Real-world experience with cladribine in the two years since treatment start: A systematic review and meta-analysis

Cladribine tablets are considered an oral selective immune reconstitution therapy (IRT) and characterized by preferential B and T lymphocytes reduction properties. In clinical practice, it is administered in two short courses of treatment per annual cycle over 2 years while in years 3 and 4 further treatment is not necessary. Since EMA approval, cladribine tablets' real-world experience has been starting and observational data coming from real life is currently emerging from different countries. Up to date, the many cohorts reported are characterized by a medium follow-up and differ a bit in the outcomes and timepoints assessed.

A comprehensive online search of the literature to detect the most relevant RW cohorts published until February 2024 was performed in Scopus, Web of Science, PubMed. The main search tools consider as key inclusion criterion the presence of real-world data on patients who had taken the 3.5 mg/kg cumulative dose of Cladribine tables and reach on average 24 months of follow up. The quality and the risk of bias of the selected articles was evaluated according to the NIH Quality Assessment Tool for Observational Cohort and Cross-sectional Studies. ARR and its variances were log-transformed before fitting a random-effects model, and a forest plot displaying the results was generated. Percentage data were analyzed via the double-arcsine transformation, the model was fitted, and then original-scale meta-analysis results were visualized using forest plots. Meta-analysis was performed using the Metafor and meta packages of R (version 4.1.3).

The first literature search revealed a total of 152 publications, 51 were excluded for potentially duplicated or overlapping data. Of the remaining 101, 11 were selected for the final analysis. Nine studies reported at second year the evaluation of ARR value (overall estimate 0.13, 95 % CI - 0.10, 0.16; I² = 94 %, p˂ 0.01) and the reduction of ARR vs baseline (overall estimate 0.81, 95 % CI - 0.72, 0.90; I² = 98 %, p˂ 0.01). Eleven studies evaluated the clinical disability worsening (CDW) (overall estimate 0.13, 95 % CI - 0.08, 0.18; I² = 90 %, p˂ 0.01), the MRI free (overall estimate 0.72, 95 % CI - 0.62, 0.82; I² = 95 %, p˂ 0.01) and NEDA-3 status (overall estimate 0.59, 95 % CI - 0.48, 0.69; I² = 94 %, p˂ 0.01).

The non generalizability of real-world experience lies in the different baseline characteristics across patient populations, which is enrolled following the clinical practice without specific inclusion and exclusion criteria, standardized evaluation during the follow-up and different treatment retention rate. Despite the incomplete overlap of these results, the evaluated real-world evidence highlights a favorable efficacy benefit profile of cladribine (Cladribine) tablets and supports the earlier use in the MS treatment algorithm.

The protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO: CRD42024604894).