Clinical trial NCT05911802: Prognostic Analyses on a Validation Series of Patients with Waldenström's Disease
Official title: Prognostic Analyses on a Validation Series of Patients with Waldenström's Disease: Validation of International Prognostic Indexes, Evaluation of Progression-free Survival As a Surrogate Endpoint for Overall Survival
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Waldenstrom's Disease
Prognostic Index
Lead sponsor: French Innovative Leukemia Organisation
Sponsor class: OTHER
First posted: 2023-06-22
Enrollment: 500
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: OTHER
Sampling method: PROBABILITY_SAMPLE
Study population: 250 symptomatic patients and 250 asymptomatic patients will be prospectively enrolled

Brief summary: Waldenström's macroglobulinemia (WM) is defined by the association of bone marrow lymphoplasmocytic infiltration and monoclonal immunoglobulin M (IgM). A mutation in the MYD88 gene is found in up to 90% of patients, and a mutation in the CXCR4 gene in approximately one third of patients. Treatment should be initiated in cases of cytopenia, bulky disease or when the physicochemical or immunological properties of IgM explain the occurrence of amyloidosis, cryoglobulin, neurological manifestations, or hyperviscosity syndrome (due to the presence of a large amount of IgM). However, approximately 30% of patients are diagnosed without any symptom and therefore they do not meet the criteria for initiating treatment.

At the time of initiation of the first treatment, the prognosis is usually estimated with the International Prognostic Index (IPSSWM) which is based on five variables: age, platelet count, haemoglobin concentrations, β2-microglobulin and monoclonal component concentration. Serum albumin and lactate dehydrogénase (LDH) levels also retain a prognostic role and these two characteristics have been incorporated in a proposal for a revision of this index.

Improving prognostic assessment at the time of the first treatment initiation and taking into account the prognostic impact of events occurring in the course of evolution, should improve the strength of treatment decision at the time of initial treatment and during the follow-up. It should also help to design clinical trial for fast and effective evaluation of new treatments. Our work should also help to adjust clinical monitoring of asymptomatic patients.

Prospective and retrospective multicenter prognostic study with a descriptive objective, associated with a biological collection appropriately annotated and stored. A retrospective series including 470 patients with symptomatic WM is already available. The follow-up of these patients will be updated and an additional series of 250 symptomatic patients will be prospectively enrolled. 250 asymptomatic patients will be also enrolled.

Detailed description: Waldenström's macroglobulinemia (WM) is defined by the association of bone marrow lymphoplasmocytic infiltration and monoclonal immunoglobulin M (IgM). A mutation in the MYD88 gene is found in up to 90% of patients, and a mutation in the CXCR4 gene in approximately one third of patients. Treatment should be initiated in cases of cytopenia, bulky disease or when the physicochemical or immunological properties of IgM explain the occurrence of amyloidosis, cryoglobulin, neurological manifestations, or hyperviscosity syndrome (due to the presence of a large amount of IgM). However, approximately 30% of patients are diagnosed without any symptom and therefore they do not meet the criteria for initiating treatment.

The prognosis of asymptomatic patients can be estimated with a prognostic index based on serum albumin, β2-microglobulin, the monoclonal component concentration and the bone marrow infiltration. Prognostic assessment of these patients could be improved by taking into account prior the free light chain concentrations and the molecular characteristics of the disease.

At the time of initiation of the first treatment, the prognosis is usually estimated with the International Prognostic Index (IPSSWM) which is based on five variables: age, platelet count, haemoglobin concentrations, β2-microglobulin and monoclonal component concentration. Serum albumin and LDH levels also retain a prognostic role and these two characteristics have been incorporated in a proposal for a revision of this index.

Thus improving prognostic assessment in patients with WM may rest on the following strategies:

* Modifying the variables to be considered before treatment initiation, particularly by considering albumin and lactate dehydrogenase concentrations or molecular characteristics of the disease in symptomatic patients, free-light chain concentration in asymptomatic patients and molecular abnormalities in both categories of patients.
* Evaluating the prognostic impact of events occurring during the course of treatment, such as response or progression in symptomatic patients.

Improving prognostic assessment at the time of the first treatment initiation and taking into account the prognostic impact of events occurring in the course of evolution, should improve the strength of treatment decision at the time of initial treatment and during the follow-up. It should also help to design clinical trial for fast and effective evaluation of new treatments. Our work should also help to adjust clinical monitoring of asymptomatic patients.

Two large subgroups of patients properly included with validated information and updated follow-up will be considered, namely: symptomatic and asymptomatic patients. This project is based on the assumption that it should be possible for each of these two cohorts to:

1. validate a new prognostic system and compare its performance with previous systems
2. to participate in a large international study of the validity of a surrogate endpoint of survival after initiation of the 1st treatment

Eligibility criteria: Inclusion Criteria:

* Patient with WM, fulfilling the diagnostic criteria defined at the 2nd Workshop on WM.
* Patient in whom follow-up is available until at least 01/01/2020. Each participating center should not enroll more 10% of patients lost to follow-up.
* Patient for whom a minimum annual follow-up is planned until 2024.
* Having given their consent for this study

Exclusion Criteria:

* Patient with other chronic lymphoid malignancy. Special attention will be paid to exclude other lymphoplasmacytic proliferations, especially marginal zone lymphoma.
* Patient with histological transformation in a diffuse large B-cell lymphoma or any other lymphoma at the time of the initiation of the 1st treatment.
* No consent for this study.

Primary outcomes:
measure: Overall survival
timeFrame: 5 years after WM diagnosis
Secondary outcomes:
measure: Progression free survival
timeFrame: 1 year after WM diagnosis
measure: Tolerance to treatment
timeFrame: 1 year after initiating WM treatment
Other outcomes:
Locations:
city: Amiens
country: France
facility: AMIENS - CH Amiens Picardie Site Sud
city: Angers
country: France
facility: Angers Chu
city: Bordeaux
country: France
facility: Institut Bergonie
city: Clermont-Ferrand
country: France
facility: Clermont-Ferrand - Chu Estaing
city: Le Mans
country: France
facility: Le Mans CH
city: Lens
country: France
facility: LENS - GHT Artois
city: Libourne
country: France
facility: LIBOURNE - Hôpital Robert Boulin
city: Lille
country: France
facility: LILLE GHICL - Hôpital Saint Vincent de Paul
city: Marseille
country: France
facility: Institut Paoli Calmette
city: Paris
country: France
facility: APHP - Hôpital Pitié Salpêtrière - Hématologie
city: Poitiers
country: France
facility: POITIERS - Hématologie et Thérapie Cellulaire
city: Reims
country: France
facility: Reims Chu
city: Strasbourg
country: France
facility: Strasbourg - Icans
city: Toulouse
country: France
facility: Toulouse - IUCT Oncopole - Service d'Hématologie
city: Versailles
country: France
facility: VERSAILLES - Hôpital André Mignot
Study officials:
References:
citation: Royston P, Altman DG. External validation of a Cox prognostic model: principles and methods. BMC Med Res Methodol. 2013 Mar 6;13:33. doi: 10.1186/1471-2288-13-33.