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.

A Phase II Study of Oral Interferon-Alpha (IFN-a) for Patients with Essential Thrombocythemia or Polycythemia Vera.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4880-4880
Author(s):  
Alfonso Quintas-Cardama ◽  
Francis Giles ◽  
Jorge Cortes ◽  
Hagop Kantarjian ◽  
Srdan Verstovsek
Keyword(s):  
Polycythemia Vera ◽  
Phase Ii ◽  
Essential Thrombocythemia ◽  
Phase Ii Study ◽  
Philadelphia Chromosome ◽  
Jak2 V617f ◽  
Myeloproliferative Disorders ◽  
Mucosal Route ◽  
Previously Treated ◽  
To Receive

Abstract Recombinant human IFN-α has been the mainstay of therapy for patients with Philadelphia chromosome-negative myeloproliferative disorders for many years. However, the response rates of IFN-α therapy have been frequently challenged by high dropout rates due to side effects and inconvenient subcutaneous dosing schedules. Accordingly, we design a phase II study to evaluate the efficacy and safety of natural human IFN-α administered by the oral mucosal route in patients (pts) with essential thrombocythemia (ET) or polycythemia vera (PV). Pts were eligible if they had failed (inability to normalize platelet count in ET, or to reduce the frequency of phlebotomy or splenomegaly by 50% in PV, after 6 months of therapy with hydroxyurea (HU) and anagrelide (AG)), were intolerant to HU and AG, or refused to receive standard cytoreductive therapy. HU or AG therapy had to be stopped at least 3 weeks prior to start of oral IFN-α. Prior exposure to IFN-α was not allowed. Oral IFN-α was administered at 150 IU three times daily as a lozenge. A total of 14 pts (8 PV, 6 ET) have been treated. Median age was 57 (range, 32 to 79), time from diagnosis to oral IFN-α therapy 2 months (range, 0 to 32), Hb 14.2 gm/dL (range, 11.2 to 15.4), WBC 9.75 ×109/L, (range, 5.6 to 17.3), platelets 812 ×109/L (range, 360 to 1389). Five patients were previously treated with HU, four with AG, and 3 with imatinib mesylate. Six pts with PV had received phlebotomies and 2 presented with marked splenomegaly. The JAK2 V617F mutation was detected in 10 of 11 evaluated pts and 2 of 14 pts (14%) had abnormal cytogenetics. All 14 pts are evaluable for response and toxicity. No responses have been observed among any of the 14 pts treated. Ten (71%) pts discontinued oral IFN-α therapy due to lack of response (n=9) or disease progression (n=1, elevation of platelets), and 4 are currently on therapy. Duration of therapy varied: 2.5 months = 2 pts, 3 months = 6 pts, 4 months = 4 pts, 6 months = 2 pts. Therapy with oral IFN-α was very well tolerated: grade 1 headache was noted in 2 pts, and grade 1 paresthesia in 1 pt. We conclude that oral IFN-α is very well tolerated but has no activity in the treatment of pts with ET or PV at the dose and schedule employed in this study.

scholarly journals A phase II study of 5-azacitidine for patients with primary and post-essential thrombocythemia/polycythemia vera myelofibrosis

Leukemia ◽  
2008 ◽  
Vol 22 (5) ◽  
pp. 965-970 ◽  
Author(s):  
A Quintás-Cardama ◽  
W Tong ◽  
H Kantarjian ◽  
D Thomas ◽  
F Ravandi ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Phase Ii ◽  
Essential Thrombocythemia ◽  
Phase Ii 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.

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.

A Case Report on Coexisting JAK2 V617F and Calr exon 9 Mutation in Essential Thrombocythemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5215-5215
Author(s):  
Munazza Rashid ◽  
Rifat Zubair Ahmed ◽  
Shariq Ahmed ◽  
Muhammad Nadeem ◽  
Nuzhat Ahmed ◽  
...  
Keyword(s):  
Essential Thrombocythemia ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Diagnostic Algorithm ◽  
Jak2 V617f ◽  
Primary Myelofibrosis ◽  
Common Mutation ◽  
Hypochondriac Region ◽  
Exon 9 ◽  
Calr Mutations

Abstract Myeloproliferative Neoplasms (MPNs) are a heterogeneous group of clonal disorders derived from multipotent hematopoietic myeloid progenitors. Classic "BCR-ABL1-negative" MPNs is an operational sub-category of MPNs that includes polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). These three disorders are characterized by stem cell-derived clonal myeloproliferation. The most common mutation in the MPNs PV, ET and PMF is JAK2 V617F. JAK2 V617F can be detected in about 95% of patients with PV while remaining 5% of PV patients carry a somatic mutation of JAK2 exon 12. Approximately one third of patients with ET or PMF do not carryany mutation in JAK2 or MPL. In December 2013 mutations were described in calreticulin (CALR) gene in 67-71% and 56-88% of JAK2 V617F and MPL negative patients with ET and PMF, respectively. Since this discovery, CALR mutations have not only been recommended to be included in the diagnostic algorithm for MPNs, but also CALR exon 9 mutations have been recognised to have clinical utility as mutated patients have a better outcome than JAK2 V617F positive patients.CALR mutations have also been reported to be mutually exclusive with JAK2 V617F or MPL mutations. According to our knowledge so farthere have been only six reports published,which described patients harbouring concurrent JAK2 V617F and CALR exon 9 mutations; seven ET, three PMF, one PV and one MPN-U. In the present study we are reporting ET patient with coexisting JAK2 V617F and CALR exon 9 mutations from our center. In July 2011, 55-years-old female patient was referred to our hospital with a history of gradual elevation of platelet counts accompanied with pain in right hypochondriac region and feet. Bone Marrow aspirate consisted of 'Stag-horn' appearance Megakarocytes. Multiple platelets aggregates and islands were seen throughout the aspirate smear. ARMS-PCR for JAK2 V617F mutation was positive whereas bidirectional Sanger sequencing for CALR exon 9 exhibited c.1214_1225del12 (p.E405_D408del) mutation pattern. Disclosures No relevant conflicts of interest to declare.

Phase II Study of Sunitinib in Patients With Primary or Post–Polycythemia Vera/Essential Thrombocythemia Myelofibrosis

2010 ◽  
Vol 10 (4) ◽  
pp. 281-284 ◽  
Author(s):  
Effrosyni Apostolidou ◽  
Hagop Kantarjian ◽  
Deborah Thomas ◽  
Ian Burger ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Phase Ii ◽  
Essential Thrombocythemia ◽  
Phase Ii Study
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