المؤلفون: Eyre, Toby A., Wilson, William, Kirkwood, Amy A., Wolf, Julia, Hildyard, Catherine, Plaschkes, Hannah, Griffith, John, Fields, Paul, Gunawan, Arief, Oliver, Rebecca, Booth, Stephen, Kothari, Jaimal, Fox, Christopher P., Martinez-Calle, Nicolas, McMillan, Andrew, Bishton, Mark, Collins, Graham P., Hatton, Chris S. R.

مصطلحات موضوعية: Hematology

الوصف: Infection-related morbidity and mortality are increased in older patients with diffuse large B-cell lymphoma (DLBCL) compared with population-matched controls. Key predictive factors for infection-related hospitalization during treatment with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and deaths as a result of infection in older patients during and after treatment with R-CHOP remain incompletely understood. For this study, 690 consecutively treated patients age 70 years or older who received full-dose or attenuated-dose R-CHOP treatment were analyzed for risk of infection-related hospitalization and infection-related death. Median age was 77 years, and 34.4% were 80 years old or older. Median follow-up was 2.8 years (range, 0.4-8.9 years). Patient and baseline disease characteristics were assessed in addition to intended dose intensity (IDI). Of all patients, 72% were not hospitalized with infection. In 331 patients receiving an IDI $80%, 33% were hospitalized with $1 infections compared with 23.3% of 355 patients receiving an IDI of,80% (odds ratio, 1.61; 95% confidence interval, 1.15-2.25; P 5 .006). An increased risk of infection-related admission was independently associated with IDI .80% across the whole cohort. Primary quinolone prophylaxis independently reduced infection-related admission. A total of 51 patients died as a result of infection. The 6-month, 12-month, 2-year, and 5-year cumulative incidences of infection-related death were 3.3%, 5.0%, 7.2%, and 11.1%, respectively. Key independent factors associated with infection-related death were an International Prognostic Index (IPI) score of 3 to 5, Cumulative Illness Rating Scale for Geriatrics (CIRS-G) score $6, and low albumin, which enabled us to generate a predictive risk score. We defined a smaller group (15%) of patients (IPI score of 0-2, albumin .36 g/L, CIRS-G score,6) in which no cases of infection-related deaths occurred at 5 years of follow-up. Whether patients at higher risk of infection-related ...

العلاقة: https://nottingham-repository.worktribe.com/output/14322764Test; Blood Advances; Volume 5; Issue 8; Pagination 2229-2236; https://nottingham-repository.worktribe.com/file/14322764/1/advancesadv2021004286Test

الإتاحة: https://doi.org/10.1182/bloodadvances.2021004286Test
https://nottingham-repository.worktribe.com/file/14322764/1/advancesadv2021004286Test
https://nottingham-repository.worktribe.com/output/14322764Test

المؤلفون: Booth, Stephen W, Eyre, Toby A, Whittaker, John, Campo, Leticia, Wang, Lai Mun, Soilleux, Elizabeth, Royston, Daniel, Rees, Gabrielle, Kesavan, Murali, Hildyard, Catherine, Kazmi, Farasat, La Thangue, Nick, Kerr, David, Middleton, Mark R, Collins, Graham P

مصطلحات موضوعية: Biomarker, HR23B, Histone deacetylase (HDAC), Lymphoma, Adult, Aged, Biomarkers, Tumor, DNA Repair Enzymes, DNA-Binding Proteins, Female, Gene Expression, Histone Deacetylase Inhibitors, Humans, Immunohistochemistry, Male, Middle Aged, Neoplasm Staging, Neoplasms, Treatment Outcome

