BSH Crucible Prize

The Crucible Prize is an innovative trainee-led initiative with a £1000 prize. The prize is open to doctors in training, nurses and other healthcare professionals (at any stage of their career). The aim of this session is to encourage reflection on what we do as healthcare providers, and why we do it.

The theme for BSH Virtual 2020 was "What lessons learnt during the COVID-19 pandemic should change future practice in haematology?”

The five best abstracts were selected for oral presentation at BSH Virtual 2020, which was held on 9-14 November 2020. Presentations were judged on the quality and originality of their content, presentation skills and response to questions.

The winner was Joshua Bomsztyk. 

Winner - Joshua Bomsztyk: A hospital avoidance strategy should be forefront in our minds

As we sit in the exacting classroom of COVID-19, with a ferocious and uncompromising viral teacher, the question of ‘lessons learnt’ might be considered premature. As we embark on a probable second wave and beyond, a particular lesson has stood out and should remain embedded in our psyche.

Undeniably, patient safety is the primary focus of our care. Haematologists are used to the idea of finely balancing the risk of treatment versus undesirable consequences. This pervades every decision surrounding chemotherapy, transfusion or anticoagulation. The benefit vs. risk conundrum.

The risk of a respiratory virus is also well recognised as the BSH guideline would attest[i]. With a mortality of up to 33%[ii] in the context of allogeneic transplant, the impact of community acquired respiratory viruses (CARV) should not be underestimated.

However, the concept of social distancing and hospital avoidance have not been considered as preventative strategies prior to COVID-19. The delivery of haematology services had shifted to large volumes of patients attending outpatient clinics and day units for review and treatment.

The lesson of COVID-19 ought to be a focus on hospital avoidance. The design of newer therapies should focus on this strategy. The development of oral and subcutaneous therapies should not be merely seen as a convenience but as a patient safety issue. COVID-19 has reminded us that hospitals are dangerous places. The challenge is to progress these novel working styles for the sake of patient safety.

[i] Fiona L Dignan et al. BCSH/BSBMT/UK clinical virology network guideline: diagnosis and management of common respiratory viral infections in patients undergoing treatment for haematological malignancies or stem cell transplantation. April 2016

[ii] Versluys AB, Boelens JJ. Morbidity and Mortality Associated With Respiratory Virus Infections in Allogeneic Hematopoietic Cell Transplant: Too Little Defense or Harmful Immunity? Front Microbiol. 2018;9:2795. Published 2018 Nov 21. doi:10.3389/fmicb.2018.02795

Kate Rogers and Naomi Dean: The elephant in the room: Escalation of care and DNACPR

Limitations of treatment and escalation decisions on admission during the COVID-19 outbreak were a pertinent discussion with haematology patients undergoing chemotherapy and urgent stem cell transplants. During the peak of COVID-19, it was made clear to patients that there may not be intensive care capacity if they become critically unwell. This was of course a very difficult conversation for patients and staff. 

This poses the question – should we be having these conversations with patients during the treatment consent process, involving ceilings of care and DNA-CPR discussion and should it be routinely discussed to try and normalise the conversation to prevent the last minute panic when a patient deteriorates?

What would be the benefits of this?

  • Prevent difficult conversations with family members should a patient deteriorate. Patient and families to have time to discuss wishes in the event of an emergency situation
  • Staff caring for the patient would have a clear pathway for ceilings of care treatment and if a patient was to deteriorate out of hours, there would already be a plan of care in place

What would be the disadvantages?

  • Taking hope away from patients
  • So many patient cohorts – one rule doesn’t fit all

What process would need to take place?

  • Absolute agreement by consultant teams
  • CNS support
  • Ward staff support
  • Clear documentation coherent with inpatient and outpatient communication
  • Consistency in care

Conversations with patients about haematological conditions tend to air on the way of positivity and often, we avoid the elephant in the room – Am I going to die from this disease? Often, patients look to us as health care professionals to be frank and truthful about the outlook and we believe that this is an area of practice that as a group of haematology professionals we can all learn from for future practice.

