BSH 2019: The Crucible Prize 2019
In its second year, an innovative trainee-led initiative with a £1000 prize.
The aim of this session is to encourage reflection on what we do as haematologists, and why we do it. The theme was "How can haematology change the world?”
Open to doctors in training and other healthcare professionals (at any stage of their career)
The five best abstracts were selected for oral presentation at the BSH 2019, and the trainees were questioned and judged by a panel of senior haematologists. Presentations were judged on the quality and originality of their content, presentation skills and response to questions.
The winner was Jennifer Darlow.
Anaemia represents a huge global burden of disease. In 2010, around one third of the world’s population was affected by anaemia, with an estimated 50% of those cases attributable to iron deficiency. The majority of these cases of iron deficiency anaemia (IDA) occur in low- and middle-income countries. IDA primarily affects children and women, due to increased iron requirements secondary to growth, pregnancy or menstrual loss. Iron deficiency in children can affect both physical growth and cognitive performance, which will potentially have a lifelong impact. Thus, iron supplementation is recommended to ensure children reach their full potential. Indiscriminate use of iron supplementation, however, has been linked to increased mortality from malaria and other infections, notably diarrhoeal disease.
Consequently, there is a need to find a reliable diagnostic test to discriminate between IDA and anaemia secondary to other causes. While there are a variety of tests currently available to diagnose anaemia (including serum haemoglobin and ferritin), there remain challenges with their use and/or interpretation, especially in the low- and middle-income setting. Serum hepcidin has been posited as a potential alternative to current tests. Hepcidin plays a key role in iron regulation; low expression increases plasma iron concentrations while high expression decreases plasma concentrations. Recent research in both developed and developing countries has demonstrated that serum hepcidin concentration may potentially be able to differentiate IDA from anaemia of inflammation. Further research is still required before hepcidin becomes widely used as a marker for IDA. A reliable hepcidin point-of-care test still needs to be developed and there must be clinical trials comparing hepcidin to the currently used test., Hepcidin does, however, have the potential to represent the “holy grail” of iron deficiency diagnostics: the ability to identify children most likely to benefit from, and least likely to be harmed by, iron supplementation.
The United Nations’ Sustainable Development Goals (SDGs) set in 2015, include the attainment of universal health coverage, as well as a reduction in mortality from non-communicable diseases (NCDs) including cancer, and conditions relating to pregnancy and childbirth.1 These issues disproportionately affect Low and Middle Income Countries (LMICs) where 78% of deaths from NCDs2 and 99% of maternal deaths occur.3 Around 25% of these maternal deaths may be due to lack of blood transfusion4 and the provision of oncology treatment is often dependent on the availability of safe transfusion. There is huge inequality in blood availability worldwide. Donation rates in higher income countries are around 32 per 1000 population per year, compared to only 4 per 1000 population per year in lower income countries.5
Increasing investment and development of new technologies and drugs is significantly improving outcomes and survival in higher income countries. However, for these benefits to be realised, countries require functioning health systems with adequate access to reliable pathology and laboratory services. This is often lacking in lower resource settings.2 6 Haematology is an essential component of laboratory and pathology departments, enabling accurate diagnostics and safe transfusion.2
There is a need to advocate for the prioritisation of laboratory and transfusion services in health system planning and funding. Development of training programmes for biomedical scientists and post-graduate physicians will enable the improvement of laboratory and transfusion services to provide support for developing health systems.2 7 Haematology services can help reduce deaths from lack of blood, improve the process of accurate diagnostics and support developing oncology programmes. Haematologists can help through advocacy and support for training in low resource settings.
In order for the SDGs to be met, significant improvements in laboratory and transfusion services worldwide are essential. This is how haematology can help to change the world for the better.
- Publications UN. Sustainable Development Goals Knowledge Platform [Available from: sustainabledevelopment.un.org accessed 21/11/2018.
- Wilson ML, Fleming KA, Kuti MA, et al. Access to pathology and laboratory medicine services: a crucial gap. Lancet 2018;391(10133):1927-38. doi: 10.1016/s0140-6736(18)30458-6 [published Online First: 2018/03/20]
- WHO. Trends in maternal mortality: 1990 to 2015. Geneva, 2015.
