Natural History Of Polycythemia Vera Research Articles

MiR-146a rs2431697 identifies myeloproliferative neoplasm patients with higher secondary myelofibrosis progression risk.

Myelofibrosis (MF) occurs as part of the natural history of polycythemia vera (PV) and essential thrombocythemia (ET), and remarkably shortens survival. Although JAK2V617F and CALR allele burden are the main transformation risk factors, inflammation plays a critical role by driving clonal expansion toward end-stage disease. NF-κB is a key mediator of inflammation-induced carcinogenesis. Here, we explored the involvement of miR-146a, a brake in NF-κB signaling, in MPN susceptibility and progression. rs2910164 and rs2431697, that affect miR-146a expression, were analyzed in 967 MPN (320 PV/333 ET/314 MF) patients and 600 controls. We found that rs2431697 TT genotype was associated with MF, particularly with post-PV/ET MF (HR = 1.5; p < 0.05). Among 232 PV/ET patients (follow-up time=8.5 years), 18 (7.8%) progressed to MF, being MF-free-survival shorter for rs2431697 TT than CC + CT patients (p = 0.01). Multivariate analysis identified TT genotype as independent predictor of MF progression. In addition, TT (vs. CC + CT) patients showed increased plasma inflammatory cytokines. Finally, miR-146a-/- mice showed significantly higher Stat3 activity with aging, parallel to the development of the MF-like phenotype. In conclusion, we demonstrated that rs2431697 TT genotype is an early predictor of MF progression independent of the JAK2V617F allele burden. Low levels of miR-146a contribute to the MF phenotype by increasing Stat3 signaling.

Natural history of polycythemia vera and essential thrombocythemia presenting with splanchnic vein thrombosis.

Patients with polycythemia vera (PV) or essential thrombocythemia (ET) presenting with splanchnic vein thrombosis (SVT) might have a specific clinico-biological profile. To investigate this hypothesis, 3705 PV/ET patients from three national registers, 118 of them presenting with SVT, were reviewed. After correction for age and sex, PV/ET patients with SVT showed an increased risk of death (HR 2.47, 95% CI 1.5-4.01, p < 0.001), venous thrombosis (IRR 3.4, 95%CI 2.1-5.5, p < 0.001), major bleeding (IRR 3.6, 95%CI 2.3-5.5, p < 0.001), and second cancer (IRR 2.37, 95%CI 1.4-4.1, p = 0.002). No case of acute leukemia was documented among patients with PV/ET presenting with SVT and seven of them (6%) progressed to myelofibrosis. SVT was not associated with lower risk of MF after correction by age and sex. Patients with SVT more frequently died from complications related to hepatic disease, major bleeding, or second cancer, resulting in a 5-year reduction of age- and sex-adjusted median survival. In conclusion, PV and ET patients presenting with SVT have shorter survival than patients with PV and ET of the same age and sex. This excess mortality is related to liver disease, major bleeding, and second cancer rather than to the natural evolution of the MPN.

Rs2431697, a Polymorphism of Mir-146a, Is a Precozing Marker of Progression to Secondary Myelofibrosis: New Epigenetic Regulation of Jak/Stat3 Signaling

