Switching

Switching-2-mitoxantrone

Last updated on November 28th, 2024 at 01:51 pm

Possible reasons to switch

  • The benefits of mitoxantrone may be greater than the potential risks from chronic immunosuppression or untreated MS in resource-poor environments.
  • Mitoxantrone is safer than other agents that are non-selective or less selective; this is relevant following treatment with ocrelizumab.
  • If mitoxantrone is available in your country, there is no reason why it cannot be used after any of the licensed DMTs, provided the baseline screening tests are within acceptable limits and there are no specific contraindications (please see individual DMTs below).

Reasons for caution

  • The presence of other specific comorbidities and adverse events.
  • The total lifetime dose should not exceed 140 mg/m².
  • Underlying cardiomyopathy (detected with ECG and echo/MUGA monitoring).
  • Low white cell counts post-alemtuzumab, -cladribine or –HSCT.
  • People with MS who have lymphopaenia on dimethyl fumarate may be more susceptible to prolonged lymphopaenia post-mitoxantrone.
  • Carry-over PML from natalizumab could be potentially fatal.
  • Patients with indwelling urinary catheters and/or recurrent urinary tract and other infections are at risk of infections post-mitoxantrone.

Mitoxantrone repeat course

As mitoxantrone is an immune reconstitution therapy (IRT), breakthrough activity may trigger the need for additional courses to be given, provided the total lifetime dose of mitoxantrone does not exceed 140 mg/m² and that cardiac monitoring (ECG and echo/MUGA) does not show signs of underlying cardiomyopathy.

Other DMTs

Mitoxantrone is licensed in the USA and in some European countries (though not the UK). Provided the baseline screening tests are acceptable and there are no specific contraindications, it is feasible (from a clinical perspective) to use mitoxantrone after another licensed DMT; please check the licensing regulations in your country.

Interferon-beta and glatiramer acetate

There are no specific cautions.

S1P modulators (fingolimod, siponimod, ozanimod and ponesimod)

The development of mitoxantrone-related cardiomyopathy and/or cardiac arrhythmia is a contraindication for using fingolimod and other S1P modulators (siponimod, ozanimod and ponesimod) after mitoxantrone. It is important to be extra-vigilant when doing the routine baseline cardiac checks post-mitoxantrone. If it has been some time since mitoxantrone’s last dose, I recommend checking a cardiac ejection fraction with echocardiography or a MUGA scan.

Alemtuzumab and HSCT (non-selective cell depleting DMTs)

A persistently low peripheral white cell count post-alemtuzumab, HSCT or other DMT, i.e. a neutrophil count < 1000/mm³ or a total lymphocyte count <800/mm³ is a relative contraindication to using mitoxantrone. Another hit on the bone marrow and primary and secondary lymphoid organs may render an individual more immunosuppressed and worsen their leukopaenia. The decision to use mitoxantrone in this situation has to be based on the potential benefits versus the risks of these treatments and the risks of untreated active MS. 

Cladribine (selective cell depleting DMT)

A persistently low peripheral lymphocyte cell count post-cladribine, i.e. a total lymphocyte count <800/mm³ is a relative contraindication to using mitoxantrone. The effect of mitoxantrone on primary and secondary lymphoid organs may worsen the lymphopaenia and is a risk factor for developing grade 3 or grade 4 lymphopaenia, i.e. <500/mm³ or <200/mm³, respectively. However, the decision to use mitoxantrone in this situation has to be based on the potential benefits of the treatment versus the risks of lymphopaenia and the risks of untreated active MS.

Anti-CD20 therapies (selective cell depleting DMTs)

Anti-CD20 therapies (ocrelizumab, ofatumumab and others) are selective B-cell depleting agents, so mitoxantrone is theoretically much safer than the other less selective and non-selective agents post-ocrelizumab.

Natalizumab

As mitoxantrone is an IRT that can’t be rapidly reversed, it is critical to ensure that there is no asymptomatic PML. Carry-over PML from natalizumab to mitoxantrone is potentially fatal. Therefore, a baseline MRI scan and possibly a CSF examination is essential to exclude the possibility of PML before starting mitoxantrone. 

Dimethyl fumarate

DMF reduces the lymphocyte count by approximately 30% and in some people with MS by more than this. Therefore, individuals with lymphopaenia on DMF may be more susceptible to developing clinically significant prolonged lymphopaenia post-mitoxantrone.

Teriflunomide

Because teriflunomide is an antiproliferative agent, it may delay or prevent the recovery of the peripheral white cell count post-mitoxantrone. One option is to do an accelerated teriflunomide washout to prevent this potential problem. Interestingly, rheumatologists who use leflunomide, a prodrug converted to teriflunomide, don’t use an accelerated washout when using antiproliferative agents post-leflunomide. I, therefore, don’t think an accelerated washout is necessary.

Special circumstances

The presence of other specific comorbidities and adverse events may make it difficult to start mitoxantrone after another DMT.