- Bates I, Chapotera GK, McKew S, et al. Maternal mortality in sub-Saharan Africa: the contribution of ineffective blood transfusion services. BJOG : an international journal of obstetrics and gynaecology 2008;115(11):1331-9. doi: 10.1111/j.1471-0528.2008.01866.x [published Online First: 2008/10/01]
- WHO. Global status report on blood safety and availability 2016. Geneva, 2017.
- Bates I, Maitland K. Are Laboratory Services Coming of Age in Sub-Saharan Africa? Clinical Infectious Diseases 2006;42(3):383-84. doi: 10.1086/499368
- Horton S, Sullivan R, Flanigan J, et al. Delivering modern, high-quality, affordable pathology and laboratory medicine to low-income and middle-income countries: a call to action. Lancet 2018;391(10133):1953-64. doi: 10.1016/s0140-6736(18)30460-4 [published Online First: 2018/03/20]
Haematology, more than many specialities, manages patients with compromised immune systems (e.g. neutropenic, bone marrow transplant patients). These patients regularly contract infections and consequently receive broad spectrum antibiotics. This includes carbapenems, particularly in the context of rising antimicrobial resistance and recent piperacillin-tazobactam shortages.
In the last decade the emergence and spread of carbapenem resistance presents antimicrobial dependent medicine with an unprecedented crisis. Globally, carbapenem resistance is rising – in parts of India, resistance rates are above 50%. Even in the developed world, carbapenem resistance is a growing problem, costing millions and leading to patient mortality. This is compounded by the fact that the new antimicrobial pipeline is sparse.
Widespread use of carbapenems contribute to this problem, by providing selection pressure that allows resistant organisms to flourish. Although haematology uses a relatively small quantity of antibiotics, its intensive use of carbapenems drives resistance disproportionately. Haematologists are therefore contributing to the aforementioned antimicrobial resistance situation. This is self-defeating in the medium-to-long term. If carbapenem resistance continues to be encouraged, immunosuppressive therapeutic interventions for haematological conditions, such as bone marrow transplant, will be unviable. Haematology is changing the world by driving a global crisis from which it will be difficult to return.
There are strategies that we can adopt to help avoid this nightmare scenario:
- With close collaboration with infection specialist colleagues, we can alter our prescribing habits to reduce antimicrobial resistance selection pressure whilst still treat patients appropriately.
- Wider and more consistent use of diagnostics, along with development and adoption of new diagnostics, can allow targeting of patients who require antibiotics and reduce unnecessary prescriptions for those that don’t.
- We can encourage investigation into the use of broad-spectrum antibiotic in haematological patients, to determine where it is necessary and where narrow therapy can be safely used instead.
“How can haematology change the world?! Devastatingly. It can take the world you thought you knew and give it back to you completely altered.
“After the diagnosis our world centred on one idea: Cure the leukaemia. ‘Chemotherapy will put it into remission, but cannot cure it – she needs a bone marrow transplant.’ (Let’s go for it!) ’She needs a plastic line in her vein.’ (Sure, whatever you say!) ’She needs weekly blood tests.’ (Okay, no worries.) ’She needs platelets twice a week.’ (But it’s a two-hour round trip!) ’We need to admit her for intravenous antibiotics.’ (What, again?) ’She needs to take these tablets – sorry there are so many.’ (Her mouth is so dry she can hardly swallow!) ‘She seems to really benefit from having you here.’ (I know, I’m trying.) ‘Look after yourself! She needs you well-rested.’ (I know. I’m trying.)
“What have you done to the woman I married? Who is this fragile person I sit with, accompanying to blood tests and clinic appointments, visiting daily on the wards? What are we fighting for, her and me? My love, whose hand I hold while she fades away on an intensive care unit? Was it all for nothing?”
When it comes to allogeneic transplantation, haematology changes the world utterly. And as haematology doctors, we offer a cure, but we do not elaborate on the price that will be paid.
We need to understand how haematology can change the world of every one of our allograft patients: our therapies have physical, social and emotional impact, and we must characterise these better in order to mitigate against them. We need to better predict outcomes to minimise failed allografts and ultimately, we need cleaner interventions so that we can leave our patients’ worlds unchanged.
Genomics is changing the medical world, and as haematologists we are at the forefront of driving this field from the bench to the bedside bringing genomic era diagnosis and treatments to our patients around the globe.
