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

Abstract

Background

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.

Methods

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).

Results

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%).

Conclusion

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.

Supplementary Information

The online version contains supplementary material available at 10.1007/s10072-023-06794-w.

Introduction

Multiple sclerosis (MS) is a central neurodegenerative disease in which adaptive immune cells, especially lymphocytes, as the front line of nerve tissue destruction, independently and by recruiting innate immune cells, have a significant contribution to the pathophysiology of this disease [1]. In particular, the presence of antigen-presenting cells (APCs) in the environment of nerve tissue and subsequent activation of TH0 CD4 + T cells and proliferation to encephalitogenic phenotypes TH1 or TH17 have been potentially seen in acute neurological lesions associated with MS [2]. In addition, molecules released from CD8 + T present in active and inactive tissues of chronic lesions play a significant role in axonal damage, tissue destruction, and cell death [3]. The importance of this pathophysiology becomes stronger with the presence of B cells. So that their dual role as antigen presenters and activation of autoreactive T cells, as well as damage to the myelin of nerve cells by producing anti-myelin antibodies, could not be ignored [4]. It is worth noting that the cumulative effect of lymphocytes on the severity of the development, progression, and treatment-resistance of the disease according to their ratio in the analysis of CSF fluid of MS patients can also have significant clinical importance [5, 6]. These findings are parallel to the interesting results of in vivo and in vitro reports that cladribine inhibits the development and exacerbation of MS by preventing the infiltration of inflammatory cells and the production of chemokine [7, 8]. All these factors can have a potential role in determining the plan and discovering new strategies for the treatment of this disease according to the lymphocyte-based mechanism of the neuro-degeneration and lymphocyte targeting action of Cladribine as well.

Cladribine (2-chloro-2′-deoxyadenosine, CdA) is a chlorinated analog of deoxyadenosine [9], which was proposed for the first time in 1977 at the Scripps Research Institute (CA, USA), due to its selective lymphotoxic effect and was proposed as a promising treatment in lymphoid neoplasms and autoimmune diseases. Several clinical trials have been conducted on the effect of this compound in the treatment of autoimmune diseases, mainly multiple sclerosis [10].

The clinical importance of the use of cladribine in the treatment of MS based on the effective presence of lymphocytes and the principle that it exerts its role via destroying them by the final process of apoptosis has been investigated in studies through three phases. In different phases I–III of clinical trials as well as in local studies, the researchers achieved significant findings [11–17]. Despite the volume of sample size and the long follow-up duration among previous studies, the findings are contradictory. These differences are observed in the progression of the Expanded Disability Status Scale (EDSS) score, radiological findings, number of relapses, and the route of administration and dosage. However, based on the available studies, the National Institute for Clinical Excellence (NICE) recommended using cladribine tablets (TA493) in relapsing–remitting MS (RRMS) [10]. It is worth mentioning that cladribine tablets received the approval of the American Food and Drug Administration (FDA) in 2019 and 2020, and received marketing authorization for the treatment of relapsing forms of MS in more than 75 countries [18].

Here, 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.

Methods

This systematic review of the safety and efficacy of cladribine in patients with MS was performed by following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement guidelines [19].

Search strategy

The three databases including PubMed, Scopus, and Web of Science were comprehensively searched in May 2022. We used a search strategy consisting of the following terms: “Multiple sclerosis” and “Cladribine” or “Mavenclad” or “Leustatin”. Furthermore, to avoid missing studies, we identified additional articles via the manual search of the reference list of review studies.

Eligibility criteria

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 (more than 6 months). Non-English studies, case reports, and review articles were excluded.

Study selection

Two independent reviewers (F. A and R. R) performed the selection process in two steps. First, they evaluated titles and abstracts and excluded irrelevant studies. Then, the remained articles entered full-text screening for final selection. Any disagreements were resolved by consulting with a third reviewer (F. N).

Data extraction

The same investigators (F. A and R. R) extracted the following information from included studies based on a prepared data form: study demographics, study design, follow-up duration, number of patients with MS, age, number of females, cladribine dosage, other medications, description of prescription, mean EDSS score before and after taking cladribine, progression-free survival (PFS), relapse-free survival (RFS), MRI free activity survival (MFAS), number of cases with infections, autoimmune disorders, malignancies, and infusion-related side effects. We obtained the data of the last time point for PFS, RFS, MFAS, and EDSS change.

