Why bother doing fancy tests in patients with CLL? Andrew R Pettitt University of Liverpool
Some basic facts about CLL Annual incidence about 5 per 100,000 per year Male:Female ratio about 2:1 Less common in individuals from the Far East Predominantly a disease of older people (7th decade)
Blood picture in CLL
Diagnosis of CLL CD19 PE Con PE CD2 PE CD22 PE CD79b PE CD19 Lambda PE Con FITC CD5 FITC FMC7 FITC CD23 FITC CD20 FITC Kappa FITC
Accumulation of CLL cells in bone marrow Low red cells and platelets
Accumulation of CLL cells in liver and spleen Low red cells and platelets
Accumulation of CLL cells in lymph nodes Immune deficiency Abnormal immune reactions Haemolytic anaemia ITP
Symptoms of CLL
Complications of CLL
CLL variability The clinical course of CLL varies between patients Basic clinical features can predict survival How much the disease has already grown by the time it is diagnosed (stage) How fast it carries on growing after diagnosis (lymphocyte doubling time)
Tumour burden and prognosis
Lymphocyte doubling time and prognosis Mollica S et al. Cancer 2001;92:713-9
Why do we need fancy tests? Tumour burden at diagnosis predicts survival but not much else Patients with low tumour burden want to know their prognosis without having to wait to see how quickly their disease grows Doctors want information that helps with specific clinical decisions
Prognostic tests in newly diagnosed patients with low tumour burden “Big picture” from patient’s perspective Chromosome abnormalities “CLL FISH panel” for 17p-, 11q-, +12 and 13q- Cell of origin IGHV mutational status
Chromosome abnormalities Fluorescence in-situ hybridisation (FISH) Dohner H et al. NEJM 2000; 343:1910-1916
Cell of origin (IGHV “mutated” or “unmutated”)
Why do we need fancy tests? Tumour burden at diagnosis predicts survival but not much else Patients with low tumour burden want to know their prognosis without having to wait to see how quickly their disease grows Doctors want information that helps with specific clinical decisions
Clinical decisions that doctors need help with When to start treatment? What treatment to give? What to do once treatment has finished?
Bendamustine ± rituximab What treatment to give? More effective Better tolerated Bendamustine ± rituximab Chlorambucil ± CD20 Mab FCR DNA-damaging chemotherapy
But… not all patients respond to chemotherapy FCR arm of German CLL8 trial Progression-free survival 17p deletion Hallek M et al. Lancet 2010;376:1164-74
CLL cell with 17p deletion What’s going on at 17p? CLL cell with 17p deletion Normal cell TP53 gene on chromosome 17p TP53 mutation p53 mRNA Non-functional mutant p53 protein p53 protein Wild-type p53 protein
TP53 mutation can occur in the absence of 17p- and vice versa; both have the same effect 17p deletion TP53 mutation
What does wild-type p53 do that’s so important? ‡ What does wild-type p53 do that’s so important? p53 activation Chemotherapy Kills CLL cells Stops CLL cells from growing Stops CLL cells from turning even nastier Non-chemo drugs Steroids* Campath* Lenalidomide* Ofatumumab Ibrutinib Idelalisib Venetoclax *Not approved in CLL
How do ibrutinib and idelalisib work?
How does venetoclax work?
What does NICE say? Idelalisib in CLL (TA359; October 2015). Approved for First-line treatment of patients with a 17p deletion or TP53 mutation Previously treated CLL relapsing within 2 years of last therapy Ibrutinib in CLL (TA429; Jan 2017). Approved for Previously treated CLL Venetoclax in CLL (STA944). Rejected Feb 2017 Further committee meeting March 2017 Final outcome June 2017 Licenced for patients who have failed a BCR inhibitor and either have a 17p deletion or TP53 mutation, or have relapsed after chemotherapy.
Standard chemo-based approach Take-home message #1 Treatment indicated FISH No 17p- or TP53 mutation 17p- or TP53 mutation Standard chemo-based approach Non-chemo drugs
Clinical decisions that doctors need help with When to start treatment? What treatment to give? What to do once treatment has finished?
When to start treatment? Trials have shown no benefit in treating patients with asymptomatic early stage disease But… blanket approach with old-fashioned drugs Ongoing studies with newer drugs targeting patients at high risk of early progression IGHV, FISH and TP53 mutation may be useful outside of trials To identify those patients who can be safely followed up infrequently and/or “remotely” To identify those patients who might benefit from starting treatment sooner rather than later: High risk of Richter transformation Likely to grow quickly
Take-home message #2 FISH IGHV New diagnosis of CLL Low-risk No 17p-/11q- No TP53 mutation IGHV mutated, no VH3-21, VH4-39 or stereotype 17p-/11q- TP53 mutated IGHV unmutated, VH3-21 VH4-39 or stereotype Low-risk Infrequent/ remote follow-up High-risk Low threshold for starting treatment
Clinical decisions that doctors need help with When to start treatment? What treatment to give? What to do once treatment has finished?
What to do when treatment has finished? If long remission predicted Infrequent or remote follow-up If high risk of early relapse Potential role for maintenance therapy If high risk of Richter transformation Potential role for allogeneic transplantation
Tests that can predict what happens after treatment has finished Pre-treatment IGHV status IGHV unmutated = faster growing = earlier relapse IGHV4-39 or stereotyped BCR = high risk of Richter transformation Pre-treatment FISH 11q- = faster growing 17p- = faster growing and higher risk of Richter transformation Pre-treatment TP53 mutation status TP53 mutation = faster growing and higher risk of Richter transformation Post-treatment minimal residual disease (MRD) Can detect 1 CLL cells among 10,000 normal white blood cells Deeper remissions = longer remissions
Infrequent/ remote follow-up Take-home message #3 Treatment completed Bone marrow for MRD MRD -ve MRD +ve Infrequent/ remote follow-up Close follow-up Maintenance?
Summary of how tests can help with decision making Result Decisions at diagnosis Treatment decisions Post treatment decisions IGHV analysis Mutated Infrequent/ remote follow-up Limited Unmutated or VH3-21 Close follow-up Maintenance? VH3-49 or stereotyped Early treatment Allograft? FISH 17p- Non-chemo drugs 11q- TP53 mutation TP53 mutated Post-treatment MRD Negative N/A Positive
Mutations in CLL – much still to learn TP53, ATM, NOTCH1, SF3B1, BIRC3, LRP1B, SAMHD1, FBXW7, PCLO, HIST1H1E, XPO1, CHD2, MYD88, POT1 and ZFPM2 Detectable with “next generation sequencing” TP53 mutation Other mutations ATM mutation Sozan Karim, PhD student
Summary of key tests available in 2017 and when they should be performed At diagnosis Pre-treatment Post-treatment IGHV status Yes Not if already done No FISH Yes (can change) TP53 mutation MRD N/A
Do currently available tests give all the answers? Our understanding of why CLL behaves differently in different patients is very incomplete Ongoing work to improve this understanding, e.g. Genomics England Ltd allocated £3.5M to sequence the entire genetic code of up to 1000 samples stored in the UK CLL Trials Biobank in Liverpool (ARCTIC, AdMIRe, RIAltO, CLL210, CLEAR) Analysis of all the proteins expressed by CLL cells to understand how alterations in the genetic code affect the expression of proteins and how this influences therapy response and disease behaviour Clinical trials, sample collection and laboratory research are essential Teamwork is paramount