Claire N Harrison

Belfast Health and Social Care Trust, Béal Feirste, N Ireland, United Kingdom

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Publications (134)1012.68 Total impact

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    ABSTRACT: Cancers result from the accumulation of somatic mutations, and their properties are thought to reflect the sum of these mutations. However, little is known about the effect of the order in which mutations are acquired. We determined mutation order in patients with myeloproliferative neoplasms by genotyping hematopoietic colonies or by means of next-generation sequencing. Stem cells and progenitor cells were isolated to study the effect of mutation order on mature and immature hematopoietic cells. The age at which a patient presented with a myeloproliferative neoplasm, acquisition of JAK2 V617F homozygosity, and the balance of immature progenitors were all influenced by mutation order. As compared with patients in whom the TET2 mutation was acquired first (hereafter referred to as "TET2-first patients"), patients in whom the Janus kinase 2 (JAK2) mutation was acquired first ("JAK2-first patients") had a greater likelihood of presenting with polycythemia vera than with essential thrombocythemia, an increased risk of thrombosis, and an increased sensitivity of JAK2-mutant progenitors to ruxolitinib in vitro. Mutation order influenced the proliferative response to JAK2 V617F and the capacity of double-mutant hematopoietic cells and progenitor cells to generate colony-forming cells. Moreover, the hematopoietic stem-and-progenitor-cell compartment was dominated by TET2 single-mutant cells in TET2-first patients but by JAK2-TET2 double-mutant cells in JAK2-first patients. Prior mutation of TET2 altered the transcriptional consequences of JAK2 V617F in a cell-intrinsic manner and prevented JAK2 V617F from up-regulating genes associated with proliferation. The order in which JAK2 and TET2 mutations were acquired influenced clinical features, the response to targeted therapy, the biology of stem and progenitor cells, and clonal evolution in patients with myeloproliferative neoplasms. (Funded by Leukemia and Lymphoma Research and others.).
    New England Journal of Medicine 02/2015; 372(7):601-12. · 54.42 Impact Factor
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    ABSTRACT: Ruxolitinib, a Janus kinase (JAK) 1 and 2 inhibitor, was shown to have a clinical benefit in patients with polycythemia vera in a phase 2 study. We conducted a phase 3 open-label study to evaluate the efficacy and safety of ruxolitinib versus standard therapy in patients with polycythemia vera who had an inadequate response to or had unacceptable side effects from hydroxyurea. We randomly assigned phlebotomy-dependent patients with splenomegaly, in a 1:1 ratio, to receive ruxolitinib (110 patients) or standard therapy (112 patients). The primary end point was both hematocrit control through week 32 and at least a 35% reduction in spleen volume at week 32, as assessed by means of imaging. The primary end point was achieved in 21% of the patients in the ruxolitinib group versus 1% of those in the standard-therapy group (P<0.001). Hematocrit control was achieved in 60% of patients receiving ruxolitinib and 20% of those receiving standard therapy; 38% and 1% of patients in the two groups, respectively, had at least a 35% reduction in spleen volume. A complete hematologic remission was achieved in 24% of patients in the ruxolitinib group and 9% of those in the standard-therapy group (P=0.003); 49% versus 5% had at least a 50% reduction in the total symptom score at week 32. In the ruxolitinib group, grade 3 or 4 anemia occurred in 2% of patients, and grade 3 or 4 thrombocytopenia occurred in 5%; the corresponding percentages in the standard-therapy group were 0% and 4%. Herpes zoster infection was reported in 6% of patients in the ruxolitinib group and 0% of those in the standard-therapy group (grade 1 or 2 in all cases). Thromboembolic events occurred in one patient receiving ruxolitinib and in six patients receiving standard therapy. In patients who had an inadequate response to or had unacceptable side effects from hydroxyurea, ruxolitinib was superior to standard therapy in controlling the hematocrit, reducing the spleen volume, and improving symptoms associated with polycythemia vera. (Funded by Incyte and others; RESPONSE ClinicalTrials.gov number, NCT01243944.).
    New England Journal of Medicine 01/2015; 372(5):426-35. · 54.42 Impact Factor
  • Claire N Harrison, Mary F McMullin
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    ABSTRACT: The differential diagnosis of haematological abnormalities, such as leucocytosis, erythocytosis, thrombocytosis or indeed anaemia, is wide and disarming. Here we report on significant updates in the differential diagnosis of erythrocyosis and thrombocytosis presenting a simplified schema for the clinician. We then move to discuss significant advances in this field which have followed a series of key molecular findings, most specifically those affecting the JAK/STAT pathway. © 2014 Royal College of Physicians.
