Cladribine In Multiple Sclerosis Research Articles

Real-World Effectiveness and Safety of Cladribine in Multiple Sclerosis: Longitudinal Data From the Nationwide Registry in Argentina.

The aim was to evaluate patient profiles, effectiveness and safety of cladribine (CLAD) in patients with relapsing-remitting multiple sclerosis in Argentina. This was a substudy included in RelevarEM (MS and neuromyelitis optica registry in Argentina, NCT03375177). Patients with MS who received CLAD tablets and were followed up for at least 24 months were included. Clinical evaluations every 3 months collect information about: a) clinical relapses; b) progression of physical disability, evaluated through Expanded Disability Status Scale, and c) new lesions found in the magnetic resonance imaging. Lymphopenia was evaluated during the follow-up and defined as grade 1: absolute lymphocyte count (ALC) 800-999/μL; grade 2: ALC 500-799/μL; grade 3: ALC 200-499/μL and grade 4: ALC <200/μL. A total of 240 patients were included from 19 centers from Argentina. The mean annualized relapse rate during the 12-month pre-CLAD initiation was 1.19 ± 0.56 versus 0.22 ± 0.18 at month 12 and 0.19 ± 0.15 at month 24 (P < 0.001). A total of 142 (59.2%) fulfilled the criteria of disease activity during the 12 months before treatment initiation, whereas 27 (11.3%) fulfilled it at month 12 and 38 (15.8%) at month 24, P < 0.001. Regarding no evidence of disease activity (NEDA), 202 (84.2%) patients achieved NEDA status at month 12 and 185 (77%) at month 24. The most frequent incidence density of lymphopenia for course 2 observed was also for grade 1, 6.1 (95% confidence interval [CI] = 5.5-7.1). The overall incidence density of lymphopenia grade 4 was 0.1 (95% CI = 0.06-0.19). This information will help when choosing the best treatment option for Argentinean patients.

Prolonged observation after the use of cladribine in multiple sclerosis: efficacy and safety

Prolonged observation after the use of cladribine in multiple sclerosis: efficacy and safety

Safety and efficacy of cladribine in multiple sclerosis: a systematic review and meta-analysis.

Previously, several studies investigated the effect of cladribine among patients with multiple sclerosis (MS) as a treatment option. Due to the contradictory results of previous studies regarding the efficacy and safety of cladribine in the MS population, we aimed to conduct a systematic review and meta-analysis by including clinical trials and observational studies in terms of having more confirmative results to make a general decision. The three databases including PubMed, Scopus, and Web of Science were comprehensively searched in May 2022. We included the studies that investigated the efficacy and safety of cladribine in patients with MS. Eligible studies have to provide sufficient details on MS diagnosis and appropriate follow-up duration. We investigated the efficacy of cladribine with several outcomes including Expanded Disability Status Scale (EDSS) change, progression-free survival (PFS), relapse-free survival (RFS), and MRI-free activity survival (MFAS). After two-step reviewing, 23 studies were included in our qualitative and quantitative synthesis. The pooled SMD for EDSS before and after treatment was - 0.54 (95%CI: - 1.46, 0.39). Our analysis showed that the PFS after cladribine use is 79% (95%CI 71%, 86%). Also, 58% of patients with MS who received cladribine remained relapse-free (95%CI 31%, 83%). Furthermore, the MFAS after treatment was 60% (95%CI 36%, 81%). Our analysis showed that infection is the most common adverse event after cladribine treatment with a pooled prevalence of 10% (95%CI 4%, 18%). Moreover, the pooled prevalence of infusion-related adverse events was 9% (95%CI 4%, 15%). Also, the malignancies after cladribine were present in 0.4% of patients (95%CI 0.25%, 0.75%). Our results showed acceptable safety and efficacy for cladribine for the treatment of MS except in terms of reducing EDSS. Combination of our findings with the results of previous studies which compared cladribine to other disease-modifying therapies (DMTs), cladribine seems to be a safe and effective drug in achieving better treatment for relapsing-remitting MS (RRMS) patients.

