Summary

HSCT (haematopoietic stem cell transplant) is not a drug, it is a procedure that involves harvesting of stem cells that first need to be mobilised from the bone marrow using a ‘conditioning’ regimen of low-dose chemotherapy and growth factors. The stem cells are harvested from the blood and frozen down or stored. People with MS undergoing HSCT then have their immune system depleted with chemotherapy to a greater (myeloablative HSCT) or lesser extent (non-myeloablative HSCT). The stem cells are re-infused to allow more rapid recovery of bone marrow and immune function. HSCT is not a ‘licensed therapy’ for MS, but it is offered as a treatment for more active disease in many countries – typically for MS that has not responded to standard DMTs. HSCT is on the list of essential off-label DMTs because it is a generic procedure available in many countries. In other words, it can also be used for treating MS where access to high-cost licensed DMTs is limited. 

What is HSCT?

HSCT is simply a ‘rebranding’ of bone marrow transplantation (BMT). BMT refers to the harvesting of stem cells using a bone marrow aspirate, whereby a thick needle is inserted into the bone and the marrow is sucked out under pressure. This procedure is painful and is done under sedation. Haematologists have now developed an effective way of mobilising and harvesting stem cells from the blood without tapping the bone marrow. A small dose of chemotherapy is given, followed by growth factors so the stem cells spill over from the bone marrow into the blood. These stem cells are harvested and frozen and can then be given after chemotherapy (immunoablation therapy) has depleted your immune cells.

The introduction of the harvested stem cells speeds up bone marrow recovery after immune system ablation (depletion). More rapid bone marrow recovery makes BMT safer because you have less chance of getting a life-threatening infection or bleeding.

The stem cells in HSCT don’t go to the brain and spinal cord to repair the damage. This is a common misconception. Recovery of neurological function seen after HSCT is spontaneous endogenous repair, which we see with all the DMTs, particularly the highly effective treatments. Like other DMTs, HSCT is most effective when used early, before MS causes too much damage, or in younger people with MS (as we age, the nervous system’s ability to repair itself decreases).

Types of HSCT

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. 

Many in the field maintain that if you treat MS with HSCT you should use the more toxic and riskier myeloablative–HSCT. They argue that non-myeloablative–HSCT is no better than the high-efficacy drugs we already use, such as alemtuzumab, natalizumab and/or ocrelizumab. Trials are currently ongoing to compare alemtuzumab with non-myeloablative–HSCT and see if the potential benefits of non-myeloablative–HSCT warrant the risks.^1,2,3

Non-myeloablative HSCT – risks

The chance of dying from non-myeloablative–HSCT is in the order of 0.3% ̶ 2%; i.e., a 1-in-330 risk 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. It seems that the more disabled you are, the worse the neurotoxicity. If you have lost a lot of nerve fibres and have reduced brain reserve, the chemotherapy worsens neurological function. This is why many BMT units stopped using this therapy in people with more advanced MS and why most units have an upper Expanded Disability Status Scale (EDSS) score limit as part of their inclusion and exclusion criteria.

Does your immune system return to normal post-HSCT? There is evidence that HSCT may rejuvenate the immune system and change the so-called ‘repertoire’ (memory) of your B and T cells. We don’t yet know what it means for MS, but we do know that HSCT may destroy memory cells from your previous vaccinations. So, you may need to be revaccinated with all your childhood vaccines at ~2 years after HSCT to restore your immune responses to these common infections. 

What about secondary autoimmunity?

There are data to suggest that people with MS treated with both myeloablative–HSCT and non-myeloablative–HSCT are at risk of developing secondary autoimmune diseases similar to those that occur after alemtuzumab treatment. This risk is lower than that seen with alemtuzumab, but there is a definite signal. At present I find it challenging to recommend non-myeloablative–HSCT over alemtuzumab, unless it is part of a controlled trial or the patient has already failed alemtuzumab.

Myeloablative HSCT – risks

The short-term risks from the intense chemotherapy needed to ablate the immune system with myeloablative–HSCT are much worse than with non-myeloablative–HSCT. Everything is worse: the diarrhoea tends to be bloody and protracted; mucositis is the norm (the lining of your mouth, throat and intestine slough); infections are more severe and are potentially life-threatening; there is the potential for solid organ toxicity (liver, lungs, kidneys and heart); your bone marrow takes longer to recover, and as a result you are more likely to need platelet and blood transfusions. Myeloablative–HSCT is not for the faint-hearted. Many HSCT enthusiasts in the autoimmune field assert that myeloablative–HSCT is the way to go; the failure rate from non-myeloablative–HSCT is too high. They argue that if you are going to take the risk of having HSCT, you might as well go for maximum efficacy with myeloablative–HSCT.

