Recent research shows that our own immune system may be used to fight cancer. This approach, immunotherapy, can be tailored to patients and is capable of adapting; as the cancer changes, the immune cells can adapt.

Chemotherapy is the mainstream treatment for many blood cancers. Despite its efficacy in eliminating the bulk of the cancer, its ‘one-size fits all’ nature, severe side effects and frequent disease relapse are major issues.

Types of cellular immunotherapy

Chimeric antigen receptor T-cell (CAR-T) therapy is a form of cellular immunotherapy. For CAR-T therapy, the immune system’s T-cells are collected from the patient’s blood and modified to recognise and attack the patient’s cancer cells. While many CAR-T therapies are being tested for clinical use, research in Blood Cancer Network Ireland (BCNI) and other laboratories investigate the use of another immune cell type — known as natural killer (NK) cells.

NK cells can also be modified to recognise a specific marker present in cancer cells (CAR-NK cells). And while CAR-T cells recognise a single target molecule on cancer cells, CAR-NK cells can identify cancerous cells via a range of receptors.

After being isolated from healthy donors, NK cells are then genetically engineered (to become CAR-NK cells) and processed for cancer treatment.

More adaptable ‘live’ treatment option

NK cells act as ‘living drugs.’ Unlike CAR-T cells, they can be from any donor. After being isolated from healthy donors, NK cells are then genetically engineered (to become CAR-NK cells) and processed for cancer treatment.

Eva Szegezdi, Director of BCNI at the University of Galway, explains: “The drugs currently used for blood cancers have serious side effects as they also kill healthy cells. These drugs also get eliminated from the body very quickly. On the other hand, live immune cells are adaptable and can persist for a long time.”

Genetic engineering of immune cells by BCNI is focused on generating therapeutic CAR-NK cells, which can eliminate cancerous cells — without affecting healthy ones. “Currently, we test these NK cells on biobanked patient samples. When we progress further, we will engage in clinical trials.” She expects the first trial in Ireland to include 20 or 30 patients. “If that is successful, it will probably become an international trial.”

Potential for improved cancer treatments

With these findings and trials ongoing, patients in Ireland could potentially have access to more targeted treatment options, alongside traditional chemotherapy treatment.

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Dr Eoghan Molloy

Consultant Haematologist, Cork University Hospital

Patients with difficult-to-treat blood cancers that are not responding to first-line therapies are starting to benefit from new targeted treatments.

Some patients suffering from certain types of blood cancer find their disease progressing even after multiple lines of therapy. Patients who go through the intense toxic effects of treatments like chemotherapy and radiotherapy may find they work initially, but the disease comes back (relapsed) or they do not respond at all (refractory). These tough-to-treat areas include relapsed/refractory blood cancers, such as diffuse large B-cell lymphoma, follicular lymphoma, as well as leukaemia and myeloma. However, recent breakthroughs have led to new treatment options for these patients that harness the body’s own immune system to fight the cancer. One promising example of this kind of treatment is bispecific antibodies. 

Bispecific antibodies as effective immunotherapy 

The body’s immune system produces antibodies to protect against infections by tagging bacteria and viruses for destruction by immune cells. Bispecific antibodies are engineered by scientists to attack diseased cells, such as cancer cells. Bispecific antibodies have two different targets on the same molecule: one sticks to the blood cancer cells and the other sticks to the patient’s immune cells, thereby binding them together and harnessing the patient’s own immune system to attack the cancer cells.

Dr Robert Henderson, who has experience administering bispecific antibodies to patients at St James Hospital Dublin, insists: “There is encouraging evidence that these drugs work even after a number of lines of therapy have failed, including some complete remissions.”

Treatment process and side effects

Dr Henderson explains: “It’s vital that when patients relapse, we treat them promptly because these diseases can accelerate quite quickly.” Patients are initially administered low doses that are gradually increased in the hospital over the first few days to monitor for side effects. They are then able to go home and continue treatment as outpatients every few weeks.

