Stem Cell Transplantation Flashcards
(24 cards)
Q Define HAEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT)
HAEMATOPOIETIC STEM CELL TRANSPLANTATION is the intravenous influsion of haematopoietic stem cells which is harvested from a donor to a matched reciepient in order to re-establish blood cell production patients whose bone marrow or immune system is damaged or defective.
The harvested ‘Healthy’ stem cells are infused into the recipient after completely or partially eliminating the ‘unhealthy cells and stem cells of the recipient.
The healthy stem cells then repopulate the marrow and peripheral blood of the recipient.
What is the difference between bone marrow transplant ans stem cell transplant?
Types of HSCT based on who the donor is?
Q What are the Sources or sites where stem cells can be harvested?
When the source of the stem cells are from bone marrow and transplanted into a patient, the procedure is known as a bone marrow transplant.
If the transplanted stem cells came from the peripheral bloodstream, the procedure is called a peripheral blood stem cell transplant—sometimes shortened to “stem cell transplant
Cells for HSCT may be obtained:
* from the patient (autologous transplant) or
* from another person, such as a sibling or * unrelated donor (allogeneic transplant) or
* an identical twin (syngeneic transplant).
Sources or sites where stem cells can be harvested include:
* bone marrow;
* peripheral blood;
* umbilical cord blood; or
* rarely, fetal liver.
* amniotic fluid
List and explain the phases of transplant
- Conditioning: period typically lasts 7-14 days. The purpose is to deliver chemotherapy, immunotherapy, and/or radiation to eliminate malignancy, prevent rejection of new stem cells, and create space for the new cells.
- Stem cell infusion is a relatively simple process that is performed at the bedside.
- Neutropenic phase lasts (2-4 wk), the patient essentially has no effective immune system. Healing is poor, and susceptibility to infection is high. Supportive care and empiric antibiotic therapy are the mainstays of successful passage through this phase.
- Engraftment phase which lasts several weeks, the healing process begins with resolution of mucositis and other acquired lesions. In addition, fever and infections often begin to clear. Management of GVHD and prevention of viral infections, especially cytomegalovirus (CMV).
- Postengraftment period which lasts for months to years, include the gradual development of tolerance, weaning off of immunosuppression, management of chronic GVHD, and documentation of immune reconstitution, recovery of haemopietic cells
Discuss the History of HSC transplantation
The starting point of HSCT may be traced to a 1939 report describing a patient who received 18ml of bone marrow intravenously from his brother as treatment of aplastic anemia. Following this report, major advances in transplantation science occurred in the 1950s.
Georges Mathé a French oncologist, who performed the first European bone marrow transplant in November 1958.
Mathé later pioneered the use of bone marrow transplants in the treatment of leukemia.
Stem cell transplantation was pioneered using bone-marrow-derived stem cells by a team at the Fred Hutchinson Cancer Research Center from the 1950s through the 1970s
The first physician to perform a successful human bone marrow transplant on a disease other than cancer was Robert A. Good at the University of Minnesota in 1968.
After decades of refinement, transplantation of allogeneic and autologous haemopoietic stem cells has become an increasingly safe and effective procedure and now plays a major role in the management of malignant and non-malignant haematological disorders.
Q List the malignant and non-malignant indications for SCT (in order)
Malignant:
Acute myeloid leukemia(AML)
Chronic myeloid leukemia CML)
Acute lymphoblastic leukemia (ALL)
Hodgkin lymphoma (HL) (relapsed, refractory)
Non-Hodgkin lymphoma (NHL) (relapsed, refractory)
Neuroblastoma
Ewing sarcoma
Multiple myeloma
Myelodysplastic syndromes
Gliomas, other solid tumors
Non-malignant:
Thalassemia
Sickle cell anemia
Aplastic anemia
Fanconi anemia
Malignant infantile osteopetrosis
Mucopolysaccharidosis
Immune deficiency syndromes
Autoimmune diseases
Q What are the Haematological Indications for HSCT?
- Disorders of HSC number – aplastic anaemia, fanconi anaemia
- Red cell disorders – thalassaemia, sickle cell anaemia, Diamond Blackfan Anaemia
- White cell disorders – congenital neutropenia, Shwachmann Diamond
- Lymphocyte disorders – immunodeficiency (SCID: Severe Combined Immunodeficiency), Haemophagocytic syndromes
- Platelet disorders – Glanzmann’s
List Non haematological indications for HSCT
- Enzyme deficiency: Mucopolysaccharide disorders (MPS), Adrenoleucodystrophy
- Disorders of Osteoclast function: Osteopetrosis
- Others (experimental): Osteogenesis imperfecta
- Autoimmune disorders: Systemic sclerosis etc
Q (Compare and contrast Autologous and Allogeneic) Discuss autologous HSCT
What are the advantages?
