Possible Reasons for the Suboptimal Response of the Cladribine Course in Daily Practice: An Independent Analysis of Data from 12 Russian Clinics and the Results of Post-Registration Studies in Other Countries

Abstract

Objectives: The purpose of this study was to analyze the effect of daily intake of cladribine tablets on the course of multiple sclerosis (MS) while monitoring for 1–4 years during and after the course in several neurological clinics from different regions of the Russian Federation. Materials and Methods: Information was collected on 235 patients from 12 neurological clinics and regional centers for MS, who were observed for an average of 3.4 years after starting treatment with cladribine. Results: An independent analysis of cases of prescription of cladribine in tablets showed that the reason for prescription of cladribine was highly active MS (HAMS) in 159 patients (67.7%), rapidly progressive MS (RPMS) in 20 patients (8.5%), active remitting MS in 50 patients (21.3%) and secondary progressive MS (SPMS) with exacerbations in 6 (2.5%). Among them, only 12 patients (5.1%) had not previously received DMTs, i.e., in these cases, the drug was prescribed as the first DMT. In total, 22 patients had previously received natalizumab, 5—ocrelizumab, and in 1 case—fingolimod. The remaining 207 patients were crossed over from the first-line DMTs. In all cases, there was a decrease in the frequency of exacerbations during and after the completion of the course of cladribine. Exacerbations between the first and second courses of cladribine were noted in 36 patients (15.3% of all treated), almost half of the cases—those who previously received natalizumab (17 exacerbations, or 47.2% of all exacerbations between the 1st and 2nd courses of cladribine), and in 3 cases—from ocrelizumab (in 60% of all patients crossed over from ocrelizumab). During 4 years of follow-up after a full course of cladribine, exacerbations were in 14 patients (6% of all patients included in the analysis), of which in 6 cases—after crossover from natalizumab. Discussion and Conclusions: The data obtained are generally consistent with the results of meta-analyses and reviews published recently, but high probability of exacerbations in patients who were crossed over from second-line drugs such as natalizumab and ocrelizumab were seen. The crossover from natalizumab is carried out more often due to the increased risk of developing progressive multifocal encephalopathy (PML). It is likely that the restoration of MS activity after the withdrawal of natalizumab is quite frequent, cladribine tablets were not able to fully prevent this. Such a crossover does not seem to be optimal, unlike the crossover from first-line DMTs. If such a crossover is still planned, it could be performed within 4 weeks after stopping natalizumab.

1. Introduction

Multiple sclerosis (MS) is an autoimmune-inflammatory and neurodegenerative disease of the central nervous system, in which adaptive immune cells, especially lymphocytes, cause local and diffuse inflammation, demyelination, damage to axons and neurons [1]. The activity of chronic (“smoldering”) inflammation is also associated with B cells, which play an important role in the progression of changes that are not always directly related to exacerbation (secondary progression), which is associated primarily with the participation of B cells of immunological memory [2]. At the same time, the presence of B lymphocytes, especially memory B cells [3,4], is important for cladribine action, which was also shown in a negative clinical study of Atacicept, which blocked the receptor of the B cell maturation antigen and caused exacerbations of MS [4,5]. It is important to monitor patients in daily practice to evaluate the efficacy and safety of medicines in real clinical practice [6,7].