Patients are monitored for side effects, including inflammatory reactions and neurological side effects. However, Dr Eoghan Molloy, Consultant Haematologist at Cork University Hospital, asserts that the side effects are manageable. “As a doctor treating lymphoma patients, I have witnessed patients achieving a much-improved quality of life, with far fewer side effects than with chemotherapy,” he says.

There is encouraging evidence that these drugs work
even after a number of lines of therapy have failed.

Dr Rob Henderson

Applications to achieve improved remission

Dr Henderson describes the treatment as ‘a great tool’ in fighting blood cancers but says: “More broadly, trials are being conducted to explore whether they work better in earlier phases in fighting diseases. Will they be used earlier on to get people cured without relapsing or needing other therapies later on? Could they work alongside — or instead of — chemotherapy; and will that achieve better remissions?” He hopes that bispecific antibodies could allow more patients to get a remission remission first.

Development of blood cancer treatments

Dr Henderson charts the progress in treating blood cancers over the past 30 years as evidence that progress can be rapid. “In the past, it was chemotherapy regimes alone. Then, monoclonal antibodies — which bind targets on cancer cells and destroy them — were added to regimes and now form the bread and butter for many B-cell lymphoma treatments. Bispecific antibodies represent the next step in this arm of immunotherapy.

“Many relapsed patients ultimately require a bone marrow transplant or CAR-T (chimeric antigen receptor T cells). CAR-T differs from bispecific antibodies, they are genetically engineered to create cells with a receptor that targets cancer cells and kills them. They have shown promising results, however, one challenge is that the engineering part takes a few weeks. Bispecifics can be available immediately and could bridge patients to these therapies”

Access to more treatment options

Bispecific antibodies provide an ‘off-the-shelf’ option that engages the body’s natural defences to recognize and eliminate cancer cells, potentially giving patients with a high risk of relapse access to more treatment options. Furthermore, as researchers continue to explore the use of bispecifics in combination with other drugs, there is hope for improved efficacy for patients throughout the treatment journey.

The primary discussion mentioned in this article is with reference to DLBCL.

M-IE-00001630 September 23

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Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, life-threatening blood disorder affecting young patients with an average age of 40 years at diagnosis. Men and women are equally affected.

There are over 50 patients living with PNH in Ireland. Patients can present with severe fatigue related to anaemia (low haemoglobin), infections or bleeding symptoms caused by bone marrow failure. They may also present with blood clots. 

Cause and effect of paroxysmal nocturnal haemoglobinuria 

PNH is caused by the acquisition of a mutation in the PIGA gene in blood stem cells, resulting in mature blood cells losing proteins that protect them from the complement system. The consequences are continuous destruction of red cells in circulation, causing anaemia, and jaundice.  

Diagnosis can be difficult as anaemia, jaundice and blood thrombosis (clotting) can be caused by many conditions. Once the diagnosis is considered, however, a haematologist can arrange a specific blood test to confirm the diagnosis.  

Classic PNH and other blood diseases 

PNH can overlap with other blood conditions, including autoimmune or inherited bone marrow failure syndromes and myelodysplasia. Optimal treatment pathways will depend on a careful investigation of an individual’s blood and bone marrow. Those with ‘classic’ PNH with red cell breakdown, jaundice and, sometimes, thrombosis need urgent consideration for anti-complement medication.  

Eculizumab is the only anti-complement therapy available in Ireland outside of a clinical trial and is extremely expensive. It is accessed through the National Centre for Pharmacoeconomics (NCPE), but there are strict criteria to be met prior to approval. 

New, expensive drugs making a difference  

During 2011 and 2016, studies demonstrated that eculizumab treatment has increased the five-year survival for PNH patients to >90%, revolutionising the outcome for PNH patients. Previously, one-third of patients would not survive more than five years from diagnosis due to complications. Eculizumab infusions are considered lifelong treatments, administered at home every two weeks. 

Optimal treatment pathways will depend on
a careful investigation of an individual’s
blood and bone marrow.

