scholarly journals Impact of JAK2V617F Mutation Burden on Disease Phenotype in Chinese Patients with JAK2V617F-positive Polycythemia Vera (PV) and Essential thrombocythemia (ET)

2016 ◽  
Vol 13 (1) ◽  
pp. 85-91 ◽  
Author(s):  
Shixiang Zhao ◽  
Xiang Zhang ◽  
Yang Xu ◽  
Yufeng Feng ◽  
Wenhong Sheng ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Jak2v617f Mutation ◽  
Chinese Patients ◽  
Disease Phenotype ◽  
Mutation Burden

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.

Survival and Prognosis of Chinese Patients with Post-Polycythemia Vera Myelofibrosis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1607-1607
Author(s):  
Jie Bai ◽  
Yuan Zhou ◽  
Lei Zhang ◽  
Mengyao Sheng ◽  
Rong Li ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Myeloid Leukemia ◽  
Platelet Count ◽  
Polycythemia Vera ◽  
Myeloid Leukemia ◽  
Jak2v617f Mutation ◽  
Chinese Patients ◽  
Kaplan Meier ◽  
Wbc Count ◽  
Acute Myeloid

Abstract Objective: Polycythemia vera (PV) is a chronic progressive myeloproliferative neoplasm (MPN) characterized by pancytosis, especially the overproduction of red blood cells (RBCs), which is often associated with thrombocytosis and leukocytosis. Post-polycythemia vera myelofibrosis (post-PV MF) is a critical hematologic evolution of PV. Up to 20% of patients with PV evolves into life-threatening myelofibrosis. The current study aims to determine the possible risk factors for the occurrence and prognosis of post-PV MF in Chinese patients with PV. Molecular genetic tests for JAK2V617F and Exon12 of JAK2 are highly informative in the progression of patients with PV. Recently, ASXL1 mutation has been proposed as a prognostic marker for risk stratification in patients with primary myelofibrosis (PMF). We, thus, evaluated the prognostic significance of JAK2V617F allele burden (V617F %) and the concomitant of JAK2 activating mutation and ASXL1 loss of function in the evolution of PV. Methods: The clinical characteristics of a large cohort of 590 PV Chinese patients were evaluated retrospectively to determine the possible risk factors for the occurrence and prognosis of post-PV MF in Chinese patients with PV. The existence of JAK2V617F mutation in mononuclear cells of PV patients was detected at diagnosis with nested allele-specific PCR. The mutation in Exon12 of JAK2 and ASXL1 were determined by Sanger sequencing, and V617F % were analyzed by Taqman Real-time PCR. Results: We have found that the 10-, 15-, and 20-year overall survival (OS) of PV was 89.3%, 75.9%, and 65%. The incidence of thrombosis, post-PV MF and acute myeloid leukemia (AML) was 75.0/1000 (95% CI: 66.3-83.9), 24.1/1000 (95% CI: 19.7-28.4), and 3.0/1000 (95% CI: 1.5-4.5) person/year, respectively. Up to 19.83% of PV patients (117 of 590) developed post-PV MF. The incidence of 10-, 15-, and 20-year post-PV MF transformation was 19.3%, 33.7%, and 49.3%, respectively. OS was much lower in patients with post-PV MF compared that in the general Chinese population matched by age, sex, and calendar year. Multivariate analyses revealed that splenomegaly, WBC count >13 x 109 /L, and platelet count >550 x 109/L were independently associated with post-PV MF transformation. In the 117 patients with post-PV MF, 13 developed acute myeloid leukemia (AML), and the 5-year leukemia-free survival after diagnosis of post-PV MF was 87.4%. The results of multivariate Cox regression analysis showed that platelet count <100 × 109/L and patient age >65 years were independent risk factors for disease transformation into AML in patients with post-PV MF. Of the 346 patients with PV screened for JAK2V617F mutation, 273 patients were found to carry the JAK2V617F allele. The V617F % was examined in 104 patients with adequate DNA samples, and the median V617F% was 81.9% and 32.5% for patients with and without post-PV MF, respectively (p < 0.001). Kaplan-Meier analysis showed that myelofibrosis-free-surviva (MFS) was significantly reduced in PV patients with V617F % ≥50% compared with patients with V617F % <50% or no JAK2V617F mutation. Thirteen patients were found to carry ASXL1 mutation among 95 patients screened ASXL1 mutation, and all of these 95 patients were divided into four groups based on V617F% and the status of ASXL1 mutation: V617F % ≥50% with mutant ASXL1 (n=12), V617F % ≥50% with wt ASXL1 (n=48); V617F %<50% with mutant ASXL1 (n=1), and V617F %<50% with wt ASXL1 (n=32). By Kaplan-Meier analysis across all four groups, patients with both V617F % ≥50% and ASXL1 mutation had the worst MFS rates, with a 5-year MFS rate of 75.0%. Conclusion: PV has a higher incidence of progression to post-PV MF in Chinese patients. The risk factors for post-PV MF transformation included WBC count >13 x 109/L, platelet count >550×109/L and splenomegaly at diagnosis of PV. Anemia (Hg <100 g/L) and age >65 years at diagnosis of post-PV MF were identified as significant risk factors for poor survival of patients with post-PV MF. MFS was significantly lower in patients with V617F % ≥50% than in patients with V617F % <50%, and patients carried both V617F % ≥50% and ASXL1 mutation had the worst MFS rate. Disclosures No relevant conflicts of interest to declare.