Effectiveness and safety of cladribine in MS: Real-world experience from two tertiary centres

Background: Oral cladribine has been approved for the treatment of relapsing multiple sclerosis (MS) yet real-world evidence regarding its effectiveness and safety remains scarce. Objective: To evaluate efficacy and safety outcomes of MS patients following induction of cladribine. Methods: We evaluated our prospective cohort of cladribine-treated MS patients from two tertiary centres in Germany. Relapses, disability worsening and occurrence of new or enlarging T2-hyperintense magnetic resonance imaging (MRI) lesions were assessed as well as lymphocyte counts and herpes virus infections. Results: Among 270 patients treated with cladribine, we observed a profound reduction of both relapses and new or enlarging MRI lesions. Treatment appeared more efficacious, especially in patients without previous therapy or following platform substances. Patients switching from natalizumab were prone to re-emerging disease activity. Among patients following dimethyl fumarate pre-treatment, severe lymphopenia was common and associated with increased rates of herpes virus manifestations. Conclusion: Overall, we observed an efficacy and safety profile of cladribine consistent with data from the phase 3 clinical trial. However, patients switching from natalizumab experienced suboptimal disease control beyond rebound activity following cessation of natalizumab. Furthermore, dimethyl fumarate pre-treatment was associated with a profound risk of developing severe lymphopenia and subsequent herpes virus infections.

A real-world single-centre analysis of alemtuzumab and cladribine for multiple sclerosis

BackgroundHighly active MS may warrant higher efficacy treatments for disease control. However, these often confer more risk and have not been compared in head-to-head clinical trials, making relative efficacy and safety difficult to interpret. Alemtuzumab and cladribine are two high-efficacy treatments given as discrete courses separated by one year, followed by a durable response that potentially does not require ongoing treatment. Before the approval of oral cladribine, our centre had been treating patients with a bioequivalent intravenous (IV) regimen since 2010. The objective of this study is to report the safety and efficacy data of alemtuzumab and cladribine in a real-world, single centre setting. MethodsWe retrospectively reviewed all patients treated with alemtuzumab or cladribine at the Ottawa Hospital MS Clinic with 2 or more years of follow-up. Information on baseline demographic variables, previous treatment, and prior disease activity was collected. Outcomes investigated were “no evidence of disease activity” (NEDA) and its constituents: new clinical relapse, new MRI activity, and Expanded Disability Status Scale (EDSS) progression; as well as any adverse events or treatment discontinuation. We performed univariate and multiple logistic regression to determine differences in 2-year NEDA and time-to-event analyses with Cox regression models to determine factors associated with each outcome through the study period. ResultsForty-six patients were treated with alemtuzumab and 65 with cladribine of whom 51 (78%) received the intravenous regimen, followed for a total of 420.1 person-years. The cladribine group was older (p=.0002), with higher baseline EDSS (p=.0015), and more likely secondary progressive (p<.0001). Alemtuzumab had a higher rate of 2-year NEDA than cladribine (OR 4.78, 95%CI: 1.57–14.50, p=.006), but beyond 2 years the difference was not statistically significant (HR 0.50, 95%CI: 0.25–1. 30, p=.061). More prior treatments were associated with lower likelihood of retaining NEDA (HR 1.26, 95%CI: 1.03-1.54, p=.027). Alemtuzumab had more infusion reactions (80% vs. 17%, p<.0001), shingles (22% vs. 2%, p=.005), and secondary autoimmunity (52% vs. 3%, p<.0001) than cladribine, but there was no difference in grade 3 or higher adverse events (21.7% vs. 18.5%, p=1.0). ConclusionIn our cohort alemtuzumab and cladribine achieved similar rates of NEDA in long-term follow-up, with overall less adverse events with cladribine. Patient registries would allow more robust comparisons, detection of adverse events, and assessment of a durable response.

Long-term peripheral immune cell profiling reveals further targets of oral cladribine in MS.

ObjectivesTo expand the knowledge about the immunological consequences of cladribine (CLAD), a pulsed immune reconstitution therapy approved for active multiple sclerosis (MS), beyond the known short‐term effects on peripheral immune cell subsets.MethodsIn this study, we characterized depletion and restitution kinetics as well as cytokine profiles of peripheral immune cell subsets in 18 patients with MS following treatment with oral CLAD. The methods involved blood collection prior to CLAD and every three months over a period of 24 months, and extensive characterization of various immune cells subsets by multiparametric flow cytometry.ResultsWe found a selectivity of CLAD towards central memory T cells and memory B cells and detected a hyper‐repopulation of maturing B cells. Counts of classical (−65%) and various nonclassical TH17 cells (−84% to −87%) were markedly reduced 24 months after treatment start, and were comparable with depletion rates of class‐switched memory B‐cell phenotypes (−87% to −95%). The nadir of TH cells was more pronounced in the second treatment year. We observed a proportional surge of CD20 T‐cell subsets and an expansion of regulatory T, B and NK cells. Natural killer T cells (NKT) were only depleted in year two and did not recover.InterpretationPeripheral immune cell profiling revealed more differentiated insights into the immunological effects of CLAD. While some immune cell subsets expanded, we also observed additive depleting effects after the second treatment course. Further studies are required to elucidate whether these changes are paramount for the consistent and prolonged disease‐modifying effect of CLAD.

