Haematopoietic Stem Cell Transplantation for Autoimmune Diseases

Most patients with autoimmune disease have their conditions controlled by immunosuppressants or immunomodulatory agents. In some severe cases, the condition continues to progress or persist despite standard therapy, with potentially life-threatening or disabling consequences. Autologous haematopoietic stem cell transplant (HSCT) has been applied to the treatment of some autoimmune diseases since the late 1990s. Its underlying rationale is the delivery of high-dose immunosuppression to deplete self-reactive T and B lymphocytes. Haematopoietic stem cells (HSC) are first mobilised and collected from the patient, then cryopreserved. The patient will then receive lympho-depleting agents in various combinations such as Cyclophosphamide with Fludarabine or anti-thymocyte globulin (ATG), or Rituximab. These would deplete lymphocytes, but would also lead to pancytopenia (deficiency of red blood cells, white blood cells, and platelets). The collected HSC are infused back to the patient, shortening the period of cytopenia (reduced blood cells), and hastening recovery.

In addition, a new immune system is regenerated from the hematopoietic stem cells (HSC), and does so in the absence of the environmental factors that might have triggered the autoimmunity.

In so doing, self-tolerance is restored and the autoimmune disease is brought under control. Patients who respond to the treatment would usually be able to discontinue immunosuppressants after the treatment.

HSCT for Multiple Sclerosis (MS)

Multiple Sclerosis is the autoimmune disorder with the most number of patients transplanted to date. Since the first report in 1997, over 700 cases have been recorded. The transplant is not designed to repair nerves but aims at restoring tolerance and halts further inflammation of the Central Nervous System. The experience over the last two decades suggests that patients with relapsing remitting disease, in which active inflammation is mediating demyelination (damage to myelin sheath) and CNS damage, respond best. Early secondary progressive MS patients may experience a halt in the further progression of neurological conditions but may not see objective improvement in neurological function. Patients who undergo a transplant would have usually failed at least one to two lines of disease-modifying drugs (DMDs) such as beta-interferon, copaxone, natalizumab or fingolimod. Common failures include ongoing flares or progression of disability despite appropriate doses of the drugs. Patients that respond well to transplant would usually have a relatively lower Expanded Disability Status Score (EDSS) (i.e. below 6) and have had MS for a shorter duration. While some patients still relapse after the procedure, majority no longer have flares and are able to discontinue DMDs after transplant. Over time, some experience an improvement in their function due to the halting of further active CNS inflammation which allow for nerve repair, With physiotherapy, one’s strength and flexibility will also be improved.

In Raffles Hospital, we perform autologous HSCT in patients with relapsing remitting MS and early secondary progressive MS that have continued to flare or progress after the consumption of at least one DMD. The suitability for transplant is assessed on an individual basis, which takes into account the patient’s disease status, EDSS, DMDs received and ease of access to DMDs, history of flares and evolution of disease and the presence of other co-morbidities. Patients may either be referred to a neurologist or self-referrals for consideration for transplant. The transplant team will review the patients’ medical reports, history and MRI scans to determine suitability.

Transplant procedure:

Autologous transplant for MS is a two-stage procedure.

Stage 1. Mobilisation and peripheral blood stem cell harvest

This is the process of moving stem cells from the bone marrow to the peripheral blood so they can be collected. Cyclophosphamide is given to control MS activity and cause the blood count to fall slightly. In the process of recovering from the slight drop in blood count, more blood stem cells are produced. Subcutaneous injections of filgrastim (GCSF) are then given to boost the number of circulating stem cells in the blood. Ten days after cyclophosphamide, the patient undergoes apheresis, which involves drawing blood out from a big vein, separating and collecting the stem cells in a bag, while the rest of the blood returns back to the patient. This process takes approximately six hours and can be done as an outpatient. The cells are collected over one to three consecutive days until the desired number for the transplant is reached. The harvested cells are sent to the stem cell processing laboratory, where they are put through a CD34-selection column so as to enrich the product in stem cells and reduce the number of lymphocytes substantially, before being frozen.

Following this, a minimum 2-week period of rest is required, to allow the body to recover.

Stage 2. Autologous HSCT

The patient is then admitted to the hospital for the actual transplant. This begins with the conditioning regimen comprising of Fludarabine and Cyclophosphamide. These two drugs are chosen because they are lympho-depleting but non-myeloablative, which means even in the absence of an infusion of hematopoietic stem cells (HSC), patients would recover normal blood counts with time. However, the recovery process will be slower than when HSC are given. The chemotherapy would cause pancytopenia and this may pose as a risk for those undergoing HSCT. Low white blood cell count puts the patient at risk of infections, while low platelet counts are associated with bleeding. The risk of a life-threatening complication is estimated at 1 per cent. Neutrophil engraftment usually occurs between 9 to 14 days after the transplant, with platelet recovery several days later. The patient is discharged when the blood counts are acceptable and any infections are treated and resolved. He or she will require close monitoring for several weeks after discharge.

