Faculty Opinions recommendation of A phase 1 study of the Janus kinase 2 (JAK2)V617F inhibitor, gandotinib (LY2784544), in patients with primary myelofibrosis, polycythemia vera, and essential thrombocythemia.

2018 ◽  
Author(s):  
William Vainchenker ◽  
Isabelle Plo
Keyword(s):  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Phase 1 ◽  
Jak2 V617f ◽  
Primary Myelofibrosis ◽  
Janus Kinase ◽  
Janus Kinase 2 ◽  
Phase 1 Study

A Phase I Study of XL019, a Selective JAK2 Inhibitor, in Patients with Primary Myelofibrosis, Post-Polycythemia Vera, or Post-Essential Thrombocythemia Myelofibrosis

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 98-98 ◽  
Author(s):  
Neil P. Shah ◽  
Patrycja Olszynski ◽  
Lubomir Sokol ◽  
Srdan Verstovsek ◽  
Ronald Hoffman ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Jak2 V617f ◽  
Primary Myelofibrosis ◽  
Reversible Inhibitor ◽  
Hematologic Toxicity ◽  
Low Grade ◽  
Costal Margin ◽  
Spleen Size ◽  
Activating Mutation

Abstract JAK2 V617F has been identified as a constitutive activating mutation in approximately half of patients with myelofibrosis (MF). MF, a myeloproliferative disorder comprised of primary myelofibrosis and the clinically indistinguishable entities of post-polycythemia vera or post essential thrombocythemia MF, has been reported to have a median survival of 4 years [Dupriez et al. (1996) Blood88:1013–18]. No effective therapies exist for patients with MF. XL019 is a potent, highly selective and reversible inhibitor of JAK2 which may have utility in treating MF, by ameliorating hepato-splenomegaly, constitutional symptoms, and progressive anemia. The objectives of this phase 1 study include safety evaluation, preliminary assessments of efficacy using International Working Group (IWG) response criteria for MF, and evaluation of pharmacokinetic and pharmacodynamic endpoints. Pharmacodynamic evaluations include quantitative PCR for peripheral blood JAK2 V617F allele burden and erythropoietin-independent colony formation. In addition, plasma and fixed blood samples are being collected to evaluate changes in protein biomarkers and JAK2 signaling pathways. To date, XL019 has been studied in 21 patients over multiple dose levels ranging from doses of 25 mg to 300 mg using different schedules of administration (3 weeks on, 1 week off; QD; and QMWF). Median age was 64 years (range, 47–87 years) and 16 patients (76%) carried the JAK2V617F mutation. Additionally, one patient had a MPLW515F mutation in the absence of a JAK2 mutation. No treatment-related hematologic adverse events (i.e. thrombocytopenia, anemia, neutropenia) have been observed to date. Reversible low-grade peripheral neuropathy (PNP) was observed in 7/9 patients treated at daily doses of ≥100 mg (Grade 1: 5 patients; Grade 2: 2 patients). XL019 doses below 100 mg using 2 different dosing schedules are currently being evaluated. To date, XL019 has resulted in reductions in splenomegaly and leukocytosis, stabilization of hemoglobin counts, improvements in blast counts, and resolution or improvement in generalized constitutional symptoms. The median spleen size in 15 patients measured below the costal margin by palpation was 14cm (range, 3–26cm). Three of 15 patients with palpable splenomegaly at baseline were JAK2 V617F mutation negative and did not experience spleen size reduction. Twelve of 12 (100%) evaluable patients with an activating mutation (JAK2 V617F: 11 patients; MPLW515F: 1 patient) experienced reduction in spleen size and 5 (42%) had a ≥50% decline from baseline. Ten of 11 patients with JAK2V617F activating mutations and baseline constitutional symptoms, reported improvements in generalized constitutional symptoms which include pruritus and fatigue. No significant non-hematologic or hematologic toxicity has been observed at the current dose level. On 25 mg dosing schedules, no signs of PNP have been observed with a follow-up period of up to 4 months. Overall, XL019 has demonstrated encouraging clinical activity and is generally well tolerated.

