Better diagnosis and treatment for patients with myeloproliferative neoplasms
Submitting InstitutionKing's College London
Unit of AssessmentClinical Medicine
Summary Impact TypeHealth
Research Subject Area(s)
Medical and Health Sciences: Cardiorespiratory Medicine and Haematology, Clinical Sciences
Summary of the impact
Myeloproliferative neoplasms (MPN) are a group of blood disorders that
affect more than 9,000 people in the UK every year. King's College London
(KCL) research on the biology, diagnosis and treatment of MPN has had the
following significant impacts:
- International criteria for diagnosing MPN were revised to incorporate
testing for specific mutations.
- The treatment of patients with two specific types of MPN, essential
thrombocythaemia and myelofibrosis, has changed and been incorporated
into national and international guidelines. Changes to treatment of
essential thrombocythaemia are saving the NHS an estimated £20
million/year while the first specific therapy for myelofibrosis - a drug
called ruxolitinib — has been introduced and is benefitting patients.
- International guidelines for the management of pregnant women with MPN
have been changed based on KCL research.
MPN: People with MPN make far too many blood cells, but these are
mostly defective and not able to do their job properly. The specific type
of MPN depends on whether too many red blood cells, white blood cells, or
platelets are being made. As the number of extra blood cells increases,
the patients run an increased risk of strokes, heart attacks and blood
clots, as well as an increased risk of acute leukaemia. The result is that
their quality of life deteriorates and they are likely to die early.
Treatment is based on the type of MPN the patient has, since some are more
aggressive than others. This means it is important to diagnose MPN
correctly in order to plan treatment.
KCL research to improve the diagnosis of MPN: The research has
been led by Professor Claire Harrison (KCL and Guy's and St Thomas'
Hospitals [GSTT], 2001-present). Biological analyses originally performed
by Professor Harrison at University College London Hospitals (UCLH) showed
that essential thrombocythaemia, one of the six types of MPN, is not
always a clonal disorder — it does not always derive from uncontrolled
reproduction of a single aberrant cell, as previously thought (1). The
research showed that when the cause of essential thrombocythaemia was
non-clonal, patients had less risk of thrombosis.
After moving to KCL, Professor Harrison and her colleagues together with
collaborators in Cambridge analysed the prevalence and clinical impact of
genetic mutations in a large group of MPN patients (2,3,4). Samples were
generated at KCL and in Cambridge, laboratory work was performed in
Cambridge and jointly analysed at KCL. This research provided important
biological insights regarding specific mutations in a protein called JAK,
that led to changes to international diagnostic and treatment criteria.
Work directed by Professor Harrison with collaborators in Cambridge, and
performed at KCL/GSTT, systematically analysed bone marrow biopsies from
MPN patients. This research demonstrated critical inadequacies in the
World Health Organization (WHO) diagnostic criteria in use at the time
(5). The researchers also discovered novel prognostic features for
predicting likely outcomes for patients (6).
Clinical trials that demonstrated superior treatments: The Medical
Research Council Primary Thrombocythaemia 1 (MRC-PT1) trial which started
in 1997 was developed at KCL/GSTT and in Cambridge. Professor Harrison
joined the trial team as joint leader in 2001 (based at KCL), and has
joint oversight of the trial and the scientific and clinical work arising
from it. MRC-PT1 comprises three clinical trials, two of which are still
ongoing. The first trial was reported in 2005 (7) and showed that
hydroxyurea and aspirin were superior to anagrelide and aspirin in
treating high- risk essential thrombocythemia.
Novel treatment for myelofibrosis: KCL researchers led the
European phase III trial COMFORT II, one of two first-ever phase III
trials for drugs treating myelofibrosis, another MPN. This trial was among
the most significant trials of novel drugs known as JAK (or janus kinase)
inhibitors (8). Professor Harrison led study design, data collection,
interpretation and publication of findings from this trial. The trial
evaluated the JAK inhibitor ruxolitinib and showed it prolonged the life
of patients with myelofibrosis. This was the first time that any drug had
been shown to do this. The trial was reported in the New England
Journal of Medicine in 2012 and directly contributed to the
approval, in 2012, of ruxolitinib as the first targeted therapy for
Clinical research to improve the management of MPN in pregnancy:
KCL researchers analysed half of all reported cases worldwide of another
MPN, polycythaemia vera (9), as well as cases of idiopathic myelofibrosis
(10), in pregnant women. They showed that there were appreciable negative
health effects for both mother and foetus unless the mother received
aggressive management to normalise blood parameters. They proposed a
management strategy which has been adopted in treatment guidelines
References to the research
The work in papers 2-7 was carried out in collaboration with Cambridge
University. Professor Harrison was co-chief investigator for the research
published in papers 4-7. Co-author Dr Wilkins and Dr van der Walt are also
1. Harrison CN, Gale RE, Machin SJ, Linch DC. A large proportion
of patients with a diagnosis of essential thrombocythemia do not have a
clonal disorder and may be at lower risk of thrombotic complications. Blood
2. Campbell PJ, Scott LM, Buck G, Wheatley K, East CL, Marsden JT, Duffy
A, Boyd EM, Bench AJ, Scott MA, Vassiliou GS, Milligan DW, Smith SR, Erber
WN, Bareford D, Wilkins BS, Reilly JT, Harrison CN, Green AR;
United Kingdom Myeloproliferative Disorders Study Group; Medical Research
Council Adult Leukaemia Working Party; Australasian Leukaemia and Lymphoma
Group. Definition of subtypes of essential thrombocythaemia and relation
to polycythaemia vera based on JAK2 V617F mutation status: a prospective
study. Lancet 2005;366:1945-53.