Quality of studies

The quality of observational studies was assessed using the Newcastle–Ottawa scale (NOS) [20]. Moreover, we used the Cochrane risk of bias assessment tool to assess the quality of clinical trials.

Statistical analysis

The R software (version 3.3.3; R Foundation for Statistical Computing, Vienna, Austria) was used for all statistical analyses. The medians and interquartile range converted to mean and standard deviation based on the Hozo et al. method [21]. We investigated the EDSS change after treatment using a standardized mean difference (SMD) methodology with a 95% confidence interval (CI). The prevalence of adverse events after treatment was measured using Freeman-Tukey’s double arcsine transformation. To assess the heterogeneity among studies, we used I-squared (I²) statistics. The random effect model was used if heterogeneity was high (I² > 50%), and the fixed effect model was used if I² < 50%. Also, sensitivity analysis was performed to further validate our analysis. Outlier studies that affected heterogeneity or pooled effect size were detected using the leave-one-out approach. Outlier studies were removed at each step (both overall analysis and subgroup analysis), and all analyses were repeated and results were compared with previous results. Subgroup analyses were conducted to evaluate the effect of follow-up duration and study type on our results.

Results

Search results and characteristics of included studies

Our initial search and manual hand searching yielded 2024 articles (Fig. 1). After duplicate removal, the title and abstract of 1570 studies were screened and 1494 papers were excluded. Finally, after a full-text review, 23 studies were included in our qualitative and quantitative synthesis [12, 22–43]. A total of 15 clinical trials and eight observational studies involving 7244 MS patients were included in our study (Table 1). The mean NOS score for observational studies was 7.12. Among clinical trials, the risk of bias was low in seven studies while two studies had a high risk of bias (Supplementary 1). Furthermore, there were some concerns regarding the risk of bias in six studies.

Fig. 1.

PRISMA flow diagram depicting the flow of information through the different phases of a systematic review

Table 1.

