Bone Marrow Transplant

Question 1

What are the indications for BM transplants? (kind of conditions - 5+)

Answer 1

Malignant & Non-malignant indications

Malignant: both autologous (more common) or allogenic

• Acute and Chronic Leukaemia
• Lymphoma, including Hodgkin’s
• Multiple Myeloma

Non-malignant: mostly Allogenic, not autologous

• Aplastic anaemia, Fanconi’s anaemia
• Thalassaemia
• Sickle cell dsiease
• Severe combined immunodeficiency

Question 2

What are the reasons for conditioning the BM prior to SCT? (3)

Answer 2

To kill tumour cells

Prevent GvHD

Create space for new stem cells

Question 3

Difference between myeloablative vs. non-myeloablative (reduced-regime, aka - reduced intensity regime - RIC) conditioning? What is the main pros + cons for each? (2)

Answer 3

• Myeloablative → wipes out the BM. If they don’t get SCT they will remain aplastic and BM will not recover
  
  • Reduces GvHD
  • Higher risk of infections
• Reduced intensity → BM will recover without SCT
  
  • Reduces life threatening infections
  • HIgher risk of GvHD
  • Allows us to offer allogeneic transplants to older patients

Question 4

What are the complications of BM transplant? (6)

Answer 4

Specific to BM: Mucositis, GvHD, Cytopaenia

General transplant associated:

Infection - including CMV, EBV, BK, encapsulated bacteria, VZV, PJP, Aspergillous, toxoplasma

Steroid-related complications: diabetes and osteoporosis

VOD (aka SOS) Hepatic Sinosoidal Obstructive Syndrome

Secondary malignancy

Relapse

Question 5

How WOULD you describe transplant patient in the long case presentation? (must know)

Answer 5

• Up to 100 days since stem cell engraftment (day 0)
• How many month after this
• Really helps what could be going wrong
• E.g. Mr Jones is 65yo male who is day (X) after his reduced/full intensity regime, matched/unmatched (type of – sibling/MUD/Haplo) transplant for (indication – e.g. high risk AML) that was (in remission or not) at the time of transplant

Question 6

How does acute GvHD present? (4)

Answer 6

Maculopapular rash - in severe cases desquamation

Pruritis

Derranged LFTs

Diarrhoea

Question 7

Risk factors for GvHD? (5) - what is the prevalence?

Answer 7

1. Degree of HLA mismatch

~40% of recipients of fully matched sibling donor

~70% in those with 1 antigen mismatch from unrelated donor

2. Previous blood product exposure
3. Previous pregnancy
4. Source of graft (risk higher with peripheral blood or BM compared with cord-blood)
5. GvHD prophylactic regime used

Question 8

BMT - examination (5)

Answer 8

Anaemia, Cachexia

Lymphadenopathies

Signs of infection: especially for HSV, EBV, chest infection

Stigmata of chronic GvHD: skin changes similar to scleroderma, dry eyes, mouth (sicca), alopecia, signs of bronchiolitis obliterans (wheeze)

Hepatomegaly + Ascites (VOD)

Question 9

How would you support this patient undergoing a BM transplant (3)?

Answer 9

1. Cytopaenia: transfusion support (irradicated blood, PLT - must be CMV -ve if CMV -ve recipient) until the engraftment occur. G-CSF (to support engraftment + speed recovery)
2. GvHD prophylaxis (allo): Prednisolone + MTX +/- Cyclosporin
3. Infection prophylaxis: valganciclovir if CMV +ve, use sero -ve blood, fungal (fluconazole/posiconazole), PCP (Bactrim: 6-12 months)

Question 10

How would you manage complications of BM transplant? (8)

Answer 10

ABCDEFG

Acute GvHD: Methylpred + Cyclosporin. If steroid refractory - Rituximab, ATG, Alemtuzumab (anti-CD52)

Chronic GvHD: presents with skin thickening like scleroderma, difficulty eating due to pain, GI upset. Prednisolone, extra-corporial photophresis → WCC isolated and exposed to UVA irradiation then returned.

Bone marrow: cytopaenia support transfusion support + G.CSF in consultation

Cancer surveillance: age-appropriate cancer screening - full skin checks, mamogram, PSA, FOBT/Colonoscopy…etc.

Dry mouth - Mucositis: Big problem (results in feeding difficulties and malnutrition) sodibic mouth wash, LA, analgesia, screen for HSV and Aciclovir if present

EEnfection: Infection: prophylaxis, vaccination, hygiene. Education + Action plan.