Autologous HSCT is the second line treatment for what?
It requires the extraction (apheresis) of haematopoietic stem cells (HSC) from the patient and storage of the harvested cells in a freezer, which can be reinfused to the same patient after the ‘conditioning’
The conditioning involves the patient receiving high-dose chemotherapy with or without radiotherapy with the intention of eradicating the patient’s malignant cell population at the cost of partial or complete bone marrow ablation (destruction of patient’s bone marrow’s ability to grow new blood cells).
Autologous transplants have the advantage of lower risk of infection during the immune-compromised portion of the treatment since the recovery of immune function is rapid.
Also, the incidence of patients experiencing rejection and graft-versus-host disease is very rare due to the donor and recipient being the same individual.
These advantages have established autologous HSCT as one of the standard second-line treatments for such diseases as lymphoma.
Q (Compare and contrast Autologous and Allogeneic) Discuss Allogeneic HAEMOPOIETIC Stem cell Transplantation
What is required of the donor?
Allogeneic HSCT involves two people: the (healthy) donor and the (patient) recipient.
Allogeneic HSC donors must have a tissue (HLA) type that matches the recipient.
Even if there is a good match at the critical alleles, the recipient will require immunosuppressive medications to mitigate graft-versus-host disease
What are the type of Allogeneic transplant donors?
- related (usually a closely HLA matched sibling), syngeneic (a monozygotic or ‘identical’ twin of the patient ( extremely rare, but offering a source of perfectly HLA matched stem cells)
- or unrelated (donor who is not related and found to have very close degree of HLA matching).
- Unrelated donors may be found through a registry of bone marrow donors such as the National Marrow Donor Program
Discuss the Site or organ Sources of HSC
- Bone marrrow
removed from a large bone of the donor, typically the pelvis, through a large needle that reaches the center of the bone. The technique is referred to as a bone marrow harvest and is performed under general anesthesia
about 1% of marrow MNC are CD34+ - Mobilised peripheral blood
Peripheral blood stem cells are now the most common source of stem cells for HSCT.
They are collected from the blood through a process known as apheresis.
The donor’s blood is withdrawn through a sterile needle in one arm and passed through a machine that removes white blood cells. The red blood cells are returned to the donor.
The peripheral stem cell yield is boosted with daily subcutaneous injections of, Granulocyte-colony stimulating factor, serving to mobilize stem cells from the donor’s bone marrow into the peripheral circulation.
Can mobilise vast quantities of CD34+ cells
G-CSF to recipient
Leukapheresis of mononuclear cells (MNC) fraction
- Umbilical cord blood (about 1% of CB MNC are CD34+)
Umbilical cord blood is obtained when a mother donates her infant’s umbilical cord and placenta after birth.
Cord blood has a higher concentration of HSC than is normally found in adult blood.
However, the small quantity of blood obtained from an umbilical cord (typically about 50 mL) makes it more suitable for transplantation into small children than into adults.
Newer techniques using ex-vivo expansion of cord blood units or the use of two cord blood units from different donors allow cord blood transplants to be used in adults.
- Amniotic fluid
It is also possible to extract stem cells from amniotic fluid for both autologous or heterologous use at the time of childbirth.
The HLA genes fall in two categories (Type I and Type II) discuss
Mismatches of the which genes generally increases the risk of graft rejection?
Mismatches of the which genes generally increases the risk of GVHD?
In general, mismatches of the Type-I genes (i.e. HLA-A, HLA-B, or HLA-C) increase the risk of graft rejection.
A mismatch of an HLA Type II gene (i.e. HLA-DR, or HLA-DQB) increases the risk of graft-versus-host disease.
In addition a genetic mismatch as small as a single DNA base pair is significant, so perfect matches require knowledge of the exact DNA sequence of these genes for both donor and recipient.
Race and ethnicity are known to play a major role in donor recruitment drives, as members of the same ethnic group are more likely to have matching genes, including the genes for HLA.
List the Transplant Donor types
- Identical twin donors
- Matched related donors: 1:4 chance of matching where they are of same parents
- Matched unrelated donors
* From donor registry
* Largely caucasian donors
* Unrelated UCB (umbilical cord blood) donor pools reflect ethnic mix of population better - Mismatched related donors
- Haploidentical donors (half matched): mother, father or child, when desperate and urgently needed.
- Umbilical cord blood donors
What are Qualities of Stem cell THAT IS USEFUL IN SCT?
