Open‐label study of oral CEP‐701 (lestaurtinib) in patients with polycythaemia vera or essential thrombocythaemia with JAK2‐V617F mutation

  title={Open‐label study of oral CEP‐701 (lestaurtinib) in patients with polycythaemia vera or essential thrombocythaemia with JAK2‐V617F mutation},
  author={Elizabeth O. Hexner and Gail J. Roboz and Ronald Hoffman and Selina M. Luger and John O. Mascarenhas and Martin P. Carroll and Regina Clementi and Debra M. Bensen-Kennedy and Alison R. Moliterno},
  journal={British Journal of Haematology},
JAK2‐V617F is central to the pathogenesis of myeloproliferative neoplasms. We examined whether lestaurtinib decreased JAK2‐V617F allele burden and evaluated its clinical benefits and tolerability in patients with polycythaemia vera (PV) and essential thrombocythaemia (ET). This phase 2, open‐label, multicentre study was designed to detect ≥15% reduction in JAK2‐V617F allele burden in 15% of patients. Eligible patients received lestaurtinib 80 mg twice daily for 18 weeks and could participate in… 
Phase I dose escalation study of lestaurtinib in patients with myelofibrosis
Although gastrointestinal adverse events were common, significant clinical activity with lestaurtinib was observed and the maximum tolerated dose was 140 mg twice daily.
Current and future treatment options for polycythemia vera
The discovery of mutations in Janus kinase 2 (JAK2) as the underlying molecular basis of PV has led to the development of several targeted therapies, including JAK inhibitors, and results from the first phase 3 clinical trial with a JAK inhibitor in PV are now available.
Polycythemia vera disease burden: contributing factors, impact on quality of life, and emerging treatment options
Patients with PV have an increased risk of mortality compared with the general population that often results from cardiovascular complications or disease transformation, and healthcare utilization and costs are higher in patients with PV than noncancer controls.
Novel and emerging therapies for the treatment of polycythemia vera
A better understanding of PV pathophysiology, including the role of the JAK/STAT pathway, has inspired the development of new therapies and histone deacetylase inhibitors have been developed to manage PV at the level of chromatin-regulated gene expression.
The future of JAK inhibition in myelofibrosis and beyond.
Ruxolitinib: evolution or revolution in treatment of patients with polycythemia vera?
Ruxolitinib, a potent JAK1/2 inhibitor, initially approved for myelofibrosis, was recently approved for patients with polycythemia vera refractory or intolerant to hydroxycarbamide.
Inhibitors of the JAK/STAT Pathway, with a Focus on Ruxolitinib and Similar Agents
The utilization of inhibitors of JAK/STAT activation may benefit those individuals with lymphoma that are not served adequately by conventional therapies, whilst others are under evaluation in clinical trials, and more efficacious drugs are being developed.
Resistance of Targeted Therapies Excluding Antibodies for Lymphomas
  • Ferreri
  • Biology, Medicine
    Resistance to Targeted Anti-Cancer Therapeutics
  • 2018
In CLL and WM patients progressing on ibrutinib, BTK and downstream kinase Phospholipase Cγ2 (PLCγ2) mutations have been identified leading to resistance, suggesting the evolution of clonal dynamics under treatment pressure.


Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis.
CEP-701 resulted in modest efficacy and mild but frequent gastrointestinal toxicity in MF patients and no improvement was seen in bone marrow fibrosis or JAK2(V617F) allele burden.
Clinical correlates of JAK2V617F presence or allele burden in myeloproliferative neoplasms: a critical reappraisal
JAK2 and MPL mutations are recurrent in myeloproliferative neoplasms (MPNs). A JAK2 mutation, primarily JAK2V617F, is almost invariably associated with polycythemia vera (PV). However, JAK2V617F also
Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis.
PURPOSE Myelofibrosis is a myeloid malignancy associated with anemia, splenomegaly, and constitutional symptoms. Patients frequently harbor JAK-STAT activating mutations that are sensitive to
EZH2 mutational status predicts poor survival in myelofibrosis.
EZH2 mutations are independently associated with shorter survival in patients with PMF and in multivariate analysis, survival of PMF patients was predicted by IPSS high-risk category, a < 25% JAK2V617F allele burden, and EZh2 mutation status.
Pegylated Interferon-Alfa-2a Induces Complete Hematologic and Molecular Responses with Low Toxicity in Essential Thrombocythemia
This is the first study addressing the effects of pegasis in essential thrombocythemia and finding that it is effective and effective in patients, and the proportion of mutant JAK2 being always similar or lower in the last sample compared with the previous one and none of the responding patient experienced an increase of %V617F during follow-up.
JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis.
Continuous ruxolitinib therapy, as compared with the best available therapy, was associated with marked and durable reductions in splenomegaly and disease-related symptoms, improvements in role functioning and quality of life, and modest toxic effects.
High molecular response rate of polycythemia vera patients treated with pegylated interferon alpha-2a.
The results seem to confirm the hypothesis that IFN-alpha preferentially targets the malignant clone in PV and show that %V617F assessment using a quantitative method may provide the first tool to monitor minimal residual disease in PV.
Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera.
Results show that pegylated IFN-alpha-2a yields high rates of hematologic and molecular response in PV with limited toxicity, and could even eliminate the JAK2 mutated clone in selected cases.
A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis.
Ruxolitinib provided significant clinical benefits in patients with myel ofibrosis by reducing spleen size, ameliorating debilitating myelofibrosis-related symptoms, and improving overall survival.