MODULE: I BLOOD AND MARROW TRANSPLANT

LEARNING OBJECTIVES

At completion of this module you will be able to:

💢 outline the therapeutic intent of treatment with blood and marrow transplantation

💢 distinguish the key differences between the different types of transplants 

💢outline the different stages within the transplant process and describe the purpose for each stage

💢 identify treatments and agents used at various stages of the transplant process and apply this to assist in clinical practice.

What is blood and marrow transplant and why is it used?

Blood and marrow transplant (BMT), also called stem cell transplant (SCT) or haematopoietic stem cell transplant (HSCT), is a procedure used to treat disorders of the haematopoietic system. Following the administration of high dose chemotherapy, patients (recipients) are infused with healthy stem cells to replace dysfunctional or diseased bone marrow and/or recondition the immune system. The patient can either be infused with their own cells (autologous BMT) or cells from a donor person (allogeneic BMT). 

BMT is a treatment option used to achieve cure, long-term remission, or slow down the rate of disease progression in patients with malignant or non-malignant haematological conditions. BMT is increasingly used in non-malignant diseases such aplastic anaemia, sickle cell disease and more recently autoimmune diseases such as multiple sclerosis and systemic lupus erythematosus. This module will discuss the use of BMT in malignant haematological conditions.

Bone marrow is the spongy tissue inside some bones and its job is to produce blood cells. If the bone marrow isn’t functioning properly because of cancer or another disease a patient may receive a blood and marrow transplant. To prepare for a transplant, the patient receives chemotherapy to kill the diseased cells and malfunctioning bone marrow, then the collected stem cells are put into the blood stream. The transplanted stem cells find their way to the marrow where ideally they begin to produce new healthy blood cells.

Source of cells

Stem cells used for BMT can be harvested from three sources:

 

The stem cells most commonly used for BMT are peripheral blood stem cells (PBSC), as the collection process is the least invasive. To obtain PBSC, haematopoietic stem cells (HSC) in the bone marrow are stimulated to move out into the bloodstream. This process is known as mobilisation. Once the cells are mobilised into the peripheral blood, they are collected via a process called apheresis. During apheresis, blood is removed from the body via one intravenous (IV) access point and the required cells (stem cells) are separated out by the machine and collected, with the remaining blood returned to the body at another IV point.

The bone marrow contains the largest concentration of HSC with the iliac crest of the pelvis being the most common site for harvest (collection). Bone marrow harvesting is a procedure where a large needle is inserted into the rear pelvic bone, and the bone marrow is extracted with a syringe. The harvesting procedure is invasive and requires the donor to undergo sedation or general anaesthetic.

Cord blood can be collected once a baby and the placenta have been safely delivered by the mother. The blood left in the placenta and umbilical cord is a rich source of HSC. Once the umbilical cord is clamped and cut, the cord blood can be removed, cleaned, and stored for later use. Due to limited volume of cells collected from cord blood compared to the amount of HSC that is required for an adult BMT, this source is not commonly used for adult BMT, but may be used for paediatric BMT.

The different stages of the BMT process

BMT is a lengthy process and can be divided into different stages. The timeline to the left is a rough guide of the process and will vary depending on patient factors, type of transplant, and regimen used. 

During this process, patients will be seen by various members of the BMT multidisciplinary team, including doctors, the BMT coordinator, nurses, and allied health members.

We will now look at each stage of the transplant process and learn more about it.

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Recipients undergo extensive testing prior to transplant to ensure they are physically and mentally fit enough to undertake the BMT process. Patient specific factors such as age, diagnosis and performance status are important considerations when determining the BMT treatment plan. Patients may commence transplant workup soon after initial diagnosis, before/during initial treatment, or prior to starting induction or consolidation treatment.

Some of the tests and procedures may include, but are not limited to: 

For further reading: Click below link

HCT comorbidity index score

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In the days leading up to the transplant, the patient will receive chemotherapy and sometimes radiation therapy in the form of  total body irradiation (TBI). 