    Clinical medicine (London, England) 12/2014; 14 Suppl 6:s66-70. · 1.69 Impact Factor
  • Leukemia 09/2014; · 9.38 Impact Factor
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    ABSTRACT: The discovery of somatic mutations, primarily JAK2V617F and CALR, in classic BCR-ABL1-negative myeloproliferative neoplasms (MPNs), has generated interest in the development of molecularly targeted therapies, whose accurate assessment requires a standardized framework. A working group, comprised of members from European LeukemiaNet (ELN) and International Working Group for MPN Research and Treatment (IWG-MRT), prepared consensus-based recommendations regarding trial design, patient selection, and definition of relevant endpoints. Accordingly, a response able to capture the long-term effect of the drug should be selected as the endpoint of phase II trials aimed at developing new drugs for MPNs. A time-to-event, such as overall survival, or progression-free survival or both, as co-primary endpoints, should measure efficacy in phase III studies. New drugs should be tested for preventing disease progression in MF patients with early disease in randomized studies, and a time to event, like progression-free or event-free survival should be the primary endpoint. Phase III trials aimed at preventing vascular events in PV and ET should be based on a selection of the target population based on new prognostic factors, including JAK2 mutation. In conclusion, we recommended a format for clinical trials in MPNs which facilitates communication between academic investigators, regulatory agencies and drug companies.Leukemia accepted article preview online, 25 August 2014 doi:10.1038/leu.2014.250.
    Leukemia 08/2014; · 9.38 Impact Factor
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    ABSTRACT: YKL-40 regulates vascular endothelial growth factors and induces tumor proliferation. We investigated YKL-40 before and after treatment with vorinostat in 31 polycythemia vera (PV) and 16 essential thrombocythemia (ET) patients. Baseline PV patient levels were 2 times higher than in healthy controls (P < 0.0001) and 1.7 times higher than in ET (P = 0.02). A significant correlation between YKL-40 at baseline and neutrophils, CRP, LDH, JAK2V617F and platelets in PV patients was observed, as well as a significantly greater reduction of YKL-40 levels in PV patients responding to therapy. YKL-40 might be a novel marker of disease burden and progression in myeloproliferative neoplasms.
    Leukemia Research 07/2014; · 2.69 Impact Factor
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    British Journal of Haematology 07/2014; · 4.94 Impact Factor
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    British Journal of Haematology 06/2014; · 4.94 Impact Factor
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    British Journal of Haematology 06/2014; · 4.96 Impact Factor
  • Sofia Galli, Donal McLornan, Claire Harrison
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    ABSTRACT: Introduction: In 2005, the JAK2 V617F mutation was identified and found to be highly prevalent in the 'Philadephia Chromosome-negative' Myeloproliferative neoplasms (MPN). This led to new diagnostic criteria for MPN in addition to the development of the first targeted therapy for myelofibrosis (MF), ruxolitinib . Areas covered: Ruxolitinib was approved within 5 years of 'first-in-man' trials; it has been assessed in two large Phase III trials, and to date, several thousand patients have been prescribed this drug. This article reviews the latest data from the Phase III trials concerning efficacy and safety in addition to post-authorisation data for this agent. Ruxolitinib is an extremely well-tolerated drug; it is associated with bruising, headaches, dizziness, anaemia and thrombocytopaenia. In addition, an augmented risk of infections has been documented. Expert opinion: Ruxolitinib has radically altered the therapeutic landscape for MF with demonstrated advantages over standard therapy, irrespective of JAK2 mutational status and a signal suggesting survival benefit. Other JAK inhibitors are also in late stages of development, although the furthest advanced has just been withdrawn due to cases of encephalopathy (not documented with ruxolitinib). This reminds the clinical community of the need for post-marketing surveillance of safety for these agents. Challenges ahead are identification of appropriate surrogates for survival benefit and perhaps how to best use ruxolitinib either alone or in combination with other therapies.
