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

Blood ◽  
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.

High Rates of Molecular Response After Long-Term Follow-up of Patients with Advanced Essential Thrombocythemia (ET) or Polycythemia Vera (PV) Treated with Pegylated Interferon-ALFA-2A (PEG-IFN-α-2A; PEGASYS)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 461-461
Author(s):  
Alfonso Quintás-Cardama ◽  
Ross Levine ◽  
Taghi Manshouri ◽  
Outi Kilpivaara ◽  
Hagop M. Kantarjian ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Covalent Attachment ◽  
Molecular Response ◽  
Molecular Responses ◽  
Allele Burden ◽  
Mutational Status ◽  
Starting Dose ◽  
Jak2v617f Allele Burden

Abstract Abstract 461 Background: The use of IFN-α in polycythemia vera (PV) and essential thrombocythemia (ET) has been hampered by poor tolerance and inconvenient dosing schedules. The covalent attachment of polyethylene glycol to IFN-α renders a molecule with prolonged serum half-life, which can be administered weekly. Objectives: We conducted a phase II study of subcutaneous PEG-IFN-α-2a (Pegasys) in 84 patients (pts) with high-risk PV (n=44) or ET (n=40). We performed high throughput mutational analysis of JAK2, MPL, TET2, and ASXL1 in all pts. Patients and Therapy: Median age was 51 years (range, 18–79), time from diagnosis to PEG-IFN-α-2a 51 months (range, 0–355), and number of prior therapies was 1 (range, 0–6), including hydroxyurea (HU; n=47), anagrelide (AG; n=26), IFN-α (n=12: 5 oral and 7 sc), imatinib (n=7), and dasatinib (n=1). PEG-IFN-α-2a was initial therapy in 16 (19%) pts (7 PV) that refused HU. JAK2V617F was detected in 19/40 (48%) ET and in 42/44 (95%) PV pts. Nine (11%) pts had abnormal cytogenetics. Initial PEG-IFN-α-2a starting dose was 450 mcg/wk, but that was modified to the current starting dose of 90 mcg/wk. Results: After a median follow-up of 40 months (range, 8–62), 66/83 (80%) assessable pts have responded. Median time to response was 4 weeks (range, 0.5–26). Complete response (CR) was achieved by 62 (75%) pts (for ET: platelets <440×109/L, in the absence of thromboembolic events; for PV: Hb <15 g/dL, no phlebotomy, disappearance of splenomegaly) whereas 4 (5%) pts (2 PV, 2 ET) had a partial response ([PR]; no phlebotomy, off HU and AG, still palpable spleen). Of 5 pts with abnormal karyotype at study entry who were evaluable for response, 2 reverted to diploid cytogenetics. JAK2V617F to total JAK2 ratio was determined by quantitative pyrosequencing assay in all 84 pts prior to PEG-IFN-α-2a. Sixty-one (73%) pts carried the JAK2V617F mutation, which was