Impact case study database

Marked Improvement in Treatment Options for People with MPNs.

The QUB Haematology group has had a major impact on patient management at different levels. At local Northern Ireland (NI) level, in the last 10 years approximately 120 patients (Figures from Northern Ireland Cancer Trials Network) have entered into MPN trials giving them the opportunity to receive new and state-of-the-art treatment and the most advanced investigation of their disease [5.1]. These are rare disorders and it is usually only patients, who are intolerant or refractory to first line treatments, are eligible for trials, therefore providing these patients with a treatment option that is not routinely available as part of standard care.

With a stable population of approximately 200 MPN patients in the greater Belfast area and referrals from all of NI, the number entering trials represents a substantive proportion of the MPN population in NI. All patients with MPNs in NI are referred to the myeloid multi-disciplinary meeting (MDM) in Belfast Health and Social Care Trust or via their local MDM to this meeting for opinion on their disease and thus are referred for trials as appropriate.

At national and international level, this work has led to new and improved treatments for patients with MPNs. The MAJIC trial has shown that ruxolitinib is of benefit second line in the treatment of PV improved response rates and significant reduction of symptoms including itch, fatigue, night sweats, early satiety weight loss and bone pain [5.2], while in ET it only helped with disease related symptom control [5.3].

Ruxolitinib has been marketed under the brand name Jakafi® (US name)/Jakavi® (elsewhere name). For the twelve months ended December 31, 2019, net product revenues of Jakafi® were USD1,700,000,000 [5.4]. For the first three quarters of 2020 (finishing in 30 September 2020), net product revenues of Jakafi® were USD1,870,000,000 [5.4].

.

In the multinational trial of vorinostat in MPNs, the treatment was effective but due to the side effect profile, the company did not take it forward as a treatment option. This avoided the costs of further development, which can be as much as GBP500,000,000. In contrast, as a result of the phase II trial, givinostat is being developed further. The Vice President Research and Development of Italfarmaco states that

“*Italfarmaco S.p.A based on the results…of the trials conducted in PV in which Prof McMullin actively worked, decided to continue the development program in givinostat in PV…A long term Phase II study is currently ongoing in Europe (NCT01761968)”* [5.5].

Thus, the group’s work on trials in MPNs brings practice-changing benefits to patients with improvements and rationalisation of therapy. The data from McMullin’s MPN trials contributed to the development and publication of a new prognostication tool, published in 2018, which allows patients’ clinical, laboratory and molecular data to be entered, resulting in an individual prediction of likely survival and risk of complications at any particular time point [5.6]. Commenting on the importance of the prognostication tool, the Editor of the MPN Forum stated that,

“Classification and Personalized Prognosis in Myeloproliferative Neoplasm, is a landmark document in the history of MPNs, reminiscent of William Dameshek’s “Some Speculations on the Myeloproliferative Syndromes,” (Blood, 1951)” [5.7].

Lower Costs for Health Systems

The MAJIC trial showed that ruxolitinib was not effective second line for the treatment of ET. As such, this would represent a potential cost saving to the NHS of about GBP7,000,000 per year (GBP44,000 per treatment and a conservative estimate of 160 refractory/intolerant high –risk ET patients) (Cost from NICE guidance TA386).

In the primary thrombocythaemia -1 trial (PT-1), the largest randomised trial in this disorder in the world; it was shown that hydroxycarbamide chemotherapy was not of benefit to intermediate risk patients (previously standard practice). This changed practice so that patients under the age of 60 with no high-risk features are no longer treated with the cytotoxic hydroxycarbamide (which causes increased skin cancers and may have a role in progression to acute leukaemia with attendant morbidity, costs and years of life lost). This is also a saving to the NHS as many patients are spared exposure to a drug which would cause complications requiring further treatment and associated costs [5.8].

Professor of Haematology and Clinical Director at Guys and St Thomas’ Hospitals in London confirmed the benefit to the NHS:

*“ Professor McMullin has been at the forefront of progress nationally and internationally in the understanding of the genetic basis of these disorders as well as in developing novel approaches to therapy. She has led, analysed & published enormous clinical trials which have defined and refined treatment approaches, allowing appropriate risk stratification and actually leading to savings in the NHS drug budget. She has also been at the forefront of development/approval of novel agents for MPNs” [5.8].**

Development of Treatment Guidelines from Trial Results

The evidence base from the MPN clinical trials was evaluated by various guideline writing groups and is the basis for recommendations in national and international guidelines for patient management. Prof. McMullin has led and contributed to guidance for the management of PV, ET and MF most recently extensively revising and publishing new guidelines for the management of PV and erythrocytosis for the British Committee for Standards in Haematology [5.9].

The guideline for the diagnosis and management of polycythaemia vera was the recipient of the British Journal of Haematology editors pick Top Guideline 2018. These guidelines are all open access on the British Society for Haematology website and are extensively used for the management of MPN on a daily basis in the UK and worldwide. Thus, they have a major impact on patient management and are referenced in treatment guidelines in English health trusts e.g. in London, Northern Cancer Alliance, West Essex and Merseyside & Cheshire [5.9]. The guidelines for the diagnosis and management of polycythaemia vera were downloaded over 22,000 times in 2019.

Data from the trials above contributed to the evidence for formulation of the European LeukemiaNet guidelines which are widely used across Europe and beyond by treating clinicians and as the gold standard for response in clinical trials [5.10]. Prof McMullin was also a member of the group who evaluated the evidence and wrote the guideline.

In summary, the work of the QUB Haematology group in trials of MPNs and related laboratory research has had major impacts on the treatment and management of MPNs.