NEWS & VIEWS MULTIPLE SCLEROSIS
Natalizumab to fingolimod —the washout whitewash Martin Stangel and Olaf Stüve
A recent multicentre study has assessed the risk of relapse in patients with multiple sclerosis who switched from natalizumab to fingolimod treatment. Despite such efforts, no effective exit strategy from natalizumab treatment has yet been demonstrated for these patients. Stangel, M. & Stüve, O. Nat. Rev. Neurol. 10, 311–313 (2014); published online 20 May 2014; doi:10.1038/nrneurol.2014.82
The approval of natalizumab for the treatment of patients with multiple sclerosis (MS) introduced a new era of highly effective immunomodulation. Unfortunately, not all patients respond well to natalizumab treatment, and its therapeutic benefits are overshadowed by an increased risk of progressive multifocal leukoencephalopathy (PML). A recently published multicentre study assessed the issues surrounding the safety and practicality of transitioning patients with MS from natalizumab to fingolimod therapy, particularly with regard to the risk of relapse.1 Cohen and colleagues1 prospectively collected survey data from 333 patients, across 36 referral centres, who switched from natalizumab to fingolimod treatment for the active phase of relapsing–remitting MS. These patients mostly switched due to fear of natalizumab-associated PML, with more than 65% of patients having at least two risk factors for this condition. Other common reasons for cessation of natalizumab were perceived lack of efficacy, adverse effects and the development of neutralizing antibodies. No hypothesis for this trial was explicitly stated, but we can probably assume that the investigators hypothesized that a switch from natalizumab to fingolimod would be feasible and safe. If this was the case, however, the design of this study, like others before it, may have diminished the possibility that such a hypothesis would be supported. Most importantly, the protocol included a natalizumab washout period before initiating fingolimod, probably to mitigate the increased risk of PML that is presumed to result from a compounded effect of sequential
immunosuppressive therapies. The washout period of natalizumab was in the range of 2–156 weeks (mean 17 weeks), and was less than 3 months in 31.3% of patients. A previously demonstrated risk of MS disease reactivation within 3–6 months of cessation of natalizumab seems to have been largely ignored.2
‘‘
…evidence is growing that a [natalizumab] washout period adversely affects the health of patients
’’
Perhaps not surprisingly, the strongest risk factor for disease reactivation was the length of the washout period, with 59.1% of patients experiencing relapse after waiting more than 6 months to resume treatment, which confirms what was demonstrated in a much larger cohort several years ago.2 Other risk factors included a high relapse rate before natalizumab initiation, as well as a lack of tolerance to natalizumab or a lack of treatment efficacy, though the assessment criteria for these risk factors were not described by the authors. Unfortunately, the annualized relapse rate under natalizumab treatment during this study was not provided. Even during the short followup period under fingolimod—less than 6 months for one-third of patients—relapses occurred in 20% of the cohort. Other recent studies confirm the risk of disease reactivation during a natalizumab washout phase. Clinical data from an international registry identified 89 patients with MS who had switched from natalizumab to
NATURE REVIEWS | NEUROLOGY
fingolimod,3 and patients with a washout period of less than 2 months had a significantly lower risk of relapse than did those with longer washout periods. A randomized trial presented at a recent conference meas ured disease activity, via clinical relapses and contrast-enhancing lesions on MRI, in patients with MS who switched to fingolimod 1, 8, 12, or 16 weeks after the last natalizumab infusion. 4 Disease activity seemed to increase with the length of the washout period. In the Cohen et al. study, 1 20–50% of patients who were stable on natalizumab developed clinical and/or MRI-visible disease activity when switched to fingolimod, which is consistent with the results from several smaller case series. As stated above, this study did not assess disease activity during natalizumab treatment, but we can probably assume that the relapse rate decreased from baseline. In patients with MS receiving natalizumab treatment, the risk of PML needs to be weighed against that of disease reactivation. A recent risk- stratification algorithm identified three risk factors for natalizumab-associated PML: presence of anti-JC virus antibodies in serum, more than 2 years of natalizumab therapy, and a history of pharmacological immunosuppression. 