Introduction: Transformation to secondary myelofibrosis (MF) occurs as part of the natural history of polycythemia vera (PV) and essential thrombocythemia (ET), the two more indolent Ph-negative myeloproliferative neoplasms (MPN). Once transformed, survival is remarkably shorted. Chronic inflammation plays a critical role in the progression of MPN, driving clonal expansion toward end stage disease. Importantly, MPN are characterized by the production of inflammatory cytokines, by both malignant and non-malignant clone. Inflammation and cancer share a common pathway, i.e. NF-κB. Interestingly, miR-146a regulates TLR/NF-κB pathway through the inhibition of its targets, IRAK1 and TRAF6, decreasing the production of cytokines. Based on: i) miR-146a-/- mice develop an MF-like phenotype with aging; and ii) miR-146a polymorphism (miRSNPs) rs2431697, influences its expression levels (50% decrease in TT individuals); we hypothesized that lower miR-146a-5p levels associated to this miRSNPs may result in high risk to develop MF.Objective: To evaluate the association of rs2431697 with MF transformation and to study the molecular mechanisms beyond this association.Methods: We genotyped rs2431697 in 938 patients (312 MF, 299 PV, and 327 ET) recruited from 13 tertiary Spanish institutions belonging to GEMFIN and 600 controls. The levels of miR-146a and IRAK1 were evaluated by qRT-PCR in total blood RNA of homozygous patients (TT=30, CC=25) with PV or ET and in healthy subjects (TT=7, CC=7). In miR-146a-/- mice, 2 and 9 months old, we evaluated spleen size and cellularity: degree of fibrosis in bone marrow (H&E and silver staining); and STAT3 and pSTAT3 in granulocytic lysates by western blot.Results: Association analysis, taken controls as reference, showed that TT genotype (associated in the literature with low levels of mir-146a) is associated to MF with an OR of 1.36 (1.01-1.82, p=0.04). Among MF patients, the subgroup with the greatest differences was the one of secondary MF (OR = 1.47, CI: 0.98-2.20) (Table 1 a,b). Next, we compared the genetic frequencies of rs2431697 SNPs between the secondary MF patients and the population in risk. Confirming our hypothesis, we observed an enrichment of TT genotype in the post-PV/TE MF group (n=132) compared to the PV+TE group (n=626) (OR=1.51; p<0.05), Table 1c. In patients with PV or true-ET (WHO criteria) and known clinical follow-up (n=243), excluding pre-fibrotic MF, 8.6% were transformed. The median time to transformation was 27 years, being significantly shorter in patients with PV (vs. ET); homozygous for JAK2V617F; and in TT carriers (vs. TC+CC) (Figure 1A). The mayor differences were seen at early time points (Wilconxon test, p=0.001). In fact, 7 out of 10 TT patients who progress to MF, did so in the first 10 years after diagnosis (70%) as compared with 2 out of 11 CC/CT patients (18%).Both groups (TT and TC+CC) were similar in age, sex, cell counts, initial diagnosis (PV/ET), driver mutations and fibrosis grade 1. In the multivariate analysis, TT genotype remained statistically significative [OR 2.87; CI: 1.19-6.94; p=0.019], independently of phenotype (PV/ET) or V617F allele burden. Both in JAK2 mutated and wild type patients, the time to progression to secondary MF was significantly shorter among TT patients (p=0.027) (Figure 1B). Moreover, TT genotype helped to categorize the risk of progression to MF independently of the driver mutation (JAK2 or CALR) or JAK2 burden allele (p=0.06) (Figure 1C). Consistently, TT patients showed a trends towards a lower expression of miR-146a (p=0.08) and higher IRAK1 (p=0.07) with a significant correlation between both (p<0.01). Finally, we evaluated the association between the JAK-STAT3 and TLR/NF-κB pathways in mice miR-146a-/-. We observed higher total STAT3 and pSTAT3 expression levels in miR-146a-/- than in WT mice (Figure 1D). This increase correlated with aging, and were associated with the appearance of splenomegaly, extramedular hematopoyesis and bone marrow fibrosis at 9 months of age (Figure 1E).Conclusion: rs2431697-TT is an independent marker of early progression to secondary MF. The lower expression of miR-146a that this SNP confers is associated with an increase in JAK-STAT3 signaling. Our findings include, for the first time, miR-146a in the MPN signaling pathways. Thus, miR-146a, modulating the activation of NF-kB-IRAK1, could indirectly regulates JAK-STAT3 signalling.CINC424AES05T [Display omitted] DisclosuresFerrer Marin:Novartis: Consultancy, Research Funding; Incyte: Consultancy. Hernandez Boluda:Incyte: Consultancy; Novartis: Consultancy. García Gutiérrez:Incyte: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau. Gómez-Casares:Bristol-Myers Squibb: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau. Besses:Novartis: Honoraria, Research Funding; Shire: Honoraria.

