Stem cell Transplantation Flashcards
How do we choose a donor?
- Well matched for tissue type - also known as HLA type
- Ideally a sibling (one in four chance of matching with each sib)
- If not, a volunteer unrelated donor or minimally mismatched family member
- More recently, increased use of haploidentical family member – almost every patient has a donor
What is the HLA system?
A person’s tissue type comprises a set of distinct proteins called Human Leukocyte Antigens (HLA), found on the surface of most nucleated cells.
What HLA molecules are relevant in transplantation?
•HLA-A, -B, -C, (class I), present peptide to CD8+ (cytotoxic T-cells)•HLA-DP,-DQ and -DR (class II), present peptide to CD4+ (helper T-cells)
Where is HLA encoded?
HLA encoded by the Major Histocompatibility Complex, MHC, on chromosome 6
What is the function of HLA?
•Function – present foreign peptides to T cells
What HLA do we type in transplantation?
•Routinely, HLA-A, -B and DR are typed for compatibility purposes.
What is the chance of an HLA match within siblings?
Each sibling has a 35% chance of being HLA identical with the patient
Given n siblings the probability that at least one with be HLA0identical is given by the formula 1 – 3n/4n
What is autologous transplantation?
- Stimulate with GCF by SC injection
- Collect stem cells and freeze
- Thaw and rein fuse after chemotherapy
Good use: Multiple Sclerosis
What is allogeneic transplantation?
What are the principles of transplantation?
Where do we get stem cells from?
- Bone marrow
- Peripheral blood - done more now
- Umbilical cord
We need 2 million/kg CD34+ cells - easier to get this for BM and PB
What are the complications of SCT?
- Graft Failure
- Infections
- Graft-versus-host disease (GVHD):allografting only
- Relapse
What is GvHD?
- An immune response when donor cells recognise the patient as ‘foreign’•
- Acute GvHD affects skin, gastrointestinal tract and liver•
- Chronic GvHD affects skin, mucosal membranes, lungs, liver, eyes, joints - very like an AI disease like scleroderma
What has happened?
GvHD
What is the pathophysiology of GvHD?
What are the risk factors for acute GvHD?
- Degree of HLA disparity
- Recipient age
- Conditioning regimen
- R/D gender combination (male patients with female donors)
- Stem cell source
- Disease phase
- Viral infections
What is the treatment of acute GvHD?
- Corticosteroids
- Calcineurin inhibitors: cyclosporin A, tacrolimus, sirolimus
- Mycophenylate mofetil
- Monoclonal antibodies
- Photopheresis
- Total lymphoid irradiation
- Mesenchymal stromal cells
How do we prevent acute GvHD?
- Methotrexate
- Corticosteroids
- Calcineurin inhibitors: cyclosporin A, tacrolimus, sirolimus
- CsA plus MTX
- T-cell depletion•Post-transplant cyclophosphamide
What are the consequences of chronic GvHD?
- Immune dysregulation
- Immune deficiency,
- Impaired end-organ function
- Decreased survival.
What is the prognosis of chronic GvHD?
- Diagnosis within 6 months of transplant, lasts 2-5 years
- 85% of survivors can discontinue treatment at that time
- 5-year survival is 70–80%, in persons with low risk cGVHD and those responding to corticosteroids.
- Five-year survival is 30–40% for those with high-risk disease +/- failure of steroids
What are the signs of chronic GvHD?
What are the RFs for chronic GvHD?
- Prior acute GvHD
- Increased degree of HLA disparity
- Male recipient: female donor
- Stem cell source (PB>BM>UCB)
- T-cell replete
- Older donor age
- Use of DLI
When do patients tend to get the infections?
Bacterial - early when pt is neutropenic
Viruses - much later - more to do with macrophages
Fungi - some very early like candida but aspergillus develops a little later
Pneumocystis - any time in the first couple of years
What are the main sources of infection in neutropenic patients?
Describe bacterial infections in transplants? Who are tested? Which bacteria are usually isolated? What are most deaths caused by?
- In neutropenic patients, the causative organism is identified in approximately one third of patients•
- The most frequently isolated organisms are gram positive eg, staph epidermidis
- Most deaths from sepsis are due to gram negative organisms eg e.coli, pseudomonas aeruginosa
- Reduced incidence of infection using isolation measures and broad spectrum oral antibiotics
How do we manage neutropenic sepsis in these patients?
Emergency situation
- Defined as temperature >38 sustained for one hour, or single fever >39, in a patient with neutrophils <1.0 x 109/L
- Assess patient: temperature, pulse, oxygen saturation and blood pressure. History and examination for evidence of source
- Blood cultures, MSU, CXR•
- Initiate empirical broad spectrum antibiotics and supportive care
Describe fungal acquisitions in these patients? Where do they come from?
- Yeasts from translocation from the intestinal mucosa, or indwelling catheters•
- Moulds: inhalation, chronic sinusitis, skin, mucosa
What is the time scale for viral infections?
Describe the CMV in these patients?
- Member of herpes virus family: primary infection usually as a child, remains latent•
- Can be reactivated if immunosuppressed•
- Reactivation does not always result in infection
What is the manifestation of CMV disease in these patients?
- Pneumonitis•
- Retinitis•
- Gastritis – colitis•
- Encephalitis
How can CMV disease be prevented?
- Twice weekly quantitative monitoring of peripheral blood viraemia to day 100•
- Thresholds for treatment together with evidence of increasing viral load•
- Ganciclovir/valganciclovir: oral and IV preparations.•
- Minimum of 2/52 treatment with clear evidence of reduction in viral load
Name other viral complications of SCT.
- EBV: acute infection, PTLD•
- Respiratory viruses: influenza, parainfluenza, respiratory syncytial virus, rhino, metapneumovirus, COVID-19•
- PAPOVA viruses: BK and haemorrhagic cystitis•
- Adenovirus
What affects the outcome of transplant?
Question
Prior acute GVHD
