Haem 9 - Bone marrow transplantation Flashcards
What is the principle of cyclical chemotherapy?
• Normal cells recover more efficiently than malignant cells
o Myeloablation vs
o Non-myeloablation
o Myeloablation = Threshold of radiation that you can give to the patient above which the haematopoietic system will not recover and unless supported the patient will inevitably die
o Non-myeloablation = There is also a threshold where you get temporary ablation of the haematopoietic system but if you can support the patient through it (abx, blood transfusions, platelet transfusions), haematopoiesis will recover
How are the HLA encoded?
Encoded by MHC on Chr 6
Chance of an HLA match within the family
Each sibling has a x% chance of being HLA-identical with the patient
Each sibling has a 35% chance of being HLA-identical with the patient
Given n siblings the probability that at least one with be HLA identical is given by the formula 1 – 3^n/4^n
How is autologous transplantation carried out
- GCSF (granulocyte colony stimulating factor) given BM proliferation release of stem cells (CD34+ cells) into peripheral blood collect + freeze stem cells
- Patient given high-dose chemoradiotherapy is given to eradicate the bone marrow thaw + reinfuse the stem cells
Allogenic SCT indication + how is it carried out
- Used when patient’s disease is unlikely to be eradicated from the bone marrow by standard chemotherapy e.g. Thalassaemia, sickle cell disease, congenital immune deficiencies
- Give them high dose chemoradiotherapy to ablate the bone marrow (malignant and normal cells) infuse haemopoietic system/BM from a healthy donor
Principles of transplantation `
o Identify disease unlikely to respond to standard treatment
o Treat patient to remission
o Identify donor collect stem cells
o Give patient myeloablative therapy
o Infuse stem cells
o Continue immunosuppression and support patient through period of cytopaenia (neutropenia, thrombocytopenia, anaemia) until the donor cells engraft and start producing cells of their own
Marker of stem cells
CD34+
Which organs does acute chronic gvhd affect and whtn do they present?
acute <100 days/ within first 3 months of transplant skin - rash itchy dry GIT - D Liver - jaundice hepatitis
chronic >100 days/ after first 3 months of transplant skin - rash liver - jaundice hepatitis mucosal membranes - dry mouth, ulcers eyes - dry joints - arthritis lungs - SOB
Cell responsible for gvhd?
Mx?
Cell - donor lymphocytes
mx - CSA (cyclosporin)
Why do we get acute gvhd?
- High dose chemoradiotherapy dividing cells are killed
- Dying cells release cytokines + chemokines, IL, IFN, TNF
- Infusion of stem cell product contains donor lymphocytes
• Lymphocytes get stimulated by
o All of the products released from dying cells
o Peptides from dead cells presented on HLA molecules
• Then T cells begin to stimulate the B cells
cytokines also activate APCs which then present the antigens to the donor lymphocytes immune reaction against the host tissue
Why are donor lymphocytes important and why dont we get rid of them to prevent gvhd?
the donor lymphocytes are important in the prevention of relapse
Graft vs leukaemia effect = Donor lymphocytes throughout the patient’s bodies are capable of recognising any emerging leukemic cells as foreign and killing it before it can cause relapse
How is gvhd staged and graded?
o Depends on how bad the skin/liver/GIT are affected
grade = add the stages of the organs together
RF for acute gvhd
o Degree of HLA disparity
o Recipient age
o Conditioning regimen
Worse if you use irradiation in the preparative regimens
o R/D (recipient/donor) gender combination
Worse for M patients with F donors
Why? Because may F donors will have had male children sensitised against proteins that are produced by the Y antigen
o Stem cell source
You get more lymphocytes in peripheral blood than in the bone marrow
Therefore more GvHD with peripheral blood
o Disease phase
The more advanced the disease, the worse the GvHD
o Viral infections
Viral infection activate T cells which can aggravate GvHD and vice versa
Treatment of acute GvHD
o Corticosteroids
o Calcineurin inhibitors – Cyclosporin A, tacrolimus, sirolimus
o Mycophenolate mofetil
o Monoclonal antibodies against T cells, IL, TNF
Can be used to suppress T cell activation
o Photopheresis
Patient sensitised to UV light by the administration of a drug
Then put on a pheresis machine
When the cells come out and are exposed to UV radiation destroys lymphocytes
o Total lymphoid irradiation
o Mesenchymal stromal cells
Have an anti-inflammatory role
GVHD prophylaxis
o Methotrexate
Effective in prophylaxis
Not effective in the treatment
o CS
o Calcineurin inhibitors – cyclosporin A, tacrolimus, sirolimus
o CsA plus MTX
o T-cell depletion from donor product before we infuse it
o Post-transplant cyclophosphamide
To turn of the T-cell response that is caused by the cytokine storm
RF for chronic gvhd
o Prior acute GvHD
Strongest RF
o Increased degree of HLA disparity
o Male recipient : Female donor
o Stem cell source (PB>BM>UCB)
o T-cell replete
Remove T cells from the product before it goes into the patient
o Older donor age
o Use of DLI (donor lymphocyte infusion)
Infection in the first 30 days post transplant
type
reason
commonest
most fatal
Bacterial infections –> Most common when the patient is neutropenic + there is barrier breakdow
o The most frequently isolated organisms are gram +ve e.g. staph epidermidis (e.g. Central vascular access becomes colonised)
o Most deaths from sepsis are due to gram -ve organisms e.g. e.coli, pseudomonas aeruginosa (Chemoradiotherapy causes a lot of mucosal damage (e.g. damaged bowel wall allows gut bacteria to spread))
Which T cells recover first after translant?
NK + CD8 first
B cells and CD4 recover slowly later on
viral infection post transplant
acute
chronic
acute - HSV first, then CMV (CMV within the first 30 days)
Chronic - EBV first, then VZV
HSV –> CMV –> EBV –> VZV
Define sepsis
• = temperature >38 sustained for 1 hour or single fever >39 in a patient with neutrophils <1.0 x 10^9/L
CMV disease manifestations
Pneumonitis
Retinitis
Gastritis - colitis
Encephalitis
CMV disease prevention
o 2x weekly quantitative monitoring of peripheral blood viraemia to day 100 (PCR)
o Ganciclovir/valganciclovir – oral and IV preparations
o Minimum of 2/52 treatment with clear evidence of reduction in viral load
myeloma/lymphoma transplant
o Treat the patient with normal chemotherapy get the BM as free as possible of malignant cells
o At that point, collect + freeze stem cells
o Give dose a bigger dose of chemoradiotherapy to eradicate the bone marrow
o Then give them back the stem cells
o Allogeneic transplant is very dangerous and risky in these patients so this is why you go for autologous transplantation
Autografting rather than allografting is the preferred option for treating myeloma because
transplant related mortality after allografting is unacceptably high in most patients with myeloma
• Affecting the outcomes of transplants = EBMT risk score
• Affecting the outcomes of transplants = EBMT risk score:
o Age
<20=0, 20-40=1, >40=2
o Disease phase
Early=0, int=1, late=2
o Gender of R/D
Female into male = 1
o Donor
Sibling = 0, VUD (volunteer unrelated donor) = 1
o Time to BMT
<1 yr = 0, >1 yr = 1