quantitated at least once on therapy in 54 (64%). Overall, 29 (54%) had >20% reduction in JAK2V617F allele burden, including 10 (19%) in whom the mutation became undetectable (complete molecular response [CMR]) and 15 (28%) who had a >50% reduction (partial molecular response). Molecular responses have not yet reached a plateau among pts with PV. We also analyzed pts for mutations in exon 12 of JAK2, MPL, and the tumor suppressors TET2 and ASXL1 to determine their impact on response to PEG-IFN-α-2a. No pts carried JAK2 exon 12 mutations. One JAK2V617F−negative pt with ET had a MPLW515L mutation, achieved CHR but did not achieve a molecular response. Full length resequencing of all exons of TET2 and ASXL1 genes identified somatic TET2 mutations in 9/71 (13%) and somatic ASXL1 mutations in 3/71 (4%) pts; we identified TET2 (3 JAK2V617F− ET, 2 JAK2V617F+ ET, 3 JAK2V617F+ PV, 1 JAK2V617F− PV) and ASXL1 (1 pt with ET JAK2V617F+, ET JAK2V617F−, and PV JAK2V617F+) mutations in PV and ET pts who were JAK2V617F–positive and negative. TET2 or ASXL1 mutational status did not impact the likelihood of achievement of JAK2 molecular responses, and there was no difference in JAK2V617F allele burden with PEG-IFN-α-2a according to TET2 or ASXL1 mutational status. One pt with baseline mutations in JAK2, TET2, and ASXL1 became JAK2V617F–negative on PEG-IFN-α-2a. Most pts had grade 1–2 toxicities but at doses ≤90 mcg/wk, grade 3–4 toxicity was infrequent. Twenty-five (30%) patients were taken off study after a median of 9 months (range, 3–36) but only 13 (15%) of them due to therapy-related toxicity: g3 neutropenia, anorexia, depression (n=3), ischemic retinopathy, g2 fatigue (n=5), dyspnea, g2 neuropathy. The remaining 59 pts are currently receiving 450 mcg/wk (n=1), 360 mcg/wk (n=1), 240 mcg/wk (n=1), 180 mcg/wk (n=2), 135 mcg/wk (n=3), 90 mcg every 1 (n=8), 2 (n=12), 3 (n=2), or 4 wks (n=1), 45 mcg every 1 (n=9), 2 (n=5), 3 (n=6), or 4 wks (n=8). Conclusion: PEG-IFN-α-2a is remarkably active and acceptably safe in advanced, previously treated PV and ET. Clinical responses are frequently accompanied by significant reduction of JAK2V617F allele burden, which becomes undetectable in a proportion of them suggesting selective targeting of the JAK2V617F clones. Quantitative analysis of ASXL1 and TET2 mutational allele burden during PEG-IFN-α-2a therapy to determine clonal evolution, and methylcellulose-based clonogenic assays in pts who achieved CMR to assess for the presence of erythropoietin independent colony formation are ongoing and will be presented. Disclosures: No relevant conflicts of interest to declare.

