HSCT

Summary

HSCT (hematopoietic 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 low dose chemotherapy and growth factors. The stem cells are harvested from the blood and frozen down or stored. MSers undergoing HSCT then have their immune system depleted to a greater (myeloablative) or lesser extent (non-myeloablative) with chemotherapy. The stems cells are re-infused to allow more rapid recovery of bone marrow and immune function. In general HSCT not a 'licensed therapy' for treating MS, but is offered as a treatment in many countries for more active disease. HSCT is typically used to treat highly active MS that has not responded to standard DMTs. HSCT is on the list of essential off-label DMTs because it is a generic procedure and is available in many countries. In other words it can be used for treating MS where access to high-cost licensed DMTs may be limited.

What is HSCT?

HSCT is simply a rebranding of bone marrow transplantation or BMT. BMT was the term we used when the stem cells had to be harvested by doing a bone marrow aspirate; i.e. a thick needle was inserted into the bone and the marrow sucked out under pressure. This procedure is painful and is done under sedation. I remember it very well when I was a houseman and junior medical registrar, or trainee, I worked on a haem-oncology unit and had to do this procedure. Fortunately, the haematologists have now developed an effective way of mobilising and harvesting stem cells from the blood without having to tap the bone marrow. This is done by giving a small dose of chemotherapy followed by growth factors so that the stem cells spillover from the bone marrow into the blood. These stem cells are harvested and frozen and can then be given after immunoablation therapy. Immunoablation therapy refers to chemotherapy to get rid of your immune cells.

Please note that all that these stem cells do is allow you to receive more potent chemotherapy and work by allowing your bone marrow to recover more quickly. There is nothing magic about HSCT. HSCT simply speeds up bone marrow recovery after immune system ablation, nothing more and nothing less. More rapid bone marrow recovery makes BMT safer, i.e. 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 misperception. People think the hematopoietic stem cells are being given to repair the damage that has accrued from having MS. Recovery of neurological function that is seen after HSCT is spontaneous endogenous repair, which we see with all of our DMTs, but particularly the highly effective DMTs. This is why HSCT, like other DMTs, is more effective when used early before MS causes too much damage and in younger MSers (as you get older your nervous system's ability to repair itself drops off).

Types of HSCT

There are different intensities of bone marrow ablation therapy. So-called myeloablative therapy is aimed at wiping out your immune system completely and replacing it with a new immune system. Non-myeloablative therapy is less intense in that it simply depletes your immune system partially and allows it to be rebooted (partially). The non-myeloablative therapy is clearly less risky than the myeloablative therapy but less effective. In other words, more MSers have a recurrence of their disease activity after non-myeloablative HSCT (NM-HSCT), when compared to ablative-HSCT (A-HSCT). The chemotherapy that is used for NM-HSCT is less toxic.

Many in the field are of the opinion that if you are going to treat MS with HSCT you need to go the more aggressive route and use the more toxic and risky A-HSCT. They argue that NM-HSCT is not really better than the current high-efficacy drugs we are currently using to manage MS, i.e. alemtuzumab and/or natalizumab and/or ocrelizumab. This is why we are proposing to do a trial comparing alemtuzumab with NM-HSCT to see if NM-HSCT is more efficacious than alemtuzumab and to see if the potential benefits of HSCT warrant the risks.

What are the risks of NM-HSCT?

The chances of dying from the NM-HSCT is in the order of 0.3%-1%; i.e. 1-in-330 to a 1-in-100 chance of dying. Then there is the toxicity associated with the chemotherapy; nausea, vomiting, diarrhoea, hair loss, bleeding, infections, infertility and neurotoxicity to name a few. It seems that the more disabled you are the worse the neurotoxicity. If you have lost a lot of nerve fibres already and have reduced brain reserve you handle chemotherapy poorly. The chemotherapy worsens neurological function. This is why a large number of BMT units stopped using this therapy in MSers with more advanced MS and is the reason why most units have an upper EDSS limit as part of their inclusion and exclusion criteria.