No correlation of intensity of phlebotomy regimen with risk of thrombosis in polycythemia vera: evidence from European Collaboration on Low-Dose Aspirin in Polycythemia Vera and Cytoreductive Therapy in Polycythemia Vera clinical trials

The natural history of polycythemia vera (PV) is marked by arterial and venous thromboembolism and evolution into myelofibrosis and/or acute myeloid leukaemia/myelodysplastic syndrome. One of the major goals of treatment is to reduce the thrombotic events which account for 40% of causes of

Epidemiology and clinical relevance of mutations in postpolycythemia vera and postessential thrombocythemia myelofibrosis: A study on 359 patients of the AGIMM group

Transformation to secondary myelofibrosis (MF) occurs as part of the natural history of polycythemia vera (PPV-MF) and essential thrombocythemia (PET-MF). Although primary (PMF) and secondary MF are considered similar diseases and managed similarly, there are few studies specifically focused on the latter. The aim of this study was to characterize the mutation landscape, and describe the main clinical correlates and prognostic implications of mutations, in a series of 359 patients with PPV-MF and PET-MF. Compared with PV and ET, the JAK2V617F and CALR mutated allele burden was significantly higher in PPV-MF and/or PET-MF, indicating a role for accumulation of mutated alleles in the process of transformation to MF. However, neither the allele burden nor the type of driver mutation influenced overall survival (OS), while absence of any driver mutation (triple negativity) was associated with significant reduction of OS in PET-MF, similar to PMF. Of the five interrogated subclonal mutations (ASXL1, EZH2, SRSF2, IDH1, and IDH2), that comprise a prognostically detrimental high molecular risk (HMR) category in PMF, only SRSF2 mutations were associated with reduced survival in PET-MF, and no additional mutation profile with prognostic relevance was highlighted. Overall, these data indicate that the molecular landscape of secondary forms of MF is different from PMF, suggesting that unknown mutational events might contribute to the progression from chronic phase disease to myelofibrosis. These findings also support more extended genotyping approaches aimed at identifying novel molecular abnormalities with prognostic relevance for patients with PPV-MF and PET-MF. Am. J. Hematol. 91:681-686, 2016. © 2016 Wiley Periodicals, Inc.

Thrombocytopenia and hemorrhagic pleural effusion as an initial presentation of polycythemia vera

Polycythemia vera (PV) is a chronic myeloproliferative disorder in which there is an alteration in the pluripotent progenitor cell leading to excessive clonal proliferation of erythroid, myeloid and megakaryocytic progenitor cells. The natural history of PV can be divided into several stages, beginning with asymptomatic, isolated erythrocytosis, progressing to more generalized myeloid proliferation, splenomegaly, and thrombosis, followed by myelofibrosis, leukoerythroblastosis, cytopenia, and myeloid metaplasia and sometimes, acute leukemia. Isolated erythrocytosis, leukocytosis, or thrombocytosis or in combination are usually present at the onset of disease. We present the case of a 65-year-old man, who developed thrombocytopenia and hemorrhagic pleural effusion as an initial presentation of PV that is extremely rare.

