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MBBS II HIS > L23 – Leukaemias: Principles of management and diagnosis > Flashcards

L23 – Leukaemias: Principles of management and diagnosis Flashcards

1
Q

Define acute leukaemia?

A

Clonal haematological disorder of precursor myeloid/lymphoid cell origin

≥ 20% leukaemic blasts in the bone marrow or peripheral blood

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2
Q

4 major genetic mechanisms of leukaemogenesis?

A
  • Transcription dysregulation and differentiation block
  • Activation of proto-oncogenes
  • Inactivation of tumour-suppressor genes
  • Activation of signalling genes or receptor tyrosine kinases
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3
Q

List some common genetic mutations in acute leukaemia?

A
  • RUNX1-RUNX1T1** : fusion t(8;21)(q22;q21)
  • PML-RARα** :
  • TP53 mutation
  • CBCF-MYH11 **: t(16;16)
  • Various chromosomal translocations

these 3 genetic mutations can classify AML even if <20% blast in PB/BM

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4
Q

Mechanism of RUNx1-RUNX1T1 in acute leukaemia.

A

Fusion of RUNX1 from chromosome 21 + RUNX1T1 from chr. 8

RUNX1 codes for CBFa transcription factor

RUNX1T1 binds to CBFa and disrupt connection with co-activator&raquo_space; cannot start transcription of target gene

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5
Q

Mechanism of CBFβ-MYH11

in acute leukaemia.

A

MYH11 binds to CBFβ transcription factor&raquo_space; block co-activators from binding to CBFβ&raquo_space; block transcription of target gene

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6
Q

Classify AML into 5 classes?

A
  • AML with recurrent genetic abnormalities
  • AML with myelodysplasia-related changes/ after MDS
  • Therapy-related myeloid neoplasm/ AML
  • Myeloid sarcoma (isolated myeloid sarcoma is rare)
  • Miscellaneous types with diff. morphology
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7
Q

What is the concurrent condition of isolated myeloid sarcoma?

A

AML

rarely exists alone

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8
Q

List the 3 mutations used to classify AML?

A

t(8;21)&raquo_space; RUNX1-RUNX1T1

inv(16) or t(16;16)&raquo_space; CBCF-MYH11

APL with PML-RARA

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9
Q

Genetic mutation that marks APL?

A

PML-RARα

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10
Q

List 2 Precursor lymphoid neoplasms.

A
  • B-ALL & B-lymphoblastic lymphoma

* T-ALL & T-lymphoblastic lymphoma

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11
Q

Walk through sequence of investigations for acute leukemias?

A

1) Specific diagnosis
2) Detect and predict disease complications + prognosis
3) Determine fitness for treatment
4) Detect treatment response and complications

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12
Q

List 4 blood metrics* checked for Acute leukaemia.

A
  • CBC with manual review and differential count
  • Clotting profile, d-dimer and fibrinogen (check for DIC, esp. for APL)
  • Serum electrolytes (Na, K, Ca, PO4)
  • LDH and urate levels (Tumor lysis syndrome)
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13
Q

List 4 tests for fitness for chemotherapy treatment in acute leukemia?

A

Liver, lung and renal function tests

ECG and transthoracic echocardiogram (anthracycline, cardiotoxicity)

HBV, HCV, HIV serology

G6PD assay (oxidative hemolysis with Co-trimoxazole)

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14
Q

Which tests give diagnositic and prognostic indicators for acute leukemia?

A

bone marrow aspiration and trephine biopsy

Cytogenetic e.g. FISH

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15
Q

Which investigation is used to delineate AML from ALL?

A

Cytochemistry with Myeloperoixdase and Sudan black B&raquo_space; specific for myeloid lineage

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16
Q

Which investigation is used to SUBCLASSIFY lineages of AML and ALL?

A

Flow cytometry

best for finding concurrent CD antigens

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17
Q

Which investigations for finding chromosomal/ genetic abnormalities in AML/ ALL?

A

Molecular genetics (PCR based)

Cytogenetics: Karyotype and FISH

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18
Q

Which investigation for identifying morphology of leukaemic cells?

A

Peripheral blood smear

BM biopsy exam

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19
Q

Investigation for suitability of allogeneic HSCT for acute leukaemia patients?

A

HLA-typing of patient and siblings

or HLA-typing of related donor if family is not HLA identical

20
Q

Walk through phases of treatment for acute leukaemia? (not including APL)

A

1) Induction phase: High dose, reduce tumour burden
2) Consolidation phase: high dose, curative
3)
i) Maintenance for APL, ALL. Normally not for AML
ii) High- risk, relapsed, refractory = HSCT

21
Q

First line treatment for APL?

