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Transplant Surgeries


Bone Marrow Transplant

What is Bone Marrow Transplantation?

Bone Marrow Transplantation is a procedure, where healthy stem cells are transplanted into a patient’s body after appropriate treatment. Healthy stem cells can be collected from the patient, when he becomes disease free after treatment. They can also be collected from fully / half HLA matched family donor, unrelated donor and cord blood. Stored stem cells of the patient / donor / cord blood are transfused into patient’s blood stream, quite similar to blood transfusion.

What are stem cells?

Stem cells are the most primitive cells which can differentiate into various other dedicated cells, such as nerve cells, bone cells, liver cells, blood cells etc. The most primitive stem cell gets committed to organ-specific stem cells and thus forms either blood stem cells or nerve stem cells.

What are the sources of Blood Stem Cells?

Bone Marrow : The spongy material inside large bones of adults and all bones of children is called bone marrow, which is a normal reserve for blood stem cells. Depending on body’s requirement, stem cells can produce desired number of Red blood cells, white blood cells and Platelets. When a patient needs blood stem cells, they can be collected from healthy donor’s hip bones under anesthesia.

Peripheral Blood : Normally, there is only an occasional blood stem cell in our circulation. However, when a blood growth factor (G-CSF) is injected, it stimulates the committed stem cells from the bone marrow to spill over in the circulation. If we count the number of blood stem cells after 3 doses of G-CSF daily, this would have increased by several hundred times. This is called mobilization of stem cells into peripheral blood. At this time, we can collect and concentrate these stem cells from the blood itself by a machine called cell separator, without the use of anesthesia.

Umbilical Cord Blood : Placenta along with the umbilical cord are waste products of pregnancy. However, in the mid-1980s, it was found that an amazingly high concentration of stem cells was present in the cord blood, which is discarded. Since the efforts have been made to collect and store cord blood units from random pregnancies and also directed collections from further childbirth in an affected family where BMT is found necessary.

Who needs Bone Marrow Transplantation

Blood Cancers

Any blood cancer (leukemia) or lymph gland cancer (Lymphoma) which is not completely cured with chemotherapy or recurs after completion of chemotherapy (relapse), can be cured with Allogenic or Autologous BMT in about half of the patients.

Thalassemia and Other Genetic Conditions

In these conditions, the defective bone marrow cells can be killed by chemotherapy and replaced by marrow from a healthy donor. The chances of success in these conditions, if carried out early enough are 80 – 90%.

Aplastic Anaemia and Related Conditions

In these conditions, the bone marrow does not produce enough stem cells and healthy stem cells can repopulate the bone marrow with less amount of ‘conditioning’.

Other Cancers

Many other cancers which do not arise from the bone marrow can be cured by infusing patient’s own stem cells which could be collected and frozen before administration of high dose chemotherapy. Lymphomas, Brain Tumours and many other cancers of childhood respond to this treatment called ‘Autologous Transplantation’.

Autologus Bone Marrow Transplantation

Autologous bone marrow transplant is a process of administering High doses of chemotherapy or radiotherapy to eliminate maximum number of cancer cells which cannot be achieved by standard doses of drugs. The drugs or radiation at such high doses kill not only the cancer cells, but also the bone marrow stem cells. Patient’s own marrow stem cells can be used to replenish his/her own marrow after high dose of chemo-radiotherapy. This is called Autologous BMT.

How are the stem cells collected during the transplant?

  • Using peripheral blood STEM cell APHERESIS technique, stem cells are taken from the blood of patient.
  • G-CSF being a growth factor is used to stimulate the movement of stem cells from the marrow to the circulating blood.
  • This takes around 4 days. On the fifth day, the blood is collected from the patient's vein in a machine called cell separator. In a continuous process, the blood is spun down inside the machine and the required cells are collected in a bag. The entire process might take 3-4 hours.
  • However, this does not involve any surgery and the patient sits on a couch or lies in a bed and can comfortably read a book or watch the television.

This process of collecting stem cells is known as “Apheresis”.

Process of stem cell transplantation in autologous transplants

The process starts with the Insertion of central venous catheter (CVC) in the arm or chest of the patient. The high doses of chemotherapy are administered through the CVC. A day or two following this, the frozen stem cells of the patient are revived by immersing them in a water bath. They are immediately infused through the CVC.. The bone marrow stem cells have an uncanny ability to reach their home ie the marrow itself travelling through various organs of the body. Production of new cells starts within 2-3 weeks.