3. Scott LM, Tong W, Levine RL, Scott MA, Beer PA, Stratton MR, Futreal
PA, Erber WN, McMullin MF, Harrison CN, Warren AJ, Gilliland DG,
Lodish HF, Green AR. JAK2 exon 12 mutations in polycythemia vera and
idiopathic erythrocytosis. N Engl J Med. 2007;356:459- 68.
4. Campbell PJ, Baxter EJ, Beer PA, Scott LM, Bench AJ, Huntly BJ, Erber
WN, Kusec R, Larsen TS, Giraudier S, Le Bousse-Kerdilès MC, Griesshammer
M, Reilly JT, Cheung BY, Harrison CN, Green AR. Mutation of JAK2
in the myeloproliferative disorders: timing, clonality studies,
cytogenetic associations, and role in leukemic transformation. Blood
5. Wilkins BS, Erber WN, Bareford D, Buck G, Wheatley K, East CL, Paul B,
Harrison CN, Green AR, Campbell PJ. Bone marrow pathology in
essential thrombocythemia: interobserver reliability and utility for
identifying disease subtypes. Blood 2008;111:60-70.
6. Campbell PJ, Bareford D, Erber WN, Wilkins BS, Wright P, Buck G,
Wheatley K, Harrison CN, Green AR. Reticulin accumulation in
essential thrombocythemia: prognostic significance and relationship to
therapy. J Clin Oncol. 2009;27:2991-9.
7. Harrison CN, Campbell PJ, Buck G, Wheatley K, East CL,
Bareford D, Wilkins BS, van der Walt JD, Reilly JT, Grigg AP, Revell P,
Woodcock BE, Green AR; United Kingdom Medical Research Council Primary
Thrombocythemia 1 Study. Hydroxyurea compared with anagrelide in high-risk
essential thrombocythemia. N Engl J Med. 2005;353:33-45.
8. Harrison C, Kiladjian JJ, Al-Ali HK, Gisslinger H, Waltzman R,
Stalbovskaya V, McQuitty M, Hunter DS, Levy R, Knoops L, Cervantes F,
Vannucchi AM, Barbui T, Barosi G. JAK inhibition with ruxolitinib versus
best available therapy for myelofibrosis. N Engl J Med.
9. Robinson S, Bewley S, Hunt BJ, Radia DH, Harrison CN. The
management and outcome of 18 pregnancies in women with polycythemia vera.
10. Tulpule S, Bewley S, Robinson SE, Radia D, Nelson-Piercy C, Harrison
CN. The management and outcome of four pregnancies in women with
idiopathic myelofibrosis. Br J Haematol. 2008;142:480-2.
Details of the impact
Marked improvements in diagnosis and treatment for people with MPN:
Improved diagnosis and treatment of MPN are the greatest impacts resulting
from this research. The existing WHO diagnostic criteria for these
disorders were difficult to interpret and were not applied consistently by
haemato-pathologists. KCL research contributed to changes in UK, European
and WHO guidelines for diagnosis as well as treatment. The research has
also lowered the costs of therapy, improved management of MPN in
pregnancy, and raised public awareness of MPN and MPN treatments.
Findings used to improve international diagnostic criteria: The
studies carried out by the KCL team together with collaborators in
Cambridge have radically changed the understanding (11) of MPN - as
neoplasms or clonal cancers rather than simply "disorders" - and
identified specific mutations and subtypes. As a direct result, WHO
improved and expanded its diagnostic criteria for MPN, incorporating the
JAK2 V617F mutation testing into diagnostic processes (12). More accurate
diagnosis directly affects patients, as correct diagnosis ensures that
they receive appropriate treatment and prognosis. Refining diagnostic
criteria and the criteria for assessing improvements (response criteria)
also leads to better standardisation of clinical trials, and makes it
easier to compare treatments.