The days that the conditioning regimen is administered are known as “minus” days (e.g. Day -3) and counts down to the day of transplant (Day 0). 

The aims of conditioning are to:

💦 destroy cells (diseased and healthy) in the patient’s bone marrow to create space for the new healthy cells

💦 destroy any residual diseased cells in the patient’s body

💦 suppress the patient’s immune system, reducing the risk of graft rejection and graft versus host disease (only in allogeneic transplants).

There are 3 types of conditioning regimens: 

High-dose chemotherapy +/- TBI that “ablates” or wipes out the bone marrow and causes profound cytopenia. 

E.g. busulfan and cyclophosphamide , high dose melphalan  or etoposide and total body irradiation (TBI).

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Lower doses and less intensive than MAC, but more intensive and higher doses than NMA. RIC protocols are designed to reduce organ toxicity but can cause prolonged cytopenia and require HSC support (somewhere between MAC and NMA treatment). 

E.g. fludarabine and melphalan  or fludarabine and cyclophosphamide.

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Less intensive and lower doses of chemotherapy (than MAC and RIC)  +/- TBI which causes minimal cytopenia and does not require HSC support. NMA protocols are used to suppress recipient immune system and allow engraftment. E.g. fludarabine, cyclophosphamide and TBI.

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Some conditioning protocols may include 1 or 2 rest days before the day of transplant. This allows time for the conditioning treatment to take effect.   

During this period, the patient does not receive any chemotherapy or radiation. Depending on the specific transplant protocol, other supportive treatments (such as immunosuppression medications) may commence during this time.

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On the day of transplant, stem cells are slowly infused into the patient through a central intravenous line. 

The day of transplant is referred to as day 0.

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In the early stages of recovery during the weeks after the transplant, frequent tests and intensive follow up with the BMT multidisciplinary team are necessary to monitor for any post-transplant complications. Some common post-transplant complications may include  fever, mucositis, malnutrition, fatigue, and fluid or haematological imbalances requiring transfusion and electrolyte management.

The team will also monitor cell recovery. This is known as engraftment and usually happens two to three weeks after transplant. 

Depending on many factors, including the type of transplant, patients can either be an inpatient or outpatient during the initial recovery stage. 

The days after the transplant are known as “plus” days (e.g. the day after transplant is Day +1).

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Follow-up care and ongoing monitoring once the patient has returned home is an essential part of recovery as the BMT team monitors for late side effects from the transplant or signs of relapse. 

Long term follow-up appointments initially occur more frequently after the patient returns home, and in the months to years after transplant, gradually reduce in frequency depending on the type of transplant and individual patient recovery rate. During this period, some vaccinations will need to be re-administered to prevent infection given the low immunity of the patient.

Lets take a patient as an example to know more about Autologous!!!

A 67 year old patient who was diagnosed with stage 3 multiple myeloma. 

He is in the stage of remission. To prolong his  period of remission and reduce his risk of relapse, his hematologist recommends he undergo an autologous BMT.

An autologous BMT is a transplant using the patient's own stem cells. Autologous BMTs are used for malignancies that are chemo-sensitive (i.e. can achieve remission by giving high doses of chemotherapy), such as lymphomas and multiple myeloma.

The patient begins his pre-transplant evaluation and workup and is deemed fit enough to proceed with an autologous BMT. Prior to transplant, the transplant team organize for patient to undertake a PBSC collection. He starts the mobilisation process and is given granulocyte-colony stimulating factor (G-CSF) for up to five days. 

The G-CSF increases stem cell production in the bone marrow and moves stem cells into the peripheral circulation so that they are in high enough quantities for collection. Occasionally an additional drug called plerixafor or chemotherapy, such as cyclophosphamide, is required to assist the mobilisation process. Some people will experience bone pain and flu-like symptoms when using these medications. Bert has blood tests regularly to monitor his blood count to ensure enough cells have mobilised into the peripheral circulation.

