Combination of JAK2 Inhibitor and Erythropoiesis-stimulating Agent in Myelofibrosis

Study Overview
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Brief Summary
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In patients with myelofibrosis, ruxolitinib is a current therapeutic option, which has demonstrated rapid and durable reduction in splenomegaly and improved disease-related symptoms. Anemia is another frequent issue in myelofibrosis. Consistent with its JAK2 signalling inhibition, ruxolitinib therapy has been shown to be detrimental on the hemoglobin level, increasing the depth of anemia or transfusion need. Despite potential antagonistic mechanisms of action on Janus Kinase 2, some responses on anemia have been reported with the addition of Erythropoiesis-stimulating Agent to ruxolitinib in a small subset of patients in the COMFORT II study. Ruxo-EPO is an observational study aimed to better assess the combination of Erythropoiesis-stimulating Agent and a Janus Kinase 2 inhibitor for therapeutic efficacy on anemia, Myelofibrosis evolution and for tolerance, in a larger cohort of patients treated for myelofibrosis in general practice.

Detailed Description
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Myeloproliferative Neoplasms are chronic diseases; they encompass Polycythemia Vera, Essential Thrombocythemia, and Primary Myelofibrosis with shared mutations that constitutively activate the physiologic signal-transduction pathways responsible for hematopoiesis. Myelofibroses may arise either as primary or antecedent to Polycythemia Vera and Essential Thrombocythemia. Myelofibrosis is the least common and the most aggressive of these diseases leading to death in 5 to 7 years due to bone marrow failure, massive splenomegaly related to extra medullary hematopoiesis, constitutional symptoms and cachexia. Until recently, treatment of Myelofibrosis consisted of supportive care only, especially transfusions. Since 2005 driver mutations have been identified in more than 90% of patients with myeloproliferative neoplasms, providing substantial insight into their pathogenesis and leading to the development of JAK inhibitor drugs. Ruxolitinib, the first one available, has shown activity whatever the presence of Janus Kinase 2 mutation, in reducing splenomegaly, improving cytopenias, alleviating constitutional symptoms and finally improving survival (COMFORT I and II studies). In France, access to ruxolitinib has been possible since April 2011, before wider availability in November 2012. Anemia is a frequent issue in Myelofibrosis, which may be managed by the use of Erythropoiesis-stimulating Agent, leading to a 40-50% response rate in small studies. Consistent with its Janus Kinase 2 signalling inhibition, ruxolitinib therapy has been shown to be detrimental on the hemoglobin level, increasing the depth of anemia or transfusion need, especially during the first 12-24 weeks of treatment in the COMFORT studies. Despite potential antagonistic mechanisms of action on Janus Kinase 2, some responses on anemia have been reported with the addition of Erythropoiesis-stimulating Agent to ruxolitinib in a small subset of patients in the COMFORT II study. Ruxo-EPO is an observational study aimed to better assess the combination of Erythropoiesis-stimulating Agent and a Janus Kinase 2 inhibitor for therapeutic efficacy on anemia, Myelofibrosis evolution and for tolerance, in a larger cohort of patients treated for myelofibrosis in general practice.

Official Title
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Patients With Myelofibrosis Treated With Combination of Janus Kinase 2 Inhibitor and Erythropoiesis-stimulating Agent. A French Observational Study.

Conditions
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Myelofibrosis; Anemia

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: patients with primary myelofibrosis or post-polycythemia myelofibrosis or post-essential thrombocythemia myelofibrosis previously started with a combination of Janus Kinase 2 Inhibitor and Erythropoiesis-stimulating Agent, whatever the date during the course of their disease Exclusion Criteria: - patients who denied participating to this observational study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect on anemia of the combination Janus Kinase 2 Inhibitor and Erythropoiesis-stimulating Agent | Response rate assessed with 2006 International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European Leukemia Network (ELN) criteria | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patterns of the combination Janus Kinase 2 Inhibitor and Erythropoiesis-stimulating Agent | Modalities of the combination (drugs of interest begun at the same or at different dates, order of the drug combination if started at different dates, duration of combination, doses of each drug) | 6 months | 
| Patients and Myelofibrosis characteristics | Demographic characteristics of included patients, Characteristics of diseases (date of diagnosis, primary or secondary myelofibrosis, prognostic scores, level of hemoglobin, transfusion dependency, splenomegaly, mutations, delay between myelofibrosis diagnosis and Jak2 inhibitor treatment) | at inclusion | 
| Response rate of the combination treatment on constitutional symptoms of myelofibrosis |  | 3 years | 
| Response rate of the combination treatment on splenomegaly | Splenomegaly size assessment | 3 years | 
| Efficacy of the combination treatment on bone marrow fibrosis | Assessment of bone marrow fibrosis change if bone marrow biopsy has been done | 3 years | 
| Efficacy of the combination treatment on Janus Kinase 2 allelic burden change | Assessment of Janus Kinase 2 allelic burden change if molecular evaluation has been done in blood | 3 years | 
| Adverse Events on combination treatment |  | 3 years | 
| Overall survival on combination treatment |  | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myelofibrosis, Erythropoiesis-stimulating Agents, Janus Kinase 2 inhibitors, Ruxolitinib