5 Patients with all three risk factors have approximately a 1:90 risk of developing PML, and should probably be advised to discontinue natalizumab. Patients who only have one or two recognized risk factors should be monitored closely to determine if and when they should switch treatments. The results of these studies do not pro vide patients or their neurologists with an answer to one of the most pressing questions in clinical neuroimmunology: what is the ‘exit strategy’ for patients who are being treated with natalizumab, but who want or need to discontinue? Immunological and pharmacological data suggest that a treatment hiatus after natalizumab is inadvisable. 6,7 Specifically, evidence is growing that a washout period adversely affects the health of patients. Furthermore, none of the preceding studies have addressed the issue of whether any benefits gained during treatment with natalizumab are lost in those patients who discontinue this medication. VOLUME 10 | JUNE 2014 | 1
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS Natalizumab
1 2
CNS
Peripheral blood vessel Fingolimod
3
Lymph node
Figure 1 | Biological effects of natalizumab and fingolimod. Natalizumab is an effective therapy for patients with relapsing forms of multiple sclerosis. However, disease activity returns in a predictable manner after discontinuation,2 which might be explained by the treatment’s biological activities. Natalizumab sequesters antigen-reactive leukocytes away from the CNS and into the peripheral blood (1), where leukocytes assume a more inflammatory phenotype (2).6,7 By contrast, fingolimod antagonizes the sphingosine-1-phosphate receptors on leukocytes (3), which prevents the egress of lymphocytes—predominantly CD4+ T-helper cells—from lymphatic tissues.10
It is also unknown whether neurological deficits acquired during a treatment hiatus can be reversed. Given these uncertainties associated with natalizumab cessation, perhaps we should contemplate treatment overlap instead of treatment hiatus. Disease activity returns in a predictable manner after discontinuation of natalizumab,2 which might be explained by the drug’s biological effects (Figure 1). Natali zumab sequesters CNS-antigen-reactive leukocytes to peripheral blood, where these cells assume an inflammatory phenotype. One experiment demonstrated that natalizumab therapy led to 2–3-fold increases in the number of CD19+ mature B cells in peripheral blood, and 7.4-fold increases
2 | JUNE 2014 | VOLUME 10
in immature CD19+CD10+ pre-B cells, compared with pretreatment levels. 6 Another experiment showed that treatment with natalizumab for 6 months led to increases in the number of cells producing the cytokines IFNγ, tumour necrosis factor and IL17 after anti-CD3 stimulation.7 The return of clinical disease activity in patients who stopped taking natalizumab correlates with the reconstitution of CD4+ and CD8+ T cells in the cerebrospinal fluid.9 In contrast to natalizumab, fingolimod antagonizes leukocyte sphingosine-1- phosphate receptors, thereby blocking the egress of lymphocytes—predominantly CD4+ T-helper cells—from lymphatic tis sues.10 These cells account for only around 2% of all lymphocytes, and the biological functions of lymphocytes circulating in peripheral blood—the proinflammatory cells that would accumulate during natalizumab treatment—are probably not affected. Consequently, it is biologically plausible that initiation of fingolimod immediately after discontinuation of nata liz umab will not lead to a compounded immunosuppressive effect, and thus any beneficial effect of a treatment hiatus will be minor. Furthermore, immediate fingolimod treatment might ameliorate MS disease activity by preventing the egress of additional myelin-reactive CD4+ T cells from lymphoid tissues. Physiological mechanisms of follow-up therapies should be considered when planning trials, and patients should be carefully tested via imaging and laboratory methods for any evidence of PML before initiating the intervention. Natalizumab monotherapy carries an increased risk of PML even after its discontinuation, and regardless of whether sequential therapies are used.8 Finding the right strategy to keep patients with MS safe and healthy after discontinuing natalizumab will not be easy, and will require a concerted effort that takes into account the results from successful and failed clinical trials alike.
Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Hannover, Germany (M.S.). Neurology Section, VA North Texas Health Care System, Medical Service Dallas, VA Medical Centre, 4500 South Lancaster Road, Dallas, TX 75216, USA (O.S.). Correspondence to: O.S. [email protected] Competing interests M.S. has received honouraria or consultancy payments from Bayer Healthcare, Biogen Idec, Baxter, CSL Behring, Grifols, Merck-Serono, Novartis, SanofiAventis, and Teva. His institution has received research support from Bayer Healthcare, Biogen Idec, Merck-Serono, Novartis, and Teva. O.S. declares no competing interests. 1.
