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What role does viral hepatitis play in HSCT?

Viral hepatitis
- third most common cause of liver disease in transplant patients
- can reactivate HBV at 3-6 months due to impaired cellular immunity
- HBsAg +ve = prophylactic antiviral tx pre-chemotherapy and for 3/12 after.
- if -ve, need vaccination before transplant
- HCV has little impact but is a risk factor for hepatic veno-occlusive disease and GVHD
- faster progress of HCV to fibrosis and cirrhosis, decompensation and malignancy in HSCT.  Third leading cause of late deaths after transplant - need definitive management after 6 months and no evidence of GVHD.


What causes GVHD in HSCT?  Who gets it?  How do you reduce it?

Donor immunocompetent T-cells and NK cells recognise host antigen as foreign —> immune reaction
- mainly in allograft setting (not auto or syngeneic (twin)
- severity of GVHD inversely related to risk of relapse due to relationship with graft-versus-leukaemia effect.
- reduction achieved by optimising donor and graft type and post-transplant immunosuppresion.
- least with peripheral blood HSCT, worst with umbilical cord HSCT


When does acute GVHD occur, what does it affect, what are the risk factors, pathogenesis and treatment?

- common, within first 100 days
- skin, mucosa, gut, and liver
- erythematous macular skin rash —> blistering (like burns), severe abdominal pain, profound diarrhoea, hyperbilirubinaemia.
- Stage 1 skin up to stage IV (systemic).  III-IV have a bad prognosis.
- RFs:  HLA mismatch, MUD grafts, grafts from a parous female donor, older age
- pathogenesis:  acute cytokine storm (TNF and IL-1) released due to damaged host tissue from induction —> increased MHC expression —> recognition of minor HLA differences by T-cells —> proliferation and cytokine release —> further recruitment of t-cells and macrophages —> release of TNF and IL-1 —> vicious cycle of inflammation and tissue damage
-prophylaxis better than treatment:  graft t-cell depletion (but increased risk of graft failure and rate of relapse due to graft vs tumour effect
- prevention:  CNi (renal toxicity) + MTx (but mucositis), sirolimus and MMF have less toxicity.  Can also use gut decontamination with metro, IVIG or less intensive regiment
- high dose steroids and ATG does not work.


Who gets chronic GVHD?
What are the risk factors?
What are the clinical features
How do you manage it?

- 40-80% of long term survivors, incidence rising as older patients get transplants
- RFs:  peripheral blood transplants, mismatch or unrelated donors, second transplant, donor leukocyte infusions
- greatest risk for chronic GVHD is acute GVHD
- 2-12 months post transplant - skin, eyes, mouth, liver, fascia, any organ
- chronic lichenoid skin changes, dry eyes and mouth, impaired ROM from fibrosis of dermis and fascia.  Resembles scleroderma or other autoimmune diseases
- immunosuppression with steroids, tacrolimus and MMF are mainstays, hydroxychloroquine works well too.
- major cause of death:  profound immunodeficiency, need prophylaxis against encapsulated organisms
- patients with frequent infections and low Ig levels should get IVIG


What are the risk factors for, and treatment of HSCT graft failure?

Graft failure
- associated with HLA mismatch, more frequent in MUD grads
- other RFs: aplastic anaemia, t-cell depletion, infusion of lower number of stem cells (cord blood), nonmyeloablative transplants, GVHD, splenomegaly
- poor graft function can be treated with growth factors (G-CSF or GM-CSF), and EPO.
- Failure: second stem cell infusion


What are the early pulmonary complications of HSCT transplant?  Treatment?

