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Haematology > Myeloid Haematological Malignancies > Flashcards

Myeloid Haematological Malignancies Flashcards

1
Q

What are the three types of myeloid malignancy?

A

Acute myeloid leukemia (AML)
Myeloproliferative neoplasms (MPN) including CML
Myelodysplastic syndromes

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2
Q

Symptoms of AML

A

non specific symptoms evolving over days to weeks
- fatigue, pallor, or otrher Sx of anaemia
- abnormal bleeding or bruising
- Sore gums, motuh ulcers
- Fevers, sweats
- recurrent / persistent infection or fever
- Bone pain, LOW

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3
Q

What is monocytic lekaemia? What is a distinguishing clinical feature of monocytic leukaemia?

A

Monocytic leukaemia is a subtype of AML in which the predominant cells in the bone marrow are monocytes

Clinical feature - gingival hyperplasia due to gingival infiltration

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4
Q

What is sweet syndrome?

A

This is a complication of AML or myelodysplastic syndromes in which acute neutrophilic infiltration of the skin results in fever and inflamed or blistered skin and mucosal lesions.

Also known as Acute febrile neutrophilic dermatosis

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5
Q

Risk factors for AML?

A
  • Older age
    • median age is 69
  • Previous myelodysplastic or myeloproliferative disorders
  • prior chemo or radio
  • First degree rel with AML
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6
Q

What are some basic investigations in AML?

A

Most improtant tests are FBE, blood film and bone marrow Bx

FBE:
- FBE shows evidence of bone marrow dysfunction such as anaemia and thrombocytopoenia
- WCC can be low, normal or high.m Generally see less healthy white blood cells and more immature / unhealth oines (blasts)

Coags
- raised APTT is concerning for DIC

Blood film:
- may see immature blasts (can be myeloid or lymphoid, difficult to tell)
- If see auer rods then it is myeloid

Dx based on Bone marrow aspirate and trephine

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7
Q

What are the 4 tests on bone marrow aspirate and trephine for leukaemia (including AML)?

A
  • Morphology
    • Is it acute leukaemia ie blasts >20% in BM
  • Immunophenotype - shows what cell surface markers there are in order to determine ? myeloid vs lymphoid
  • Chromosome analysis
  • Mutation analysis
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8
Q

What are the three avenues for treatments of AML?

A

Intensive chemotherapy (if young and fit)
Azacitidine (antimetabolite) + Venetoxclax (BCL2i) (if not fit for chemo)
Best supportive care (if frail)

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9
Q

What chemo regime is used for AML?

A

Intensive induction - cytarabine (anti metabolite) and an anthracycline (idarubicin or daunorubicin)

If they go into remission following induction then continue cytarabine based consolidation chemotherapy for 2-3 cycles

+/- allogenic stem cell transplant depending on genetic risk

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10
Q

How does intesive chemotherapy for AML work and what is the main side effects / risks?

A

Intensive chemo works by killing all the bone marrow (healthy and unhleathy)
After approx 4 weeks the healthy bone marrow will begin to recover and start to regenerate

The main risks are due to the destruction of the bone marrow and pancytopenias
- Severe infections
- Bleeding / DIC
- Anaemia
- TLS

these pts have low blood counts for approx 4 or more weeks which is a significant time

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11
Q

Who receives chemo for AML?

A

usually <60yrs and ECOG 1 or 2
Can consider for 60-70yrs wif very fit

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12
Q

Is there any role for targeted therapies in AML? if so, what is/are the target/s?

A

Yes there is a role
Addition of small molecule TKI for targetable mutations such as FLT3 mutations

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13
Q

Cytarabone and an anthracycline is used in the cehmo induction for AML pts. What is the main side effect of anthrocyclines?

A

Cardiac toxicity
- these pts should be screened for cardiac disease prior to treatment

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14
Q

What is an example of a FLT3 TKI used in AML?

A

Midostaurin

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15
Q

What is azacitidine and how is it used in AML treatment?