The Natural History Of Polycythemia Vera In Two Diagnostic Eras

IntroductionThe 2005 identification of the JAK2 V617F mutation ushered in a new era of discovery for Polycythemia Vera (PV), allowing for its molecular classification, improved diagnostic capabilities, and a potential for targeted therapy. In this era, aspirin has been shown to lower the risk of thrombosis, the hematocrit (hct) target has been validated, and there has been renewed interest in interferon (IFN). These changes in diagnosis (dx) and therapy may impact the natural history of PV in its modern era. To this end, we analyzed 399 PV patients (pts) diagnosed in two eras (pre-2005 and post-2005) from two tertiary centers. (JHH, N=294; NU, N=105). MethodsPts were seen between 2005 and 2013. Testing to verify PV included an absolute erythrocytosis, JAK2 status, erythropoietin assay, red blood cell mass testing, and bone marrow biopsy. Pts were diagnosed by treating physicians using criteria relevant to the era of dx, between 1968 and 2013. Pts in each era were compared with regard to differences in demographic and clinical factors. The prevalence of myelofibrotic (MF) and leukemic (AML) transformation, as well as deaths was also determined. ResultsOf 105 NU and 294 JHH pts, 45 (43%) and 113 (38%) were diagnosed post-2005 (p=0.43). Pre-2005 and post-2005 pts were similar in age at dx at NU (52 vs. 57 yrs) and JHH (53 vs. 59 yrs). As expected, median disease duration was longer in pre-2005 NU (12 vs. 3 yrs) and JHH pts (9 vs. 2 yrs). 52% and 60% of pre-2005 pts, and 62% and 60% of post-2005 pts were women at NU (p=0.28) and JHH (p=1), respectively. JAK2 V617F testing was positive 33/37 (89%) and 41/44 (93%) of pre-2005 and post-2005 NU patients. At JHH, JAK2 V617F was positive in 286/294 (97%); JAK2 exon 12 was positive in 6/294 (0.02%). RBC mass testing was infrequently done at NU (9/105); only 2 were performed post-2005. At NU, pre-2005 and post-2005 pts had similar median leukocyte counts (8.9 and 8.7 x 109/L) and hct below 45% (40.5 vs. 42.9%). The prevalence of current anti-platelet and hydroxyurea use was similar at NU (pre-2005: 79%, 49% vs. post-2005: 82%, 48%, respectively). 5% and 11% of pre-2005 and post-2005 pts were on IFN.At NU and JHH, 29% and 27% of pre-2005 and 18% and 21% of post-2005 pts had thrombosis (pre vs. post: p=0.2 for NU; p=0.26 for JHH). Thrombosis in pre-2005 NU pts occurred at a median of 8 yrs from dx compared to post-2005 pts that frequently had events at presentation (median 0 yr; p=0.017). Similarly, fewer pre-2005 JHH pts had events at presentation compared to post-2005 pts (19/49 (39%) vs. 16/24 (67%); p=0.025). At NU, 19/105 (18%) developed MF, at a median of 12 yrs. Only 2/19 (11%) occurred in post-2005 pts, due to shorter disease duration. At JHH, 49/294 (15%) developed MF at a median of 11 yrs, but only in 4/49 (8%) post-2005 pts. At NU and JHH, 5/105 (5%) and 11/294 (4%), developed AML at a median of 15 and 8 yrs from dx. 1 and 4 post-2005 NU and JHH pts developed AML. At NU and JHH, 20/105 (19%) and 42/294 (14%) died. At NU, 16 were pre-2005 pts and 4 were post-2005 pts. At JHH, 35 were pre-2005 pts and 7 were post-2005 pts. AML-deaths were overrepresented in the post-2005 pts (25% NU, 57% JHH). ConclusionRemarkably, the epidemiology and natural history of PV was quite similar between two eras of diagnosis and between two large tertiary centers. Age at dx in pre and post-2005 patients was similar, arguing against a notion that pts are diagnosed earlier in adulthood. At NU, hct was typically below 45%, implying adherence to a recently validated target and aspirin use was prevalent regardless of the era of dx. Regardless, thrombosis at presentation was more common in modern era PV patients, whereas pre-2005 patients had more thrombotic events after an official PV diagnosis. As expected, time-dependent complications such as MF and death were more common in pre-2005 pts, and occurred within the 2nd decade of disease. MF was rare in post-2005 pts, who remain in their 1st decade of disease. Overall, AML was rare, but each cohort still had 1st decade transformations (post-2005 pts), over-representing deaths in this group. While the JAK2 mutation discovery has modernized PV dx, the natural history of PV has not changed. It is in this modern era of PV that we will learn whether or not new (JAK-inhibitors) and renewed (IFN) therapies can prevent or delay onset of feared time-dependent complications. Disclosures:No relevant conflicts of interest to declare.

Risk Factors for Thrombosis Among 1,545 Patients with Polycythemia Vera: An International Study.

