Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

PathY5 > Bone Marrow Transplantation > Flashcards

Bone Marrow Transplantation Flashcards

1
Q

What is the marker of maximum tolerated dose?

A

Bone Marrow

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What is the most resistant to radiation?

A

CNS

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What is the least resistant to radiation?

A

Bone Marrow

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What is the risk of dying from a bone marrow transplant?

A

>50%

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What is an Autologous transplant?

A

o GCSF given and obtain a CD34+ population of cells from the bone marrow (the stem cells)
o These are preserved in the freezer
o A high dose of chemotherapy is given to eradicate the bone marrow -> reinfuse the stem cells

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What is an autologous SCT suitable for?

A

Acute leukaemia, myeloma, lymphoma, CLL

Solid tumours

Autoimmune disease

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What is an allogenic SCT?

A

o Used when patient’s disease is unlikely to be eradicated from the bone marrow by standard chemotherapy
o Give them high dose chemoradiotherapy to ablate the bone marrow (malignant and normal cells)
o Then give them some bone marrow from a healthy donor
o Issue with BM transplantation is that donor immune cells recognise patient as foreign

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What is an allogenic SCT used for?

A

Acute leukaemia, Chronic leukaemia, Myeloma, Lymphoma

Thalassaemia, SCD

Bone marrow failure

Congenital immune deficiencies

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What are the principles of transplantation?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What are the standard parameters of outcome?

A

Overall survival (OS)

Disease-free survival (DFS) – better than OS

Transplant-related mortality (TRM)

Relapse incidence (RI)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

How do you select a donor?

A

HLA matching

Serological vs DNA matching

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

How do HLA types contribute to donor selection?

A

• Donors are selected based upon -> well matched for tissue type (HLA type):

o Ideally a sibling (1 in 4 chance with each sibling)
Probability of having a match with a sibling is = 1-(3/4) number of siblings

o If not, a volunteer unrelated donor or minimally mismatched family member

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Why is serological vs DNA matching important?

A

o Low-resolution / SEROLOGICAL -> A*02
o High-resolution / DNA -> A*0201, A*0202, A*0203, …, A*0260

More likely to match at high resolution in a sibling match

Allele frequencies vary depending upon the ethnicity of the patient (for each allele – i.e. A*0202)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What is required for harvesting?

A

Procedure and Harvesting – required 2 x 10^6 CD34+ cells/harvest

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What is bone marrow sampling?

A

• Bone marrow sampling (1.5L, 1% CD34+ -> 15mL CD34)
o Difficult -> involves anaesthetising the patient and sampling some bone marrow from their pelvis
o Puncturing the bone and getting into the medulla damages it, meaning that the first few millilitres that you collect will contain stem cells, however, the rest of it will be blood flooding into the damages site
o So, you keep re-puncturing the bone, collecting a small amount at a time until you have a good harvest

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What is peripheral blood sampling?

A

(10L, 1% CD34+  100mL CD34)
o Hormones (e.g. G-CSF) can be used to stimulate granulocyte production (given 5 days before)
o This leads to the bone marrow releasing some white cells as well as some stem cells
o The donor is connected to a centrifuge device which spins the blood, removes the white cell component, reassembles the red cells and plasma and reinfuses it into the patient

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

What is umbilical cord stem cells?

A

(0.1L, 1% CD34+ -> 1mL CD34) -> stem cells can be harvested at the time of delivery

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Which method of harvesting is best?

A

out of all the methods of harvesting, CD34+ stem cells will only make up about 1% of the sample
o Important because success of transplant depends on the number of CD34 cells per kg of weight of the recipient
o Therefore, in cord blood (only harvest 0.1L), there is fewer CD34 cells and so can only really be used for babies

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

What are the complications of SCT?

A

o Graft failure
o Infections
o Graft-versus-host disease (GVHD): allografting only
o Relapse

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

What is the EBMT risk score?