JAK2 Mutation Status in Granulocytes, Platelets and Erythrocytes Differs Between Polycythemia Vera and Essential Thrombocythemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5228-5228
Author(s):  
Kohtaro Toyama ◽  
Norifumi Tsukamoto ◽  
Akio Saito ◽  
Hirotaka Nakahashi ◽  
Yoko Hashimoto ◽  
...  
Keyword(s):  
T Cells ◽  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Mononuclear Cells ◽  
Rna Extraction ◽  
Jak2 V617f ◽  
Janus Kinase ◽  
Jak2 V617f Mutation ◽  
Mutation Status ◽  
V617f Mutation

Abstract Background The gain-of-function point mutation in Janus kinase 2 exon 14 gene (JAK2-V617F) influences the diagnosis of bcr/abl-negative chronic myeloproliferative disorders (CMPDs). We previously reported that analyzing platelets is advantageous in detecting the JAK2-V617F mutation, particularly in essential thrombocythemia (ET), when compared to granulocytes. However, there have been few reports analyzing the JAK2-V617F mutation in erythroid lineage cells, and comparing the mutation status in all three lineages. Method Study protocols were approved by the Institutional Review Board of Gunma University Hospital, and written informed consent was obtained from all the patients. Heparinized peripheral blood was obtained from 113 patients with CMPDs (82 with ET, 25 with polycythemia vera (PV), and 6 with primary myelofibrosis (PMF). After centrifugation, platelets were collected from the upper plasma layer. Remaining blood was mixed with Hank’s Balanced Salt Solution and was subjected to Ficoll-Hypaque density gradient centrifugation. Granulocytes were obtained from the pellet. Mononuclear cells were resuspended in RPMI 1640 medium; 5 × 105 cells were plated in duplicate in 1 ml of methylcellulose medium and cultured in a humidified atmosphere of 5 % of carbon dioxide at 37°C for 14 days in the presence of erythropoietin to obtain erythroid colonies (BFU-E). T-cells were obtained from the remaining mononuclear cells using anti-CD3 immunoconjugated magnetic beads. After extraction of DNA from granulocytes, T-cells and BFU-E, and RNA extraction from granulocytes and platelets, PCR amplification and sequencing of exon 14 of the Jak2 gene was performed to confirm the presence of JAK2-V617F mutations. To confirm the mutation status of granulocytes, T-cells and BFU-E, allele-specific PCR (AS-PCR) was performed. Results For ET, 57 out of 82 patients (69.5%) had the JAK2-V617F mutation. In the 57 patients with the JAK2-V617F mutation, 38 (67%) had the mutation in all three lineages, 5 had the mutation in granulocytes and platelets, 2 had the mutation in platelets and BFU-E, 10 patients had the mutation only in platelets and 2 patients had the mutation only in BFU-E. In contrast, for PV, 22/25 patients (88%) had the JAK2-V617F mutation. Of note, in 22 patients having JAK2-V617F mutation, 20 (91%) were JAK2-V617F mutation-positive in all three lineages; the remaining two patients had the mutation in either platelets or BFU-E. The frequency of JAK2-V617F in all three lineages was significantly higher in PV than in ET (p < 0.05). For PMF, 5 of 6 patients had the mutation in granulocytes, and 3 of these had it in all three lineages. Conclusion Among JAK2-V617F mutation-positive CMPDs, most PV patients had the JAK2-V617F mutation in all three lineages, thus suggesting that the JAK2-V617F mutation occurs in progenitor cell(s) common to granulocytes, platelets and erythrocytes. In contrast, only 67% of ET patients had the JAK2-V617F mutation in three lineages; in the remaining cases, not all of the three lineages have the mutation. This difference in lineages showing the JAK2-V617F mutation between the ET and PV may be related to the pathophysiological differences in ET and PV. Furthermore, the heterogeneous mutation status in ET may be related to its heterogeneous clinical manifestation.

