scholarly journals Familial polycythemia vera with non-germ line JAK2V617F mutation sparing the abnormal and clonal granulopoiesis

Leukemia ◽  
2007 ◽  
Vol 21 (12) ◽  
pp. 2566-2568 ◽  
Author(s):  
K Hussein ◽  
O Bock ◽  
M Ballmaier ◽  
G Göhring ◽  
D Steinemann ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Germ Line ◽  
Jak2v617f Mutation

scholarly journals Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms

Blood ◽  
2010 ◽  
Vol 115 (15) ◽  
pp. 3109-3117 ◽  
Author(s):  
Alfonso Quintás-Cardama ◽  
Kris Vaddi ◽  
Phillip Liu ◽  
Taghi Manshouri ◽  
Jun Li ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Interleukin 6 ◽  
Myeloproliferative Neoplasms ◽  
Primary Cultures ◽  
Myeloproliferative Neoplasm ◽  
Primary Myelofibrosis ◽  
Experimental Models ◽  
Jak2v617f Mutation ◽  
Erythroid Progenitor ◽  
Therapeutic Implications

AbstractConstitutive JAK2 activation in hematopoietic cells by the JAK2V617F mutation recapitulates myeloproliferative neoplasm (MPN) phenotypes in mice, establishing JAK2 inhibition as a potential therapeutic strategy. Although most polycythemia vera patients carry the JAK2V617F mutation, half of those with essential thrombocythemia or primary myelofibrosis do not, suggesting alternative mechanisms for constitutive JAK-STAT signaling in MPNs. Most patients with primary myelofibrosis have elevated levels of JAK-dependent proinflammatory cytokines (eg, interleukin-6) consistent with our observation of JAK1 hyperactivation. Accordingly, we evaluated the effectiveness of selective JAK1/2 inhibition in experimental models relevant to MPNs and report on the effects of INCB018424, the first potent, selective, oral JAK1/JAK2 inhibitor to enter the clinic. INCB018424 inhibited interleukin-6 signaling (50% inhibitory concentration [IC50] = 281nM), and proliferation of JAK2V617F+ Ba/F3 cells (IC50 = 127nM). In primary cultures, INCB018424 preferentially suppressed erythroid progenitor colony formation from JAK2V617F+ polycythemia vera patients (IC50 = 67nM) versus healthy donors (IC50 > 400nM). In a mouse model of JAK2V617F+ MPN, oral INCB018424 markedly reduced splenomegaly and circulating levels of inflammatory cytokines, and preferentially eliminated neoplastic cells, resulting in significantly prolonged survival without myelosuppressive or immunosuppressive effects. Preliminary clinical results support these preclinical data and establish INCB018424 as a promising oral agent for the treatment of MPNs.

Loss of Wild-Type Jak2 Allele Enhances Myeloid Cell Expansion and Accelerates Myelofibrosis in Jak2V617F Knock-in Mice

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 809-809
Author(s):  
Hajime Akada ◽  
Saeko Akada ◽  
Dongqing Yan ◽  
Robert Hutchison ◽  
Golam Mohi
Keyword(s):  
Polycythemia Vera ◽  
Cell Expansion ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Philadelphia Chromosome ◽  
Myeloid Cell ◽  
Negative Regulator ◽  
Jak2v617f Mutation ◽  
Common Mutation ◽  
Wild Type

Abstract Abstract 809 The activating JAK2V617F mutation is the most common mutation found in Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs), which include polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). Although a majority of MPN patients carry heterozygous JAK2V617F mutation, loss of heterozygosity (LOH) on chromosome 9p involving JAK2 has been observed in ∼30% of patients with MPNs particularly in PV and PMF. JAK2V617F homozygosity through 9pLOH has been linked to more severe MPN phenotype. However, the contribution of 9pLOH in the pathogenesis of MPNs remains unclear. To investigate the role of wild-type JAK2 in MPNs induced by JAK2V617F, we have utilized conditional Jak2 knock-out and Jak2V617F knock-in alleles and generated heterozygous, hemizygous and homozygous Jak2V617F mice. Whereas heterozygous Jak2V617F expression results in a polycythemia vera-like disease in mice, loss of wild-type Jak2 allele in hemizygous or homozygous Jak2V617F mice results in a significantly greater increase in reticulocytes, white blood cells, neutrophils and platelets in the peripheral blood and larger spleen size. We also have found that hemizygous or homozygous Jak2V617F expression significantly increased megakaryocyte-erythroid progenitors in the bone marrow and spleens and marked infiltration of neutrophils in the liver compared with heterozygous Jak2V617F. More importantly, hemizygous or homozygous Jak2V617F mice show accelerated myelofibrosis compared with heterozygous Jak2V617F-expressing mice. Thus, loss of wild type Jak2 allele increases myeloid cell expansion and enhances the severity of the MPN. Together, these results suggest that wild-type Jak2 serves as a negative regulator of MPN induced by Jak2V617F. Disclosures: No relevant conflicts of interest to declare.