Fertility: sperm/ovum banking pre-transplant, GnRH agonist for ovarian protection

Hepatic Sinusoidal Obstructive Syndrome (SOS or known as VOD - Veno Occlusive Disease): monitor LFTs, hepatomaly, jaundice and ascites. Prevent with UDCA prophylaxis if having hyeloablative transplant. Tx with Defibrotide. Consider tPA.

Question 11

What are the BMT details you must obtain in the long-case (P?) 7.

Answer 11

1. Indication - was other treatment unsuccessful? relapse? Important to know as prognosis is worse if BMT was done due to failed tx.
2. Autologous or allogenic
3. Who was the donor? parent, sibling or unrelated
4. HLA match (allogenic, matched out of 8 or 10)
5. Source (mobilised peripheral blood, BM [aspirate] or cord blood)
6. Conditioning/Full (or myeloablative - BM wiped out completely with radiation of chemo) or reduced-regime (full or reduced intensity)
7. Has the patient had GvHD prophylaxis (if allogenic)

Question 12

BMT - PRICMCP?

Answer 12

P: when was it, indication, prior tx, matching, graft source, conditioning vs. reduced regime, GvHD prophylaxis

C: complications - how long was the patient in the hospital?

• Transplant itself: graft rejection, GvHD (acute <3m or chronic >3m), Hepatic SOS (jaundice, RUQ pain, LFT derrangement), recurrence of original disease
• Therapy related: mucositis, cytopaenia, infection (PJP, CMV, BK…etc), infertility, steroid complications (DM + OP), secondary malignancy

M:

• Current medications: ImmunoSx
• Infection prophylaxis, vaccinations - does patient have an action plan for symptoms of infection?
• Hepatic SOS prophylaxis (UDCA, defibrotide)
• Transfusion support
• Sperm/ovum banking

C: Why is patient in hospital now? ask about symptoms of GvHD and VOD. Does patient feel better after transplant? _How is patient coping (enough support at hom_e)? Infertility is big issue for young patients

P: Insight re: long-term complications of transplant e.g. infection - understand importance of vaccines/hygiens…etc. Insights into prognosis.

Question 13

Timing of Acute and Chronic GvHD?

Answer 13

Acute - by definition, occur within 3 months after transplant.

Question 14

What are measures to prevent GvHD? (2) what is the problem associated with the latter approach?

Answer 14

Prophylaxis: prednislone + immunosuppressives (e.g. MTX and Cyclosporin/tacrolumus)

Donor BM maybe treated to remove T-cells but this increases the risk of Graft rejection

Question 15

Management of severe acute GvHD?

Answer 15

High dose prednisolone

Antithymocyte globulin (ATG)

Monoclonal Ab to T-cells

Question 16

What is the long-term problem of GvHD?

Answer 16

Increased risk of tumour recurrence.

Question 17

Chronic GvHD clinical features?

Answer 17

Develops after 3 months following the transplant.

Autoimmune like-illness with sicca, sclerooderma-like skin thickening, arthritis, cholestasis, bronchiolitis obliterans.

Question 18

Why is it important to know indication for BM transplant, whether it was done as a primary or secondary therapy when all else has failed?

Answer 18

Because if latter is the case, the prognosis is worse.

Question 19

5yr survival rates of BM transplant patients?

Acute Leukaemia

CLL

CML

Hodgkin’s

NHL

Answer 19

Acute Leukaemia ~50%

CLL ~50%

CML ~70% (chronic), 40% (accelerated), 15% (blast crisis)

Hodgkin’s ~50%

NHL ~40%

Question 20

Explain the phases of stem-cell transplant? (4)

Answer 20

Conditioning - with chemo or RTx to eliminate malignancy

Neutropaenic phase

Engraftment

Post-engraftment phase (main problems are infection and GvHD)

Question 21

Timing and type of infections following the BMT? (3 time periods)

Answer 21

First month (neutropaenc phase): bacterial, fungal

Upto 3 months: viral - CMV, EBV, BK, RSV

After 3 months - Atypicals: PJP, Aspergillous, Toxoplasma, encapsulated bacteria.

Infections are a lot less frequent after 100 days, as immunosuppressive are generally weaned off (if all goes well with minimal GvHD) unless of course, they are being treated for GvHD (chronic) - which may require prolonged immunosuppressive therapy.

Question 22

DDx for derranged LFTs post BMT? How would you distinguish between them? (3)

Answer 22

GvHD - acute <100d (rash, diarrhoea) vs. chronic >100d (scleroderma like skin-thickening)

Hepatic SOS (VOD) - usually within 3 weeks. Ascites & RUQ pain.

