Faculty Opinions recommendation of Non-driver mutations in patients with JAK2V617F-mutated polycythemia vera or essential thrombocythemia with long-term molecular follow-up.

Abstract Introduction : Hydroxyurea (HU) is the most widely used cytoreductive treatment for patients with essential thrombocythemia (ET) and polycythemia vera (PV) at high risk of thrombosis. It remains unknown whether long-term HU therapy modulates or promotes the acquisition of mutations in non-driver (ND) genes, especially, when assessing hematological (HR) and molecular (MR) response. The objective of the study was to analyze the clonal dynamics of ND genes in HR and MR with HU in a cohort of JAK2V617F-mutated PV and ET patients. Method s: The study included 144 JAK2V617F positive patients (PV n = 73, TE n = 71) receiving HU as first-line cytoreductive treatment. The baseline sample (before HU treatment) and at the timepoint of best molecular response to JAK2V617F were analyzed. The allelic burden of J AK2V617F was assessed by allele-specific PCR and the mutational profile of ND genes was analyzed by next generation sequencing with a custom panel including 27 myeloid-associated genes. HR was defined according to the criteria of the European LeukemiaNet 2009 and MR of JAK2V617F was defined as complete, major, partial and no response (Table I). Results : Median molecular follow-up was 54.1 months for PV and 55.5 months for ET. Patients with PV were more likely to be males (p<0.001), and displayed higher leukocyte count (p<0.001) compared to those with ET. The respective numbers of deaths, leukemic transformations and fibrotic progressions were: 22 (30%), 4 (5%), 6 (8%) for PV cases, and 19 (27%), 1 (1%), 0 (0%) for ET patients. At baseline, a total of 62 somatic mutations in ND genes were detected in 42/73 (57%) PV patients while 58 were detected in 36/71 (51%) ET patients. Complete HR was observed in 102 patients: 44 (60%) PV and 58 (81%) ET. Partial MR in 67 cases: 35 (48%) PV and 32 (45%) ET and major or complete MR in 21 cases: 8 (11%) PV and 13 (18%) ET. The median duration of HU treatment was 45.8 months (range: 17.5-189.5) for PV and 45.6 months (range: 14.6-168.6) for ET. The most frequently mutated genes detected at pre-therapy samples were TET2 (34%), ASXL1 (12%), SF3B1 (7%) and EZH2 (5%) in PV patients, and TET2 (34%), ASXL1 (13%), DNMT3A (13 %) and SRSF2 (5%) in ET patients. No significant differences were observed in the MR (p=0.358) or HR (p=0.917) according to the presence or absence of mutations in ND genes at baseline. Clonal dynamics of DNMT3A, ASXL1, and TET2 (DAT) genes were not modulated by HU therapy to the same extent as JAK2V617F. Disappearance and emergence of additional mutations in DAT genes were observed independently of the molecular response achieved by the JAK2V617F clone. These findings suggest the existence of clones with mutations in ND genes independent from the pathogenic driver clone, and the lack of modulation by HU treatment. Finally, an increase of allelic burden or the appearance of mutations in TP53, a gene related to progression, and in other DNA repair genes (PPM1D and CHEK2) was observed in 14 (19.1%) PV patients and 9 (12.6%) ET cases during HU treatment. However, no increased risk of myelofibrotic transformation or progression to acute myeloid leukemia was observed in these patients. Conclusion s: Pre-treatment ND mutations are not associated with HR and MR to HU in JAK2V617F-mutated patients. 2. The clonal dynamics of ND mutations (decrease, increase, appearance, disappearance) are not related to the evolutionary dynamics of JAK2V617F. 3. An increase or appearance of progression-related mutations in TP53 and/or other genes of the DNA repair pathway such as CHEK2 and PPM1D is observed during HU treatment. Acknowledgments : Instituto de Salud Carlos III-FEDER, PI16/0153, PI19/0005, 2017SGR205, PT20/00023 and XBTC. Figure 1 Figure 1. Disclosures Salar: Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Gilead: Research Funding; Celgene: Consultancy, Speakers Bureau. Besses: Gilead: Research Funding. Bellosillo: Thermofisher Scientific: Consultancy, Speakers Bureau; Qiagen: Consultancy, Speakers Bureau; Roche: Research Funding, Speakers Bureau.