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 >12G/L or immature granulocytes >2% or erythroblasts >1%; anemia or thrombocytopenia not related to treatment toxicity; development or progressive splenomegaly; thrombocytosis on cytoreductive therapy; inadequate control of the patient's condition using the treatment (defined by at least one treatment change for reasons other than an adverse event). Results As expected, the JAK2 V617F mutation was found in all patients with the use of NGS. In addition, we found 27 other mutations in 10 genes out of the 18 genes studied by NGS (mean 0.54 mutations per patient). Overall, 29 of 50 patients had only the JAK2 V617F mutation and no other mutation in any of the genes analysed. No CALR mutation was detected. Nine mutations that were not previously described in myeloid malignancies were found. The genes involved in the epigenetic regulation were those most frequently mutated: TET2, ASXL1, IDH1, IDH2 and DNMT3A. In particular, TET2 mutations were the most frequent and occurred in 20% of cases. There was no difference in the number or in the presence of mutations between PV and ET. At 3y, 4 mutations appeared in 4 patients and 15 out of 50 patients (9 PV and 6 ET) were affected by an allele burden increase of at least one mutation. At 3y, 24/50 patients suffered an aggravation of the disease as defined by the primary outcome criterion (16 PV and 8 ET). The presence of a mutation (JAK2 V617Fomitted) at the time of the diagnosis was significantly associated with the aggravation of the disease (p=0.025). Retaining only mutations with an allele burden greater than 20%, the association with disease aggravation is more significant (p=0.011). Moreover, a mutation of ASXL1, IDH1/2 or SRSF2, which is a poor prognostic factor in primary myelofibrosis, was found in 8 patients, all having presented an aggravation of their disease (p=0.001). Only 4 patients had more than one somatic mutation other than JAK2 V617F and all of them also had an aggravation at 3y (p=0.046). In this cohort, appearance of a mutation at 3y was not associated with the course of the disease. Conversely, the increase of allele burden of at least one mutation was associated with an aggravation (p=0.019). Discussion and conclusion Despite the short follow-up and the limited number of patients, this study suggests that the presence of additional mutations at the time of the diagnosis in PV and TE is correlated to a poorer disease evolution. The increase of mutation allele burden, which reflects clonal evolution, also seems to be associated with the course of the disease. These results argue for a clinical interest in large mutation screening by NGS at the time of the diagnosis and during follow-up in ET and PV. Disclosures Ugo: Novartis: Membership on an entity's Board of Directors or advisory committees, Other: ASH travel.

scholarly journals Vitamin D Deficiency and Janus kinase 2 V617F Mutation Status in Essential Thrombocythemia and Polycythemia Vera

2020 ◽  
Vol 27 (1) ◽  
pp. 70-77
Author(s):  
Aysun Şentürk Yikilmaz ◽  
◽  
Sema Akinci ◽  
Şule Mine Bakanay ◽  
İmdat Dilek ◽  
...  
Keyword(s):  
Vitamin D ◽  
Polycythemia Vera ◽  
Vitamin D Deficiency ◽  
Essential Thrombocythemia ◽  
Janus Kinase ◽  
Janus Kinase 2 ◽  
Mutation Status ◽  
V617f Mutation

From Janus kinase 2 to calreticulin: the clinically relevant genomic landscape of myeloproliferative neoplasms

Blood ◽  
2014 ◽  
Vol 123 (24) ◽  
pp. 3714-3719 ◽  
Author(s):  
Mario Cazzola ◽  
Robert Kralovics
Keyword(s):  
Essential Thrombocythemia ◽  
Myeloproliferative Neoplasms ◽  
Jak2 V617f ◽  
Primary Myelofibrosis ◽  
Janus Kinase ◽  
Driver Mutations ◽  
Mutation Status ◽  
Genomic Landscape ◽  
Exon 10 ◽  
Stat Pathway

Abstract Our understanding of the genetic basis of myeloproliferative neoplasms began in 2005, when the JAK2 (V617F) mutation was identified in polycythemia vera, essential thrombocythemia, and primary myelofibrosis. JAK2 exon 12 and MPL exon 10 mutations were then detected in subsets of patients, and subclonal driver mutations in other genes were found to be associated with disease progression. Recently, somatic mutations in the gene CALR, encoding calreticulin, have been found in most patients with essential thrombocythemia or primary myelofibrosis with nonmutated JAK2 and MPL. The JAK-STAT pathway appears to be activated in all myeloproliferative neoplasms, regardless of founding driver mutations. These latter, however, have different effects on clinical course and outcomes. Thus, evaluation of JAK2, MPL, and CALR mutation status is important not only for diagnosis but also for prognostication. These genetic data should now also be considered in designing clinical trials.