Cohen, M. et al. Switching from natalizumab to fingolimod in multiple sclerosis: a French prospective study. JAMA Neurol. 71, 436–441 (2014). 2. O’Connor, P. W. et al. Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis. Neurology 76, 1858–1865 (2011). 3. Jokubaitis, V. G. et al. Fingolimod after natalizumab and the risk of short-term relapse. Neurology 82, 1204–1211 (2014). 4. Kappos, L. et al. Disease control and safety in relapsing–remitting multiple sclerosis (RRMS) patients switching from natalizumab to fingolimod: a 32-week, rater- and patient-blind, randomized, parallel-group study (TOFINGO). Mult. Scler. 19 (Suppl. 1), 50 (2013). 5. Bloomgren, G. et al. Risk of natalizumabassociated progressive multifocal leukoencephalopathy. N. Engl. J. Med. 366, 1870–1880 (2012). 6. Krumbholz, M., Meinl, I., Kümpfel, T., Hohlfeld, R. & Meinl, E. Natalizumab disproportionately increases circulating pre-B and B cells in multiple sclerosis. Neurology 71, 1350–1354 (2008). 7. Kivisakk, P. et al. Natalizumab treatment is associated with peripheral sequestration of proinflammatory T cells. Neurology 72, 1922–1930 (2009). 8. Fine, A. J., Sorbello, A., Kortepeter, C. & Scarazzini, L. Progressive multifocal leukoencephalopathy after natalizumab discontinuation. Ann. Neurol. 75, 108–115 (2014). 9. Stüve, O. et al. Immunologic, clinical, and radiologic status 14 months after cessation of natalizumab therapy. Neurology 72, 396–401 (2009). 10. Brinkmann, V. et al. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J. Biol. Chem. 277, 21453–21457 (2002).
www.nature.com/nrneurol © 2014 Macmillan Publishers Limited. All rights reserved
Natalizumab to fingolimod —the washout whitewash Martin Stangel and Olaf Stüve
A recent multicentre study has assessed the risk of relapse in patients with multiple sclerosis who switched from natalizumab to fingolimod treatment. Despite such efforts, no effective exit strategy from natalizumab treatment has yet been demonstrated for these patients. Stangel, M. & Stüve, O. Nat. Rev. Neurol. 10, 311–313 (2014); published online 20 May 2014; doi:10.1038/nrneurol.2014.82
The approval of natalizumab for the treatment of patients with multiple sclerosis (MS) introduced a new era of highly effective immunomodulation. Unfortunately, not all patients respond well to natalizumab treatment, and its therapeutic benefits are overshadowed by an increased risk of progressive multifocal leukoencephalopathy (PML). A recently published multicentre study assessed the issues surrounding the safety and practicality of transitioning patients with MS from natalizumab to fingolimod therapy, particularly with regard to the risk of relapse.1 Cohen and colleagues1 prospectively collected survey data from 333 patients, across 36 referral centres, who switched from natalizumab to fingolimod treatment for the active phase of relapsing–remitting MS. These patients mostly switched due to fear of natalizumab-associated PML, with more than 65% of patients having at least two risk factors for this condition. Other common reasons for cessation of natalizumab were perceived lack of efficacy, adverse effects and the development of neutralizing antibodies. No hypothesis for this trial was explicitly stated, but we can probably assume that the investigators hypothesized that a switch from natalizumab to fingolimod would be feasible and safe. If this was the case, however, the design of this study, like others before it, may have diminished the possibility that such a hypothesis would be supported. Most importantly, the protocol included a natalizumab washout period before initiating fingolimod, probably to mitigate the increased risk of PML that is presumed to result from a compounded effect of sequential
immunosuppressive therapies. The washout period of natalizumab was in the range of 2–156 weeks (mean 17 weeks), and was less than 3 months in 31.3% of patients. A previously demonstrated risk of MS disease reactivation within 3–6 months of cessation of natalizumab seems to have been largely ignored.2
‘‘
…evidence is growing that a [natalizumab] washout period adversely affects the health of patients
’’
