L23 – Leukaemias: Principles of management and diagnosis

Question 1

Define acute leukaemia?

Answer 1

Clonal haematological disorder of precursor myeloid/lymphoid cell origin

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

Question 2

4 major genetic mechanisms of leukaemogenesis?

Answer 2

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

Question 3

List some common genetic mutations in acute leukaemia?

Answer 3

• 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

Question 4

Mechanism of RUNx1-RUNX1T1 in acute leukaemia.

Answer 4

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

Question 5

Mechanism of CBFβ-MYH11

in acute leukaemia.

Answer 5

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

Question 6

Classify AML into 5 classes?

Answer 6

• 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

Question 7

What is the concurrent condition of isolated myeloid sarcoma?

Answer 7

AML

rarely exists alone

Question 8

List the 3 mutations used to classify AML?

Answer 8

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

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

APL with PML-RARA

Question 9

Genetic mutation that marks APL?

Answer 9

PML-RARα

Question 10

List 2 Precursor lymphoid neoplasms.

Answer 10

• B-ALL & B-lymphoblastic lymphoma

* T-ALL & T-lymphoblastic lymphoma

Question 11

Walk through sequence of investigations for acute leukemias?

Answer 11

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

Question 12

List 4 blood metrics* checked for Acute leukaemia.

Answer 12

• 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)

Question 13

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

Answer 13

Liver, lung and renal function tests

ECG and transthoracic echocardiogram (anthracycline, cardiotoxicity)

HBV, HCV, HIV serology

G6PD assay (oxidative hemolysis with Co-trimoxazole)

Question 14

Which tests give diagnositic and prognostic indicators for acute leukemia?

Answer 14

bone marrow aspiration and trephine biopsy

Cytogenetic e.g. FISH

Question 15

Which investigation is used to delineate AML from ALL?

Answer 15

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

Question 16

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

Answer 16

Flow cytometry

best for finding concurrent CD antigens

Question 17

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

Answer 17

Molecular genetics (PCR based)

Cytogenetics: Karyotype and FISH

Question 18

Which investigation for identifying morphology of leukaemic cells?

Answer 18

Peripheral blood smear

BM biopsy exam

Question 19

Investigation for suitability of allogeneic HSCT for acute leukaemia patients?

Answer 19

HLA-typing of patient and siblings

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

Question 20

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

Answer 20

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

Question 21

First line treatment for APL?

Answer 21

ATRA

Arsenic trioxide

Question 22

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

Answer 22

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

Question 23

What determines the prognosis of leukaemia treatment?

Answer 23

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

Question 24

B-ALL: which blood cell lineages are affected?

Answer 24

Anemia and/or thrombocytopenia + leukocytosis

Question 25

Clinical presentation of B-ALL?

Answer 25

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

Question 26

List the histological features of APL?

Answer 26

Faggot cells | Auer rods

Question 27

Describe the clotting profile in APL?

Answer 27

Disseminated Intravascular Coagulopathy: | Increased PT/APTT + D-dimer

Question 28

Why does acute leukaemia cause concurrent anemia and thrombocytopenia?

Answer 28

Blasts infiltrate and occupy BM >> disrupt architecture for normal haematopoiesis

Question 29

WHich type of acute leukaemia is associated with toxins?

Answer 29

AML usually associated with toxic exposure

Question 30

DDx clonal causes of leukocytosis?

Answer 30

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

Question 31

DDx reactive causes of leukocytosis?

Answer 31

Search for underlying cause: - Infection - Autoimmune or inflammatory diseases - Paraneoplastic - Reactive to solid tumours

Question 32

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

Answer 32

Febuxostat and IV fluids Methotrexate to prevent CNS penetration

Question 33

Which metrics from flow cytometry can identify B-ALL?

Answer 33

early precursor B-cell immunophenotype: CD19+**, CD79a+**, CD22+, weak CD34+ CD10 and cytoplasmic µ chain negative

Question 34

Common genetic abnormality for B-ALL?

Answer 34

Pre-B progenitor with blocked maturation KMT2A-AFF1 fusion confirm by FISH Karyotype: t(4;11)

Question 35

Induction therapy of ALL?

Answer 35

doxorubicin, vincristine, corticosteroids and L-asparaginase

Question 36

AML clinical presentation?

Answer 36

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

Question 37

List the cell lineages affected in AML?

Answer 37

Granulocytic progenitor with blocked maturation ``` Anemia Thrombocytopenia leukocytosis Neutropenia *no abnormal promyelocytes* ```

Question 38

Clotting profile and fibrinogen levels of AML and ALL?

Answer 38

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

Question 39

LRFT and serum electrolyte levels in AML and ALL?

Answer 39

Normal in both (provided no severe tumour lysis syndrome)

Question 40

Name one genetic abnormality in AML?

Answer 40

Chromosome 9, 11 translocation

Question 41

Therapy regimen for AML?

Answer 41

Induction: Daunorubicin (3 days) + Cytarabine (7 days) = 3 + 7 induction Consolidation: 4 cycles of high dose cytarabine Indicate allogeneic HSCT if high-risk AML

Question 42

Phases of CML pathogenesis?

Answer 42

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

Question 43

Genetic mutation hallmark of CML?

Answer 43

– Philadelphia chromosome (translocation t(9;22)

Question 44

Treatment of choice for CML?

Answer 44

tyrosine kinase inhibitors (TKI, e.g. imatinib) ** Incurable with conventional chemotherapy ** HSCT for unresponsive or blastic phase CML

Question 45

Treatment of choice for CLL?

Answer 45

Early stages = no treatment Purine analogues +/- monoclonal Ab/ alkylating agents for elderly: e.g. 6-metcaptopurine +/- Rituximab or cyclophosphamide HSCT indicated for younger patients