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3. RNA-seq of newly diagnosed patients in the PADIMAC study leads to a bortezomib/lenalidomide decision signature

Author

Chapman, Michael A., Sive, Jonathan, Ambrose, John, Roddie, Claire, Counsell, Nicholas, Lach, Anna, Abbasian, Mahnaz, Popat, Rakesh, Cavenagh, Jamie D., Oakervee, Heather, Streetly, Matthew J., Schey, Stephen, Koh, Mickey, Willis, Fenella, Virchis, Andres E., Crowe, Josephine, Quinn, Michael F., Cook, Gordon, Crawley, Charles R., Pratt, Guy, Cook, Mark, Braganza, Nivette, Adedayo, Toyin, Smith, Paul, Clifton-Hadley, Laura, Owen, Roger G., Sonneveld, Pieter, Keats, Jonathan J., Herrero, Javier, and Yong, Kwee

Published
2018
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4. Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma

Author

Facon, Thierry, Dimopoulos, Meletios A., Dispenzieri, Angela, Catalano, John V., Belch, Andrew, Cavo, Michele, Pinto, Antonello, Weisel, Katja, Ludwig, Heinz, Bahlis, Nizar J., Banos, Anne, Tiab, Mourad, Delforge, Michel, Cavenagh, Jamie D., Geraldes, Catarina, Lee, Je-Jung, Chen, Christine, Oriol, Albert, De La Rubia, Javier, White, Darrell, Binder, Daniel, Lu, Jin, Anderson, Kenneth C., Moreau, Philippe, Attal, Michel, Perrot, Aurore, Arnulf, Bertrand, Qiu, Lugui, Roussel, Murielle, Boyle, Eileen, Manier, Salomon, Mohty, Mohamad, Avet-Loiseau, Herve, Leleu, Xavier, Ervin-Haynes, Annette, Chen, Guang, Houck, Vanessa, Benboubker, Lotfi, and Hulin, Cyrille

Published
2018
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5. The complex genetic landscape of familial MDS and AML reveals pathogenic germline variants

Author

Rio-Machin, Ana, Vulliamy, Tom, Hug, Nele, Walne, Amanda, Tawana, Kiran, Cardoso, Shirleny, Ellison, Alicia, Pontikos, Nikolas, Wang, Jun, Tummala, Hemanth, Al Seraihi, Ahad Fahad H., Alnajar, Jenna, Bewicke-Copley, Findlay, Armes, Hannah, Barnett, Michael, Bloor, Adrian, Bödör, Csaba, Bowen, David, Fenaux, Pierre, Green, Andrew, Hallahan, Andrew, Hjorth-Hansen, Henrik, Hossain, Upal, Killick, Sally, Lawson, Sarah, Layton, Mark, Male, Alison M., Marsh, Judith, Mehta, Priyanka, Mous, Rogier, Nomdedéu, Josep F., Owen, Carolyn, Pavlu, Jiri, Payne, Elspeth M., Protheroe, Rachel E., Preudhomme, Claude, Pujol-Moix, Nuria, Renneville, Aline, Russell, Nigel, Saggar, Anand, Sciuccati, Gabriela, Taussig, David, Toze, Cynthia L., Uyttebroeck, Anne, Vandenberghe, Peter, Schlegelberger, Brigitte, Ripperger, Tim, Steinemann, Doris, Wu, John, Mason, Joanne, Page, Paula, Akiki, Susanna, Reay, Kim, Cavenagh, Jamie D., Plagnol, Vincent, Caceres, Javier F., Fitzgibbon, Jude, and Dokal, Inderjeet

Published
2020
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6. The impact of cytogenetics on duration of response and overall survival in patients with relapsed multiple myeloma (long‐term follow‐up results from BSBMT/UKMF Myeloma X Relapse [Intensive]): a randomised, open‐label, phase 3 trial

Author

Cook, Gordon, Royle, Kara‐Louise, O'Connor, Sheila, Cairns, David A., Ashcroft, A. John, Williams, Cathy D., Hockaday, Anna, Cavenagh, Jamie D., Snowden, John A., Ademokun, Debo, Tholouli, Eleni, Andrews, Vivienne E., Jenner, Matthew, Parrish, Christopher, Yong, Kwee, Cavet, Jim, Hunter, Hannah, Bird, Jenny M., Pratt, Guy, Drayson, Mark T., Brown, Julia M., and Morris, Treen C. M.