A

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 Donor
o Time to BMT <1 yr = 0, >1 yr = 1
o Donor Sib = 0, VUD = 1

Higher score = less chance of successful outcome

VUD = Volunteer Unrelated

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

How does the EBMT score predict survival?

A

Overall 80% survival in 0-1 score
70% survival in 2 score
50% survival in 3 score
30% survival in 4 score
15% survival in 5-7 score

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

What are the RFs for infection?

A

Neutropenia
Breakdown of protective barriers
Decreased antibody levels
Depressed T cell immune responses

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

What’s the problem with immunodeficiency in allogenic BM transplants?

A

o Different infections at different times
o Immune defect is frequently of long duration
o Risk of infection is mostly disease-independent

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

What is aspergillosis?

A
  • This is ubiquitous (i.e. is found everywhere)
  • Invasive aspergillosis = high mortality (10-15% deaths due to aspergillosis -> 92% mortality)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

What is CMV?

A
  • Remains latent because T cells are able to keep it under control
  • CMV pneumonia is a large cause of deaths in HSCT
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

What are RFs for CMV?

A

Patient’s serological status

Donor’s serological status

Type of stem cells donor (monocytes)

Type of transplant

CMV viral load

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

What is GvHD?

A

• An immune response when the donor cells recognise the patient as foreign

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

What is Acute GvHD?

A

<100 days
Skin: rash, itchy, red

GI tract : diarrhoea

Liver :hepatitis, jaundice

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

What is chronic GvHD?

A

(>100 days) effects – similar to Sjögren’s; ranked by severity (04):
o Skin rash
o Liver hepatitis, jaundice
o Mucosal membranes dry, mouth ulcers
o Lungs SoB
o Eyes dry
o Joints arthritis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

How does chemo interact with SCT?

A
  • Damaging the skin, GI tract and various other tissues by giving chemotherapy will cause the release of cytokines which activates APCs, which then present the antigens to the donor lymphocytes -> immune reaction against the host tissue
  • You could wait for longer after the chemoradiotherapy for the effects to die down before giving the stem cell transplant, however, this increases the time during which they are susceptible to infection
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

What are the RFs for GvHD?

A

N.B. twins have no risk of GvHD…

o Degree of HLA disparity

Recipient age

o Conditioning regimen

R/D gender combination (D: M -> R: F get worse GvHD)

o Stem cell source

Disease phase

o Viral infections

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
32
Q

What is the treatment of GvHD?

A

o Corticosteroids
o Cyclosporin A
o FK506
o Mycophenolate mofetil
o Monoclonal antibodies
o Photopheresis
Total lymphoid irradiation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
33
Q

How do you prevent GvHD?

A

Corticosteroids
Ciclosporin A + methotrexate
FK506
T-cell depletion
Post-transplant cyclophosphamide

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
34
Q

What is the goal of autologous GvHD?

A

Autologous HSCT -> goal to kill all leukaemia with radio/chemo

35
Q

What is the goal of allogenic GvHD?

A

• Allogenic HSCT -> accepted you cannot kill leukaemia from radio/chemo -> rely on BM from donor

36
Q

• Infusion of more donor lymphocytes can restore remission in one where a leukaemia begins to reappear

A

• Infusion of more donor lymphocytes can restore remission in one where a leukaemia begins to reappear

37
Q

Where do the lymphocytes come from in GvHD?

A

because GvHD happens soon after the transplant, it is likely that the reaction is happening because of the mature lymphocytes in the donated sample rather than because of the lymphocytes that are produced from the stem cells

38
Q

Is it possible to identify and select out the specific T cells?

A

it is impossible to identify and select out the specific T cells, you just insert a population of cells that contains stem cells (some of the other cells will be mature lymphocytes)
o However, you also do NOT want to isolate the stem cells and give them alone because it increases the risk of relapse (i.e. the donor lymphocytes are important in the prevention of relapse)

39
Q

What future therapies may exist?

A

CAR-T cells

Chimeric antigen receptor

40
Q

What is CAR-T?

