Thèse de Maya ZEINEDDINE

Cancer Risk for High Efficacy Disease-Modifying Therapies in Multiple Sclerosis Patients

Background and Significance:
Multiple Sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system (CNS) and the leading non-traumatic cause of neurological disability in young adults. At diagnosis, most patients are started on a disease-modifying therapy (DMT), an immunomodulating or immunosuppressive therapy, that will likely be continued for life. While the DMT therapies have offered substantial benefit for MS patients, they have also introduced the potential for causing cancer as an adverse effect. With more than 17 DMTs available for the treatment of MS, clinicians are faced with the critical decision of how to screen MS patients for potential risk of malignancy with currently available DMTs and how to manage DMTs in MS patients who either had prior history of cancer or newly develop cancer while on a DMT.

The immune system plays an important role in both MS and cancer.It is possible that activation of the immune system in MS results in protective effects against cancer by increasing immunosurveillance, while chronic inflammation and use of certain immunosuppressive therapies could result in loss of immune protection against cancer or activation of the immune system to become pro-tumoragenic.At the same time, many of the available MS disease-modifying therapies (DMTs) had been used for years as cancer treatments prior to being re-purposed for MS, such as rituximab, cladribine, and methotrexate, while other DMTs are actively being evaluated for their anti-tumor potential, such as dimethyl fumerate, fingolimod, and teroflunomide.

This interesting dichotomy between the potential for cancer induction and cancer inhibition suggests that immunomodulatory and immunosuppressive MS medications may be acting in a context dependent manner in susceptible individuals.

Data on cancer prevalence and incidence in MS patients has been conflicting. Prior to the advent of oral and intravenous (IV) DMTs, studies suggested that the risk of cancer was equal or lower in untreated MS patients or in MS patients treated with interferons and glatiramer acetate while other studies suggested a higher risk of certain cancers.Incidence of breast and gastrointestinal cancers has been found to be increased , decreased, or the same in MS patients.Urogenital, central nervous system , and skin cancers appear to be higher in the MS population.

Several studies have found that while cancer risk in MS patients may not differ from the general population, the risk appears to be lower in male patients compared to female patients, and increases with age. Currently in the Middle East, fingolimod, natalizumab, rituximab/ocrelizumab, alemtuzumab and cladribine are the most frequently used DMTs for therapeutic escalation or initial treatment of more aggressive disease.

Accumulating real-world evidence now supports the notion of a superior effect of newer DMTs in protecting against disability and conversion to SPMS. However, despite the widespread use of these newer highly effective DMTs (Natalizumab,Fingolimod, Cladribine, Rituximab/Ocrelizumab and Alemtuzumab), evidence from large comparative studies on important safety outcomes, such as cancer, is still lacking.

Considering these therapies’ impact on immune competence, such studies are highly warranted. Randomized controlled trials have limited ability to detect rare safety outcomes due to small cohort sizes and short study durations, and have known limitations in the generalizability to real-world patient populations.

In contrast, the Middle East North Africa Committee for Treatment and Research in MS (MENACTRIMS) registry is well suited for investigating safety outcomes in the MS setting and allow for monitoring of rare events without attrition in clinically relevant patient populations.

Main Purpose of the Project:

Aim: Using the prospectively collected data from the MENACTRIMS registry, our objective is to compare the risk of cancer in a large Middle Eastern population of multiple sclerosis treated with high efficacy DMTs such as fingolimod, cladribine, natalizumab, ocrelizumab, rituximab and alemtuzumab.

Research Methods and Design: This is a register-based cohort study of fingolimod, cladribine, natalizumab, ocrelizumab, rituximab and alemtuzumab therapy episodes started between 2011 and (including) 2020 in patients with MS, matched to non-MS general population subjects, using data from the MENACTRIMS registry as well as data from Cancer Registries and other health care registries in the selected Middle Eastern countries (most likely Lebanon, Kuwait, Tunisia and Egypt).

Outcomes definition :

  • Time to first: invasive cancer, basal-cell carcinoma, and cervical intraepithelial neoplasia grade 3 (CIN3)
  • Basal cell carcinoma and CIN3 were chosen as they are relatively common and have been associated with immune suppression and infection with human papillomavirus, respectively
  • Several pre-specified, specific invasive cancers were also assessed: breast cancer, prostate cancer, melanoma, non-melanoma skin cancer (NMSC, not including basal cell carcinoma), and lymphoma
  • Significance and Innovation: There is a great interest currently in investigating the long-term side effects of the newly approved high efficacy DMTs. A major strength of this study is the high quality of the data sources used: MENACTRIMS Registry. These registers make it possible to follow patients without attrition and are therefore ideal for studying rare safety outcomes in a population-based setting. There is still very little data on cancer risk in MS in the MENA region.

    The results of this study would be highly innovative and have implications for patient care. Long term cancer risk of each DMT would guide the physician in selecting in-between high efficacy drugs and between high-efficacy DMTs versus safer but less efficacious treatments.


    Mots clés :Cancer, Multiple Sclerosis, Disease-Modifying Therapies

    [Janvier 2021 – Janvier 2024]


    Maya ZEINEDDINE

    Doctorante
    maya.zeineddine@unilim.fr


    Sous la direction de

    Farid BOUMEDIENE

    Directeur de thèse
    IGR HDR

    Co-tutelle

    Amal AL-HAJJE

    Co-direction
    PharmD, PhD, PU-PH

    Pascale SALAMEH

    Co-direction
    PharmD, MPH, PhD, HDR


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