Bone Marrow Transplantation

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Bone Marrow Transplantation

The Center of Bone Marrow (Stem Cell) Transplantation at the Anadolu Medical Center features an outpatient and inpatient clinic, HLA typing laboratory, hemapheresis laboratory, cryopreservation, and stem cell processing laboratory. Molecular level diagnostics are provided through flow cytometry and PCR, which allow for direct monitoring of treatment efficiency. Specialists analyze each patient’s molecular risk profile and design an individually tailored treatment schedule.

Diseases Treated with Bone Marrow Transplant

• Acute Myeloblastic Leukaemia
• Acute Lymphoblastic Leukaemia
• Non-Hodgkin’s Lymphoma
• Hodgkin’s Lymphoma
• Multiple Myeloma
• Myelodysplastic Syndrome
• Chronic Myelocytic Leukaemia
• Chronic Lymphocytic Leukaemia
• Aplastic Anaemia
• Paroxysmal Nocturnal Haemoglobinuria
• Primary Amyloidosis
• Solid Cancers: Testicle Cancer, Ovarian Cancer / Ewing Sarcoma
• Hereditary Diseases: Haemoglobinopathies
• Autoimmun disease (Scleroderma, Lupus, Rhomateid arthrite)

Bone Marrow Transplant Process

The transplant process involves a number of stages starting from the initial decision for transplantation to pre-transplant patient assessments, hospitalization and post-discharge long-term monitoring. Prior to the procedure the transplant coordinator provides detailed information to the patient to answer any outstanding questions and making an appointment for initial assessment at the bone marrow transplant clinic. Transplant specialists inform patient on potential complications, success rate and long term results. The assessment results are the basis to proceed with the transplant. Patients will be asked to sign a consent form prior to having the operation performed. The process starts with transplant preparation tests.

Initial Assessment
Initial assessment begins at an appointment with a transplant physician at the bone marrow transplant outpatient clinic. This meeting involves:
Review of patient’s medical history (background) and previous treatments;
Discussion of treatment options and providing information on the recommended treatment plan.
A transplant coordinator nurse gives the patient an orientation tour of the bone marrow transplant department.
A transplant coordinator nurse directs patients to the authorized service for referral or medical coverage procedures. Patients will be asked to sign a consent form after agreeing to the transplantation. The following steps are then taken:

1. Forward Planning
Selecting caretaker: A relative or close friend who is to help the patient in every routines, including monitoring health condition, providing physical support, helping patient to acquire and take medication, perform hospital related administrative procedures, establish contact with physician and nurse and offer emotional and psychological support. The transplant coordinating nurse will train this person on every aspect of his duties.
Accommodation in Istanbul or Kocaeli: Patients are advised to have their housing near the hospital for 1- 4 months following the transplant. Transplant team is to help with the necessary arrangements.
Financial planning: Financial arrangements are made for the entire transplant procedure.

2. Preparing for Transplant
Choosing donor
Allogeneic Transplantation: The first step for allogeneic transplant is finding a HLA (human leukocyte antigens) matching sibling or relative. A matching donor should share all 12 HLA with the patient.

Autologous Transplantation: In autologous transplantation, the patient is also the donor. Depending on patient’s condition and diagnosis, the transplant team determines the type of bone marrow mobilization as well as the timing and method.
Examining donors at Anadolu Medical Centre: Donors (patient, sibling etc.) are initially examined at the hospital. First visit: Physician and nurse evaluate the patient at the transplant clinic to determine background, perform examination and blood tests, and provide information on the transplant clinic.

Information for the donor and patient’s relatives: Physician and nurse make an appointment for the patient and family/friend to explain the transplantation process, its benefits and risks and answer any further questions.

Examination: Tests for outpatient are performed for 1-2 weeks to determine overall medical condition; additional examinations like bone marrow aspiration, lung X-ray, EKG are performed if necessary.
Examination review appointment: The physician shares examination and test results with the patient, answers his questions and explains the findings.
Education: Patients and caretakers are trained on the transplantation process; they are informed about the procedure, side effects, what to do following discharge, etc.
Donor: Donors are also educated and informed on the transplant process and post-procedure care. Bone marrow is collected and frozen according to a pre-determined regime.
Peripheral stem cells are also collected and frozen according to a pre-determined stem cell mobilization regime should the transplantation be autologous. Bone marrow mobilization procedure takes 7 to 20 days depending on the regime.