Perhaps not surprisingly, the strongest risk factor for disease reactivation was the length of the washout period, with 59.1% of patients experiencing relapse after waiting more than 6 months to resume treatment, which confirms what was demonstrated in a much larger cohort several years ago.2 Other risk factors included a high relapse rate before natalizumab initiation, as well as a lack of tolerance to natalizumab or a lack of treatment efficacy, though the assessment criteria for these risk factors were not described by the authors. Unfortunately, the annualized relapse rate under natalizumab treatment during this study was not provided. Even during the short followup period under fingolimod—less than 6 months for one-third of patients—relapses occurred in 20% of the cohort. Other recent studies confirm the risk of disease reactivation during a natalizumab washout phase. Clinical data from an international registry identified 89 patients with MS who had switched from natalizumab to
NATURE REVIEWS | NEUROLOGY
fingolimod,3 and patients with a washout period of less than 2 months had a significantly lower risk of relapse than did those with longer washout periods. A randomized trial presented at a recent conference meas ured disease activity, via clinical relapses and contrast-enhancing lesions on MRI, in patients with MS who switched to fingolimod 1, 8, 12, or 16 weeks after the last natalizumab infusion. 4 Disease activity seemed to increase with the length of the washout period. In the Cohen et al. study, 1 20–50% of patients who were stable on natalizumab developed clinical and/or MRI-visible disease activity when switched to fingolimod, which is consistent with the results from several smaller case series. As stated above, this study did not assess disease activity during natalizumab treatment, but we can probably assume that the relapse rate decreased from baseline. In patients with MS receiving natalizumab treatment, the risk of PML needs to be weighed against that of disease reactivation. A recent risk- stratification algorithm identified three risk factors for natalizumab-associated PML: presence of anti-JC virus antibodies in serum, more than 2 years of natalizumab therapy, and a history of pharmacological immunosuppression. 5 Patients with all three risk factors have approximately a 1:90 risk of developing PML, and should probably be advised to discontinue natalizumab. Patients who only have one or two recognized risk factors should be monitored closely to determine if and when they should switch treatments. The results of these studies do not pro vide patients or their neurologists with an answer to one of the most pressing questions in clinical neuroimmunology: what is the ‘exit strategy’ for patients who are being treated with natalizumab, but who want or need to discontinue? Immunological and pharmacological data suggest that a treatment hiatus after natalizumab is inadvisable. 6,7 Specifically, evidence is growing that a washout period adversely affects the health of patients. Furthermore, none of the preceding studies have addressed the issue of whether any benefits gained during treatment with natalizumab are lost in those patients who discontinue this medication. VOLUME 10 | JUNE 2014 | 1
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS Natalizumab
1 2
CNS
Peripheral blood vessel Fingolimod
3
Lymph node
Figure 1 | Biological effects of natalizumab and fingolimod. Natalizumab is an effective therapy for patients with relapsing forms of multiple sclerosis. However, disease activity returns in a predictable manner after discontinuation,2 which might be explained by the treatment’s biological activities. Natalizumab sequesters antigen-reactive leukocytes away from the CNS and into the peripheral blood (1), where leukocytes assume a more inflammatory phenotype (2).6,7 By contrast, fingolimod antagonizes the sphingosine-1-phosphate receptors on leukocytes (3), which prevents the egress of lymphocytes—predominantly CD4+ T-helper cells—from lymphatic tissues.10
It is also unknown whether neurological deficits acquired during a treatment hiatus can be reversed. Given these uncertainties associated with natalizumab cessation, perhaps we should contemplate treatment overlap instead of treatment hiatus. Disease activity returns in a predictable manner after discontinuation of natalizumab,2 which might be explained by the drug’s biological effects (Figure 1). Natali zumab sequesters CNS-antigen-reactive leukocytes to peripheral blood, where these cells assume an inflammatory phenotype. One experiment demonstrated that natalizumab therapy led to 2–3-fold increases in the number of CD19+ mature B cells in peripheral blood, and 7.4-fold increases