Treatment does not mean cure 

While complement inhibitor treatment improves survival, it is not a cure. Patients require lifelong monitoring. Intravenous eculizumab is time-consuming for patients and often inconvenient. Frequent medical visits are required for treatment of associated infections, regular vaccination and monitoring for silent clotting and associated heart, lung, liver and kidney disease. Moreover, PNH can evolve into other blood conditions, and continued surveillance is required.   

Emerging treatment options for PNH 

Access to eculizumab is not easy in Ireland due to cost and the strict criteria used to determine patient eligibility. However, many new complement-blocking treatments are on the horizon for Irish patients. These include biosimilar preparations of eculizumab — which are less expensive — and longer-acting preparations such as ravulizumab — which can be given every eight weeks, giving patients more freedom.  

A self-administrated complement inhibitor is in the clinical trial phase (Commodore-1) and is actively recruiting Irish PNH patients who are still anaemic on eculizumab. This medicine hopes to allow more independence for patients, as it only requires administration every four weeks. Newer agents, which inhibit the complement pathway at different points, are going through the approval processes of the NCPE and are sometimes available in exceptional cases.  

What’s the price of living a normal life? 

For Irish patients with this chronic rare condition, the only curative treatment is a bone marrow transplant — a procedure carrying significant risk. For most patients and haematologists, it is a last resort.  

Many patients who live with this chronic condition seek a long-term solution, which will allow them to live comfortably. The approval pathway for new drugs is challenging, and these new medications are all costly. Our healthcare system continues to face the economic challenges of expensive medications, and haematologists continue to advocate for our PNH patients who want to live a ‘normal’ life. 

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Innovation in haemophilia treatment has increased exponentially in recent years with new approaches, new therapies and several ongoing clinical trials.

Since the 1970s, the standard therapies for haemophilia were intravenous injections of the missing clotting factor — factor VIII (FVIII) for haemophilia A and factor IX (FIX) for haemophilia B. These were typically infused two to three times per week to maintain a base or trough factor level and prevent most spontaneous bleeding. In Ireland, since the late 1990s, these were recombinant or synthetic products.

Progression of haemophilia therapies

In 2014, a new generation of extended half-life recombinant factor concentrates became available. This allowed for less frequent infusion or greater protection (or both, in FIX cases). For individuals with severe FVIII deficiency, treatment was required twice weekly. In FIX deficiency, treatment was required once per week or even once every two weeks due to the longer half-life of the infused FIX in the body.

In the last year, the first licensed gene therapies for both FVIII and FIX deficiencies were introduced.

Subcutaneous therapies

Novel approaches targeted the other side of the coagulation cascade. Instead of merely replacing the missing factor through infusion, a new category of therapies emerged, known as rebalancing agents. They are subcutaneous therapies aiming to inhibit or reduce the impact of naturally occurring anticoagulants, such as antithrombin, anti-tissue factor pathway inhibitor (TFPI) or protein C. These therapies allow the blood to clot as required.

Several such products are currently in advanced stages of clinical trials; one is already licensed in Canada for some indications. The first FVIII mimetic was licensed in 2018 and is now widely used in Ireland. This is a subcutaneous therapy, which can be used weekly or every two to four weeks.

Gene therapies for haemophilia

In the last year, the first licensed gene therapies for both FVIII and FIX deficiencies were introduced. These new therapies use an adeno-associated virus (AAV) vector to deliver a FVIII or modified FIX gene to the liver where the liver cells start producing FVIII or FIX, respectively. The durability of these therapies is unknown but postulated to be at least five to seven years for FVIII and at least 10 years for FIX. These therapies have been a positive step forward for haemophilia patients.

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Multiple myeloma (MM) is a blood cancer that affects the immune system, blood counts and bones and can lead to significant disability and distress for patients. Nearly all patients experience relapse, but there are treatment options that can help.

Enormous advances have been made in the treatment of multiple myeloma, particularly in the past decade. However, it remains incurable in the long term. This means that patients require close monitoring after the initial disease has been successfully treated (remission) and will require further treatment once the disease comes back (relapse).

Finding treatment for relapsed myeloma

A number of factors will influence which treatment is suitable for a patient when the disease relapses. In most cases, treatment will be somewhat personalised to that patient, ensuring that they get the most suitable drug(s) for them at the right time.