Subjects
Male, relapsed multiple myeloma, overall survival, Kaplan-Meier Estimate, Transplantation, Autologous, cytogenetics, Disease-Free Survival, Translocation, Genetic, Humans, Multicenter Studies as Topic, duration of response, Antineoplastic Agents, Alkylating, Cyclophosphamide, In Situ Hybridization, Fluorescence, Aged, Proportional Hazards Models, Randomized Controlled Trials as Topic, Sequence Deletion, Chromosomes, Human, Pair 14, Salvage Therapy, Haematological Malignancy, Hematopoietic Stem Cell Transplantation, Middle Aged, Combined Modality Therapy, Clinical Trials, Phase III as Topic, salvage ASCT, Female, Chromosomes, Human, Pair 4, Multiple Myeloma, Chromosomes, Human, Pair 16, Research Paper, Chromosomes, Human, Pair 17, Follow-Up Studies
Abstract

Summary The Myeloma X trial (ISCRTN60123120) registered patients with relapsed multiple myeloma. Participants were randomised between salvage autologous stem cell transplantation (ASCT) or weekly cyclophosphamide following re‐induction therapy. Cytogenetic analysis performed at trial registration defined t(4;14), t(14;16) and del(17p) as high‐risk. The effect of cytogenetics on time to progression (TTP) and overall survival was investigated. At 76 months median follow‐up, ASCT improved TTP compared to cyclophosphamide (19 months (95% confidence interval [95% CI] 16–26) vs. 11 months (9–12), hazard ratio [HR]: 0·40, 95% CI: 0·29–0·56, P

Published
2019

7. NK cells CD56brightand CD56dimsubset cytokine loss and exhaustion is associated with impaired survival in myeloma

Author

Seymour, Frances, Cavenagh, Jamie D., Mathews, Janet, and Gribben, John G.

Abstract

Natural killer (NK) cells are the key cells of the innate immune system that share many characteristics with T lymphocytes; their activation, however, is based on the integration of a range of activatory and inhibitory signals via receptors recognizing recurrent pathogen-associated molecular patterns. Two important populations of NK cells with differing functions are recognized: CD56brightand CD56dim. NK cells have the potential to recognize and kill malignant plasma cells, which offers therapeutic opportunities. We used mass cytometry to examine the phenotype and function of NK cell subsets from patients with newly diagnosed multiple myeloma (NDMM). We show that NK cells in NDMM are shifted toward a CD56brightbut dysfunctional cytotoxic phenotype, which exhibits selective loss of cytokine production. The CD56dimsubset has features of exhaustion with impaired proliferation, upregulation of programmed cell death protein 1, and loss of T-cell immunoglobulin and mucin domain 3 expression. Poor expression of NK cell activation markers is seen and is associated with inferior long-term survival. These results suggest that NK cell exhaustion is already present by the time of myeloma diagnosis and likely contributes to the loss of immunologic control of malignant plasma cells. Restoring NK cell function via immune-directed therapies offers a route to restoring immunologic control in multiple myeloma.

