The UK CML patient seminar 2008
UK CML Patient Seminar
Royal College of Physicians, Regents Park, London.
November 15th 2008
The day started at 9.15 with a welcome from Professor Jane Apperley and a brief overview of the days agenda.
Professor John Goldman,
Imperial College, London
Biology of CML and the mechanism of action of imatinib
Prof Goldman recognised the difficulty in 'pitching' to a mixed audience of new and expert patients and referred to the fact that there is a large patient community of 'old timers'. This is due to the effectiveness of imatinib as a therapy for CML and the prevelance of this diseasse will inevitably increase as time goes on.
He started by outlining the biology of CML with it’s 3 phases – Chronic Phase, Accelerated Phase and Blast Crisis (Blast from the Greek: meaning 'to grow') and mentioned once again that the only known causal factor is exposure to ionising radiation. He stessed that there is still no evidence which would include exposure to power cables, electromagnetic radiation or viruses.
Incidence:
CML is roughly consistent world-wide at approximately 1.5/100,000 population. This is in contrast to CLL, the most common leukaemia and which shows a higher incidence in the western countries.
The marker for CML is the Philadelphia Chromosome, which is present in approximately 95% of patients with a further 2.5% who do not show evidence of the PH chromosome but who test positive for the protein Bcr/ABL.
He went on to identify the individual researchers like Noel and Hungerford, Herbert Ableson and Janet Rowley to name just a few, and the outstanding contribution made by them which led directly to the development of the life saving therapy we have today.
He went on with a detailed history of imatinib (Glivec) starting with the investigational compound produced in 1992 following work between scientists at Harvard and Ceiba-Geigy.
Dr Brian Druker’s pioneering work in the development of this compound was described and he mentioned the contribution made by Dr Deininger who was then working as a junior doctor at Hammersmith.
Ceiba-Geigy, originally an independant pharmaceutical company based in Switzerland, was taken over and eventually became Novartis. The compound named as STI-571 went into phase l clinical trials in 1998 at 3 centres in the US.
It proved to be extremely effective and is now marketed as Glivec/Gleevec (imatinib).
Earlier this year, Marin et al published results of their study of patients treated with imatinib at Hammersmith. At six years the results were :
CHR – 98.5%MCR – 85.1%
CCR – 82.7%
MMR – 50.1%
4-log reductions were 19.9% and those with a complete molecular response (CMR) were 8.3%. This data is broadly in line with the data from the IRIS study. The estimated survival (ES) at 6 years is around 88%. He said that survival has been “fundamentally and radically prolonged for about 2 out of 3 of patients” and suggested that the Chronic Phase could now be expected to last for at least 20 years.
Although approximately 60-70% do very well on imatinib, for the rest a better therapy is needed. For those patients, dasatinib and nilotinib are now available, and there are more drugs in trial.
Dr David Marin, Director of Clinical Trials Unit,
Hammersmith Hospital, London
Results of imatinib – why does it stop working?
Dr. Marin started his talk by pointing to the fact that the majority of patients ,over 90%, treated with imatinib continue to survive long term and we might say that the CML patient, rather than the ph+ cell, have become 'immortal'. Introducing the idea of immortality to an audience of cancer patients was highly amusing.
Effective treatment is widely available and only about 10% of patients show disease progression every year. He pointed out that if a patient has a complete cytogenetic response (CCyR) to imatinib, the chance of disease progression is greatly reduced as time goes on and is now only about 0.01% per year. Resistance is most likely to develop in the first 3-4 years of imatinib treatment, particularly if the patient is not in CCyR but it must be said that there are a significant number of patients that respond more slowly to therapy and will not relapse or develop resistance but do go on to a cytogenetic response within a longer timeframe.
The mechanisms of drug resistance is multi-faceted and is not yet properly understood. Primary resistance [ie the drug has little or no effect in reducing the percentage of Philadelphia Chromosome] occurs in 10%-15% of patients. The incidence of mutations is an important factor in patients showing either primary or secondary resistance, but many people showing resistance do not have an identifiable mutation so other factors must be at work, including variations in the cell's influx/outflux mechanisms. This might influence the way that any one individual will show differing plasma concentrations of the drug. The different mutations are understood to respond to different drugs – some are highly resistant to imatinib but remain sensitive to either dasatinib and/or nilotinib.