The Lazarus effect

The seemingly miraculous treatment effects of people with MS in wheelchairs getting up and walking are not unique to HSCT. We see these ‘Lazarus effects’ with other highly effective DMTs. Provided you have sufficient reserve capacity in the brain (brain reserve) and spinal cord (neurological reserve) you will see spontaneous recovery from relapse-related disability once inflammation is switched off and recovery mechanisms can proceed. Tragically these Lazarus-like examples create unrealistic expectations for people with more advanced disease. Once you have a fixed or progressive disability, you have most likely lost your neurological reserve. Even if you switch off inflammation with HSCT or another anti-inflammatory DMT, any significant recovery of function is unlikely. Many progressive MS trials have failed because the benefit:risk ratio changes with more advanced disease. This is why most HSCT or BMT units have age and disability cut-offs for people with MS.

Would I refer patients for HSCT?

Yes, I do. HSCT is indicated as part of routine clinical care in the small number of patients with malignant MS who has already failed licensed treatment options. In such patients, the benefits of HSCT outweigh the risks of the disease. In practice, however, people with MS are concerned chiefly about the infertility risk from HSCT. The risk of premature ovarian failure, or early menopause, following chemotherapy is over 40%; this dissuades many women. Similarly, for men, cyclophosphamide (the chemotherapy) hits the testes hard, so if you want to start or extend your family after HSCT you will need to bank sperm.

Weighing the risks

Please remember the human brain is hard-wired to be optimistic. I like the analogy of the gambler’s dilemma. No gambler places a bet or goes into a casino to lose money; they believe they will win. 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. In the same way, I warn my patients who sign up for alemtuzumab treatment that they should expect to develop a secondary autoimmune complication; if they don’t, they should count themselves lucky. If they are not prepared to develop a second autoimmune disease, they shouldn’t be treated with alemtuzumab.

Mode of action

HSCT is an immune reconstitution therapy (IRT). It works by depleting your immune system and allowing it to reconstitute. The hope is that when the immune system has reconstituted, the autoimmune cells that cause MS are absent.

Efficacy

Very high.

Class

Non-selective IRT, short-term immunosuppression.

Immunosuppression

Yes, short-term, whilst the immune system is depleted. Once it reconstitutes itself, the immune system is competent.

Protocols

The following are some examples of HSCT protocols used to treat MS.

Low intensity (non-myeloablative)

• Cyclophosphamide plus anti-thymocyte globulin.
• Cyclophosphamide plus fludarabine phosphate.

Intermediate intensity (non-myeloablative)

• BEAM – a combination of BiCNU/carmustine, etoposide, Ara-C/cytarabine and melphalan.
• BEAM plus anti-thymocyte globulin.
• Cyclophosphamide plus thiotepa.
• Total lymphoid irradiation plus melphalan.
• Carmustine plus cyclophosphamide plus anti-thymocyte globulin.

High intensity (myeloablative)

• Cyclophosphamide plus total body irradiation plus anti-thymocyte globulin.
• Busulfan plus cyclophosphamide plus anti-thymocyte globulin.
• Busulfan plus anti-thymocyte globulin.

Adverse events and events of special interest

This is not a complete list of adverse events associated with HSCT. Please note some of the complications can be life-threatening.

Infection

During the first 6 weeks after HSCT, until the new stem cells start making white blood cells (engraftment), you can easily develop serious infections. Bacterial infections are most common, but viral infections that were controlled by your immune system can become active again. For example, cytomegalovirus (CMV) is a common cause of pneumonia in people who have had transplants and in people with MS who were already infected with CMV. Fungal infections can also be an issue. Even infections that cause only mild symptoms in people with normal immune systems can pose a danger. For instance, pneumocystis pneumonia (often called PCP) is easy to catch and can cause fever, cough, and serious breathing problems if your immune system is compromised. Antibiotics are often used to keep HSCT patients from getting this. You may be given antibiotics to try to prevent other infections until your blood counts reach a certain level.

While in the hospital, everyone who enters your room must wash their hands well. They may also wear gowns, shoe coverings, gloves, and masks. Since flowers and plants can carry bacteria and fungi, they are not allowed in your room. After engraftment, the risk of infection is lower, but it still can happen. It takes 3 months to one year after transplant for the immune system of most patients to work as well as it should. Because of the increased risk, you will continue to be watched closely for signs of infection, such as fever, cough, shortness of breath, or diarrhoea. Your doctor may check your blood often, and extra precautions will be needed to avoid exposure to germs. For the same reason, you may be told not to eat certain fresh fruits and vegetables. All your food must be well cooked and handled very carefully by you and family members. Certain foods may need to be avoided for a while. You will also be told to avoid contact with soil, faeces (both human and animal), aquariums, reptiles, and exotic pets. Your team may tell you to avoid being near disturbed soil, bird droppings, or mould. You need to wash your hands after touching pets. If you have a cat, you may need to remove the cat’s litter tray from where you eat or spend time.