 

Marquita Camilleri - Clinical trial during COVID-19: Embracing the move towards patient-centric clinical research

The COVID-19 pandemic has disrupted clinical research worldwide, affecting up to 732,176 participants across England[1]Many are haemato-oncology patients[2], who were shown to be particularly vulnerable to COVID-19 infection[3], and in need of shielding. Self-isolation and physical distancing measures inevitably led to most clinical trials halting recruitment, with actively enrolled patients either having their treatment modified, paused or stopped altogether due to difficulties in continuing under lockdown conditions[4]. Various guidelines were issued at unprecedented speed[5],[6],[7] to help stakeholders better manage trials during this pandemic – striking a balance between patient safety, maintaining trial integrity, and ensuring adherence to good clinical practice standards.

Remote healthcare access and service delivery was encouraged. Trial sponsors adapted protocols to facilitate remote assessment via telephone/video conferencing and performing investigations outside the site and in the patient’s local community with more flexible test scheduling. Despite reluctance in allowing patients to self-administer subcutaneous chemotherapy at home, investigational medicinal products were sometimes delivered through community facilities like Healthcare at Home, with courier services used to distribute oral medications, including cytotoxics. Wider adoption of electronic case report forms (eCRF) replacing paper versions enabled faster data collection, preserving data integrity through more efficient data cleaning and improved data management processes.

Although meant to be temporary, many physicians and patients hope that some of these adaptations continue beyond the pandemic[8]. Also, longstanding concerns that clinical trial populations insufficiently resemble real-world patients can be addressed by having more inclusive patient-centric study designs that better reflect real-world treatment provision and maximise translatability to routine practice. 

The risks posed to haematology patients by COVID-19 demand rapid structural changes in healthcare delivery, with positive trends encouraged to continue long-term. Given the considerable uncertainty around duration of restrictions, an immediate critical reassessment of trial methodology is essential to ensure resilience in clinical research and optimise patient-centred care.

[1] National Institute for Research Health (NIRH) Annual Statistics. Available from:  https://www.nihr.ac.uk/about-us/our-contribution-to-research/research-performance/annual-statistics.htm [Accessed 10th September 2020]

[2] The Association of the British Pharmaceutical Industry. Clinical Trials – How the UK is Researching Clinical Trials of the Future (Autumn 2019).  Available from:  https://www.abpi.org.uk/media/7607/rmi-0128-0919-clinical-trials-report.pdf [Accessed 10th September 2020]   

[3] Williamson E.J., Walker A.J., Bhaskaran, K. et al. Factors associated with COVID-19-related death using OpenSAFELY. Nature. 2020; 584: 430–436. Available from: https://doi.org/10.1038/s41586-020-2521-4.

[4] Van Dorn, A.  COVID-19 and readjusting Clinical Trials. The Lancet. 2020; 396(10250):523-524.

[5] European Medicines Agency and Heads of Medicines Agency. Guidance on the Management of Clinical Trials During the COVID-19 (Coronavirus) Pandemic. Version 3 (28/04/2020) Available from: https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/guidanceclinicaltrials_covid19_en.pdf [Accessed 28th August 2020].

[6] European Medicines Agency. Points to consider on implications of Coronavirus disease (COVID-19) on methodological aspects of ongoing clinical trials. EMA/158330/2020 Rev. 1 3 (26 June 2020). Available from: https://www.ema.europa.eu/en/documents/scientificguideline/points-consider-implications-coronavirus-disease-covid-19-methodologicalaspects-ongoing-clinical_en-0.pdf. [Accessed 28th August 2020]. 

[7] Medicines and Healthcare products Regulatory Agency. Managing Clinical Trials During Coronavirus (COVID-19). Available from: https://www.gov.uk/guidance/managing-clinicaltrials-during-coronavirus-covid-19 [Accessed 28th August 2020].

[8] Doherty G.J., Goksu M. and de Paula B.H.R. Rethinking cancer clinical trials for COVID-19 and beyond. Nature Cancer. 2020; 1:568–572. Available from: https://doi.org/10.1038/s43018-020-0083-x

Abdul Adamu: Home transfusion service may change future practice in haematology

The problem:

Responding to the difficult and challenging time that COVID-19 pandemic has brought to healthcare provision, such as difficulties to provides regular treatments to high risks and vulnerable transfusion dependent thalassemia patients during the national lockdown.

It became extremely concerned for our several thalassemia patients with complex medical problems that are considered high risk to travel to Whittington hospital clinics or outpatient Units for their regular scheduled transfusion. Many of these high risk patients were living far away from Whittington hospital, from 2 to 100 miles away. This became a serious problem for the haematology team to maintain the regular essentials treatment for these patients at this critical National lockdown time when they were instructed to be shielding at home from March 2020.

