MRI activity, low doses linked to disease recurrence after cladribine

About three-quarters of multiple sclerosis (MS) patients given an under-the-skin formulation of cladribine had no disease activity or didn’t receive any additional therapies 4.5 years after starting treatment, a study shows.

Cladribine is the active ingredient in the oral therapy Mavenclad and is typically given in two short treatment courses, leading to the long-term suppression of certain immune cell populations. Preexisting MRI disease activity and lower doses during the second course were associated with a risk of disease activity, the research showed.

A few participants had a third course a median of three years after completing the second dose, supporting “the case for re-treatment in [people with relapsing MS] receiving CladT [Mavenclad], after the regular interval of 4 years.” The study, “Disease activity 4.5 years after starting cladribine: experience in 264 patients with multiple sclerosis,” was published in Therapeutic Advances in Neurological Disorders.

Cladribine depletes certain populations of immune cells implicated in MS. Mavenclad, an oral formulation from EMD Serono, is cleared in the U.S. for relapsing forms of MS and is generally recommended for patients who won’t tolerate or don’t respond to other therapies. In Europe, it’s indicated for adults with highly active disease, including those having disability progression, relapses, and MRI activity.

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Disease activity recurrence after cladribine treatment

A standard course involves two short treatment cycles administered at the start of two consecutive treatment years. This is thought to lead to long-lasting immune cell suppression. Real-world data from the CLASSIC-MS Phase 4 trial (NCT03961204) indicated the short-course therapy can help prevent disease activity for up to 15 years.

Disease activity recurs for some, however, but why this happens isn’t fully understood.

Cladribine is also sold in Europe as an under-the-skin (subcutaneous) formulation named Litak to treat hairy-cell leukemia, a rare blood cancer. Before Mavenclad’s 2017 approval there, some MS patients in the researchers’ clinic in England were treated off-label with Litak.

Here, researchers at The Royal London Hospital reviewed data from those patients to determine which clinical characteristics might predict recurring disease activity after cladribine treatment. The analysis included 236 patients who received subcutaneous cladribine between October 2014 and May 2022.

The treatment was administered in two courses over a year. During the first course, patients received subcutaneous injections of the therapy on three consecutive days during week 1, and again during week 5, with doses varying by patient weight and immune cell counts.

The second course depended on a person’s immune cell counts. Those with higher counts received injections during week 48 and week 52. Those with lower counts only received injections during week 48.

The participants were a median age of 39.1 at the start of treatment. Of them, 109 (46.2) had relapsing-remitting MS and 127 (53.8%) had progressive MS.

Over a median of 4.5 years since the treatment started, 57 people (24%) saw some form of disease activity — such as relapses, new MRI activity, or other signs of clinical worsening — making them eligible for another round of immunotherapy. Among them, 22 received a third course of cladribine a median of 36.7 months (a little over three years) after their second course. Half received the subcutaneous formulation and half were given Mavenclad. Another 22 people received another type of immunotherapy a median of 18.9 months (about 1.5 years) after the second cladribine course.

MRI activity, low second-course dose predict recurrence

Two factors significantly predicted new disease activity in these patients — the presence of new MRI activity before treatment and receiving a lower cladribine dose during the second course.

Particularly, for every 10 mg increase in dose in the second course, the risk of disease activity decreased by about 24% in a statistical model that also adjusted for patients’ weight. The flexible dose adjustments were introduced to avoid excessive immune cell depletion.

“Thus, in some [MS patients] reducing the cladribine dose for safety reasons comes at the cost of incomplete long-term disease control,” the researchers wrote.

Patients with any type of MRI activity before starting treatment were at about a doubled risk of new disease activity compared to patients without activity. That’s especially important in light of the fact that in Europe, prescribing guidelines for Mavenclad indicate MRI activity is required to be eligible for treatment, the scientists said.

While the framework for re-treating after cladribine relies on waiting for signs of disease recurrence before initiating a new round, the present results are, “in line with the apparent tailing off of the treatment effect over time and should caution against a ‘wait and see’ approach beyond 4.5 years from starting cladribine treatment,” the researchers wrote.