During this period-

Antibiotics and medications are given in order to prevent or treat any infection.

Blood tests are repeated regularly in order to check RBC, WBC and Platelets count.
Transfusions are given to patient until, the infused stem cells start producing platelets and blood cells.

Diseases which can be cured

  • Myeloma
  • Lymphoma –Hodgkin’s and Non-Hodgkin’s
  • Acute Myeloid Leukemia- sometimes
  • Paediatric solid tumours
  • Multiple sclerosis
  • Auto-immune diseases not responding to medical treatment

What are the Advantages of Autologous bone marrow transplantation over standard chemotherapy?

In patients suffering from myeloma, for example, the maximum killing of myeloma cells is achieved above the dose of 120 mg/m2 of Melphalan. However, doses above this result in complete and irreversible destruction of bone marrow function, while the effect on other parts of the body are minimal or temporary. This effect on the cancer cells are not achievable with repeated small doses of the same drug.

The same principle is used for curing patients with lymphoma, pediatric solid tumours such as neuroblastoma, ewings sarcoma etc and some selected cases of breast cancers.

Do I Need an Autologous BMT or an Allogenic BMT

This will be decided by your doctor in discussion with you. In certain diseases, Autologous BMT might be sufficient, whereas in others, where the bone marrow is diseased, marrow from a healthy donor is preferred.

Advantages of Autologous BMT

  • Does Not Need a Donor
  • Rejection is Rare
  • Less Risk Involved
  • Shorter Hospital Stay
  • Less Risk of Infections in the Long Run

Disadvantages of Autologous BMT

  • Higher Chance of Relapse (Return of Original Disease)

Autologous BMT for Autoimmune Diseases

This is an area of growing interest and research. When our own immune system turns rogue and attacks our own body, any organ can be affected starting from Brain (Multiple Sclerosis) to the Kidneys (Lupus) or the Skin (Scleroderma). Medicines often fail to cure or contain these conditions.

The self-destructive immune system can be eliminated by the use of high doses of chemotherapy and other immunosuppressive drugs. The frozen marrow or blood stem cells of patient can be used to rescue the patient from marrow destruction.

When the stem cells are infused back, there are two possibilities. One, the stem cells would wake up to produce more well behaved immune system which shall no longer behave like a truant child. Second, the immune system might again acquire the self-destructive properties in due time.

However, the adoption of Autologous BMT for conditions like Multiple Sclerosis and Scleroderma has often resulted in marked improvement in the life of these patients who were destined to perish in agony.

What is Allogenic BMT?

‘Allogenic’ BMT means transplantation of blood or bone marrow cells from "another individual’’. The bone marrow and the immune system of the patient is suppressed or destroyed by the use of high dose chemo-radiotherapy and replaced by the blood stem cells from another person. This is a more complex process compared to Autologous BMT involving correct selection of the donor, prevention of rejection of the blood stem cells or marrow of the donor (Graft Rejection) and prevention of attack from donor cells on the patient’s body (Graft-versus-host-disease, GVHD). At the same time the donor cells also attack the cancer cells producing a Graft-versus-Tumour Effect (GVT).

Who needs an Allogenic BMT?

  • Patients whose disease primarily involves the bone marrow: such as patients suffering from leukemia, myeloma, Thalassemia, Sickle Cell Anemia, Aplastic Anemia and Primary Immunodeficiency.
  • Patients whose disease does not involve the bone marrow, but the disease is susceptible to a GVT effect: such as Lymphoma & some Metastatic Solid tumors.
  • Patients whose disease does not involve the bone marrow, but is due to inherited deficiency of certain key enzymes which are produced by certain bone marrow derived cells: such as Hurler’s Disease, Gaucher’s Disease, Adrenoleukodystrophy etc.

What is the difference between Autologous and Allogenic BMT

  • Autologous BMT is a way of administering high doses of chemoradiotherapy to the patient which would otherwise irreversibly damage the bone marrow and subsequently rescuing the bone marrow function by infusing previously collected blood stem cells from the same patient. Whereas the main aim of Allogenic BMT is to introduce a healthy marrow to replace the diseased marrow (as in Thalassemia, Aplastic anemia and leukemia) and introduce a new immune system which has the capability to fight infections (as in Primary immunodeficiency) and/ or fight the cancer cells remaining in the body after ‘ÇONDITIONING’ treatment with chemoradiotherapy.
  • In Autologous BMT, the graft is rarely rejected as it belongs to the patient himself/herself, whereas in Allogenic BMT, there is always a risk of graft rejection. Thus immunosuppressive drugs are given before and after allogenic BMT which are not needed for Autologous BMT.
  • GVHD is an accepted complication after Allogenic BMT and not a part of Autologous BMT.
  • Because of the above reasons, cure rate is much higher with Allogenic BMT compared to Autologous BMT at the cost of a higher risk of complications or mortality.
  • Due to the same reasons, the cost for Allogenic BMT is higher than Autologous BMT.

