To describe characteristics of patients from our real world cohort (RWC) of >250 pwMS who underwent a third course of cladribine immune reconstitution therapy (Clad-IRT).

Cladribine immune reconstitution therapy (Clad-IRT) is an effective disease modifying treatment (DMT) in people with relapsing MS (pwRMS). However, disease activity may resume after variable delay. Characteristics of pwRMS that develop disease breakthrough after Clad-IRT remain unknown.

RWC observation. Patient demographics, clinical and magnetic resonance imaging (MRI) variables were extracted from medical records.

Nine pwMS (seven women, two men) received a third course of Clad-IRT a mean of 33 months (range 16-43) after completing their second course. Mean age was 46 years (range 33-68), disease duration 14 years (5-29). Median EDSS was 4 (0-7.5). The decision for administering a third course was based on MRI-evidence of disease activity only in six (6 new T2 lesions, 2 new Gd+ lesions), clinical relapse in one, and both in two (including 1 new T2 lesion and 3 Gd+ lesions). In four/9 patients, the third course of cladribine was administered via subcutaneous injection, 5/9 received cladribine tablets (Mavenclad). DMTs prior to initial Clad-IRT included dimethyl-fumarate (n=2 patients), fingolimod (2), mitoxantrone (1), interferon beta-1a (2), glatiramer acetate (1) and none (4). Reviewing cladribine doses administered during the initial 2 treatment courses, only 5/9 had received the full dose of Clad-IRT for their first, and 4/9 for their second course.  Mean total lymphocyte count at baseline and 20 weeks was 1.6x10^9/L (0.8-3) and 1x10^9/L (0.6-1.6), respectively.

Similar to pwMS experiencing breakthrough activity on alemtuzumab, pwMS may benefit from a third treatment course of Clad-IRT. In this sample from our RWC, dose adjustment during initial Clad-IRT course(s) may have contributed to resuming disease activity. Clinical monitoring and mechanistic studies continue to address this question.