Download Full-text

Long-term follow-up of young patients with essential thrombocythemia treated with pipobroman

Annals of Hematology ◽

10.1007/s00277-004-0882-7 ◽

2004 ◽

Vol 83 (8) ◽

Cited By ~ 22

Author(s):

Francesco Passamonti ◽

Elisa Rumi ◽

Lucia Malabarba ◽

Luca Arcaini ◽

Ester Orlandi ◽

...

Keyword(s):

Essential Thrombocythemia ◽

Young Patients ◽

Long Term Follow Up

Download Full-text

JAK2V617F Complete Molecular Remission in Long-Term Follow-up of Patients with Polycythemia Vera and Essential Thrombocythemia Treated with Ruxolitinib

Blood ◽

10.1182/blood.v124.21.3185.3185 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3185-3185

Author(s):

Lisa Pieri ◽

Alessandro Pancrazzi ◽

Annalisa Pacilli ◽

Claudia Rabuzzi ◽

Giada Rotunno ◽

...

Keyword(s):

Polycythemia Vera ◽

Essential Thrombocythemia ◽

Research Funding ◽

Jak2v617f Mutation ◽

Prolonged Treatment ◽

Molecular Response ◽

Molecular Remission ◽

Allele Burden ◽

Jak2v617f Allele Burden

Abstract Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms (MPN) characterized by the presence of JAK2V617F mutation in >95% and 60% of patients (pts), respectively. This mutation usually affects one allele in ET while most PV pts are homozygous due to mitotic recombination. Acquisition of the JAK2V617F mutation is strongly associated with the germline 46/1 predisposition haplotype. Ruxolitinib is a JAK1/JAK2 inhibitor recently approved for myelofibrosis (MF) and under investigation in PV and ET pts intolerant or resistant to hydroxyurea. We enrolled 24 pts, 11 with PV and 13 with ET, in the phase II INCB18424-256 trial that overall included 34 PV and 39 ET pts. 21/24 pts were still on treatment at 5 years (yr), of which 19 JAK2V617F mutated. Results of the PV cohort have been reported recently (Verstovsek et al. Cancer, 2014): with a median follow up of 35 months (mo), the JAK2V617F allele burden decreased by a mean of 8%, 14%, and 22%, respectively, after 12, 24 and 36 mo. The proportion of pts who achieved a reduction ≥50 % at any time during the 1st yr, 2nd yr, and 3rd yr were 5.9%, 14.7%, and 23.5%, respectively, but no patients achieved a complete remission. In our series of pts we evaluated the JAK2V617F allele burden by two RTQ-PCR methods, according to Lippert (sensitivity, 0.8%) and to Larsen (sensitivity, 0.08%) method. We also analysed by next generation sequencing (NGS; Ion Torrent platform) a series of MPN-associated mutations including TET2, ASXL1, IDH1/2, LNK, CBL, SRSF2, EZH2 and MPL at baseline and at 5 yr of treatment in ruxolitinib treated pts who achieved a >25% JAK2V617F allele burden reduction at 5 yr (n=13/19). JAK2V617F allele burden decreased by a mean of 7%, 11%, and 19% at 12, 24 and 36 mo, and decreased further by a mean of 28% after 60 mo. Three (1 PV, 2 ET) of 19 pts (16%) achieved a 50% or greater allele burden reduction after 2 yr; no additional pts achieved this degree of allele burden reduction even in prolonged follow up. These 3 pts further improved their molecular response to a complete molecular response (CMR) after 5 yr of treatment. Their mean JAK2V617F allele burden was 46.6% at baseline, 28.3%, 16.3%, 8.7% and 0% after 1 yr, 2 yr, 3 yr and 5 yr, respectively. The JAK2 CMR was confirmed in at least one independent sample at 3 mo after first discovery. At this last timepoint, the PV pt was in complete haematological remission according to ELN criteria, the 2 ET pts were in partial remission due to platelet count still >400x109/L: 422x109/L and 812x109/L, respectively. BM histopathology in the 2 ET pts at 5 yr, while they were in CMR, showed still evidence of megakaryocyte hyperplasia. In the PV pt, histopathology at 5 yr is pending; evaluation at 3 yr, a time when she was in complete hematologic remission and JAK allele burden had decreased from 69 to 8%, showed normalization of cellularity, megakaryocyte and myeloid lineage compared to baseline but still slight erythroid hyperplasia. All 3 pts had normal karyotype at baseline that remained unchanged thereafter. CMR for JAK2V617F was confirmed by NGS. The 2 ET pts achieving CMR did not show any additional mutations, while the PV pts presented a TET2 Y867H mutation with an allele burden of 48.9% and 52%, respectively at baseline and 5 yr. No recurrent mutations in genes other than JAK2 were found in all other examined cases at baseline or at 5 yr. In 3 informative pts, we also analysed the proportion of JAK2V617F homozygous, heterozygous and wild type clones by the method of Hasan et al (Leukemia 2013) based on allelic discrimination of 46/1 haplotype and JAK2. We found that JAK2V617F/V617F clones were reduced by a mean of 95.5%, JAK2V617F/WT showed an uneven trend with a mean reduction of 45.54% while JAK2WT/WT conversely increased (mean 61.43%) at 5 yr, suggesting that in a subset a patients who present significant reduction of VF allele burden ruxolitinib may preferentially target the homozygous clones. Until now, complete molecular remission in PV pts has been described only in patients treated with interferon. Our data suggest that a subset of pts who present a rapid and sustained reduction of the JAK2V617F allele burden under ruxolitinib may eventually reach a condition of CMR with prolonged treatment. However, similar to findings with interferon, mutations establishing clonality, such as in TET2, may still persist in patients who eventually show the disappearance of JAK2V617F mutated subclones. Disclosures Verstovsek: Incyte: Research Funding. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Download Full-text