His mobilisation was successful, and he is in the outpatient ward for his PBSC collection. The stem cells are collected via an apheresis machine. This process can take about 5 to 6 hours and can be repeated if an insufficient number of stem cells are collected. Once collected, the cells are transported to the processing laboratory where they are cryopreserved for later use. 

During the cryopreservation process, harvested stem cells are mixed with dimethyl sulfoxide (DMSO) and frozen and stored until they are required. The DMSO prevents the water in the cells forming into ice crystals during the freezing process, which can damage the cells.

Once his stem cells have been mobilised and collected, he is ready to undergo conditioning treatment.

The patient receives an autologous conditioning protocol for high dose melphalan 200mg/m2. This protocol is commonly administered in the outpatient setting.

High dose melphalan is a MAC treatment. MAC aims to kill cancer cells and usually consists of high doses of chemotherapy which also destroys the healthy cells in the bone marrow. Conditioning regimens vary, and choice of regimen is influenced by several factors including type of disease or condition, type of transplant, donor type, and previous chemotherapy or radiation therapy received.

After undergoing conditioning, he is ready to proceed to transplant (Day 0), where his own stem cells are intravenously infused back into him. This process allows the healthy stem cells to repopulate the bone marrow, which was wiped out by the intensive conditioning and is sometimes referred to as ‘stem cell rescue’. 

On the day of his transplant, it is noted that his current creatinine clearance is 45 mL/min. 

When planning melphalan administration, the peripheral blood stem cells on day 0 must be given at least 12 hours after the completion of melphalan for patients with normal renal function. For patients with CrCl < 30 mL/min, stem cells on day 0 are given at least 24 hours after completion of melphalan. Timing of stem cell infusion may vary depending on the protocol selected. 

Prior to the stem cell infusion, the patient will receive pre-medications (which may include a steroid, antipyretic, and antihistamine) to prevent infusion-related reactions. 

The previously collected (and frozen) stem cells are thawed and then infused intravenously. Patients remain awake throughout the infusion. The process is similar to any blood product infusion and takes approximately 30 – 60 mins, depending on the number of stem cells being infused. 

If using stem cells that have been frozen and then thawed, the patient may experience some side effects related to the dimethyl sulfoxide, which is mixed in with the stem cells. This may include nausea, vomiting, coughing, abdominal cramping, headache, chills, facial flushing, red coloured urine, garlic/corn odour, metallic taste during infusion. 

After receiving the transplant, the new stem cells travel through the bloodstream to the bone marrow where they will begin to multiply and make new, healthy cells. This process is called engraftment and can take several weeks to occur. Until the cells engraft, his immune system remains compromised, and he will be closely monitored for adverse effects of the melphalan or complications associated with cytopenia and may require additional trans support.

As the patient is having an autologous transplant, receiving his own stem cells, these cells will not be ‘rejected’ by the body as being foreign. However, there is a risk of relapse from the underlying disease.

Allogeneic transplants are more commonly used for diseases that affect the bone marrow (e.g. AML) or do not respond well to chemotherapy alone (this is known as chemo-refractory disease). Allogeneic BMTs are complex procedures and can be associated with greater toxicity and a higher risk of complication, however they can also provide lasting benefits such as lower relapse rate and long-term disease-free survival.

Allogeneic transplants work in two ways:

👉 Restoring haematopoietic function: donor stem cells repopulate and restore hematopoiesis in the recipient’s bone marrow that was destroyed by conditioning treatment.

👉 Graft versus tumour effect (GvT effect): Healthy donor cells are transplanted into the recipient and regenerate a new immune system which has the capability to identify and eradicate remaining cancer cells in the recipient’s body.

