Q: When should switching of disease modifying therapy be considered?

A: Formal guidelines on switching disease-modifying therapy are not clearly defined. The decision to switch therapy is a highly personalized decision between the clinician and each patient, taking into consideration a variety of factors including goals of treatment, disease activity, medication history, and personal preferences. Reasons to switch may include the following:

  • Breakthrough disease activity and inadequate response to therapy
  • Intolerability or specific side effects
  • Adverse events
  • Family planning
  • Compliance/adherence issues
  • Psychosocial reasons
  • Economic/financial reasons

Switch due to disease activity

None of the currently available disease modifying therapy is 100% effective in halting disease activity; therefore, it is not unexpected that patients may experience breakthrough disease activity while on therapy during their disease courses. If breakthrough disease activity is observed while the patient has been confirmed to be treatment-compliant, and sufficient time has passed to allow for full physiologic effect of disease modifying therapy since initiation, then a switch should be considered. Response to disease modifying therapy is difficult to define given ambiguity of monitoring criteria. Various treatment targets have been proposed (including no evidence of disease activity (NEDA3 and NEDA4), the Rio score and modified Rio Score) but there is no well-defined consensus in the clinical setting. In general, we consider any clinical relapse or radiographic relapse (new T2 lesions or new contrast-enhancing lesions*) an indication of suboptimal response to therapy. A more potent agent with higher efficacy should be considered rather than agents with similar or lower efficacy to reduce risk of relapse recurrence1. In certain cases, a low level of new disease activity may be unavoidable, but this is becoming less tolerated as more potent agents are now becoming available.

We do not recommend combining disease modifying therapies given limited benefits and risk of additive toxicity and side effects.

* Brain volumetrics in clinical practice are difficult to implement and most disease modifying therapies are designed to halt inflammatory activity, therefore, we currently do not use atrophy measures in the clinical setting to make treatment decisions.

Switch due to intolerability and/or adverse events

Patient tolerance to drug side effects and adverse events plays an important role in the decision to switch therapy, in addition to the clinician’s judgment with regards to risk-benefit profile of each drug. Prior to switching, efforts should be made to implement side effect mitigation strategies (for example, aspirin for flushing due to dimethyl fumarate, headache management for patients on fingolimod, non-steroidal anti-inflammatory drugs for flu-like illnesses due to interferons, steroids and anti-histamines for infusion related reactions dues to infusion therapies). One should generally avoid switching to a medication with similar mechanism of action and/or side effect profile to avoid similar tolerability issues.

Cautious monitoring needs to be applied in patients with other comorbidities. For example, a switch in therapy should be considered in patients on dimethyl fumarate who develop gastrointestinal disorders, in diabetic patients on fingolimod who develop macular edema, in patients on fingolimod who develop cardiac disease and conduction abnormalities. In patients with cancer, it’s unclear whether disease modifying therapy use should be continued. The association between disease modifying therapies in MS and cancer has not been proven. We recommend working with the patient’s oncology team to determine next best step.

For patients with persistent laboratory abnormalities, such as elevated liver enzymes or cytopenia, switch to a therapy with different safety profile should be considered. Patients on natalizumab who become John Cunningham Virus seropositive are at risk for progressive multifocal leukoencephalopathy (PML). In general, we discontinue natalizumab and switch to a different disease modifying therapy, unless there are no other alternatives or in extenuating circumstances. Of note, there have been rare incidences of PML reported in patients on fingolimod, dimethyl fumarate, rituximab and ocrelizumab2, however the . In 6% of patients, anti-natalizumab antibodies can develop within months of initiation, leading to infusion reactions and limiting the therapeutic effects of natalizumab. In patients with persistently positive anti-natalizumab antibodies, we also recommend switching therapy.

Modified dosing schedules for certain agents have been suggested to alleviate side effects and mitigate adverse events risks. For example, every other day dosing of fingolimod can be considered in patients with absolute lymphocyte count (ALC) < 0.2 k/uL 3. Extended interval dosing natalizumab (every 5-8 weeks) has been associated with reduced PML risk 4,5. Lower dose of dimethyl fumarate may be tried for patients experiencing significant gastrointestinal side effects. However, whether efficacy is preserved with modified dosing is uncertain; several ongoing clinical trials are investigating this.

Switch due to drug adherence concerns

As reasons for non-adherence are multi-factorial, each reason should be thoroughly evaluated and the decision to switch individualized. While minor and temporary deviation in administration schedule such as those due to occasional forgetfulness often do not pose risk of disease worsening, a persistent pattern of non-adherence can increase risk for rebound disease activity, especially in those who are on agents such as natalizumab and fingolimod. Drug adherence should be addressed at each clinical visit and attempts should be made to address concerns prior to considering therapy switch.