The Jak2V617F mutation, PRV-1 overexpression, and EEC formation define a similar cohort of MPD patients

Blood ◽  
2005 ◽  
Vol 106 (8) ◽  
pp. 2862-2864 ◽  
Author(s):  
Philipp S. Goerttler ◽  
Cordula Steimle ◽  
Edith März ◽  
Peter L. Johansson ◽  
Björn Andreasson ◽  
...  
Keyword(s):  
Molecular Markers ◽  
Polycythemia Vera ◽  
Dna Sequence ◽  
Essential Thrombocythemia ◽  
Myeloproliferative Disorder ◽  
Janus Kinase ◽  
Jak2v617f Mutation ◽  
Idiopathic Myelofibrosis ◽  
Polycythemia Rubra Vera ◽  
Highly Correlated

AbstractRecently, a Jak2V617F mutation has been described in the vast majority of patients with polycythemia vera (PV) as well as in subsets of patients with essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF). The question arises whether this mutation is observed in those patients with ET and IMF who have also displayed previously described molecular markers, notably the ability to form endogenous erythroid colonies (EECs), overexpression of polycythemia rubra vera 1 (PRV-1), and decreased c-Mpl expression. We therefore analyzed the Janus kinase 2 (Jak2) DNA sequence, EEC growth, PRV-1 expression, and c-Mpl (myeloproliferative) levels in a cohort of 78 myeloproliferative disorder (MPD) patients (42 ET, 22 PV, and 14 IMF). Presence of the Jak2V617F mutation was very highly correlated with PRV-1 overexpression and the ability to form EECs in all 3 subtypes of MPDs (P &lt; .001). (Blood. 2005;106:2862-2864)

JAK2V617F mutation and hydroxyurea treatment as determinants of immature platelet parameters in essential thrombocythemia and polycythemia vera patients

Blood ◽  
2011 ◽  
Vol 118 (9) ◽  
pp. 2599-2601 ◽  
Author(s):  
Marina Panova-Noeva ◽  
Marina Marchetti ◽  
Sabrina Buoro ◽  
Laura Russo ◽  
Annamaria Leuzzi ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Myeloproliferative Neoplasms ◽  
Jak2v617f Mutation ◽  
Favorable Effect ◽  
Thrombotic Risk ◽  
Mutational Status ◽  
Hydroxyurea Treatment ◽  
Increased Risk ◽  
Hydroxyurea Therapy

Abstract Immature platelets (IPFs), which are hemostatically more active than mature platelets, have been found elevated in essential thrombocythemia and polycythemia vera, 2 myeloproliferative neoplasms (MPN) characterized by an increased risk of thrombosis. It is not known whether the IPF levels are influenced by pathogenetic factors, including JAK2V617F mutational status, or by treatment regimen. To address this point, in 46 essential thrombocythemia and 38 polycythemia vera consecutive patients, we measured IPF and correlated the results to JAK2V617F mutation and myelosuppressive treatment with hydroxyurea. This analysis provides 2 new elements regarding IPF and MPN. The first finding is that the JAK2V617F mutation is linked to the quantity of IPF in patients with MPN, which might contribute to the prothrombotic phenotype in these patients. The second finding is that IPF is susceptible to myelosuppressive treatment, which may additionally explain the favorable effect of hydroxyurea therapy on MPN outcome as well as the associated thrombotic risk.