Pregnancy outcomes with cladribine in multiple sclerosis

Pregnancy outcomes with cladribine in multiple sclerosis

Pregnancy Outcomes During the Clinical Development Program of Cladribine in Multiple Sclerosis: An Integrated Analysis of Safety.

IntroductionAlthough use of contraception was pre-specified during cladribine clinical trials for multiple sclerosis, some pregnancies did occur.ObjectiveThis analysis reports on pregnancy outcomes in the cladribine clinical development program.MethodsPregnancy outcomes in female patients (direct pregnancies) and those arising from partner pregnancies (i.e., female partners of male study participants with multiple sclerosis) were evaluated from an integrated safety analysis of ten studies of cladribine in multiple sclerosis (nine clinical trials and a long-term safety registry), with patients treated with cladribine tablets, parenteral cladribine, or placebo (all-exposed cohort; 1976 patients received cladribine and 802 received placebo). Pregnancies that occurred during the ‘at-risk’ period for cladribine (during treatment or within 6 months thereafter) are reported as a separate group.ResultsIn the all-exposed cohort, 70 direct pregnancies occurred among 62 female patients (cladribine, n = 49; placebo, n = 21). Pregnancy outcomes were: live births (cladribine, n = 19 [38.8%]; placebo, n = 9 [42.9%]), elective terminations (cladribine, n = 14 [28.6%]; placebo, n = 4 [19.0%]), spontaneous abortions (cladribine, n = 11 [22.4%]; placebo, n = 5 [23.8%]), and therapeutic terminations (cladribine, n = 5 [10.2%]; placebo, n = 2 [9.5%]); in the remaining placebo recipient, the pregnancy outcome was unknown. There were two reports of congenital malformations (cladribine, n = 1; placebo, n = 1), both of which occurred with pregnancies arising > 2 years after exposure to the last dose of study medication. Sixteen direct pregnancies occurred during the ‘at-risk’ period for cladribine; outcomes for these were: live births, n = 3 (18.8%); elective terminations, n = 10 (62.5%); spontaneous abortions, n = 2 (12.5%); and therapeutic terminations, n = 1 (6.2%). Corresponding findings for direct pregnancies among placebo recipients were (n = 11): live births, n = 5 (45.5%); elective terminations, n = 2 (18.2%); spontaneous abortions, n = 3 (27.3%); and unknown, n = 1 (9.1%). No cases of congenital malformation were reported for pregnancies during the ‘at-risk’ period. There were an additional nine partner pregnancies in female partners of cladribine-treated male patients, all of which resulted in live births; of these, two pregnancies occurred within the ‘at-risk’ period for cladribine.ConclusionsWhile limited by the small number of pregnancies and related data from the cladribine clinical development program, highlighting the need for further study, the observations made in the present analysis were generally consistent with epidemiological data on pregnancy outcomes for the general population or women with multiple sclerosis. There were no congenital malformations in pregnancies that occurred during cladribine treatment or within 6 months after the last dose. As the data available for cladribine-exposed pregnancies in patients with multiple sclerosis are limited, a non-interventional post-authorization safety study has been initiated to obtain more information on this subject.Clinical Trial RegistrationCLARITY: NCT00213135; CLARITY Extension: NCT00641537; ORACLE MS: NCT00725985; ONWARD: NCT00436826; PREMIERE: NCT01013350.

Safety of cladribine tablets in the treatment of patients with multiple sclerosis: An integrated analysis