Your transplant team will tell you and your family about the precautions you need to follow. Despite all these precautions, many patients develop fevers, one of the first signs of infection. If you do get a fever or other signs of infection, contact your doctor right away. Tests will be done to determine the cause of the infection (chest X-rays, urine tests, and blood cultures), and antibiotics will be started.

Nausea and vomiting

A common side effect from the chemotherapy given with HSCT, nausea and vomiting, is treated with antiemetics. No one drug can fully prevent or control chemotherapy-related nausea and vomiting; hence, combination therapies are often required.

Mouth and throat pain

Mucositis (inflammation or sores in the mouth) is a short-term side effect that happens with high-intensity chemotherapy. It usually gets better within a few weeks of treatment, but it can make eating and drinking painful.

Hair loss

Hair loss is likely during HSCT, typically beginning within 2 ̶ 3 weeks of treatment. However, hair growth will return to normal once the treatment is finished.

Bleeding and transfusions

After HSCT, you are at risk for bleeding because the conditioning treatment destroys your body’s ability to make platelets (the blood cells that help blood to clot.) While you wait for your transplanted stem cells to start working, you must take special precautions to avoid injury and bleeding. Platelet counts are typically low for at least 3 weeks after HSCT. During this time, you might notice easy bruising and bleeding, such as nosebleeds and bleeding gums. A platelet transfusion may be required if your platelet count drops below a certain level. It also takes time for your bone marrow to start making red blood cells. If you become too anaemic, you might require red blood cell transfusions.

Cardiotoxicity

High doses of chemotherapy used as part of HSCT can cause cardiotoxicity. This is most common in older people with MS and people who have received prior cardiotoxic drugs, for example, mitoxantrone.

Neurotoxicity

Both the central and peripheral nervous systems are susceptible to the toxic effects of chemotherapy used as part of the conditioning regimen in HSCT. People with more advanced MS and significant disability are particularly sensitive to chemotherapy-induced worsening of disability. The effects on the peripheral nervous system are mainly due to length-dependent neuropathy, with loss of feeling in the ends of the extremities. Neurotoxicity is rarely a problem with low- and intermediate-intensity chemotherapy regimens.

Interstitial pneumonitis and other lung problems

Pneumonitis is a type of lung inflammation most common in the first 100 days after HSCT. Pneumonia caused by infection happens more often, but pneumonitis may be caused by chemotherapy rather than germs. It results from damage to the areas between the cells of the lungs (the so-called interstitial spaces). Pneumonitis tends to occur only with more intensive conditioning regimens.

Hepatic veno-occlusive disease

Hepatic veno-occlusive disease is a serious problem in which tiny veins and other blood vessels inside the liver become blocked. It is very uncommon, and only happens in individuals who received the drugs busulfan or melphalan as part of their conditioning regimen and as part of allogeneic HSCT (from a donor) rather than autologous HSCT (AHSCT, i.e. from the patient).

Infertility

Many people with MS who have HSCT become infertile and cannot have children. This is not caused by the transplanted stem cells but rather by the high doses of chemotherapy and/or radiation therapy used to ablate the immune system. These treatments affect normal and abnormal cells and damage the reproductive organs. If having children is important to you, or if it might be important in the future, there are ways to protect your fertility. If indicated, women should be offered GnRH agonists as ovarian protection throughout therapy or the possibility of egg harvesting and storage. The risk of infertility depends on the specific conditioning regimen. After chemotherapy, women find their menstrual periods become irregular or stop completely (amenorrhea). This doesn’t always mean you cannot get pregnant, so birth control should still be used before and after HSCT.

The drugs used during HSCT can also damage sperm, so men should use birth control to avoid starting a pregnancy during and for some time after the HSCT process. HSCT may cause temporary or permanent infertility for men as well; it is worth considering storing sperm before having a transplant (this process can take several days). Fertility returns in some men, but the timing is unpredictable.

Secondary autoimmunity

People with MS treated with HSCT are at risk of developing secondary autoimmune diseases similar to those that occur after alemtuzumab treatment. The risk of secondary autoimmunity after HSCT is about 10%, which is lower than after alemtuzumab. Does this mean that you must participate in the same type of pharmacovigilance required by patients treated with alemtuzumab? I am not sure about this, but all the patients I have referred for HSCT who have come through the procedure successfully are not enrolled in an intensive pharmacovigilance programme. All study subjects in our current trial of alemtuzumab versus non-myeloablative–HSCT are undergoing monthly blood and urine monitoring, which should allow us to assess the current pharmacovigilance requirement.