Selective Targeting of the JAK2V617F Mutation in Polycythemia Vera and Essential Thrombocythemia by ITF2357, a Novel Histone Deacetylase Inhibitor.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 555-555 ◽  
Author(s):  
Vittoria Guerini ◽  
Valentina Barbui ◽  
Orietta Spinelli ◽  
Anna Salvi ◽  
Chiara Dellacasa ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Progenitor Cells ◽  
Histone Deacetylase ◽  
Essential Thrombocythemia ◽  
Colony Formation ◽  
Mononuclear Cells ◽  
Jak2v617f Mutation ◽  
Wild Type ◽  
Blood Mononuclear Cells ◽  
Hel Cells

Abstract A somatic point mutation in the JAK2 gene (JAK2V617F) is the key pathogenetic lesion of Polycythemia Vera (PV) and Essential Thrombocythemia (ET) and a significant effort is now paid to identify drugs which may be able to interfere with the JAK2V617Fmutated protein. Among others, one potentially interesting drug family is represented by the Histone Deacetylase Inhibitors (HDACi), which may modify the chromatin structure and ultimately the transcription of many genes, the cell cycle progression and the programmed cell death. ITF2357 is a new HDACi (Italfarmaco, Milan, SpA) that shows a potent anti-proliferative and pro-apoptotic activity against acute myeloid leukemia and multiple myeloma cells and little toxicity against normal hematopoietic and mesenchymal stem cells (Golay J et al.: Leukemia 2007). The most common side effects after its administration to normal volounteers and MM patients are represented by thrombocytopenia and gastrointestinal toxicity. These observations prompted us to investigate the inhibitory activity played by ITF2357 on the autonomous proliferation of cells obtained by PV and ET patients carrying the JAK2V617F mutation and to elucidate the mechanism of action of this inhibition. We first investigated the effect of ITF2357 on the clonogenic activity of cell lines carrying or not the JAK2V617F mutation. ITF2357 inhibited colony formation of HEL cells (an erythroleukemia cell line carrying a JAK2V617F homozygous mutation) with an IC50 of about 0.001 μM. In contrast, the doses of drug required to block colony formation by K562, KG1, NB4 and GF-D8 (all negative for the JAK2V617F mutation) were 100–500 fold higher (IC50 ranging from 0.1 to 0.5 μM). Clonogenic assays were then performed using blood mononuclear cells obtained from 4 PV and 7 ET patients, all carrying the JAK2V617F mutation. Either in the presence or absence (EEC assay) of exogenous growth factors, colonies obtained from JAK2V617F mutated progenitor cells were inhibited at much lower doses of ITF2357 (IC50 0.001 μM) as compared to colonies obtained from JAK2 wild type progenitor cells (IC50 0.1–0.25 μM). When single colonies were picked randomly and analyzed by PCR for the presence of wild type or mutated JAK2V617F alleles, a striking reduction of mutated colonies was detected when ITF2357 was added at 0.001 μM and 0.01 μM, confirming that low doses of ITF357 allow the preferential outgrowth of unmutated over mutated colonies from the peripheral blood mononuclear cells of PV patients bearing JAK2V617F. By Western blotting we also showed that ITF2357 treatment for 24 hours, led to virtual disappearance of total and phosphorylated JAK2V617F in HEL cells whereas it did not affect the wild type JAK2 protein in the control K562 cell line, even after 48 hours in the same conditions. Down-modulation of mutated JAK2V617F was accompanied by specific disappearance of p-STAT5 protein. Finally, by Real time PCR analysis of PV cells treated with ITF2357 for 24 hours, we could demonstrate that this drug does not affect JAK2 mRNA but rather it induces a significant decrease of the PRV1 gene, a known JAK2 target. These data suggest that ITF2357 down-modulates the mutated JAK2V617F protein by post-transcriptional mechanisms and that is followed by inhibition of p-STAT5 protein and PRV1 gene expression. The specific inhibition induced by ITF2357 on cells bearing the JAK2V617F mutation underlines its therapeutic potential as a new drug for PV and ET patients.

High-Resolution SNP 6.0 Array Profiling Discloses Novel Genomic Aberrations in Polycythemia Vera and Essential Thrombocythemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1898-1898
Author(s):  
Marta Anna Sobas ◽  
Teresa Gonzalez ◽  
Manuel Perez-Encinas ◽  
Celsa Quinteiro ◽  
Jose Diaz ◽  
...  
Keyword(s):  
High Resolution ◽  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Analytical Data ◽  
Snp Array ◽  
Jak2v617f Mutation ◽  
Molecular Material ◽  
Genomic Aberrations