Repopulating ability e.g. able to reconstitute a lethally irradiated host
Self renewal e.g. the bone marrow cells of the lethally irradiated recipient is itself capable of rescuing the recipient.
List other stem cells
Embryonic stem cells (ES)
Mesenchymal stem cells (MSC)
Multipotent adult progenitor cells (MAPC)
Neural stem cells (NSC)
Discuss the usual doses of cells
- Allogeneic BMT
300 000 000 cells / kg
3 000 000 CD34+ cells / kg
Won’t achieve anything like that number during UCB transplants - Autologous HSCT – can probably settle for only about 25% of this cell dose
Explain what happens when the donor and recipient immune systems compete?
Recipient wins:
Rejection
Relapse
Transplant fails
Donor wins:
Graft versus host disease
Remission of malignant disease
Transplant is a success
What is the Donor Hierarchy stem cell Transplantation?
Matched Family Donor
Matched Unrelated donor
10/10 MUD = 6/6 UCB
Mismatched family donor
Mismatched unrelated donor
9/10 MUD = 5/6 cord
Haploidentical – maternal donor
Discuss the Procedure for stem cell transplantation
- HARVESTING OF STEM CELLS of a matched donor from any of i) Bone marrow ii) Peripheral blood film or iii) cord blood
- Myelosuppresion (Myeloabaltive or non-Myeloablative) to prevent graft rejection
- Infusion of Stem cells : Stem cell products are infused in the same way as other blood products, except that on-line blood filters should not be used. They must not be irradiated.
Cryopreserved products are usually defrosted in a water bath at the bedside and then infused without delay. - Hydration: Patients should be adequately hydrated and their urine output monitored closely.
- The supportive care of patients with neutropenia (asepsis, antibiotics, antifungal, antiviral) is given
- Appropriate and timely use of blood products is required during the period of myelosuppression and post transplant.
- All cellular blood products should be irradiated using 25Gy prior to administration in order to prevent transfusion-related GvHD.
What is the Supportive care for stem cell transplantation?
This should be commenced 6 weeks prior to transplant and is continued for 6 months after an autograft or indefinitely for allogeneic transplants.
In patients undergoing allogeneic SCT, where there is a major ABO incompatibility between donor and recipient (for example, a group O recipient receiving group A bone marrow),
the graft must be depleted of red cells prior to administration
unless PBSCs are being transplanted, in which case red blood cells are effectively depleted during leucapheresis.
The subsequent choice of blood group for platelets or red cells depends upon the precise nature of the ABO incompatibility, the time from SCT and the results of blood grouping.
Delayed erythroid engraftment or haemolysis, caused by continuing synthesis of isohaemagglutinins by host lymphocytes, may occur several weeks after stem cell infusion
And is associated with the presence of a positive direct antiglobulin test and anti-donor red cell antibodies in serum or red cell eluates.
What is the CONDITIONING REGIMENS for SCT?
Full Intensity ( or Myeloablative) and
Reduced Intensity ( or Non-Myeloablative)
Myeloablative regimens – These are designed to kill all residual cancer cells in autologous or allogeneic transplantation and to cause immunosuppression for engraftment in allogeneic transplantation;
They may be further subclassified as radiation-containing or non–radiation-containing
Nonmyeloablative regimens – These are immunosuppressive but not myeloablative and rely on the graft-versus-tumor effect to kill tumor cells with donor T cells
A. Full Intensity (Myeloablative) can use
1. Cyclophosphamide / TBI
2. Busulfan / Cyclophosphamide
B. Reduced Intensity (Non-Myeloablative) can use
Fludarabine with /or Melphalan
The following drugs can also be used in transplant conditioning:
Alemtuzumab (Campath IH) ,Anti-Lymphocyte Globulin (ALG), Cyclophosphamide and MESNA, Fludarabine, Melphalan,Treosulfan
What are the Post Transplant Immunosuppressive Drugs?
Ciclosporin (CsA),
Methotrexate ,
Mycophenolate (MMF)
Q What are the Complications of HSCT
Infections due to neutropaenia (from myeloabation) may lead to death,
Graft rejection
Infertility
Graft vs host disease. (fever, rashes, diarrhea etc)
Graft failure
Recurrence of primary disease
Prognosis
HSCT has led to the cure of
diverse forms of cancer,
bone marrow failure,
hereditary metabolic disorders,
hemoglobinopathies, and
severe congenital immunodeficiencies that would otherwise have been fatal.
Transplantation-related mortality and morbidity rates have considerably decreased because of
improved conditioning regimens,
human leukocyte antigen (HLA) typing,
supportive care, and prevention and
treatment of serious infections.
Currently, overall and event-free survival rates are based on the individual’s disease pathology and on the stage of disease.