Haematology Malignancy Diagnostic Service (HMDS) laboratories provide ever-increasing insight into the genomic complexity of our patient’s cancers, and allow us to prescribe new medication targeted to their cancer, for example, FLT-3 inhibitors in acute myeloid leukaemia (1).
In low- and middle-income countries (LMICs) GeneXpert PCR machines are enabling molecular diagnosis of CML (2). Therefore, drug funding can be released for patients who would have a prognosis of a few years without treatment and transform them into a functional chronic disease patient, with a life expectancy of near normal.
Genomics is also advancing the field of blood transfusion, where haematology has traditionally had the bulk of its global impact, by utilising next generation sequencing to identify extended red cell phenotypes. This technology has the potential to increase the efficiency of identification of rare blood types within our blood banks and save more patients with complex allo-antibodies (3).
Gene therapy has recently been used with success in Haemophilia B, sickle cell disease and β-thalassaemia. Liver-directed gene therapy has reduced the frequency of bleeds (4) in Haemophilia B. Sickle cell and β-thalassaemia patients receiving lentiviral transformed autologous transplantation of a normally functioning β-globin gene have experienced cessation of sickle crises (5) and achieved transfusion independence (6). These treatments could become a ‘one-hit-wonder’ curative therapy, which may also be useful in LMICs where access to chronic treatment can be logistically fraught, and associated with a high cumulative cost.
As haematologists we are the clinical leaders of the genomic era, and by pushing the genomic medicine frontier we can help create a world with a lower burden of life-limiting and chronic disease.
- NIHR Horizon Scanning Research and Intelligence Centre, Quizartinib for FLT3-ITD positive acute myeloid leukaemia – second line, June 2016, http://www.jo.nihr.ac.uk/wp-content/uploads/migrated/Quyizartinib-June16.pdf, accessed 30/11/2018.
- The Max Foundation, The Max Foundation-Cepheid Collaboration Agreement Improving clinical outcomes by strengthening diagnostics capacity, September 2015, https://themaxfoundation.org/wp-content/uploads/reports/The-Max-Foundation-Cepheid-Collaboration-Agreement-2015.pdf, accessed 30/11/2018
- Wu et al, Blood group genotyping goes next generation: featuring ABO, RH and MNS, ISBT Science Series, March 2018, 13(3):290-297.
- Miesbach et al, Gene therapy with adeno-associated virus vector 5–human factor IX in adults with hemophilia B, Blood 2018 131:1022-1031.
- Ribeil et al, Gene Therapy in a Patient with Sickle Cell Disease, The New England Journal of Medicine, March 2017, 376:848-855.
- Thompson et al, Gene Therapy in Patients with Transfusion-Dependent β-Thalassemia, The New England Journal of Medicine, April 2018, 378:1479-1493
It’s already changed my world by allowing me the privilege of being a part of my patients' journey during the most difficult time of their lives. My world has been moulded by the incredible bravery, heartache and sheer determination I witness on a daily basis. From this standpoint, haematology is already changing countless worlds.
How will it change THE world? It is going to bring a whole new meaning to the word CAR and revolutionise the market! Jeremy Clarkson will be back in business and will have some super-duper CAR’s to discuss!
It will bring a whole new meaning to make and model, we already have a T class, unlike any other manufacturer, and this is just the start!
In years to come, science and not Mercedes will be the elite in CAR production! Our starting point is already a game changer and we have entered the CAR market at an advanced level.
The CAR’s belonging to haematology have an advanced spec that is not an additional option, it is included in all models
Sat nav will continue to guide us on our journey to reach our destination. It’s not just any sat nav, it’s not on Amazon, it is unique in the world of haematology and borne out of ongoing research and hard work in a fast moving, ever changing field.
Newer and better models of CAR’s will emerge through trials and in time the UK will engineer their own CAR’s rather than importing, replicating the historical conventional car market
Unfortunately, there will be criteria that will exclude potential buyers. This is only NOW though, there are exciting, world changing times ahead which will mean that haematology CAR’s will be available to a majority, unlike other brands such as Ferrari, which will only ever be accessed by a minority.
Edwin Smith's papyrus, 3000BC
5 millennia have past since the first written description of cancer and yet it remains the emperor of all maladies, a grim diagnosis for every patient. Since then, human civilisation has made huge leaps in science, technology and healthcare. We have also tried to treat cancer...