Sequential Analysis By Next Generation Sequencing of 18 Genes in Polycythemia Vera and Essential Thrombocythemia Reveals a Association Between Mutational Status and Clinical Outcome after 3-Year Follow-up

Blood ◽

10.1182/blood.v126.23.2808.2808 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2808-2808

Author(s):

Damien Luque Paz ◽

Aurelie Chauveau ◽

Caroline Buors ◽

Jean-Christophe Ianotto ◽

Francoise Boyer ◽

...

Keyword(s):

Polycythemia Vera ◽

Essential Thrombocythemia ◽

Jak2 V617f ◽

Primary Myelofibrosis ◽

Jak2 V617f Mutation ◽

Poor Prognostic Factor ◽

Disease Evolution ◽

Allele Burden ◽

V617f Mutation

Abstract Introduction Myeloproliferative neoplasms (MPN) are molecularly characterized by driver mutations of JAK2, MPL or CALR. Other somatic mutations may occur in epigenetic modifiers or oncogenes. Some of them have been shown to confer a poor prognosis in primary myelofibrosis, but their impact is less known in Polycythemia Vera (PV) and Essential Thrombocythemia (ET). In this study, we investigated the mutational profile using NGS technology in 50 JAK2 V617F positive cases of MPN (27 PV and 23 ET) collected at the time of diagnosis and after a 3 year follow-up (3y). Patients and Methods All patients were JAK2 V617F positive and already included in the prospective cohort JAKSUIVI. All exons of JAK2, MPL, LNK, CBL, NRAS, NF1, TET2, ASXL1, IDH1 and 2, DNMT3A, SUZ12, EZH2, SF3B1, SRSF2, TP53, IKZF1 and SETBP1 were covered by an AmpliseqTM custom design and sequenced on a PGM instrument (Life Technologies). CALR exon 9 mutations were screened using fragment analysis. Hotspots that mutated recurrently in MPN with no sequencing NGS coverage were screened by Sanger sequencing and HRM. A somatic validation was performed for some mutations using DNA derived from the nails. The increase of a mutation between diagnosis and follow-up has been defined as a relative increase of twenty percent of the allele burden. An aggravation of the disease at 3y was defined by the presence of at least one of the following criteria: leukocytosis >12G/L or immature granulocytes >2% or erythroblasts >1%; anemia or thrombocytopenia not related to treatment toxicity; development or progressive splenomegaly; thrombocytosis on cytoreductive therapy; inadequate control of the patient's condition using the treatment (defined by at least one treatment change for reasons other than an adverse event). Results As expected, the JAK2 V617F mutation was found in all patients with the use of NGS. In addition, we found 27 other mutations in 10 genes out of the 18 genes studied by NGS (mean 0.54 mutations per patient). Overall, 29 of 50 patients had only the JAK2 V617F mutation and no other mutation in any of the genes analysed. No CALR mutation was detected. Nine mutations that were not previously described in myeloid malignancies were found. The genes involved in the epigenetic regulation were those most frequently mutated: TET2, ASXL1, IDH1, IDH2 and DNMT3A. In particular, TET2 mutations were the most frequent and occurred in 20% of cases. There was no difference in the number or in the presence of mutations between PV and ET. At 3y, 4 mutations appeared in 4 patients and 15 out of 50 patients (9 PV and 6 ET) were affected by an allele burden increase of at least one mutation. At 3y, 24/50 patients suffered an aggravation of the disease as defined by the primary outcome criterion (16 PV and 8 ET). The presence of a mutation (JAK2 V617Fomitted) at the time of the diagnosis was significantly associated with the aggravation of the disease (p=0.025). Retaining only mutations with an allele burden greater than 20%, the association with disease aggravation is more significant (p=0.011). Moreover, a mutation of ASXL1, IDH1/2 or SRSF2, which is a poor prognostic factor in primary myelofibrosis, was found in 8 patients, all having presented an aggravation of their disease (p=0.001). Only 4 patients had more than one somatic mutation other than JAK2 V617F and all of them also had an aggravation at 3y (p=0.046). In this cohort, appearance of a mutation at 3y was not associated with the course of the disease. Conversely, the increase of allele burden of at least one mutation was associated with an aggravation (p=0.019). Discussion and conclusion Despite the short follow-up and the limited number of patients, this study suggests that the presence of additional mutations at the time of the diagnosis in PV and TE is correlated to a poorer disease evolution. The increase of mutation allele burden, which reflects clonal evolution, also seems to be associated with the course of the disease. These results argue for a clinical interest in large mutation screening by NGS at the time of the diagnosis and during follow-up in ET and PV. Disclosures Ugo: Novartis: Membership on an entity's Board of Directors or advisory committees, Other: ASH travel.