BackgroundTreating patients with relapsing multiple sclerosis (MS) with cladribine tablets (two times 4 or 5 days of treatment each year for 2 years) results in long-lasting efficacy, with continued stability in many patients for 4 or more years. Safety and tolerability outcomes from individual clinical studies with cladribine tablets have been reported previously. ObjectiveReport safety data from an integrated analysis of clinical trials and follow-up in patients with MS to further characterize the safety profile of cladribine tablets. MethodsData for patients treated with cladribine tablets 10 mg (MAVENCLAD®; 3.5 mg/kg cumulative dose over 2 years, referred to as cladribine tablets 3.5 mg/kg) as monotherapy (n = 923) or placebo (n = 641) in Phase III clinical trials (CLARITY, CLARITY Extension and ORACLE-MS) and followed up in the PREMIERE registry were aggregated (Monotherapy Oral cohort). To better characterize rare events, additional data from earlier studies which involved the use of parenteral cladribine in patients with MS, and the ONWARD study, in which patients were given cladribine tablets in addition to interferon (IFN)-β or placebo plus IFN-β were included in an All Exposed cohort (cladribine, n = 1926; placebo, n = 802). Adjusted adverse events incidences per 100 patient-years (Adj-AE per 100 PY) were calculated for the integrated analyses. ResultsThe incidence rate of treatment-emergent adverse events (TEAEs) in the Monotherapy Oral cohort was 103.29 vs. 94.26 Adj-AEs per 100 PY for placebo. TEAEs that occurred more frequently with cladribine tablets were mainly driven by the TEAEs of lymphopenia (Adj-AE per 100 PY 7.94 vs. 1.06 for placebo) and lymphocyte count decreased (Adj-AE per 100 PY 0.78 vs. 0.10 for placebo) as anticipated due to the mode of action of cladribine. An increase in TEAE incidence rate was also observed in the cladribine tablets 3.5 mg/kg group vs. placebo for herpes zoster (Adj-AE per 100 PY 0.83 vs. 0.20, respectively). There were no cases of systemic, serious disseminated herpes zoster attributed to treatment with cladribine tablets. In general there was no increase in the risk of infections including opportunistic infections with cladribine tablets versus placebo, except for herpes zoster. Periods of severe lymphopenia (< 0.5 × 109 cells/L) were associated with an increased frequency of infections, but the nature of these was not different to that observed in the overall patient group treated with cladribine tablets 3.5 mg/kg. Within the constraints of a limited sample size, malignancy rates in the overall clinical program for cladribine in MS did not show evidence of an increase compared to placebo-treated patients and there was no increase in the incidence of malignancies over time in cladribine-treated patients. ConclusionThe AE profile for cladribine tablets 3.5 mg/kg as a monotherapy has been well-characterized in a pooled population of patients from early to more advanced relapsing MS. There was no increased risk for infections in general except for a higher incidence of herpes zoster. Lymphopenia was amongst the most frequently observed TEAEs that occurred at a higher incidence with cladribine relative to placebo. There was also no increase in malignancy rates for cladribine relative to placebo.

Pregnancy Outcomes During the Clinical Development of Cladribine in Multiple Sclerosis: An Integrated Analysis of Safety

Background: Despite contraception being specified for men and women of child-bearing potential in clinical trials of cladribine in patients with MS, pregnancies occurred. Objective: Report pregnancy outcomes from an integrated analysis of safety for patients with MS exposed to cladribine.

Cladribine: mechanisms and mysteries in multiple sclerosis

ObjectivesThe aims of this manuscript were to review the evidence for the efficacy and safety of cladribine in multiple sclerosis (MS) and to review the molecular and cellular mechanisms by...

Two-Year Extension Study of Cladribine for Multiple Sclerosis

The original CLARITY study demonstrated an improvement in clinical and radiological outcomes in patients with relapsing–remitting multiple sclerosis

PO139 Integrated safety analysis; cladribine in multiple sclerosis (ms)

Background Efficacy and safety of cladribine tablets (CT) has been investigated in patients with early MS and relapsing MS (RMS). Objective Report the AE profile from integrated safety data for CT3.5 mg/kg (CT3.5) monotherapy. Methods The monotherapy oral CT3.5 cohort comprised 923 patients (3432.65 patient years [PY] exposure); 641 patients received placebo (2025.97 PY). Results Mean study period for CT3.5 was 194 weeks; placebo 165 weeks. Adj-AE per 100 PY rates for CT3.5 and placebo respectively: treatment emergent AEs, 103.3 and 94.3; serious AEs, 4.0 and 3.6; serious AEs leading to death, 0.26 and 0.25. For events expected with CT treatment, adj-AE per 100 PY for lymphopenia were 7.94 (CT3.5) and 1.06 (placebo), and for system organ class (SOC) infection and infestations, 24.93 (CT3.5) and 27.05 (placebo); herpes zoster, 0.83 (CT3.5) and 0.20 (placebo). Adj-AE per 100 PY for SOC neoplasms, benign, malignant and unspecified were 1.14 and 1.01, for CT3.5 and placebo, respectively. Conclusions The AE profile for CT3.5 monotherapy has been well-characterised. Lymphopenia was expected from cladribine tablets’ mode of action; herpes zoster was reported more frequently in patients experiencing Grade 3/4 lymphopenia; no clustering of types of malignancy, and no malignancies commonly associated with immunosuppression were observed.