Once your immune system recovers post-HSCT does it go back to normal? There is evidence that HSCT may result in a rejuvenation of your immune system and changes the so-called repertoire of your B and T cells; i.e. it changes the memory of B and T cells. At the moment we don't know if this is a good or bad thing and what it means for MS. What we do know is that HSCT may destroy memory cells from your previous vaccinations. This is why you have may have 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 is data in the literature that MSers treated with HSCT are at risk of developing secondary autoimmune diseases similar to that which occurs after alemtuzumab treatment. At present we think the risk of secondary autoimmunity after HSCT is lower than that with alemtuzumab, but there is definitely a clear signal. At present I find it difficult to recommend NM-HSCT, over alemtuzumab, unless it is part of a controlled trial, or the MSer had already failed alemtuzumab.

What about A-HSCT?

A-HSCT is a different beast compared to NM-HSCT in that the short-term risks associated with the intense chemotherapy needed to ablate the immune system are much worse. 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. A-HSCT is not for the faint-hearted. A large number of HSCT enthusiasts in the autoimmune field are of the opinion A-HSCT is the way to go; the failure rate from NM-HSCT is too high. They argue that if you are going to take the risk, you might as well go for maximum efficacy.

The Lazarus Effect

The seemingly miraculous treatment effects with HSCT, for example of MSers in wheelchairs getting up and walking, is not unique to HSCT. We see these 'Lazarus effects' with other highly-effective DMTs. 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 are allowed to proceed. Tragically these Lazarus-like examples create unrealistic expectations for MSers with more advanced disease. Once you have fixed or progressive disability it is likely that you have lost your neurological reserve and hence even if you switch off inflammation with HSCT, or any other anti-inflammatory DMT for that matter, it is unlikely that there will be a significant recovery of function. This is one reason why so many progressive MS trials have failed in the past. Therefore the benefit:risk ratio changes with more advanced disease. This is the reason why most HSCT or BMT units have age and disability cut-offs for MSers.

Would I refer pwMS for HSCT?

Yes, I do. The situation where HSCT is indicated as part of routine clinical care is in the occasional patient with more malignant MS, who has already failed licensed treatment options. In these patients, the benefits of HSCT outway the risks of the disease. In practice, however, I find the main reason why MSers say no to HSCT is the infertility risk. The risk of premature ovarian failure, or early menopause, as a result of the chemotherapy is over 40%. From my experience this figure dissuades many women. Similarly, for males, the cyclophosphamide hits the testes hard and if you want to start, or extend, your family after HSCT you will need to bank sperm.

Please remember the human brain is hard-wired to be optimistic. I like to use the gambler’s dilemma as an analogy. No gambler places a bet, or goes into a casino, to lose money; they always believe they are going to be the one that wins the jackpot. No person will sign-up to HSCT believing that they are going to die or develop complications. However, there will always be the unlucky ones who have the serious complications and occasionally die from the procedure, or develops serious delayed adverse complications. If you decide to have HSCT as part of a trial, or as part of routine care, you need to ask yourself the questions: What if I am the unlucky one? Am I am ready to leave my family and loved ones prematurely? If you answer yes to both, then you are ready to take the risks. In the same way, I always tell 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.

The following are our local eligibility criteria for HSCT and the referral template:

More specifics about HSCT

Mode of action of HSCT: HSCT is an immune constitution therapy. It works by by depleting your immune system and allowing it to reconstitute. Hopefully when the immune system has reconstituted the autoimmune cells that cause MS are not present.

