Report London Meeting 3 December 2013

The historic Great Hall at St Bartholomew’s Hospital, London, was the magnificent venue for the London meeting of the CLLSA. The meeting was well attended, filling the Hall, and with a good balance between recently diagnosed and pre and post treatment.

Presentations were made by:

Professor Daniel Catovsky is one of the original medical advisors to the CLL Support Association (CLLSA), which celebrates its 8th anniversary this year.

Dr Samir Agrawal MRCP FRCPath PhD Consultant Haemato-Oncologist at St Bartholomew’s Hospital (Barts), and The London NHS Trust. He is a leading expert in CLL and one of the Trustees of the CLLSA, and a Medical Advisors to the association,

Dr Timothy Farren, Post doctoral researcher and Clinical Scientist at St Bartholomew’s Hospital (Barts), and the London School of Medicine and Dentistry.

Two Barts Patients also talked about their journey with CLL

Professor Daniel Catovsky - notes from Presentation

A wide-ranging presentation suitable for all backgrounds

Difference in response to CLL: Male and Female

There are differences in response to CLL between Male and Female patients. CLL in Women: Occurs at an older age, Staging is generally lower, Prognostic markers are better, Less cases of aggressive disease

Treatment for Women: Overall response rate (ORR) is better, Progression free survival (PFS) is longer, Overall survival (OS) is longer.

This despite the fact he ratio of Male to Females starts the same for Monoclonal B-cell lymphocytosis (MBL) the precursor to CLL.

Mutations

Some of the newer mutations of interest are TP53 , NOTCH1, SF3B1, MYD88

Monoclonal Antibodies (mAB)

Rituximab, the “R” in “FCR” is a monoclonal antibody targeted against the B-cell surface CD20 antigen. Trials are running using Ofatumumab and Obinutuzumab. Tests are showing worthwhile improvements in PFS over Rituximab. These studies have been for older patients, with Chlorambucil used for the Chemotherapy component.

Chimeric Antigen Receptor modified T-cells (CART) Therapy

CART - Patient Power Video interviews explain developments past and present in this area.

2012 Prof John Gribben (Barts)

Driving CLL Away with CARs

2013 The Promising Path for CAR Immunotherapy

The latest version of CART research now involves the further modifying T cells from unmatched donors, it is hoped to produce a pre prepared infusion. So that when the graft versus leukaemia response is activated these modified T cells will it is hoped only remove tumour cells and not healthy B cells as well. This method may allow production of cells capable of use for patients whose own T cells function is already compromised.

This is extremely expensive and at this stage highly experimental.

You can also view the latest developments in immunotherapy discussed this year by Prof John Gribben of Bart's in the patient Power video:

How Existing Immunotherapy Might Fight CLL:

New Drugs exploiting B-Cell Receptor (BCR) signalling pathways

We are aware of the new drugs on trial, most well known Ibrutinib (now called: Imbruvica), that interrupt the signalling pathway from the B-Cell Receptor (BCR) on the B-Cell surface, to the nucleus within. As these drugs do not create a lasting remission as sole agents when used to treat CLL they need to be taken continuously to maintain this or used in combination to strengthen remission. there is not enough long term data yet to see the long term picture.

There are three groups of kinase inhibitor each with many different agents coming into trial that will be targeting them. Several new ones are added to the list below of those you may already be familiar with.:

BTK: (Bruton’s Tyrosine Kinase) Ibrutinib, CC-292/AVL-292

PI3: (Phosphoinositide 3 Kinase) Idelalisib (GS1101/CAL101), IPI-145, TGR-1202

Syk: (Spleen Tyrosine Kinase) GS9973, Fostamatinib (R-788), PRT2070

These pathway inhibitor drugs are planned to be combined with other agents in many ways over the coming years.

It may be some time before this approach is available for first line treatment for the majority As these new drugs have and are mainly being trialled in relapsed and refractory patients to start..

A few observations of Fludarabine / Cyclophosphamide / Rituximab (FCR) Chemoimmunotherapy

Some groups of patients within CLL are still in complete remission ten years after treatment. This group have been identified as those with mutated IGHV.

FCR is the current gold standard treatment in the UK for fit patients, and has dramatically improved outcomes for many requiring treatment. Originally developed under the guidance of Dr. Michael Keating, CLL specialist at MD Anderson.

Combination Therapy

Various potential combination therapies involving novel inhibitors were described, and the general idea was that actions of different novel drugs probably don’t overlap, and combinations create synergy as each operates on different mechanisms. Long term we will see combinations involving different antibody therapies, modulators and novel inhibitors together. These may create MRD status and strong remissions using less toxic footprints.

In the UK Chemotherapeutics are also in trial in combination with novel small molecule inhibitors to develop strategies that may also produce MRD status and a lasting remission.

Questions

•(Q)With the new drugs & technologies should we be considering starting treatment earlier? (A) With current knowledge the answer is no, but we may be able to guess which treatment might be the most effective.

•(Q)Do the new treatments give an improvement in the condition of the bone marrow, given that this is difficult to test? (A)Thought to be yes, but may be indirectly.

•(Q)When best to look at patients prognostic factors?(A) Currently only used when treatment is being considered

This allowed Prof Catovsky to point out that what are considered poor prognostic markers today relate to the treatments available now. Novel therapies are producing good responses in these categories; therefor what is considered a poor prognostic marker today may not be in the future.

Prof Daniel Catovsky’s presentation ended with a warm round of applause for his presentation and lifetime’s contribution to medicine and CLL.