Treatment guidelines influenced by KCL research: Findings of the
long-term Medical Research Council clinical trial MRC-PT1, which assessed
the value of a new treatment for essential thrombocythaemia (ET),
demonstrated that hydroxycarbamide with aspirin should be the first line
of treatment for ET rather than a newer, more expensive drug, anagrelide.
These have been incorporated into national and international treatment
New class of drugs developed for myelofibrosis and first JAK inhibitor
approved: Trials of a new class of drugs, JAK inhibitors, prompted
by the findings of the biological studies have paved the way for targeted
therapies. The KCL-led phase III trial, COMFORT II, showed that the JAK
inhibitor ruxolitinib prolonged the life of patients with myelofibrosis
(8). This is a major advance because patients with myelofibrosis have the
most symptoms and the worst prognosis among the different MPN. The US Food
and Drug Administration (FDA) approved ruxolitinib in November 2011 and
Europe approved it in 2012 (17,18). Ruxolitinib is the first approved
medication for myelofibrosis.
Lower costs for health systems: The research showing that
hydroxycarbamide is a more effective treatment than the more expensive
drug anagrelide for essential thrombocythemia (7) has altered management
of this disease and been estimated to save the NHS alone around £20
million/ year (£20k pa treatment costs and a conservative estimate of 1000
high risk ET patients). Since these changes have been incorporated into
international guidelines, this also means lower costs internationally.
Improved management of pregnant women with MPN: The work of KCL
researchers on pregnant women with polycythaemia vera and myelofibrosis
resulted in a new management strategy that has been taken up in treatment
guidelines nationally and internationally (13,14,15,16). The KCL
researchers were also instrumental in setting up a European Union-wide
reporting process to gather information on MPN in pregnancy, with the aim
of improving outcomes.
Improved awareness of MPN and patient advocacy: Professor Harrison
and her colleague at GSTT Dr Deepti Radia set up MPD Voice (19, 20), the
UK patient advocacy group for MPN to educate both physicians and patients.
MPD Voice has over 1500 members and the website receives over 100,000 hits
Sources to corroborate the impact
Improvements in diagnosis
- Barosi G, Birgegard G, Finazzi G, Griesshammer M, Harrison C,
Hasselbalch HC, Kiladjian J- J, Lengfelder E, McMullin MF, Passamonti F,
Reilly JT, Vannucchi AM and Barbui T. Response criteria for essential
thrombocythemia and polycythemia vera: result of a European LeukemiaNet
consensus conference. Blood 2009;113:4829-33. (Cites ref  p.
- Vardiman JW, Thiele J, Arber DA et al. The 2008 revision of
the World Health Organization (WHO) classification of myeloid neoplasms
and acute leukemia: rationale and important changes. Blood
2009;114:937-51. (Cites ref  p.940, ref  p.941))
International guidelines influenced by the work of KCL researchers
- Barbui T, Barosi G, Birgegard G et al. Philadelphia-negative
classical myeloproliferative neoplasms: critical concepts and management
recommendations from European LeukemiaNet. J Clin Oncol.
2011;29:761-70. (Cites ref  p.762, ref  p.764)
- Reilly JT, Mcmullin MF, Beer PA et al. Guideline for the
diagnosis and management of myelofibrosis. Br J Haematol.
2012;158:453-71 (Cites ref  p.454; ref  p. 460, ref  p.464, ref
- Harrison CN, Bareford D, Butt N et al. Guideline for
investigation and management of adults and children presenting with a
thrombocytosis. Br J Haematol 2010;149:352-75.
- Mcmullin MF, Reilly JT, Campbell P et al. Amendment to the
guideline for diagnosis and investigation of
polycythaemia/erythrocytosis. Br J Haematol 2007;138:821-22.
FDA and European approval for ruxolitinib as a treatment for
- US Food and Drug Administration. 2011. FDA approves first drug to
treat a rare bone marrow disease. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm280102.htm
- UK Medicines Information. 2012. New Drugs Online Report for
Public-facing communication about MPN
- MPD Voice is a registered UK charity under the auspices of Guy's and
St Thomas' Charity. www.mpdvoice.org.uk
- Spotlight on MPN - an international website on myeloproliferative
neoplasms, intended for patients and caregivers. http://www.spotlightonmpn.com/sompn/MPN/symptoms-and-management/what-are-the-symptoms.aspx