Efficacy and Safety of Pegylated Interferon Alpha-2a in Patients with Essential Thrombocythemia and Polycythemia Vera: Results after a Median 7-Year Follow-up of a Phase 2 Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 60-60 ◽  
Author(s):  
Lucia Masarova ◽  
Srdan Verstovsek ◽  
Keyur P. Patel ◽  
Kate J Newberry ◽  
Jorge E. Cortes ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Interferon Alpha ◽  
Essential Thrombocythemia ◽  
Research Funding ◽  
Pegylated Interferon ◽  
Molecular Remission ◽  
Molecular Responses ◽  
Pegylated Interferon Alpha ◽  
Allele Burden

Abstract Introduction: It has been previously reported that pegylated interferon alpha-2a can induce hematologic and molecular responses in patients with essential thrombocythemia "ET" and polycythemia vera "PV", but the follow up in these studies were relatively short. Objective: We present longer-term efficacy and safety results of a prospective phase II study of pegylated interferon alpha-2a in patients with ET and PV after a median follow up of 82.5 months (range, 8-107). Methods: Patients with a diagnosis of ET or PV, in a need of therapy, either newly diagnosed or previously treated, were eligible for this study. Median interferon starting dose of 180 mcg/week SQ (range, 450-90; 39% started on 90mcg/week) was modified in majority of the patients based on toxicity or lack of efficacy. Clinical and molecular responses were assessed every 3 to 6 months. Results: Among 83 enrolled patients (43 PV, 40 ET), 32 patients (39%) are still on study (but in 8 therapy is on hold: 5 due to toxicity, and 3 for financial reasons). Median age was 53 years (range, 19-78). Overall 37% of patients did not receive prior cytoreductive treatment. The overall median exposure to therapy was 87 months (range, 58-107) and was no different for patients still enrolled on the study and those who stopped study participation. Nine (28%) patients still on study are currently on a dose equal or higher than 90 mcg/week and 15 (47%) are on dose equal or smaller than 45mcg/week. JAK2 status or allele burden had no impact on achievement of response (clinical or molecular), time to response or duration of therapy. 55 of 59 (71%) JAK2V617F positive patients were evaluable for molecular response (Figure); 8 patients carried CARL mutation, 3 carried MPL and in 13 were triple negative. Median duration of hematologic and molecular response was 66 and 53 months, respectively; and directly correlated with treatment length and type of response (CMR had the longest duration of response). Overall yearly discontinuation rate were gradually decreasing for first 5 years, from 17% to 5%, and slowly increasing afterward to 10%. Of the 51 patients not on the study anymore, 27 (35% of the total) discontinued therapy primarily due to treatment toxicity. New late (≥24 months from start of therapy) G3/4 toxicity occurred in 17% of patients. Among patients in complete hematologic response treatment failure due to vascular adverse event or disease transformation was seen in 5 patients each. Three patients died on study (not related to therapy or disease), and 8 after stopping participation. Mean changes in allele burden over time in JAK2 positive patients are depicted in figure. Conclusions: Although pegylated interferon alpha-2a can induce significant hematologic and molecular responses; toxicity still limits its use over longer period of time and loss of response or transformation is encountered. Table.ResponseCharacteristicsFirst responseLast responseHem Resp, N. of patients (No), (%)CHR62 (76)25 (40)aPHR4 (5)1 (25)ORR66 (79)26 (39)aMol Resp, No, (%)CMR10 (18)9 (90)PMR20 (36)5 (25)*mMR5 (9)2 (40)ORR35 (74)16 (46)SafetyAny gradeGrade≥3Overall Adverse Events (AE), No, (%)any AE83 (100)57 (67)recurrent AE74 (89)13 (16)AE subtypes, No, (%)musculoskeletal73 (88)6 (8)neurological53 (64)2 (4)psychiatric38 (46)4 (11)gastrointestinal54 (65)11 (20)LFT elevation27 (33)5 (18)skin18 (22)2 (11)infection/fever26 (31)3 (12)respiratory23 (28)2 (9)cardiovascular13 (16)3 (23)metabolic16 (19)2 (13)neutropenia37 (45)21 (57)thrombocytopenia18 (22)a1 (6)anemia36 (43)1 (3)Autoimmune toxicity, No, (%)hepatitis1 (2.5)CNS vasculitis1 (2.5)lupus nephritis1 (2.3)Sjogren sy & dermatitis1 (2.5)Vascular AE (TEE/bleeding),Unprovoked6 (7)5 (83)No, (%)Provoked4 (5)3 (75)Disease transformation, No, (%)Myelofibrosis6 (7)AML1 (1)Safety over ≥24 months**Any gradeGrade≥3New AE, No (%)3th year10 (17)4 (40)4th year6 (11)4 (67)5th year5 (10)1 (20)≥ 6th year10 (24)1 (10)**Effective sample size for patients on therapy/year: Initial number of patients at risk at the beginning of period minus half of patients censored during that period*% calculated from 19 patientsastatistically significant differences by Fisher's exact testAbbr. CMR= complete molecular remission (undetectable JAK2 allele burden), PMR= partial molecular remission (>50% decrease in allele burden), mMR= minor molecular remission (20-49% decrease in allele burden) Figure 1. Figure 1. Disclosures Off Label Use: Pegylated Interferon alfa-2a used for patients with essential thrombocythemia and polycythemia vera. Cortes:Novartis: Consultancy, Research Funding; BerGenBio AS: Research Funding; Teva: Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding.