    Expert Opinion on Drug Safety 06/2014; · 2.74 Impact Factor
  • R.B. Goody, G.G. Hanna, C. Harrison
    Clinical Oncology 06/2014; 26:S5–S6. · 2.83 Impact Factor
  • Bruna Velosa Ferreira, Claire Harrison
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    ABSTRACT: The discovery of the activating mutation JAK2 V617F ushered a new era in MPN which included new diagnostic and prognostic criteria as well as a potential therapeutic target. JAK2 inhibition became a reality with first patients receiving drugs that targeted JAK2 in 2007 and was marked by the first approval in 2011 of Ruxolitinib a JAK 1 and 2-inhibitor to treat myelofibrosis (MF). In this article entitled “How many JAK inhibitors for myelofibrosis” we discuss JAK2 as a target, review briefly the benefits to patients with MF of JAK inhibition and highlight some of the differences between the number of JAK inhibitors currently being evaluated. Reflecting upon what we have learnt from the chronic myeloid leukemia field and for MF regarding disease complexity as well as individual patient factors including resistance we discuss why it is likely we will need several different agents with JAK inhibitory activity. The next chapter discusses combination therapies for myelofibrosis which is a logical step in both trying to cure this disease and improve patient outcome and toxicities with JAK inhibitors.
    Bailli&egrave re s Best Practice and Research in Clinical Haematology 06/2014; · 2.55 Impact Factor
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    ABSTRACT: The BCR-ABL1 negative myeloproliferative neoplasms (MPNs) are associated with an increased risk of both venous and arterial thromboembolic events. Thromboses may be the presenting clinical feature of an MPN or may occur during the course of the disease. Treatment comprises anticoagulant and antiaggregant agents as in non- MPN thromboses, and treatment of the particular MPN. The duration of anticoagulant treatment that is required for MPN thrombosis is unknown. This study was performed to survey the opinion of hematologists who treat patients with MPN regarding the duration of anticoagulation or antiaggregant therapy in patients in whom thrombosis is the presenting feature of MPN. Five clinical scenarios in which thromboembolism (cerebral vein thrombosis, pulmonary embolism, cerebrovascular accident, splanchnic vein thrombosis, portal vein thrombosis) was a presenting feature of MPN were created using a web-based tool and were sent by email to hematologists in Israel, Italy and England and to hematologists identified as key opinion leaders in the field of MPN. Physicians were asked to recommend duration of anticoagulation and/or aspirin use choosing from 4 alternatives provided. Seventy-three physicians responded to the survey. 42 physicians considered MPNs to be their main area of clinical interest, and 31 did not. 21 physicians saw more than 20 MPN patients per week, and 50 physicians had been in hematology practice for more than 10years. Responses regarding the duration of anticoagulation and/or the use of aspirin varied for all of the clinical vignettes. Neither physician area-of-interest, volume of MPN patients treated nor years in practice were related to the responses obtained. This study demonstrates that hematologists, including those specializing in MPNs, lack consensus in their approach to the long-term treatment of thromboses as the presenting feature of an MPN. Controlled clinical studies are needed to inform appropriate decision making in this area.
    Thrombosis Research 05/2014; · 2.43 Impact Factor
  • Claire N Harrison, Michael Bennett
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    ABSTRACT: Introduction: Myelofibrosis (MF), classified as a myeloproliferative neoplasm (MPN) by the WHO, is an orphan disorder in which therapeutic strategies have been slow to develop, likely due to a lack of understanding of the disease pathogenesis. Areas covered: In this article, progress dating from the seminal descriptions of a highly prevalent mutation in the JAK2 gene, JAK2 V617F in 2005 is reviewed. This article describes, in brief, the current status of our scientific understanding in this field and reflects on how this is now stimulating a change in therapeutic strategies for patients. Information was gathered from a review of the medical literature and conference abstracts, in particular the most recent American Society of Haematology meeting. Each novel therapy is described, in turn, and then future strategies for evaluating this plethora of potential agents are discussed. Concerns are highlighted regarding the difficulty in comparing some data and the lack of a clear surrogate marker such as BCR/ABL transcript levels as used in cell-mediated lympholysis. Expert opinion: Overall, for the field of MF and MPNs as a whole, this is a time of unprecedented interest, activity, and a very real opportunity to make significant inroads into this difficult disorder. The approval of ruxolitinib demonstrates already the great potential for benefit in this field. However, economic constraint also impinges upon its reimbursement and collection of proper data with regard to both disease burden and health benefit is necessary to ensure patient access after clinical efficacy and safety approval.
    Expert Opinion on Orphan Drugs. 04/2014; 2(4).