A

Azacitidine is a methylating agent
Used for the older population with AML who have completed intensive chemotherapy but are not fit for allogenic stem cell tranplant for some reason

PBS listed

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16
Q

What is venetoclax and how is it used in the treatment of AML?

A

Venetoclax is a BCL2 inhibitor

it is used in combination with azacitidine for pts that are not fit for intensive chemo but who are not frail enough for best supportive care.

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17
Q

What sort of genetic defect is chromosomal analysis / karyotyping useful for detecting?

A

translocation or chromosomal deletions
- cannot be used to see small mutations (ie base pair mutations)

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18
Q

What are some examples of tests that can be used for mutation analysis in leukaemia?

A

FISH - florescent in situ hybridization
- need to know what you are looking for
- Advantage: can be done rapidly for example in APML (t(15:17))

PCR
- need to know what you are looking for
- amplification fo specific mutation ie FLT3, IDH, NPM

NGS - next generation sequencing
- Panel of primers that detects 10s to 100s of mutations in one assay
- more time consuming and intensive

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19
Q

Why do we test for specific gene mutations in AML?

A

Informs prognosis and therapy

For example, can divide AML into three categories based on specific mutations present and specific combination of mutations
- Favorable
- Intermediate
- Adverse

For example, pts with adverse risk category would require bone marrow transplant to have best chance at survival

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20
Q

What are the main causes of early morbidity and mortality in acute AML?

A

DIC - catastrophic bleeding, particularly with APML

Hyperleukocytosis (ie WCC >100) - pul infiltrates and hypoxia

Febrile neutropenia and overwhelming sepsis

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21
Q

What are some key aspects of supportive care for pts with AML?

A

Coagulopathy
- Monitor coags and fib fro evidence of DIC
- Mnx as appropriate

Tumor lysis prophylaxis
- BD monitoring of UEC and CMP for pts on induction therapy
- Support with IVF +/- sodium bicarb for renal protection
- Allopurinol
- Can consider rasburicase if severe TLS

Venous access devices

Neutrophil support
- G-CSF injections until neutrophil recovery. Only given once in remission

Plt and red cell transfusions as required
- need to give irradiated cellular products if consideration of allo SCT to reduce risk of GVHD

Anti-infection prophylaxis

fertility preservation

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22
Q

What anti-infection prophylaxis is used in AML pts undergoing chemo?

A

Antiviral - valaciclovir

Antifungal - aspergilosis cover with Posaconazole is essential for pts undergoing induction

+/- PJP prophylaxis - Bactrim is first choice. Otherwise dapsone, atovaquone or pentamidine

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23
Q

What is the most important progostic factor in AML?

A

The specific genetics (ie what mutations they have)

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24
Q

APML is a subtype of AML. How does APML typically present?

A

Pancytopenia and DIC (unwell pts)

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25
Q

What is APML?

A

It is a subtype of AML in whicht eh predominate cell is a promyelocytes (a little bit more differentiated than myeloid blasts)

represents 10-15% of all AML

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26
Q

What is the characteristic genetic mutation in APML?

A

Characterised by t(15:17) resulting in PML/RAR fusion gene on both chrome 15 qnd 17
- can be rapidly Dx by FISH

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27
Q

What is the main treatment regime of APML?

A

All trans retinoic acid (ATRA) + arsenic trioxide (ATO) +/- chemo

Pts respond very well, 90% go into remission
- prompt initiation reverses DIC

28
Q

What is the main side effect of ATRA in APML? How is this prevented?

A

ATRA promotes promyelocyte differentiation
Rapid differentiation induced by ATRA leads to rising WCC and cytokine release
- leaky capillaries -> resp distress / fluid overload
- appears like flash APO

Prevented with steroid and chemotherapy

29
Q

What is the differenece between hyperleukocytosis and hyperviscosity syndrome?