Final Results from PROUD-PV a Randomized Controlled Phase 3 Trial Comparing Ropeginterferon Alfa-2b to Hydroxyurea in Polycythemia Vera Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 475-475 ◽  
Author(s):  
Heinz Gisslinger ◽  
Christoph Klade ◽  
Pencho Georgiev ◽  
Aleksander Skotnicki ◽  
Liana Gercheva-Kyuchukova ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Research Funding ◽  
Thrombotic Event ◽  
Phase Iii ◽  
Prolonged Treatment ◽  
Molecular Response ◽  
Phase Ii Trials ◽  
Phase Iii Trial ◽  
Allele Burden ◽  
Randomized Controlled

Abstract Background: Interferon alfa (IFNa) based therapies have been successfully applied in myeloproliferative neoplasms (MPN) for over thirty years. Several uncontrolled phase II trials have independently shown high rates of hematologic, splenic and sustained mutant JAK2 molecular responses in Polycythemia vera (PV) patients. However, a head-to-head assessment versus other treatment options in confirmatory trials has been lacking so far. Here we report 12 month data from a randomized controlled phase III trial comparing the novel, long-acting Ropeginterferon alfa-2b (AOP2014) with hydroxyurea (HU) in PV patients. Study design: Randomized, controlled, parallel group multicenter phase III trial assessing efficacy, safety and tolerability in patients diagnosed with PV according to WHO2008 criteria, either naïve to cytoreduction or HU experienced (but neither intolerant nor complete responders, cumulative HU exposure max. 3 years). The primary endpoint was non-inferiority of AOP2014 vs. HU at 12 months of therapy in terms of complete hematological response (CHR) rate. CHR was defined as normal hematocrit, leukocyte and platelet counts, spleen size and absence of phlebotomy in the preceding 3 months. As important secondary endpoint the effect of treatment on mutant JAK2 allele burden was assessed as rate of complete and partial molecular response (C/PMR) rate according to modified ELN criteria. Both cohorts are followed up further maintaining the original randomization for assessing effects of prolonged therapy. Results: 257 patients were randomized in 48 sites in 13 European countries and treated with response-driven escalating doses of either AOP2014, or HU. 62% of patients were naïve to cytoreduction, 38% HU experienced; 19% had a previous thrombotic event. Response-driven dose escalation was done in both treatment arms applying up to 10 dose levels (50-500µg AOP2014 every other week, or 250-3000 mg HU daily). Both treatments were well tolerated. The drop-out rate after 12 months was low with ~15% in both arms, the majority of drop-outs were due to administrative reasons (bi-weekly hospital visits). This presentation will provide the detailed analysis of primary and secondary endpoints of the trial, which is still blinded as of 4th Aug 2016. Preliminary pooled analysis revealed that at 12 months 45% of patients had a hematologic response: mean Hct values dropped from 48% to 42%, leukocyte counts from 12 to 6 *109/L and platelets from 530 to 260 *109/L. Need for phlebotomy within 3 months dropped from 86% to 6%. 37% of patients achieved a JAK2 molecular response (PMR or CMR), mean mutant JAK2 allele burden went from 42,5% to 28,7%. Conclusions: This is the first phase III trial formally assessing efficacy, safety and tolerability of Ropeginterferon alfa-2b versus HU. Both cohorts are followed-up for prolonged treatment duration, and it is expected that the currently available and emerging data will establish the role of Ropeginterferon alfa-2b as first-line treatment for PV. Disclosures Gisslinger: AOP Orphan Pharmaceuticals AG, Novartis, Celgene, Baxalta: Consultancy, Honoraria, Research Funding. Klade:AOP Orphan: Employment. Georgiev:Alnylam Pharmaceuticals: Consultancy. Illes:University of Debrecen faculty of medicine department of hematology: Employment. Mayer:AOP Orphan Pharmaceuticals: Research Funding; Novartis: Research Funding. Grohmann-Izay:AOP Orphan Pharmaceuticals AG: Employment. Kralovics:AOP Orphan: Research Funding; Qiagen: Membership on an entity's Board of Directors or advisory committees. Kiladjian:Novartis: Research Funding; AOP Orphan: Research Funding.