So timing is the key and clinical features are quite different.

Medication (MTX - hepatotoxicity, CsA - raised bilirubin/AST)

Question 23

Sibling has what % chance of a 6/6 match?

Answer 23

25%

Question 24

What is 10/10, 8/10 match?

Answer 24

• Just means that more of HLA genes, other than A,B,D are tested (e.g. C and DQ)
• 8/10 match → less well matched (mismatched transplant) → really high risk of GvHD

Question 25

What is Syngeneic vs. Haploidentical transplant?

Answer 25

Syngeneic = from identical twin Haploidentical transplant - 50% exact match. * 75% of sibling will have 50% exact match (1/4 sibling will have no match and hence useless) * Your parents have 50% HLA types that match (as you have inherited 1 from each) * You can extend search to include extended families * High-likelihood of finding a match

Question 26

What are indications for autologous SCT?

Answer 26

* **MM** * **Lymphoma** * Follicular * Relapsed chemo-responsive DLBCL * Hodgkin’s (50% respond even if chemo-refractory) * T-cell lymphoma * If patient tells you that they had autologous SCT for other disease – may not be true as this is very rare

Question 27

Would you give childhood vaccination to patient who had SCT? Why?

Answer 27

* Yes because the chemotherapy to cook the BM will wipe out memory cells. * _As per_ **childhood vaccination program** * PCP and Shigles prophylaxis

Question 28

What is the mortality risk with allogenic transplant? (siblig, haplo and MUD)

Answer 28

About 20-25% over 6 months

Question 29

What is the purpose of “conditioning”?

Answer 29

* To allow engraftment * Prevent GvHD * Not to directly kill tumour cells * So over the years we have been using less toxic regime (from whole body radiation + high dose cyclophosphamide\* (i.e. full-intensity regime) ⇒ Mephalane + fludarabine) – aka. Reduced Intensity Allograft (RIC)

Question 30

What are the indications of Allogenic SCT?

Answer 30

* Acute leukaemia\* (AML, ALL) – high risk cytogenetics * MDS\* (BM failure) – high risk cytogenetics * Aplastic anaemia (5yr survival 90% - particularly good) * Refractory lymphoma

Question 31

Pros and cons of **BM harvest** over peripheral blood? (2)

Answer 31

•Advantages * Very few lymphocytes → less risk of GvHD * Especially important for Aplastic Anaemia\*\* •Disadvantages * Painful * Has lot of RBCs – so if ABO incompatible, can incur essentially transfusion reaction

Question 32

What are the clinical features of chronic GvHD? (\>100 days) - 5

Answer 32

**Skin** * Lichen planus (violaceous papules & plaques) * Similar to _scleroderma – sclerotic skin_ changes * Wide spectrum **GIT** * _Mouth ulcers – THEY CANT EAT_\*\* * Dysphagia, weight loss * Chronic diarrhoea & malabsorption **Liver**: abnormal LFTs (see later – what condition in particular)? **Lung** – bronchiolitis obliterans **Renal** – nephrotic syndrome

Question 33

What if someone relapse post transplant? – what are tx options? (Leukaemia) - 5.

Answer 33

* Know that there is **very high mortality** rate * **Donor lymphocyte infusion** (or frozen ones) – idea is to give T-cells to _incur Graft versus Leukaemia effect_ * **Second allograft** * **Novel chemotherapy** – e.g. FLT3 inhibitors, venetoclax * **CAR-T cell therapy** (modified T-cells Taylor made to recognise tumour cells)

Question 34

Allogenic BMT - early graft assessment

Answer 34

= Recovery of Neutrophils (\>2.0) and PLT (\>50) Assess with FBC Should recover within 3-4 weeks - if not, failure of engraftment (i.e. rejection). 5%.

Question 35

Is immunosuppressants given long term in patients with allogenic BMT?

Answer 35

No. They are all initially put on ImmSx post transplant but aim to cease ALL immunosuppressants **unless** there is evidence of ongoing GvHD. This is to enable Graft-Versus- Tumour effect - so if you suppress immune system too much, you are not treating the Cancer So the duration of ImmSx therapy for each patient varies - depends on transplant type, underlying disease, degree of GvHD and toxicities. Those patient who has had GvHD - maybe on immunosuppressants as they are tapering corticosteroids...etc. So - if they are well maintained, they should not be on any ImmSx