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.

Successful Treatment of HU-Refractory Polycythemia Vera with Atorvastatin and Low Dose Hydroxyurea. Results from a Pilot Study in Bolivia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5621-5621
Author(s):  
Ricardo Amaru ◽  
Ariel Amaru ◽  
Hortensia Miguez ◽  
Gina Torres ◽  
Josue Mamani ◽  
...  
Keyword(s):  
Pilot Study ◽  
High Risk ◽  
Polycythemia Vera ◽  
Mononuclear Cells ◽  
Jak2v617f Mutation ◽  
World Health ◽  
La Paz ◽  
Healthy Donors

Abstract Background Polycythemia Vera (PV) is a clonal myeloproliferative neoplasm, characterized by the JAK2V617F mutation. The main goal of current therapies for PV is to prevent thrombotic events and delay transformation to Myelofibrosis (MF) or Acute Myeloid Leukemia (AML).Treatment for PV to keep an hematocrit (Hct) level <45 %, has been associated with a reduction in cardiovascular deaths and thrombotic events (Marchioli, R et al. NEJM 2013). Currently, low-risk PV patients (<60 years and no previous thrombotic events) are treated with aspirin and phlebotomy while high-risk patients require additional cytoreductive therapy, usually with Hydroxyurea (HU). Resistance to HU is associated with an increased risk of transformation and reduced survival. This is why for HU-refractory patients, second line treatments with interferon alpha, anagrelide or even ruxolitinib are recommended. In Latin America, because of high cost and drugs availability, this last group reflects difficulties to be treated. Because statins have been reported to modulate the erythroid clonogenic activity of normal BM erythroid colonies we performed a pilot study to investigate in vitro and in vivo the biologic and clinical activity of atorvastatin in PV patients Patients and Methods Ten high risk PV patients with a median age of 64.3 years (range 58-73) entered into this study. The diagnosis of PV was done according to the 2008 World Health Organization diagnostic criteria and patients were stratified according to an algorithm proposal provided by Griesshammer et al. (Ann Hematol, 2015). The definition of HU resistance (Barosi, G et al.: BJH 2009) was applicable to five patients (median age 63.9 years) failing to achieve a satisfactory hematologic response upon treatment with more than 2 g of HU, 100 mg of Aspirin and phlebotomies. The assessment of the JAK2V617F mutation was performed as previously described (Guerini et al.: Leukemia 2009). Colony assay, proliferation and apoptosis tests were performed with or without Simvastatin (3.5 uM), as previously described (Amaru, A, Experimental Hematology 2012), on cell lines (UKE1 and K562) and bone marrow mononuclear cells obtained from PV patients and healthy donors. Patients with HU refractory PV (n=5) and high risk PV with hypercholesterolemia (n=5) were eligible to receive Atorvastatin (20 mg/day) added on the top of the ongoing treatment with phlebotomies, Aspirin (100 mg/day) and cytoreductive HU therapy (500 mg/day). All treated patients were high altitude residents (> 3.600 m.a.s.l.) of La Paz (Bolivia) where the normal Hct level of healthy subjects is 48-57% for men and 44-54% for women. This pilot study was approved by the Review Board of the Hospital and the University of San Andres, La Paz. Results In a preliminary set of in vitro proliferation cell assays, simvastatin (3.5 uM), added for 5 days, induced a 33% inhibition of cell proliferation of UKE-1 (JAK2V617F mutated) as compared to 5 % of K562 (BCR/ABL positive). A comparable result was obtained in a 7-day clonogenic cell assay where the colony inhibition was 50 % for UKE-1 and 10 % for K562. On the basis of these results similar experiments were also performed using BM mononuclear cells derived from PV patients and healthy donors. In these experiments performed with the addition of simvastatin, it induced a 41% of inhibition in BFU-E colonies of PV patients and a 25% of inhibition in healthy donors. Furthermore, BFU-E colonies inhibited by simvastatin presented a decrease in hemoglobinization and the size of colonies. HU refractory PV patients and High-risk PV patients with hypercholesterolemia treated with the addition of Atorvastatin, Aspirin, cytoreductive HU and phlebotomies; after a follow-up of 2.6 years (1-7 years), induced a decrease of WBC from 16.500 to 9.270/ul, Hct 61.1 to 52.3% and PLT 457.900,000 to 324.7000/ul. The number of required phlebotomies is reduced in comparison to the required at starting treatment. None of the patients presented thrombotic or cardiopulmonary event. One patient died within two years of starting treatment, due to complications of diabetes mellitus. Conclusions In vitro and in vivo, statins showed some evidence of inhibitory activity of the hematopoiesis of PV patients. These preliminary results might indicate the opportunity to further investigate the potential clinical value of these molecules in the treatment of PV. Disclosures Off Label Use: Atorvastatin was used for its antiproliferative activity on myeloid progenitor cells shown by in vitro experiments.

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)

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