scholarly journals Clonal Dynamics of JAK2V617F and Non-Driver Mutations in Polycythemia Vera and Essential Thrombocythemia Patients Receiving Hydroxyurea Therapy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3623-3623
Author(s):  
Lierni Fernández-Ibarrondo ◽  
Joan Gibert ◽  
Concepción Fernández-Rodríguez ◽  
Laura Camacho ◽  
Anna Angona ◽  
...  
Keyword(s):  
Dna Repair ◽  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Research Funding ◽  
Evolutionary Dynamics ◽  
Driver Mutations ◽  
Molecular Response ◽  
Increased Risk ◽  
Cytoreductive Treatment ◽  
Allelic Burden

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&lt;0.001), and displayed higher leukocyte count (p&lt;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.

scholarly journals JAK2V617F allele burden and thrombosis: A direct comparison in essential thrombocythemia and polycythemia vera

2009 ◽  
Vol 37 (9) ◽  
pp. 1016-1021 ◽  
Author(s):  
Alessandra Carobbio ◽  
Guido Finazzi ◽  
Elisabetta Antonioli ◽  
Paola Guglielmelli ◽  
Alessandro M. Vannucchi ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Allele Burden ◽  
Jak2v617f Allele Burden

SAR302503: Interim Safety, Efficacy and Long-Term Impact on JAK2 V617F Allele Burden in a Phase I/II Study in Patients with Myelofibrosis,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3838-3838 ◽  
Author(s):  
Animesh Pardanani ◽  
Jason Gotlib ◽  
Catriona Jamieson ◽  
Jorge E. Cortes ◽  
Moshe Talpaz ◽  
...  
Keyword(s):  
Platelet Count ◽  
Research Funding ◽  
Jak2 V617f ◽  
Intermediate Risk ◽  
Spleen Size ◽  
Safety And Efficacy ◽  
Allele Burden ◽  
Jak2v617f Allele Burden

Abstract Abstract 3838 Background: SAR302503 (SAR503, formerly TG101348), a potent, oral JAK2-selective inhibitor was studied in a Phase I/II trial for the treatment of patients with high- or intermediate-risk primary, post-polycythemia vera (PV) and post-essential thrombocythemia (ET) myelofibrosis (MF). SAR503 was administered orally once daily in 28-day cycles. Eligibility criteria included platelet count of ≥50 × 109/L. Interim safety and efficacy data from this study up to April 2010 have been previously published (JCO 2011, 29(7):789–796). The aim of this presentation is to report updated safety and efficacy of ongoing patients as well as an analysis of the JAK2V617F allele burden in this cohort. Results: Overall, 59 subjects (median age 64 years) were treated. Forty four patients had PMF, 12 post-PV MF and 3 post-ET MF; 86% were JAK2 V617F-positive. Median palpable spleen size was 18 cm at study enrollment. Twenty eight patients were treated in the dose-escalation cohort (30–800 mg administered as a single daily dose); thirty one patients were treated at the MTD (680 mg) in the dose confirmation cohort. 43/59 patients (73%) completed 6 cycles of treatment and continued treatment on the extension study. Currently, 22 patients (37%) remain on treatment with a median number of 28.5 cycles (24–41 range) and a median of last dose of 440 mg/day. Safety: Treatment-emergent toxicities in cycle 1–6 have been previously reported; toxicities were dose-dependent and generally alleviated with dose-reduction. Five patients discontinued treatment beyond cycle 6 for treatment-related adverse events: thrombocytopenia, depression, mental status changes, creatinine elevation and subdural hematoma. For the subgroup of patients with a baseline platelet count between 50–100 × 109/L (n =13; median 73, range 51–94); the platelet count at defined times points during follow up was: cycle 3; median 50, range 21–138 (p=0.09) and cycle 6; median 47, range 13–85 (p=0.01). Despite 7 of the 13 patients being treated at ≥680 mg/day, only 2 instances of Grade 4 thrombocytopenia were noted in this group Spleen response: As previously reported, spleen responses were seen early, usually within first 3 cycles, with half or more patients in each dose level ≥240 mg/day showing a durable ≥50% decrease in palpable spleen size. Spleen size (mean, median, range, and proportion with ≥50% reduction) at the following time points was: Baseline (n=58; 18.33cm, 18cm, 4–38cm, NA) ; 6 months (n=57; 9.05cm, 9cm, 0–30cm, 54.4%;) 12 months (n=42; 8.55cm, 9cm, 0–28cm, 66.7%) 18 months (n=36; 8.03cm, 8.5cm, 0–33cm, 52.8%); 24 months (n=31; 8.10cm, 8cm, 0–30cm, 54.8%,) 30 months (n=18; 6cm, 7.5cm, 0–16cm, 61.1%,and) 36 months (n=9; 5.89cm, 3cm, 0–16cm, 66.7%). JAK2V617F allele burden: We previously reported a significant decrease in JAK2V617F allele burden at the end of cycles 6 and 12. A durable decrease was also demonstrable after 24 cycles of treatment (n =21; median 9%, range 0–100%) relative to baseline (n =51; median 20%, range 3–100%) (p=0.03). Similarly, for patients with JAK2 V617F allele burden >20% at baseline; there was a significant decrease after cycle 24 (n =12; median 21%, range 6–100%) relative to baseline (n =23; median 60%, range 23–100%) (p=0.03). Conclusions: SAR503 is safe and efficacious treatment with long term effect on spleen size and JAK2V617F allele burden in patients with high- and intermediate-risk myelofibrosis. Additional follow up information will be updated at the time of meeting. Disclosures: Jamieson: Wintherix: Equity Ownership; Pfizer Oncology: Research Funding; Celgene: Research Funding; Novartis: Honoraria. Gao:Sanofi-Aventis: Employment. Zhang:Sanofi-Aventis: Employment. Neumann:Sanofi-Aventis: Employment.

