Narnatumab is approved for the treatment of multiple sclerosis, opening a new era of highly effective immune regulation. Unfortunately, not all patients respond well to narnatumab treatment, and its benefits are also overshadowed by the risk of progressive multifocal leukoencephalopathy (PML). Dr. Cohen and his team conducted a multi-center study to evaluate the safety and practicality of MS patients switching treatment (narnatumab to fennimod treatment), especially the risk of MS recurrence.
The researchers prospectively collected 333 MS patients who were converted from narnatumab to fingolimod in 36 research centers. Most of these patients undergoing conversion therapy are afraid that narnatumab may cause progressive multifocal leukoencephalopathy (PML), and more than 65% of patients have at least two disease-related risk factors. Other common reasons for stopping narnatumab include: patients believe that the drug lacks efficacy, drug side effects and the production of neutralizing antibodies.
The research protocol involved the study of the washout period of narnatumab before the use of fingolimod. And the results suggest that the interval between narnatumab conversion to fingolimod should be less than 3 months.
"The evidence that the elimination period of narnatumab is not conducive to the health of patients is gradually increasing"
The most important risk factor for disease recurrence is the length of the clearance period. Previous studies have confirmed that as many as 59.1% of patients who have a waiting period of more than 6 months to resume treatment will have disease recurrence. Other risk factors include high recurrence rate before narnatumab treatment, and low tolerance or poor efficacy of narnatumab.
Unfortunately, this study did not provide data on the annual MS recurrence rate during narnatumab treatment. However, only a short-term follow-up of less than 6 months for 1/3 of patients during Fingolimod treatment revealed that the risk of disease recurrence reached 20%.
Recent studies have confirmed the risk of disease recurrence during the eradication phase of narnatumab. Its clinical data included 89 MS patients whose narnatumab was converted to fingolimod treatment as determined by the international registry. The results showed that patients with a clearance period of less than 2 months had a significantly lower MS recurrence rate. Another result published at a recent conference was to detect the recurrence rate of MS patients whose drug intervals are 1, 8, 12, and 16 months in the conversion therapy, and found that the risk of recurrence is proportional to the length of the drug elimination period.
In addition, in MS patients receiving narnatumab, it is necessary to weigh the occurrence of PML and the risk of disease recurrence. A recent risk stratification algorithm summarized 3 risk factors for narnatumab-related PML: (1) the presence of anti-JCV antibodies; (2) long-term use of narnatumab (more than 2 years); (3) History of other immunosuppressive therapy.
Patients with three risk factors at the same time have an estimated risk of 1:90 PML, so these high-risk patients should be advised to stop the use of narnatumab. When the patient has only one or two risk factors, close monitoring should be used to determine whether the conversion treatment should be implemented and the specific timing of the conversion.
Unfortunately, the results of these studies have not provided patients and their neurologists with answers to the most pressing questions in clinical neuroimmunology: “Withdrawal when patients who use narnatumab want or need to stop treatment” What exactly is the strategy? Immunological and pharmacological data show that intermittent narnatumab treatment is not advisable. In particular, there is evidence that prolonging the elimination period is not conducive to patient health.
Moreover, none of the previous studies has been able to solve a problem-whether patients who stop narnatumab treatment will lead to the loss of the obtained efficacy. It is also unknown whether the neurological deficits in the intermittent period of treatment can be reversed. Taking into account the uncertainty of the discontinuation of narnatumab, we should consider overlapping treatments instead of treatment interruptions.
After narnatumab is stopped, the recurrence of the disease can be explained in a predictable manner by the biological effects of the drug.
Narnatumab is an effective drug for the treatment of patients with relapsed MS. By regulating the antigen-reactive white blood cells away from the central nervous system into the peripheral blood, the white blood cells in the peripheral blood have more inflammatory phenotypes. On the contrary, fingolimod is a sphingosine-1-phosphate receptor modulator, which reduces the infiltration of lymphocytes into the central nervous system by preventing the overflow of lymphocytes in the lymph nodes (mainly CD4 helper T cells).
A study showed that narnatumab treatment increased the expression of CD19+ mature B cells in peripheral blood by 2-3 times, and compared with the pretreatment level, the immature CD19+CD10+ pre-B cells increased by 7.4 times. Studies have also shown that narnatumab treatment for 6 months can lead to an increase in the number of cells that produce cytokine IFNγ, tumor necrosis factor TNF, and interleukin IL17. The recurrence of the disease after the patient stopped narnatumab was related to the remodeling of CD4+/CD8+ cells in the cerebrospinal fluid.
On the contrary, fingolimod mainly blocks CD4+ helper T cells, while the pro-inflammatory progenitor cells that increase during narnatumab treatment may not be affected. In this way, starting fingolimod treatment immediately after narnatumab is stopped may not result in a mixed immunosuppressive effect. Moreover, immediate treatment of fingolimod may reduce the activity of MS disease by preventing the myelin response of CD4+ T cells in lymphoid tissues.
When designing the trial, the physiological mechanism of follow-up treatment should also be taken into consideration, and patients should be strictly examined through laboratory and imaging methods to explore any PML-related evidence before intervention treatment. narnatumab treatment alone will increase the risk of PML, even after discontinuation of the drug, regardless of whether sequential therapy is used. Finding an appropriate treatment strategy to ensure the safety and health of MS patients after narnatumab is stopped is still a long way to go.