Transplantation-relation lung injury (TRLI)
- acute inflame response —> severe lung injury
- allogenic transplant
- early tx w/ corticosteroids and etanercept (anti-TNF) reduces extent

Interstitial pneumonitis (usually CMV) is frequently fatal - reduced w/ anti-infective prophylaxis and CMV-ve blood products (leukodepletion, CMV -ve donors), tx w/ ganciclovir or foscarnet + IvIg

Autograft - diffuse alveolar haemorrhage

RTx or pulm toxins, MTx or carmustine


What is Sinusoidal Obstruction Syndrome?  What are the risk factors?  Pathogenesis?  Treatment?  Outcomes?

Hepatic veno-occlusive disease (Sinusoidal Obstruction Syndrome)
- very common, potentially lethal
- 10-60% of patients, 50% of post-transplant deaths
- weight gain, tender hepatomegaly, jaundice and ascites —> fulminant multiorgani failure
- 8-10 days post inductions
- RFs: prior liver damage, high levels of busulphan, >10-12 Gy total body irradiation, heavy induction, C282Y positivity of haemochromatosis gene
- pathology: elevated TNF —> sinusoidal endothelial damage —> sloughs —> obstructs hepatic circulation —> centrilobular hepatic injury and portal hypertension.
- Prevention is best treatment: avoid fludarabine or cyclophosphamide, use nonmyeloablative regiment
- Ursofalk reduces risk of this and grades III-IV GVHD
- Treatment is supportive, with defibrotide which is antithrombotic and fibrinolytic (avoid heparin and TpA)


What are the late complications of HSCT transplant?

- organ toxicity from chemo
- posttransplanation immunosuppression
- Chronic GVHD
- endocrine disease and heart failure
- increased risk of malignancy years later: acute leukaemia’s, solid tumours, MDS, disease and regimen dependent, increased prevalence after total-body irradiation
- late infections (months), usually in assoc w/ GVHD or GVHD therapy
- Vaccines:  pneumococcus, H.influenzae, Hep-B, polio, ADT, influenza - recommence at 18 months

- cataract formation
- dry eyes due to chronic GVHD

Bronchiolitis obliterans
- HSCT recipients, fatality rate 50%
- no response to steroids

- OP, and avascular necrosis
- bisphosphonates

Neuropsych disorders
- usually due to cranial irradiation


What are the long-term immune effects of HSCT transplant?

- host immunity suppressed months-years
- worse after allograft
- related to severity of induction, acute GVHD, ongoing immunosuppression for GVHD
- complete reconstitution may take years due to less active (or even absent) thymic function the older you get.


Which HLA loci must be matched in allo-HSCT?

Donor must be matched with the patient (recipient) at the HLA loci (HLA A, B, C, DR) that specify major histocompatibility antigens.


Where are donor stem cells collected from in allo-HSCT?

- umbilical cord blood units may also be used. 
- bone marrow
- more commonly through leukopheresis of the blood after mobilizing hematopoietic stem cells from the bone marrow with filgrastim (G-CSF). 


What is the initial period of pancytopaenia following induction and HSCT-transplant?

There is a period of pancytopenia in the gap between the effect of the chemotherapy given to the patient and the time it takes the infused hematopoietic stem cells to grow into bone marrow, usually 10–14 days.


What is the major cause of morbidity and mortality in allo-HSCT?
How is it managed?

GVH is the major cause of morbidity and mortality during an allogeneic SCT. Immunosuppression must be given during allogeneic stem cell transplantation to reduce the incidence and severity of GVH reaction.

CnI plus MTx


Assuming no complications, when does immunosuppression post HSCT transplant cease?

In most cases of allogeneic stem cell transplantation, the immunosuppression can be tapered and discontinued 6 or more months after transplantation.


What is the graft-versus malignancy (GVM) effect?

How does this relate to graft-versus-host disease?

What is the treatment implication?

Residual cancer cells can be recognized as foreign by the donor immune system and killed.

Intensity of GVHD correlates with GVM (rate of graft failure is inversely proportional to severity of GVHD)

Reducing the intensity of the induction regimen, relying for cure more on the GVM effect than the myeloablation.  Allo-SCT is now being offered up to age 60 in some cases.


