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dc.contributor.authorO'Sullivan, JM
dc.contributor.authorHamblin, A
dc.contributor.authorYap, C
dc.contributor.authorFox, S
dc.contributor.authorBoucher, R
dc.contributor.authorPanchal, A
dc.contributor.authorAlimam, S
dc.contributor.authorDreau, H
dc.contributor.authorHoward, K
dc.contributor.authorWare, P
dc.contributor.authorCross, NCP
dc.contributor.authorMcMullin, MF
dc.contributor.authorHarrison, CN
dc.contributor.authorMead, AJ
dc.date.accessioned2019-10-21T10:03:09Z
dc.date.issued2019-12-05
dc.identifier.citationBlood, 2019, 134 (23), pp. 2107 - 2111
dc.identifier.issn0006-4971
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3385
dc.identifier.eissn1528-0020
dc.identifier.doi10.1182/blood.2019001861
dc.description.abstractEssential Thrombocythemia (ET) patients at high-risk of thrombosis require cytoreductive treatment, typically with hydroxycarbamide. Many patients are resistant or intolerant to hydroxycarbamide (HC-RES/INT) and are at increased risk of disease progression. MAJIC-ET is a randomized phase 2 study comparing ruxolitinib (RUX) to best available therapy (BAT) in HC-RES/INT ET, which showed no difference between the two arms in rates of hematological response or disease progression. The impact of additional non-MPN driver mutations (NDM) on the risk of disease complications in HC-RES/INT ET patients is unknown. Since the presence of NDM may influence trial outcomes, we expand the primary MAJIC-ET analysis to serially evaluate NDM in MAJIC-ET patients using a targeted myeloid 32-gene panel. NDM at baseline were detected in 30% of patients, most frequently affecting TET2 (11%) followed by TP53 (6.4%) and SF3B1 (6.4%). The presence of a NDM was associated with inferior 4-year transformation-free survival (TFS; 65.4% [95% CI 53.3 – 75%] vs. 82.8% [95% CI 73.2 – 89.1%], p=0.017). Specifically, TP53 (p=0.01) and splicing factor (SF, SF3B1, ZRSR2, SRSF2; p<0.001), but not TET2 mutations were associated with reduced TFS which was not mitigated by RUX treatment. Longitudinal analysis identified new mutations in 19.3% of patients; primarily affecting TET2, TP53 and SF3B1. We report the first comprehensive mutational analysis of HC-RES/INT ET patients and highlight the clinical/prognostic utility of serial mutation analysis for NDM in HC-RES/INT ET, including the importance of SF and TP53 mutations which identify HC-RES/INT ET patients at increased risk of disease transformation.
dc.formatPrint
dc.format.extent2107 - 2111
dc.languageeng
dc.language.isoeng
dc.publisherAMER SOC HEMATOLOGY
dc.rights.urihttps://www.rioxx.net/licenses/under-embargo-all-rights-reserved
dc.subjectHumans
dc.subjectHydroxyurea
dc.subjectPyrazoles
dc.subjectDisease-Free Survival
dc.subjectSurvival Rate
dc.subjectRisk Factors
dc.subjectDrug Resistance
dc.subjectFemale
dc.subjectMale
dc.subjectThrombocythemia, Essential
dc.titleThe poor outcome in high molecular risk, hydroxycarbamide-resistant/intolerant ET is not ameliorated by ruxolitinib.
dc.typeJournal Article
rioxxterms.versionofrecord10.1182/blood.2019001861
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/under-embargo-all-rights-reserved
rioxxterms.licenseref.startdate2019-12
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfBlood
pubs.issue23
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Trials & Statistics Unit
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Trials & Statistics Unit
pubs.publication-statusPublished
pubs.volume134
pubs.embargo.termsNot known
icr.researchteamClinical Trials & Statistics Unit
dc.contributor.icrauthorYap, Christina


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