Post-Transplant Care

Patients remain vulnerable to infections for approximately six months after the transplant, though some viral infections like shingles can occur later. They are thus given preventative antibiotics and antiviral medications for up to 12 months after the transplant. They are advised to observe food and hand hygiene, avoid crowds and situations where they may catch an infection. They would need to continue under the care of a haematologist after the transplant, either in a hospital or in their home country. Appropriate vaccines will be given to the patient six months after the transplant. The transplant is expected to affect fertility, particularly if done in patients above 30 years of age. There is also a low risk of late secondary cancers related to chemotherapy exposure.

Patients should also continue to see their neurologist after the transplant to follow up on their progress and chart their EDSS. Patients sometimes continue to improve up to one to two years after the transplant due to the halt in inflammatory damage within the CNS, allowing for nerve repair and with physiotherapy, function may improve. Patients may benefit from ongoing supervision by a physiotherapist after the transplant. In Raffles Hospital, the process begins when patients come for pre-transplant evaluation, with physiotherapists assigned to work with them throughout the procedure.

HSCT for Systemic Sclerosis / Scleroderma

Effective treatments for severe systemic sclerosis (SSc) are lacking. Most treatments deal with the complications or symptoms of the condition and are not curative. Patients with severe SSc would often develop progressive disabling skin thickening, irreversible contractures or digital infarcts or organ dysfunction such as lung fibrosis or heart disease. Despite its relative rarity, HSCT for SSc has been gaining ground as there is an unmet need for effective therapy.

The pathogenesis of SSc is still unclear but includes endothelial cell activation, activation of the immune system with production of autoantibodies, release of cytokines and T cell activation. Even though it’s not purely an autoimmune disease, the immune system does play an intrinsic role in its development and evolution, aside from its origin. Autologous HSCT for SSc has been employed since 1997, the first transplant being done in Europe. Patients with SSc often have major organ involvement such as the heart, kidney, or lung, patients. Hence, stringent screening is required so that only those who can tolerate the rigors of transplant are included. The screening tests include an extensive cardiac evaluation including echocardiogram, right heart catheterisation to exclude pulmonary hypertension and cardiac MRI. In addition, pulmonary function and kidney function tests may be required. This is supported by data from both USA and Europe which showed that treating related mortality can be significant in patients with heart involvement, while stringent screening for occult pulmonary hypertension and careful selection of transplant candidates allows the transplant to be done safely.

Patients with severe skin involvement and moderate lung involvement have the potential to improve after the transplant. However, longstanding digital contractures, atrophy of infarcts are unlikely to resolve. Thus, it’s always best to conduct the transplant before disability is advanced and before significant organ impairment occurs. Patients are considered for transplant if they have had evidence of worsening despite cyclophosphamide, which to date is the only disease modifying therapy shown to cause some improvement.

Transplant procedure

Mobilisation and peripheral blood stem cell (PBSC) harvest

This is the process of moving stem cells from the bone marrow to the peripheral blood so they can be collected. Cyclophosphamide is given to control disease activity and cause the blood count to fall slightly. In the process of recovering from the slight drop in blood count, more blood stem cells are produced. Subcutaneous injections of filgrastim (GCSF) are then given to boost the number of circulating stem cells in the blood. Ten days after cyclophosphamide, the patient undergoes apheresis, which involves drawing blood out from a big vein, separating and collecting the stem cells in a bag, while the rest of the blood returns back to the patient. This process takes approximately six hours and can be done as an outpatient. The cells are collected over one to three consecutive days until the desired number for the transplant is reached. The cells are then frozen in liquid nitrogen and stored.

After a minimum period of two weeks has elapsed, the patient is admitted for the transplant.

Autologous transplant

This begins with the conditioning regimen that comprises cyclophosphamide and anti-thymocyte globulin (ATG). The PBSC harvested is then thawed at the patient’s bedside and infused through a vein. The chemotherapy would cause low blood count and this may pose as a risk for those requiring HSCT. Low white blood cell count put the patient at risk of infections, while low platelet count is associated with bleeding. In addition, patients with SSc who have kidney involvement may develop a renal crisis. Hence, medications are given to reduce the risk. They are also at risk of fluid overload if they have kidney or heart involvement. In this case, judicious and careful monitoring of fluid balance is important. Potentially, those with pulmonary fibrosis may have worsening lung function should they develop an infection. All these factors lead to a potential treatment related mortality estimated at only 5 percent. Neutrophil engraftment usually occurs between 9 to 14 days after the transplant, with platelet recovery several days later. The patient is discharged when the blood counts are acceptable and any infections are treated and resolved. He or she will require close monitoring for several weeks after discharge.