Patient factors that influence treatment choice include age, general health, other diseases (eg. cardiac disease, diabetes) and side effects from previous treatment (eg. neuropathy). Disease factors include how long it has been since the last treatment (remission duration) and how aggressively the disease is behaving. For example, at relapse, some patients may require dialysis for kidney failure or radiation to treat bone or spinal fractures.

A number of factors will influence which treatment is suitable for a patient when the disease relapses.

Drugs and clinical trials offering treatment

The drugs chosen to treat MM at relapse will also depend on side effects, previous drugs the patient may have received and which therapies have shown to be most effective in clinical trials. Indeed, clinical trials form an important part of treatment for relapsed MM patients as they offer the patient the best available treatment for the disease; and often, these treatments are not available outside of clinical trials.

The categories of drugs available in Ireland to MM patients include a combination of immunomodulatory drugs (pomalidomide, lenalidomide), proteasome inhibitors (bortezomib, carfilzomib, ixazomib), monoclonal antibodies (daratumumab, isatuximab) and traditional chemotherapy agents like cyclophosphamide.

Newer categories of drugs include bispecific antibodies (teclistamab, elranatamab) and antibody-drug conjugates (belantamab mafodotin) are currently only available in Ireland in clinical trials. These therapies offer patients a chance to receive a completely new class of drug for their disease and have resulted in excellent remission rates in clinical trials.

Trialling cellular therapies for multiple myeloma

The development of cellular therapies such as CAR-T cells for MM has also produced unprecedented results for patients in terms of reducing — or completely removing — all traces of MM. These are also currently still undergoing clinical trials.

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Treatments for the blood cancer myeloma are emerging, with many at the final stages of clinical trials. Myeloma treatment aims to either bring patients into remission or manage its effects to improve their quality of life.

Multiple myeloma is caused by abnormal cells called plasma cells. Currently, myeloma patients are continuously monitored and undergo treatment throughout their lives. However, many new treatments are emerging. The two main ones are chimeric antigen receptor T-cell (CAR-T cell) therapy and bispecific antibodies.

Modern myeloma treatment

CAR-T-cell therapy is a new modality of treatment that harnesses genetic engineering. We collect immune cells from the patients (T-cells), and through genetic engineering, we insert receptors into those cells and re-infuse them back to patients. These genetically modified cells circulate in the blood to identify abnormal plasma cells and then stimulate the immune system to kill these plasma cells.

A new group of medicines, called bispecific antibodies, is also emerging. It is a ready-made medicine infused to the patient. Similarly to CAR-T-cells, it identifies plasma cells and stimulates the host’s immune system to get rid of them.

CAR-T-cell therapy is a new modality of
treatment that harnesses genetic engineering.

Unmet needs for myeloma

Despite advances in myeloma treatment, there are still unmet needs, including:

• Lack of a cure. However, with improved treatment, or combined treatments, it might be achieved in the near future.
• Reducing the toxicity of treatment (especially stem cell transplant), which many patients cannot tolerate.
• Improving survival rates for young patients, as prolonging life by 8–12 years is not sufficient for many patients.
• Reducing treatment time, as almost all myeloma patients require continuous treatment, which negatively impacts their quality of life.
• Treatment for elderly, frail patients who may not tolerate the same treatment as younger patients.

If these unmet needs are addressed as promising treatments advance, patients with myeloma could live longer, healthier lives.

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Relapsed Refractory Multiple Myeloma (RRMM) presents a multifaceted and challenging scenario for healthcare professionals involved in the care and management of these patients.

The landscape of RRMM treatment is continually evolving, with emerging therapies and clinical trials offering great hope to patients. However, they also come with specific individualised side effects and management concerns. 

Guidance and optimising treatment for myeloma patients

The increasing number of haematology advanced nurse practitioners and nurse specialists have demonstrated that they are pivotal in the management of patients by providing appropriate and holistic care and support. They play a critical role in educating patients regarding the nature of relapse, the available therapeutic options and potential side effects.