For practical considerations, patients who cannot tolerate injections or have coagulation disorders, consider switching to an oral or infusion therapy. For patients who have trouble taking daily medications, therapies with infrequent administration may be more convenient.

For patients with cost concerns due to lack of coverage, appeals can be submitted for insurance denials, and financial assistance may be achieved through co-pay assistance or free drug programs offered by corresponding pharmaceutical companies.

It is also important to address any psychosocial concerns that are barriers to drug adherence. Health psychologists and social workers are valuable resources who can be consulted for at-risk patients.

Switch due to family planning

MS most commonly affects women of childbearing age. As there are no controlled trials on pregnancy or breastfeeding safety for any of the currently available agents, in general we discontinue therapies completely rather than switch therapy during pregnancy/breastfeeding. Caveats regarding specific therapies are discussed below.

Glatiramer acetate and interferons are considered safest in pregnancy, in fact, they are approved to be used during pregnancy in Europe. For patients who are already on glatiramer acetate or interferons and are trying to conceive or are already pregnant, it may be reasonable to continue without switching. In patients with higher risk of relapse during pregnancy following discontinuation of their current therapies, it may be reasonable to switch to glatiramer acetate or interferons prior to conception or at time of unplanned pregnancy.

For fingolimod, siponimod, and dimethyl fumarate, there are limited data on safety in pregnancy, and we do not recommend continuing these agents during conception or pregnancy. For patients who are trying to conceive, we recommend stopping 2 months prior to attempted conception. For patients who are already pregnant, we recommend stopping the disease modifying therapies immediately.

FDA used pregnancy categories up to 2014 to designate risk. Teriflunomide was labeled pregnancy category X prior to the label update, which indicates that it has known teratogenic effects. For patients planning to conceive or those with unplanned pregnancies on teriflunomide, an accelerated elimination protocol should be followed prior to conception or immediately following unplanned pregnancy (see details below). Laboratory testing to ensure elimination of teriflunomide is available from the manufacturer through LabCorp laboratories (accelerated elimination procedure). This needs to be set up through the manufacturer.

We no longer use mitoxantrone in our practice but it was labeled pregnancy category D prior to the FDA label update, indicating risk to fetus.

For natalizumab, there are no evidence of teratogenicity in human studies6. In available pregnancy registry data, there is a higher rate of birth defects but without specific drug-related teratogenic patterns, and spontaneous abortion rates were not higher than that of controls7. The decision to discontinue or switch, or remain on natalizumab in pregnancy should be thoroughly discussed with the patient. We recommend stopping natalizumab at time of conception or unplanned pregnancy in most patients. However, in patients with severe and active disease who are at high risk of rebound disease activity, it may be reasonable to continue natalizumab throughout pregnancy instead of switching therapy. Frequency of infusion may be reduced to every 8 weeks during pregnancy to reduce fetal exposure, with the caveat that treatment efficacy of this alternative dosing is unclear. The last dose of natalizumab should be given prior to 34 weeks since the compound does cross the placenta in the second and third trimester.

Ocrelizumab and rituximab are infused infrequently (every 6 months), therefore, strategic planning prior to conception can avoid a need to switch therapy. We recommend waiting at least 6 months after the last infusion prior to attempting conception. If blood pregnancy test is negative, then it is okay to proceed with scheduled infusion. If blood pregnancy test is positive, then skip the next infusion and resume as soon as possible after delivery (of note, we do not recommend ocrelizumab or rituximab while breastfeeding).

For specific pregnancy related issues in MS and disease modifying therapies, please review Mellen Center Approach for pregnancy.

Q: When should MRI be obtained after switching therapy?

A: Disease modifying therapies in MS vary in the amount of time it takes to reach active therapeutic threshold. Obtaining MRI too early after switching therapy can confound efficacy evaluation of the new therapy. New lesion detected before the drug becomes fully active should not be considered breakthrough disease. We recommend re-establishing MRI baseline 3-6 months after switching, and thereafter every 6-12 months for ongoing monitoring depending on disease activity and disease modifying therapy.

Q: How long to wait after discontinuation of one therapy prior to starting another one?

A: In general, there is little data on the optimal timing between therapies. Necessity and length of washout periods depend on the pharmacokinetics, mechanisms of action, and safety profiles of the drugs in consideration, as well as reasons for switching. Efforts should be made to minimize the washout period since there are risks of disease worsening during washout period for certain agents. At the same time, potential compounding toxicities of overlapping therapies must be considered.

