dc.contributor.author | O'Sullivan, JM | |
dc.contributor.author | Hamblin, A | |
dc.contributor.author | Yap, C | |
dc.contributor.author | Fox, S | |
dc.contributor.author | Boucher, R | |
dc.contributor.author | Panchal, A | |
dc.contributor.author | Alimam, S | |
dc.contributor.author | Dreau, H | |
dc.contributor.author | Howard, K | |
dc.contributor.author | Ware, P | |
dc.contributor.author | Cross, NCP | |
dc.contributor.author | McMullin, MF | |
dc.contributor.author | Harrison, CN | |
dc.contributor.author | Mead, AJ | |
dc.date.accessioned | 2019-10-21T10:03:09Z | |
dc.date.issued | 2019-12-05 | |
dc.identifier.citation | Blood, 2019, 134 (23), pp. 2107 - 2111 | |
dc.identifier.issn | 0006-4971 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3385 | |
dc.identifier.eissn | 1528-0020 | |
dc.identifier.doi | 10.1182/blood.2019001861 | |
dc.description.abstract | Essential 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.format | Print | |
dc.format.extent | 2107 - 2111 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER SOC HEMATOLOGY | |
dc.rights.uri | https://www.rioxx.net/licenses/under-embargo-all-rights-reserved | |
dc.subject | Humans | |
dc.subject | Hydroxyurea | |
dc.subject | Pyrazoles | |
dc.subject | Disease-Free Survival | |
dc.subject | Survival Rate | |
dc.subject | Risk Factors | |
dc.subject | Drug Resistance | |
dc.subject | Female | |
dc.subject | Male | |
dc.subject | Thrombocythemia, Essential | |
dc.title | The poor outcome in high molecular risk, hydroxycarbamide-resistant/intolerant ET is not ameliorated by ruxolitinib. | |
dc.type | Journal Article | |
rioxxterms.versionofrecord | 10.1182/blood.2019001861 | |
rioxxterms.licenseref.uri | https://www.rioxx.net/licenses/under-embargo-all-rights-reserved | |
rioxxterms.licenseref.startdate | 2019-12 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Blood | |
pubs.issue | 23 | |
pubs.notes | Not 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-status | Published | |
pubs.volume | 134 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Clinical Trials & Statistics Unit | |
dc.contributor.icrauthor | Yap, Christina | |