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 ◽  
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 &gt;12G/L or immature granulocytes &gt;2% or erythroblasts &gt;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.

scholarly journals Phenotypes of JAK2-Mutated Polycythemia Vera and Essential Thrombocythemia with and without Thromboembolic Events: Results of the Hinc-207 (OSHO #91) Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 13-13
Author(s):  
Tony Hennersdorf ◽  
Nadja Jaekel ◽  
Susann Schulze ◽  
Dietrich Kaempfe ◽  
Claudia Spohn ◽  
...  
Keyword(s):  
Risk Factors ◽  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Research Funding ◽  
Thrombotic Event ◽  
Patient Questionnaire ◽  
Allele Burden ◽  
History Of ◽  
Group A ◽  
Group B

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&gt;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 &gt;60y was 90.4% vs. 89.2% for pts &lt;60y (p=0.8) and that of a thrombotic event &gt;3y after diagnosis in pts &gt;60y was 3.7% vs. 4.9% for pts &lt;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 &gt;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&lt;0.00) with A1. JAK2 allele burden (median 19%) and Hct &gt;45% (median 45%) at diagnosis correlated strongly with age &gt;60y (p=0.005) but not with A, A1, or A2, although Hct &gt;45% at diagnosis correlated with A2 in PV (p=0.001). Surprisingly, a Hct &gt;45% at thrombosis was more frequently present in A1 (55%) vs A2 (30%) (p&lt;0.00). Median WBC at diagnosis was higher in B compared to A (p=0.004), strongly associated with age &gt;60y (p&lt;0.00) but not with A2. WBC &gt;15% at thrombosis did not correlate with A. Age rather than thrombosis was the trigger for cytoreduction [82% hydroxyurea (HU) in B pts &gt;60y vs 53% in A pts &lt;60y] (p&lt;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 &gt;45%, high WBC, and JAK2 allele burden were associated with age &gt;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.

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

Blood ◽  
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.

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

Blood ◽  
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

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