Specific disease modifying therapy switch protocols

Prior to starting any new therapy, ensure that required vaccination (i.e. varicella, meningitis, pneumococcal vaccines) and necessary screening tests are performed.

From injectable medications (interferons, glatiramer acetate)

Switching to and from injectable medications are generally considered safe, and no washout period is required.

From S1P modulators (fingolimod, siponimod)

There is risk of rebound disease activity following discontinuation of fingolimod8. We recommend no washout period in general. In cases of markedly low ALC (< 0.2 k/uL), it is advised to discontinue the agent, recheck ALC in a few weeks and confirm recovery or at least trend of rising counts prior to starting another agent that may also lower ALC (i.e. dimethyl fumarate, alemtuzumab, cladribine, rituximab, and ocrelizumab). There is also a theoretical concern that lymphocyte sequestration agents might lower the efficacy of cell depleting agents.

From dimethyl fumarate

We typically don’t perform a washout period for dimethyl fumarate prior to starting another agent. However, for patients experiencing dimethyl fumarate related lymphopenia, the levels may take months to normalize, if at all. The degree of lymphopenia and safety profile of the future agent can guide decision regarding whether a washout period is needed. Unless there is severe infection risk or markedly low ALC (< 0.2 k/uL), we don’t wait for normal ALC levels prior to switching.

From teriflunomide

Teriflunomide has a long elimination half-life (approximately 19 days), therefore, it may take 8 months to 2 years after discontinuation to reach undetectable blood levels (<0.02mg/L). In cases such as pregnancy planning or intolerability/severe adverse events, a rapid elimination protocol should be followed (cholestyramine 4g-8g three times daily for 11 days or activated charcoal 50g twice daily for 11 days). Teriflunomide level should be checked at end of the elimination protocol to ensure completion (to be set up by the manufacturer to LabCorp laboratories). In cases of switching to injectable agents, it has been shown to be safe when teriflunomide has been used in combination with injectables 9,10, thus, rapid elimination protocol is not necessary. When switching to an oral or infusion therapy, the decision to perform rapid elimination protocol depends on each case, such as for reasons mentioned above.

From natalizumab

There is risk of severe rebound disease activity within 6 months of stopping natalizumab with the highest risk peaking at 3-4 months11,12. Therefore, efforts should be made to minimize time between therapy switching. A short or no washout period could be considered when switching from natalizumab, especially if the patient has significant disease activity prior to natalizumab. Drugs with efficacy comparable to natalizumab than less efficacious drugs are generally preferred.

Switching to oral agents after discontinuing natalizumab has been found to be safe within 8-12 weeks13,14. Safety of switching from natalizumab to ocrelizumab has not been studied, but there have not been reports of major breakthrough disease or safety concerns thus far. In addition, switching from natalizumab to rituximab has been found to be safe15.

We usually initiate new agents within 4-6 weeks after stopping natalizumab. For patients with highly active disease prior to natalizumab initiation, pulse intravenous steroids can be used for bridging between agents. However, current evidence do not show that steroids are sufficiently effective in preventing rebound activity.

From anti-CD20 agents (ocrelizumab, rituximab)

Timing of switch after anti-CD20 agents depends on reason for switching. It is reasonable to switch due to side effects or adverse events such as recurrent or serious infections, and/or low IgG levels. Breakthrough disease activity is rare in patients on anti-CD20 agents, it may be worthwhile to reconsider diagnosis if the patient is experiencing breakthrough activity.

We generally do not perform a washout period when switching from anti-CD20 agents. It’s important to minimize time in between therapies to avoid the resurgence in disease activity that can be seen following B-cell repopulation. B-cell repopulation following discontinuation of anti-CD20 agents has been reported as early as 3-6 months16. CD19 levels can be monitored in high risk cases.

From alemtuzumab

It is uncommon for patients to start on a different disease-modifying therapy following alemtuzumab17,18, therefore, there exists the least amount of published data and clinical experiences to guide this transition. To date, no significant safety concern has been reported in patients who received other disease modifying therapies following completion of alemtuzumab treatment protocol17,18. B-cell therapies may be more preferable following alemtuzumab given safety data that has been published with regards to its use in treatment of idiopathic thrombocytopenic purpura, an alemtuzumab adverse event19.

Q: Are there any additional precautions to consider when switching from branded drug to its generic version or bioequivalent drug?