Published
2022
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9. Final analysis of overall survival from the first trial

Author

Facon, Thierry Dimopoulos, Meletios A. Dispenzieri, Angela and Catalano, John V. Belch, Andrew Cavo, Michele Pinto, Antonello Weisel, Katja Ludwig, Heinz Bahlis, Nizar J. and Banos, Anne Tiab, Mourad Delforge, Michel Cavenagh, Jamie D. and Geraldes, Catarina Lee, Je-Jung Chen, Christine Oriol, Albert De La Rubia, Javier White, Darrell Binder, Daniel and Lu, Jin Anderson, Kenneth C. Moreau, Philippe Attal, Michel and Fermand, Jean-Paul Avet-Loiseau, Herve Ervin-Haynes, Annette and Chen, Guang Houck, Vanessa Hulin, Cyrille Benboubker, Lofti

Subjects
Health Sciences, Επιστήμες Υγείας
Published
2016

10. Outcome of Azacitidine Therapy in Acute Myeloid Leukemia Is not Improved by Concurrent Vorinostat Therapy but Is Predicted by a Diagnostic Molecular Signature

Author

Craddock, Charles F., primary, Houlton, Aimee E., additional, Quek, Lynn Swun, additional, Ferguson, Paul, additional, Gbandi, Emma, additional, Roberts, Corran, additional, Metzner, Marlen, additional, Garcia-Martin, Natalia, additional, Kennedy, Alison, additional, Hamblin, Angela, additional, Raghavan, Manoj, additional, Nagra, Sandeep, additional, Dudley, Louise, additional, Wheatley, Keith, additional, McMullin, Mary Frances, additional, Pillai, Srinivas P., additional, Kelly, Richard J., additional, Siddique, Shamyla, additional, Dennis, Michael, additional, Cavenagh, Jamie D., additional, and Vyas, Paresh, additional

Published
2017
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11. Variable Penetrance Is Linked with Monoallelic Gene Expression in Inherited GATA2-Mutated MDS/AML

Author

Al Seraihi, Ahad, primary, Rio-Machin, Ana, additional, Tawana, Kiran, additional, Bödör, Csaba, additional, Araf, Shamzah, additional, Heward, James A, additional, Smith, Matthew, additional, Iqbal, Sameena, additional, Best, Steven, additional, Lea, Nicholas, additional, McLornan, Donal, additional, Ellison, Alicia, additional, Tummala, Hemanth, additional, Romualdo Cardoso, Shirleny, additional, Cavenagh, Jamie D., additional, Vulliamy, Tom, additional, Dokal, Inderjeet, additional, and Fitzgibbon, Jude, additional

Published
2016
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12. Final Analysis of Overall Survival from the First Trial

Author

Facon, Thierry, primary, Dimopoulos, Meletios A, additional, Dispenzieri, Angela, additional, Catalano, John V., additional, Belch, Andrew, additional, Cavo, Michele, additional, Pinto, Antonello, additional, Weisel, Katja, additional, Ludwig, Heinz, additional, Bahlis, Nizar J., additional, Banos, Anne, additional, Tiab, Mourad, additional, Delforge, Michel, additional, Cavenagh, Jamie D., additional, Geraldes, Catarina, additional, Lee, Je-Jung, additional, Chen, Christine, additional, Oriol, Albert, additional, De La Rubia, Javier, additional, White, Darrell, additional, Binder, Daniel, additional, Lu, Jin, additional, Anderson, Kenneth C., additional, Moreau, Philippe, additional, Attal, Michel, additional, Fermand, Jean-Paul, additional, Avet-Loiseau, Herve, additional, Ervin-Haynes, Annette, additional, Chen, Guang, additional, Houck, Vanessa, additional, Hulin, Cyrille, additional, and Benboubker, Lofti, additional

Published
2016
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13. Immune Biomarkers Identify Sustained Quantitative and Functional Immune Reconstitution in the Setting of Adjunctive Lenalidomide Following T-Depleted RIC-Allo SCT for Multiple Myeloma

Author

Cook, Gordon, primary, Carter, Clive R, additional, Brock, Kristian, additional, McQuaker, Grant, additional, Snowden, John A, additional, Crawley, Charles, additional, Hunter, Hannah, additional, Cavenagh, Jamie D., additional, Lobb, Mark, additional, Cullen, Katherine, additional, Hodgkinson, Andrea, additional, Sirovica, Mirjana, additional, and Cook, Mark, additional

