK AND SURVIVAL

Mediterranean Journal of Hematology and Infectious Diseases ◽

10.4084/mjhid.2020.008 ◽

2020 ◽

Vol 12 (1) ◽

pp. e2020008

Author(s):

Vincenzo Accurso ◽

Marco Santoro ◽

Salvatrice Mancuso ◽

Angelo Davide Contrino ◽

Paolo Casimio ◽

...

Keyword(s):

Risk Factors ◽

Cardiovascular Risk ◽

Cigarette Smoking ◽

Cardiovascular Risk Factors ◽

Polycythemia Vera ◽

Essential Thrombocythemia ◽

Thrombotic Event ◽

Bleeding Events ◽

Thrombotic Risk ◽

The Impact

Abstract Thromboembolic and bleeding events pose a severe risk for patients with Polycythemia Vera (PV) and Essential Thrombocythemia (ET). Many factors can contribute to determine the thrombotic event, including the interaction between platelets, leukocytes and endothelium alterations. Moreover, a very important role can be played by cardiovascular risk factors (CV.R) such as cigarette smoking habits, hypertension, diabetes, obesity and dyslipidemia. In this study we evaluated the impact that CV.R plays on thrombotic risk and survival in patients with PV and ET.

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Perspectives on thrombosis in essential thrombocythemia and polycythemia vera: is leukocytosis a causative factor?

Blood ◽

10.1182/blood-2009-02-206797 ◽

2009 ◽

Vol 114 (4) ◽

pp. 759-763 ◽

Cited By ~ 87

Author(s):

Tiziano Barbui ◽

Alessandra Carobbio ◽

Alessandro Rambaldi ◽

Guido Finazzi

Keyword(s):

Risk Factors ◽

Polycythemia Vera ◽

Essential Thrombocythemia ◽

Independent Predictor ◽

Prognostic Significance ◽

Causative Factor ◽

Vascular Events ◽

Standard Clinical Practice ◽

Leukocyte Counts ◽

Wbc Count

Abstract Leukocyte (WBC) count has been recently identified as an independent predictor of major thrombosis in both essential thrombocythemia (ET) and polycythemia vera (PV). However, whether leukocytosis should be simply considered a marker for vascular disease or whether elevated WBC levels actually contribute directly to causing such disorders is presently matter of many studies. By adopting epidemiologic criteria for causation, we have examined the characteristics to support this association such as (1) strength, (2) consistency, (3) specificity, (4) temporality, (5) biologic gradient, (6) plausibility, (7) experimental evidence, and (8) analogy. Our conclusion supports the notion that baseline leukocytosis in ET and PV patients adds prognostic significance to existing risk factors and that may be considered causative of vascular events. These developments could induce clinicians to incorporate WBC count into standard clinical practice. However, we need prospective clinical studies with stratification of patients according to their baseline leukocyte counts. Until such evidence is available, the decision on how to manage these patients should continue to follow conventional criteria.

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Recurrent Thrombosis in Patients with Polycythemia Vera or Essential Thrombocythemia: Efficacy of Treatment in Preventing Rethrombosis in Different Clinical Settings.

Blood ◽

10.1182/blood.v108.11.119.119 ◽

2006 ◽

Vol 108 (11) ◽

pp. 119-119 ◽

Cited By ~ 2

Author(s):

V. De Stefano ◽

T. Za ◽

E. Rossi ◽

A.M. Vannucchi ◽

M. Ruggeri ◽

...

Keyword(s):

