Clinical trial NCT03208803: Combination of JAK2 Inhibitor and Erythropoiesis-stimulating Agent in Myelofibrosis
Official title: Patients With Myelofibrosis Treated With Combination of Janus Kinase 2 Inhibitor and Erythropoiesis-stimulating Agent. A French Observational Study.
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Myelofibrosis; Anemia
Keywords: Myelofibrosis
Erythropoiesis-stimulating Agents
Janus Kinase 2 inhibitors
Ruxolitinib
Lead sponsor: Centre Hospitalier Annecy Genevois
Sponsor class: OTHER
First posted: 2017-07-06
Enrollment: 65
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: OTHER
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients with myelofibroses treated with a combination of Janus Kinase 2 Inhibitor and Erythropoiesis-stimulating Agent in one of the France Intergroup Myeloproliferative neoplasms centers

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Effect on anemia of the combination Janus Kinase 2 Inhibitor and Erythropoiesis-stimulating Agent
timeFrame: 6 months
Secondary outcomes:
measure: Patterns of the combination Janus Kinase 2 Inhibitor and Erythropoiesis-stimulating Agent
timeFrame: 6 months
measure: Patients and Myelofibrosis characteristics
timeFrame: at inclusion
measure: Response rate of the combination treatment on constitutional symptoms of myelofibrosis
timeFrame: 3 years
measure: Response rate of the combination treatment on splenomegaly
timeFrame: 3 years
measure: Efficacy of the combination treatment on bone marrow fibrosis
timeFrame: 3 years
measure: Efficacy of the combination treatment on Janus Kinase 2 allelic burden change
timeFrame: 3 years
measure: Adverse Events on combination treatment
timeFrame: 3 years
measure: Overall survival on combination treatment
timeFrame: 3 years
Other outcomes:
Locations:
Study officials:
affiliation: Hôpital René Huguenin - Institut Curie - St Cloud - France
name: Sandra Malak, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital Henri Mondor - Créteil - France
name: Lydia Roy, MD
role: STUDY_DIRECTOR
affiliation: CH Annecy Genevois - Pringy - France
name: Pascale Cony-Makhoul, MD
role: STUDY_DIRECTOR
affiliation: CH Arras
name: Mathieu Wemeau, MD
role: STUDY_DIRECTOR
References:
citation: Cervantes F. How I treat myelofibrosis. Blood. 2014 Oct 23;124(17):2635-42. doi: 10.1182/blood-2014-07-575373. Epub 2014 Sep 16.
citation: James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C, Garcon L, Raslova H, Berger R, Bennaceur-Griscelli A, Villeval JL, Constantinescu SN, Casadevall N, Vainchenker W. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005 Apr 28;434(7037):1144-8. doi: 10.1038/nature03546.
citation: Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, Catalano JV, Deininger MW, Miller CB, Silver RT, Talpaz M, Winton EF, Harvey JH Jr, Arcasoy MO, Hexner EO, Lyons RM, Raza A, Vaddi K, Sun W, Peng W, Sandor V, Kantarjian H; COMFORT-I investigators. Efficacy, safety, and survival with ruxolitinib in patients with myelofibrosis: results of a median 3-year follow-up of COMFORT-I. Haematologica. 2015 Apr;100(4):479-88. doi: 10.3324/haematol.2014.115840. Epub 2015 Jan 23.
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