Published
2016
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14. Vorinostat Does Not Improve Outcome in Patients with Acute Myeloid Leukemia and High Risk Myelodysplasia Treated with Azacitidine: Results of the UK Trials Acceleration Programme Ravva Trial

Author

Craddock, Charles, primary, Houlton, Aimee E, additional, Ferguson, Paul, additional, Raghavan, Manoj, additional, Fox, Sonia, additional, Dudley, Louise, additional, Quek, Lynn Swun, additional, Cavenagh, Jamie D., additional, Dennis, Michael, additional, McMullin, Mary Frances, additional, Pillai, Srinivas P, additional, Kelly, Richard, additional, Siddique, Shamyla, additional, Wheatley, Keith, additional, and Vyas, Paresh, additional

Published
2016
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15. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial

Author

San-Miguel, Jesus F. Hungria, Vania T. M. Yoon, Sung-Soo and Beksac, Meral Dimopoulos, Meletios Athanasios Elghandour, Ashraf and Jedrzejczak, Wieslaw Wiktor Guenther, Andreas Nakorn, Thanyaphong Na Siritanaratkul, Noppadol Corradini, Paolo and Chuncharunee, Suporn Lee, Je-Jung Schlossman, Robert L. and Shelekhova, Tatiana Yong, Kwee Tan, Daryl Numbenjapon, Tontanai Cavenagh, Jamie D. Hou, Jian LeBlanc, Richard and Nahi, Hareth Qiu, Lugui Salwender, Hans Pulini, Stefano and Moreau, Philippe Warzocha, Krzysztof White, Darrell Blade, Joan Chen, WenMing de la Rubia, Javier Gimsing, Peter and Lonial, Sagar Kaufman, Jonathan L. Ocio, Enrique M. and Veskovski, Ljupco Sohn, Sang Kyun Wang, Ming-Chung Lee, Jae Hoon Einsele, Hermann Sopala, Monika Corrado, Claudia and Bengoudifa, Bourras-Rezki Binlich, Florence Richardson, Paul G.

Subjects
Health Sciences, Επιστήμες Υγείας
Abstract

Background Panobinostat is a potent oral pan-deacetylase inhibitor that in preclinical studies has synergistic antimyeloma activity when combined with bortezomib and dexamethasone. We aimed to compare panobinostat, bortezomib, and dexamethasone with placebo, bortezomib, and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma. Methods PANORAMA1 is a multicentre, randomised, placebo-controlled, double-blind phase 3 trial of patients with relapsed or relapsed and refractory multiple myeloma who have received between one and three previous treatment regimens. Patients were randomly assigned (1:1) via an interactive web-based and voice response system, stratified by number of previous treatment lines and by previous use of bortezomib, to receive 21 day cycles of placebo or panobinostat (20 mg; on days 1, 3, 5, 8, 10, 12, orally), both in combination with bortezomib (1.3 mg/m(2) on days 1, 4, 8, 11, intravenously) and dexamethasone (20 mg on days 1, 2, 4, 5, 8, 9, 11, 12, orally). Patients, physicians, and the investigators who did the data analysis were masked to treatment allocation; crossover was not permitted. The primary endpoint was progression-free survival (in accordance with modified European Group for Blood and Marrow Transplantation criteria and based on investigators’ assessment) and was analysed by intention to treat. The study is ongoing, but no longer recruiting, and is registered at ClinicalTrials.gov, number NCT01023308. Findings 768 patients were enrolled between Jan 21, 2010, and Feb 29, 2012, with 387 randomly assigned to panobinostat, bortezomib, and dexamethasone and 381 to placebo, bortezomib, and dexamethasone. Median follow-up was 6.47 months (IQR 1.81-13.47) in the panobinostat group and 5.59 months (2.14-11.30) in the placebo group. Median progression-free survival was significantly longer in the panobinostat group than in the placebo group (11.99 months [95% CI 10.33-12.94] vs 8.08 months [7.56-9.23]; hazard ratio [HR] 0.63, 95% CI 0.52-0.76; p