Download Full-text

Concomitant essential thrombocythemia with JAK2 V617F mutation in a patient with chronic myeloid leukemia with major molecular response with imatinib and long-term follow-up

Oncology Letters ◽

10.3892/ol.2016.4631 ◽

2016 ◽

Vol 12 (1) ◽

pp. 485-487 ◽

Cited By ~ 5

Author(s):

KATIA BORGIA BARBOSA PAGNANO ◽

MÁRCIA TORRESAN DELAMAIN ◽

MARIANA MUNARI MAGNUS ◽

JOSÉ VASSALLO ◽

CARMINO ANTONIO DE SOUZA ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Essential Thrombocythemia ◽

Myeloid Leukemia ◽

Jak2 V617f ◽

Jak2 V617f Mutation ◽

Molecular Response ◽

Major Molecular Response ◽

Long Term Follow Up

Download Full-text

Solid Tumors in Post-Polycythemia Vera and Post-Essential Thrombocythemia Myelofibrosis: A Study on 2220 Patients

Blood ◽

10.1182/blood-2018-99-115318 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3039-3039

Author(s):

Barbara Mora ◽

Elisa Rumi ◽

Paola Guglielmelli ◽

Daniela Barraco ◽

Margherita Maffioli ◽

...

Keyword(s):

Polycythemia Vera ◽

Board Of Directors ◽

Solid Tumors ◽

Essential Thrombocythemia ◽

Cumulative Incidence ◽

Research Funding ◽

Time Dependent ◽

Jak Inhibitors ◽

Advisory Committees

Abstract Background: Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms (MPN) that can progress to post-PV (PPV) myelofibrosis (MF) and post-ET (PET) MF, from now on referred to as secondary myelofibrosis (SMF). Recent studies have shown an increased risk of developing solid tumors (ST) in MPN patients in comparison to the general population. Information on development of ST in SMF is scant. Objectives of this study are to investigate ST in SMF correlating clinical phenotypes and treatments and to evaluate differences in the incidence of ST between PV and ET patients who developed SMF and those who did not. Methods: The SMF group (including only PV and ET who developed SMF) was from the MYSEC cohort with ST-data collected (n=768 SMF); the PV/ET group including only patients who did not evolved into SMF at the time of this analysis was from the Pavia cohort (n=1452, 611 PV and 841 ET). SMF diagnosis was performed according to the IWG-MRT criteria (2008), PV and ET diagnosis was reviewed according to the most recent WHO criteria. We performed time-to-event analysis with Cox regression models using either the time elapsed after ET or PV diagnosis or the time elapsed after SMF diagnosis, events being defined as the diagnosis of ST. Concomitant JAK inhibitor therapy was considered a dynamic (time-dependent) covariate present from the date of drug start. Likewise, the pre- and post-SMF periods were compared considering SMF as a time-dependent state. This study was approved by the Review Board of each Institution and conducted in accordance with the Declaration of Helsinki. Results: Within 768 SMF, 394 were PET and 374 PPV MF. Median follow up time was 14.5 years (range, 0.9-45.9) from ET/PV diagnosis and 3.0 years (range, 0.6-27.3) from SMF diagnosis. We identified 71 patients (9.2% of the entire cohort) who developed a ST (included one multiple myeloma and four lymphoproliferative disorders). We excluded from the analysis myelodysplastic syndromes, acute leukemias, carcinomas in situ, breast fibroadenomas, superficial bladder carcinoma and non-melanoma skin cancers. The most frequent (≥10%) ST subtypes