The problem that arises after two years of therapy with Natalizumab (Tysabri®) I had already described in a previous blog post: After two years of therapy, the risk of progressive multifocal leukoencephalopathy (PML) increases for JCV antibody positive patients. Understandably, the information about this risk increase often leads to great uncertainty among MS patients who receive the active ingredient – but also very often among treating doctors who administer Tysabri® . Often the result is the desire to stop the medication. However, it is a poor choice to stop Natalizumab therapy without replacement after two years due to fear of side effects – which, however, often happens in practice. MS patients who receive Tysabri® need a drug of this strength to control their disease. If you stop the medication, you can assume that the disease will return with full force.
From scientific studies, we know that after about 3 months there is again MRI activity; within 6 months of stopping therapy, most Tysabri dropouts also have (severe) clinical relapses. It is often discussed whether one has to expect a so-called rebound, i.e. an excessive recurrence of disease activity, after stopping Natalizumab. In general, however, it is rather the continuation of the active course of the disease, which is often perceived as very dramatic and violent after years of stability under the medication.
So what are the alternatives if you want to stop the medication out of fear of PML, but want to keep the risk of recurrence of old disease activity as low as possible? A frequently chosen strategy, which I also offer primarily, is switching to Gilenya® (Fingolimod). It is important not to choose the transition interval too large. It is probably sensible to start with Fingolimod 1-2 months after stopping Natalizumab – otherwise a therapeutic gap will arise with the risk that the original disease activity will return. However, you must also be aware that it is often not possible to successfully treat Tysabri patients with Gilenya. It is probably realistic to assume that sufficient therapeutic success is achieved in about 50% of switched patients. This is not bad – but of course it means that a therapeutic alternative is needed for the other 50%.
Therefore, a lot was expected from the approval of Lemtrada® (Alemtuzumab). However, the reality shows that switching a JCV-positive Tysabri patient to Lemtrada is quite complicated in practice. Because of the danger that Tysabri dropouts could potentially already have PML, German MS experts recommend waiting six months to switch to Alemtuzumab. From this point on, you can be relatively sure that no PML caused by Natalizumab will occur anymore. However, as already described above, this would mean that active MS can be expected again at this time – a danger that one wants to avert from the patient. On the other hand, a Lemtrada infusion would mean the death of the patient in the case of a developing PML. You are thus caught between two risk constellations. This is why Alemtuzumab is probably used as an alternative to Natalizumab in the second line – i.e. when Fingolimod has failed as a switch option. It is better to think of Lemtrada as an alternative to therapy optimization with Tysabri from the beginning.
Because of the described dilemma, I try to talk to my patients about the last alternative – namely to continue Tysabri despite the increased PML risk beyond two years. One should not ignore the risk of active MS either. The return of old activity is a bigger and more realistic risk than PML under Tysabri medication. Many patients who have experienced the effect of Tysabri and want to maintain this condition are willing to accept this benefit-risk assessment. In this case, the doctor should support the patient’s wish and be extremely vigilant regarding side effects. With early detection, there is a good chance of surviving a Tysabri PML well. Therefore, in the current therapy situation, I recommend patients who can deal with their fear to stay on Tysabri. Of course, I hope that we will soon have medications that have the effectiveness of Natalizumab but are not associated with such serious side effects.