Matching HLA type is important for a successful allogeneic BMT. A close HLA match means the immune system is less likely to identify donor stem cells as ‘foreign’ which lowers the risk of graft rejection (which can result in graft failure).

A close HLA match also means there is a lower risk of the recipient developing graft versus host disease (GVHD), a serious, and potentially life-threatening, transplant-related side effect.

Incomplete HLA matching between recipient and donor is referred to as ‘mismatched’. Because HLAs are inherited from parents, siblings from the same biological parents are often the closest match and best candidate to be the donor. Up to 30% of patients will find a suitable sibling donor match.

A sibling donor who has the same HLA markers as the recipient is considered a perfect match. A haploidentical donor is a sibling or parent who is only a 50% HLA match.

An unrelated donor who matches between 8-10 key HLAs with the recipient is considered an acceptable match. This is known as a matched unrelated donor (MUD).

The patient receives  conditioning treatment and, after a rest day, is infused  donor cells (Day-0 of the treatment protocol).

Fludarabine and melphalan are conditioning agents that are given to patient before transplant to prepare the bone marrow and create space for the new donor stem cells. Ciclosporin and methotrexate are immunosuppressants used in allogeneic BMT to help regulate the immune system post-transplant. They can be initiated day(s) prior to stem cell infusion and continue for many months afterwards. As the newly infused stem cells are from a donor, there is a risk that the immune cells from the donor may attack patient’s own healthy cells. This is called graft versus host disease (GVHD), and the risk of this occurring can be reduced by using:

💦 immunosuppressants such as ciclosporin, mycophenolate, and sometimes low dose chemotherapy (methotrexate)

💦T-cell depleting antibodies such as alemtuzumab and thymoglobulin.

Immunosuppressants play an important role in post-transplant recovery. Routine blood tests are taken to monitor the level of immunosuppressant drug in the body, and doses may be adjusted to ensure the dose is correct for the individual. Patient education highlighting the importance of continuing immunosuppressants after transplant is essential as this lowers the risk of complications (e.g. GVHD) occurring post-transplant, which can impact overall outcomes and duration of immunosuppression can vary. 

In addition to chemotherapy and immunosuppressants, some allogeneic BMT conditioning regimens also include radiation therapy (usually in the form of TBI).

Both chemotherapy and TBI are used to eliminate cancer cells prior to BMT and suppress the immune system to allow engraftment. TBI uses high energy x-rays (called ionizing radiation) to treat the whole body and is particularly effective for eliminating cancer cells in areas of low blood supply where it is difficult for chemotherapy to reach.

The TBI procedure

Prior to receiving TBI, patients attend a simulation and planning appointment. During this appointment, individual patient parameters and measurements are collected by the team to calculate a treatment plan. On the day of treatment, the patient is positioned at a calculated distance from the machine delivering the radiation to ensure the dose is evenly distributed to the whole body and the required dose of TBI is delivered rapidly. The patient must stay still during treatment but can breathe normally. Pre-medications may also be administered to prevent radiation induced side effects such as nausea.

Patient care post -TBI

After the transplant, The patient will remain in hospital as an inpatient whilst waiting for the donor cells to engraft and for his/her blood counts to recover. Once the blood counts reach acceptable levels, patient will discharge to home. Over the following weeks and months, he/she will have regular follow-up appointments in the outpatient clinic to monitor  recovery and response to the allogeneic BMT.

For Further reading:

Understanding total body irradiation (TBI) - Single fraction treatment

Understanding total body irradiation (TBI) - Multi-fraction treatment

Reference:

1. American Society of Clinical Oncology. 2020. “What is a Bone Marrow Transplant (Stem Cell Transplant)?” American Society of Clinical Oncology, accessed August 2020

2. BMT InfoNet. 2020. “What is a blood stem cell transplant?”. BMT InfoNet, accessed August 2020 

3. American Cancer Society. 2020. “Getting a stem cell or bone marrow transplant.” American Cancer Society, accessed August 2020