Choice of Donor

Matched Family Donor is always the preferred choice irrespective of all other conditions. However, only 20% of patients have a matched family donor. This is called a ‘Perfect Match Donor’

The other donors are called alternative donors and are as under :

  • Half Matched Family Donor (Haploidentical)
  • Matched or Mismatched unrelated donor from Volunteer Registries
  • Matched or Mismatched Unrelated Cord Blood Unit from Public Cord Blood Banks

Unrelated Donor BMT

In India, such registries are in their infancy and the chance of finding a match from the foreign registries is less than 10%.

These are four stages involved in BMT.

Stage 1: Evaluate the patients for BMT (WORK-UP) usually 14-30 days before

One will undergo complete medical check-up to evaluate one’s suitability to go through the BMT procedure. This involves the following:

  • Blood Tests
  • Chest X- ray and CT Scans
  • Tests to assess the condition of heart and lungs
  • Bone Marrow Tests

Patients will be counseled in detail about the procedure, the complications, the chances of success, the cost and the possible length of stay in the hospital. Patient will be encouraged to go through the educational material/booklet and discuss any queries or doubts that he / she might have.

Stage2: Prepare the patient for BMT (CONDITIONING) usually 2-10 days

High dose of chemotherapy or radiotherapy is given to destroy the diseased marrow or destroy the cancer elsewhere and the bone marrow gets damaged as a result. This is needed to create space for new blood stem cell and also to suppress the patient’s own immune system (in case of allogenic transplant), so that the blood stem cells are not rejected.

The actual process of transplantation

The transplant procedure is actually fairly simple, the stem cells or bone marrow cells to be transplanted are given through the Central Venous line (CVL). The procedure is just like getting a blood transfusion, except the following precautions which has to be taken care of :

  • Just before the infusion of the new bone marrow, the patient may be given medication to help avoid any allergic reactions.
  • A monitor is used to check breathing, heart rate and blood pressure during the procedure. The nurse monitors closely throughout the infusion of stem cells or bone marrow.
  • A doctor is available in the unit and will check the patient periodically. Medications may be given to deal with problems that may arise, such as high blood pressure or a fast heart rate.

Stage 3: Pre-engraftment (before the transplanted blood stem cells start working): (Usually 2-3 weeks)

After high dose chemo-radiotherapy the blood stem cells are destroyed and normal blood cells are not produced. The patients need to be kept in a clean room within the BMT unit in strict isolation during this time. They also need a lot of blood and platelet transfusion. Most patients get serious infections during this period and need treatment with antibiotics.

Stage 4: Post-engraftment (after the transplanted blood stem cells start working)

Early phase (first 3 months)

There are two types of white blood cells: neutrophils and lymphocytes. Neutrophils save us from acute infections and lymphocytes prevent repeated or chronic infections. Once the neutrophil count is above the critical value of 500 cells per microlitre, the patient can come out of critical isolation. This is called engraftment or the first sign that the transplanted blood stem cells are functioning. Soon after the neutrophil increase to normal or near-normal levels and if there is no other complication, the patient can be discharged home. However, regular check-up and blood tests (2-3 times a week) are required. There is also a risk of graft-versus-host disease (GVHD) at this stage.

Late Phase (3 months-12 months)

The immunity against viruses takes a very long time to recover. Even though some of the immunity is restored, the patient is still at risk of infections with viruses and fungus. This is more so if they are being treated for GVHD, which can become chronic and lingering. If the patient is well, the frequency of check-ups and blood tests reduce over several months.

