Chronic lymphocytic leukaemia

Question 1

What is a leukaemia?

Answer 1

Blood cancer that arises due to failure of hematopoietic differentiation –> accumulation of immature or dysfunctional leucocytes

Question 2

How does the peripheral blood of the a patient with acute leukaemia differ to that of a patient with chronic leukaemia?

Answer 2

In acute:

• hematopoiesis arrests early on resulting in immature leukocytes in bone marrow.
• they are too immature to leave bone marrow –> low peripheral blood cells

In chronic:
- high WCC
(majority of CLL have B cell malignancy)

Question 3

What is CLL?

Answer 3

Commonest leukaemia worldwide

Clonal disorder of mature CD5+/CD19+ B cells

Question 4

Wheres is the tumour found in CLL?

Answer 4

• Bone marrow
• Peripheral blood
• Secondary lymphoid tissues (spleen, lymph nodes)

Question 5

What are the characteristic features of CLL

Answer 5

• infection
• autoimmunity
• bone marrow failure

Question 6

What is the age distribution of patients with CLL?

Answer 6

• Greater incidence in those >60

- Although 20-30% of cases are diagnosed in patients under 55
Albeit the incidence of this is 2-5/10000

Question 7

Up to 50% of patients are diagnosed following an incidental blood test finding.

In those who are symptomatic how would you expect them to present?

Answer 7

Symptoms

• repeat infections (pneumonia, Herpes)
• night sweats
• fever
• weight loss
• muscle wastage
• bruising
• abdominal pain (splenomegaly)

Signs

• enlarged lymph nodes
• splenomegaly
• anaemia

Question 8

What causes CLL?

Answer 8

Idiopathic: is it infection? chemical exposure? AI? DM?

Genetic component

• 5% of cases are familial
• incidence doubles if a first degree relative with CLL or another lymphoproliferative disease

Question 9

What is the scoring system predominantly used to diagnose CLL?

Answer 9

Matutes scoring system
- a flow cytometry system which measures surface immunoglobulins (cd5, cd23, cd79b (a component of B cell receptor) and antigen FMC7

(used to differentiate CLL from other B cell lymphoproliferative disease, not that great at differentiating from atypical/mixed CLL)

Question 10

What is the role of doing a blood film in diagnosis?

Answer 10

Differentiate between other B cell neoplasms

- CLL B cells have a structural membrane defect which leads to the development of SMEAR CELLS on microscopy

Question 11

How does Rawstron et (2017) diagnostic system differ from the Matutues scoring system?

Answer 11

• Also base don flow cytometry

Measures different cellular components

• kappa/lambda light chain
• CD5+/CD19+ (and CD20+, CD23+)
• CD200, ROR1 (and CD43, CD79b, CD81, CD10)

(FYI: better at discriminating between other B cell lymphoproliferative disorders such as Mantle cell lymphoma)

Question 12

Describe how the characteristic of CLL cells in the lymph node, peripheral blood and bone marrow differ and the implications for treatment

Answer 12

Peripheral blood CLL cells

• good at surviving but do not proliferate
• react well to chemotherapy

Lymph node CLL cells

• high proliferative drive (receive proliferative signals from CD3+ T cells in LN as they are in close proximity. Known as Ki67 proliferating cells) THIS IS WHERE PROLIFERATION PRIMARILY TAKES PLACE
• good at surviving
• hidden in “protective hiding space”

Bone marrow CLL cells

• moderate proliferative drive
• hidden in “protective hiding space”
• resistant to chemotherapy

Question 13

A good marker for CLL should….

Answer 13

• predict which patients are likely to progress
• predict which patients will respond to treatment
• be reproducible
• be cheap and easy to perform

(ideally also give information about the biology of the disease and represent a tractable therapeutic range)

Question 14

Outline the Binet classification system

Answer 14

A

• 70% of cases
• mean survival >10 years
• no disease progression, don’t need treatment

B

• 20%
• mean survival: 5-7 years
• receive treatment if symptomatic

C

• 10%
• mean survival: 1-3 years
• require treatment

Question 15

What is the prognosis of CLL?

Answer 15

1/3- wont progress, wont need treatment (Binet A)

1/3- indolent disease in the beginning, later progresses

1/3- aggressive disease which requires immediate treatment

Question 16

Why doesnt the Binet classification completely help us risk stratify patients?

Answer 16

• CLL is a highly variable disease
• Classification is poor for younger patients and those in early stages (they may progress)

Instead need to risk stratify based on individual disease characteristics

Question 17

Summarise the key findings from Pepper et at (2012) cohort analysis of prognostic tools in Stage A disease

Answer 17

• If lymphocyte doubling time (LDT) if low, time to first treatment (TTFT) is faster and overall survival is worse
• Patients with high risk genetic changes (TP53 mutation, 11q deletions) require earlier treatment and have inferior survival rates than those with low risk genetic changes (changes in Chr13q, trisomy 12)
• IGHV mutated status have better response
• IGHV unmutated status required earlier treatment and inferior survival

Prognostic significant markers are LDT, age, IGHV mutation status and CD49 expression in early stages

Question 18

Risk stratify the following markers of disease

a) IGHV unmutated
b) CD38
c) B2M
d) long telomeres

Answer 18

a-c) poor indicators

d) better response

Question 19

Generally speaking what therapies are used in CLL

Answer 19

• High intensity combinations (FCR/BR)
• New biologics: BTKi, P13K8i (Ibrutinib, Idelalisib)
• BCL2 mimetic (Veneteclax)
• Allo transplantation

Question 20

What are the mechanisms by which targeted antibodies have an effect?

Answer 20

Complement mediated lysis
- antibody binds to surface receptor causing the recruitment of complement molecules

AB dependent cytotoxicity
- binding flags to macrophages to phagocytose cell

Direct cytotoxic effect

• bind to receptor directly causes intracellular toxicity
• Obinutuzumab

Question 21

What kind of patients may still respond well to standard treatment?

What is standard treatment?

Answer 21

The young, fit patient with negative 17p/TP53 mutations

Chemoimmunotherapy
FCR (fludarabine + cyclophosphamide + rituximab)

or BR

Question 22

Bendamustine + rituximab (BR) is a chemoimmunotherapy regimen used primarily for which group of patients?

Answer 22

• Older patients

+ 17p /TP53 mutations

Question 23

Advantages and disadavantages of Ibrutinib?

Answer 23

Brutons tyrosine kinase inhibitor

ADV

• significantly less lymphoid tissues (cells spread out peripherally instead)
• show much less disease progression compared to ofatumumab

DADV
- side effects: fatigue, anaemia, thrombocytopenia, neutropenia, diarrhoea, MSK pain, URTI, rash, nausea, fever

Question 24

How does management differ between those with mutated IGHV status and those unmutated?

Answer 24

IGHV mutated
- respond well and can enter remission on standard FCR

IGHV unmutated
- do not benefit long term from FCR

Question 25

Briefly outline the key principles of CAR-T therapy

Answer 25

Chimeric antigen receptor T cells T cell collection - patients own T cells are extracted from peripheral circulation T cell transfection - transformed through genetic manipulation to express a CAR (CD19) T cell adaptive transfer - reinfused into same patient (autologous) These T cells can now recognise CD19 targeting B cell malignancies as the T cell response can be redirected towards specific surface antigen.