1. Join us today and together we will fight CLL

2. The basics Ram Jayaprakash Consultant Haematologist
Poole NHS Foundation Trust

3. Normal maturation of white cells

4. Chronic lymphocytic leukaemia
Leukaemia is a cancer of white blood cells
Acute vs chronic
Myeloid vs lymphoid

5. Lymphocytes Lymphocytes are a type of white cell
They include NK cells, B and T cells
NK cells part of innate immunity- release cell damaging toxins destroy cells
T cells- a direct cytotoxic effect, memory cells and regulates immune response
B cells produce antibodies which mark cells for killing

6. Blood film appearances

7. CLL Abnormal clonal B lymphocyte population
Acquired genetic changes, cells divide more than normal and less prone to death
Accumulation and proliferation of small, mature, long living lymphocytes in the blood, bone marrow and lymphoid tissues (lymph nodes and spleen
CLL requires abnormal lymphocyte population of >5x 109

8. Characteristic pattern:
Abnormal B cells will be tested for surface proteins- this is immunophenotyping
Characteristic pattern:
Marker
Score 1
Score 0
CD5
Positive
Negative
CD23
FMC7
CD22/ CD79b
Weak
Strong
SmIg
Weak-moderate

9. MBL/SLL
Monoclonal B lymphocytosis- increase in B cells that mark like CLL. Lymphocyte <5. ?Normal variant/ precursor to CLL
SLL- preferentially affects lymph nodes rather than blood. 10% of patients present with lymphadenopathy with blood involvement (bone marrow normally involved)

10. CLL The most common Leukaemia
Average age 72, very rare under 40, 10% of patients are under 55
Twice as many men as women
10% first degree relative with CLL
Significant proportion of patient present without symptoms- incidental finding
Commoner in white populations

11. CLL Progression is normally associated with tumour bulk and symptoms
Incurable (but usually manageable)
Natural history of relapsing and remitting over years/ decades

12. Presentations Incidental finding
Systemic symptoms: fatigue, fevers, generalised malaise, reduced excerise tolerance
Recurrent infections (viral, bacterial, fungal)
Lymphadenopathy (enlarged lymph nodes)
Splenomegaly (mild to moderate in 50% pts)
Hepatomegaly

13. Presentation 2
Bone marrow failure (Symptoms related to anaemia/ low platelets)
Auto- immune complications: Haemolytic anaemia, ITP

14. Clinical course for Early Stage CLL
Rule of thirds
1/3 indolent disease course- never require treatment
1/3 slowly progress
1/3 aggressive clinical course
Risk of Richters (high grade) transformation

15. Staging for CLL: Rai Stage Clinical charcteristics OS Lymphocyte >5
Lymphocyte >5
180 1
Lymphadenopathy
108 2
Splenomegaly/Hepatomegaly +/- LN 60 3
Hb < 110g/l 24 4
Platelets <100

16. Binet Staging Stage Survival (months) A
Lymphocytosis, <3 lymphoid areas
120 B
3 or more lymphoid areas 84 C
Hb <100g/l, Platelets <100 60

17. Watch and wait
There is no evidence that treat CLL early, before symptoms arise- is helpful in prolonging life or reduces complications
Previous trials suggests that it may shorten life span
Psychologically difficult

18. IWCLL Criteria for treatment
Evidence of bone marrow failure Hb <100, Platelets <100
Progressive splenomegaly >6cm below costal margin
Massive nodes >10cm in diameter
Progressive lymphocytosis >50% in 2 months or lymphocyte doubling time <6 months
Auto-immune complications poorly responsive to steroids

19. IW CLL (2)
Symptomatic/ functional extranodal involvement (skin, kidney, lung, spine)
Disease related symptoms
Unintentional weight loss in 6 months
Significant fatigue (ECOG2)
Fevers >38 for >2 weeks
Night sweats > 1month

20. Infection
CLL clone has a significant effect on normal immune system- lower levels of normal protective antibodies
Prophylaxis
Annual influenza vaccination
Pneumoccoccal and haemophilus B vaccination at diagnosis
If IgG <5, recurrent infections, regular IVIg
Fludarabine/ Bendamustine chemotherapy- need prophylaxis against varicella zoster and PJP

21. Prognosis in CLL Many factors influence outcome
Patient factors such as age, gender and co-morbidities
Disease factors such as clinical stage and biological markers
Treatment factors- response to treatment and tolerability

22. Prognostic markers

23. Immunoglobin V gene rearrangment
B cells generated in the BM
Lots of different antibodies made by rearrangements of the V,D,J Ig gene segments in healthy people in order to general most precise antibody to fight infection

24. Mutated form of heavy Ig: 293months OS
Hamblin et al: Blood 1999;94(6):
Slower growing disease
May never need treatment
Respond very well to FCR chemotherapy
Less likely to develop other genetic abnormalities

25. Unmutated CLL OS 117 months
Faster pace of disease
Usually need treatment
Respond well to treatment but often shorter responses
More likely to develop other cytogenetic abnormalities

26. Chromosomes (Cytogenetics)

27. Chromosomal abnormalities
Abnormality
Prognosis (months)
Del 13q
133
Normal
111
Trisomy 12
114
Del 11q 79
Del 17p 32

28. TP53- located on chromsome 17p
25,000 genes in human body
P53 signals cell death if a cell is damaged (such as cancer)
If p53 is damaged or missing then the cell will not die
Loss of p53 either through deletions or mutations confers poor prognosis in many cancers and poor responses to chemotherapy

29. Blood 2009;114(26):

30. p53 Poor response rates to FCR/ BR chemotherapy
Only genetic abnormality which will alter treatment decisions
In UK- NICE has approved ibrutinib/ Rituximab&idelalisib in this setting
Conventional high risk features may not be so important in the era of novel therapies

31. Only 50% of fludarabine refractory patients have a p53 deletion
What accounts for the rest?
Major improvement in gene sequencing
- NOTCH1
- SF3B1
- BIRC3

32. NOTCH1 10% of patients with newly diagnosed
20% of Fludabarine refractory and 30% Richters transformation
Drugs in clinical trial targetting this pathway

33. NOTCH 1

34. SF3B1 mutation 7-15% of all patients with CLL
Preferentially targets more aggressive stages- rarely seen in monoclonal B cell lymphocytosis
New diagnosed patients with CLL have a poor prognosis (10yr survival 30-40%)
Also found in a significant number of patients with Myelodysplasia
Again there are preclinical developments looking into SF3B1 inhibitors

35. SF3B1 mutations

36. BIRC3
Often associated with ATM mutations (co-located on chromosome 11)
BIRC3- absent in monoclonal B cell lymphocytosis, 4% new diagnosed CLL
BIRC3 disruption occurs in ~25% fludarabine-refractory CLL
If found at diagnosis- outcomes are similar to patients with p53 abnormalities

37. Join us today and together we will fight CLL