Fingolimod traps lymphocytes in the bone marrow and lymph glands and causes depletion in some individuals. The problem is that when you come off fingolimod, how long do you wait before starting the next treatment? Wait too long and you get disease rebound, as occurs with natalizumab also, which is a mega relapse. Here are three individuals swapped onto cladribine. However, don’t wait long enough and it may hide the lymphocytes in tissues not reached effectively by antibodies such as alemtuzumab.
In these cases cladribine was not good enough to stop MS after fingolimod.
Although it is suggested that cladribine depletes lymphocytes after 4 weeks, which appears to be the case for B cells in the blood, for the T cells to be fully depleted takes 8 weeks and it takes some time to become effective based on the ORACLE optic neuritis trial.
In all these three individuals disease had become active by the end of the wash-out 8-12.
Patient#1 initiated fingolimod after a relapse while on interferon beta-1a. After one year of treatment, she experienced a polysymptomatic relapse with evidence of multiple brain gadolinium-enhancing lesions and fingolimod was dis-continued. Cladribine was started after a 12-weeks wash-out. At cladribine start, brain MRI still exhibited ongoing disease activity.In the 6 following months, she experienced 3 relapses with incomplete recovery and persistent MRI activity. Given the aggressive course of the disease, she discontinued cladribine and underwent autologous hematopoietic stem cell transplantation (aHSCT).
Patient#2 initiated fingolimod after a relapse under treatment with dimethyl-fumarate. After 6 months of treatment, one silent gadolinium-enhancing lesion was detected on brain MRI. After three years, a further lesion appeared on brain MRI and fingolimod was discontinued. After 8 weeks of wash-out, she received the first course of cladribine. Although her neurological exam remained stable, brain MRI scans at cladribine start, after 3 and 6 months showed new widespread active lesions. Given the sustained radiological inflammatory activity they switched to ocrelizumab therapy.
Patient#3 initiated fingolimod because of suboptimal disease control while on interferon beta-1a. After 2 years of treatment, she experienced a spinal relapse with evidence of new active lesions and fingolimod was discontinued. After 10 weeks of wash-outcladribine was administered. In the following 10 months, she presented with 2 relapses and her follow-up brain MRI scans revealed several tumefactive lesions. She discontinued cladribine and underwent aHSCT.
“We cannot rule out that a shorter wash-out before starting treatment with cladribine would have yielded a better control of the disease. Although evidence is limited, we suggest that cladribine should be used with caution as a rescue strategy for MS patients with persistent disease activity during fingolimod treatment. Further studies are needed to characterize the best therapeutic strategy after fingolimod discontinuation”.
I will leave it to ProfG and ProfK to explain what they would do to transition to cladribine from fingolimod and it can get complicated if fingolimod has caused persistent lymphopenia (low levels of lymphocytes) it makes the point that when ever you start a therapy, you should always consider where next if the treatment fails.
Hello MD, ProfK here: As you say time is of the essence, and the problem, of course, is the ‘mandatory’ lymphocyte level of 1.0 x 109/L before starting oral cladribine treatment. Since pwMS on S1P modulators, such as fingolimod, can develop severe rebound disease despite subnormal lymphocyte counts, it is key not to delay starting follow-on treatment. However, all of the above cases were well within the “rebound-window” prior to starting cladribine treatment. Based on the immune cell kinetics, we expect the effect of cladribine to kick in from month 2, and this is probably fully developed from month 3 after treatment initiation. During this period, pwMS remain at risk of rebound disease, which is why at BartsMS we have moved to a different strategy when switching from S1P modulators to cladribine. We wait until a clear upward trend of the total lymphocyte count is established, which could be, for example, from 0.1 to 0.5 x 109/L four weeks after stopping fingolimod, and then start cladribine. Using this individualized approach, we have not experienced any rebound disease so far.