Toxic chemotherapies, radical mastectomies and painful operations with limited results have added extra pain to the martyrdom of cancer patients. Aiming for remission, not cure. Patients in the role of Sysiphus, who pushes the boulder until relapse.
Haematology shouldn’t be shy of its achievements in some types of cancer though. The success of chemotherapy in Hodgkin’s lymphoma, the revolutionary tyrosine kinase inhibitors in CML and the monoclonal antibodies in B-cell lymphomas achieved survival rates unprecedented in cancer patients before.
But the dawn of the immunotherapy era offers hope that we will tackle every form of cancer by reprogramming our immune system, changing cancer’s biology and attacking its unique weaknesses ferociously. Targeted therapies with no stigmatising hair loss or deleterious side-effects will become first line.
Haematology should continue to pioneer in this field and employ more tools to intensify our research. CRISPR can enable us to better manipulate cells, artificial intelligence can assist us in analysing vast amounts of data and identifying patterns, while well designed clinical trials can accelerate the approval of new treatments
Haematology can change the world, when it finally transforms ‘Cancer’ from a dire diagnosis to a manageable and treatable disease
It is really surreal when you look back on what patients had to go through. The atrocious procedures and the futile treatments with such dreadful results. While now, we cure tuberculosis by prescribing a long treatment course
Did I say tuberculosis? I meant to say cancer…
The world today is quite unlike what it used to be, and it is continuing to change at an alarming pace. Over a short number of years, there appears to have been an increasingly growing trend to favour and prioritise the needs of the individual, even when that comes at the expense of the collective wellbeing. As such, a significant proportion of our daily lives currently revolves around discussing conflict and division, and the future has never seemed more uncertain.
So this begs the question: what needs to change? If one spends a moment to think about what could make the world better, it becomes clear that what it is lacking is unity. At a time when people seem to be drifting further and further away from each other, togetherness has never been more necessary – and this is where Haematology comes in. No other discipline is more deeply rooted in the knowledge that success can only be achieved through people working together towards a common universal aim. Whether it is the laboratory staff analysing samples, the clinical teams on the wards and in clinic treating patients, or the research teams conducting cutting-edge clinical trials, every single person in the field of Haematology comes together in a long line which begins and ends with the desire to improve the lives of others.
Haematology has already given the world so much: from revolutionary blood transfusions, to life-giving stem cell transplants, and now to the ground-breaking advent of CAR T-cells, haematology has been changing the world in different ways for centuries. And now it has the opportunity to lead by example and continue doing so by giving the world the future it needs: one where unity can be recognised and upheld as the key towards a better tomorrow.
Haematologists not only treat the patient, but play a role in saving lives by performing trials on cell lines or researching to reduce the side-effects of an old treatment. They have also helped in the research of reducing blood-transfusion reactions and worked on stem cell-related techniques over the years. In this presentation, we explain how this can change the life of leukaemic patients. A routine check–up of the complete blood count can serve as early detection for chronic myeloid leukaemia (CML) with rising leukocytes, eosinophilia and basophilia. This early detection technique prevented and reduced the complication of CML, and aided in the detection of Philadelphia chromosome and BCR-ABL transcripts, along with the detection of clinically significant mutations (T3151, Y253H, Y253F, E225K, and E255V) that caused CML. This has led to an array of treatment opportunities for CML. Continuous detection of BCR-ABL levels by RT-PCR assisted in the detection of minimal residual disease, which played a major role in the relapsing process of this disease. In treatment and clinical trials relating to CML, looking back at the history of treatments, previously, you could treat CML patients with the first drug of choice, arsenic. This was followed on in the 19th century, wherein Busulfan, hydroxyl urea, and interferons treated CML. All these drugs had many side-effects and did not increase the survival rates of CML patients. In 2001, IRIS trials succeeded to get the imatinib treatment. This treatment played a key role in increasing survival by 50% in patients aged <79 years old. I think this was such a ground-breaking success for haematologists in treating CML patients. Recently, second and third generation tyrosine kinase inhibitors and incoming parts of RNA (micro RNA) are emerging in the treatment of CML for imatinib-resistant patients. Finally, stem cell transplantation has also been saving lives of these patient groups suffering from CML. Without the research and dedication of a haematologist, we would not be where we are in terms of curing such life-threatening blood disorders.