In the research studies where patients in CCyR/MCR have discontinued therapy with imatinib, CML had not recurred in 30-40% of study patients. All of this group had been pretreated with interferon and he postulated that “possibly they are cured”. However this needs further study and stopping Glivec should only be done within a clinical trial.
Dr Philipp LeCoutre,
Campus Virchow Klinikum,
Charité Universitätsmedizin,
Berlin, Germany
2nd Generation Tyrosine Kinase Inhibitors [TKIs]
For a significant minority of patients who show resistance or intolerance to imatinib, alternative drug therapies are shown to be beneficial. Patients moving onto 2nd Generation TKI’s are currently those showing a sub-optimal response, failure to respond or intolerance to imatinib.
Patients relapse because of –
- overproduction of the Philadelphia Chromosome
- imatinib resistant mutations
- clonal evolution
- lowered plasma levels of the drug
The current recommended dosing for 2nd Generation TKI’s according to European LeukaemiaNet is:
- Dasatinib – 100mg once daily
- Nilotinib – 400mg twice daily *
- SKI-606 [Bosutinib] 500mg once daily
- INNO-406 – dose still to be determined
There are more drugs in clinical trial.
Dr Le Coutre quoted Dr Kantarjian’s report at ASCO 2008 on a clinical trial for nilotinib for chronic phase patients who had failed imatinib. This gave the following results:
- CHR – 77%,
- Partial CR– 58%
- CCR – 42%
Patients who changed therapy because of intolerance to imatinib rather than resistance showed slightly better responses.
Progression free survival was:
- 79% at 12 months
- 67% at 18 months
Similar results were available for dasatinib, where patients had failed imatinib –
Progression free survival was:
- 91% at 12 months
- 80% at 24 months
The main side effects of nilotinib were:
- anaemia - 10% had grade 3-4
- neutropaenia - 30% grade 3-4
- thrombocytopaenia - 28% grade 3-4
- some elevation of lipase which might indicate pancreasitis -16-17%
- hyperglycaemia (elevation of blood glucose levels) -13%
The main side effects of dasatinib -
- pleural effusion - 9% grade 3-4
- dyspnea - 6% grade 3-4
- bleeding - 4% grade 3-4
Cross intolerance did not seem to be an issue on changing therapy. It was unlikely that patients would experience one set of side effects on imatinib and then exactly the same on a second generation TKI.
Dr Le Coutre provided a way of choosing between the 2nd generation drugs when treating CML patients with other medical conditions.
| First choice | Second choice | |
| CML and pancreatitis | dasatinib | nilotinib |
| CML and pulmonary disorders | nilotinib | dasatinib |
| CML and cardiac disorders | nilotinib | dasatinib |
| CML and diabetes | dasatinib | nilotinib |
| Post allo-SCT | nilotinib | dasatinib |
| CML and auto-immune disorders | nilotinib | dasatinib |
Patient Experiences:
Alan Humphreys: A Journey with CML
Alan related his experiences as a CML patient at Hammersmith Hospital. He told us about his autologous transplant and his subsequent therapy with dasatinb and nilotinib.
Sylvia Morris: My daughter my inspiration.
Sylvia set up the Karen Morris Memorial Trust in memory of her daughter Karen who lost her struggle to survive CML in 1997. The trust raises money to fund the Karen's Home from Home unit at Hammersmith and Birmingham Hospitals in order to support families who's loved ones are undergoing transplants. The units enable family members to stay close to transplant patients in comfortable rooms. You can support the work the Karen Morris Trust does by logging on to their website.
11.20: 2nd session.
Dr Eduardo Olivarria,
Medical Director of the Transplant Unit,
Hammersmith Hospital, London
Transplant in CML
Transplant in CML patients is a lengthy process, not a single event. It can take weeks or months to find a compatible donor, the pre-transplant conditioning treatment with chemotherapy and radiotherapy takes between one and 2 weeks, then there is the infusion of donor stem cells on Day 0, followed by engraftment of the stem cells 2-4 weeks later. Finally, it can take the patient’s immune system between 6 and 12 months to recover completely.
Stem Cell Transplant [SCT] still remains the only proven curative treatment currently available for CML. The conditioning treatments before the transplant will cure 20-30% of patients alone. For the rest of the patients receiving transplants, the donor stem cells infused on Day 0 have a potent anti-CML effect.
But SCT is a very dangerous procedure. There can be problems due to direct toxicity from the conditioning chemotherapy and radiotherapy which can be from graft rejection which is immediately life threatining, on to infection and Graft Versus Host Disease [GVHD] which can be acute or chronic.