AbstractAbstract 2849 BackgroundWe have previously reported on the natural history of polycythemia vera (PV), focusing primarily on overall and leukemia-free survival (ASH Annual Meeting Abstracts. 2011;118(21):277-). In the current study, we present, on behalf of the International Working Group for Myeloproliferative neoplasms Resarch and Treatment (IWG-MRT), our analysis regarding risk factors for thrombosis. MethodsUnder the auspices of IWG-MRT, seven international centers of excellence for myeloproliferative neoplasms participated in the current study. The two principle investigators (AT and TB) reviewed all the cases and selected 1,545 patients who met the 2008 WHO criteria for PV, were age 18 years or older, diagnosed after 1970, and whose submitted data included diagnostically essential information. Results I: Presenting FeaturesMedian age was 61 years (range, 18–95; 51% females). Arterial and venous thrombosis history before or at diagnosis was documented in 246 (16%) patients and 114 (7.4%) patients, respectively. Major hemorrhage hemorrhage before or at diagnosis was documented in 17 (4.5%) patients. Other features at diagnosis included pruritus (36%), microvascular disturbances (28.5%), palpable splenomegaly (36%), abnormal karyotype (12%), leukoerythroblastosis (6%), increased LDH (50%), thrombocytosis (53%), extreme thrombocytosis (platelets >1 million mm3; 4%) leukocytosis (49%), JAK2 V617F (95%), other JAK2 mutations (3%), subnormal serum erythropoietin (Epo) level (81%), and endogenous erythroid colonies (EEC; 73%). History of hypertension (46%), hyperlipidemia (18.3%), diabetes (8.4%), and tobacco use (16%) was also obtained. Results II: Clinical CourseTo date, 347 (23%) deaths, 50 (3%) leukemic progressions, and 138 (9%) fibrotic transformations have been recorded. Overall, cytoreductive treatment was not used in 416 (27%) patients and the remaining were exposed to different agents based on physician discretion. Post-diagnosis arterial or venous thrombosis occurred in 184 (12%) and 137 (9%) patients, respectively. Results III: Risk Factors for thrombosisArterial and venous thrombosis-free survival, from time of diagnosis, were separately analyzed using the occurrence of thrombosis as the endpoint (uncensored variable) and last follow-up or death before thrombosis as the censored variable. In univariate analysis, the following were significantly associated with post-diagnosis arterial thrombosis: advanced age, leukocyte count, presence of a leukoerythroblastic smear (LES), history of hypertension and history of arterial thrombosis before or at diagnosis; multivariable analysis using all these five parameters identified arterial thrombosis history (RR 2.5, 95% CI 1.6–4.0; p<0.0001), LES (RR 2.3, 95% CI 1.3–4.2; p=0.005) and history of hypertension (RR 1.6, 95% CI 1.1–2.4; p=0.02) as independent predictors of post-diagnosis arterial thrombosis. Only two parameters predicted post-diagnosis venous thrombosis, in univariate analysis, and both remained significant during multivariable analysis: abnormal karyotype (RR 3.1, 95% CI 1.7–5.4; p=0.0001) and history of venous thrombosis (RR 2.4, 95% CI 1.2–4.9). Of note, the type of JAK2 mutation or presence of either subnormal Epo or EEC did not influence either arterial or venous thrombosis. Results IV: Risk Stratification for arterial and venous thrombosisThe figures below illustrated arterial or venous thrombosis-free survival of patients stratified by the absence of all risk factors or presence of one or ≥2 risk factors. For arterial thrombosis, the presence of ≥2 risk factors clearly delineated a high risk group (RR 3.1, 95% CI 1.9–5.0) whereas the presence of one (RR 2.4, 95% CI 1.4–4.2) or two risk factors (RR 10.1, 95% CI 3.6–28.2) for venous thrombosis delineated an intermediate and high risk group, respectively. Conclusions:History of arterial thrombosis and venous thrombosis are key risk factors, respectively, for recurrent arterial and venous thrombosis in PV. In addition, abnormal karyotype is a strong independent risk factor for venous thrombosis and the presence of leukoerythroblastosis and hypertension, for arterial thrombosis. This information allows for a simple and practical risk stratification and raises interesting pathogenetic implications that require further clarification. [Display omitted] [Display omitted] Disclosures:Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees. Gisslinger:Novartis: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Passamonti:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Survival and Prognosis Among 1,263 Patients with Polycythemia Vera: An International Study

