Functional and Phenotypic Characterization of Monocytes in Myeloproliferative Syndromes

Primary Myelofibrosis Clinical Trial

— PHEMOP  

Official title:

Functional and Phenotypic Characterization of Monocytes in Myeloproliferative Syndromes-PHEMOP

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06361641
• Other study ID #: 49RC23_0259
• Secondary ID: AO2721-44
• Status: Recruiting
• Phase: N/A
• Start date: May 29, 2024
• Est. completion date: October 19, 2027

Study information

• Verified date: January 2024
• Source: University Hospital, Angers
• Contact: Agathe GOUBAND, PharmD
• Phone: 02 41 35 55 96
• Email: Agathe.Gouband[@]chu-angers.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Prospective study for functional and phenotypic characterization of monocytes in philadelphia-negative myeloproliferative neoplasms

Description:

Philadelphia-negative myeloproliferative neoplasms (MPN) are clonal disorders of the hematopoietic stem cell characterized by an excessive production of mature myeloid cells. MPNs are characterized by the presence of somatic gain-of-function mutations present in more than 80% of cases and affecting JAK2, CALR or MPL genes. These mutations lead to a constitutive activation of the JAK-STAT signaling pathway at the origin of cell proliferation.

MPN include polycythemia vera (PV), essential thrombocythemia (ET), prefibrotic primary myelofibrosis (pre-PMF), and primary myelofibrosis (PMF). Despite the classification of MPNs into distinct subtypes based on clinical and pathological features, the precise mechanisms underlying the phenotypic diversity within these disorders remain poorly understood. One aspect that has received limited attention is the role of monocytes and macrophages, key components of the innate immune system, in MPN pathogenesis.

Monocytes, circulating precursors of tissue-resident macrophages, play essential roles in inflammation, immune surveillance, and tissue repair. Upon recruitment to tissues, monocytes differentiate into macrophages with diverse phenotypes and functions influenced by local microenvironmental cues. Macrophages, in turn, exhibit a spectrum of activation states ranging from pro-inflammatory (M1) to anti-inflammatory or pro-repair (M2), with implications for various physiological and pathological processes. Recent studies have implicated monocytes and macrophages in the pathogenesis of MPNs. Circulating monocytes in MPN patients display altered functional characteristics, including dysregulated cytokine production and enhanced fibrotic potential. Additionally, monocytosis, an elevated monocyte count, has been identified as an adverse prognostic factor in MPNs, particularly in PMF.

Based on these observations, investigator propose that monocytes and macrophages contribute to the phenotypic expression of MPNs and that distinct phenotypic and functional signatures of these cells may be associated with different MPN subtypes. By leveraging available techniques for genetic and functional analysis, study team aims to elucidate the role of monocytes and macrophages in MPN pathogenesis and identify potential biomarkers associated with disease phenotype and prognosis. Through comprehensive characterization of these immune cell populations, investigator seek to gain insights into the underlying mechanisms driving the heterogeneity of MPNs and identify novel therapeutic targets for precision medicine approaches.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 50
• Est. completion date: October 19, 2027
• Est. primary completion date: October 19, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Diagnosis of PV, ET, pre-myelofibrosis or primary myelofibrosis according to WHO 2022 criteria (including BOM for ET, premyelofibrosis and primary myelofibrosis)

• Patient who has not received treatment specific to hemopathy at the time of sampling

• Obtaining the signature of consent to participate in the study

• Patient having consented to be included in the "Malignant Hemopathy" collection of Angers University Hospital and in FIMBANK database

Exclusion Criteria:

• Person not affiliated to a social security scheme or beneficiary of such a scheme

• Patient with another hemopathy or another active cancer at the time of diagnosis

• Minor patient at diagnosis (< 18 years old)

• Patient not capable or without agreement from the guardian or legal representative

Related Conditions & MeSH terms

• Essential Thrombocythemia
• Myeloproliferative Disorders
• Myeloproliferative Neoplasm
• Polycythemia
• Polycythemia Vera
• Primary Myelofibrosis
• Thrombocythemia, Essential
• Thrombocytosis

Intervention

Diagnostic Test:
• Monocytes signatures in myeloproliferative neoplasms at diagnosis
The monocytes signatures will be perform from a peripheral blood sample. The signature will be derived from (i) surface marker expression, (ii) cytokines profiles, (iii) genes expression.

Locations

Country	Name	City	State
France	GOUBAND Agathe	Angers	Maine Et Loire
France	BESCOND Charles	Cholet	Maine Et Loire
France	TRUCHAN-GRACZYK Malgorzata	Saumur	Maine Et Loire

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Angers

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	WHO 2016 criteria for polycythemia vera, prefibrotic myelofibrosis, essential thrombocytosis and overt myelofibrosis diagnosis	Assessment of the monocytic signature against the WHO diagnosis (AUC will be determined)	Day 0
Secondary	Identify correlation between the monocytic signature and driver mutations (mutation in JAK2, CALR or MPL gene).	The monocytic signature will be derived from surface marker expression, cytokines profile and genes expression using a principal component analysis	24 months
Secondary	Identify correlation between the monocytic signature and the grade of fibrosis	The monocytic signature will be derived from surface marker expression, cytokines profile and genes expression using a principal component analysis The monocytic signature will be compared between the different stages of fibrosis (WHO definition for fibrosis grading)	24 months
Secondary	prognostic value of the monocytic signature using a principal component analysis Response criteria according to Barosi et al., Leukemia, vol. 29,1 (2015): 20-6	Evaluate the prognostic value of the monocytic signature for treatment response; The monocytic signature will be derived from surface marker expression, cytokines profile and genes expression using a principal component analysis Response criteria according to Barosi et al., Leukemia, vol. 29,1 (2015): 20-6 : Complete response: normal blood counts; Partial response: platelets between 400 and 600 G/L; No response: absence of complete or partial response	12, 24 months
Secondary	Prognostic value of the monocyte signature for disease worsening according to Sureau et al., Blood Cancer Journal, vol. 12,4, 56. 8 Apr. 2022	Evaluate the prognostic value of the monocyte signature for disease worsening The monocytic signature will be derived from surface marker expression, cytokines profile and genes expression using a principal component analysis; Disease worsening criteria according to Sureau et al., Blood Cancer Journal, vol. 12,4, 56. 8 Apr. 2022): - Worsening is defined by the presence of at least one of the following criteria: i) leukocytosis >12 G/L or presence of immature granulocytes >2% or erythroblasts >1%; (ii) anemia (hemoglobin <12 g/dL in a woman or <13 g/dL in man) not related to treatment toxicity; (iii) thrombocytopenia (platelet count <150G/L) not related to treatment toxicity; (iv) onset of splenomegaly or progression of pre-existing splenomegaly; (v) thrombocytosis despite cytoreductive therapy	24 months
Secondary	leukemia-free survival	The monocytic signature will be derived from surface marker expression, cytokines profile and genes expression using a principal component analysis Outcome measure : leukemia-free survival and myelofibrosis-free survival Evaluate the prognostic value of the monocytic signature for hematological progression (acute myeloid leukemia or myelofibrosis)	24 months
Secondary	myelofibrosis-free survival	The monocytic signature will be derived from surface marker expression, cytokines profile and genes expression using a principal component analysis Outcome measure : leukemia-free survival and myelofibrosis-free survival Evaluate the prognostic value of the monocytic signature for hematological progression (acute myeloid leukemia or myelofibrosis)	24 months
Secondary	Monocytes parameters for hematological progression	Evaluate the prosnostic value of monocytes parameters for hematological progression Hematological free survival wil be evaluated by cox models	24 months