There is a newer form of SCT called a mini-SCT (or reduce intensity condintioning or RIC SCT), when there is only a comparitively minimal dose of chemotherapy and no TBI. The aim is get a 100% survival rate whilst giving just enough chemotherapy to allow supress the host immune system to such low levels that the donor cells are able to grow in the marrow and populate the peripheral blood, this is called engraftment. However the risk of GVHD remains the same as for a full SCT. There is a weak anti CML effect, and a strong graft versus leukaemia effect.
There are now many different kinds of donors, and it should be possible to find a donor for everyone needing a SCT. 30% of patients receiving an SCT have a match unrelated donor, 30% have a match sibling donor, and the remaining 40% have a cord blood donor, or have a haplo-identical donor. Haplo-identical donors are other family members where there is around a 50% genetic match with the patient. Dr Olivarria thought that the future may be in cord blood donors, partly due to the speed with which a cord blood donor could be found, on average 11 days. Some SCT centres already prefer to use cord blood donors, it is thought that a mixed donation from 2 cord blood donors may have a stronger anti-leukaemic effect. However, there is no possibility of Donor Lymphocyte Infusion when a cord donor is used.
Over 500 transplants are being carried out every year in Europe on Chronic Phase CML patients, and it is the cheapest treatment by far for CML.
Survival figures for SCTs for 2003-2006 is 88% at 5 years. All of these patients had previously failed imatinib. Does pre-treatment with imatinib interfere with the success of transplant? Probably not.
What is the effect of delaying a transplant? The best time to have a transplant would seem to be 1-3 years post diagnosis, this information came from surveys conducted at the Hutch in Seattle, USA. The best results from transplant come in those patients who take imatinib, respond well, and then have a transplant – in that subset of patients, results are excellent.
Professor Jane Apperley,
Chief of Service for Clinical Haematology,
Hammersmith Hospital, London
Blood trough levels
Blood trough levels are a surrogate marker of response to imatinib. Patients who do not respond as expected to the standard dose of imatinib may have lower plasma levels of imatinib. The reasons for individual differences in plasma levels may be:
- 1. Adherence to therapy (taking drug holidays)
- 2. GI tract problems
- 3. Liver metabolism
- 4. Cell processes *
Initially, studies by Picard et al in France showed that there were higher levels of imatinib in the plasma of those patients who had MMR (major molecular response) and lower levels in the blood of patients in CCyR (Compete cytogenetic response). More recent studies, including the IRIS study, have shown no significant difference in results between these subsets of patients. However, when the results were split into 4 quartiles and looked at progression-free survival (PFS) over 5 years, then some differences emerged.
Quartile 1 had the lowest levels, and quartile 4 the highest. For those patients with the lowest plasma levels [quartile 1], PFS at 5 years was 78%, for those in the mid ranges [quartiles 2 and 3], PFS was 83%, and for those with the highest plasma levels, [quartile 4], PFS was 89%.
However - Clinicians are not sure how to interpret the results at present. The therapeutic range of plasma levels is not really known, nor is the overall optimal level of the drug. More studies are ongoing with the European Treatment Outcome Study (EUTOS*) coordinated by Professor F-X Mahon's team in Bordeaux, France.
* See CML Support Group's website for details of the EUTOS programme.
Professor Dina Ben-Yehuda,
Director of Haematology,
Hadassah University Hospital,
Jerusalem, Israel.
Complementary and Alternative Medicine [CAM]
Approximately 50% of patients use complementary and alternative forms of medicine alongside their CML treatment, that figure rises to over 70% when prayer and megavitamins are included. It is very difficult to apply evidence based on medicine to CAM. CAM might be very dangerous to it’s user because of side effects, and also because of drug/drug interactions eg it is dangerous for a patient on imatinib to take St John’s Wort because of the drug/drug interaction.
Professor Ben-Yehuda listed her “10 commandments for the CAM User”
- It is important to know that despite what is written about ‘natural substances’ or ‘dietary supplements’ it does not mean that they are safe to use and have no side effects.
- Children, pregnant and nursing mothers need to be particularly careful.
- People receiving medications should consult their physician about drug/herb interactions.
- Patients with the following conditions should consult their physician before using CAM: hypertension, DM, epilepsy, allergy, clotting disturbances.