Cladribine (2-chloro-2′-deoxyadenosine) is a chlorinated analog of deoxyadenosine [8], which, due to its selective lymphotoxic effect on activated cells, has been proposed for the treatment of autoimmune diseases, including MS [9,10]. It has also been shown that the drug can penetrate the blood–brain barrier (BBB), and its concentration in the cerebrospinal fluid (CSF) is up to 25% of the content in the blood, reaching a maximum concentration in the CSF of 0.019–0.025 μM [11]. The effect of the drug on local immunity was subsequently shown decreasing the amount of activated microglia and decreasing the production of inflammation-activating cytokines interferon-Ɣ and IL17 [12,13]. Following phase 1 and phase 2 studies, a large multicenter, randomized, placebo-controlled clinical trial was conducted to examine the effect of cladribine tablets on the frequency of exacerbations and a number of other secondary endpoints in relapsing-remitting MS compared to placebo as an immune reconstitution therapy (IRT) [14]. Based on these results, cladribine was approved for use in the treatment of MS in the Russian Federation and Australia in 2011–2012, later in North America and the European Union after a number of additional studies [15,16,17,18]. The data from a 10-year follow-up of patients confirmed the long-term efficacy and safety of the drug, as well as the importance of early initiation of IRT [19,20].

The purpose of this study was to analyze the effect of cladribine tablets in daily practice on the course of MS during treatment and follow-up for 3–4 years after IRT in several neurological clinics of different regions of the Russian Federation.

2. Materials and Methods

According to the developed short questionnaire, information was collected on 235 patients from 12 neurological clinics and regional MS centers, who were observed for an average of 3.4 years after starting the cladribine course (164 women, 69.8% of the total, average age 36.0 years ± 0.25 years, average MS duration—10.0 years ± 0.11 years). Only neurologists certified in EDSS (Expanded Disability Status Scale) scoring participated. In total, 52 patients’ data were excluded from the analyses because of uncomplete data received. The questionnaire was filled out by neurologists, MS specialists, who directly observed these patients. It was a retrospective cross-sectional study. The indications for prescribing a course of orally administered cladribine, previous therapy and the course of MS, including the frequency of exacerbations and EDSS, were analyzed. Statistical processing of the obtained data was carried out using the capabilities of the SPSS program (version 21) using Mann–Whitney U test for comparison of mean levels and χ² level with Yetes correction to compare distribution, statistical significance—with p < 0.05.

The study was conducted independently, without financial or organizational support from the pharmacological company manufacturing the drug. All data had no personal information. The protocol of this retrospective cross-sectional study was approved by the Local Ethnic Committee of Federal Center of Brain Research and Neurothechnology.

3. Results

An independent analysis of cases of prescription of orally administered cladribine showed that cladribine was most often prescribed as the second or third drug in cases of clinical inefficiency or safety problems with the previously administered DMT, with high risk of progressive multifocal encephalopathy (PML). The reason for prescribing cladribine was the course of MS defined as highly active (HAMS) in 159 patients (67.7%), rapidly progressive MS (RPMS) in 20 patients (8.5%), active relapsing MS in 50 patients (21.3%) and SPMS with exacerbations in 6 patients (2.5%) (

Table 1. Characteristics of patients before the start of cladribine and during follow up.

Parameters	Number of Patients (% for the Whole Group)
The reason for prescribing cladribine
highly active (HAMS)	159 (67.7%)
rapidly progressive MS (RPMS)	20 (8.5%)
active relapsing MS	50 (21.3%)
SPMS with exacerbations	6 (2.5%)
active relapsing MS	50 (21.3%)
Previously received DMTs
No previous DMTs	12 (5.1%)
One therapy	120 (51.1%))
Two therapies	82 (34.8%)
Three therapies	21 (8.9%)
Confirmed disability progression (CDP) 6 months before cladribine orally started
Yes	186 (79.1%)
No	49 (20.9%)
DMTs before switching to cladribine
No DMTs	12 (5.1%)
natalizumab	22 (9.4%)
ocrelizumab	5 (2.1%)
fingolimod	1 (0.4%)
interferons-beta-1a	116 (49.4%)
glatiramer acetate	39 (16.6%)
teriflunomide	40 (17.0%)
Frequency of exacerbations
before cladribine	325 (1.38 ± 0.05 per year)
on and 4 years after cladribine	62 (0.26 ± 0.02 per year) *
Presence of exacerbations between 1st and 2nd course of cladribine
1–2 years switched	36 (15.3%)
from natalizumab	17 **
from ocrelizumab	3 **
from the first-line DMTs	19
Presence of exacerbations between after 2nd course of cladribine 3 or 4 years later
from natalizumab	6 **
from the first-line DMTs	8
Change from RRMS to SPMS after 2nd course of cladribine	4

DMT—disease modifying therapy, RRMS—relapsing-remitting MS, SPMS—secondary progressive MS. *—difference from the level before cladribine with p < 0.05. **—difference from the first-line DMTs with p < 0.05.