Thrombocytosis

Hematology ◽  
2009 ◽  
Vol 2009 (1) ◽  
pp. 159-167 ◽  
Author(s):  
Radek C. Skoda
Keyword(s):  
Polycythemia Vera ◽  
Mouse Models ◽  
Essential Thrombocythemia ◽  
Jak2 V617f ◽  
Primary Myelofibrosis ◽  
Heterozygous State ◽  
Platelet Production ◽  
Thrombopoietin Receptor ◽  
Major Progress ◽  
Stimulation Of

Abstract Major progress in understanding the pathogenesis in patients with thrombocytosis has been made by identifying mutations in the key regulators of thrombopoietin: the thrombopoietin receptor MPL and JAK2. Together, these mutations can be found in 50% to 60% of patients with essential thrombocythemia or primary myelofibrosis and in 10% to 20% of hereditary thrombocytosis. A decrease in expression of the Mpl protein can cause thrombocytosis even in the absence of mutations in the coding sequence, due to a shift in the balance between stimulation of signaling in megakaryopoiesis and removal of thrombopoietin by receptor mediated internalization in platelets. When present in a heterozygous state the JAK2-V617F mutation preferentially stimulates megakaryopoiesis and in most cases manifests as essential thrombocythemia (ET), whereas homozygous JAK2-V617F reduces megakaryopoiesis in favor of increased erythropoiesis, resulting in polycythemia vera and/or myelofibrosis. In 30% to 40% of patients with ET or primary myelofibrosis (PMF) and in 80% to 90% of pedigrees with hereditary thrombocytosis the disease-causing gene remains unknown. Ongoing genetic and genomic screens have identified genes that, when mutated, can cause thrombocytosis in mouse models. A more complete picture of the pathways that regulate megakaryopoisis and platelet production will be important for finding new ways of controlling platelet production in patients with thrombocytosis.

Phase II Study of CEP701, an Orally Available JAK2 Inhibitor, in Patients with Primary Myelofibrosis and Post Polycythemia Vera/Essential Thrombocythemia Myelofibrosis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3543-3543 ◽  
Author(s):  
Srdan Verstovsek ◽  
Ayalew Tefferi ◽  
Steven Kornblau ◽  
Deborah Thomas ◽  
Jorge Cortes ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Polycythemia Vera ◽  
Phase Ii ◽  
Essential Thrombocythemia ◽  
Phase Ii Study ◽  
Subcutaneous Administration ◽  
Jak2 V617f ◽  
Primary Myelofibrosis ◽  
Common Mutation ◽  
Tyrosine Kinase 2

Polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are myeloproliferative disorders (MPDs) associated with activating mutations of Janus tyrosine kinase 2 (JAK2) gene. The most common mutation, JAK2 V617F, has been reported in ∼97% of patients with PV, ∼50% with ET, and ∼50% with PMF. The resultant JAK2 protein is continuously autophosporylated and therefore always active. It is believed that this mutated tyrosine kinase contributes to the existence and progression of MPDs. CEP701 is an orally available potent low nanomolar inhibitor of wild type and mutated JAK2 tyrosine kinase in enzymatic and cellular assays. Significant inhibition (growth stasis) was observed following CEP-701 subcutaneous administration to V617F-mutated JAK2-dependent HEL.92 xenografts grown in immunocompromised mice. These results indicate that CEP-701 is an attractive candidate for clinical evaluation in patients with MPD carrying a mutated, constitutively activated JAK2. CEP701 is also a potent inhibitor of FLT3 and is being evaluated as FLT3 inhibitor in Phase II/III studies in patients with acute myeloid leukemia, at the starting dose of 80mg PO BID. We designed a Phase II study of CEP701, at the dose of 80 mg PO BID, in patients with PMF and post PV/ET MF, who harbor JAK2 V617F mutation. Eleven patients have been treated so far, seven males, median age 56 years (range, 38–69), median 3 prior therapies (range 0–6); 7 with abnormal cytogenetics; 8 with enlarged spleen (2 had splenectomy); 4 with enlarged liver; 5 transfusion dependent. Five patients have been followed for at least 1 month and have had stable disease. Response will be evaluated using International Working Group for MF Consensus Response Criteria. JAK2 V617F allele burden is being measured monthly. Except for Grade 2 nausea in one patient, no toxicities have been noted so far. Updated results will be presented at the meeting.

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