الوصف: BACKGROUND: This Phase 2a dose expansion study was performed to assess the safety, tolerability and preliminary efficacy of the maximum tolerated dose of the oral histone de-acetylase (HDAC) inhibitor CXD101 in patients with relapsed / refractory lymphoma or advanced solid organ cancers and to assess HR23B protein expression by immunohistochemistry as a biomarker of HDAC inhibitor sensitivity. METHODS: Patients with advanced solid-organ cancers with high HR23B expression or lymphomas received CXD101 at the recommended phase 2 dose (RP2D). Key exclusions: corrected QT > 450 ms, neutrophils < 1.5 × 109/L, platelets < 75 × 109/L, ECOG > 1. Baseline HR23B expression was assessed by immunohistochemistry. RESULTS: Fifty-one patients enrolled between March 2014 and September 2019, 47 received CXD101 (19 solid-organ cancer, 28 lymphoma). Thirty-four patients received ≥80% RP2D. Baseline characteristics: median age 57.4 years, median prior lines 3, male sex 57%. The most common grade 3-4 adverse events were neutropenia (32%), thrombocytopenia (17%), anaemia (13%), and fatigue (9%) with no deaths on CXD101. No responses were seen in solid-organ cancers, with disease stabilisation in 36% or patients; the overall response rate in lymphoma was 17% with disease stabilisation in 52% of patients. Median progression-free survival was 1.2 months (95% confidence interval (CI) 1.2-5.4) in solid-organ cancers and 2.6 months (95%CI 1.2-5.6) in lymphomas. HR23B status did not predict response. CONCLUSIONS: CXD101 showed acceptable tolerability with efficacy seen in Hodgkin lymphoma, T-cell lymphoma and follicular lymphoma. Further studies assessing combination approaches are warranted. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01977638 . Registered 07 November 2013.

وصف الملف: Electronic; application/pdf

العلاقة: https://www.repository.cam.ac.uk/handle/1810/328502Test

الإتاحة: https://doi.org/10.17863/CAM.75950Test
https://www.repository.cam.ac.uk/handle/1810/328502Test

المؤلفون: Booth, Stephen W., Eyre, Toby A., Whittaker, John, Campo, Leticia, Wang, Lai Mun, Soilleux, Elizabeth, Royston, Daniel, Rees, Gabrielle, Kesavan, Murali, Hildyard, Catherine, Kazmi, Farasat, La Thangue, Nick, Kerr, David, Middleton, Mark R., Collins, Graham P.

المساهمون: Oxford Experimental Cancer Centre

المصدر: BMC Cancer ; volume 21, issue 1 ; ISSN 1471-2407

مصطلحات موضوعية: Cancer Research, Genetics, Oncology

الوصف: Background This Phase 2a dose expansion study was performed to assess the safety, tolerability and preliminary efficacy of the maximum tolerated dose of the oral histone de-acetylase (HDAC) inhibitor CXD101 in patients with relapsed / refractory lymphoma or advanced solid organ cancers and to assess HR23B protein expression by immunohistochemistry as a biomarker of HDAC inhibitor sensitivity. Methods Patients with advanced solid-organ cancers with high HR23B expression or lymphomas received CXD101 at the recommended phase 2 dose (RP2D). Key exclusions: corrected QT > 450 ms, neutrophils < 1.5 × 10 9 /L, platelets < 75 × 10 9 /L, ECOG > 1. Baseline HR23B expression was assessed by immunohistochemistry. Results Fifty-one patients enrolled between March 2014 and September 2019, 47 received CXD101 (19 solid-organ cancer, 28 lymphoma). Thirty-four patients received ≥80% RP2D. Baseline characteristics: median age 57.4 years, median prior lines 3, male sex 57%. The most common grade 3–4 adverse events were neutropenia (32%), thrombocytopenia (17%), anaemia (13%), and fatigue (9%) with no deaths on CXD101. No responses were seen in solid-organ cancers, with disease stabilisation in 36% or patients; the overall response rate in lymphoma was 17% with disease stabilisation in 52% of patients. Median progression-free survival was 1.2 months (95% confidence interval (CI) 1.2–5.4) in solid-organ cancers and 2.6 months (95%CI 1.2–5.6) in lymphomas. HR23B status did not predict response. Conclusions CXD101 showed acceptable tolerability with efficacy seen in Hodgkin lymphoma, T-cell lymphoma and follicular lymphoma. Further studies assessing combination approaches are warranted. Trial registration ClinicalTrials.gov identifier NCT01977638 . Registered 07 November 2013.

الإتاحة: https://doi.org/10.1186/s12885-021-08595-wTest

المؤلفون: Booth, Stephen, Plaschkes, Hannah, Kirkwood, Amy A, Gibb, Adam, Horgan, Patrick, Higham, Claire, Oladipo, Joanna M, Browning, Joe, Khan, Usman, Tseu, Bing, Chen, Lucia, Willan, John, Wolf, Julia, Gunawan, Arief, Fields, Paul, Ebsworth, Tim, Lown, Robert, Gordon-Walker, Dominic, Shah, Nimish, Linton, Kim M, Collins, Graham P, Kothari, Jaimal, Hildyard, Catherine, Eyre, Toby A

المصدر: Booth , S , Plaschkes , H , Kirkwood , A A , Gibb , A , Horgan , P , Higham , C , Oladipo , J M , Browning , J , Khan , U , Tseu , B , Chen , L , Willan , J , Wolf , J , Gunawan , A , Fields , P , Ebsworth , T , Lown , R , Gordon-Walker , D , Shah , N , Linton , K M , Collins , G P , Kothari , J , Hildyard , C & Eyre , T ....

