The Royal Marsden

1

Dr Claire Dearden

Consultant Haematologist

The Royal Marsden

Chronic Lymphocytic Leukaemia

The Royal Marsden

Chronic Lymphocytic Leukaemia

2

– Commonest leukaemia in western world

– Incidence of 4/100,000 pa

– Familial risk (7-8 fold)

– Median Age 72 years

– M:F = 2:1

– Diagnosis is usually made as an incidental

finding on a routine FBC

– Highly variable natural history

– Clinical and genetic heterogeneity

– Prognostic markers (IGVH, TP53)

The Royal Marsden

Case History

• A 78 year old man

• Fit and well

• Routine monitoring for PSA

• FBC also taken

• Noted to have a raised WBC 11 x 109/l

• Lymphocytes 6 x 109/l (normal range 1-3)

• Report states- “ smear cells seen on film ? CLL”

3

The Royal Marsden

What would you do?

4

A. Ignore the result

B. Repeat the FBC in a year when the PSA is next due

C. Repeat the FBC in 3 months

D. Refer for a standard haematology specialist appointment

E. Tell the patient they may have leukaemia and refer on an urgent two-week-wait rule with suspected malignancy

F. Phone/write to the Haematologist for advice

Ignore

the re

sult

Repeat the FB

C in a

year..

.

Repeat the FB

C in 3

month

s

Refer f

or a st

andard h

a...

Tell th

e patie

nt they m

a...

Phone/writ

e to th

e Hae...

0% 0%

39%

27%

21%

13%

The Royal Marsden

Chronic Lymphocytic Leukaemia

5

– Most patients are asymptomatic at

the time of diagnosis

– Clinical features

– Immune dysfunction

– Infection

– Autoimmunity (affecting components

of blood)

– Tissue infiltration

– Lymph nodes, spleen & other tissues

– Eventual BM failure (cytopenia)

The Royal Marsden

Case History

• A 52 year old woman

• Mild fatigue, no other B symptoms (fevers, sweats ,

weight loss)

• No recent infections or dental problems

• Cervical lymph nodes present for 2 months –about 1-

1.5 cm, painless, mobile

• No other palpable disease or signs of local infection

6

The Royal Marsden

What would you do?

7

A. Ask her to return in a

month if the nodes have

not gone

B. Check viral screen

C. Check a FBC

D. Send a TWW referral to

the head and neck team

E. All of B-D

F. None of the above

Ask h

er to re

turn

in a

m...

Check v

iral s

creen

Check a

FBC

Send a TW

W re

ferr

al to ..

.

All of B

-D

None of t

he above

4%0% 0%

27%

9%

60%

The Royal Marsden

Case History

• The patient was sent to the head and neck surgeons

• Lymph node biopsy reported as Small Lymphocytic

Lymphoma

• Referred for full TAP CT which showed generalised low-

volume lymphadenopathy (<1.5 cm)

• Referred to haematology

• Had a FBC – lymphocyte count of 35, otherwise normal

• Flow cytometry confirmed CLL !!

8

The Royal Marsden

• CLL and SLL are the same disease. About 10% patients may

present with lymphadenopathy alone with normal FBC (BM

usually involved)

• About 1/3rd patients with CLL may never require any treatment

• Infection is a risk even in patients with untreated CLL

• Progression is associated with increased tumour bulk and genetic

complexity

• Treatment requirement is based on a set of criteria confirming

disease activity/progression

• Natural History- remissions /relapses over years-decades

• Incurable (but often manageable) with current therapy

9

Chronic Lymphocytic Leukaemia

The Royal Marsden

A 52 year old man with untreated CLL presents

with a painful rash on his right chest wall

10

The Royal Marsden

What would you do?

11

A. Send him home

B. Send him to A&E

C. Phone his haematology

team

D. Prescribe topical aciclovir

cream

E. Prescribe oral aciclovir

F. Administer the zoster

vaccine Send h

im h

ome

Send him

to A

&E

Phone his

haemato

logy

...

Presc

ribe to

pical a

ciclo

vi...

Presc

ribe o

ral a

ciclo

vir

Admin

ister t

he zost

er v...

0% 0% 0%

68%

0%

32%

The Royal Marsden

• Common: 0.26- 0.47 per patient year

• Mainly bacterial respiratory tract (S pneumonia, S

aureus, H influenzae )

• Chronic sinusitis and bronchiectasis

• Herpes virus re-activation (shingles)

• Fungal and opportunistic infections rare in untreated

patients

• Infection is major cause of morbidity and mortality

(50%) in advanced CLL

Infectious complications in CLL

12

Early-Stage CLL:

Watch & Wait Remains the Standard Approach

Chlorambucil

No

Therapy

Low risk: W&W

High risk: FCR

High risk: W&W

French-German CLL7 Trial French Binet-A Trial

Dighiero et al. N Engl J Med 1998 Schweighofer et al. ASH 2013

Patients on W&W should be encouraged to follow a normal healthy lifestyle

13

The Royal Marsden

2010s

Chemo-immunotherapy

1980s 1960-70s

Alkylating agents

chlorambucil

cyclophosphamide

1990s

Purine analogs

fludarabine

pentostatin

cladribine

2000s

Purine analogs + alkylators

FC, PC

The evolution of treatment options in CLL

bendamustine* Novel therapies …….chemo-free!

