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

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

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

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

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

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)

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)

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

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

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

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

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

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

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

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

Questions?