مصطلحات موضوعية: Aged, Antineoplastic Combined Chemotherapy Protocols/adverse effects, Cyclophosphamide/adverse effects, Doxorubicin/adverse effects, Humans, Lymphoma, Large B-Cell, Diffuse/drug therapy, Retrospective Studies, Rituximab/adverse effects, Vincristine/adverse effects, ResearchInstitutes_Networks_Beacons/mcrc, Manchester Cancer Research Centre

الوصف: Diffuse large B-cell lymphoma (DLBCL) and osteoporotic fracture are both more common in older patients. Exposure to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) is likely to increase the risk of fracture, but evidence is lacking to define fracture incidence in this group. Data on consecutive patients with DLBCL aged ≥70 years treated with 1 to 8 cycles of full or attenuated R-CHOP were retrospectively collected across 10 UK centers (2009-2019). Patients were followed up from starting R-CHOP for a minimum of 6 months and censored at 18 months; at last follow-up if <18 months; or at progression or death. Of 877 patients identified, 148 were excluded: 121 had progression or died before 6 months; 23 had follow-up <6 months. Across 729 remaining patients, the median age was 77 years, and 68% had an Eastern Cooperative Oncology Group performance status of 0 to 1. Eighty-one fractures occurred within 18 months of follow-up; 42 were symptomatic, including 30 requiring hospital attendance or admission. The cumulative fracture incidence was 6.2% (95% confidence interval [CI], 4.7-8.2) at 6 months; 9.7% (95% CI, 7.8-12.1) at 12 months; and 11.4% (95% CI, 9.3-14.0) at 18 months. Multivariate analysis identified a predisposing history (osteoporosis, osteopenia, prior fracture, and rheumatoid arthritis [RhA]), DLBCL bone involvement at baseline, and receipt of prephase steroids as independent risk factors for fracture. There is a clinically relevant fracture risk and significant associated morbidity in older patients receiving R-CHOP. Careful attention to bone health is warranted in older patients receiving R-CHOP. Randomized studies are required to better define the most effective strategies to reduce fracture risk.

الإتاحة: https://doi.org/10.1182/BLOODADVANCES.2020002553Test
https://research.manchester.ac.uk/en/publications/eb959c06-89d1-46b1-aa0f-dda1a7688dd4Test
http://www.scopus.com/inward/record.url?scp=85091496260&partnerID=8YFLogxKTest

المؤلفون: Tivey, Ann, Shotton, Rohan, Eyre, Toby A, Lewis, David, Stanton, Louise, Allchin, Rebecca, Walter, Harriet Sarah, Miall, Fiona, Zhao, Rui, Santarsieri, Anna, McCulloch, Rory, Bishton, Mark, Beech, Amy, Willimott, Victoria Clare, Fowler, Nicole, Bedford, Claudia, Goddard, Jack, Protheroe, Samuel, Everden, Angharad, Tucker, David L, Wright, Joshua, Dukka, Srivasavi, Thomson, Miriam, Paneesha, Shankara, Prahladan, Mahesh, Hodson, Andrew, Qureshi, Iman, Koppana, Manasvi, Owen, Mary, Ediriwickrema, Kushani, Marr, Helen, Wilson, Jamie, Lambert, Jonathan, Wrench, David J, Burney, Claire N, Knott, Chloe, Talbot, Georgina, Gibb, Adam, Lord, Angela, Jackson, Barry, Stern, Simon, Sutton, Taylor, Webb, Amy Caitlin, Wilson, Marketa, Thomas, Nicky, Norman, Jane, Davies, Elizabeth, Lowry, Lisa, Maddox, Jamie, Phillips, Neil, Crosbie, Nicola, Flont, Marcin, Nga, Emma Lm, Virchis, Andres, Guerrero Camacho, Raisa, Swe, Wunna, Pillai, Arvind Radhakrishna, Rees, Clare, Bailey, James, Jones, Steve Gareth, Smith, Susan, Sharpley, Faye, Hildyard, Catherine, Mohamedbhai, Sajir, Nicholson, Toby, Moule, Simon, Chaturvedi, Anshuman, Linton, Kim

المصدر: Tivey , A , Shotton , R , Eyre , T A , Lewis , D , Stanton , L , Allchin , R , Walter , H S , Miall , F , Zhao , R , Santarsieri , A , McCulloch , R , Bishton , M , Beech , A , Willimott , V C , Fowler , N , Bedford , C , Goddard , J , Protheroe , S , Everden , A , Tucker , D L , Wright , J , Dukka , S , Thomson , M , Paneesha , S ....