Demographical and clinical characteristics of the included studies

Author	Country	Mean age, years	Dosage of cladribine	Other medications	Mean duration of disease, years	Type of study	Number of MS patients	Number of controls	Number of female	Number of patients RRMS	Description of prescription	Mean EDSS baseline	Follow-up duration, month	NOS
De Stefano et al. 2020	Multicenter	37.7	10 mg	NR	83.4 ± 83.9 months	RCT	260	NR	172	NR	tablet	2.5	24	_
Vermersch et al. 2018	Germany	38.1 ± 10.6	3.5 mg/kg	NR	3.86 ± 4.68	RCT	98	NR	67	98	tablet	3.01	NR	_
Thrower et al. 2019	USA	38.3018	3.5 mg/kg	NR	8.4	RCT	870	437	288	870	tablet	2.85	24	_
Stelmasiak et al. 2009	Poland	Range: 21 − 51 years	5 mg/day	NR	NR	RCT	80	42	49	80	SC	3.9	24	_
Selby et al. 1998	Canada	43	0.07 mg/kg/day	NR	12.6	RCT	19	NR	NR	NR	SC	6.7	17.6	_
Rice et al. 2000	USA and Canada	44.2025	0.7 mg/kg or 2.1 mg/kg	NR	11.2	RCT	159	54	91	NR	IV	5.6	12	_
Patti et al. 2020	Italy	38.7 ± 10.2	3.5 mg/kg or 5.25 mg/kg	IFN β-1a or 1b 47 Natalizumab 31 Fingolimod 17 Glatiramer acetate Teriflunomide Dimethyl fumarate Azathioprine Cyclophosphamide Laquinimod Mitoxantrone Rituximab Other	NR	Observational	80	NR	46	60	tablet	NR	60	7
Oh et al. 2021	Canada	NR	3.5 mg/kg	NR	NR	RCT	636	641	NR	NR	tablet	NR	3	_
Niezgoda et al. 2001	Poland and USA	Range: 20 to 50	5 mg/day	NR	4.5 ± 2.2	RCT	35	10	24	25	SC	NR	NR	_
Lizak et al. 2021	Australia	47	1.75 mg/kg	Interferon β, natalizumab, and glatiramer acetate	13	Observational	88	NR	65	70	tablet	4.7	42	7
Montalban et al. 2018	Multicenter	38.9465	3.5 mg/kg	IFN-β	NR	RCT	172	48	120	107	tablet	2.92	24	_
Möhn et al. 2019	Germany	49.2941	NR	Natalizumab	Median: 15.3	RCT	17	NR	11	17	tablet	3.34	9.7	_
Moccia et al. 2021	Italy and UK	39.4555	3.5 mg/kg and 5.25 mg/kg	NR	9.86	RCT	13	14	17	27	tablet	NR	NR	_
Martinez-Rodriguez et al. 2007	USA and Spain	28.2 ± 8.45	0.07 mg/kg/day	NR	NR	Observational	6	NR	4	6	NR	6.47	49.3	7
Kalincik et al. 2018	Multicenter	45	3.5 mg/kg	Interferon beta-1a, fingolimod, and natalizumab	11	Observational	679	599	NR	679	NR	3.57	NR	8
Galazka et al. 2017	USA and Canada	36.5409	3.5 mg/kg	NR	8.34	RCT	923	641	1036	NR	tablet	NR	> 96	_
Giovanni et al. 2018	Multicenter	41.1223	3.5, 5.25, 7, and 8.75 mg/kg	NR	11	RCT	806	244	531	806	tablet	2.65	24	_
Allen-philbey et al. 2021	UK	44	10 mg	NR	11	Observational	208	NR	131	100	SC	NR	19	7
Alshamrani et al. 2020	USA	Median: 47	0.07 mg/kg/day	NR	Median: 13	Observational	24	NR	19	NR	IV	4	84	6
Barros et al. 2020	Germany	Median: 39	3.5 mg/kg	Dimethyl fumarate, fingolimod, natalizumab	Median: 6	Observational	270	NR	231	270	tablet	1.99	25	8
Bose et al. 2021	Canada	40.609	Two courses of 1.75 mg/kg per year, delivered over two treatment weeks separated by 1 month, each consisting for 4 or 5 days of taking one or two 10-mg tablet each day, depending on weight	Alemtuzumab	8.4	Observational	111	46	84	111	IV	NR	24	7
Comi et al. 2018	Multicenter	NR	3.5, 5.25, 7, and 8.75 mg/kg	NR	NR	RCT	806	244	NR	806	tablet	NR	24	_
Cook et al. 2017	Multicenter	NR	3.5 mg/kg or 5.25 mg/kg	NR	NR	RCT	884	437	NR	NR	tablet	NR	NR	_

RCT, randomized control trial; NR, not reported; MS, multiple sclerosis; RRMS, relapsing–remitting MS; NOS, Newcastle–Ottawa scale; IV, intravenous; SC, subcutaneous

Efficacy of cladribine

We investigated the efficacy of cladribine with several outcomes including EDSS change, PFS, RFS, and MFAS. The pooled SMD for EDSS before and after treatment was − 0.54 (95%CI: − 1.46, 0.39; P: 0.03, I² = 72%) (Fig. 2). Our analysis showed that the PFS after cladribine use is 79% (95%CI 71%, 86%; I² = 93%) (Fig. 3). Also, 58% of patients with MS who received cladribine remained relapse-free (95%CI 31%, 83%; I² = 99%). Furthermore, the MFAS after treatment was 60% (95%CI 36%, 81%; I² = 98%).

Fig. 2.

Forest plot of EDSS score before and after treatment

Fig. 3.

Forest plot of PFS (A), RFS (B), and MAFS (C) treatment

Sub-group analysis showed 79% (95%CI 64%, 91%; I² = 96%) PFS in RCTs and 78% (95%CI 67%, 87%; I² = 80%) PFS in observational studies. Furthermore, the PFS was 81% (95%CI 73%, 89%; I² = 95%) in studies with less than 24 months of follow-up and 72% (95%CI 55%, 87%; I² = 84%) in studies with more than 24 months of follow-up.

