06 - Leukaemia Flashcards by Stuart Gillies

What is the common cytogenetic rearrangement found in CML

t(9;22) - Philadephia chromosome. BCR-ABL

How well did you know this?

Not at all

Perfectly

What is the activity of the fusion protein

BCR-ABL has tyrosine kinase activity. the fusion constitutively activates the tyrosine kinase activity to drive cellular proliferation

How well did you know this?

Not at all

Perfectly

What treatment options are available in CML

> Imatinib can be used in Ph+ CML cases. Recognised as a ‘wonder drug’, can result is complete cytogenetic remission in 80% patients

> Bone Marrow transplant (need suitable donor and is age restricted)

> Interferon alpha - glycoprotein. Induced haematological remission in 70-80% patients, but only complete cytogenetic response in 6-20%

How well did you know this?

Not at all

Perfectly

what is the recommended testing pathways for diagnosis and monitoring in CML

> Cytogenetic analysis (FISH and karyotype) at diagnosis in Bone Marrow samples.
Continued cytogenetic testing 3-6months on BM.
Routine cytogenetic investigation every 6 months until negative / normal result obtain (CCR - complete cytogenetic remission).
Should analyse 30 metaphases and 100 interphases. >Following this, RT-qPCR is recommended to monitor residual disease and to monitor relapse

How well did you know this?

Not at all

Perfectly

Patients with CML present with…..

> Fatigue (anemia)
weight loss
night sweats
splenomegaly

How well did you know this?

Not at all

Perfectly

what are the 3 phases of CML

1) Chronic phase - 90% of patients diagnosed here (may be asymptomatic and detected via routine blood test) Blasts <5%
2) Accelerated phases, inceased WCC, blasts >10%
3) BLAST crisis - >20% Blasts

How well did you know this?

Not at all

Perfectly

what additional cytogenetic findings may be detected as patient transforms from Accelerated Phase to blast phase

> +8 (50%)
i(17q) (35%)
der22

How well did you know this?

Not at all

Perfectly

ALL is considered a _____________ leukaemia

childhood - 75% all childhood Leukaemia

How well did you know this?

Not at all

Perfectly

What are the 2 types of ALL, which is more common

B-cell ALL (most common) & T-cell ALL

How well did you know this?

Not at all

Perfectly

Precursor B or T cells may form a mass known as a

Lymphoma

How well did you know this?

Not at all

Perfectly

Which types of cytogenetic findings are associated with a GOOD prognosis in ALL

> B-ALL with hyperdiploidy (>50chr)

> B-ALL with ETV / RUNX1

How well did you know this?

Not at all

Perfectly

Which types of cytogenetic findings are associated with a BAD prognosis in ALL

> B-ALL with BCR-ABL1
B-ALL with MLL rearrangement
B-ALL with near hypodiploid (23-29chr)

How well did you know this?

Not at all

Perfectly

What rearrangement is associated with infant B-ALL

> 11q23 rearrangement - MLL gene: t(4;11)

note: poor prognosis

How well did you know this?

Not at all

Perfectly

What is the most common translocation in childhood B-ALL associated with a good prognosis

t(12;21) - ETV6/RUNX1

note: children like butterflies and running - both GOOD - 12;21 butterfly
RUNX1 - running

How well did you know this?

Not at all

Perfectly

what is the rearrangement associated with Burkitt Lymphoma

t(8;14) MYC / Igh

also
t(8;2) - MYC / IgK
t(8;22) - MYC / IgL

How well did you know this?

Not at all

Perfectly

Was is the common rearrangement found in adult onset ALL.

t(9;22) BCR/ABL

POOR prognosis

How well did you know this?

Not at all

Perfectly

what is the proportion of T-cell ALL (T-ALL), in ALL

15%

How well did you know this?