الوصف: During the Covid-19 pandemic, ibrutinib +/- rituximab was approved in England for initial treatment of mantle cell lymphoma (MCL) instead of immunochemotherapy. As limited data are available in this setting, we conducted an observational cohort study evaluating safety and efficacy. Adults receiving ibrutinib +/- rituximab for untreated MCL were evaluated for treatment toxicity, response and survival, including outcomes in high-risk MCL (TP53 mutation/deletion/p53 overexpression, blastoid/pleomorphic, or Ki67 >/=30%). 149 patients from 43 participating centres were enrolled: 74.1% male, median age 75, 75.2% ECOG 0-1, 36.2% high-risk, 8.9% autologous transplant candidates. All patients received >/= 1 cycle ibrutinib (median 8 cycles), 39.0% with rituximab. Grade >/= 3 toxicity occurred in 20.3%, 33.8% required dose reductions/delays. At 15.6 months (mo) median follow-up, 41.6% discontinued ibrutinib; 8.1% due to toxicity. Of 104 response-assessed patients, overall (ORR) and complete response (CR) rates were 71.2% and 20.2% respectively. ORR was 77.3% (low-risk) vs. 59.0% (high-risk), p=0.05, and 78.7% (ibrutinib-rituximab) vs. 64.9% (ibrutinib), p=0.13. Median progression-free survival was 26.0mo (all patients); 13.7mo (high-risk) vs. not reached (NR) (low-risk), p=0.004. Median overall survival was NR (all); 14.8mo (high-risk) vs. NR (low-risk), p=0.005. Median post-ibrutinib survival was 1.4mo, longer in 41.9% patients receiving subsequent treatment (median 8.6 vs 0.6mo, p=0.002). Ibrutinib +/- rituximab was effective and well tolerated as first-line treatment of MCL, including older and transplant-ineligible patients. PFS and OS were significantly inferior in one-third of patients with high-risk disease and those unsuitable for post-ibrutinib treatment, highlighting the need for novel approaches in these groups.

العلاقة: https://research.manchester.ac.uk/en/publications/832e386e-b563-4be7-ac30-1c50daf8e097Test

الإتاحة: https://doi.org/10.1182/bloodadvances.2023011152Test
https://research.manchester.ac.uk/en/publications/832e386e-b563-4be7-ac30-1c50daf8e097Test

المؤلفون: Eyre, Toby A., Kirkwood, Amy A., Wolf, Julia, Hildyard, Catherine, Mercer, Carolyn, Plaschkes, Hannah, Griffith, John, Fields, Paul, Gunawan, Arief, Oliver, Rebecca, Booth, Stephen, Martinez‐Calle, Nicolas, McMillan, Andrew, Bishton, Mark, Fox, Christopher P., Collins, Graham P., Hatton, Chris S. R.

المساهمون: National Institute for Health Research

المصدر: British Journal of Haematology ; volume 187, issue 2, page 185-194 ; ISSN 0007-1048 1365-2141

الوصف: Summary Central nervous system (CNS) relapse following R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) occurs in 2–5% of patents with diffuse large B‐cell lymphoma (DLBCL). Many patients aged ≥70 years are unsuitable for high‐dose methotrexate (HDMTX) prophylaxis and therefore often receive stand‐alone intrathecal prophylaxis. The CNS international prognostic index (CNS‐IPI) is a clinical CNS relapse risk score that has not specifically been validated in elderly patients. The value of CNS prophylaxis in patients aged ≥70 years remains uncertain. Data on 690 consecutively R‐CHOP‐treated DLBCL patients aged ≥70 years were collected across 8 UK centres (2009–2018). CNS prophylaxis was administered per physician preference. Median age was 77·2 years and median follow‐up was 2·8 years. CNS‐IPI was 1–3 in 60·1%, 4 in 23·8%, 5 in 13·0% and 6 in 3·3%. Renal and/or adrenal (R/A) involvement occurred in 8·8%. Two‐year overall CNS relapse incidence was 2·6% and according to CNS‐IPI, 1–3:0·8%, 4:3·6%, 5:3·8% and 6:21·8%. Two‐year CNS relapse incidence for R/A was 10·0%. When excluding HDMTX ( n = 31) patients, there remained no change in unadjusted/adjusted CNS relapse for intrathecal prophylaxis effect according to CNS‐IPI. CNS‐IPI is valid in elderly R‐CHOP‐treated DLBCL patients, with the highest risk in those with CNS‐IPI 6 and R/A involvement. We observed no clear benefit for stand‐alone intrathecal prophylaxis but observed an independent increased risk of infection‐related admission during R‐CHOP when intrathecal prophylaxis was administered.