A: No. We view generic versions or bioequivalent drugs of branded drugs as the same agent. It is not considered a therapy switch, therefore we do not expect any interruptions in the administration schedule.

Q: What to consider for therapy switching in pediatric onset MS?

A: There are very limited data to guide therapy switching in pediatric onset MS. The International Pediatric Multiple Sclerosis Study Group’s consensus statement regarding evaluating existing therapies can be reviewed for reference20, but updated guidelines are needed.

References

  1. Rae-Grant A, Day GS, Marrie RA, et al. Comprehensive systematic review summary: Disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018;90(17):789-800.
  2. Berger JR. Classifying PML risk with disease modifying therapies. Multiple sclerosis and related disorders. 2017;12:59-63.
  3. Longbrake EE, Kantor D, Pawate S, et al. Effectiveness of alternative dose fingolimod for multiple sclerosis. Neurol Clin Pract. 2018;8(2):102-107.
  4. Zhovtis Ryerson L, Frohman TC, Foley J, et al. Extended interval dosing of natalizumab in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2016;87(8):885-889.
  5. Yamout BI, Sahraian MA, Ayoubi NE, et al. Efficacy and safety of natalizumab extended interval dosing. Mult Scler Relat Disord. 2018;24:113-116.
  6. Marrie RA. Maternal and fetal risks of natalizumab exposure in utero. A fine balance. 2018;90(10):443-444.
  7. Friend S, Richman S, Bloomgren G, Cristiano LM, Wenten M. Evaluation of pregnancy outcomes from the Tysabri(R) (natalizumab) pregnancy exposure registry: a global, observational, follow-up study. BMC Neurol. 2016;16(1):150.
  8. Hatcher SE, Waubant E, Nourbakhsh B, Crabtree-Hartman E, Graves JS. Rebound Syndrome in Patients With Multiple Sclerosis After Cessation of Fingolimod Treatment. JAMA Neurol. 2016;73(7):790-794.
  9. Freedman M, Wolinsky J, Truffinet P, et al. A randomized trial of teriflunomide added to glatiramer acetate in relapsing multiple sclerosis. In: Mult Scler J Exp Transl Clin. Vol 1.2015.
  10. Freedman MS, Wolinsky JS, Wamil B, et al. Teriflunomide added to interferon-beta in relapsing multiple sclerosis: a randomized phase II trial. Neurology. 2012;78(23):1877-1885.
  11. O'Connor PW, Goodman A, Kappos L, et al. Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis. Neurology. 2011;76(22):1858-1865.
  12. Fox RJ, Cree BA, De Seze J, et al. MS disease activity in RESTORE: a randomized 24-week natalizumab treatment interruption study. Neurology. 2014;82(17):1491-1498.
  13. Cohan SL, Moses H, Calkwood J, et al. Clinical outcomes in patients with relapsing-remitting multiple sclerosis who switch from natalizumab to delayed-release dimethyl fumarate: A multicenter retrospective observational study (STRATEGY). Mult Scler Relat Disord. 2018;22:27-34.
  14. Kappos L, Radue EW, Comi G, et al. Switching from natalizumab to fingolimod: A randomized, placebo-controlled study in RRMS. In: Neurology. Vol 85.2015:29-39.
  15. Alping P, Frisell T, Novakova L, et al. Rituximab versus fingolimod after natalizumab in multiple sclerosis patients. Annals of neurology. 2016;79(6):950-958.
  16. Ellwardt E, Ellwardt L, Bittner S, Zipp F. Monitoring B-cell repopulation after depletion therapy in neurologic patients. Neurology - Neuroimmunology Neuroinflammation. 2018;5(4):e463.
  17. Coles AJ, Cohen JA, Fox EJ, et al. Alemtuzumab CARE-MS II 5-year follow-up: Efficacy and safety findings. In: Neurology. Vol 89.2017:1117-1126.
  18. Pelletier D, Arnold DL, Boyko AN, et al. Improved Clinical and MRI Disease Activity Outcomes, Including Slowing of Brain Volume Loss, in Alemtuzumab-Treated RRMS Patients: 8-Year Follow-up of CARE-MS I (TOPAZ Study) (P3.2-037). Neurology. 2019;92(15 Supplement):P3.2-037.
  19. Gomez-Almaguer D. Monoclonal antibodies in the treatment of immune thrombocytopenic purpura (ITP). Hematology. 2012;17 Suppl 1:S25-27.
  20. Chitnis T, Tenembaum S, Banwell B, et al. Consensus statement: evaluation of new and existing therapeutics for pediatric multiple sclerosis. Mult Scler. 2012;18(1):116-127.