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“Intensive research and successive clinical trials have led to incremental advances in survival of patients” Michael O’Dwyer P6 IMAGE: GETTYIMAGES

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Personalised approach to treatment has given significant hope Professor Mark Lawler PhD, FRCPath Chair in Translational Cancer Genomics, Queens University Belfast

In December 2015, during the Luxembourg European Union (EU) Presidency, the Council of the EU issued its Conclusions on Personalised Medicine for Patients, highlighting how “the development of personalized medicine may offer new opportunities for the treatment of patients in the European Union … allowing healthcare Follow us

providers to offer bettertargeted treatment, avoid medical errors and reduce adverse reactions to medicinal products.”

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owhere has the success of personalised medicine been more evident than in the treatment of chronic myeloid leukaemia (CML) and Irish patients have benefited greatly from the breakthroughs in the treatment of this disease. If I were writing this article in the 1980s, there

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would be very little to say, as CML was essentially a death sentence with ineffective treatments and little hope for patients. But our understanding of what is happening at the gene level inside the CML cell has led to a more personalised approach to treatment, which has given significant hope to patients and greatly extended their life expectancy.

Understanding the molecular ‘switch’ that makes CML cells resistant to standard treatments has led to the development of targeted therapies with a type of medicine @MediaplanetIE

known as a tyrosine kinase inhibitor (TKI). Since TKIs became available in 2001, the treatment landscape has been revolutionised and TKIs are now the standard of care for CML.

TKIs have been a game changer I have been fortunate to work closely with one of the people who developed this new therapy, Professor Charles Sawyers from Memorial Sloan Kettering Cancer Centre in New York described by the prestigious Journal of Clinical @MediaplanetUK

Investigation as, “the greatest cancer researcher of our time.”

Charles told me how it still gives him goose bumps when he remembers his fax machine whirring as the critical laboratory results came in to show that the treatment seemed to have worked. The patient, who was from Santa Barbara, is alive and well some 25 years after that first clinical trial.

Ireland – and more importantly Irish patients – played a key role in the further development of TKIs, participating in some of the early Please Recycle

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What is the true cost of innovation in cancer research?

Professor Stephen O’Brien Consultant Haematologist, Newcastle Hospitals NHS Foundation Trust Professor of Haematology Newcastle University

clinical trials on an all-Ireland basis through the Haematology Association of Ireland.

Quality of patient pathways is increasingly important So, TKIs have truly been a game changer in the treatment of CML, but important challenges remain. The cancer cell is clever and can develop resistance to treatment, so we need to be clever, too, and outwit the cancer cell through the development of innovative approaches. Science and its application must inform medicine.

We also need to consider the quality of life of patients and support people to live beyond their cancer and return to normal living. Our research at a European level has shown that cancer patients increasingly value

their quality of life and this must be included as part of the joint dialogue between the doctor and the patient when treatment decisions are (jointly) being made.

We also need to support the supporters, those who care for their loved ones as they go through the difficult cancer journey. And we need to consider cost – innovation comes at a price and we must ensure that we deliver value-based care for our patients.

Recognising his pioneering contribution to personalised medicine and the treatment of CML, Queen’s University Belfast awarded Professor Charles Sawyers an honorary degree in the summer of 2018.

The huge advances in treatment for patients with chronic myeloid leukemia has transformed patients’ lives, but the challenge is balancing innovation and affordability.

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rofessor Stephen O’Brien, Consultant Haematologist at the Newcastle Hospitals NHS Foundation Trust says “Improvements in the treatment of chronic myeloid leukaemia (CML) is one of the greatest success stories in cancer treatment.” Just 20 years ago, patients diagnosed with the condition could expect to live for around five years. Today, some are completely cured, and others can live a normal life on medication.

Not only are survival rates impressive, but the fact that the drug can be taken in tablet form at home has revolutionised the way that cancer patients are treated.

“Follow-up calls can be taken at home, patients don’t have to take time out of their lives to come to an institutional setting and we even have one patient, who’s a farmer, who receives his delivery of medication when he’s out on his tractor,” says O’Brien.

As a clinician and scientist, this is a really exciting time Of course, the benefits all come at a cost and, when they first arrived on the market, treatments for CML cost in excess of £20,000 per patient per year. Considering the majority of patients are on the

tablets for the rest of their lives, the cost was significant. However, the patent expired in 2017, which means the drugs are now available for hundreds of pounds a year – a fraction of the cost.

This is clearly a positive step forward, but the tension between innovation and affordability remains ever-present. “As a clinician and scientist, this is a really exciting time,” says O’Brien.

“But I’m acutely aware of the costs.

We have to be stringent in evaluating new technology and drugs to ensure the best outcomes for patients and ensure affordability for the health service.”