Purpose:

After a department meeting to discussed this problem, a contingency plans was developed and agreed to consider providing 'Home transfusion' in order to deliver the essential health care needs for the high  risk shielding thalassemia patients.

It became fully cleared that administering blood at home to the high risk thalassemia patients may be possible but can also be challenging.

Home transfusion service is very uncommon practice in the United Kingdom. However, this practice has been taking place in other countries. Therefore, COVID-19 pandemic triggered the needs to establish home transfusion services at Whittington hospital in order to provide the necessary treatment for our high risk thalassemia patients shielding at home.

Result:

Fourteen patients were identified and enrolled on the service. Since 24th March 2020 almost 200 home transfusions had taken place uneventfully. Patient’s care was maintained in their safe environment and the level of patient’s satisfaction remained high.

There is good evidence to support home transfusion service may change future haematology practice.

Wei Yee Chan: The COVID-19 pandemic: An unintentional opportunity to evaluate whether less is more

The COVID-19 pandemic brings challenges to delivering clinical care due to a range of factors: the generally immunocompromised patients, the shielding requirements, the need to protect those who had to receive treatment in-person and the staff who continued working. As the pandemic first gathered momentum, so did emails communicating clinical decisions to rationalise care. One unsurprising decision was for treatments which only prolong progression-free survival to be stopped. A comment from a colleague struck a chord, “well at least now we will know if as haematologists we are doing more harm than good”.

The concept of progression-free survival remains a double-edged sword. It has driven the innovation for new treatments in haematological diseases, of which a number are chronic. On the other hand, it has made haematologists focus on intervention that can be offered, rather than whether we should. Intervention almost always appear more attractive than not. And this is inevitably what is needed to prolong progression-free survival. Interventions include increasing the visits we expect patients to attend both in clinics and treatment appointments. The pandemic is an unintended opportunity for us to re-evaluate what the definition of haematological care and quality of life is, weighing up the additional time, costs, travel and exposure our patients take in order to access the care we recommend. We should pause and consider the impact even one routine clinic appointment has on our patients; a whole day often, waiting, when they could have been picking up their grandchildren, helping their sister run their new business, hiking up Snowdonia or caring for their spouse with metastatic cancer. Only time will tell, in our strive to offer more, whether we are doing good and not harm. Perhaps our patients’ attitudes to the rationale of the treatment they receive will evolve too.

The theme for the 2019 Crucible Prize was 'How can haematology change the world?'. The winner was Jennifer Darlow. 

Winner: Jennifer Darlow: Antimicrobial resistance: Biting the hand that feeds

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:

  1. With close collaboration with infection specialist colleagues, we can alter our prescribing habits to reduce antimicrobial resistance selection pressure whilst still treat patients appropriately.
  2. 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.
  3. 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.
Jessica Dunphy: Measurement of serum hepcidin: A future tool to reduce the global burden of iron deficiency anaemia?

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.

 

Megan Kell: Working towards universal healthcare: A role for haematology

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. 

  1. Publications UN. Sustainable Development Goals Knowledge Platform [Available from: sustainabledevelopment.un.org accessed 21/11/2018.
  2. 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]
  3. WHO. Trends in maternal mortality: 1990 to 2015. Geneva, 2015.
  4. 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]
  5. WHO. Global status report on blood safety and availability 2016. Geneva, 2017.
  6. 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
  7. 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]
Edmund Watson: A brave new world: Life after an allograft

“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.

Amelia Fisher: Advancing the global impact of haematology through genomic medicine

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.

References

  1. 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.
  2. 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
  3. Wu et al, Blood group genotyping goes next generation: featuring ABO, RH and MNS, ISBT Science Series, March 2018, 13(3):290-297.
  4. Miesbach et al, Gene therapy with adeno-associated virus vector 5–human factor IX in adults with hemophilia B, Blood 2018 131:1022-1031.
  5. Ribeil et al, Gene Therapy in a Patient with Sickle Cell Disease, The New England Journal of Medicine, March 2017, 376:848-855.
  6. Thompson et al, Gene Therapy in Patients with Transfusion-Dependent β-Thalassemia, The New England Journal of Medicine, April 2018, 378:1479-1493