3. Preparation Regime
Patients are admitted in the hospital for a treatment regime consisting of chemotherapy and/or radiotherapy designed by the physician specifically for the condition to completely (myeloablative) or partially (reduced intensity treatment or non-myeloablative) kill cancer cells. Treatment regime duration and its components differ for each condition but continue for 2 to 8 days on the average. This treatment regime weakens the immune system and the patient is more prone to infections. Treatment will also cause symptoms like nausea, difficulty in swallowing, stomach ache, fatigue and loss of appetite. Preventive measures are taken to minimize side effects.

4. Stem Cell Transplant
Peripheral stem cells transfusion is performed 1 or 2 days after the chemotherapy and/or radiotherapy is completed. The procedure is similar to blood transfusion.

With both autologous and allogeneic transplantations the harvested bone marrow or peripheral stem cells from the donor is administered intravenously through the central venous catheter.

With allogeneic transplantations, stem cells are harvested after the donor is given 5 days of shots to help stem cells move from the bone marrow into the blood. Then blood is removed from the donor through an intravenous system. The part of white blood cells that contains stem cells is then separated in a machine and removed to be later given to the recipient. The red blood cells are returned to the donor.

Donor’s bone marrow is collected in the operation room under general anesthesia on transplantation day and infused intravenously to the patient without a delay. This method is generally preferred for patients with aplastic anaemia and chronic myelocytic leukaemia.

5. Waiting for Engraftment
Engraftment is the successful incorporation of grafted bone marrow into the body of the host resulting in proliferation of blood cells. This process takes between 10 to 35 days. Infection and bleeding are the two major complications during this period. An absolute neutrophil count (ANC) of 500 or more for 3 days in a row is a sign of engraftment. A thrombocyte count of more than 20,000 for two consecutive days is a sign of engraftment. Neutrophil engraftment time can be reduced by 2-3 days by employing growth factors such as G-SCF. Patient should be hospitalized during this period. Following engraftment, patient’s discharge depends on factors like infection, intravenous medication and regular eating.

6. Post-Engraftment Recuperation
First signs of recovery after engraftment appear about 3 months after the procedure. This period is to be spent near the hospital in Istanbul or Kocaeli. Patient will be asked to come to the hospital for regular blood tests (once a week or more often) during this period. Patient’s caretaker should be prepared to assist the patient. Patient and caretaker are trained accordingly. Physician or nurse may be contacted by phone at any time during this period on any issue or complication. Check-up intervals will become less frequent as the patient recovers further.

7. Post-Recovery Long Term Monitoring
Once engraftment is complete and the healing process begins, patient and caretaker will be informed on long-term transplant monitoring. Patient will receive in-depth evaluation and a status report for the referred monitoring physician. The final appointment to take place with the physician and nurse will provide comprehensive information to the patient and caretaker on to do’s, instances demanding notification, monitoring parameters, lifestyle, diet and exercise. The referred physician performs long-term monitoring; the patient is generally asked at the first assessment in approximately 3 months. Long-term monitoring plan is developed specifically for the patient depending on medication, degree of immune system recovery, graft versus host disease and other complications that may occur. Patients are also called to join a vaccination programme at 12 and 24 months after engraftment.

Rules for Bone Marrow Transplant Patients

These rules and guidelines are prepared to help you and your family
• Stick to physician’s prescription in using all medications.
• Make sure to come for regular check-ups. Please, arrive on an empty stomach and without having used any medication.
• Chemotherapy will inhibit optimum functioning of immune system for about a year. This is why it is very important to give extra care and attention to personal hygiene, nutrition, use of protective mask, accepting visitors, handshakes and sexual relations throughout the entire year.

Guidelines on Daily Life:

• Your home should be especially clean following the transplant. Allocate a separate room for the patient. Remove dust magnets like thick carpets and curtains from this room. Do not clean and air patient’s room whilst he/she is still inside. If the room/home lacks central heating make sure to light and clean fire stove when patients is out of the room. Keep room temperature steady.
• Patient room must be away from any type of indoor/outdoor construction activity.
• All house plants and any kind of pet including cats, dogs, fish and birds must be removed from the house for a year due to risk of infection.
• Make sure to keep the rest of the house equally clean and tidy.
• Pay attention to hand hygiene, take a wash at least two times a day, allocate a separate towel for the patient and prevent its use by anyone else. Wash and iron towel after each use. Take showers instead of baths. Only use moisturizing soaps.
• Use paper towel for hand and face hygiene.
• Do not have guests for the first 100 days. Narrow down the number of guests as much as possible in the period immediately after the transplantation. Refrain from close contact including kissing, handshaking and cuddling.
• Change patient’s bed linen at least twice a week, frequently air the mattress.
• Do not use feather and wool-stuffed pillows.
• Make sure to wash all new clothes before use. Do not use corduroy or plush textiles.
• Make sure that patient uses two masks whilst travelling or outdoors.
• Patient should not swim for a year (sea or pool) and should not use saunas.
• Prevent direct contact with sunlight for one year. Walks should be taken at dusk.
• Women should not get epilation for one year. Depilatory creams may be used if physician approves.
• Give extra care to hygiene during getting patient’s haircut.
• Brush teeth with soft brush 3 times a day. Try not to get gums bleeding.
• Do not use deodorants, perfumes, makeup or hair dye for a year.
• Do not smoke or consume alcohol. Steer clear of smoky, dusty and dirty environments.
• Do not come in contact with people who have colds, flu or infections.
• Immediately seek medical attention in case of bleeding, bruising, and swelling.
• Dress according to climate. Avoid getting ill.
• Menstruation irregularities may develop in women following the transplant. Seek medical attention from gynaecology department in accordance with physicians’ recommendations.
• Treatment will cause a loss in sense of thirst, hunger and taste for the first three months after the transplant. This is why patients have to drink three liters of water per day. Drinking less can result in serious electrolyte disorder thus increasing the risk of getting sick. Liquid intake may also be supported by drinking milk, diluted yoghurt, tea, fruit juice or soup. Chew sugar-free chewing gum for building an appetite or suck on sweets for a sense of taste. Drink homemade lemonade 30 minutes before meals, if feeling nauseous.
• Do not drink spring water from unknown sources. Only drink bottled water.
• All milk taken outside should be boiled for at least 15 minutes.
• Use single use pasteurized or homemade yoghurt.
• Thoroughly rinse all fruit and vegetables, leave them in water with vinegar for 30 minutes and peel all skin before consuming.
• Eat seasonal fruit and vegetables. Avoid consuming processed foods and drinks with additives.
• Thoroughly cook all food.
• Strictly avoid eating processed meat (salami, sausage, bacon, cured meat) spices, raw onions and garlic, tomato paste, animal fat, innards, legumes, pickles, creams, kebabs, pizzas, burgers and any sort of fast foods. Only eat home cooked meals from fresh produce.
• Thoroughly cook all meats and vegetables, make sure eggs are not cracked.
• Do not crack nuts with your teeth.
• Refrain from eating strawberries as they grow too close to the soil.
• Do not eat frozen, stale or canned food. Consume all food within 24 hours.
• Store food in airtight containers.
• Use latex gloves to prepare food.
• Use mask whilst preparing food for the patient.
• Pay attention to expiration dates for all products and foods.
• Do not discuss distressing issues with the patient. Keep patient’s spirit high.

Frequently asked questions

What is bone marrow and hematopoietic stem cell?
Bone marrow is the soft, sponge-like tissue located inside the bones. It produces hematopoietic or blood-making stem cells.
Hematopoietic stem cells give rise to more blood making stem cells and differentiate into various types of blood cells such as red blood cells (erythrocytes), white blood cells (leukocytes) and thrombocytes. Hematopoietic stem cells are located in bone marrow but also in the umbilical cord and blood. Regardless of where they are harvested from, stem cells can be used for transplants.

What is bone marrow transplant?
Bone marrow transplant and peripheral blood stem cell transplant is a therapy for certain cancers and some other conditions. It is usually combined with chemotherapy and/or radiation therapy. BMT is performed after a treatment aimed to kill abnormal cells. The goal of bone marrow transplant is to infuse healthy bone marrow cells and thus promote healthy blood cells production.

There are three types of transplant
Autologous transplant: Transplant from patients own stem cells.
Syngeneic transplant: Transplant of stem cells harvested from identical twin.
Allogeneic transplant: Transplant of stem cells harvested from siblings or parents. Genetically matching unrelated donors may also be used.

How is bone marrow transplant performed?
The patient’s own bone marrow or peripheral blood is used in autologous transplants. Prior to harvesting stem cells, patient is treated under a protocol specifically devised by his physicians. Then stem cells are harvested and frozen. Patient then undergoes a medication therapy or chemotherapy and/or radiotherapy for about a week. The purpose of this treatment is to kill cancerous cells and/or damaged bone marrow. The last stage of the procedure is the infusion of healthy stem cells to regenerate normal hematopoietic stem cells.

Are there risks involved with autologous transplant?
Harvesting stem cells from the patient presents the risk of collecting cancerous cells as well. In other words, re-introducing frozen stem cells to the patient may cause a relapse of the illness due to cancerous cells.