Until this century no significant change in the natural history of CLL

Significant improvements in CR and ORR rates

bendamustine*

14

Tailoring treatment for CLL patients

CIRS, Cumulative Illness Rating Scale Eichhorst et al. Leuk Lymphoma. 2009; 50:171–178.

Many factors must be considered in order to optimise management in patients with CLL

Comorbidities and vital organ

status

Quality of life Supportive

care

Life expectancy

Patient preference

(administration)

What is the personalised goal of treatment?

Toxicity

Medical fitness (CIRS)

Disease evaluation (Stage, prognostic/predictive

markers- TP53)

Age

The Royal Marsden

Tailoring First-line therapy for patients with CLL: what are the challenges ?

16

A. Patient assessment

B. Defining treatment goals

C. Selection of appropriate therapy

D. Improving remissions and survival

E. Improving quality of life

Patie

nt ass

essm

ent

Definin

g treatm

ent goals

Select

ion o

f appro

priate

...

Impro

ving re

miss

ions a

nd...

Impro

ving q

uality

of l

ife

0% 0% 0%

100%

0%

Challenge 1: Patient Assessment

Assessing co-morbidity

Single assessments Combined assessments

Comorbidity scores

Nutrition scores

Comprehensive global assessment

Locomotion scores

Ability scores

Frailty scores

Cognition scores Toxicity scores

17

CLL patients are older and most have some co-

morbidity

75 years

31%

42%

27%

65–74 years

0–64 years

Minor co-morbidity Major co-morbidity

No co-morbidity

46% 43%

11%

Median Age at diagnosis 72 years

18

• All cause mortality increased in co-morbid patients

• However, CLL related deaths major determinant of lower OS

• Maintenance of dose intensity is a problem

• Key issue is being able to deliver safe and effective therapy in this group of patients

Goede V et al. Haematologica. 2014; 99: 1095-1100.

Co-morbidity and outcome

19

The Royal Marsden

• Life expectancy in the UK has improved

• Patients with CLL still have reduced survival compared with the general population

• Good remissions can be achieved with therapy and result in longer survival

• Longer remission is associated with improved quality of life

• Simple palliation/symptom control is not appropriate for most patients with CLL

Lowest

Highest

20.9 years

Challenge 2: Defining Treatment Goals

20

The Royal Marsden

SLOW-GO GO-GO NOT–SO-GO-GO

Hypertension Creatinine

clearance < 50ml

Fitness is more important than age

Challenge 3: Selection of appropriate therapy 21

Median observation time 25.5 months

Med. PFS (6yr FU)* FCR: 57 months* FC: 33 months*

The Go-Go patient

FCR is the ‘gold standard’1

1. Hallek et al. Lancet. 2010; 376: 1164-1174; *Fischer et al. Blood. 2012; 120: 435.

FCR (n=408)

FC (n=409)

Overall survival

Main toxicities-: neutropenia and infection

22

The Royal Marsden

A 65 year old woman who has recently been treated for CLL presents with a dry cough and SOB, chest sounds clear. Do you:

23

A. Send her to A&E

B. Call her specialist team

C. Conclude that this is

likely viral and send her

home

D. Give a course of

antibiotics

Send her t

o A&E

Call her s

pecialis

t team

Conclude th

at this

is lik

el...

Give a co

urse o

f antib

iotic

s

17%

30%

5%

48%

Opportunistic Infections in CLL

• Particularly related to treatment (steroids, purine analogues, alemtuzumab, idelalisib)

• Increased risk in heavily pre-treated patients

• A good response to CLL therapy may reduce infection risk

• Listeria monocytogenes, pneumcystis jerovcii, nocardia, mycobacteria, fungal

• Viral reactivation (herpes, CMV, EBV, Hepatitis B&C)

• Respiratory viruses (Para Flu, RSV)

• PML (JC virus)

PJP Pneumonia

24

Mr AW 65 y man with heavily pretreated fludarabine-refractory CLL treated with CamPred and achieved a good PR. Presented 3 months after completing

treatment with blurred vision in one eye. Otherwise asymptomatic.

Ophthalmology review revealed mass.Biopsy showed aspergillus. MRI revealed small fungal lesion. Treated with voriconazole as OP

and all completely resolved.

25

CLL10 Study: FCR vs BR in front-line

The Not-So-Go-Go patient

Eichhorst et al Lancet Oncology 2016; 17:928-42.

