Switching

Switching-2-HSCT (haematopoietic stem cell transplant)

Last updated on November 28th, 2024 at 01:46 pm

Possible reasons to switch

  • HSCT is indicated as part of routine clinical care in the occasional patient with malignant MS who has failed licensed treatment options. In such patients, the benefits of HSCT outweigh the risks of the disease.
  • Provided you have sufficient reserve capacity in the brain and spinal cord, you will see spontaneous recovery from relapse-related disability once inflammation is switched off, and recovery mechanisms can proceed.
  • Please note the benefit ̶ risk ratio changes with more advanced disease; most HSCT units have age and disability cut-offs for people with MS.

Reasons for caution

  • There is a 0.3% ̶ 2% chance of dying from non-myeloablative HSCT, i.e. 1 in 330 to as high as 1 in 50.
  • The toxicity associated with the chemotherapy is severe, including nausea, vomiting, diarrhoea, hair loss, bleeding, infections, infertility and neurotoxicity.
  • There is a chance of developing a secondary cancer.
  • The short-term risks and side effects from the intense chemotherapy used in myeloablative HSCT are much worse than with non-myeloablative–HSCT, including possible solid organ toxicity or the need for platelet and blood transfusions.
  • The risk of infertility from the chemotherapy used in HSCT is high in both men and women; pregnancy is contraindicated.
  • You may need to be revaccinated with all your childhood vaccines about 2 years after HSCT to restore your immune responses to these common infections. 

Weighing the risks

There are different intensities of bone marrow ablation. So-called myeloablative therapy aims to wipe out your immune system entirely and replace it with a new immune system. Non-myeloablative therapy is less intense: it partially depletes your immune system and allows it to be rebooted (partially). Non-myeloablative therapy is less toxic and less risky than myeloablative therapy, but also less effective. A recurrence of disease activity is therefore more likely after non-myeloablative HSCT than after myeloablative–HSCT. 

No person will sign up to HSCT believing they will die or develop complications. However, inevitably some will be unlucky and have serious complications, delayed adverse events or even die from the procedure. If you decide to have HSCT as part of a trial or routine care, you need to ask yourself: What if I am the unlucky one? Am I ready to leave my family and loved ones prematurely? If you answer ‘yes’ to both questions, you are ready to take the risks.

HSCT repeat course

HSCT is not a typical IRT in that it is usually given as a single one-off treatment. Therefore, breakthrough MS disease activity after HSCT usually triggers the introduction of another licensed DMT. However, there are case reports of patients with MS and other autoimmune diseases having repeat HSCT.

DMTs

HSCT is indicated as part of routine clinical care in the occasional patient with malignant MS who has already failed licensed treatment options. In such patients, the benefits of HSCT outweigh the risks of the disease. Provided the baseline screening tests are acceptable and there are no specific contraindications in an individual patient, I see no reason why HSCT can’t be used after any licensed DMTs. However, there are some specific caveats highlighted below.

Interferon-beta and glatiramer acetate

HSCT is indicated as part of routine clinical care in the occasional patient with malignant MS who has already failed licensed treatment options. In such patients, the benefits of HSCT outweigh the risks of the disease. No contraindications or specific issues.

Alemtuzumab and mitoxantrone (non-selective cell depleting DMTs)

A persistently low peripheral white cell count post-alemtuzumab or post-mitoxantrone, i.e. a neutrophil count <1000/mm³ or a total lymphocyte count <800/mm³, is a relative contraindication to HSCT. Another hit on the bone marrow and the primary and secondary lymphoid organs may worsen your leukopaenia and render you more immunosuppressed. The decision to use HSCT in this situation must be based on the potential benefits of HSCT versus its risks and the risks of untreated active MS. Please see the section on Special circumstances, below, relating to the possible development of chemotherapy-related cardiomyopathy post- mitoxantrone.

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 HSCT. The effect of HSCT on primary and secondary lymphoid organs may worsen lymphopaenia. However, the decision to use HSCT after cladribine must be based on the potential benefits of HSCT versus the risks of lymphopaenia and the risks of untreated active MS. 

Anti-CD20 therapies (selective cell depleting DMTs)

As ocrelizumab, ofatumumab, rituximab and ublituximab are selective B cell-depleting agents, it is theoretically much safer to use HSCT after one of these DMTs than after the other less selective and non-selective agents. An anti-CD20 is the safest cell depleting DMT to use before HSCT.

S1P modulators (fingolimod, siponimod, ozanimod and ponesimod)

Chemotherapy is used before HSCT to ‘mobilise’ the stem cells (that is, cause them to move from the bone marrow into the blood). Therefore, an adequate wash-out period is needed after stopping an S1P modulator before starting the HSCT procedure to allow recovery of peripheral lymphocyte counts. To prevent persistent lymphopaenia post-HSCT, the peripheral lymphocyte counts must return towards normal (>800/mm³) or be normal (>1,000/mm³) before starting HSCT.  

Natalizumab

As HSCT is a non-selective IRT that can’t be rapidly reversed, it is critical to ensure against asymptomatic PML. Carry-over PML from natalizumab to HSCT would potentially be fatal. A baseline MRI scan and possibly a CSF examination must therefore be done before starting HSCT, to exclude possible PML.

Fumarates

Fumarates reduce the lymphocyte count by approximately 30% in people with MS, or by even more in some individuals. Therefore, patients with lymphopaenia while taking a fumarate may be more susceptible to developing clinically significant prolonged lymphopaenia post-HSCT. 

Teriflunomide

Because teriflunomide is an antiproliferative agent, it may delay or prevent the recovery of the peripheral white cell count post-HSCT. 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.

Special circumstances

Specific comorbidities and adverse events may make it difficult to start HSCT after certain DMTs, for example, the development of chemotherapy-related cardiomyopathy post-mitoxantrone.