A

 (1) Leukapheresis (T-cells are collected)
 (2) T-cell activation (engineered chimeric-TCR put into a virus which infects the collected T-cells)
 (3) Modified T-cell expansion (new T cells are expanded)
 (4) Quality and release testing: potency checks and infection checks
 (5) Chemotherapy
 (6) Modified T-cell infusion

41
Q

What is chimeric antigen receptor?

A

o Retains the more effective intracellular components of the TCR (CD28 and CD3 intracellular components)
o Extracellular portions (non-TCR) are engineered in
o These extracellular portions recognise CD19

42
Q

What can CAR-T do?

A
  • ALL relapsed in adults has a very poor outcome
  • CAR T can achieve remission in children and adults in relapsed ALL
43
Q

What are the side effects of CAR-T?

A

o Tumour lysis syndrome (rarely occurs)
o Cytokine release syndrome (potentially fatal – chimeric T-cells can release massive amounts of cytokines)
o Neurologic toxicity, cytopaenia (macrophage activation syndrome), B-cell aplasia (hypogammaglobulinaemia)

44
Q

What are the principles of cyclical chemotherapy?

A

Normal body cells should mostly be ok eventually

Cancer cells should die due to their rapid division

HOWEVER, you can’t keep doing chemo because it will affect haemopoeisis (if AML therapy)

45
Q

How are genes important in AML?

A

There are a lot of implicated genes

46
Q

What is the survival post transplant in the 3 risk categories?

A

Early - about 60% in 5yrs

Intermediate - a little less than early

Advanced - closer to 20% in 5 yrs

47
Q

What did we find out about radiation during the cold war?

A

Identifying something in the spleen and bone marrow that protected against irradiation and restored blood counts

The concept of the blood (haemopoietic) stem cell

48
Q

What did Medawar, Billingham and Brent find?

A

Autologous skin grafts survive, grafts from donors do not

Early in life, develop ability to distinguish self and non-self (Frank Burnet)

Injected cells from murine embryos across strains and demonstrated subsequent survival of skin grafts between adults of different strains.

Introduce concept of acquired tolerance

49
Q

What did Vinca and George Mathe do?

A

Accidental exposure of 6 workers at a nuclear powerplant in Vinca in 1958

5 treated in Paris with infusion of bone marrow by George Mathe, all survived

50
Q

Why did they initially stop BMT?

A

GvHD- diffuse maculopapular rash

51
Q

What did Loutit and Barnes do?

A

The transplanted graft must contain immunologically competent cells

The recipient must be incapable of rejecting or eliminating transplanted cells

The recipient must express tissue antigens that are not present in the transplant donor, thus the recipient antigens are recognized as foreign by donor cells

52
Q

What is the HLA system?

A

A person’s tissue type comprises a set of distinct proteins called Human Leukocyte Antigens (HLA), found on the surface of most nucleated cells.

HLA molecules, or proteins, 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)

HLA encoded by the Major Histocompatibility Complex, MHC, on chromosome 6.

Function – present foreign peptides to T cells

Routinely, HLA-A, -B and DR are typed for compatibility purposes.

53
Q

How good are siblings as matches?

A

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

54
Q

What is the difference between low resolution and high resolution?

A

Serology gives low resolution (e.g. allele)

DNA gives high resolution (e.g. mutations within HLA type)

55
Q

What are the principles of transplantation?

A

Identify disease unlikely to respond to standard treatment

Treat patient to remission

Identify a donor and collect stem cells

Give patient myeloablative therapy

Infuse stem cells

Continue immunosuppression & support patient through period of cytopenia

56
Q

How do point mutations cause problems?

A

Within a HLA, there may be point mutations which switch things within HLA genes (e.g. within HLA-A2 gene, there may be multiple point mutations on loci which may cause a reaction)

57
Q

What is the timeline of WBC in the first transplants?

A

(first transplants lecture)
Restricted interaction
Positive pressure ventilation

58
Q

Where do HSC come from?