Published
2014

16. Panobinostat Plus Azacitidine in Adult Patients with MDS, CMML, or AML: Results of a Phase 2b Study

Author

Garcia-Manero, Guillermo, primary, Sekeres, Mikkael A., additional, Egyed, Miklos, additional, Alimena, Giuliana, additional, Graux, Carlos, additional, Cavenagh, Jamie D., additional, Salman, Huda, additional, Illes, Arpad, additional, Fenaux, Pierre, additional, DeAngelo, Daniel J., additional, Stauder, Reinhard, additional, Yee, Karen, additional, Zhu, Nancy Y, additional, Lee, Je-Hwan, additional, Valcarcel, David, additional, MacWhannell, Alan, additional, Borbenyi, Zita, additional, Wegener, Antje, additional, Gazi, Lucien, additional, Acharyya, Suddhasatta, additional, Binlich, Florence, additional, and Ottmann, Oliver G., additional

Published
2015
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25. Incidence of ZAP70 Positivity in FreshSamples from UnselectedPatients Presenting with a B-Cell Lymphoproliferative Disorder.

Author

Petrie, James A., Milne, Tim, Ebrahim, Fatema, Cavenagh, Jamie D., and Agrawal, Samir G.

Abstract

The expression of ZAP70 has been shown to strongly correlate with unmutated immunoglobulin VH in chronic lymphocytic leukaemia (CLL) cells, which in turn has been shown to distinguish a CLL subgroup of poor prognosis. Retrospective studies have linked ZAP70 expression to a more aggressive clinical course and poorer overall survival in CLL. Previous studies on ZAP70 have largely utilised frozen material. We wanted to avoid the biases of using stored material, potential artefacts of the freeze/thawing process and expand our study beyond CLL. Hence, we analysed ZAP70 by flow cytometry in 184 consecutivecases of B-cell lymphoproliferative disorder (LPD). Only freshperipheral blood (PB) samples were used. A combination of ZAP 70 (Upstate Biotechnology), CD3 PE and CD56 PE (Coulter Immunotech) antibodies (Ab) were used to exclude the contaminating effects of T and NK cells. CD3 and CD56 staining was followed by fixation and permeabilisation (Dako Intracellular Antigen Kit) and addition of anti-ZAP70 Ab. Indirect labelling of ZAP70 was performed using a secondary conjugate IgG(H+L)-FITC (Southern Biotechnology). Positivity was established at the 20% threshold. 143 cases of CLL were examined for ZAP70 expression: 47 (33%) were positive, with the level of positivity ranging from 20 to 91% (median 41%). Three cases initially ascribed as negative, were subsequently found to be positive upon retesting at a later date. The ZAP70 negative cases of CLL had a median value of 1% (range, 0 – 14%). 41 non CLL cases were examined for ZAP70 expression, mantle cell lymphoma (MCL, 16 cases), hairy cell leukaemia (HCL, 3), diffuse large B-cell lymphoma (2) and 20 cases of B-cell LPD that could not be categorised further. Of these non CLL cases, only 4 were positive for ZAP 70 expression and all of these were cases of MCL (24 – 39% positivity.) The ZAP70 negative cases of MCL had a median value of 0% (range 0–17%). No other non CLL B-cell LPD showed levels of expression >10%. This study of flow cytometric analysis of ZAP70 expression in fresh, presentation PB of allLPDs referred to our laboratory revealed that 33% of CLL and 25% of MCL cases were positive. ZAP70 expression in CLL is bimodal (clearly positive or negative using the 20% threshold) with very few cases in the 10–19% range. No other B-cell LPDs were positive for ZAP70. As ZAP70 testing is now part of our routine LPD panel, ZAP70 positivity provides both diagnostic and prognostic information in CLL, helping to distinguish difficult CLL cases from non CLL (other than MCL). Our 3 cases of changing status may reflect improvements in our protocol or may indicate that ZAP70 status is variable over the course of the disease.

Published
2004
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