Risk Factors ◽

Protective Factors ◽

Venous Thrombosis ◽

Polycythemia Vera ◽

Essential Thrombocythemia ◽

Antiplatelet Agents ◽

Clinical Event ◽

Antithrombotic Prophylaxis ◽

Coronary Syndrome

Abstract Background: Thrombosis is a common cause of morbidity in polycythemia vera (PV) and essential thrombocythemia (ET). Prior thrombosis is a major risk factor for rethrombosis; yet optimal strategy for prevention of recurrence has been scarcely addressed. Objective: To assess in PV or ET patients with prior thrombosis the rate of recurrence, the risk factors for recurrence, and the efficacy of antithrombotic or cytoreductive strategies in preventing rethrombosis. Methods: We retrospectively investigated a cohort of 470 patients (M/F 227/243, PV/ET 235/235, median age at diagnosis 62 yrs, range 19–88) with a first arterial (n=328, 69.8%) or venous thrombosis (n=142, 30.2%). First thrombosis was cerebrovascular disease (CVD) in 184 cases, acute coronary syndrome (ACS) in 102, venous thromboembolism of limbs (VTE) in 102, and venous thrombosis of unusual sites (un-VTE) in 40. Microcirculatory events were not computed. Multivariate time-dependent models were developed having first recurrence as dependent variable and putative predictive or protective factors as covariates. Results: 158 patients (33.6%) had one or more recurrences during a total time from the first thrombosis of 2,821 pt-yrs (median 5.3 yrs); the overall incidence of events was 7.54% pt-yrs (4.60% arterial and 2.94% venous recurrences). Major bleeding occurred in 25 patients (84% receiving antithrombotic prophylaxis) with an incidence of 0.88% pt-yrs. The cumulative incidence of recurrence at 10 years after the first event was 64.7% (95%CI 49.1–80.3) in VTE patients, 51.9% (95%CI 37.8–66.0) in ACS, 46.6% (95%CI 35.1–58.1) in CVD, and 30.2% (95%CI 8.8–51.6) in un-VTE. In VTE patients analysis restricted to venous recurrences showed at 10 years a rate of 49.4% (95%CI 32.8–66.1). Sex, diagnosis (PV or ET), and presence of vascular risk factors did not affect the overall probability of recurrence. Age >60 years predicted recurrence (multivariate hazard ratio 1.76, 95%CI 1.24–2.49); arterial or venous first thrombosis predicted either arterial (HR 4.43, 95%CI 1.22–16.07) or venous recurrence (HR 8.48, 95%CI 1.62–44.48), respectively. Cytoreductive treatment halved the probability of all types of recurrence in the overall cohort (HR 0.54, 95%CI 0.38–0.76). In the overall model long-term antiplatelet or anticoagulant treatment did not result as independent protective factors. However, analysis of patient groups showed that a significant efficacy in preventing rethrombosis was achieved in VTE only by long-term oral anticoagulation (HR 0.42, 95%CI 0.19–0.91), in ACS by cytoreduction (HR 0.37, 95%CI 0.17–0.78), and in CVD by antiplatelet agents (HR 0.34, 95% CI 0.16–0.69). Conclusions: In PV or ET the rate of recurrent VTE seems higher than the usually observed in patients with unprovoked first VTE. Moreover our findings suggest that strategies for preventing rethrombosis and based on cytoreduction or antithrombotic prophylaxis should be tailored according to the type of first clinical event. Further studies are needed to confirm such hypothesis.

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Hemorrhage in Essential Thrombocythemia or Polycythemia Vera: Epidemiology, Location, Risk Factors, and Lessons Learned from the Literature

Thrombosis and Haemostasis ◽

10.1055/s-0040-1720979 ◽

2020 ◽

Author(s):

Christophe Nicol ◽

Karine Lacut ◽

Brigitte Pan-Petesch ◽

Eric Lippert ◽

Jean-Christophe Ianotto

Keyword(s):

Risk Factors ◽

Polycythemia Vera ◽

Essential Thrombocythemia ◽

Myeloproliferative Neoplasm ◽

Young Patients ◽

Lessons Learned ◽

Published Data ◽

Bleeding Events ◽

Future Studies ◽

Increased Risk

AbstractHemorrhage is a well-known complication of essential thrombocythemia (ET) and polycythemia vera (PV), but evidence-based data on its management and prevention are lacking to help inform clinicians. In this review, appropriate published data from the past 15 years regarding bleeding epidemiology, classification, location, and risk factors are presented and discussed. Research was conducted using the Medline database. The bleeding classifications were heterogeneous among the collected studies. The median incidences of bleeding and major bleeding were 4.6 and 0.79% patients/year, in ET patients and 6.5 and 1.05% patients/year in PV patients, respectively. The most frequent location was the gastrointestinal tract. Bleeding accounted for up to 13.7% of deaths, and cerebral bleeding was the main cause of lethal hemorrhage. Thirty-nine potential risk factors were analyzed at least once, but the results were discrepant. Among them, age >60 years, bleeding history, splenomegaly, myeloproliferative neoplasm subtype, and platelet count should deserve more attention in future studies. Among the treatments, aspirin seemed to be problematic for young patients with ET (especially CALR-mutated ET patients) and anagrelide was also identified as a bleeding inducer, especially when associated with aspirin. Future studies should analyze bleeding risk factors in more homogeneous populations and with common bleeding classifications. More tools are needed to help clinicians manage the increased risk of potentially lethal bleeding events in these diseases.

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PS1458 RISK FACTORS AND OUTCOME OF ACUTE MYELOID LEUKEMIA SECONDARY TO POST-POLYCYTHEMIA VERA AND POST-ESSENTIAL THROMBOCYTHEMIA MYELOFIBROSIS: AN ANALYSIS OF THE MYSEC COHORT

HemaSphere ◽

10.1097/01.hs9.0000564096.75769.8f ◽

2019 ◽

Vol 3 (S1) ◽

pp. 671 ◽

Cited By ~ 1

Author(s):

B. Mora ◽

P. Guglielmelli ◽

E. Rumi ◽

M. Maffioli ◽

D. Barraco ◽

...