A

they have similar effects, but are due to different etiologies
- Hyperleukocytosis is due to too many White cells in the blood
- Hyperviscosity syndrome is due to excessive protein (most often due to Hypergammaglobulinemic purpura of Waldenström

30
Q

What is myelodysplastic syndrome?

A

This is a clonal myeloid neoplasm characterized by dysplasia of myeloid cells and ineffective haematopoesis

It presents as a wide spectrum of disease - from mild low blood counts, the life threatening low blood counts

31
Q

How is myelodysplastic syndrome different from AML?

A

MDS is a precursor lesion to AML. Most will not develop AML but some can transition to AML

These pts have 5-20% blasts in the bone marrow, and evidence of myeloid dysplasia

32
Q

Features of MDS on BM?

A

Dysplasia in 1-3 lineages
Often have an increase in myeloid blasts (ie more than 5% but less than 20% as this would be AML)
Other features - ring sideroblasts

33
Q

What are some poor prognosis features of MDS?

A

Specific mutations (ie Inv3 mutation)

High number of blasts (ie 19% - very close to AML)

Very low cell counts

34
Q

WHo gets MDS?

A

Elderly (approx 70yrs)

35
Q

MDS exists on a spektrum with CHIP. What is CHIP?

A

Clonal haematoipesis of indeterminate potential (CHIP)
- this is when we detect evidence of clonality in a pt bone marrow, but they have no dysplasia, nil cytopenias and normal blasts

  • These pts are at slightly hjigher risk of going on to develop MDS, AML. but overall are still very low risk

Sort of analagous to MGUS and MM relationship

36
Q

How is management of MDS stratified?

A

Stratified based on early / low risk, or intermediate / high risk stages

37
Q

How is early / low risk stage MDS treated?
How is intermediate / high risk stage MDS treated?

A

Early / low risk:
- Usually managed with observations
- Can support with PRBC and plt transfusions PRN

Intermediate / high risk:
- Azacitidine (hypomethylating agent) can improve survival and prolong transformation to AML
- Decitabine is similar to azacitidine but is easier to administer option
- Allogenic stem cell transplant is the only curative option

38
Q

How is MDS with deletion of chm 5q treated?

A

Lenalidomide targeted therapy

39
Q

What are the main types of myeloproliferative neoplasms?

A

CML
Polycythaemia vera
Primary myelofibrosis
ET

40
Q

What is the characteristic genetic abnormality in CML?

A

Philidelphia chromosome - t(9:22)
- leading to formation of fusion BCR-ABL gene which has tyrosine kinase activity

41
Q

How do pts with CML typically present? What will bloods and BM show (briefly)?

A

usually reasonabbly well pts elderly pts with slow onset of constitutional symptoms. Pts often incidentally found to have very high WCC incidental

FBE:
- Usually neutrophilia with increased left shift (myelocytes)

BM
- hyper cellular, packed with myeloid cells (more differentiated than MDS and AML)

42
Q

What are the classic phases of CML?

A

Chronic phase:
- typically 5-10% blasts

Accelerated phase:
- Bone marrow or peripheral blood blasts 10-19%
- OR basophils >20% in peripheral blood

Blast phase:
- blasts >20% in blood or BM
- usually what results in death (at least in pts without treatment)

43
Q

What is the classic mainstay treatment of CML?

A

Imatinib is a BCR-ABL inhibitor
It is a TK molecule

Nowadays there is range of other similar drugs

44
Q

What are some examples of second and 3rd generation treatments in CML? what are some side effects?

A

1st gen - imatinib

2nd gen - Dasatinib (pleural effusions), Nilotinib (CV toxicity)

3rd gen - Ponatinib (CV toxcicity)

45
Q

When are 2nd gen and 3rd gen drugs used for CML?

A

If have side effects to one agent, or develop resistance to an earlier generation drug

46
Q

How is CML monitored?

A

Monitor BCR/ABL level

Aim for <0.1% by 12 months -> will indicated very good response

47
Q

How long is TKI continued in CML?

