Case study 2

Case scenario

The patient has highly-active DMT having failed a trial of dimethyl fumarate (DMF). She had a brain-stem relapse and her MRI had shown several new lesions. She was switched to oral cladribine and had her first-cycle of 5 days of treatment two weeks ago. She is due for her second cycle of oral cladribine in 2 weeks time. She is very concerned about COVID-19 infection. She works in London and commutes daily to work on the overground.

How are you going to manage this patient?

ADVISE

The COVID-19 ABN guidelines advise us not to do give her her second cycle of oral cladribine.

There is no right or wrong answer her only an opinion and an informed choice.

This patient has highly-active MS and needs it treated. As she has committed herself to treatment with oral cladribine she will likely be mildly lymphopaenic already from the first cycle of cladribine.

If we stick to the SIN or ABN guidelines we would have to suspend dosing. However, we may not have given her sufficient cladribine to have an effect on her MS. We do know that one course of cladribine does work and there is published data from Australia that shows this quite convincingly (see MS-Base data below).

If we don’t complete her course of cladribine could we use an alternate DMT? I would not recommend platform therapies as she has failed on DMF, although teriflunomide may be a holding strategy. Why teriflunomide? It works better second or third-line and has broad antiviral properties that may make it an ideal DMT in this situation.

Natalizumab would also be an option, but as she does not fulfil the current guidance for being treated with natalizumab under the NHSE DMT treatment algorithm this is not an option at present. Fingolimod will leave her immunosuppressed and starting her on fingolimod when she has a cladribine-induced lymphopaenia is unknown territory and likely to increase her level of immunosuppression.

My recommendation would be for her to complete her first course of cladribine and to be extra-vigilant about hygiene and social distancing and avoiding high-risk travel. I also want to remind you that the level of immunosuppression after one course of cladribine is relatively moderate. Cladribine only drops T-cell counts by about 40-50% and the levels usually don’t fall into the range that is associated with opportunistic infections. When you analyse the safety profile of those subjects in the CLARITY and CLARITY EXTENSION studies, even those that develop grade 3 or 4 lymphopaenia (lymphocyte counts less than 500/mm3), there really is no obvious viral or severe viral, infection signal apart from herpes zoster. Therefore, I suspect the risk to this patient from severe COVID-19 infection is low.

Based on the lymphocyte pharmacodynamics and the integrated safety analysis I would classify cladribine as an intermediate risk DMT in relation to severe COVID-19 infection in the same class as ocrelizumab. I really don’t know why it is being put in the same risk category as HSCT and alemtuzumab.

MS-BASE single course of oral cladribine data

Kalincik et al. Cladribine Versus Fingolimod, Natalizumab and Interferon β for Multiple Sclerosis. Mult Scler, 24 (12), 1617-1626 Oct 2018.

Objective: This propensity score-matched analysis from MSBase compared the effectiveness of cladribine with interferon β, fingolimod or natalizumab.

Methods: We identified all patients with relapse-onset multiple sclerosis, exposure to the study therapies and ⩾1-year on-treatment follow-up from MSBase. Three pairwise propensity score-matched analyses compared treatment outcomes over 1 year. The outcomes were hazards of first relapse, disability accumulation and disability improvement events. Sensitivity analyses were completed.

Results: The cohorts consisted of 37 (cladribine), 1940 (interferon), 1892 (fingolimod) and 1410 patients (natalizumab). The probability of experiencing a relapse on cladribine was lower than on interferon ( p = 0.05), similar to fingolimod ( p = 0.31) and higher than on natalizumab ( p = 0.042). The probability of disability accumulation on cladribine was similar to interferon ( p = 0.37) and fingolimod ( p = 0.089) but greater than natalizumab ( p = 0.021). The probability of disability improvement was higher on cladribine than interferon ( p = 0.00017), fingolimod ( p = 0.0025) or natalizumab ( p = 0.00099). Sensitivity analyses largely confirmed the above results.

Conclusion: Cladribine is an effective therapy for relapse-onset multiple sclerosis. Its effect on relapses is comparable to fingolimod and its effect on disability accrual is comparable to interferon β and fingolimod. Cladribine may potentially associate with superior recovery from disability relative to interferon, fingolimod and natalizumab.

Lymphocyte depletion kinetics and impact on subsets post cladribine

Stuve et al. Effects of Cladribine Tablets on Lymphocyte Subsets in Patients With Multiple Sclerosis: An Extended Analysis of Surface Markers. Ther Adv Neurol Disord, 12, 1756286419854986 2019 Jun 18 eCollection 2019

Background: Cladribine tablets 3.5 mg/kg cumulative over 2 years (CT3.5) had significant clinical/imaging effects in patients with clinically isolated syndrome (CIS; ORACLE-MS) or relapsing-remitting MS (RRMS; CLARITY and CLARITY Extension).

Objective: This analysis compared the effect of cladribine tablets on the dynamics of immune cell reduction and reconstitution in ORACLE-MS, CLARITY, and CLARITY Extension during the first year of treatment (i.e. the first course of CT1.75) in patients randomized to CT3.5.

Methods: Lymphocyte subtypes were analyzed using multiparameter flow cytometry. Changes in cell counts and relative proportions of lymphocytes were evaluated at weeks 5, 13, 24, and 48.

Results: Across studies, consistent and comparable selective kinetics of immune cell populations occurred following the first treatment year with CT. A rapid reduction in CD16+/CD56+ cells (week 5 nadir), a more marked reduction in CD19+ B cells (week 13 nadir), and a less-pronounced effect on CD4+ (week 13 nadir) and CD8+ T cells (week 24 nadir) was shown. There was little effect on neutrophils or monocytes. Lymphocyte recovery began after treatment with CT3.5. Regarding relative proportions of naïve and memory T-cell subtypes in ORACLE-MS, the proportion of naïve-like naturally occurring T-regulatory cells (nTregs) decreased, and the proportion of memory-like nTregs increased, relative to total CD4+ T cells.

Conclusions: CT3.5 has comparable effects on the immune systems of patients with CIS or RRMS. The pronounced reduction and recovery dynamics of CD19+ B cells and relative changes in the proportion of some immune cell subtypes may underlie the clinical effects of CT3.5.

The safety profile of cladribine showing that severe viral infections are not a clinical problem

Cook et al. Safety of Cladribine Tablets in the Treatment of Patients With Multiple Sclerosis: An Integrated Analysis. Mult Scler Relat Disord, 29, 157-167 Apr 2019.

Background: Treating 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.

Objective: Report 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.

Methods: Data 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.

Results: The 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.

Conclusion: The 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.

Date & Disclaimer: 18-March-2020; please note the information and advice in this case study may change with time.