Efficacy: Very high

Class: Non-selective IRT, short-term immunosuppression

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

Protocols: The following are some examples for protocol used when HSCT is used to treat MS:

Low intensity (non-myeloablative)

• Cyclophosphamide plus antithymocyte globulin
• Cyclophosphamide plus fludarabine phosphate

Intermediate intensity (non-myeloablative)

• BEAM ( BiCNU/carmustine, etoposide, Ara-C/cytarabine, and melphalan) plus antithymocyte globulin
• BEAM
• Cyclophosphamide plus thiotepa
• TLI (total lymphoid irradiation) plus melphalan
• Carmustine plus cyclophosphamide plus antithymocyte globulin

High intensity (myeloablative)

• Cyclophosphamide plus TBI plus antithymocyte globulin
• Busulfan plus cyclophosphamide plus antithymocyte globulin
• Busulfan plus antithymocyte 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 about the first 6 weeks after HSCT, until the new stem cells start making white blood cells (engraftment), you can easily get serious infections. Bacterial infections are most common during this time, but viral infections that were controlled by your immune system can become active again. Fungal infections can also be an issue. And even infections that cause only mild symptoms in people with normal immune systems can be quite dangerous for you. You may be given antibiotics to try to prevent infections until your blood counts reach a certain level. For instance, pneumocystis pneumonia (often called PCP) is a common infection that’s easy to catch. Even though the germ doesn’t harm people with normal immune systems, for others it can cause fever, cough, and serious breathing problems. Antibiotics are often used to keep HSCT patients from getting this. Your doctor may check you before the transplant for signs of certain infections that may become active after transplant, and give you special medicines to keep those germs under control. For example, the virus called CMV (cytomegalovirus) is a common cause of pneumonia in people who have had transplants. It typically happens to MSers who were already infected with CMV. After engraftment, the risk of infection is lower, but it still can happen. It takes 3 months to a year after transplant for the immune systems of most patients to work as well as they should. Because of the increased risk, you will 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. 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. 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 move the cat’s litter box away from places you eat or spend your time. Your transplant team will tell you and your family in detail about the precautions you need to follow. There are many viruses, bacteria, and fungi that can cause infection after your transplant. Despite all these precautions, patients often 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 look for 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. It is treated with anti-emetics. Please note that no one drug can fully prevent or control chemo-related nausea and vomiting and hence often combination therapies are 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 after treatment, but it can make it very painful to eat and drink.
• Hair loss: Hair loss is likely during HSCT; typically beginning within 2-3 weeks of treatment. However, it will 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 (platelets are the blood cells that help blood to clot.) While you wait for your transplanted stem cells to start working you have to take special precautions to avoid injury and bleeding. Platelet counts are typically low for at least three weeks after HSCT. During this time you might notice easy bruising and bleeding, such as nosebleeds and bleeding gums. If your platelet count drops below a certain level, a platelet transfusion may be required. 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 more common in older MSers and people who have received prior drugs that are cardiotoxic, for example mitoxantrone.
• Neurotoxicity: Both the central and peripheral nervous system are susceptible to the toxic effects of chemotherapy used as part of the conditioning regimen in HSCT. MSers with more advanced MS with significant disability are particularly sensitive to chemotherapy induced worsening of disability. The effects on the peripheral nervous system are mainly due to a length-dependent neuropathy with loss of feeling in the ends of the extremities. Please note that with low and intermediate intensity chemotherapy regimens used neurotoxicity is rarely a problem.
• Interstitial pneumonitis and other lung problems: Pneumonitis is a type of lung inflammation that is most common in the first 100 days after HSCT. Pneumonia caused by infection happens more often, but pneumonitis may be caused by the chemotherapy rather than germs. It is caused by damage to the areas between the cells of the lungs, which are called the interstitial spaces. Pneumonitis tends to only occur with the more intensive conditioning regimens.
• Hepatic veno-occlusive disease (VOD): Hepatic veno-occlusive disease (VOD) 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 those who got the drugs busulfan or melphalan as part of conditioning regimen and as part of allogeneic rather than autologous HSCT.
• Infertility: A large number of MSers who have HSCT become infertile and are unable to have children. This is not caused by the stem cells that are transplanted, but rather by the high doses of chemo and/or radiation therapy used to ablate the immune system. These treatments affect both normal and abnormal cells, and damage the reproductive organs. If having children is important to you, or if you think it might be important in the future, there are ways to protect your fertility. If indicated, women should either be offered GnRH agonists as ovarian protection during the course of therapy or the possible option of egg harvesting and storage. The risk of infertility depends on the particular 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. Men might want to consider storing their sperm before having a transplant. This process can take several days. Fertility returns in some men, but the timing is unpredictable.
• Secondary autoimmunity: MSers treated with HSCT are at risk of developing secondary autoimmune diseases similar to that which occurs after alemtuzumab treatment. The risk of secondary autoimmunity after HSCT is lower than that with alemtuzumab, and is in the order of 10%. Does this mean that you have to participate in the same type of pharmacovigilance that MSers treated with alemtuzumab have to? 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. If and when we start our trial of alemtuzumab vs. HSCT all study subjects will have monthly blood and urine monitoring so this may provide us with an opportunity to see if this is necessary.
• Graft-versus-host disease or 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 (donor) transplants are not used to treat MS. Despite this GCD may occur with autologous HSCT if you receive a blood transfusion that contains live lymphocytes from the donor. The latter is prevented by radiating all fresh blood products before administering them to HSCT patients. It is useful to ask if blood products have been radiated before receiving them. Please note the latter also applies to other IRTS with profound immune depletion, for example alemtuzumab.
• HSCT graft failure: Grafts fail when the body does not accept the stem cells or the stem cells did not survive the mobilisation and storage procedure and is due to you getting a low number of stem cells. As there are no stem cells we have to wait for your bone marrow to recover spontaneously. Depending in the intensity of the conditioning regimen this can take many weeks to occur. During this period you are very susceptible to infections and bleeding. Grafts rarely fail, but if they do it can result in death.
• Secondary cancers caused by HSCT: There is small a chance of developing a secondary cancer after HSCT. Cancers that are typical after HSCT are mainly lymphomas, especially the B-cell types and tend to be caused by Epstein-Barr virus, or EBV. The immune system normally keeps the virus under control, but when the immune system is suppressed after HSCT EBV may result in B-cells proliferating and causing post-transplant lymphoproliferative disease. PTLD typically occurs in patients receiving allogeneic HSCT. Acute leukemia is a type of cancer that can develop a few years after HSCT. Another disorder of the bone marrow called myelodysplasia or myelodysplastic syndrome, in which the bone marrow makes defective blood cells, can also happen a few years after HSCT. Secondary cancers that happen many years later may include solid tumor cancers, for example of the skin, mouth, brain, liver, cervix, thyroid, breast, and bone. Risk factors for developing a second cancer a include TLI (total lymphoid irradiation), which is seldom used as part of HSCT regimens for treating MS, the type of high-dose chemotherapy used as part of the conditioning treatment, age (being older than age 40 at the time of transplant) and being infected with certain viruses, i.e. EBV, cytomegalovirus (CMV), hepatitis B (HBV), or hepatitis C (HCV).