). Only 12 patients (5.1%) had not previously received DMTs, i.e., in these cases, the drug was prescribed as the first DMT. More than half of the patients (120 patients) (51.1%) had received 1 drug, 82 patients (34.8%) had already received 2 drugs and 21 patients (8.9%) had already received 3 or more drugs. Confirmed disability progression (CDP) 6 months before the start of therapy had been noted in the majority of patients—in 186 cases (79.1%) (Table 1).

Among the patients who received second-line DMTs before switching to cladribine (28 patients or 12.6%), 22 patients had previously received natalizumab (9.4% of all patients and 78.6% of patients crossed over from the second line), 5—ocrelizumab (2.1% and 17.9%, respectively) and only in 1 case (0.4% and 3.6%, respectively)—fingolimod. The remaining 195 patients were switched from the first-line DMT; the last one was interferon-beta (116 or 59.5% of all crossed over from first-line DMTs), glatiramer acetate (39 or 20.0%) or teriflunomide (40 or 20.5%) (Table 1).

In all cases, a decrease in the frequency of exacerbations was noted during and after completion of cladribine (62 exacerbations during the follow-up period, 0.26 ± 0.02 per patient per year) compared to 325 before the start of therapy (1.38 ± 0.05 per patient per year, p < 0.001).

Exacerbations between the first and second courses of therapy were observed in 36 patients (15.3% of all treated patients). Among them, almost half of the cases concerned those who were crossed over from natalizumab (17 exacerbations, or 47.2% of all exacerbations that developed between the first and second courses of therapy, and 77.3% of these exacerbations were observed in patients who were crossed over from natalizumab to cladribine, mostly due to the risk of PML in cases with high JC-virus antibodies titer), and in 3 cases—from ocrelizumab (8.3% of exacerbations that developed between the first and second courses of therapy, in 60% of all those crossed over from ocrelizumab) (Table 1).

In patients switched to cladribine from first-line drugs, exacerbations were recorded in 9.2% of cases, with a total of 19 exacerbations during this period. The level of comparison of number of patients with exacerbation using χ² with Yetes correction between first-line DMTs and natalizumab was 60.36 with p < 0.001, between first-line DMTs and ocrelizumab −7.97 with p = 0.005.

After completion of the full course of treatment with cladribine for 3–4 years of follow up, exacerbations were observed in 14 patients (6% of all patients included in the analysis), of which 6 cases occurred after crossover from natalizumab, no one from ocrelizumab and 8 from the first-line DMTs (Table 1). The level of comparison of number of patients with exacerbation at this period between the first-line DMTs and natalizumab with Yetes correction was significant with χ² 13.96 with p < 0.001.

In 4 cases (1.7% of patients who had a relapsing-remitting course of MS before the start of the course), a change in the type of MS course from relapsing to secondary progressive was observed. Most patients (80.4%) showed stabilization or even a decrease in the EDSS score.

4. Discussion

A significant decrease in the frequency of exacerbations and a low level of disability progression between courses, as well as during the first years after a full 2-year course, was confirmed. The attention is drawn to the high probability of exacerbations in patients who were crossed over from second-line drugs such as natalizumab and ocrelizumab, seen in some publications before [20,21,22,23,24,25,26,27,28,29] (

Table 2. Results of independent studies of cladribine efficacy in real clinical practice.