A

Bone marrow

  • Aphoresis (and G-CSF) for 5 days (more than 5 days the cells go back into the bones and it doesn’t work)
  • Surgery (old)

Umbilical cord/ placenta
- Foetal

Then centrifugation:

  • red cells sent back
  • white cells harvested

Need 2 million (CD34+) stem cells per kg of recipient weight

59
Q

What are the complications of SCT?

A

Graft failure

Infections

Graft-versus-host disease (GVHD): allografting only

Relapse

60
Q

What is GvHD?

A

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

61
Q

What is this?

A

GvHD of the skin

62
Q

Why do we get GvHD?

A

Alloimmune response:
Acute: cytokine storm, dead cells in radiation release loads of cytokines which causes massive inflammation

63
Q

How do you stage and grade GvHD?

A

(picture)

64
Q

What are the RFs for acute GvHD?

A

Degree of HLA disparity
Recipient age
Conditioning regimen
R/D gender combination
Stem cell source
Disease phase
Viral infections

65
Q

What is the treatment of acute GvHD?

A

Corticosteroids
Calcineurin inhibitors: cyclosporin A, tacrolimus, sirolimus
Mycophenylate mofetil
Monoclonal antibodies
Photopheresis
Total lymphoid irradiation
Mesenchymal stromal cells

66
Q

What is the prevention of acute GvHD?

A

Methotrexate
Corticosteroids
Calcineurin inhibitors: cyclosporin A, tacrolimus, sirolimus
CsA plus MTX

T-cell depletion
Post-transplant cyclophosphamide

67
Q

What is Chronic GvHD?

A

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

(Immune dysregulation
Immune deficiency,
Impaired end-organ function
Decreased survival.)

68
Q

What does Chronic GvHD look like?

A

Autoantibodies
M-skeletal
Infections
Endocrine
Metabolism
Nutrition
Pain
Quality of life
Disability

69
Q

What are the RFs for chronic GvHD?

A

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

Affects 50% of patients who survive >1 year from transplant

70
Q

What are the main sources of neutropenic sepsis?

A 
Vascular access (G+ve) 
GI tract (Gram -ve)
71
Q

How do bacteria cause problems in transplant?

A

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

72
Q

How do you manage neutropenic sepsis?

A

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

73
Q

Where do fungi come from?

A

Yeasts from translocation from the intestinal mucosa, or indwelling catheters

Moulds: inhalation, chronic sinusitis, skin, mucosa

74
Q

What is CMV?

A

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

75
Q

How does CMV manifest?

A

Pneumonitis

Retinitis

Gastritis – colitis

Encephalitis

76
Q

How do we prevent CMV?

A

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

77
Q

What are the other viral complications of SCT?

A

EBV: acute infection, PTLD

Respiratory viruses: influenza, parainfluenza, respiratory syncytial virus, rhino, metapneumovirus, COVID-19

PAPOVA viruses: BK and haemorrhagic cystitis

Adenovirus

78
Q

What affects the outcome of transplant?

A 
Age (20+ = 1, 40+ = 2) 
Disease phase (Intermediate = 1, late = 2) 
Gender of R/D (F to M = 1) 
Time to BMT (\>1yr = 1) 
Donor (sibling = 0, VUD = 1)
79
Q

What are the pros and cons of lymphocytes in BMT?

A

Control infection, no leukaemia transplant BUT GvHD

80
Q

How does survival change with EBMT score in allo-BMT pts in CML?

A

Higher score (higher mismatches) = lower survival

81
Q

When patients re-transfuse with donor cells in relapse what happens?

A

They go back into remission

82
Q

Autografting, rather than allografting, is the preferred option for treating myeloma because…

A

Transplant related mortality after allografting is unacceptably high in most patients with myeloma

83
Q

What is the strongest prognostic factor for cGvHD?

A

Prior acute GvHD

84
Q

When is Cytomegalovirus reactivation more common?

A

is more common in CMV seropositive compared to seronegative

PathY5 (98 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions