Crucible Prize

Wasn’t that the goal—living longer? As centenarians become increasingly common, ageing research is challenging assumptions about the inevitability of decline. What does this mean for haematology? Is it time to redefine expectations and, controversially, should we be doing more?

Lessons may lie at the opposite end of the spectrum: neonatal care. Advances in neonatology have pushed viability to as early as 22 weeks, driven by technological leaps and a willingness to innovate. (McBain, 2024) Many very premature neonates now grow up to lead fulfilling lives. Neonatal care also demonstrates the value of minimising unnecessary tests and hospitalisation through judicious testing and community-based care. Yet, these advances come with a cost. Some ex-NICU patients are left with profound neurological and physical disabilities, requiring lifelong care and placing extraordinary demands on families. This raises difficult questions: What quality of life justifies costly interventions? How do we navigate informed consent amid expanding possibilities?

These cautionary lessons must guide haematology’s response to ageing. Neonatology highlights the value of family involvement, community care, and restrained testing while warning against over-intervention. Promoting advance care planning, strengthening communication, expanding community haematology services, and critically reassessing testing could transform patient experiences and optimise resources.

Paediatrics and geriatrics share a history of exclusion from clinical trials. Haematology must ensure elderly populations are included in research, enabling evidence-based risk/benefit decisions.

Adapting to an ageing population demands introspection. By balancing caution with innovation, reforming service structures, and rethinking trials, haematology can better meet the needs of ageing patients without overreach.

References

1.       McBain, S. (2024). ‘‘Look, they’re getting skin!’: are we right to strive to save the world’s tiniest babies?’, The Guardian, 19 November. Available at: https://www.theguardian.com/society/2024/nov/19/look-theyre-getting-skin-the-moral-challenge-of-saving-the-worlds-tiniest-babies (Accessed: 30 January 2025)

“Brexit means Brexit” Theresa May.

The UK has fallen behind in commercial based clinical trials participation, falling from 4^th to 10^th worldwide in recruitment to phase 3 trials from 2017 to 2021 (1). Lord O’Shaughnessy’s review describes the MHRA clinical trial process as “slow” and “bureaucratic” (2).

The Medicines and Healthcare products Regulatory Agency (MHRA) is now the standalone medicines and medical devices regulator of the United Kingdom (UK). However Northern Ireland (NI) remains under European Union (EU) pharmaceutical law (3). 

Brexit enables the UK to collaborate with regulatory procedures outside the EU, notably the United States (US) Food and Drug Administration (FDA). Accelerated approval of imatinib for Chronic myeloid leukaemia by the US FDA facilitated worldwide use (3). But accelerated approval processes bring inherent dangers.

Following withdrawal from EU processes the UK joined Project Orbis, coordinated by the US FDA. Osirmetinib, approved through Project Orbis, saw approval in Great Britain before NI (3) due to the legislative differences brought about by Brexit. Accelerated approval processes, particularly those used by US FDA, base approval on only surrogate end points (4).  Data shows medications frequently remain within clinical guidance despite confirmatory trials showing no clinical benefit in primary end points (5). Does this call into question the safety of accelerated approval processes for patients?

The consequences of the UK government prioritising time and resources sourcing alternative approval relationships contributes to the socio-economic disparity within the nations of the UK. What does the future hold for drug availability for haematology patients?

References:

1. The Association of the British Pharmaceutical Industry. Rescuing patient access to industry clinical trials in the UK [Internet]. 2023 [cited 2024 Jan 7]. Available from: https://www.abpi.org.uk/publications/rescuing-the-uk-industry-clinical-trials/
2. O’Shaughnessy, Lord. Commercial clinical trials in the UK: The Lord O’Shaughnessy review – final report [Internet]. UK Government ; 2023 [cited 2024 Jan 8]. Available from: https:// www.gov.uk/government/publications/commercial-clinical-trials-in-the-uk-lord-oshaughnessy- review/commercial-clinical-trials-in-the-uk-the-lord-oshaughnessy-review-final- report#part-4-implementing-these-recommendations
3. Lythgoe MP, Krell J, Bower M, Murphy R, Marriott J, Blagden SP, Aggarwal A, Sullivan R. From the European Medicines Agency to Project Orbis: new activities and challenges to facilitate UK oncology drug approval following Brexit. The Lancet Oncology. 2023;24(4). doi: 10.1016/S1470-2045(22)00701-X.
4. Lythgoe MP, Sullivan R. Project Orbis: The UK experience after 1 Year. The Lancet Oncology. 2022; 23(8):978–81. doi:10.1016/s1470-2045(22)00377-1
5. Gyawali B, Rome BN, Kesselheim AS. Regulatory and clinical consequences of negative confirmatory trials of Accelerated Approval Cancer Drugs: Retrospective observational study. BMJ. 2021; doi:10.1136/bmj.n1959

Whilst haematological research has become increasingly advanced, we still lag behind when interrogating the decisions that underpin this research. Here, we can learn from historiography. Historiography is the history of history; it looks not at an event itself but considers how it was studied, the writers’ biases, and even why the event was studied at all.

Like historiographers we too must ask about how something was studied, considering not just the methodology of any single study but the shifts in methodology across multiple studies, such as increasing use of PFS rather than OS^{1, 2}. We too must ask about bias, not just within studies, but external to this, in our choice of research and study design, and even in who is able to take part in research³.

And most importantly, we too must ask why something was studied. History is shaped by ‘turns’ – shifts in the lens through which it is analysed. These shifts are rooted within the societal ideas of the day, and what haematologists study is shaped by the same winds - we need only look at sickle cell disease, which for many years was underfunded and under researched because of institutional racism and a western-centric research focus^{4, 5}. The other great determinant of research focus is funding, often provided by a relatively small number of pharmaceutical companies; a system which inevitably sways attention towards more commercially profitable research.  

We want to believe in science as objective but we do ourselves and, more importantly, our patients a disservice if we do not look deeper. And if we want to continue to improve the treatment of those patients it is essential that, like historiographers, we examine the forces which shape our research and which, ultimately, determine the data upon which we rely.

1. Del Paggio JC, Berry JS, Hopman WM, et al. Evolution of the Randomized Clinical Trial in the Era of Precision Oncology. JAMA Oncol. 2021;7(5):728-734. doi:10.1001/jamaoncol.2021.0379
2. Kovic B, Jin X, Kennedy SA, et al. Evaluating Progression-Free Survival as a Surrogate Outcome for Health-Related Quality of Life in Oncology: A Systematic Review and Quantitative Analysis. JAMA Intern Med. 2018;178(12):1586–1596. doi:10.1001/jamainternmed.2018.4710
3. Tanne J H. White male authors still dominate top academic medical publishing, two studies report BMJ 2022; 377 :o1044 doi:10.1136/bmj.o1044
4. Farooq F, Mogayzel PJ, Lanzkron S, Haywood C, Strouse JJ. Comparison of US Federal and Foundation Funding of Research for Sickle Cell Disease and Cystic Fibrosis and Factors Associated With Research Productivity. JAMA Netw Open. 2020;3(3):e201737. Published 2020 Mar 2. doi:10.1001/jamanetworkopen.2020.1737
5. Mahase E. Sickle cell disease: inquiry finds serious care failings and racism towards patients BMJ 2021; 375 :n2782 doi:10.1136/bmj.n2782

Physicians of the past who often imposed harmful, unproven treatments are scorned by modern medics and their patients pitied. However, a recent BMJ project reviewed 3,000 current medical practices finding half to be of uncertain benefit and 15% to be harmful.¹

In haematology, there are numerous practices that are incompatible with a rational approach to medicine. We have taken up academic positions that are supported by rhetoric but not by evidence and are in fact contradictory and illogical.

Firstly, we use assumption of benefit to adopt powerful treatments unsupported by evidence and with a real risk of harm such as anticoagulant reversal and granulocyte infusions.^2,3 We continue harmful practices such as CNS prophylaxis for lymphoma because we have no gold-standard evidence to refute them despite the best available evidence showing no benefit.^4,5 In these situations, we show limited appetite to do proper trials. We use these treatments as we feel we have to do something but in so doing, contravene primum non nocere. Furthermore, we often ignore what matters most to patients - quality of life⁶ - focusing instead on clinically meaningless changes in objective parameters.⁷ Worst of all, we collaborate with pharma in the exploitation of patients for pointless, low-priority trials such as those in premalignancy^8,9 and randomised controlled trials with suboptimal control arms.¹⁰    

By the middle of the century, haematologists will reflect on our time with sadness at wasted opportunities to learn from and ameliorate suffering. However, by 2050 I am optimistic that we will have organised ourselves to better pursue the truth and advocate for patients. We will stop adopting unproven therapies and demand better evidence, we will say no to pointless or unethical trials, prioritise where we expend our energy and patients’ risk, and regain independence from pharma.

1. Clinical evidence | The BMJ [Internet]. [cited 2021 Nov 30]. Available from: https://www.bmj.com/specialties/clinical-evidence
2. National Institute for Health and Clinical Excellence. Appraisal consultation document: Andexanet alfa for reversing anticoagulation. 2020;1–13.
3. Pagano MB, Morton S, Cohn CS, Gross S, Kutner J, Lewin A, et al. An International Registry of Granulocyte Transfusions. Transfus Med Hemotherapy. 2018;45(5):318–22.
4. McKay P, Wilson MR, Chaganti S, Smith J, Fox CP, Cwynarski K. The prevention of central nervous system relapse in diffuse large B-cell lymphoma: a British Society for Haematology good practice paper. Br J Haematol. 2020;190(5):708–14.
5. Bobillo S, Joffe E, Sermer D, Mondello P, Ghione P, Caron PC, et al. Prophylaxis with intrathecal or high-dose methotrexate in diffuse large B-cell lymphoma and high risk of CNS relapse. Blood Cancer J. 2021;11(6):5–10.
6. Haslam A, Herrera-Perez D, Gill J, Prasad V. Patient Experience Captured by Quality-of-Life Measurement in Oncology Clinical Trials. JAMA Netw Open. 2020;3(3):1–19.
7. Fenaux P, Platzbecker U, Mufti GJ, Garcia-Manero G, Buckstein R, Santini V, et al. Luspatercept in patients with lower-risk myelodysplastic syndromes. N Engl J Med. 2020;382(2):140–51.
8. Mateos M-V, Hernández M-T, Giraldo P, de la Rubia J, de Arriba F, Corral LL, et al. Lenalidomide plus Dexamethasone for High-Risk Smoldering Multiple Myeloma. N Engl J Med. 2013;369(5):438–47.
9. Langerbeins P, Zhang C, Robrecht S, Cramer P, Fürstenau M, Al-Sawaf O, et al. The CLL12 trial: Ibrutinib versus placebo in treatment-naïve, early stage chronic lymphocytic leukemia. Blood [Internet]. 2021 Nov 10 [cited 2021 Nov 30]; Available from: https://pubmed.ncbi.nlm.nih.gov/34758069/
10. Hilal T, Sonbol MB, Prasad V. Analysis of Control Arm Quality in Randomized Clinical Trials Leading to Anticancer Drug Approval by the US Food and Drug Administration. JAMA Oncol. 2019;5(6):887–92.

On the day that you started on your training path to where you are today, you unwittingly started on a journey to learn the art of a new language – the language of medicine. From there you have now flourished into someone who uses this complicated language fluently and expertly. This skill took years, perhaps decades, to truly master. Medical jargon allows for efficient and clear discussions to be had between medical professionals and is critically important in this respect.

Now imagine that you are a person who has suddenly become very unwell and you are being immersed into this language with absolutely no prior training or interest in the subject. In fact, you wish you didn’t have to hear any of this. You feel really ill – the worst you’ve ever felt in your life - and just want to go to sleep and let this all wash over your head. You’re being hit with a barrage of scary-sounding words that you don’t know. They said “acute” - you think that means painful… or does it mean small? You don’t even have the energy to ask.

Linguistics theorises that jargon has two main effects, the first being to increase efficiency of communication. However, the second is to exclude outsiders who do not have prior understanding of the topic being discussed. This unfortunate side-effect is causing a rift between haematologists and patients which can only be bridged by conscious attempts to simplify communication based on our audience.

As haematological treatment options become more plentiful and advanced, the language we use becomes more complicated by the day. I propose that haematology learns this simple lesson of the unwanted effects of jargon to allow patients to join the conversation with us.

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

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.