CLL - When to treat, how to treat

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 2006-2012 • 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 FCR FLAIR ECOG O+C BR FCR BR I+V I+R I CLL14 iLLUMINATE US Alliance O+I V+R I O+V I+R I+R R/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?