- CAM can possibly cause complications during surgery – bleeding or anaesthetic
- Beware of charlatans, receive care from professional CAM care-givers
- Beware of physicians who are not open-minded and do not respect your wishes to utilise CAM
- Ask your CAM care-giver to give you his recommendation in writing [sense of accountability]
- Tell your health care providers about any CAM practices you use.
- Do not recommend your CAM to other patients, it might not be suitable for them.
Professor Letizia Foroni,
Consultant Clinical Scientist,
Molecular Diagnostic and Minimal Residual Disease Lab,
Hammersmith Hosptal,
London, UK
Monitoring CML
Professor Letizia gave an excellent presentation even though her talk was technical she took time to explain the complexities and made great efforts to help the audience understand.
She stressed that Hammersmith Hospital is a widely respected reference laboratory for monitoring CML, doing 300-400 PCRs a week. Samples need to be received within 72 hours of the blood draw, and it is necessary for the referring clinician to state the breakpoint to enable an accurate test to be done. The sensitivity of the Hammersmith lab is 1/100,000 with a margin of error of approximately 10%.
At diagnosis, CML has has a definitive marker which is the presence of BCR/ABL gene, located on an abnormal chromosome formed when normal chromosomes 9 and 22 'swop' parts with each other. This is called the Philadelphia Chromosome.
Regardless of what causes this event, the presence of this ongo-gene can be detected and therefore monitored by using a very sensitive method of testing called polymerase chain reaction or PCR. This test was developed in the late 1980's and works by making multiple copies of small segments of DNA. It was subsequently refined to include amplification and quantification of mRNA molecules (messenger RNA) which are copies of the gene sequence of the chromosomal DNA.
Monitoring response the therapy is very important to the best clinical mangement of CML patients and compares the amount of disease present at diagnosis with the differing levels at various stages after the start of therapy.
Effective response to therapy is means that the PH+ cell population is reduced over some months. An optimal response is a 3 or 4 log reduciton and is maintained by continued therapy, at very low or undetectable levels. To measure such low levels it is essential to have a method of detecting the residual disease that is inevitably present in the vast majority of patients treated with TKI's like imatinib, dasatinib or nilotinib. RT-PCR is the most sensitive method of detecting MRD available at this time.
Minimal Residual Disease:
In order to maintain optimal response it is essential to detect any changes in disease levels. PCR can be used on tissue from the bone marrow (BMA/BMB) or from peripheral blood. Control genes are used in order to calcluate the ratio of the normal -ABL- to the abnormal BCR/ABL fusion gene. This is expressed as a percentage and is what you see when you get the results of your test.
The ideal level of reduction expressed as a % is... from the baseline at diagnosis.... a reduction from 100% to 0.001% or even 0.0001%. These figures represent 3 and 4 log reductions. Continued therapy with IM over the long term may effect a completely negative PCR in some patients. This does not mean that the disease is not there, but rather that it is at such low levels to be undetectable by current methods.
Professor Jane Apperley,
Clinical Trial including SPIRIT II
The phasing of trials was explained
- Phase 1 – Is it safe? What is the right dosage?
- Phase 2 – Does if work?
- Phase 3 – How does it compare with the current best treatment?
- Post licensing studies – side effects, quality of life issues etc
There is an extremely lengthy, and very involved, process in the UK in order to get permission to do a clinical trial.
Trials currently open in the UK include
- SPIRIT I
- SPIRIT II
- Bosutinib for patients failing 400mg imatinib
- Bosutinib versus imatinib in newly diagnosed patients
- A vaccination study opening at Hammersmith -opening very soon
- Compliance and side effects whilst on imatinib
- Response to flu vaccine [Hammersmith]
- Dasatinib after mini-transplant [EBMT]
Results of the recent TOPS study showed that front-line high-dose (800 mg) imatinib showed a rapid response and a trend toward a higher MMR at 12 months, although the improvement was not statistically significant compared with the standard 400 mg dose:
| 400mg imatinib | 800mg imatinib | |
| CCR at 12 months | 66% | 70% |
| CCR at 6 months | 45% | 57% |
The SPIRIT II study is ongoing, and is comparing imatinib 400mg to dasatinib 100mg in newly diagnosed patients.
A vaccination study is due to open at Hammersmith soon. Inclusion criteria for the study are:
- Patients must be in stable CCyR but not in CMR
- Patients must have been treated with imatinib for over 2 years
- Patients must be HLA – A2 positive
JP 11/08
SC 11/08