Kate Sharma

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New myeloma treatments are prolonging lives

Professor Peter O’Gorman MD PhD FRCPath Director of Pathology/Consultant Haematologist Mater University Hospital

Innovative drug trials have doubled the average survival for people with myeloma in Ireland and, in the future, could make this a chronic rather than a terminal disease.

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urvival rates for people with multiple myeloma have doubled in the last decade in Ireland and new approaches to treatment mean more people are surviving longer. Professor Peter O’Gorman, Director of Pathology and Consultant Haematologist at Mater Misericordiae University Hospital (MMUH) in Dublin, says, “Ten years ago, the median survival rate for people with myeloma was three years or fewer. Now it is seven years, and a minority survive even longer.

“We are hoping that continued research and clinical trials will increase those numbers.”

In future, it is possible that advances in treatment could turn myeloma into a chronic, rather than a terminal illness.

O’Gorman says, “A small group of patients has achieved long-term control of the disease by using a maintenance dose of drugs after initial treatment. We are exploring that development to try to make that a possibility for a majority.”

Currently three generations of IMIDs are licensed in Ireland and more are in development.

The third class of valuable myeloma drugs are the monoclonal antibodies. These target the myeloma cells directly and mobilise the immune system against them.

How this was achieved The last decade has seen three major breakthroughs in drug treatment for myeloma as three new classes of drugs have emerged.

The first was proteasome inhibitors (PIs), which are now the backbone of myeloma treatment. Then immunomodulatory drugs (IMIDs) were unexpectedly discovered to be a valuable treatment.

O’Gorman explains, “The first of the IMIDs was being used to treat a patient with another disease when it was shown to have an effect on their coexisting myeloma.

Trials in the USA and further research showed that myeloma has a complex support network of cells. The IMIDs disrupt that support network.”

“Unprecedented” response rates Combining PIs and IMIDs has been shown to have greater effect, as has a three-way combination of IMIDs, PIs and a steroid. Recent studies have examined the effect of combining drugs from all of the three classes with steroids.

“This ‘triple therapy’ has been shown to have unprecedented rates of response, especially in patients who have had a relapse and where all other forms of treatment management have failed,” says O’Gorman. “We got fast approval for the use of this triple therapy treatment.

“Trials are also taking place now on earlier stage patients and we expect

to see unprecedented results from those too, because work we did with researchers in the USA showed a 93% response rate.”

Ask about trials O’Gorman urges people newly diagnosed with myeloma: “Ask your doctors about trials that will give you early access to drugs.” He is a lead researcher with Blood Cancer Network Ireland, funded by Science Foundation Ireland and the Irish Cancer Society, and is working to get patients early access to clinical trials.

“In Ireland, trials have led to us having novel treatments for myeloma, which is one of the reasons our survival rates are comparable to those in the top centres worldwide. We engage actively in clinical trials, primarily through Cancer Trials Ireland, and patients on trials are exceptionally well cared for and monitored.”

Trials also save the exchequer money, because there is no charge for the drugs. “Each trial saves millions of euros,” says O’Gorman.

Community treatment is expanding Meanwhile, the increasing availability of myeloma drugs in oral form means more patients can be treated in the community.

IMIDs have always been taken orally, but now an oral version of a PI is available and others are in development. Many other drugs, formerly delivered intravenously, are now available for subcutaneous administration, making them quick to deliver in a day ward visit.

Patients in some areas of the country can also get treatment with one of the PIs delivered at home by a visiting nurse.

“We are aiming at making treatment available in the community wherever possible,” says O’Gorman. “It improves quality of life for patients and saves money.”

Linda Whitney

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Genetic markers have improved treatment strategies

Professor Patrick Thornton Consultant Haematologist, Senior Lecturer RCSI, Clinical Director Hermitage Medical Clinic Laboratory, Beaumont Hospital

CLL is the most common leukaemia in the western world, affecting around 1 in 30,000 individuals.

Ireland sees around 250 new cases each year. It is generally a disease of the over-60s and is a blood cancer of B lymphocytes, which are white blood cells of the immune system.

than traditional chemotherapies and less toxic, enabling people who were previously ineligible for treatment to have effective treatment and achieve remission for their leukaemia. These drugs include more targeted antibody therapy and oral medications, which target the cell surface and the cancer cell self-destruct pathways.

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Ireland has fallen behind Europe in getting drugs to market The process for new treatments becoming available world-wide normally follows a process of phase 1, 2 and 3 clinical trials before the drug is licensed. Normally a drug is licenced in Europe shortly after or at a similar time to the USA. Once the drug is licensed in Europe each country then decides whether the drug will be available to patients; this is known as reimbursement. Unfortunately, Ireland has fallen behind the rest of Europe. Some of these newer agents are licensed but still not available in

n many instances, treatment is not needed initially and the disease can be observed, which is known as a ‘watch and wait’ disease, but around three quarters of people will eventually require treatment.