Are there any risks involved in allogeneic transplant?
Allogeneic transplant also introduces the patient with the donor’s immune system. This is an advantage. But there is the risk of immune system incompatibility in allogeneic transplants: the transplanted stem cells recognize the patient’s body as foreign and attack it, causing adverse symptoms. There is the risk of damage to liver, skin, bone marrow and intestines. This is called Graft Versus Host Disease (GVHD). It requires immediate treatment to avoid organ damage or failure. There is no such risk involved with autologous transplantation.

How do donor’s stem cells match patient’s stem cells in allogeneic and syngeneic transplant?
Physicians use transplant stem cells that are as close to the patient’s stem cells as possible. This is done to minimize potential side effects. Humans have different protein systems on cell surfaces called human leukocyte antigen (HLA). These protein systems are defined using a blood test called HLA typing.
In most cases the success of allogeneic transplant is based on the degree of compatibility of HLA antigens in donor’s stem cells with those of the host. The chance of host body accepting donor’s stem cells rises as the number of compatible HLA antigens increase. In general terms, a good degree of compatibility between donor’s stem cells and those of the host minimizes the risk of developing a complication known as graft-versus-host disease (GVHD).
The chance of close relatives and especially siblings being HLA compatible is higher as compared non-relatives. However, only about 25 to 35 % of patients have a HLA compatible sibling. The chance of locating a HLA compatible stem cell from a non-relative donor is slightly higher – about 50%. HLA compatibility amongst non-relative donors greatly improves when donor and host come from the same ethnic and racial background. Although the number of donors is on a general rise individuals from certain ethnic and racial groups have a lower chance of finding suitable donors. Comprehensive voluntary donor records may be helpful to locate a suitable non-relative donor.
Identical twins have the same genes; hence they have the same HLA antigen system. As a result patient’s body will accept a transplant from identical twin. However, the number of identical twins is not that great so syngeneic transplant is rather rare.

How is bone marrow obtained for transplant?
Stem cells used in bone marrow transplant are obtained from a liquid pelvic bone core called marrow. The procedure for obtaining bone marrow, usually called “harvesting”, is similar in all three types of bone marrow transplant (autologous, allogeneic, syngeneic). During the procedure the donor is either under general anaesthesia or local anaesthesia inducing numbness below the waist. Needles are inserted into the bone marrow of the pelvic bone for extraction. Marrow harvesting takes about one hour.
Harvested bone marrow is processed to remove traces of bone and blood. A preservative may be added to the harvested bone marrow and later frozen to keep the stem cells ready until needed. This method is known as cryopreservation. Stem cells may be kept for long years using the cryopreservation method.

How are peripheral blood stem cells obtained?
Peripheral blood stem cells are obtained from blood circulation. PBSC’s for transplant are obtained using a procedure called aphaeresis or leukaphaeresis. Donors may be given special medication 4 or 5 days before aphaeresis to increase the number of stem cells in blood circulation. Blood for aphaeresis is collected from a large vein in the arm or with the help of a central venous catheter (flexible tube placed in a wide vein in the neck, chest or pelvic region). Blood is pumped through a machine that collects stem cells. Blood is later returned to the donor and collected cells are stored. Aphaeresis typically takes 4 to 6 hours. Stem cells are then frozen until the recipient is ready for infusion.

Are there any risks involved with donating bone marrow?
Usually, it does not cause significant complications since the quantity of extracted marrow is very little. The majority of risks involved in donating is complications related to anaesthetics used during the procedure.
The area where bone marrow was collected may feel swollen and hard for a few days. Donor may feel tired during this period. Donor’s body will replenish lost marrow in a few weeks, however convalescence time differ from donor to donor. Whilst some people are able to return to their daily routine in 2-3 days, some might need 3-4 weeks to recover.

Are there any risks involved with donating peripheral blood stem cells?
Aphaeresis usually causes minimal discomfort. Person may feel faintness, shivers, numbed lips and hand cramps. Unlike bone marrow transplant, peripheral blood stem cell does not require anaesthesia. The medication used to induce the release of stem cells from bone into blood circulation may cause bone and muscle pain, headaches, fatigue, nausea, vomiting and/or sleeping difficulties. Side effects usually recede 2-3 days after taking last dose of medication.

What happens once stem cells are transplanted to the patient?
After entering the circulation system stem cells settle in the bone marrow where they start producing red blood cells, white blood cells and thrombocytes. These cells will generally start producing blood cells within 2 to 4 weeks after the transplant. Physicians monitor the process by frequent blood counts. Full recovery of the immune system however take much longer. This period is usually a few months for autologous transplant hosts and up to 1-2 years for allogeneic and syngeneic transplants.