Post-Transplant Care

Patients will remain vulnerable to infections for approximately six months after the transplant, though some viral infections like shingles can occur later. They are thus given preventative antibiotics and antiviral medications for up to 12 months after the transplant. They are advised to observe food and hand hygiene, avoid crowds and situations where they may catch an infection. They would need to continue under the care of a haematologist after the transplant, either in a hospital or in their home country. Appropriate vaccines will be given six months after the transplant. The transplant is expected to affect fertility, particularly if the patient is above 30 years of age. There is also a low risk of late secondary cancers related to chemotherapy exposure. It is recommended they continue to be cared for by a haematologist and rheumatologist after the transplant, whether in a hospital or their home country.

HSCT for Systemic Lupus Erythematosus

SLE is a multi-system autoimmune disorder that has a myriad of manifestations including skin and joint inflammation, renal disease, heart, intestinal, central nervous system or haematological manifestations. While the majority of patients are controlled by standard therapies, there remains a subset that continues to have disease activity and progressive organ dysfunction despite multiple lines of immunosuppression. In addition, one also needs to factor in the inherent toxicities of prolonged steroid use and that of other immunosuppressants. Some patients have progressive disease, develop irreversible kidney failure or die from SLE, and it is this group of patients that may potentially benefit from HSCT. The issue, however, is these patients are often very ill, immunocompromised and have organ dysfunction from SLE, making even a non-myeloablative HSCT a procedure with significant risk. Patient selection is important, with the aim of transplanting patients with lupus severe enough to warrant it, yet before irreversible and life-threatening organ impairment. Despite the many new immunotherapy agents being introduced into the lupus armamentarium, many patients are often referred for transplant when these fail to work and their condition is severe.

Mobilisation and peripheral blood stem cell (PBSC) harvest

This is the process of moving stem cells from the bone marrow to the peripheral blood so they can be collected. Depending on the physical condition of the patient, it may be done inpatient or outpatient. Cyclophosphamide is given to control disease activity and cause the blood count to fall slightly. In the process of recovering from the slight drop in blood count, more blood stem cells are produced. Subcutaneous injections of filgrastim (GCSF) are then given to boost the numbers of circulating stem cells in the blood. Ten days after cyclophosphamide, the patient undergoes apheresis, which involves drawing blood out from a big vein, separating and collecting the stem cells in a bag, while the rest of the blood returns back to the patient. This process takes approximately six hours. The cells are collected over one to three consecutive days until the desired number for the transplant is reached. The cells are then frozen in liquid nitrogen and stored.

Autologous transplant

After at least 2 weeks’ rest, the patient is admitted for the transplant. This begins with the conditioning regimen that comprises cyclophosphamide and anti-thymocyte globulin (ATG). The PBSC harvested is then thawed at the patient’s bedside and infused through a vein. The chemotherapy would cause low blood count and this may pose risk for those undergoing HSCT. Low white blood cell count put the patient at risk of infections, while low platelet count is associated with bleeding. If patients have pulmonary involvement such as pneumonitis and pulmonary hemorrhage, low platelets may exacerbate it. In addition, patients with who have lupus nephritis or heart disease may be at risk of fluid overload, mandating careful monitoring of fluid balance. Due to the immunosuppressive burden that many patients with severe lupus have, the infectious risks are high and patients are covered with broad spectrum antibiotics, antifungals and antiviral medications.

All these factors lead to a potential treatment related mortality estimated at 6 to 10 per cent depending on the underlying lupus severity and organ impairment in the patient. Neutrophil engraftment usually occurs between 10- to 4 days after the transplant, with platelet recovery several days later. The patient is discharged when the blood counts are acceptable and any infections are treated and resolved. He will need close monitoring for several weeks after discharge.

Post- Transplant Care

Working together with a rheumatologist, corticosteroids and other immunosuppressants can eventually be tapered and in some patients, stopped. Data from Northwestern University showed that 75 per cent of patients respond to the transplant, although of these, one-third may relapse or have persistent disease activity. Their experience showed that these patients may respond to immunosuppressive agents that had not previously worked for them, suggesting the transplant may restore their tolerance partially but not fully.

Overall, HSCT for SLE should not be taken lightly. However, it has the potential to induce sustained remission in patients with refractory disease, and allow the eventual discontinuation of immunosuppression in responding patients. It may reverse nephritis but not in patients already on chronic dialysis. It can also potentially reverse cardiac and pulmonary dysfunction.