were: breast (17 cases), prostatic (10) and kidney cancer (7). In 11 patients the date of ST occurrence was unreported and therefore they were excluded from time dependent analysis. As for the other 60 cases, 13 (21.7%) were diagnosed before ET/PV development, 22 (36.7%) during the ET/PV phase and 25 (41.6%) after SMF transformation. The cumulative incidence of ST was 0.44% person-year of follow up for ET/PV developing SMF and 0.98% person-year of follow up for SMF. There was a trend of association between male gender and ST occurrence after ET/PV (P=0.054) and after SMF diagnosis as well (P=0.055). No other statistically significant differences in demographics, driver mutations, karyotype, bone marrow fibrosis, and MYSEC-PM strata were found at the time of SMF diagnosis between SMF patients with and without ST. Then, we focused on 165 SMF patients treated with JAK inhibitors (of whom 10 during ET and 15 during PV phase): 128 received ruxolitinib, 11 fedratinib, 11 momelotinib, one XL019 and 14 JAK inhibitors sequentially. We did not find any correlation between JAK inhibitors treatment given at any time point of the follow-up and occurrence of ST (Log-rank P=1). Of note, the four patients with lymphoma did not receive JAK inhibition. In the Pavia cohort, within a median follow up of 4.7 years (range, 0.6-39.7), 24 (3.9%) PV and 40 (4.8%) ET patients developed a ST. The incidence of ST in the Pavia dataset was 0.74% person-year of follow up. We eventually merged the MYSEC and the Pavia cohorts. As for the latter dataset we can not exclude SMF evolution with a longer follow-up, we treated SMF occurrence of the merged group as a time dependent covariate. The probability of developing ST was similar in the group of patients evolved into SMF and in those who did not (P=0.7, Figure 1). Conclusions: This study provides evidence that: 1) the cumulative incidence of ST is about 1% person-year of follow up in SMF patients; 2) JAK inhibitors given during ET/PV or SMF phase are neutral for ST development within the limit of current follow up; 3) developing SMF in patients with PV or ET does not imply a higher risk of ST. These findings highlight the need of studies aimed at identifying patients at higher risk of ST occurrence. Disclosures Rambaldi: Roche: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Italfarmaco: Consultancy; Omeros: Consultancy; Amgen Inc.: Consultancy; Pfizer: Consultancy. Komrokji:Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding. Gotlib:Kartos: Consultancy; Promedior: Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Blueprint Medicines: Consultancy, Honoraria, Research Funding; Deciphera: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Kiladjian:Celgene: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Cervantes:Hospital Clinic Barcelona: Employment; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees. Devos:Celgene: Consultancy; Novartis: Consultancy; Takeda: Consultancy. Palandri:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Passamonti:Janssen: Consultancy, Speakers Bureau; Roche: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Speakers Bureau.

Download Full-text

Essential Thrombocythemia: A Prospective Analysis of Efficacy and Safety of Anagrelide for Long Term Treatment in Patients Below and Above the Age of 60 Years.