  • Claire Harrison, Donal McLornan
    Hematology (Amsterdam, Netherlands) 03/2014; 19(2):120-1. · 1.33 Impact Factor
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    ABSTRACT: Symptom burden in myeloproliferative neoplasms (MPNs) is heterogeneous even amongst patients within the same MPN diagnosis. Utilizing cluster analysis from prospectively gathered symptom burden data in 1470 international patients with essential thrombocythemia (ET), polycythemia vera (PV), or myelofibrosis (MF), we assessed for the presence of clusters and relationship to disease features and prognosis. In myelofibrosis (4 clusters identified), clusters significantly differed by DIPSS risk (p<0.001), leukopenia (p=0.009), thrombocytopenia (p<0.001) and spleen size (p=0.02). Although an association existed between cluster and DIPSS risk, high symptom burden was noted in some low and intermediate-1 risk MF patients. In PV (5 clusters identified), total symptom score increased across clusters (p<0.001) but clusters did not significantly differ by PV risk or the risk assessment variable of age. Amongst ET patients (5 clusters identified), clusters differed by gender (p=0.04), anemia (p=0.01), and prior hemorrhage (p=0.047). Total symptom score increased across clusters (p<0.001) but clusters did not significantly differ by IPSET risk including the risk assessment variables. Significant symptom heterogeneity exists within each MPN subtype sometimes independent of disease features or prognosis.
    Blood 02/2014; · 9.78 Impact Factor
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    ABSTRACT: The JAK1/JAK2 inhibitor Ruxolitinib produced significant reductions in splenomegaly and symptomatic burden and improved survival in patients with myelofibrosis (MF), irrespective of their JAK2 mutation status, in two phase III studies against placebo (COMFORT I) and best available therapy (COMFORT-II). We performed a comprehensive mutation analysis to evaluate the impact of 14 MF-associated mutations on clinical outcomes in 166 patients included in COMFORT-II. We found that responses in splenomegaly and symptoms, as well as the risk of developing ruxolitinib-associated anemia and thrombocytopenia, occurred at similar frequencies across different mutation profiles. Ruxolitinib improved survival independent of mutation profile and reduced the risk of death in patients harboring a set of prognostically detrimental mutations (ASXL1, EZH2, SRSF2, IDH1/2) with an hazard ratio of 0.57 (95% CI:0.30-1.08) versus best available therapy. These data indicate that clinical efficacy and survival improvement may occur across different molecular subsets of patients with myelofibrosis treated with ruxolitinib.
    Blood 01/2014; · 9.78 Impact Factor
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    ABSTRACT: The international prognostic scoring system [IPSS] provides reliable risk assessment in patients with primary myelofibrosis (PMF). Recent clinical trials in PMF patients with intermediate-2 or high IPSS risk have shown a survival advantage of ruxolitinib over placebo (COMFORT-1) or best available therapy (COMFORT-2). Since crossover was allowed in these studies, we analyzed the cohort of ruxolitinib-naive patients used for developing the dynamic IPSS (DIPSS). By adopting ad hoc statistical analyses, we compared survival from diagnosis of 100 PMF patients receiving ruxolitinib within COMFORT-2 with that of 350 patients of the DIPSS study. Subjects were properly matched, and both left-truncation and right-censoring were accounted in order to compare higher IPSS risks exclusively. Patients receiving ruxolitinib had longer survival (5 years, 95% CI 2.9-7.8, versus 3.5 years, 95% CI 3.0-3.9) with a hazard ratio of 0.61 (95% CI 0.41-0.91, P=.0148). This observation suggests that ruxolitinib may modify the natural history of PMF.
    Blood 01/2014; · 9.78 Impact Factor
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    ABSTRACT: The BCR-ABL1 negative myeloproliferative neoplasms (MPNs) are associated with an increased risk of both venous and arterial thromboembolic events. Thromboses may be the presenting clinical feature of an MPN or may occur during the course of the disease. Treatment comprises anticoagulant and antiaggregant agents as in non- MPN thromboses, and treatment of the particular MPN. The duration of anticoagulant treatment that is required for MPN thrombosis is unknown. This study was performed to survey the opinion of hematologists who treat patients with MPN regarding the duration of anticoagulation or antiaggregant therapy in patients in whom thrombosis is the presenting feature of MPN. Five clinical scenarios in which thromboembolism (cerebral vein thrombosis, pulmonary embolism, cerebrovascular accident, splanchnic vein thrombosis, portal vein thrombosis) was a presenting feature of MPN were created using a web-based tool and were sent by email to hematologists in Israel, Italy and England and to hematologists identified as key opinion leaders in the field of MPN. Physicians were asked to recommend duration of anticoagulation and/or aspirin use choosing from 4 alternatives provided. Seventy-three physicians responded to the survey. 42 physicians considered MPNs to be their main area of clinical interest, and 31 did not. 21 physicians saw more than 20 MPN patients per week, and 50 physicians had been in hematology practice for more than 10 years. Responses regarding the duration of anticoagulation and/or the use of aspirin varied for all of the clinical vignettes. Neither physician area-of-interest, volume of MPN patients treated nor years in practice were related to the responses obtained. This study demonstrates that hematologists, including those specializing in MPNs, lack consensus in their approach to the long-term treatment of thromboses as the presenting feature of an MPN. Controlled clinical studies are needed to inform appropriate decision making in this area.