Abstract Abstract 1898 Poster Board I-921 Introduction: JAK2V617F mutation is detected in more than 90% of cases of polycythemia vera (PV) and in about 50% of cases of essential thrombocythemia (ET). Recently, JAK2-exon 12 and MPL mutations have been reported in myeloproliferative neoplasms (MPN). All these three mutations have a disease causing potential. There are still 50% of ET and PMF patients negative for JAK2V617F mutation. Thus, further genetic analysis to identify novel disease-related aberrations in MPN is required. Methods: We performed whole genome analysis on granulocytic DNA of 45 MPN patients (19 PV and 26 ET) using the single nucleotide polymorphism (SNP) Array 6.0 platform [Affymetrix 6.0]. Genotypes were analyzed using Genotyping Console 3.0.2. Data were normalized against a commercial and an own set of reference samples. All patients had JAK2V617F screening performed. Clinical and analytical data and results of cytogenetics study performed at diagnosis of MPN were colected from clinical reports. Results: From 45 MPN patients, 41 had normal cytogenetics at diagnosis; there were no data concerning cytogenetics study from the rest 4 patients. Using SNP-A 6.0 platform, we detected aberrations (gain or loss of the molecular material) in the following regions: 1q12, 9p1, 17q21, 4q, 3q26 and 8p12. Aberrations in a region 1q12 (n=14) were presented in 8 of PV (gain in 3 and loss in 5) and in 6 of ET (gain in 2 and loss in 4) patients. Aberrations in a region 9p1 (n=27) were observed in 11 of PV (gain in 6 and loss in 5) and in 16 of ET (gain in 10 and loss in 6) patients. Aberrations in a region 17q21 (n=26) were presented in 11 of PV (gain in 3 and loss in 8) and in 15 of ET (gain in 9 and loss in 6) patients. Aberrations in the region 4q (n=20) were detected in 8 of PV (gain in 5 and loss in 3) and in 12 of ET (gain in 9 and loss in 3) patients. Interestingly, only the gain of the molecular material was detected in a region 3q26 (n=12; 5 PV and 7 ET patients). In case of aberration in a region 8p12 (n=20), all 12 ET patients presented gain of the molecular material, whereas PV patients had gain (n=3) or loss (n=3) of the molecular material. There were no relation between the presence of these aberrations and the status of the JAK2V617F mutation, analytical data or clinical outcome of the patients. Conclusions: 1. As we know, patients with ET have low frequency of cytogenetics aberrations. Nevertheless, using SNP-A 6.0 platform [Affymetrix 6.0], it is possible to detect new genomic aberrations in these group of patients. 2. According to our results, gain in 8p12 region is especially related to ET patients. Recently has been reported that, in a 8p12 region there is localized gen INDOL1 that, may be involved in the inhibition of immune response to tumours. 3. Gain in a 3q26 region can be related with both PV and ET. In this region, there are localized two microRNA: hsa-mir-1263 and has-mir-720. 4. SNP-A 6.0 technology should not replace conventional cytogenetics in study of MPN patients. However, SNP-A 6.0 platform, as a high resolution assay, can be useful in identification of new genomic abnormalities that may be relevant for pathogenesis of MPN. Disclosures: No relevant conflicts of interest to declare.

Efficiency of interferon therapy in patients with essential thrombocythemia or polycythemia vera

2016 ◽  
Vol 88 (12) ◽  
pp. 69-77
Author(s):  
M A Sokolova ◽  
A G Turkina ◽  
A L Melikian ◽  
A B Sudarikov ◽  
S A Treglazova ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Mutant Gene ◽  
Jak2v617f Mutation ◽  
Relative Reduction ◽  
Molecular Response ◽  
Morphological Pattern ◽  
Recombinant Interferon ◽  
Long Term Treatment

Aim. To evaluate the efficiency of interferon (IFN) therapy in patients with essential thrombocythemia (ET) and polycythemia vera (PV). Subjects and methods. A total of 61 patients (41 with ET and 20 with PV) were examined. Prior to study enrolment, 44 (72%) patients with ET or PV received one or other therapy (aspirin was not taken into account). The mean Jak2V617F mutant allele at baseline was 23% (6—54%) in the patients with ET and 40% (11—88%) in those with PV. The median time from diagnosis to enrollment was 49 months. Results. The paper presents the clinical and molecular findings of long-term INF-α therapy in patients with ET or PV. The median follow-up was 52 months. Recombinant IFN-α2 showed its ability to induce complete hematologic remission (ET (76%), PV (70%)) and a complete molecular response. 22 (69%) out of 32 patients were noted to have a smaller number of cells with the Jak2V617F mutation. In the patients with PV and in those with ET, the relative reduction in the proportion of cells with the Jak2V617F mutant gene averaged 85% and 56% of the baseline values, respectively. There was a reduction in the proportion of cells expressing the Jak2V617F mutation in both the ET (from 12 to 2.2%; p=0.001) and PV (from 32.7% to 3.2%) groups (р=0.001). Ten (31%) patients achieved a deep molecular remission (≤2% Jak2V617F allele); among them, 5 patients were not found to have Jak2V617F mutation. The obtained molecular response remained in 7 of the 10 patients untreated for 11 to 86 months. The long-term treatment with IFN-α led to normalization of the morphological pattern of bone marrow in 5 of the 7 PV or ET patients. Conclusion. Significant molecular remissions achieved by therapy with recombinant interferon-α2 confirm the appropriateness of this treatment option in in the majority of patients with ET or PV.

Sign in / Sign up

Export Citation Format

Share Document