Complications of Bone Marrow Transplantation

Immediate

  • Sickness, Vomiting, Diarrhoea and Mucositis: (Painful erosion of mucous membranes of mouth and rest of the gut) As a result of high-dose chemotherapy or radiotherapy. These are usually short-lasting, varying between 3-15 days ranging from mild to severe symptoms. Medicines are there to control these problems.
  • Infections and Bleeding: (As a result of lack of blood cells in the interim period before the donor stem cells start working). The main risk at this stage is that of bacterial infections, often coming from the stomach to the blood through the damage caused by high-dose chemotherapy. Fungus infections also happen at this stage. This is why we give antibiotics and antifungal against both bacteria and fungus to prevent serious infections.
  • Acute Graft-Versus-Host Disease: It occurs when the new bone marrow from the donor, called graft, does not recognize the person who receives it, called the host. This leads to reaction of the donor white cells. The graft sends out fighter. The graft then sends out fighter white blood cells, called lymphocytes, to attack the host. It can be mild, moderate or severe and can involve the skin, the liver or the bowel. Rashes and diarrhea are symptoms. Sometimes tissue samples of symptomatic areas are taken to diagnose the disease. This complication is seen with Allogenic transplants, in which the transplant comes from either a related or unrelated donor. GVHD may settle down in a month or two. Occasionally it last much longer.
  • Intensive Cart: It may be necessary to be transferred to the ICU. The ICU is the best place if he or she needs special monitoring, mechanical help to breathe or very close medical and nursing attention. The medical and nursing staff will keeps the relatives well informed about whether the patient likely to be transferred to the ICU. The transplant physician will continue to work with the intensive care staff to provide the necessary care.

Late

  • Virus Infections: (As a result of lack of proper immunity against viruses for the first 3-12 months). The main viruses likely to cause problems are CYTOMEGALOVIRUS (CMV), EPSTEIN BAR VIRUS (EBV), ADENO VIRUS and RESPIRATORY VIRUSES. We check for these viruses routinely for the first three months. CHICKEN PDX VIRUS can also infect very late after transplant and often presents with pain on one side of the chest, belly or face followed by blisters.

Chronic Graft-Versus-Host Disease: (As a result of the lingering reaction of donor white cells against the patient's body). This often manifests with dry and tight skin, joint pains, dry and irritable eyes and mouth ulcers. A bit of this nay be needed to get rid of difficult blood cancers. These symptoms might need prolonged treatment with steroids and other medicines.

Results of Bone Marrow Transplantation

The outcome of BMT depends on four factors

  • Fitness of the patient
  • Choice of conditioning
  • Choice of Donor
  • Nature of Disease

Fitness of the Patient

The ability of various organs of the body to withstand the assault of high dose chemotherapy is the key to the success of BMT. We can assess the suitability of the patient to undergo a particular type of conditioning by several scoring systems such as HCT-CI (Haematopoietic Cell Transplantation – Co-morbidity Index). For example, if the HCT-CI score is 0, the chance of transplant related mortality is only 10%. On the other hand, if the HCT – CI score is 3, the chance of transplant related mortality is 40%.

Choice of Conditioning

The aim of conditioning is to eliminate the diseased bone marrow, whether it is leukemia or Thalassemia. In addition, the patient’s immune system needs to be dampened, so that the donor cells are not rejected.

The backbone of conditioning has been total body irradiation. However, this has a lot of short and long term side effects, especially in children. Hence, only chemotherapy based conditioning has been developed particularly for children.

Over the last decade, several ground breaking researches have shown that high dose chemo-radiotherapy might not be essential to prevent rejection or eliminate leukemia, when the patient has low disease burden. This is called REDUCED INTENSITY CONDITIONING (RIC). The Results of RIC in most conditions are similar to conventional conditioning.

In older patients, we prefer RIC. In younger patients and in those with high risk leukemia or lymphoma, conventional conditioning is preferred.

Choice of Donor

Matched Family Donor is always the preferred choice irrespective of all other conditions. However, only 20% of patients have a matched family donor.

The other donors are called alternative donors and are as under :

  • Matched or Mismatched unrelated donor from Volunteer Registries
  • Matched or Mismatched Unrelated Cord Blood Unit from Public Cord Blood Banks
  • Half Matched Family Donor (Haploidentical)

Nature of Disease

It is now well established that the chances of success are highest if a patient with leukemia undergoes BMT when the disease is in remission (not detected by routine testing). When leukemia recurs, the chances of cure are reduced by 50 – 80%, even with BMT. In addition, certain leukemia are at high risk of relapse because of the aggressive nature inherent in the chromosomes of the cancer cells.

Similarly, the best results in non malignant diseases such as Thalassemia, Sickle Cell Anaemia and Aplastic Anaemia are obtained when they are transplanted early.



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