Clonal Architecture of ASXL1-mutated Myelofibrosis

Study Overview
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Brief Summary
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Prospective study to decipher the clonal architecture of ASXL1-mutated primary and secondary myelofibrosis and its impact on prognosis

Detailed Description
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The clonal architecture of myelofibrosis patients is still little described. Inconsistent results in terms of the prognostic value of some mutations are observed in the literature, in particular concerning ASXL1 mutations. We assume that a better understanding of the clonal architecture of ASXL1-mutated myelofibrosis could help refining the prognostic impact of ASXL1 mutations. This study aims to evaluate a multicenter cohort of 50 patients. Blood of patients will be collected within 18 months of diagnosis. After 4 years of follow-up of the patient as part of his usual care, data on survival and leukemic transformation will be collected.

Official Title
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Clonal Architecture of ASXL1-mutated Myelofibrosis

Conditions
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Myelofibrosis

Intervention / Treatment
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* Biological: Clonal architecture determination


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults (age ≥18 years), Affiliated to the national social security system, ASXL1 mutated primary or secondary myelofibrosis, Signed the consent to participate in the study, Included, or consenting to be included, in the national clinical-biological database of France Intergroupe Syndrome Myéloprolifératifs (FIM). Exclusion Criteria: Patient with another active hematological disease or cancer at the time of diagnosis, Person subject to legal protection scheme or incapable of giving consent.

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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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CLONEMF cohort<br> | Biological: Clonal architecture determination<br>* Biological: Determination of clonal architecture by sorting of circulating CD34 positive cells followed by cell culture and colony genotyping and/or single-cell DNA-sequencing Secondary outcome: transcriptomic study by RNA-sequencing<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Identify subgroups of ASXL1-mutated myelofibrosis based on clonal architecture data | The clonal architecture is defined by the number of mutations (numerical), the order of acquisition of the mutations (categorial, pre/post/separated), the mutational branching (categorial, yes/no), the presence of distinct clones (categorial, yes/no) and the transition towards homozygosity of each clone (categorial, yes/no). All parameters of clonal architecture will be analyzed together using a multivariate classification (Factor Analysis for Mixed Data) followed by a clustering which allow us to identify homogeneous cluster of patients. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Description of previously constituted prognostic genomic groups (according to Luque Paz et al. 2021) within identified clusters of clonal architecture | The repartition of patients onto genomic groups will be reported for each clusters of clonal architecture (number and percentage). | 24 months | 
| Studying the functional characteristics of each subtype of clonal architecture by transcriptomics | Gene Set Enrichment Analysis (GSEA) will be performed for each cluster of clonal architecture | 24 months | 
| Comparison of male proportion within the subtypes of clonal architecture | Repartition of gender will be compared | 24 months | 
| Comparison of age at the time of diagnosis within the subtypes of clonal architecture | Age at the time (years) of diagnosis will be compared | 24 months | 
| Comparison of blood counts within the subtypes of clonal architecture | Blood counts (g/dL or G/L) at the time of diagnosis will be compared | 24 months | 
| Comparison of LDH levels within the subtypes of clonal architecture | LDH levels (UI/L) at the time of diagnosis will be compared | 24 months | 
| Comparison of splenomegaly proportion within the subtypes of clonal architecture | Proportion of patients with splenomegaly will be compared | 24 months | 
| Comparison of constitutional symptoms proportion within the subtypes of clonal architecture | Proportion of patients with constitutional symptoms will be compared | 24 months | 
| Evaluation of overall survival of the patients at 4 years according to their clonal architecture profile | Overall survival will be evaluated by Cox models | 72 months | 
| Evaluation of the leukemia-free survival of the patients at 4 years according to their clonal architecture profile | Leukemia-free survival will be evaluated by Cox models | 72 months |