Specialist nurses who are consistently seeing these patients — often in nurse-led clinics — are suitably placed to provide clinical expertise and compassionate care, as well as advocate for the patients within the broader multidisciplinary team to ensure they receive optimal treatment at the most appropriate time.

Patients being monitored and managed
closely by nurse specialists benefit
from better side effect management.

Side effect management and emotional support

Monitoring of side effects and response to treatment is a vital part of the care of these complex patients who, very often, have many other health issues and complications from previous treatments.

Patients being monitored and managed closely by nurse specialists benefit from better side effect management and tend to tolerate treatment better and remain on it for longer. They also provide vital emotional support to patients and their families and link them with appropriate counselling and support services, such as the Irish charity Multiple Myeloma Ireland (MMI).

Accessible multiple myeloma care information

MMI focuses exclusively on supporting patients, families and carers with multiple myeloma and other related conditions. This registered charity provides patient information days and facilitates support groups around the country. Its website contains a wealth of information in many formats including a comprehensive library of podcasts addressing all aspects of myeloma care which has proven to be a very valuable resource to myeloma patients.

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Regulated clinical cancer trials in Ireland have contributed to advances in blood cancers. They have promoted patient access, awareness and involvement. Clinical trials have helped over 33,500 patients since the year 2000.

Current cancer treatments are approved with evidence-based data from many clinical trials. Clinical trials in Ireland are highly regulated by Health Products Regulatory Authority (HPRA), and the clinical trial team closely monitor participating patients.

Impact of clinical trials on blood cancer

Haematology clinical trials examine new — or a combination of existing and new — therapies for newly diagnosed and relapsed patients with blood cancers. There are several clinical trials ongoing in Ireland for patients with lymphoma, CLL, acute leukaemia, multiple myeloma and myeloproliferative neoplasms.

Translational studies examine disease markers for diagnostic and prognostic information. Other translational studies examine non-pharmacological interventions for improving comfort and quality of life in cancer patients. For example, Sleepio After Cancer Study (SACS) is recruiting women with current or prior cancer diagnoses who have difficulty sleeping.

Clinical trials helping patients in Ireland

Cancer Trials Ireland is a registered charity and the leading cancer research trials organisation in Ireland. It aims to provide every patient with access to high-quality and potentially life-altering cancer trials and to make Ireland an attractive location to open cancer trials.

Since 2000, 623 cancer trials have opened in Ireland, with over 33,500 patients taking part. In 2022, a survey of public attitudes revealed that three in five people in Ireland would take part in a clinical trial. The Charity is partly funded by the Health Research Board and the Irish Cancer Society. It also receives income from pharmaceutical companies and international research groups, as well as through philanthropic giving and donations from members of the public.

In 2022, a survey of public attitudes revealed
that three in five people in Ireland
would take part in a clinical trial.

Giving patients power over their journeys

Cancer Trials Ireland also promotes public awareness and understanding of clinical trials through ‘Just Ask’ campaigns. The Patient Consultants Committee (PCC) is a sub-group of the Charity and focuses on public and patient involvement in clinical trials. This patient group contributes to the delivery and design of clinical trial activities.

In addition, educational events for individual disease areas within Haematology deliver information and support to targeted groups of patients, families and carers. Patient information days for Myeloproliferative neoplasms (MPN), Chronic Lymphocytic Leukaemia (CLL) and Lymphoma are hosted annually at different locations around Ireland.

By guiding patients and including them in every step, clinical trials and support initiatives can create a greater impact. This can help improve the lives of more patients and their families.

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Prof Ruth Clifford MD PhD

Consultant Haematologist, University Hospital Limerick

Paul Murray

Professor of Molecular Pathology in the Health Research Institute, University of Limerick

The Limerick region is increasing its research profile through ground-breaking advances in blood cancers.

A rich portfolio of cancer clinical trials has been developed over the last decade at University Hospital Limerick (UHL) under the leadership of Professor Linda Coate and Maureen O’Grady. This has already led to more effective and safer treatments for patients.

