Switching to Alemtuzumab in MS, Keep Washout to a Minimum

October 24, 2018

BERLIN — New data from two new studies suggest that for patients with multiple sclerosis (MS) for whom treatment with natalizumab (Tysabri, Biogen) or fingolimod (Gileyna, Novartis) fails, switching to alemtuzumab (Campath, Genzyme) can be an effective strategy, but a shorter switch period is better for reducing breakthrough disease activity.

The two studies were presented at the 34th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2018.

"These were very complementary studies. Both show more relapses during the switching period with longer washouts," Anne Cross, MD, Barnes Jewish Hospital, St. Louis, Missouri, who was co-chair of the session at which the studies were presented, told Medscape Medical News.

"These studies both involved patients not doing well on their present drug — natalizumab or fingolimod," she added. "My impression from these data is that switching from a drug that is aimed at stopping cells transitioning into the CNS [central nervous system] like natalizumab or fingolimod to a drug like alemtuzumab, which is depleting immune cells, is a seemingly effective move in the majority of patients, but we don't want to wait a long period of time between the drugs."

Natalizumab-to-Alemtuzumab Switch

The natalizumab-to-alemtuzumab study, known as ANSWERS MS, was presented by Paul Gallagher, MD, University of Glasgow, United Kingdom.

"This study reflects the unique experience of using alemtuzumab after natalizumab failure in the UK and Ireland, where alemtuzumab has been used on a preapproval basis since 1999," he explained.

"Our long-term data show no unexpected safety signals from the use of alemtuzumab after natalizumab. A shorter switch without bridging was associated with the best outcomes, and no evident risk," Gallagher concluded.

The study involved data on 79 patients from 13 centers in the United Kingdom and Ireland who had switched to alemtuzumab from natalizumab. More than 2 years' follow-up was available for 51 patients.

The data were analyzed in five phases: before natalizumab treatment, during natalizumab treatment, during the switch period (after natalizumab was stopped but before alemtuzumab was started); during alemtuzumab treatment, and after alemtuzumab treatment (starting 2 years after the first alemtuzumab infusion).

The median switch period was 115 days. During the switch period, the annualized relapse rate increased with increasing duration (<3 months, 0.36; 3 - 6 months, 0.5; 6 - 9 months, 1.9). The Expanded Disability Status Scale (EDSS) score also increased during the switch period if this exceeded 3 months.

Mean EDSS increased from 3.4 in the prenatalizumab period to 4.7 during the switch, but then fell to 4.4 in the alemtuzumab treatment period and to 4.3 in the post-alemtuzumab treatment period. But this was not maintained long term.

The mean annualized relapse rate fell from 2.3 before treatment with natalizumab to 0.8 during treatment with natalizumab and fell further to 0.4 after alemtuzumab treatment.

The mean number of new or worsened lesions apparent on MRI was highest during the switch period (4.32/MRI/year). This was lowest in the alemtuzumab treatment period (0.006/MRI/year) and remained low in the post-alemtuzumab period (0.017/MRI/year).

Three serious adverse events occurred (one urinary infection, one cytomegalovirus infection, and one death from sepsis unrelated to alemtuzumab treatment). Other significant infections occurred in eight patients: three cases of zoster, two urinary tract infections, one fungal infection, one case of tonsillitis, and one case of norovirus infection. Thyroid disease developed in 12 patients, and thrombocytopaenia occurred in two patients. Proteinuria developed in one patient in the post-alemtuzumab period.

Gallagher concluded: "There were no new safety concerns with almost 5 years of follow-up after alemtuzumab was initiated, and rates of secondary immunity were lower than expected.

"Alemtuzumab was effective at reducing inflammatory disease activity after natalizumab had failed, with 35 out of 51 patients (69%) requiring no further disease-modifying treatment after alemtuzumab treatment."

Alemtuzumab was also effective at reducing disability in the first 2 years, but improvement was not maintained after that, he added.

Commenting for Medscape Medical News, Cross suggested that the lack of long-term improvement in disability may be a reflection of the aggressiveness of the disease in these patients. "These patients have already failed natalizumab, which is a very effective drug, so these are a very different type of patient from the normal MS patient," she said.

"People failing on natalizumab is not a common occurrence. People do become positive for JCV [John Cunningham virus] and then need something else, but some of these patients had disease progression on natalizumab, which is quite unusual," she added.

Fingolimod-to-Alemtuzumab Switch

The fingolimod-to-alemtuzumab study was presented by Jessica Frau, MD, University of Cagliari, Italy.

"In this study in patients switching from fingolimod to alemtuzumab, there was a dramatic reduction in MS inflammation after alemtuzumab treatment, and a rapid initiation of alemtuzumab after fingolimod did not seem to be a risk factor for MS escalation. There was also a trend towards an improvement in the EDSS between fingolimod and the last follow-up after alemtuzumab," she concluded.

The study involved 77 Italian patients with relapsing MS who had experienced disease progression on fingolimod and were switched to alemtuzumab. The average age of the patients was 38 years, 79% were women, the average duration of disease was 13.7 years, and 37 patients received more than one course of alemtuzumab.

The mean washout period was 2.7 months, and for about half the cohort, the lymphocyte count was normal before the start of alemtuzumab.

The annualized relapse rate was 0.60 during fingolimod treatment, 1.33 during washout, and 0.20 after alemtuzumab treatment. After alemtuzumab treatment, seven patients experienced one relapse, and two patients experienced two relapses. The median time to first relapse during washout was 28 days; after the initiation of alemtuzumab, it was 315 days.

The last MRI during fingolimod treatment showed new T2 lesions in 69.2% of patients and gadolinium-enhancing lesions in 58.6% patients. The first MRI during alemtuzumab showed new T2 lesions in 10.4% and gadolinium-enhancing lesions in 2.2% of patients.

"In our cohort, alemtuzumab was able to dramatically reduce MS inflammation, both in terms of relapses and new T2/gadolinium-enhancing lesions, as compared to the previous fingolimod treatment and the washout period. This was true despite washout and a normal lymphocyte count in about half of our cohort. Thus, a rapid initiation of alemtuzumab after fingolimod does not seem to be a risk factor for MS reactivation," Frau stated.

Cross said the two studies together provided important information on switching to alemtuzumab after other therapies. "We don't have data on these types of switches, so this is very practical information — it tells us that we shouldn't wait a long period of time between stopping natalizumab or fingolimod and starting alemtuzumab.

"I think these studies will encourage clinicians who are thinking of making this switch to make it quickly," she added. "The two studies were well aligned. They tell me that if I have to make this type of switch, I'm going to do it quickly. I'm not going to wait months with the patient not receiving any treatment as the disease reactivates."

The ANSWERS MS project was funded by Sanofi Genzyme. Dr Gallagher received salary payment from Sanofi Genzyme for this project and has received travel funding for educational events from Sanofi Genzyme, Novartis, and Biogen. Dr Frau serves on scientific advisory boards for Biogen and Genzyme and has received honoraria for speaking from Merck Serono, Genzyme, Biogen, and Teva.

34th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2018. Abstracts 264 265, presented October 12, 2018.

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