Composite Endpoint Analyses for Alemtuzumab and for Cladribine in Multiple Sclerosis: Two Reports

In a previous phase II trial of alemtuzumab, researchers reported that multiple sclerosis (MS) patients had a 74% lower relapse rate and a 71% lower

Novel Agents and Emerging Treatment Strategies in Multiple Sclerosis. What Role for Cladribine?

Multiple sclerosis (MS), a chronic inflammatory-degenerative illness of the central nervous system (CNS), remains at the moment a treatable but incurable disease. Currently available disease-modifying agents (DMA-s), the majority of which are being injected, mainly relieve the inflammatory phase of MS with little beneficial effect, if any, in halting neurodegeneration. Cladribine is an immunosuppressive agent that can be administered orally and by cycles of short-course dosing as opposed to continuous administration. Cladribine has been shown to be effective in reducing inflammatory activity of MS but much remains unknown regarding its potential beyond the control of CNS inflammation. In addition, knowledge on the safety profile of cladribine in MS is limited. Data from on going clinical studies and registries on its safety profile will shed more light on the actual benefit/risk ratio of cladribine.

Emerging oral treatments in multiple sclerosis &amp;ndash; clinical utility of cladribine tablets

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS) that represents one of the first causes of neurological disability in young adults. Although the pathogenesis of MS is still unclear, an autoimmune mechanism has been demonstrated. According to this evidence in the last 15 years different treatments acting on the immune system have been developed. Current disease-modifying drugs (DMDs) for MS require regular and frequent parenteral administration and are associated with limited long-term treatment adherence. Moreover the clinical efficacy of these disease-modifying drugs is suboptimal. Thus, there is an important need for the development of new therapeutic strategies. Several oral therapies (fingolimod, fumaric acid, teriflunomide, laquinimod) are in development; Among these cladribine is the only therapy with the potential for short-course dosing. Cladribine is an immunosuppressant that offers sustained regulation of the immune system through a preferential lymphocyte depleting action. Cladribine has a well-characterized and well-known safety profile, derived from more than 15 years of use of the parenteral formulation both in the oncology field and in MS. This paper reviews the new oral emerging treatments and presents the available data about the use of cladribine in MS and the future perspective of its clinical use.

Cladribine: An Investigational Immunomodulatory Agent for Multiple Sclerosis

To review the pharmacology, pharmacokinetics, efficacy, and safety of cladribine, a purine analog undergoing Phase III trials for approval of its use in the treatment of multiple sclerosis (MS). A MEDLINE search (1966-September 2006) was conducted using the key words cladribine and multiple sclerosis. No limits were placed on the search. Studies and review articles related to cladribine and MS were reviewed. The trials examining the role of cladribine in MS were analyzed. Cladribine is a purine analog that demonstrates lymphocytotoxic activity. Recent data suggest that cladribine may have a role in the treatment of relapsing-remitting and the progressive forms of MS. In these studies, cladribine has shown mixed results in decreasing neurologic disability, as measured by various rating scales, but has consistently shown positive results in reducing the number of enhancing lesions, which reflects a measure of disease activity. To date, there is one ongoing study examining the role of oral cladribine in the treatment of relapsing-remitting MS. The incidence of adverse effects with cladribine has been significantly greater than with placebo, with the most common being myelosuppression. While data do not support its use as a first-line MS treatment, cladribine may be a promising agent for refractory patients with secondary progressive MS. Further studies are warranted.

Cladribine for multiple sclerosis: review and current status

In the 1990s, cladribine was developed as an adenosine deaminase-resistant nucleoside analog with selective lymphotoxic specificity in the hope that it might become useful in the treatment of some lymphoid neoplasms and autoimmune disorders. Several clinical trials demonstrated very significant effectiveness and safety of cladribine in the cure of hairy-cell leukemia, and the control of many other lymphoid malignancies. Cladribine was also extensively tested in selected autoimmune disorders, most notably in multiple sclerosis, with evidence of efficacy, tolerability and acceptable side effects/toxicity. The previous clinical studies and current status of cladribine for the treatment of multiple sclerosis are considered in this drug profile. In January 2005, Serono and IVAX announced plans to initiate a Phase III study of a specially formulated oral tablet of cladribine (Mylinax®, Serono and IVAX) for the treatment of relapsing forms of multiple sclerosis. The proposed study will be the first large multicenter randomized controlled clinical trial of oral cladribine in multiple sclerosis.