RFS was 49% (95%CI 26%, 72%; I² = 97%) in observational studies. Also, sub-group analysis based on follow-up duration revealed that the RFS was 50% (95%CI 10%, 91%; I² = 98%) in studies with less than 24 months of follow-up and 33% (95%CI 6%, 68%; I² = 99%) in studies with more than 24 months of follow-up.

Furthermore, the MFAS was 67% (95%CI 48%, 84%; I² = 92%) in RCTs and 72% (95%CI 57%, 85%; I² = 92%) in observational studies. Also, the MFAS was higher in studies with less than 24 months of follow-up and 71% (95%CI 55%, 86%; I² = 95%) compared to studies with more than 24 months of follow-up 62% (95%CI 57%, 68%; I² = 0%).

Sensitivity analysis showed that after omitting each study, the SMD for EDSS remained insignificant (Supplementary 2). The similar results were obtained for PFS, RFS, and MFAS and the results remained significant (Supplementary 3).

We re-analyzed the data after removing outlier studies (Supplementary 4).

Safety of cladribine

Our analysis showed that infection is the most common adverse event after cladribine treatment with a pooled prevalence of 10% (95%CI 4%, 18%; I² = 95%, P < 0.01) (Fig. 4). Moreover, the pooled prevalence of infusion-related adverse events was 9% (95%CI 4%, 15%; I² = 56%, P: 0.11). Also, the malignancies after cladribine were present in 0.4% of patients (95%CI 0.25%, 0.75%; I² = 32%, P: 0.16). In the next step, sensitivity analysis showed that omitting each study did not influence the results (Supplementary 5). Re-analysis after removing outlier studies detailed in the Supplementary 5.

Fig. 4.

Forest plot of pooled prevalence of infusion related complications (A), infections (B), and malignancies (C)

Discussion

The current systematic review and meta-analysis aimed to determine the safety and efficacy of cladribine for MS patients to update clinical decisions for a better therapeutic plan. We have entered 7244 MS patients from 23 included studies. Based on our result, cladribine seems to be a safe and effective drug for the treatment of RRMS patients.

This is the first systematic review and meta-analysis study to categorize individual adverse events (AE) to estimate the safety of cladribine therapy in patients with MS. Based on current data analysis, infection with 10% is the most common AE after treatment with cladribine, followed by infusion-related AEs with 9% prevalence and malignancy with 0.4%. In Siddiqui et al., a network meta-analysis was performed to consider an overall AE of each randomized controlled trial [44]. Results showed that there was no significant difference in the safety of cladribine versus the placebo and other disease-modifying therapies (DMT). Results of Albanese et al. also showed that hospitalization and death rates for MS patients with COVID-19 treated with cladribine were 9.36% and 0% respectively; however, these numbers in a similar situation with alternative treatments were higher for both indexes [45]. Therefore, cladribine seems to be a safe treatment for RRMS patients, especially in times of the COVID-19 pandemic and the emergence of new SARS-CoV-2 strains [46]. Furthermore, compared to other commonly used DMTs, such as dimethyl fumarate [47, 48], fingolimod [49, 50], and natalizumab [51], cladribine is a safer therapeutic option with less known or rare AEs [52].

We also investigated the efficacy of cladribine by measuring several outcomes including MFAS, PFS, RFS, and change in EDSS. However, MFAS, PFS, and RFS seem to be acceptable. Our findings revealed that cladribine has no significant effect on EDSS reduction among MS patients. For a synthetic drug known as a first-line DMT, cladribine can target both B and T (CD4⁺ and CD8⁺) lymphocytes and exploit the enzymatic deoxycytidine degradation [10, 53, 54]. With a 40% estimated bioavailability, cladribine can properly penetrate CNS. However, with blood–brain barrier (BBB) disruption as a common pathological finding at all MS disease stages, cladribine can penetrate better to the CNS of MS patients [55–57]. Cladribine can interfere with DNA repair and synthesis processes through inclusion with enzymes that contributed to DNA metabolism, ribonucleotide reductase, and DNA polymerase, for example, leading to DNA breakage and cell death [58].