When is allo-HSCT curative?

Acute leukaemias (AML, ALL)
CML (refractory to TKIs)
Severe aplastic anaemia


What is the main dose-limiting toxicity of chemotherapy?

How can you improve it?

Bone marrow failure

Autograft - G-CSF is given --> stem cells are collected from peripheral blood pre treatment --> induction Ctx (to kill cancer) --> reinfused post


How long does the severe pancytopaenia post induction and HSCT transplant last?  How is it managed?

7-10 days
Transfusion and antibiotics


When is autografted stem cell transplant used?

DLBCL recurrence after chemo but still responsive to chemo
Responsive relapsed Hodgkin's lymphoma
Recurred testicular germ cell tumours


What is the role of autologous stem cell transplant in mantle cell lymphoma and multiple myeloma?

Autologous stem cell transplantation is currently part of the standard of care for the treatment of mantle cell lymphoma and multiple myeloma, based not on curative potential, but the prolongation of remission and overall survival.


What are acanthocytes?

What causes them?

Acanthocytes arise from either of two mechanisms. Alterations in membrane lipids are seen in abetalipoproteinemia and liver dysfunction. Alteration in membrane structural proteins are seen in neuroacanthocytosis and McLeod syndrome.
In liver dysfunction, apolipoprotein A-II deficient lipoprotein accumulates in plasma causing increased cholesterol in RBCs. This causes abnormalities of membrane of RBC causing remodeling in spleen and formation of acanthocytes.


What is leucodepletion?

On what is it performed?

What are the benefits?

Leucodepletion is the removal of white blood cells from a blood component. 

Applies to whole blood, red cells and platelets.

- Reduction in platelet refractoriness

- Reduction in febrile non-haemolytic transfusion reactions.  (FNHTR)

- Reduction in CMV transmission risk

- Improved chance of finding an organ transplant match if required

- Reduction in storage lesion effect

- Possible reduction in transfusion associated graft vs host disease (TA-GVHD) risk


Leucodepletion by filtration of blood for transfusion is most likely to reduce the risk of which one of the following transfusion-associated events in the transfused recipient? 
A. Hepatitis C. 
B. Citrate toxicity. 
C. Cytomegalovirus infection. 
D. Malaria. 
E. Anaphylactic reaction.



A 48-year-old previously well man is receiving a transfusion of four units of packed red cell concentrate via a peripheral intravenous line after presenting with melaena secondary to a bleeding duodenal ulcer.  He has not been previously transfused.  Admission biochemistry (including urea, electrolytes and creatinine) is normal and pre-transfusion blood counts are normal apart from anaemia (haemoglobin 64 g/L [135-170]).  Less than five minutes after transfusion of the third unit of blood is commenced, he complains of feeling very unwell and abruptly develops fever, chills, rigors and profound hypotension. 
In the absence of ABO, Rhesus or minor blood group donor-recipient incompatibility, the most likely diagnosis is: 
A. bacterial contamination of the transfused blood. 
B. transfusion-associated graft-versus-host disease. 
C. electrolyte disturbance. 
D. citrate toxicity. 
E. reaction to plasticiser in infusion bag. 



What blood can an AB- person receive?

O, A, and B negative blood only

(Negative can only receive negative, never positive)


What blood can an AB+ person receive?

A, B and O all positive or negative

Positive blood groups can receive negative matches.


What blood can an A+ person receive?

A-, A+ or O +/-

(Positive can receive negative or positive)
(O bloods do not have A or B antigens)


What blood can an A- person receive?

A- or O- only

Negative can only receive negative
O does not have A or B antigens but still carries rhesus status.


What blood can an B+ person receive?

B +/-, O+/-

Positive can receive positive or negative
O does not carry A or B antigens, only rhesus status


What blood can an B- person receive?

B- or O- blood.

Negative can only receive negative
O has no A or B antigens, only rhesus.