Abstract▪277▪This icon denotes a clinically relevant abstract Background:Current information on the natural history of polycythemia vera (PV) is mostly derived from early studies based on the PV Study Group diagnostic criteria. The World Health Organization (WHO) diagnostic approach to PV is currently the gold standard. The main objective of the current study was to describe survival, disease complication rates and risk factors in WHO-defined PV. Methods:Under the auspices of an International Working Group, seven international centers of excellence for myeloproliferative neoplasms submitted a total of 1,430 patients, locally diagnosed with “WHO-defined PV”. The two principle investigators (AT and TB) reviewed all the cases and selected 1,263 patients who were age 18 years or older, diagnosed after 1970, and whose submitted data included diagnostically essential information. Results I: Presenting Features:Median age was 60 years (range, 18–95; 51% females). The number of patients diagnosed between 1970–1990, 1991–2000, and 2001–2011 were 136 (11%), 337 (27%) and 790 (62%), respectively. Arterial/venous thrombosis history before or at diagnosis was documented in 142/73 and 80/42 patients, respectively. Other features at diagnosis included pruritus (37%), microvascular disturbances (29%), palpable splenomegaly (37%), abnormal karyotype (13%), and leukoerythroblastosis (6%). History of hypertension (45%), hyperlipidemia (17%), diabetes (9%), and tobacco use (15%) was also obtained. Results II: Clinical Course:To date, 228 (18%) deaths, 42 (3%) leukemic progressions, and 101 (8%) fibrotic transformations have been recorded. Post-diagnosis arterial or venous thrombosis occurred in 139 (11%) and 85 (7%) patients, respectively. Cytoreductive therapy had not been used in 342 (27%) patients whereas 154 (12%) patients were exposed to two or more cytoreductive drugs. Results III: Risk Factors:Multivariable analysis identified advanced age, leukocytosis, venous thrombosis history and abnormal karyotype as significant (p<0.01) risk factors for overall survival (OS). Receiver operating characteristic (ROC) plots delineated ages 69 (AUC 0.83) and 59 (AUC 0.61) years and leukocyte count 13 × 109/L (AUC=0.61) as the best discriminant levels in this regard; HR (95% CI) were 11.4 (7.7–16.9) for age ≥70 years, 3.8 (2.6–5.7) for age 60–69 years, and 2.0 (1.5–2.6) for leukocyte count ≥15 × 109/L. Results IV: Risk Stratification:HR-based risk scores were assigned to age ≥70 years (3 points), age 60–69 years (2 points) and leukocyte count ≥15 × 109/L (one point), in order to create four risk groups: low (zero points; n=492; median survival 322 months), intermediate-1 (one or 2 points; n=353; median survival 208 months; HR 3.8, 95% CI 2.5–5.8), intermediate-2 (3 points; n=286; median survival 132 months; HR 10.7, 95% CI 6.9–16.5), and high (4 points; n=56; median survival 90 months; HR 22.7, 95% CI 13.9–37.1) (Figure 1). Similar results were obtained when analysis was restricted to the 1,011 JAK2 mutation-positive patients (Figure 2). The particular risk model was equally robust in predicting leukemia-free survival (p=0.001). [Display omitted] Conclusions:Age and leukocyte count matter the most in predicting survival in PV. The current study suggests additional prognostic value from karyotype and venous thrombosis history. [Display omitted] Disclosures:Vannucchi:Novartis: Honoraria. Gisslinger:Novartis: Speakers Bureau; Celgene Austria: Speakers Bureau; AOP-Orphan: Speakers Bureau.

Bone marrow histopathology and biological markers as specific clues to the differential diagnosis of essential thrombocythemia, polycythemia vera and prefibrotic or fibrotic agnogenic myeloid metaplasia.