Blood ◽

10.1182/blood.v110.11.3561.3561 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3561-3561 ◽

Cited By ~ 1

Author(s):

Heinz Gisslinger

Keyword(s):

Disease Progression ◽

Essential Thrombocythemia ◽

Term Treatment ◽

Younger Patients ◽

Platelet Counts ◽

Patient Cohort ◽

Long Term Treatment ◽

History Of

Abstract Thromboembolic complications and less frequently bleeding characterize morbidity and mortality in patients with essential thrombocythemia (ET). The average estimated risk for thrombotic episodes in ET is 6.6% per patient year and platelet counts above 1000G/L, older age (>60 years) and a history of thrombosis were identified as major risk factors for serious complications. Since a direct correlation of platelet numbers with the number of thrombotic events is suggested by numerous prospective trials, it is generally accepted that these patients should receive platelet lowering treatment. Although hydroxyurea is considered as the treatment of choice in ET, there is still major concern about leukemogenicity of this compound. Anagrelide, on the other hand seems to be better tolerated in younger patients, but this has not been proved by prospective studies. It is therefore the aim of the present study to compare tolerability and efficacy of anagrelide (Thromboreductin, a novel non-immediate release formulation of anagrelide) over a prolonged time between ET patients below the age of 60 years with those above the age of 60 years. Among a total of 722 patients with ET on anagrelide who were prospectively documented within a standardized patient registry, 386 patients were previously untreated at the time of initiation of anagrelide therapy and this therapy was prospectively documented up to 5 years. The median age of this previously untrated patient cohort was 58 years (6 to 91 years), 179 (46,4%) patients were older than 60 years and 274 (71%) patients were female. Sixtythree patients (16,3%) had a history of thrombosis. The main inclusion criteria were those defined for qualifying a patient to be at high risk. During the first two years of follow up, the group of younger patients (< 60 years) did receive higher daily doses of anagrelide as compared to the older patient cohort (2,0mg vs.1,5mg). Anagrelide reduced platelet counts from a median baseline value of 920G/L to 581G/L and 382 G/L on month 3 and month 60 respectively. The overall response rate (platelet counts< 600G/L) was 64%. The rate of complete response (platelet counts <450G/L) went up from 58% after one year to 71% after 5 years of treatment. Group comparisons showed that a significant response to anagrelide was achieveable in patients below and above the age of 60 years with no significant difference between the two groups. With regard to safety, there is no evidence that anagrelide gives concern to an increased rate of bleeding (2%) or disease progression. Over the 5 year follow up period an adverse event was recorded in 24% of patients. The rate of treatment discontinuation as a result of adverse events was low (5%), treatment was discontinued when no further response was achieved or a negative risk benefit judgement of the treating physician was made. Only 4 patients of the whole cohort discontinued anagrelide due to disease progression. A small number of patients (12/722), 1,7%) died during the 5 years observation period, all cases were described as not drug related. In summary the data confirm that anagrelide yields comparable response rates in the two age groups during long term treatment.

Download Full-text

Similar Rate of Thrombosis in Essential Thrombocythemia and Polycythemia Vera Patients after Stratification for JAK2 V617F Allele Burden.

Blood ◽

10.1182/blood.v112.11.1745.1745 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1745-1745

Author(s):

Alessandra Carobbio ◽

Guido Finazzi ◽

Elisabetta Antonioli ◽

Paola Guglielmelli ◽

Alessandro M. Vannucchi ◽

...

Keyword(s):

Polycythemia Vera ◽

Essential Thrombocythemia ◽

Vascular Complications ◽

Jak2 V617f ◽

Similar Rate ◽

Wild Type ◽

Allele Burden ◽

Real Time Quantitative Pcr ◽

Venous Thromboembolic

Abstract Patients with Essential Thrombocythemia (ET) can be categorized as either JAK2 V617F mutated (V617F+) or wild type (V617F−). Mutated patients display multiple features resembling Polycythemia Vera (PV), with significantly higher hemoglobin level and neutrophil counts, lower platelet count, more pronounced bone marrow erythropoiesis and granulopoiesis and higher tendency to transform in PV. Presence of the mutation and/or allele burden has been variably associated with the rate of vascular complications in ET and PV, but a direct comparison between the two disorders under this respect has not been performed. To tackle this issue, we compared the rate of major thrombosis in 867 ET patients (57% were JAK2 V617F+) with that in 415 PV patients (all V617F+). The median follow-up was 4.9 (0 – 39) and 3.8 (0 – 26) years in ET and PV, respectively. High risk ET patients (age ≥ 60 years and/or previous thrombosis) received Hydroxyurea whereas the vast majority of low-risk remained untreated. PV patients were treated according to the current risk-stratified recommendations. Thrombotic episodes were recorded over time and calculated as rates % per patient/year (pt/yr). After adjusting for age, the thrombosis-free survival curves of JAK2 V617F+ and V617F− ET patients were superimposable until 10 years after the diagnosis, then they diverged so that the actuarial probability of major thrombosis in mutated ET patients reached that of PV (48% vs 55%, test for trend p=0.05). We found that JAK2 V617F+ allele burden measured by real-time quantitative PCR influenced these rates in a comparable way in both ET and PV. Actually, in JAK2 wild type ET (n=376, 43%) the rate was 1.4% pt/yr. In ET patients with JAK2 V617F+ allele burden ranging from 1 to 25% (N=190; 49%) the rate was 1.9 % pt/yr compared to 1.2 in PV patients (N=64, 19%); in the group with 26–50% the rate was 2.0 % pt/yr in ET (N=177; 45%) and 3.0 in PV patients (N=118, 36%); in cases of V617F+ allele burden greater than 50% the rate was 3.8 % pt/yr in ET (N=23; 6%) and 2.9 in PV patients (N=147, 45%). In conclusion, from this retrospective analysis, we conclude that in patients with ET harboring JAK2 V617F mutation the rate of stroke, myocardial infarction and venous thromboembolic complications is similar to that of PV patients and increases in dependence of V617F allele burden, supporting the hypothesis that ET and PV may be viewed as a continuum also in terms of vascular complications