Keyword(s):

Risk Factors ◽

Acute Myeloid Leukemia ◽

Polycythemia Vera ◽

Essential Thrombocythemia ◽

Myeloid Leukemia ◽

Acute Myeloid

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Mutations and Thrombosis in Essential Thrombocythemia and Polycythemia Vera: Mayo-Careggi Alliance Study

Blood ◽

10.1182/blood-2018-99-110045 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3040-3040 ◽

Cited By ~ 1

Author(s):

Paola Guglielmelli ◽

Naseema Gangat ◽

Giacomo Coltro ◽

Terra L. Lasho ◽

Giuseppe Gaetano Loscocco ◽

...

Keyword(s):

Risk Factors ◽

Venous Thrombosis ◽

Polycythemia Vera ◽

Essential Thrombocythemia ◽

Arterial Thrombosis ◽

Older Patients ◽

Leukocyte Count ◽

Young Patients ◽

World Health ◽

Younger Age

Abstract Background : Thrombosis is a characteristic feature in essential thrombocythemia (ET) and polycythemia vera (PV). Previous studies had focused on thrombotic events occurring after diagnosis and did not always distinguish between arterial and venous thrombosis. Arterial thrombosis in ET has been associated with age >60 years, JAK2 mutations, leukocyte count >11 x 109/l, history of thrombosis and cardiovascular risk factors, and venous thrombosis with male sex (Blood 2011;117:5857). In the current two-enter study, we looked for associations between both driver and other mutations, with first incidences of arterial and venous thrombosis in ET and PV, analyzed together and separately. 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-derived mutation information. Diagnoses were according to the 2016 World Health Organization criteria (Blood. 2016;127:2391). Conventional statistics was employed to examine significance of associations, with separate analysis of arterial vs venous thrombosis, occurring at any time before or after formal diagnosis of ET or PV. For the purposes of the current study, only first events were considered. 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. Driver mutation distribution in ET was 55% JAK2, 27% CALR, 5% MPL and 13% triple-negative. Most frequent mutations, other than JAK2/CALR/MPL, were TET2 (14%; 11% in ET and 18% in PV) and ASXL1 (13%; 13% in ET and 13% in PV). 301 (33%) patients experienced first time thrombosis, before or after diagnosis, including 152 (30%) in ET and 149 (37%) in PV (p=0.03); arterial events occurred in 174 (19%) patients, including 96 (19%) in ET and 78 (19%) in PV (p=0.9); venous events occurred in 177 (20%) patients, including 82 (16%) in ET and 95 (24%) in PV (p=0.007). The number of vascular events after diagnosis was 174 (19%) for arterial and 154 (17%) for venous thrombosis, with no significant difference between ET and PV. Associations with arterial thrombosis: In multivariable logistic regression analysis that included both ET and PV (n=906), age >60 years (23% vs 16%; OR, 1.6, 95% CI 1.1-2.2) and absence of ASXL1 and RUNX1 mutations (21% vs 9%; OR 2.6, 95% CI 1.4-4.8) were associated with arterial thrombosis; these associations remained significant (or near significant) when ET and PV were analyzed separately; in addition, JAK2 mutations in ET displayed borderline significance (p=0.05). Overall incidence of arterial events in ET was estimated at 27% in the presence of all three risk factors (i.e. older age, presence of JAK2 mutations and absence of ASXL1/RUNX1 mutations), 21% with two risk factors, 13% with one risk factor and 9% in the absence of all three risk factors (p=0.01). Associations with venous thrombosis: In multivariable analysis, including both ET and PV (n=906), JAK2 mutations (p<0.001), higher leukocyte count (p=0.03) and younger age (p=0.04) were identified as being significant. Analysis of ET patients only (n=502) identified JAK2 mutations (p<0.001; OR 2.4, 95% CI 1.4-4.1), absence of SRSF2 mutations (p=0.03) and younger age (p=0.04) as independent risk factors and in PV patients (n=404), higher leukocyte count (p=0.06). Prognostic interaction between JAK2 mutations and age: In ET, the overall frequency of venous events was 27% for young patients with JAK2 mutations vs 13% for older JAK2 mutated cases vs 10% for JAK2 unmutated young patients vs 13% for JAK2 unmutated older patients (p<0.001). The corresponding percentages for arterial events were 20%, 24%, 14% and 19%, respectively (p=0.1). Conclusions: JAK2 mutations contribute to the risk of both venous (younger patients) and arterial (young and older patients) thrombosis, in an age-dependent manner; the association with venous thrombosis might explain the higher incidence of venous thrombosis in PV, compared to ET. Additional studies are required to confirm the observed lower risk of thrombosis in patients with ASXL1, RUNX1 and SRSF2 mutations and provide insight into the underlying biological explanation. Disclosures No relevant conflicts of interest to declare.

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