Graft-versus-host disease (GVHD)

This adverse event is commonly reported on HSCT and BMT unit websites. It typically happens with allogeneic (donor) transplants when the immune cells from the donor see your body as foreign. Allogeneic transplants are not used to treat MS. Despite this, GVHD may occur with autologous HSCT if you receive a blood transfusion that contains live lymphocytes from the donor. The latter is prevented by irradiating all fresh blood products before administering them to HSCT patients. 

HSCT graft failure

Grafts fail when you have too few stem cells, either because the body does not accept them or they did not survive the mobilisation and storage procedure. In this case, we must wait for your bone marrow to recover spontaneously. Depending on the intensity of the conditioning regimen, this can take many weeks. During this period, you are very susceptible to infections and bleeding. Grafts rarely fail, but graft failure can result in death.

Secondary cancers caused by HSCT

There is a small chance of developing a secondary cancer after HSCT, which is caused by the chemotherapy damaging your cell’s DNA or the associated immunosuppression.

• Lymphomas are most often associated with HSCT, especially the B cell types, which tend to be caused by Epstein-Barr virus (EBV). When the immune system is suppressed after HSCT, EBV may result in proliferation of B cells and post-transplant lymphoproliferative disease (typically in patients receiving allogeneic HSCT).
• Acute leukaemia is a type of cancer that can develop a few years after HSCT.
• Myelodysplasia or myelodysplastic syndrome is a bone marrow disorder that may develop a few years after HSCT in which the bone marrow makes defective blood cells.
• Solid tumours that develop many years later may include the skin, mouth, brain, liver, cervix, thyroid, breast or bone.

Risk factors for developing a secondary cancer include:

• total lymphoid irradiation (though it is seldom used as part of HSCT regimens for MS)
• the type of high-dose chemotherapy used in the conditioning treatment
• age (older than 40 years at the time of transplant)
• infection with certain viruses, i.e. EBV, CMV, hepatitis B or hepatitis C.

Pharmacovigilance monitoring requirements and derisking strategies

Baseline

Full blood count, urea and electrolytes, liver function tests, thyroid function tests, serum protein electrophoresis, serum immunoglobulin levels, serology (varicella zoster virus [VZV], human immunodeficiency virus-1 and -2, hepatitis B and C, syphilis, EBV and CMV), tuberculosis enzyme-linked immune absorbent spot (TB ELISpot), up-to-date cervical smear and/or human papillomavirus testing and a pregnancy test. If indicated, some centres may assess the baseline function of the heart (ECG and cardiac ejection fraction) and lungs (lung function tests).

Follow-up

• During HSCT, blood tests are frequently done to monitor for bone marrow recovery. If indicated, most units monitor peripheral blood EBV and CMV viral loads for EBV and CMV reactivation.
• Once bone marrow function has recovered, blood tests are typically done 3 monthly for the first 2 years.
• Endocrine work-up for women with persistent amenorrhea.

Infection prophylaxis

• If you are VZV seronegative, you should receive the VZV vaccine at least 6 weeks before treatment with HSCT to allow sufficient time to develop immunity and protective antibodies.
• To reduce your risk of developing listeriosis, which is a rare infection transmitted via food, you should receive advice about starting a listeriosis diet and a behavioural programme to minimise your chances of exposure to the infectious agent.

Depending on where you have your HSCT, you may also be offered antibiotic prophylaxis to reduce your chances of developing bacterial, fungal and parasitic infections.

Rebaselining

A rebaseline MRI needs to be done after HSCT. Most units do this after bone marrow recovery once patients have had time to recover from the HSCT procedure – typically at around 6 months.

Pregnancy

Pregnancy is contraindicated during HSCT as some chemotherapies are teratogenic and may harm the developing foetus. While having HSCT, women who might become pregnant should use effective birth control.

Breastfeeding

Some chemotherapy agents are excreted in human milk; therefore, breastfeeding should be discontinued before starting HSCT.

Vaccination

Immunisation is likely to be ineffective when given during or after HSCT. Immunisation with live virus vaccines is generally not recommended until after the immune system has reconstituted. Some units recommend a routine revaccination programme approximately 2 years after HSCT. The need for revaccination depends on the intensity of the chemotherapy regimen used during conditioning; the more intensive the regimen, the more likely you are to be revaccinated.

Switching-2-HSCT

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. 

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. 

References

1. RCT comparing autologous hematopoietic stem cell transplantation versus alemtuzumab, cladribine or ocrelizumab in MS (RAM-MS). ClinicalTrials.gov ID NCT03477500.
2. Best available therapy versus autologous hematopoetic stem cell transplant for multiple sclerosis (BEAT-MS). ClinicalTrials.gov ID NCT04047628.
3. StarMS HSCT trial opening at hospitals around the UK. MS Society, UK, October 2022.