A

ATRA

Arsenic trioxide

22
Q

List the criteria for allogeneic HSCT for acute leukaemia? (divide into AML and ALL)

A

AML:

i) high risk AML in first remission
ii) Relapsed AML with second remission

ALL

i) High risk ALL in first remission
ii) Persistent Measurable Residual Disease (MRD) in first remission
iii) Relapsed ALL in second remission

23
Q

What determines the prognosis of leukaemia treatment?

A

Depends on the genetic changes in leukaemic cells

Some changes&raquo_space; good prognosis, curable by chemo

Some changes&raquo_space; worse prognosis, need HSCT

24
Q

B-ALL: which blood cell lineages are affected?

A

Anemia and/or thrombocytopenia + leukocytosis

25
Q

Clinical presentation of B-ALL?

A

Pallor, shortness of breath (due to concurrent anemia + leukocyte infiltration into pulmonary vessels)

Fever

Engorged retinal veins, bleeding tedency (from concurrent thrombocytopenia)

Possible lymphadenopathy, hepatomegaly, splenomegaly
May involve CNS

26
Q

List the histological features of APL?

A

Faggot cells

Auer rods

27
Q

Describe the clotting profile in APL?

A

Disseminated Intravascular Coagulopathy:

Increased PT/APTT + D-dimer

28
Q

Why does acute leukaemia cause concurrent anemia and thrombocytopenia?

A

Blasts infiltrate and occupy BM

> > disrupt architecture for normal haematopoiesis

29
Q

WHich type of acute leukaemia is associated with toxins?

A

AML usually associated with toxic exposure

30
Q

DDx clonal causes of leukocytosis?

A

1) If blasts >= 20%: ALL or AML
2) If blasts < 20%: Myeloid malignancies like MDS, MPN, CMML
3) If no leukaemic blasts but abnormal lymphoid cells present: suspect CLL

31
Q

DDx reactive causes of leukocytosis?

A

Search for underlying cause:

  • Infection
  • Autoimmune or inflammatory diseases
  • Paraneoplastic
  • Reactive to solid tumours
32
Q

Treatment for prevention of tumour lysis syndrome? CNS prophylaxis from ALL?

A

Febuxostat and IV fluids

Methotrexate to prevent CNS penetration

33
Q

Which metrics from flow cytometry can identify B-ALL?

A

early precursor B-cell immunophenotype:

CD19+, CD79a+, CD22+, weak CD34+

CD10 and cytoplasmic µ chain negative

34
Q

Common genetic abnormality for B-ALL?

A

Pre-B progenitor with blocked maturation

KMT2A-AFF1 fusion confirm by FISH

Karyotype: t(4;11)

35
Q

Induction therapy of ALL?

A

doxorubicin, vincristine, corticosteroids and L-asparaginase

36
Q

AML clinical presentation?

A
  • Acute bleeding tendencies: Spontaneous gum bleeding and general petechiae and easy bruising (due to thrombocytopenia)
  • Pallor (due to anemia)
  • Mild hepatomegaly
37
Q

List the cell lineages affected in AML?

A

Granulocytic progenitor with blocked maturation

Anemia 
Thrombocytopenia 
leukocytosis 
Neutropenia 
*no abnormal promyelocytes*
38
Q

Clotting profile and fibrinogen levels of AML and ALL?

A

AML, ALL = normal clotting (provided no leukaemia-related DIC)

APL = abnormal*

39
Q

LRFT and serum electrolyte levels in AML and ALL?

A

Normal in both (provided no severe tumour lysis syndrome)

40
Q

Name one genetic abnormality in AML?

A

Chromosome 9, 11 translocation

41
Q

Therapy regimen for AML?

A

Induction: Daunorubicin (3 days) + Cytarabine (7 days)
= 3 + 7 induction

Consolidation: 4 cycles of high dose cytarabine

Indicate allogeneic HSCT if high-risk AML

42
Q

Phases of CML pathogenesis?

A
  1. Chronic phase: 3-4 years
  2. Acceleration: <6 months
  3. Blastic crisis: 1-2 months

Very high leukocytosis

43
Q

Genetic mutation hallmark of CML?

A

– Philadelphia chromosome (translocation t(9;22)

44
Q

Treatment of choice for CML?

A

tyrosine kinase inhibitors (TKI, e.g. imatinib)

** Incurable with conventional chemotherapy **

HSCT for unresponsive or blastic phase CML

45
Q

Treatment of choice for CLL?

A

Early stages = no treatment

Purine analogues +/- monoclonal Ab/ alkylating agents for elderly:
e.g. 6-metcaptopurine +/- Rituximab or cyclophosphamide

HSCT indicated for younger patients

MBBS II HIS (30 decks)

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