What are the potential side effects of bone marrow transplant?
The major risk in both treatment methods is increased susceptibility to infections and bleeding due to high doses of chemotherapy and/or radiotherapy. Physicians may give the patient antibiotics to prevent or treat infections. Thrombocyte transfusion may also be necessary to prevent patient bleeding whilst red blood cells may be required to treat anaemia. Patients undergoing bone marrow transplant and peripheral blood stem cell transplant might experience short-term side effects like nausea, vomiting, fatigue, loss of appetite, oral ulcers, hair loss and skin reactions.
Potential long-term side effects are usually related to pre-transplant chemotherapy and radiotherapy. They include infertility (biological inability of a person to contribute to conception), cataract (clouding in the crystalline lens of the eye), secondary cancers, and damage to liver, kidney, lung and/or heart. Risk of complications and its severity is specific to the patient’s treatment and should be handled by patient’s physician.

What is a “mini-transplant”?
Mini-transplant is a type of allogeneic transplant (termed as non-myeloablative or reduced-intensity transplant). This approach is currently investigated in clinical tests with the objective of treating various cancer types including leukaemia, lymphoma, multiple myeloma and other blood cancers.
Mini-transplant employs lower, less intense chemotherapy and/or radiation doses to prepare the patient for allogeneic transplant. Use of small dose anti-cancer medication and radiation partially eliminates some of patient’s bone marrow without entirely damaging it. On the other hand, it reduces the number of cancer cells and suppresses the immune system to prevent rejection of the transplant.
Unlike traditional bone marrow transplant or peripheral blood stem cell transplant, both donor’s and patient’s cells coexist for short period after the mini-transplant. Once the cells from the donor engraft, they begin to exercise the graft-versus-tumour (GVT) effect and destroy cancer cells left after the anticancer medication and/or radiation. Patient may be injected with donor’s white blood cells to increase the GVT effect. This procedure is called “donor lymphocyte infusion”.

Transplant Suitability Criteria

Criteria for Autologous Stem Cell Transplant (Multiple Myeloma, Hodgkin’s and Non-Hodgkin’s Lymphoma etc.):
• Age < 65,
• Heart ejection fraction > % 50,
• Liver function tests should not exceed twice the normal limits,
• Lung functions tests: DLCO > % 60,
• Good patient performance.

Criteria for Myeloablative Allogenic Stem Cell Transplant:
• Age < 55,
• HLA matching sibling (6 out of 6 or 5 out of 6 markers),
• Heart ejection fraction > % 50,
• Normal liver function tests,
• Lung functions tests; DLCO > % 60.

Criteria for Non Myeloablative (Reduced Dose Regime) Allogenic Stem Cell Transplant:
• Age < 65,
• HLA matching sibling or relative.

“Bone Marrow Transplant” suitability by disease and stage

Acute Myelodysplastic Leukaemia• Acute myeloblastic leukaemia developing after myelodysplastic syndrome,
• Acute myeloblastic leukaemia patients without (8;21), t(15;17), (Inv 16) anomalies,
• Patients non responsive to remission treatment,
• Flt-3 positive acute myeloblastic leukaemia patients.

Acute Lymphoblastic Leukaemia
• Patients presenting bad cytogenetic features such as Philadelphia chromosome, 11q23 positivity,
• Patients with white blood cell (leukocyte) count higher than 30-50 thousand /microliter at diagnosis,
• Patients with central nervous system or testicles involved,
• Patients irresponsive to first remission treatment.

Myelodysplastic Syndrome
• Patients with blast rate of > %5,
• Patients with risk score of intermediate 1, intermediate 2 or higher,
• Patients presenting cytopenia in more than one series.

Non-Hodgkin’s Lymphomas
1. Diffuse large cell lymphomas;
• At first relapse (first relapse following treatment),
• First remission for patients with high, high-intermediate risk.
2. Mantle cell lymphoma; following first treatment
3. Follicular lymphoma;
• Patients with inadequate response to first treatment,
• Patients with first remission duration less 12 months
• Second relapse patients,
• Late relapse in patients with diffuse large B cell lymphoma.

Hodgkin’s Lymphoma
• Patients of no remission with first treatment,
• Patients responding to first treatment but relapse later.

Multiple Myeloma
• Following first treatment (Regression of M protein after 2-4 cures of chemotherapy)

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