Afternoon Presentations

The afternoon session was introduced by Arthur Graley - thanking Dr Samir for making a whole day available for the gathered meeting and for his help addressing medical issues for the association

Dr Samir Agrawal Presentation – Reality Check

Dr Samir said he was honoured to be a trustee for the association and how it was a reminder of the human side of their role, which can easily be forgotten.

The new drugs, Ibrutinib, Idelalisib have shown great activity for those with advanced Refractory CLL. These new drugs are currently not licensed. Initially they will be licensed for use by those with advanced refractory disease. Use as first line treatment may be some time off.

Prof Catovsky mentioned how the treatment of CML has been transformed from a killer, to one that is managed possibly cured by use of tablet treatment for life using Imatinib,

Unfortunately CML bears no relation to CLL . In CML the scientists identified one abnormality, which in not found in any other cell in the body. Imatinib is able to use this and not affect other healthy cells.

Unlike CLL where current inhibitors in trial are not CLL cell specific. The hope is that a similar approach will work for CLL eventually but this may not be possible because of the complexity of CLL. It is still early days.

Dr Samir Agrawal Presentation - ICHOR study

ICHOR (Blood of Greek Gods) is a new innovative UK study by Bart’s to attempt to generate a future completely new kind of treatment. The ICHOR philosophy is to start with the science of the cell operating mechanisms and biology, and then try to devise a treatment from that

Chemotherapy achieves a good kill by focusing on rapidly reproducing tumour cells where they can target the cancer. CLL cells accumulate and replicate less quickly that is why treatments may not be as effective. ICHOR attempts to induce chemo sensitivity in the CLL

This approach to treatment would be a two-step process: sensitisation, followed by chemotherapy. The level of Interleukin -6 is higher in CLL and so has been identified as a potential prognostic marker. The inhibitor being trialled to sensitise CLL cells to treatment reagents blocks signal pathways that are involved with this inflammatory chemokine.

Ruxolitinib is the existing inhibitor being trialled.

Initial requirements for volunteers for the trial once opened include a normal Neutrophil & Platelet count.

Questions

Key steps in ICHOR study - Study drug, by tablet, day 1 -7, blood test day 1 , 2, 3, 4, 8, 15 and 28 days. The blood will be used to check in the laboratory whether the cells have been sensitized and whether one chemo treatment would be better than another

Does Ruxolitinib affect normal cells? Jak2 is in all cells but is not active in all cells. This drug caused a drop in Neutrophil count in normal patients but the levels recovered in days once they stopped taking drug. The trial involves taking the drug for only 7 days, which is expected to sensitise the cells without significant negative effects. The drug has been used for treating other conditions for about 5 years.

Dr Timothy Farren – Transform Outreach Cancer Care. TOCC

This pilot project aims to bring the support of the CLL specialist team into the home via the internet and follows on from work done in Leeds. The Bart’s initiative will use modern technology to reduce the cost and patients effort/risk involved with visiting the hospital for blood tests and consultations.

TOCC features include:

•Online surveys to record patient symptoms

•Blood testing kits sent to patient – so blood taken locally at GP surgery. The bloods will be fast tracked to the hospital via Royal mail.

•Blood results and charts will be available ahead of any consultation

•Ability for Video or Phone consultation with specialist

•Empowers the patient

•Feedback to : t.w.farren@qmul.ac.uk

Patient Perspectives

Two Bart’s patients then give us a perspective on how their treatments had gone.

Patient 1– Experience of novel agent Lenalidomide in a CLL clinical trial

Patient 1 was diagnosed in 2009, shortly after diagnosis and after considering all the pros and cons. was entered into the phase 3 “ORIGIN” trial of Lenalidomide . An unexpected complication meant the starting dose was not possible initially.. By the time the initial dose was reached the trial was stopped on safety grounds.

The good news is the patient has seen a drop in the ALC since coming of the trial, despite not completing the intended course of treatment.

Patient 2– Experience of a “traditional” treatment for CLL FC

The audience was moved by the honesty and sincerity of the difficult experience described to us.

Patient 2 was diagnosed in 2002 following a routine company medical check-up at the age of 41. Over time pain in the glands was noted after long days, and CT scans followed. Further test were carried out to confirm CLL. Bone marrow samples were taken, and whilst afterwards on reflection these were tolerable, the lack of knowledge beforehand was unsettling.

Fludarabine / Cyclophosphamide (FC) treatment was started as this was before Rituximab was available. Patient 2 explained several complications experienced in addition to the psychological burden of the CLL and all the treatment.

Patient 2 had the support of his company, and kept working during the long period of treatment, taking 5 days off work for each round of the chemotherapy. The good news, 6-months after treatment, Patient 2 was declared to be in remission and which has now lasted 6 years.

It took great courage to take to the lectern and share personal stories with so many, thank you to both for this at such short notice.

Final questions with Dr Samir Agrawal

Dr Samir Agrawal ended the presentations with a final question and answer session here is an example of one answer how he views CLL sweats:

•Night Sweats: CLL is not the only cause of night (and day time) sweats. The key word is “Drenching” a need to change cloths/bed sheets.. Only regular Drenching sweats would be considered a CLL diagnostic factor. There is a blood test available where ladies are not sure whether their sweating is due to CLL or the onset of menopause

Arthur Graley then concluded the meeting with thanks to all those who had helped organise the meeting especially Sarah Tobin , warmly wishing us all safe journey home, and best wishes to us all to look forward to Christmas and the New Year.

There are two meetings currently being planned for the next 6 months the first in spring at Glasgow and then at Cambridge in June/July.

Thanks to Leukaemia & Lymphoma Research, Macmillan, Lymphoma Association and Leukaemia Care for provision of educational and support literature and their support on the day.