Expert opinion on the long-term use of cladribine tablets for multiple sclerosis: Systematic literature review of real-world evidence

Background: Treatment with cladribine tablets (CladT), an immune reconstitution therapy for relapsing multiple sclerosis (RMS), involves two short courses of treatment in Year 1 and Year 2. Most patients achieve sustained efficacy with CladT, but a small proportion may experience new disease activity (DA). Following completion of the indicated dose, physicians may have questions relating to the long-term management of these patients. Since the EU approval of CladT over 5 years ago, real-world evidence (RWE) is increasing and may provide some insights and guidance for clinical practice. We describe a systematic literature review (SLR) of RWE and provide expert opinions relating to six questions regarding the long-term use of CladT.Methods: Pertinent clinical questions were developed by a steering committee (SC) of 14 international multiple sclerosis (MS) experts regarding breakthrough DA in Year 1, new DA after 2 years or more of treatment, long-term management of stable patients, and whether additional courses of CladT may be required or safe. An SLR was performed in EMBASE and PubMed using the population, intervention, comparators, outcomes, study design (PICOS) framework to identify relevant studies within the last 15 years. Searches of key congress pro-ceedings for the last 2-3 years were also performed. Following review of the results and RWE, the SC drafted and agreed on expert opinion statements for each question. Results: A total of 35 publications reporting RWE for CladT were included in this review. In the real world, breakthrough DA in Year 1 is of low incidence (1.1-21.9%) but can occur, particularly in patients switching from anti-lymphocyte trafficking agents. In most patients, this DA did not lead to treatment discontinuation. Reported rates of DA after the full therapeutic effect of CladT has been achieved (end of Year 2, 3 or 4) range from 12.0 to 18.7% in the few studies identified. No RWE was identified to support management decisions for stable patients in Year 5 or later. Views among the group were also diverse on this question and voting on expert opinion statements was required. Only two studies reported the administration of additional courses of CladT, but detailed safety outcomes were not provided. Conclusions: RWE for the long-term use of CladT in the treatment of RMS is increasing, however, gaps in knowledge remain. Where possible, the RWE identified through the SLR informed expert statements, but, where RWE is still lacking, these were based solely on experiences and opinion, providing some guidance on topics and questions that occur in daily clinical practice. More real-world studies with longer-term follow-up periods are needed and highly anticipated

Genomic instability in a Bcr-abl leukemia mouse model

The Bcr-abl translocation arises from a reciprocal translocation between chromosomes 9 and 22 and results in the augmentation of the tyrosine kinase activity of c-Abl. Chronic myelogenous leukemia (CML) is one of several hematological malignancies associated with Bcr-abl expression. The pathogenesis of CML, associated with P210Bcr-abl, is bi-phasic consisting of an initial chronic phase followed by a severe terminal phase referred to as acute blast crisis. The chronic phase of the disease is characterized by granulocytic hyperplasia but in which normal hematologic maturation is still intact. Patients ultimately enter the terminal blast crisis where hematologic maturation is lost, resulting in the accumulation of immature blast cells and a severe immuno-compromised state. Progression to the blast terminal phase is associated with genomic instability demonstrated by the accumulation of genetic and cytogenetic abnormalities. Results from in vitro cell line systems expressing Bcr-abl have suggested that the loss of cell-cycle arrest and induction of apoptosis, as a result of genotoxic stress, might be responsible for this phenotype. In this study, I utilized a transgenic mouse model which expresses P190Bcr-abl to extend those observations to an in vivo model for leukemia. I observed normal cell-cycle arrest and induction of apoptosis following the induction of DNA damage. However, using the Big Blue in vivo mutagenesis mouse assay system, I evaluated genomic instability in P190Bcr-abl mice by measuring mutation frequencies in vivo. I observed an increase in mutation frequencies in spleens and kidneys from P190Bcr-abl mice. This Bcr-abl-induced mutator phenotype may explain the inherent genomic instability associated with the progression of CML and other diseases associated with the expression of activated tyrosine kinases

Expert opinion on COVID-19 vaccination and the use of cladribine tablets in clinical practice

Background: Gaps in current evidence and guidance leave clinicians with unanswered questions on the use of cladribine tablets for the treatment of multiple sclerosis (MS) in the era of the COVID-19 pandemic, in particular relating to COVID-19 vaccination. Objective: We describe a consensus-based program led by international MS experts with the aim of supplementing current guidelines and treatment labels by providing timely recommendations relating to COVID-19 vaccination and the use of cladribine tablets in clinical practice. Methods: A steering committee (SC) of 10 international MS experts identified 7 clinical questions to answer concerning the use of cladribine tablets and COVID-19 vaccination, which addressed issues relating to patient selection, timing and efficacy, and safety. Clinical recommendations to address each question were drafted using available evidence combined with expert opinion from the SC. An extended faculty of 28 MS experts, representing 19 countries, in addition to the 10 SC members, voted on the recommendations. Consensus on recommendations was achieved when > 75% of respondents expressed an agreement score of 7-9, on a 9-point scale. Results: Consensus was achieved on all 13 recommendations. Clinical recommendations are provided on whether all patients with MS receiving cladribine tablets should be vaccinated against COVID-19, and whether they should be prioritized; the timing of vaccination around dosing of cladribine tablets (i.e. before and after a treatment course); and the safety of COVID-19 vaccination for these patients. Conclusion: These expert recommendations provide timely guidance on COVID-19 vaccination in patients receiving cladribine tablets, which is relevant to everyday clinical practice

Expert opinion on COVID-19 vaccines and cladribine tablets in MS: A plain language summary

People with multiple sclerosis (shortened to MS) who are taking cladribine tablets may have concerns about whether they can be vaccinated against COVID-19. This summary details the findings from a previously published article, in which an international committee of 10 MS experts developed recommendations to answer some important questions about COVID-19 vaccines in people with MS (including relapsingremitting or active secondary progressive disease) taking cladribine tablets

Expert opinion on the use of cladribine tablets in clinical practice

Gaps in current product labels and a lack of detailed clinical guidelines leaves clinicians' questions on the practical management of patients receiving cladribine tablets for the treatment of relapsing multiple sclerosis (MS) unanswered. We describe a consensus-based programme led by international MS experts with the aim of providing recommendations to support the use of cladribine tablets in clinical practice