Over the last decade, treatment for CLL has changed due to increasing knowledge of the biology of the disease. Various cancer genetic markers have improved the treatment strategies for CLL, enabling more targeted therapies with fewer side effects. These treatments can be more effective

Ireland or not available for their fully licensed indication.

Ireland has fortunately participated in many of the phase 3 trials, which have led to approval of these drugs in Europe. This has enabled Irish patients to benefit from these drugs ahead of their approval and Irish patients have participated in licencing of these drugs world-wide.

The results of these trials are reported in the medical press with game changing improvements in survival and remission rates.

This is of tremendous value in encouraging the HSE to make these drugs available to all of the patients who need them and maintain equal therapeutic opportunity for Irish patients in Europe.

Personalised medicine approach Advances in technology – such as next generation sequencing – have enabled efficient methods to read cancer DNA and define patients in-

to low- and high-risk groups. This will eventually lead to a personalised medicine approach, where patients will be treated with the drugs that are most likely to achieve remission, or even perhaps cure, and not be exposed to side effects of treatments that are unlikely to be effective or only effective for a short time.

Through its ongoing participation in CLL trials, Ireland has showcased its ability to perform well in clinical trials and, as a direct result of this, has been co-opted into the current German CLL trial CLL13 (through Cancer Trials Ireland) to fund Ireland’s participation. This trial is testing the combination of all the most modern treatments of CLL, looking at certain drugs in combination as initial therapy, instead of chemotherapy, is a hope this may even be a cure for CLL.

Communication improves patient pathways It is of extreme importance that patients are made aware of the availa-

bility of these trails through the media and also support groups. The past two years has seen a growing patient focus group called CLL Ireland. The group has been set up by patients, for patients, to boost awareness of the support network available. It’s an opportunity for patients to learn from each other and meet others who have been living with their leukaemia for many years.

In short, this decade has seen a revolution in knowledge of the disease. Targeted treatments have followed this knowledge and clinical trials have proven their effectiveness.

Patients are more aware of their options and appropriately asking about them, and, through their ongoing support of clinical trials, Ireland will keep in step with the rest of the world and will perhaps one day find a cure for CLL.

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250 new cases of multiple myeloma are diagnosed annually in Ireland alone

Michael O’Dwyer Professor of Haematology, NUI Galway and Director, Blood Cancer Network Ireland

Multiple myeloma is a disease of antibodyproducing plasma cells in the bone marrow. It is characterised by anaemia, bone damage and kidney failure. It is the second most common malignancy involving cells originating within the bone marrow, with approximately 250 new cases diagnosed annually in Ireland.

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hile generally a disease of older patients, one third are younger than 65 years of age at diagnosis. In some cases, it is preceded by a premyeloma state but the role of early intervention in these cases is still unclear.

Research and development has led to a significant improvement in the survival of patients. While, once having a relatively poor prognosis and limited treatment options, intensive research and successive clinical trials have led to incremental advances in survival of patients with myeloma.

Twenty-five years ago, the

average life expectancy of a newly-diagnosed patient was approximately three years.

Traditional chemotherapy was the mainstay of treatment.

While effective at controlling the disease, and improving survival, chemotherapy alone rarely – if ever – put patients into remission (an absence of detectable disease by conventional testing). Around this time, it was discovered that high doses of chemotherapy could induce much deeper responses, with a significant minority of patients for the first time achieving remission.

Since high doses are also toxic to the normal bone marrow, this necessitated the reinfusion of the patient’s own healthy stem cells following the chemotherapy to regenerate the bone marrow. These so-called autologous stem cell transplants led to a significant improvement in the survival of patients; the first major advance in the treatment of myeloma for many years.

By the end of the 1990s, a succession of new, so-called “novelagents” entered clinical trials for myeloma. These drugs, including proteasome inhibitors and immune

modulatory drugs (IMiDs) had very different mechanisms of action to traditional chemotherapy, hence the name. The successful incorporation of these agents into treatment protocols, with and without ASCT, has been a huge success in the treatment of myeloma. Coinciding with their introduction, there has been a steady improvement in the overall survival and quality of life of patients with myeloma, including in Ireland, such that 50% of newly diagnosed patients now live five years or more.

Despite advances, there is no room for complacency When broken down according to age, it is clear that younger patients have derived the greatest benefit.

There is abundant evidence now that those patients achieving the deepest responses – where even submicroscopic is no longer detectable – enjoy the longest remissions and best survival. This is referred to as minimal residual disease (MRD) negativity and this is now a major goal of treatment.

With standard treatment including a transplant, patients under the age of 65 now have a 50%

chance of surviving at least seven years and in excess of 10 years, in the absence of certain poor risk features.

This is a huge change from the 1990s.