    Thrombosis Research 01/2014; · 2.43 Impact Factor
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    ABSTRACT: Limited information is available regarding the use of cytoreductive combination therapy in high-risk patients with essential thrombocythemia. This analysis aims to evaluate the clinical relevance and patterns of cytoreductive combination treatment in European high-risk patients with essential thrombocythemia in the Evaluation of Xagrid® Efficacy and Long-term Safety study. From 3643 patients, 347 (9.5%) received combination therapy. Data were recorded at each 6-month update. Of 347 patients who received combination therapy, 304 (87.6%) received hydroxycarbamide + anagrelide. Monotherapies received before this combination were hydroxycarbamide (n=167; 54.9%) and anagrelide (n=123; 40.5%). Median weekly doses of hydroxycarbamide and anagrelide were: 7000 and 10.5 mg when used as prior monotherapy; 3500 and 7.0 mg when used as add-on treatment. Overall, median platelet counts were 581x10(9)/L and 411x10(9)/L before and after starting hydroxycarbamide + anagrelide, respectively. In patients with paired data (n=153), the number of patients with platelet counts < 400x10(9)/L increased from 33 (21.6%) to 74 (48.4%, P<0.0001), and with platelet counts < 600x10(9)/L, from 82 (53.6%) to 132 (86.3%, P<0.0001). Hydroxycarbamide + anagrelide was discontinued in 158 patients: 76 (48.1%) stopped hydroxycarbamide, 59 (37.3%) stopped anagrelide, 19 (12.0%) stopped both and 4 (2.5%) had another therapy added. The most frequent reasons for discontinuation were intolerance/side effects, lack of efficacy, and therapeutic strategy. Combination therapy, usually hydroxycarbamide + anagrelide, is used in approximately 10% of all high-risk patients with essential thrombocythemia and may be a useful approach in treating patients for whom monotherapy is unsatisfactory. This trial is registered on clinicaltrials.gov (NCT00567502).
    Haematologica 12/2013; · 5.94 Impact Factor

Publication Stats

4k Citations
1,012.68 Total Impact Points

Institutions

  • 2014
    • Belfast Health and Social Care Trust
      • Cancer Centre
      Béal Feirste, N Ireland, United Kingdom
  • 2002–2014
    • Guy's and St Thomas' NHS Foundation Trust
      • Department of Haematology
      Londinium, England, United Kingdom
  • 2013
    • University of Texas MD Anderson Cancer Center
      • Department of Leukemia
      Houston, Texas, United States
    • University College London Hospitals NHS Foundation Trust
      • Department of Haematology
      London, ENG, United Kingdom
  • 2009–2013
    • Policlinico San Matteo Pavia Fondazione IRCCS
      Ticinum, Lombardy, Italy
    • Cambridge Institute for Medical Research
      • Department of Haematology
      Cambridge, England, United Kingdom
  • 2012
    • Sheffield Teaching Hospitals NHS Foundation Trust
      Sheffield, England, United Kingdom
    • King's College Hospital NHS Foundation Trust
      Londinium, England, United Kingdom
    • IMIM Hospital del Mar Medical Research Institute
      Barcino, Catalonia, Spain
    • Assistance Publique – Hôpitaux de Paris
      Lutetia Parisorum, Île-de-France, France
    • Wellcome Trust Sanger Institute
      • Cancer Genome Project
      Cambridge, ENG, United Kingdom
  • 2011–2012
    • Imperial College London
      • Division of Experimental Medicine
      London, ENG, United Kingdom
    • Rosalind Franklin University of Medicine and Science
      North Chicago, Illinois, United States
  • 2005–2012
    • University of Cambridge
      • • Cambridge Institute for Medical Research
      • • Department of Haematology
      Cambridge, ENG, United Kingdom
    • Ospedali Riuniti di Bergamo
      • Department of Hematology
      Bergamo, Lombardy, Italy
  • 2007
    • Belfast Healthy Cities
      Béal Feirste, N Ireland, United Kingdom
  • 2002–2006
    • The Bracton Centre, Oxleas NHS Trust
      Дартфорде, England, United Kingdom
  • 2001
    • University College London
      • Department of Haematology
      Londinium, England, United Kingdom
  • 1998
    • University of Birmingham
      Birmingham, England, United Kingdom