2 | JUNE 2014 | VOLUME 10
in immature CD19+CD10+ pre-B cells, compared with pretreatment levels. 6 Another experiment showed that treatment with natalizumab for 6 months led to increases in the number of cells producing the cytokines IFNγ, tumour necrosis factor and IL17 after anti-CD3 stimulation.7 The return of clinical disease activity in patients who stopped taking natalizumab correlates with the reconstitution of CD4+ and CD8+ T cells in the cerebrospinal fluid.9 In contrast to natalizumab, fingolimod antagonizes leukocyte sphingosine-1- phosphate receptors, thereby blocking the egress of lymphocytes—predominantly CD4+ T-helper cells—from lymphatic tis sues.10 These cells account for only around 2% of all lymphocytes, and the biological functions of lymphocytes circulating in peripheral blood—the proinflammatory cells that would accumulate during natalizumab treatment—are probably not affected. Consequently, it is biologically plausible that initiation of fingolimod immediately after discontinuation of nata liz umab will not lead to a compounded immunosuppressive effect, and thus any beneficial effect of a treatment hiatus will be minor. Furthermore, immediate fingolimod treatment might ameliorate MS disease activity by preventing the egress of additional myelin-reactive CD4+ T cells from lymphoid tissues. Physiological mechanisms of follow-up therapies should be considered when planning trials, and patients should be carefully tested via imaging and laboratory methods for any evidence of PML before initiating the intervention. Natalizumab monotherapy carries an increased risk of PML even after its discontinuation, and regardless of whether sequential therapies are used.8 Finding the right strategy to keep patients with MS safe and healthy after discontinuing natalizumab will not be easy, and will require a concerted effort that takes into account the results from successful and failed clinical trials alike.
Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Hannover, Germany (M.S.). Neurology Section, VA North Texas Health Care System, Medical Service Dallas, VA Medical Centre, 4500 South Lancaster Road, Dallas, TX 75216, USA (O.S.). Correspondence to: O.S. [email protected] Competing interests M.S. has received honouraria or consultancy payments from Bayer Healthcare, Biogen Idec, Baxter, CSL Behring, Grifols, Merck-Serono, Novartis, SanofiAventis, and Teva. His institution has received research support from Bayer Healthcare, Biogen Idec, Merck-Serono, Novartis, and Teva. O.S. declares no competing interests. 1.
Cohen, M. et al. Switching from natalizumab to fingolimod in multiple sclerosis: a French prospective study. JAMA Neurol. 71, 436–441 (2014). 2. O’Connor, P. W. et al. Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis. Neurology 76, 1858–1865 (2011). 3. Jokubaitis, V. G. et al. Fingolimod after natalizumab and the risk of short-term relapse. Neurology 82, 1204–1211 (2014). 4. Kappos, L. et al. Disease control and safety in relapsing–remitting multiple sclerosis (RRMS) patients switching from natalizumab to fingolimod: a 32-week, rater- and patient-blind, randomized, parallel-group study (TOFINGO). Mult. Scler. 19 (Suppl. 1), 50 (2013). 5. Bloomgren, G. et al. Risk of natalizumabassociated progressive multifocal leukoencephalopathy. N. Engl. J. Med. 366, 1870–1880 (2012). 6. Krumbholz, M., Meinl, I., Kümpfel, T., Hohlfeld, R. & Meinl, E. Natalizumab disproportionately increases circulating pre-B and B cells in multiple sclerosis. Neurology 71, 1350–1354 (2008). 7. Kivisakk, P. et al. Natalizumab treatment is associated with peripheral sequestration of proinflammatory T cells. Neurology 72, 1922–1930 (2009). 8. Fine, A. J., Sorbello, A., Kortepeter, C. & Scarazzini, L. Progressive multifocal leukoencephalopathy after natalizumab discontinuation. Ann. Neurol. 75, 108–115 (2014). 9. Stüve, O. et al. Immunologic, clinical, and radiologic status 14 months after cessation of natalizumab therapy. Neurology 72, 396–401 (2009). 10. Brinkmann, V. et al. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J. Biol. Chem. 277, 21453–21457 (2002).
www.nature.com/nrneurol © 2014 Macmillan Publishers Limited. All rights reserved
![[Natalizumab treatment in multiple sclerosis].](/assets/img/hold.png)