However, myeloma remains largely an incurable disease. In most cases, it eventually comes back and ultimately proves resistant to therapy. Early relapse and resistance is more likely for the 20-30% of patients who have certain poor risk features, typically based on genetic analysis. Even our best standard therapies are often insufficient in these patients, highlighting the need for new treatment options.

Funding is vital for (CAR)-T therapy in Ireland Thankfully, a number of promising new drugs have either recently been approved or are being tested in clinical trials. New strategies, which engage the immune system, appear particularly promising. Among these are monoclonal antibodies and chimeric antigen receptor (CAR)-T cell approaches. Many of these new treatments are very expensive, however, and pose a major financial burden for the health service as well as representing a barrier to patient access.

Ireland once boasted among the best access to myeloma drugs in Europe, which is reflected in our excellent survival rates. However, in recent years, approvals of new myeloma drugs in Ireland has lagged behind other European countries. A more robust, transparent approval process is required if we are to avoid sliding down the international rankings.

Clinical trials have a very important role to play too. They enable access to drugs that might not otherwise be available as well as huge cost savings. With limited resources, Blood Cancer Network Ireland and Cancer Trials Ireland have made a vital contribution in making exciting new therapies available to myeloma patients in Ireland. Strategic investment, embedding clinical cancer research within our healthcare system could pay huge dividends, putting Ireland on the map internationally, but most of all benefiting patients.

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Ireland leads the way in pioneering new treatments for haemophilia Ireland is taking a leading role in the development of exciting new treatments for haemophilia, raising the spectre of a ‘cure’.

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ong gone are the days when people with haemophilia had only ice to treat their bleeds.

Thanks to development by the pharmaceutical industry, several new therapies for haemophilia are well into clinical trials, giving real promise to a future for people with haemophilia that “has never looked so bright,” says Brian O Mahony, Chief Executive of the Irish Haemophilia Society (IHS), President of the European Haemophilia Consortium, and a person with first-hand experience of the condition.

Giving patients a voice The IHS exists to give a voice to people with haemophilia as well as providing the help and support they need to live as fully as possible with this life-long condition.

In haemophilia, people inherit a defective gene that results in the liver not making make enough of a protein factor that allows blood to clot. There are two main types of haemophilia, A and B, according

to the blood clotting defect that is diagnosed.

Symptoms of uncontrolled haemophilia include bleeding that takes a long time to stop, oral health problems, skin that bruises easily, and pain and stiffness around joints, such as elbows, because of internal bleeding. People with haemophilia can experience limitations to daily life including the need to take regular injections, avoid contact sports such as rugby, and to take care with common medicines such as aspirin and ibuprofen. As a child growing up with haemophilia, Mr O Mahony remembers taking a lot of time off school.

Access to better treatment Current standard preventative care involves intravenous injections of replacement coagulant up to three times a week, combined with different treatment on demand if a bleed does occur. As well as the known side effects of haemophilia medications, people who inject themselves regularly can experience problems with vein

damage, as well as pain, stress and limitations on quality of life.

Through the IHS, people with haemophilia are given a formal say in product development and marketing, and with exciting results: there are currently eight companies developing gene therapy for haemophilia, which promises to reduce the current injection schedule from twice or three times a week to one injection every five years.

It is timely to see better treatments emerge for this greatly under-served population In gene therapy for haemophilia, missing DNA is injected into the liver, which can then manufacture the important blood clotting factor.

Brian O Mahony Chief Executive, Irish Haemophilia Society; President, European Haemophilia Consortium

The longest established and most successful gene therapy trial to date is that of University College London and the Royal Free Hospital in London. They have already treated 10 people with severe haemophilia type B and achieved steady effective coagulation rates of between 1% (minimal protection against uncontrolled bleeding) and 6%, following a single injection given up to five years ago.

Their work has prompted several other companies to begin work on gene therapy, including, for haemophilia type A, producing results that appear to more than double the coagulation rates seen in trials so far.

Ireland’s record of development Ireland has an enviable record in leading the way in novel therapy use. Since 2017, Ireland has scored two firsts by switching people with both types of haemophilia to first generation longer-lasting ‘extended half-life’ (EHL) treatments, and take-up of these drugs continues

to grow. Other approaches under development include the possibility of subcutaneous injections, which are less complex and avoid vein damage, even for people with the hardest-to-treat forms of haemophilia.

Mr O Mahony describes this as “a very exciting development. This group of people have more bleeding episodes and a marked reduction in quality of life. It is timely to see better treatments emerge for this greatly under-served population.”

In another development, drugs that mimic the effect of the defective blood clotting factor are being studied, with some trials achieving a 100% reduction in bleeds with only mild or moderate adverse effects.

This, says Mr O Mahony, raises the enticing prospect of an effective cure for haemophilia. He says: “There is a real possibility of transforming the quality of life for people with haemophilia in the next five to ten years.”

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