Pharmacovigilance monitoring requirements and derisking strategies

• Baseline: FBC, U&E, LFTs, TFTs, serum protein electrophoresis, serum immunoglobulin levels, serology (VZV, HIV-1&2, hepatitis B&C, syphilis, EBV and CMV), TB elispot, up-to-date cervical smear and/or HPV testing and a pregnancy test. If indicated some centres may assess the baseline function of heart (ECG and cardiac ejection fraction) and lungs (lung function tests).
• Follow-up:
  • During HSCT bloods are done frequently 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 MSers' with persistent amenorrhea.
• Infection prophylaxis:
  • If found to be VZV seronegative you need to be receive the VZV vaccine at least 6 weeks before being treated with HSCT to allow sufficient time to develop immunity and protective antibodies against the virus.
  • As you are at risk of developing Listeriosis after chemotherapy you should be give advice about starting a Listeriosis diet and instituting a behavioural programme to make sure you reduce your chances of getting exposed to Listeriosis.
  • Depending on the unit 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 and patients have had ime to recover from the ordeal of having HSCT. This is typically around 6 months.

Pregnancy: Pregnancy is contraindicated during HSCT as some of the chemotherapies used are teratogenic (damage the developing foetus) 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, breast-feeding should be discontinued before starting HSCT.

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

Switching from HSCT