Not at all

Perfectly

what is rearrangement is frequently found in T-ALL

Rearrangements of the T-Cell receptor gene TCR

what is a good prognosis in T-ALL

del(1)(p32q32)

What rearrangements are associated with a poor prognosis in T-ALL

> t(7;10)
t(10;14)
MLL rearrangements
Complex karyotypes

What is the common age of onset in T-ALL

Teenagers - adolescence

What rearrangements are associated with a GOOD prognosis in T-ALL

High hyperdiploidy (51-65chr)

CLL is considered a disease of the ________

elderly

What are the distinct clinical phases in CLL

1) Pre-malignant monoclonal B-cell lymphocytes
2) Overt CLL
3) transformation into aggressive lymphoma (Richter’s Syndrome)

What proportion of CLL patients develop lymphoma

5-15%

what types of lymphoma are seen in CLL

> Diffuse large B-cell lymphoma (Richter Syndrome) - POOR prognosis (1yr survival) > Classical Hodgkin Lymphoma

Why can it be difficult to karyotype CLL patients. what is the alternative

Cells in CLL are very difficult to divide even with strong mitogens. Often need to use interphase FISH

What are the common cytogenetic findings in patients with CLL

> del 13q14 - good prognosis > del 11q23 (ATM gene) - poor prognosis > del 17p13 (TP53 gene) - poor prognosis

What cytogenetic findings are associated with POOR prognosis in CLL

> del 11q23 (ATM gene) - poor prognosis > del 17p13 (TP53 gene) - poor prognosis > t(8;14) - MYC/IgH > t(14;18) - BCL2 / Igh

What is the recommended 1st tier testing strategy in CLL referrals

FISH for chromosome 13, 11 (ATM gene) and 17 (TP53)

what tests can be performed to distinguish between a myeloid of lymphoid leukaemia

1) Histology (cell staining) - Myeloid cells - express myeloperioxidase enzyme, which forms intracellular crystals known as AUER RODS 2) Immunophenotyping - the marker TdT (DNA polymerase) is found only in nucleus of lymphoid cells

How can you distinguish between a B-Cell and a T-Cell leukaemia

Cell surface markers: B-Cell = CD10 T-Cell = CD8

Outline haematopoiesis

> haematopoetic stem cell can become either a myeloid or lymphoid cell line > MYELOID cell line include: - erythrocytes (red blood cells) - thrombocytes (platelets) - granulocytes (inc. basophils, neutrophils and eosinophils) - monocytes (white blood cells) - macrophages > LYMPHOID cell line include: - T lymphocyte - B lymphocyte

Outline the pathogenic progression of leukaemia

> during haematopoesis, progenitor cells mature from blasts into mature cells - i.e. lymphoblasts mature into lymphocytes > genetic abnormalities can occur which disrupt this maturation process, resulting in the cells remaining as undifferentiated immature blast cells. > these cells are not fully functioning as immature, and so useless to the body, but still take up resources. > furthermore, many of the genetic abnormalities also drive cell proliferation and so get increase blast cells in bone marrow > normal cells have to compete for resources and proliferate less well and may even die, due to 'crowding out' > this can result in the reduction of there normal cells - cytopenia

What are the symptoms common to leukaemia?

> fatigue due to anaemia > easy bruising / bleeding due to thrombocytopenia > frequent infections due to neutropenia

what is the % blast to diagnosis AML

20%

AML is more common in __________

adults

AML accounts for ____% of childhood leukaemia

20%

Acute promyelocytic leukaemia (APML) is associated with which rearrangement? what is particularly important to consider in patients with APML

> APML ass. with t(15;17) - PML-RARA (90%) > good prognosis as can be treated using ATRA (all trans retinioc acid - which bings to RARA) > important clinical issue with APML is risk of these immature cells getting into blood stream, settling and forming a clot = Disseminated Intravascular Coagulation (DIC) - serious life threatening condition

What are AUER rods?

Auer rods are crystallised aggregates of the myeloperoxidase enzyme - found only in myeloid cells and so can help distinguish between myeloid vs lymphoid leukaemia

At a molecular level, AML is considered a multistep process, requiring mutations in at least 2 classes. What are those classes and give examples

Class 1 - activate signal transduction pathways which confer proliferation > FLT3 - receptor tyrosine kinase mutated in 1/3 AML > PTPN11 > RAS, NRAS, KRAS ``` Class 2 - Transcription Factors > many class 2 mutations target the Core Binding Factor (CBF) - heterodimer of RUNX1 and CBFB - which are essential for haematopoietic development ```

What is the most commonly mutated gene in cytogenetically normal AML

NPM1 (Nucleophosmin 1))

what are the 3 most common rearrangements in adult AML according to ELN

> t(15;17) - PML-RARA > t(8;21) - RUNX1-RUNX1TI > inv(16)(p13.1q22) - CBFB-MYH11 note: RUNX1 and CBFB key components of the Core Binding Factor (class 2 mutation target)