The REFRACT-LYMA cohort study: a French observational prospective cohort study of patients with mantle cell lymphoma

Mantle Cell Lymphoma (MCL) is a Non-Hodgkin lymphoma (NHL) defined as a unique type of B-cell lymphoma entity [1]. MCL accounts for approximately 5–10 % of all NHLs. Its incidence is estimated at around 0.5 per 100,000 person/year [2, 3]. Patients are generally Caucasian, male and elderly [2]. Some data suggests that MCL incidence may vary geographically and may possibly have increased over the last decades [2]. While some NHLs have been found to be related to specific inherited, environmental or infectious exposures, no strong and consistent relationship has been established for MCL [2, 4]. There are indeed but few studies of potential risk factors, often retrospective and primarily conducted by pooling all NHLs. However, it has been suggested that MCL might be associated with exposure to Borrelia burgdoferi [5] and with family history of hematopoietic malignancies and of genetic variation in the pro-inflammatory cytokine interleukin 10 [6, 7]. All these findings must be confirmed and remain controversial. Large prospective studies with sufficient statistical power and data quality are needed to confirm/discover risk factors associated with MCL.

MCL is usually diagnosed as a late-stage disease that has typically spread to the gastrointestinal tract and bone marrow [8]. MCL is often associated with temporary response to therapy, varying from months to decades, and the high relapse rate over time results in a poor long-term prognosis [9]. Overall survival (OS) is heterogeneous with a reported median around 5 years [3, 10]. An efficient prognostic index has been developed to predict OS: the Mantle Cell Lymphoma International Prognostic Index (MIPI) [11]. It classifies patients into three risk groups: low, intermediate and high risk. However, as emphasized elsewhere [4], the MIPI is prognostic for survival, not for therapeutic decisions and has been only validated for first-line therapy. Additional research is needed to identify associated risk factors and develop appropriate prognostic scores for all these situations.

Because MCL is classified as an incurable disease, therapeutic resistance is of great interest. In MCL, therapeutic resistance may schematically be divided in two categories: 1) primary resistance (the disease does not respond to the therapeutic agent(s) because of intrinsic characteristics and/or of a protective environment) and 2) acquired resistance (the disease was sensitive but relapse occurs as one or several resistant subclones emerge, that initially were in minority or that were acquired through therapeutic pressure) [12]. The Darwinian selective pressure and associated biological mechanisms still need to be clarified. This is crucial in order to decide whether to establish a therapy and/or to extend it or not. Biobanks of tumor samples, collected in a standardized manner before launching new therapies and at potential therapeutic failures, are required to achieve these goals.

Furthermore, MCL therapies have a huge economic impact on society. Temsirolimus, the first drug to receive EMA approval, costs £36,000 per year [13]. Estimates say that an Ibrutinib therapy (70 % of respondent patients in monotherapy) costs $110,000 per year in the United States [14]. It is strategic to identify predictors of response/sensitivity to therapies precisely. This would not only spare patients unnecessary therapies, but also optimize healthcare resources and reduce unnecessary costs. The issue is reinforced by growing availability of other promising molecules, e.g. ABT-199 (GDC-199), BTK/PI3K inhibitors or new antibodies [15‐18]. Possessing a cohort of MCL patients is a strategic asset for the pharmacoeconomic evaluation of associated therapies.

Finally, Quality of life (QOL) is recognized by clinicians and researchers to be an important indicator for cancer patients, both in clinical management and for the cost-benefit evaluation of therapies. Various studies of the impact of QOL on hematological cancers and associated therapies [19] have been performed. There have been fewer studies of NHL and even less of MCL. A recent study shows that QOL should be assessed at diagnosis and used as prognostic factor in patients with aggressive lymphoma [20]. Some studies focus on the QOL of long-term survivors of non-Hodgkin lymphoma [21]. Measuring QOL is necessary to get an integrative vision of MCL and to improve clinical management.

To address all these limitations, we have developed a multicenter prospective cohort of patients with MCL: the REFRACT-LYMA Cohort.

To our knowledge, this is the first prospective cohort of patients with MCL where medical, epidemiological and QOL data is repeatedly collected in combination with biological samples collected before treatment initiation and at treatment failure. Recruitment is expected to start by January 2016. In the mid-term, this integrative cohort will be a unique data source enabling each MCL patient to conceive the most effective personal therapy according to a large variety of data (patient tumor biological characteristics, epidemiological data, patient medical history, QOL measures and ex-vivo functional assays). Additionally, the REFRACT-LYMA Cohort will answer health and pharmacoeconomic questions about the medical care of MCL patients using “real-life data”, as opposed to clinical trials. However, larger studies may be necessary for these areas to be investigated in depth and to allow for solid and reproducible conclusions. That is why the REFRACT-LYMA Cohort uses standardized data, facilitating future collaborative data pooling as far as possible. The REFRACT-LYMA Cohort is also designed to facilitate collaboration with investigators, institutions, cooperative groups and pharmaceutical companies working in the MCL area.