Clinical, hematological and morphological peripheral blood and bone marrow characteristics, in particular, megakaryopoiesis and bone marrow cellularity, reveal diagnostic clues and pathognomonic features, which enable a clear-cut distinction between essential thrombocythemia (ET), polycythemia vera (PV) and prefibrotic and fibrotic agnogenic myeloid metaplasia (AMM). The characteristic increase of enlarged mature megakaryocytes with mature cytoplasm and multilobulated nuclei and their tendency to cluster in a normal or slightly increased cellular bone marrow represent the hallmark of ET. The characteristic increase and clustering of enlarged mature and pleiomorphic megakaryocytes with multilobulated nuclei and proliferation of erythropoiesis in a moderate to marked hypercellular bone marrow with hyperplasia of dilated sinuses are the specific diagnostic features of untreated PV. ET may precede PV for many years to more than one decade. Prefibrotic and fibrotic AMM appears to be a distinct dual proliferation of abnormal megakaryopoiesis and myelopoiesis. The histopathology of the bone marrow in prefibrotic and fibrotic AMM is dominated by atypical enlarged and immature megakaryocytes with cloud-like immature nuclei, which are not seen in ET and PV at diagnosis and during follow-up. Myelofibrosis is not a feature of ET at diagnosis and during long-term follow-up. Myelofibrosis, which is secondary to the megakaryocytic/granulocytic myeloproliferation, and extramedullary myeloid metaplasia constitute a prominent feature and usually progress more or less rapidly during the natural history of PV and AMM. Life expectancy is normal in ET, normal in the first and decreased in the second decade of follow-up in PV, but significantly shortened in thrombocythemia associated with prefibrotic AMM as well as in the various fibrotic stages of AMM. These clinical and pathological characteristics of the Ph-negative MPDs, by including bone marrow histopathology, enable a clear-cut distinction between ET, PV and prefibrotic and fibrotic AMM. The use of established and new biological markers of MPDs, like spontaneous EEC, PRV-1 gene expression etc, should be validated in large prospective multicenter studies of newly diagnosed and previously treated MPD patients using the proposed European clinical and pathological (ECP) criteria as the only gold standard available for the proper diagnosis and differential diagnosis of ET, PV and AMM.

Polycythemia Vera: The Natural History of 1213 Patients Followed for 20 Years

To reassess the natural history of polycythemia vera and to obtain reliable estimates of both incidence of thrombosis and survival for use in defining the sample size for therapeutic clinical trials.Retrospective cohort study of patients with polycythemia who had been followed for 20 years.11 Italian hematology institutions.1213 patients with polycythemia vera, which was diagnosed according to criteria established by the Polycythemia Vera Study Group and commonly used in clinical practice.All-cause mortality, venous and arterial thrombosis, and hematologic and nonhematologic neoplastic disease. Myocardial infarction and stroke were classified as major thrombotic events, and venous and peripheral arterial thrombosis were considered minor thrombotic events. The number of patients who died and the number of those who had major thrombotic events (combined end point) were used as a comprehensive measure of the benefit-risk ratio associated with the use of myelosuppressive agents.634 fatal and nonfatal arterial and venous thromboses were recorded in 485 patients (41%); 36% of these episodes occurred during follow-up in 230 patients (19%), and 64% occurred either at presentation or before diagnosis. Thrombotic events occurred more frequently in the 2 years preceding diagnosis, suggesting a causal relation between the latent myeloproliferative disorder and the vascular event. The incidence of thrombosis during follow-up was 3.4%/y; older patients or those with a history of thrombosis had a higher risk for thrombosis. Overall mortality was 2.9/100 patients per year; thrombotic events and hematologic or nonhematologic cancers had similar effects on mortality. Patients receiving chemotherapy died three to four times more frequently than those not receiving chemotherapy. The increased risk for cancer in patients receiving myelosuppressive agents was seen approximately 6 years after diagnosis. In addition, the combined end point, computed as the sum of the hardest available events (death, nonfatal myocardial infarction, or stroke), suggests that myelosuppressive agents have an overall unfavorable effect.Cytoreduction favorably affects the incidence of thrombotic events, but aggressive treatment seems to be associated with increased risk for neoplasm. These results provide a basis for reevaluating the therapeutic strategy in patients with polycythemia vera and for estimating the size of clinical trials aimed at testing new therapeutic approaches.