Download Full-text

Clinical Factors Predictive Of Myelofibrotic Evolutions In Patients With Essential Thrombocythemia and Polycythemia Vera

Blood ◽

10.1182/blood.v122.21.4082.4082 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4082-4082 ◽

Cited By ~ 1

Author(s):

Mario Tiribelli ◽

Federico De Marchi ◽

Daniela Barraco ◽

Luciana Marin ◽

Erika Codarin ◽

...

Keyword(s):

Polycythemia Vera ◽

Essential Thrombocythemia ◽

Conflicts Of Interest ◽

Myeloproliferative Neoplasms ◽

Clinical Feature ◽

Baseline Characteristics ◽

Wbc Count ◽

Prognostic Risk Factors

Abstract Introduction Evolution to myelofibrosis (MF) represents a relatively rare but always severe event in patients with essential thrombocythemia (ET) and polycythemia vera (PV). Few reports have focused on the clinical and biological features at diagnosis of ET and PV that correlate with progression to MF. Aims and Methods We retrospectively studied a series of patients with post-ET and post-PV MF and compared with a group of ET and PV patients with a long follow-up without myelofibrotic evolution, with the aim to identify prognostic factors for MF. Forty-three patients with post-ET (n=29) and post-PV (n=14) MF followed at our institution were compared with 125 ET and 75 PV patients with at least 9 years of follow-up without evolution. Diagnosis of ET and PV was confirmed according to WHO criteria (including JAK2 analysis, performed since 2006 and study), evolution to MF was defined according to IWG-MRT proposed criteria. The following parameters, available for all patients at diagnosis of ET or ET, were taken into consideration to find prognostic risk factors for myelofibrosis: age, platelet (PLT) count, hemoglobin (Hb) and hematocrit (Hct) levels, white blood cell (WBC) count. Statistical analyses were conducted using Student t test. Results Median time from diagnosis of ET/PV and progression to MF was 156 months (range: 29-314). Comparing baseline characteristics of patients who evolved to MF and those who did not, we did not found any significant correlation. Mean data at diagnosis for patients with (n = 43) or without (n=200) subsequent evolution to MF were as follow: age 52.1 vs 53.1 years (p=0.79), Hb 15.4 vs 15.7 g/dl (p=0.59), Hct 47.2 vs 47.1% (p=0.67), WBC 9.8 vs 9.1 x 109/l (p=0.11), PLT 713 vs 689 x 109/l (p=0.87). Also when considering only the 29 post-ET MF and the 125 ET patients, there was no clinical feature present at diagnosis that could foresee a future myelofibrotic evolution. Conversely, in the 14 post-PV MF and 75 PV patients, progression to MF was predicted only by higher WBC count (11.4 vs 9.3 x 109/l, p=0.046), while no correlation was found with age, Hb, Hct or PLT [Table 1]. Conclusions Concordant with some previous reports, our data suggest a possible role of leucocytosis as an adverse risk factor for progression to MF in patients with PV, though not in ET. Other clinical characteristics present at diagnosis, such as advanced age, anemia or polycythemia and thrombocytosis do not seem to be associated with higher risk of fibrotic evolution in patients with myeloproliferative neoplasms. Disclosures: No relevant conflicts of interest to declare.

Download Full-text