1. CLL - When to treat, how to treat
Andrew Pettitt
Honorary consultant Haematologist, Clatterbridge Cancer Center
(plus other things…)

2. My credentials as a CLL doctor
18 years experience as a consultant specialising in CLL
~100 peer reviewed publications, most on CLL
Member of NCRI CLL Subgroup since 2000
Chair of UK CLL Forum
Local investigator for numerous CLL trials
Chief investigator for 3 CLL trials
Co-author of BCSH CLL guidelines
Medical expert for several NICE appraisals

3. My limitations as a CLL doctor
I am human
I don’t know everything
I forget things and make mistakes
I don’t know what your priorities are in life
Importance of
Team work
Collective decision making
Peer review of treatment decisions

4. Topics (thanks to John Moore)
What informs decisions about when to treat
What the treatment options are
What guides choice of treatment (and the pros and cons to consider)
First and second line treatment considerations
Clinical trials
New treatment developments

5. What informs decisions about when to treat?
Symptoms
Complications
Rate of progression
Other stuff going on in your life
“Treatment window” concept

6. What are the treatment options (1)
Chemo drugs
Gentle – chlorambucil
Medium – bendamustine
Strong – fludarabine + cyclophosphamide
CD20 antibodies
Rituximab, ofatumumab, obinutuzumab
Chemo + CD20 antibodies
Chlorambucil + ofatumumab or obinutuzumab (O+C)
Bendamustine + rituximab (BR)
Fludarabine + cyclophosphamide + rituximab (FCR)

7. What are the treatment options (2)
BTK inhibitors
Ibrutinib
PI3K inhibitors
Idelalisib (+rituximab)
Bcl-2 inhibitor
Venetoclax
Cellular therapy
Bone marrow transplantation
(CAR-T cells)

8. What guides choice of treatment
Disease factors
TP53 disruption – chemo ineffective
IGHV mutational status – long remissions possible with FCR
Response to prior therapy
Patient factors
Age
Fitness
Other medical conditions
Availability of new drugs
Availability of clinical trials

9. What are the pros and cons to consider
Many treatment decisions are dominated by drug availability
Factors to consider if choice is involved
Likely effectiveness of the treatment
Possible side effects of the treatment
Risks of the treatment
Practicalities of the treatment
Other stuff going on in your life

10. First line treatment considerations
No TP53 disruption
Young, fit -> FCR (or BR)
Intermediate fitness -> BR
Older, unfit or multiple medical problems -> chlorambucil + CD20
TP53 disruption
No heart problems -> ibrutinib
Heart problems -> idelalisib + rituximab

11. Second line treatment considerations
FCR inappropriate (short remission, too old/unfit or TP53 disruption)
No heart problems -> ibrutinib
Heart problems -> idelalisib + rituximab
Long remission following chemo + CD20 -> Further chemo + CD20
Prior ibrutinib or idelalisib -> Venetoclax
Blueteq criteria

12. Clinical trials
How do novel agents (alone or in combination) compare with FCR, BR or O+C?

13. 1L R/R Reported at ASH 2018 EMA approved, undergoing NICE appraisal
O+C
O+I
O+V
iLLUMINATE
CLL14 BR
I+R I
US Alliance
FCR
I+R
FCR
FLAIR
ECOG
I+R I
I+V
R/R BR
V+R
Reported at ASH 2018
MURANO
EMA approved, undergoing NICE appraisal

14. New treatment developments
CAR-T cells as a safer alternative to transplantation
Main side effect is cytokine release syndrome
CAR-T cells induce remissions in >80% of patients with ALL but only 25% of patients with CLL
CLL patients who respond have a healthier immune system
One patient went into remission due to expansion of a single CAR-T cell
CAR-T cells + ibrutinib looks promising

15. Topics What informs decisions about when to treat
What the treatment options are
What guides choice of treatment (and the pros and cons to consider)
First and second line treatment considerations
Clinical trials
New treatment developments

16. Questions?