Adverse event FCR (% of pt)

BR (% of pt)

p value

All 90.8 78.5 <0.001

Haematological AEs 90.0 66.9 <0.001

Neutropenia 81.7 56.8 <0.001

Leukocytopenia 79.6 47.8 <0.001

Anemia 12.9 9.7 0.28

Thrombocytopenia 21.5 14.4 0.036

Infection 39.0 25.4 0.001

• Improved PFS with FCR • Less toxicity with BR

The Slow-Go Patient: Adding Targeted treatment CLL11 and Complement 1

• Reflected this group of patients well: • Median age 72 y, • Median CIRS score 8 • 2/3 patients creatinine

clearance < 70 • Both studies confirm that addition

of a CD20 monoclonal antibody improves efficacy- PFS • Chlorambucil: 11-13 m • R-chlorambucil: 16.3m • G-chlorambucil: 31.1m • O-chlorambucil: 22.4m

• Comparable toxicity • MRD neg remissions achieved in a

proportion

R-Chl

G-Chl

O-Chl

Goede et al NEJM 2014, Hillmen Lancet 2015

27

CLL11: Chlorambucil vs G + Clb vs R + Clb Time to next treatment (TTNT)

Goede et al. Blood 2015; 126 (23): Abstr 1733.

Obinutuzumab + Clb prolonged median TTNT by more than one year compared to R-chlorambucil and

by 3 years compared to chlorambucil alone

28

The Royal Marsden

Mr M: DOB 1936

• Referred from prostate team, aged 74y in 2010 with mild lymphocytosis and thrombocytopenia

• Asymptomatic

• Prostate cancer diagnosed 2003, IMRT 2004 hormone treatment until 2006

• No other co-morbidities

• BBC TV documentary producer

29

The Royal Marsden

Mr M: DOB 1936

• No palpable disease • FBC: Hb 141, WBC 10.1 (L 6.7) platelets 131 • Diagnosed Stage A CLL • Watch and wait • 2013 developed DVT and PE following long haul flight,

anticoagulated • Slow steady disease progression- splenomegaly, LN,

falling Hb and platelets • 2014 Wife had acute diagnosis of DLBCL, successfully

treated • Developed mild intra-cerebral bleed following a fall

2015

30

The Royal Marsden

Mr M: DOB 1936

• By Sept 2015 Hb 95, WBC 80, Platelets 57

• Commenced Chlorambucil + obinutuzumab (NICE

approved)

• WBC fell from 80 to 45 after 1st dose and to 1.2

(neutrophils 1) at day 8

• Initial Infusion reaction but no other AEs

• Completed 6 cycles Feb 2016- No palpable disease; Hb

131, WBC 8.3 (N7), platelets 128

• Re-staging investigations (CT and BM) showed CR

31

Challenge 3:Selection of Appropriate Therapy

Patient group Treatment

Fit GO-GO FCR

Intermediate NOT-SO-GO-GO (older age, renal function)

BR

Older less fit SLOW-GO Chlorambucil+ Obinutuzumab Chlorambucil+ ofatumumab

TP53 del/mutation Alemtuzumab+ steroids Idelalisib+ Rituximab Ibrutinib

All patients Available Clinical Trial

32

Challenge 4: Improving Survival

FC vs FCR Chlorambucil alone vs + GA101 or R

Addition of an Anti-CD20 monoclonal antibody to conventional chemotherapy backbone improves survival for GO-GO and SLOW-GO patients

33

Challenge 5: Improving quality of life (QoL)

• Most patients requiring treatment report impaired QoL (fatigue, reduced physical, role and social function)

Else et al. Br J Haematol. 2008; 143: 690-7. Else et al. Leuk Lymphoma. 2012; 53: 1289-98.

34

The Royal Marsden

0%

10%

20%

30%

40%

Month 3 Month 6 Year 1 Year 2 Year 3 Year 4

Assessment period

Pe

rce

nta

ge

im

pro

ve

d

Responders

Non-responders

0%

10%

20%

30%

40%

Year 1 Year 2 Year 3 Year 4

Assessment period

Pe

rce

nta

ge

im

pro

ve

d

Remission

Progressed

• Patients who respond to therapy have improved QoL compared to baseline and compared to those who do not respond

• Patients who remain in remission have better QoL than those who have progressed

• Therefore achieving a remission and remaining in remission is associated with the greatest QoL improvement

Global OoL: Percentage improved by Quality and Duration of Response to Treatment

35

The Royal Marsden

• Most patients are diagnosed on a routine FBC when they are otherwise well

• Some patients will present with lymph node enlargement, but the diagnosis can often be made from PB without need for biopsy

• A significant proportion of patients will never require treatment and others not for years or even decades

• Treatment is carefully tailored and based on numerous personal (age and co-morbidity) and disease-related factors

• Treatment is very effective at achieving durable remissions in the majority of patients, even older less fit individuals, and delivering a good quality of life

• Many new therapies (“just need to stay one drug ahead of your disease” !)

• The major complication of the disease and the therapy is INFECTION

CLL: Conclusions

36