الإتاحة: https://doi.org/10.1111/bjh.16070Test

المؤلفون: Djebbari, Faouzi, Browning, Joseph A., Stanton, Louise, Booth, Stephen, Hildyard, Catherine, Willan, John, Bosworth, Jenny, Vora, Sona M., Hatton, Chris S.R., Collins, Graham P., Eyre, Toby A.

المساهمون: Southampton Clinical Trials Unit

المصدر: British Journal of Haematology ; volume 186, issue 6 ; ISSN 0007-1048 1365-2141

الإتاحة: https://doi.org/10.1111/bjh.16071Test

المؤلفون: Bye, Alexander P, Unsworth, Amanda J, Desborough, Michael J, Hildyard, Catherine AT, Appleby, Niamh, Bruce, David, Kriek, Neline, Nock, Sophie H, Sage, Tanya, Hughes, Craig E, Gibbins, Jonathan M

الوصف: The Bruton tyrosine kinase (Btk) inhibitor ibrutinib induces platelet dysfunction and causes increased risk of bleeding. Off-target inhibition of Tec is believed to contribute to platelet dysfunction and other side effects of ibrutinib. The second-generation Btk inhibitor acalabrutinib was developed with improved specificity for Btk over Tec. We investigated platelet function in patients with non-Hodgkin lymphoma (NHL) receiving ibrutinib or acalabrutinib by aggregometry and by measuring thrombus formation on collagen under arterial shear. Both patient groups had similarly dysfunctional aggregation responses to collagen and collagen-related peptide, and comparison with mechanistic experiments in which platelets from healthy donors were treated with the Btk inhibitors suggested that both drugs inhibit platelet Btk and Tec at physiological concentrations. Only ibrutinib caused dysfunctional thrombus formation, whereas size and morphology of thrombi following acalabrutinib treatment were of normal size and morphology. We found that ibrutinib but not acalabrutinib inhibited Src family kinases, which have a critical role in platelet adhesion to collagen that is likely to underpin unstable thrombus formation observed in ibrutinib patients. We found that platelet function was enhanced by increasing levels of von Willebrand factor (VWF) and factor VIII (FVIII) ex vivo by addition of intermediate purity FVIII (Haemate P) to blood from patients, resulting in consistently larger thrombi. We conclude that acalabrutinib avoids major platelet dysfunction associated with ibrutinib therapy, and platelet function may be enhanced in patients with B-cell NHL by increasing plasma VWF and FVIII.

وصف الملف: text

العلاقة: https://e-space.mmu.ac.uk/622744Test/; http://www.bloodadvances.org/content/1/26/2610Test; https://e-space.mmu.ac.uk/622744/1/advances011999.pdfTest; Bye, Alexander P , Unsworth, Amanda J ORCID logoorcid:0000-0003-3809-5984 , Desborough, Michael J , Hildyard, Catherine AT , Appleby, Niamh , Bruce, David , Kriek, Neline , Nock, Sophie H , Sage, Tanya , Hughes, Craig E and Gibbins, Jonathan M (2017) Severe platelet dysfunction in NHL patients receiving ibrutinib is absent in patients receiving acalabrutinib. Blood Advances, 1 (26). pp. 2610-2623. ISSN 2473-9529

الإتاحة: https://e-space.mmu.ac.uk/622744/1/advances011999.pdfTest

المؤلفون: Hildyard, Catherine, Palmer, Jessica, Alhulail, Sarah, Zumbadze, George, Keeling, David

المصدر: British Journal of Haematology ; volume 172, issue 6, page 978-979 ; ISSN 0007-1048 1365-2141

الإتاحة: https://doi.org/10.1111/bjh.13547Test

المؤلفون: Hildyard, Catherine, Keeling, David

المصدر: British Journal of Haematology ; volume 169, issue 3, page 448-449 ; ISSN 0007-1048 1365-2141

الإتاحة: https://doi.org/10.1111/bjh.13223Test