The current director of the Trials Unit, Professor Ruth Clifford, is working closely with a team of internationally leading cancer researchers delivering new treatments within clinical trials. Professor Clifford highlights: “We are opening important trials across blood cancers including lymphoma, chronic lymphocytic leukaemia and acute leukaemia. International evidence confirms that higher quality services are delivered by academic centres that run clinical trials. This is a cornerstone of our vision for cancer patient treatment in the mid-west region.”

A strong focus on patient-centred research

The research profile of the Limerick region is broadening through collaborative networks. Groups working in cancer research have come together to form the UL Cancer Network (ULCaN), directed by Professor Patrick Kiely. Through ULCaN, platforms to enable the public and patients to direct research are under development. As Professor Clifford states: “It is important that people living in this region have the opportunity to contribute to the development of research. A recent survey revealed that many patients were unaware that clinical trials were undertaken in UHL.”

We hope that our patients and the public will join us in progressing cancer research for this region aiming for higher standards of care for our cancer patients.

Looking to the future – personalised cancer care

Research within the newly established Limerick Digital Cancer Research Centre, in partnership with Dell Technologies and UHL, is working towards personalised treatments for all blood cancer patients. As Professor Paul Murray confirms: “Until now, we have lacked the tools that can identify the key features of a patient’s tumour that can predict treatment response. However, this is now possible using a new technology known as ‘spatial profiling’ in which we can identify how different cells in the cancer interact with each other.”

Working with artificial intelligence experts, Professor Pepijn van de Ven and Professor Conor Ryan, the UL research team plan to design a new generation of diagnostic tests based on these features. As Dr Eanna Fennell, a post-doctoral fellow at University of Limerick (UL), says: “These new tests will ensure that only patients who will respond to a given therapy will be treated. This will improve their chance of cure and reduce the unnecessary toxicity and costs associated with the use of ineffective treatments.”

“This is a very exciting time for the team in Limerick” states Professor Clifford, “we hope that our patients and the public will join us in progressing cancer research for this region aiming for higher standards of care for our cancer patients.”

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Von Willebrand Disorder (VWD) is the most common inherited bleeding disorder with approximately 1 in 1,000 people being affected.

VWD results from the von Willebrand factor (VWF) protein in the blood being lower than normal or poor quality VWF being produced. Normal VWF levels are greater than 50% whereas in VWD, levels are less than 30%. Those with levels between 30% and 50% are said to have low VWF levels but are not categorised as having VWD although they may have some bleeding problems such as easy bruising or heavy menstrual bleeding.  

Understanding signs and symptoms

It is a complex disorder with several subtypes and with severity ranging from mild to severe. VWD affects both men and women. In men or children, easy bruising or frequent, heavy nosebleeds may be the first sign of a bleeding disorder.

The most common warning sign for women are heavy periods or excessive bleeding after childbirth. One in five of those with heavy periods will have an underlying bleeding disorder, which is often undiagnosed. It can be difficult to tell if menstrual bleeding is heavy. Comparing yourself to other women in the family can be misleading as they, too, may also have low VWF levels or VWD without knowing it.

The following symptoms should alert a woman to a potential problem:

• Bleeding which lasts longer than seven days, requires you to change pads or menstrual cup every two hours or passing clots larger than a €1 coin.
  
• Unpredictable bleeding.
  
• Menstrual bleeding which affects daily activity (needing time off work or school).
  

Both men and women with VWD can experience prolonged or heavy bleeding after dental procedures, surgery or trauma. Bleeding into joints can also occur.  

It is a complex disorder with several subtypes and with severity ranging from mild to severe. VWD affects both men and women.

Increasing awareness and diagnosis

Von Willebrand Disorder is massively underdiagnosed in many countries, including Ireland. There are currently 1,643 people in Ireland diagnosed with VWD of whom 618 are male and 1,025 are female.We would expect to have 4,900 diagnosed if all those with VWD were identified.

Treatment options for VWD include desmopressin (a synthetic hormone),tranexamic acid (an anti-fibrinolytic), fibrin glue or factor replacement therapy. For women, options can also include hormonal contraceptives or intrauterine devices.

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