Despite a great impact on reducing the relapse frequency of RRMS, DMTs mechanisms of action are limited to prevent the inevitable transition of RRMS patients to non-active primary or secondary PMS. However, cladribine is found to affect a mix of active and non-active PMS patients [59–61]. Based on Siddiqui et al. [44], cladribine tablets are equal to or considerably better than the placebo with a 58% reduction in annualized relapse rate (ARR) (P < 0.05). Similar to our findings, with a − 0.54 EDSS score and 58% better RFS, confirmed disease progression (CDP) for 6 months and no evidence of disease activity (NEDA) of cladribine were significantly higher than the placebo (P < 0.05). Compared to other DMTs, such as interferon, glatiramer acetate, and dimethyl fumarate, cladribine has a significantly lower ARR. In the subgroup of high-disease activity patients, the beneficial effect of cladribine was also amplified [62, 63]. However, ARR for cladribine was significantly higher compared to natalizumab, a possible disadvantage of cladribine tablets for MS patients [63]. In Bartosik-Psujek et al., cladribine tablets were significantly more efficient in attaining NEDA than dimethyl fumarate and teriflunomide, but there was no considerable difference compared to fingolimod, which is similar to the results of our study maintaining 79% better PFS and 60% improved MFAS after treatment with cladribine [64].

The role of cladribine is also investigated in the treatment of hematological cancers, acute myeloid leukemia (AML) for example. As one of the most severe forms of bone marrow malignancies, most attempts to uptake immune response and improve survival of AML patients remained unsuccessful; and complete remission, especially in relapsed AML patients, remained a great challenge to be addressed [65, 66]. Scientists have studied the use of cladribine, either alone or in combination with a standard regime. Results of several studies confirmed the anti-leukemic activity with a lack of prohibitive non-hematologic toxicity of cladribine for children with AML [67, 68]. The combination of cladribine with cytarabine [69] and topotecan [70] was well tolerated, and response rates were found to be hopeful for AML patients, leading to the development of safe and effective therapeutic methods for non-MS patients as well.

Limitations and future

Similar to the other works, this study was not without limitations. The longest follow-up period was extracted from studies as the end-point for assessing efficacy and safety; however, the follow-up duration varied from 3 to more than 96 months, making the selection range so extensive. The dosage and use duration of cladribine also differed among studies; a potential drawback could result in a false conclusion when gathered for the pooled analysis. However, after sub-group analysis based on follow-up duration and study design, the heterogeneity remained high. Safety should also be considered with more attention, as there was considerable heterogeneity in the analysis. Other demographical and clinical characteristics such as RRMS to MS patients ratio, as well as a form of prescription (tablet, SC, IV) of cladribine can also be a case of bias, as all are taken similarly for treatment of patients with MS. There is still a lot to investigate to address drawbacks of cladribine administration for patients with MS, for inevitable AEs (mainly in immunocompromised patients) and lower effectiveness in several outcomes. Until that time, cladribine can be considered a safe and effective DMT against patients with RRMS, and a considerable pace of further studies are required to get a better inside around the prescription of cladribine in MS patients. Also, there is need for more data on whether cladribine should prescribe as first-line therapy or used after DMTs.

Conclusion

MS is a progressive disease with no certain cure for patients who face relapsed neurological impairments after the onset of the disease. 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 DMTs, cladribine seems to be a safe and effective drug in achieving better treatment for RRMS patients.

Supplementary Information

Below is the link to the electronic supplementary material.

Author contribution

Fardin Nabizadeh, Omid Mirmosayyeb, Mobin Mohamadi, Shayan Rahmani, and Soroush Najdaghi: designed the study, analyzed the data, and wrote the paper; Fardin Nabizadeh, Rayan Rajabi, and Fatemeh Afrashteh: collected data, analyzed and interpreted the data, and wrote the draft version of the manuscript. The manuscript was revised and approved by all authors.

Data availability

The datasets analyzed during the current study are available upon request with no restriction.

Declarations

Ethical approval

Not applicable.

Consent for publication

This manuscript has been approved for publication by all authors.

Conflict of interest

The authors declare no competing interests.

Human and animal rights

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.