Country or Register, Authors	Number of Patients Included	Never Received DMTs Before Cladribine (the First DMT)	Crossover from Natalizumab	Relapses Between 1st and 2nd Course of Cladribine	Relapses at 1–2 Years After Full Course of Cladribine	Stop of Cladribine Because of Low Effectiveness
Russia (this study)	235 (mean 3.4 years)	5.2%	9.9%	15.5%	6.0%
Germany [20]	270 (all longer than 6 months)	35.9%	Elevated risk of relapses after crossover from natalizumab, adjusted RR = 4.771 (95% CI 2.074–10.972) p < 0.001
MSBase register [21]	513 (all crossed over from other DMTs)		Elevated risk of relapses after crossover from natalizumab, adjusted RR = 4.08 (95% CI 1.35–12.33) p < 0.01
MSBase register [22]	633 (after at least 6 months upon finishing full course of cladribine, mean 1.14 years)	21.7%		7.1%
Denmark [23]	268 (80%–full course)	12.7%				4.5%
Poland [24]	140 (47%–full course)	14.8%		16.3%	10.4%
Finland [25]	179 (observation for 19 months)	16.4%				5.0%
Israel [26]	128 (3–4 years, 35 for 4 years)	20.5%			31.1%–3 years 17.1%–4 years
Great Britain [27]	1934 (52%–2 years)	36.0%		9.0%	4.0%	4.0%
Belgum [28]	84 (up to 3 years)	27.5%		16.7%
Portugal [29]	182 (up to 3 years)	14.9%				5.5%

). Our data on the frequency of cases with exacerbation between and after cladribine courses were closed to receive in Poland [24] and Belgum [28], partially in Great Britain [27], different from Israel [26], with a higher level of exacerbation at year 3–4 after the course of cladribine, mainly due to different patients’ selection for this therapy. All these DMTs are used as an option for active (aggressive) MS as the first choice or, in cases with failure, of the first-line DMTs [30,31].

The presented data confirm that the switch to cladribine after natalizumab is accompanied by the risk of developing an exacerbation of MS, both between and after courses [20,21]. The same risks of withdrawal syndrome influence, according to the MSBase registry, were noted when switching from fingolimod to other drugs, including cladribine [32].

It is likely that the rebound of MS activity after discontinuation of natalizumab is quite frequent and pronounced, and replacement with orally administered TIR is not able to fully prevent it. In the special study evaluating the likelihood of developing exacerbations after the switch from other DMTs to cladribine [21], based on data from the international MSBase registry (513 cases of crossover to cladribine from other DMTs), the most significant factor influencing the likelihood of developing an MS exacerbation in the first year after the crossover to cladribine was the switch from natalizumab (relative risk (RR), in relation to first-line injectable DMTs—4.08 with 95% confidence interval (CI)—1.35–12.33) [21]. The results of our study also show the relatively low percentage of cases when cladribine was prescribed as the first drug for very active MS in Russian clinics (5.2% in Russia vs. 12.7–36.0% in other countries, Table 2). This indicates the need for more active prescribing of TIR (Therapy of Immune Reconstitution) to patients with active MS with frequent exacerbations and EDSS level increase as early as possible.

5. Conclusions

Cladribine is the drug of the first choice for active MS with exacerbations against the background of first-line drugs for MS DMT. In the Russian Federation, early prescription of cladribine for aggressive forms of MS as the drug of first choice is relatively rare. At the same time, the practice of switching to cladribine after a course of treatment with natalizumab entails an increased risk of exacerbation of the disease due to the later onset of the optimal effect of the orally drug on B- and T-cells. The issue of crossover from natalizumab to cladribine requires further study and development of recommendations in order to minimize the risk of exacerbations between the first and second years and, soon after, of IRT treatment. At the same time, MS courses can be more aggressive from the beginning at these cases. One solution may be to reduce the cancelation period up to 4 weeks, possibly thinking of even overlapping of effects of the drugs.