A

Usually continue for >2 years. if pts have very good response (ie persistent low levels of BCR/ABL) then can consider trial of ceasing medication

Otherwise can continue for life (majority)

48
Q

How is blast phase CML managed?

A

Managed with TKI
However may also need chemo and transplant occasionally

49
Q

At what plt level should you suspect ET?

A

Suspect ET if plt >450 in abscence of secondary causes

50
Q

What are some more specific symptoms of ET?

A

Erythromelalgia - burning /aching in the hands and fingers

History of arterial / venous thrombosis, especially in strange locations such as splanchnic veins etc

51
Q

Diagnosis of ET?

A

Major criteria:
- Plt >450
- Exclude other myeloproliferative disease (CML, PV, PMF, MDS)
- Presence JAK2, CALR, MPL mutation (may not have these, in which case BMB is relied upon for Dx
- BMB showing proliferation mainly of megakaryocyte lineage

52
Q

What percentage of PV pts have JAK2 mut?

A

95%

53
Q

What percentage of ET pts have JAK2 mut?

A

approx 50%

54
Q

What percentage of MF pts have JAK2 mut?

A

approx 50%

55
Q

The mutation spectrum in ET and MF is very similar. Aside from JAK2 mutations, what is the next most common mutations in both these disorders?

A

CALR
MPL

56
Q

How is ET risk stratified?

A

Very low risk
- <60
- Nil Hx thrombosis
- JAK2/MPL unmutated

Low risk
- <60
- Nil Hx thrombosis
- JAK2/MPL mutated

Intermediate risk
- >60
- nil Hx thrombosis
- JAK2/MPL unmutated

High risk
- Hx thrombosis OR
- >60 with JAK2/MPL miutation

57
Q

How is ET treated based on risk stratification?

A

Very low risk
- observation if nil CV RF
- Daily aspirin if CV RF

Low risk
- once or twice daily aspirin

Intermediate risk
- Hydroxyurea and aspirin

High risk
- hydroxyurea and twice daily aspirin

58
Q

What is treatment for ET in preg?

A

Interferon

59
Q

What is Polycythemia Vera?

A

Persistent elevation of Hb/Hct without secondary cause found (ie significant resp or CVD)

60
Q

How is Polycythemia diferentiated from PV?

A

Can consider checking EPO to distinguish between secondary polycythaemia or PV
- combination of low EPO and high Hct/Hb is PV

Absence of JAK2 is consistent with polycythemia (95% PV have JAK2 mutation)

Can identify secondary causes of poloycythema
- COPD/ smoking
- high altitude
-OSA

61
Q

Treatment for PV?

A

Aspirin for all pts to reduce clotting risk
Reduce Hct by:
- venesection to induce Fe Deficiency
- Addition of hydroxyurea if high risk (ie Hx thrombosis)

62
Q

What can ET and PV both evolve into (in rare instances)?

A

Both can evlove into MF or AML
- This is rare an hard to treat

63
Q

What are some clinical signs and symptoms of myelofibrosis?

A

Symptoms:
- Fatigue, anorexia, abdo pain, night sweats, fevers, bone pain, weight loss

Signs:
- Marked splenomegally
- Weight loss

64
Q

What are the classic blood film findings of MF?

A

Tear drop cells
leukoerythroblasic film (immature cells spilling out into peripheries)

65
Q

What are some features on BM of MF?

A

BM aspirtate typically dry tap
BM trephine: increased reticulin fibsosis with minimal cells

66
Q

What are the main treatment avenues for MF?

A

Allogenic transplant if young and fit

Ruxolitinib (JAK 1 and 2) otherwise, often used in conjunction with best supportive care as a palliative approach

67
Q

What is Ruxolitinib and what are the main benefits in MF?

A

Ruxolitinib is a non selective JAK inhibitor

It is used in intermediate and high risk MF. It works in both JAK2 pos and JAK2 neg MF

Reduces size of liver
increases resolution of constitutional sx
Does not help with blood counts

Haematology (5 decks)

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