As a psychologist, the world of haematology is perceived differently by me than it may be perceived by medics. I see it as a complex continuous collaboration and interchange of chemistry, biology, physics, luck and innovation, which in turn allies itself to the word ‘hope’. Why would hope be specifically attributed to haematology? The answer lies in blood – one of the largest tissues in the body and one that is often mistaken as an organ. Blood is the life-force that comes into contact with, affects and connects every bodily organ and enables all our organs to function, thus enabling us to function as living and rationalising organisms that find purpose and meaning in life. There are many symbolisms of blood: as a life-force, as a representation of strength and power, representing lineage, as a representation of sin and atonement of sin and as a representation of the soul. The noun itself can convey multiple meanings and impact how a person perceives themselves and their mortality. This is why haematology is such an influential field to work in. The very nature of the work that haematologists do with, and related to, blood can impact a generation’s perception of life, of mortality and of themselves as individuals. The field has the scope to moderate or change the epistemological positions of various religions and to impact the longevity of life by blending academic and clinical work by keeping abreast of technological innovations that can improve the quality and/or longevity of life of people, ranging from mild anaemia to managing haematological malignancies.
So, in answer to the question ‘how can haematology change the world?’ the answer is by giving us hope through providing opportunities for life, meaning and purpose.
By changing the way the world thinks about what cancer means as a disease.
Only a few decades ago, patients associated the word cancer with a very poor life expectancy, plagued by many cycles of standardised chemotherapy regimens with its well-known side effects, such as nausea and hair loss. However, during my training in haematology, I have seen some very exciting shifts in the way we treat blood cancers, particularly in the field of cancer immunotherapy. Cancer treatment is moving towards a more personalised approach.
In the last ten years alone, there has been exponential progress in checkpoint inhibitors, CAR-T cells and even exciting advances, such as the role of the gut microbiome, in the field of the original form of cancer immunotherapy - haematopoietic stem cell transplantation. These discoveries have already led to two Nobel Prizes - firstly in 1990 by Dr E Donnell Thomas for his pioneering work on bone marrow transplantation, and most recently this year’s Nobel Laureates, Drs James P. Allison and Tasuku Honjo, for their research on the CTLA-4 and PD-1 pathways. Along with CAR-T cells, it demonstrates our progressively deeper understanding of cancer pathways and the successful steps taken to create drugs that target specific sites. We are showing the world what an exciting and fast-moving field haematology is, and so for a patient who is diagnosed with a blood cancer, it gives them the hope that even if we can’t cure their disease today, we are taking steps every day in the right direction.
So how can haematology change the world? We are changing people’s views of what it means to have cancer. For patients, we are replacing fear with hope, and for clinicians and researchers in other specialities, we are leading by example how to individualise treatment of each person’s disease.
The era of treatments personalised to a patient’s genome is here and haematology is leading the way in this medical revolution. The NHS has recently announced the start of a national genomic medicine service at the fingertips of all clinicians, and over 10% of the indications in the national genomic test directory are for haematological conditions.
In haemato-oncology, we are using tumour genetics to choose more appropriate treatments and using genetically modified T cells to attack cancer cells with more precision than ever before. As more tumour genomes are sequenced, it will allow clinicians to rationalise treatments to only those required to treat that specific genotyped cancer as shown in a recent AML trial. In transfusion medicine we can use genotyping to determine antigens and prevent alloimmunisation, improving the outcome for many patients with transfusion reactions.
The cost of sequencing the genome is now less than £1000 and is continuing to decline; on the contrary, the cost of haematological drugs is extortionate and continuing to rise. Haematological malignancies are the fourth most expensive cancer, yet the NHS funding approval for the most expensive cancer drug in history, Chimeric antigen receptor T-cell therapy, was one of the fastest ever to be approved. A balance needs to be found to use genomics to rationalise treatments, treating patients more cost-effectively and keeping treatment accessible for all, avoiding spiral healthcare costs, affordable only to a few.
Haematology can demonstrate the efficacy and efficiency of genomics in the field of medicine and if personalised medicine is implemented well, it will change the world by bringing personalised medicine into everyday medical practice. Genomics has the potential to change the world; for the better or for the worse, the fate of this medical breakthrough is very much in the hands of the haematologists.