Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin with gemtuzumab ozogamicin improves event-free survival in younger patients with newly diagnosed aml and overall survival in patients with npm1 and flt3 mutations

Russell, Nigel H., Wilhelm-Benartzi, Charlotte ORCID: https://orcid.org/0000-0003-4927-6158, Othman, Jad, Dillon, Richard, Knapper, Steven ORCID: https://orcid.org/0000-0002-6405-4441, Batten, Leona M., Canham, Joanna ORCID: https://orcid.org/0000-0003-3482-0990, Hinson, Emily L., Betteridge, Sophie, Overgaard, Ulrik Malthe, Gilkes, Amanda, Potter, Nicola, Mehta, Priyanka, Kottaridis, Panagiotis, Cavenagh, Jamie, Hemmaway, Claire, Arnold, Claire, Freeman, Sylvie D., Dennis, Mike, Kallenbach, Maria, Severinsen, Marianne, Holm, Mette, Maxwell Norgaard, Jan, Beier Ommen, Hans, Culligan, Dominic, Tighe, Jane, Craig, Jenny, Crawley, Charles, Krishnamurthy, Pramila, Sadik, Walid, Smith, Jeffery, Dasgupta, Ranjit, Berkhan, Leanne, Bowett, Peter, Doocey, Richard, Emmett, Shannon, Hawkins, Timothy, Patton, Nigel, Pemberton, Lucy, Milne, Alison, Roy, Ashok, Simpson, Sylwia, Arnold, Claire, Cuthbert, Robert, Finnegan, Damian, Francis McMullin, Mary, Pechey, Victoria, Lovell, Richard, Milligan, Donald, Paneesha, Shankara, Cahalin, Paul, Kelsey, P., Ackroyd, Sam, Wiliams, Adrian, Evely, Roger, Marks, David, Mehta, Priyanka, Fletcher, Andrew, Al-Ani, Maryam, Ahmed, Khalil, Lush, Richard, Rye, Adam, Cutting, Robert, Fletcher, Andrew, Welch, Emma, Wodzinski, Mark, Butler, Andrew, Fernyhough, Liam, Ganly, Peter, Gibbons, Steve, Smith, Mark, Spearing, Ruth, Peniket, Andy, Hatcliffe, Faye, Patel, Amit, Lindsay, Kathrine, Brearton, Gillian, Tuegar, Salah, Gandhi Anna Cowley, S., Copplestone, Adrian, Hunter, Hannah, Medd, Patrick, Nokes, Tim, Rule, Simon, Thomas, Wayne, Cutting, Robert, Joseph, Joe, Kaul, Stuti, Sorour, Youssef, Chvuka, Shingi, Mangos, Hilda, Neylon, Annette, Farrell, Katrina, Edwards, Hugh, Hanlon, Katharine, Fail, Tom, Goodrick, Margaret, Heartin, Earnest, Hoyle, Christine, Rye, Adam, Carr, Robert, Raj, Kavita, Krogh Jensen, Morten, Janmohamed, Riaz, Kaczmarski, Richard, Sugai, Taku, Ademokun, Debo, Chalmers, Isobel, Hodson, Andrew, Gomez, Cesar, Sadullah, Shala, Kwan, Mark, Longmuir, Karyn, Wilson-Morkeh, Isaac, Hunter, Ann, Martin, Murray, Saravanamuttu, Kandeepan, Sidra, Gamal, Burns, Sarah, Gibbs, Simon, Tholouli, Eleni, Aldouri, Maadh, Andrews, Vivienne, Eden, Ayed, Dungarwalla, Moez, White, Denise, Laird, Jane, Mitchell, Lindsey, Murphy, John, Paterson, Pamela, Raafat, Alaeddin, Mannari, Deepak, Davies, Simon, Austen, Belinda, Allford, Sarah, Kakalamudi, Sudhakar, Basu, Supratik, Hada, Sunil, Jacob, Abraham, MacWhonell, Alan, McCaig, Alison, Gelly, Keith, Kerr, Ron, Meiklejohn, David, Tauro, Sudhir, Lawes, Matthew, Bowen, Angela, Krishnamurthy, Suchitra, Byrne, Jenny, Dasgupta, Emma, Russell, Nigel, Stokley, Simone, Friis, Lone, Marcher, Claus, Bake, Bart, Chapple, Mary, Moreton, Paul, Omran, Asad, Patil, Kavita, Wright, David, Jack, Fergus, Maddams, Rebecca, Corser, Robert, Cranfield, Tanya, Dignum, Helen, Ganczakowski, Mary, Jones, Christopher, Craddock, Charles, Moss, Paula, Murray, Jim, Hemmaway, Claire, Craig, Joanne, Forsyth, Peter, Lush, Chris, Wei Bjerrum, Ole, Borregaard, Niels, Kampmann, Peter, Kjeldsen, Lars, Juul Nielsen, Ove, Niemann, Carsten, Lykke Petersen, Soeren, Udby Peter Møller, Lene, Alfred, Arun, Barker, Helen, Went, Richard, Groch, Henri, Mucklow, Stuart, Sampson, Rebecca, Chacko, Joseph, Hall, Rachel, Walewska, Renata, Creach, Desmond, Pottinger, Bryson, Addada, Juanah (Jo), Hamilton, Malcolm, Kerr, Paul, Ngu, Loretta, Rudin, Claudius, Ruell, Jackie, Dalley, Chris, Kaur, Harpreet, Reilly, John, Snowden, John, Ferguson, Paul, Dyer, Peter, Chandra, Deepak, DeVos, Johannes, Grey-Davies, Elisabeth, Hendry, Louise, Corbett, Timothy, Crowe, Josephine, Knechtli, Christopher, Wexler, Sarah, Fernandes, Savio, Neilson, Jeff, Houghton, John, Jowitt, Simon, Thomas-Dewing, Rowena, Williams, Mark, Zaman, Sonya, Cullis, Jonathan, Everington, Tamara, Grand, Effie, Hasan, Yasmin, Murrin, Richard, Wandoo, Farooq, Ismail, Saad, Mohite, Unmesh, Sati, Hamdi, Jenner, Matthew, Orchard, Kim, Richardson, Deborah, McCloskey, Kayleigh, Xu Chin, Kate, Fenella Willis, Neoh, Sud, Amit, Gharib, Maged, Nicholson, Toby, Bowen, David, Janes, Sarah, Eagleton, Helen, O'Hea, Anne-Marie, Pattinson, Jonathan, Hervey, Victoria, Lyons, Simon, Marshall, Scott, Nicolle, Annette, Vavyla, Maria, Burgess, Jordan, Somervaille, Tim, Somerfield, Sven, Mamat, Mohd, Tomlins, Jo, Salesh, Sana, David, Marianna, Maddox, Jamie, Plews, Diane, Dang, Ray, Potter, Mike, Ellis, Lauren, Nicholson, Emma, Keat, Sally, Ahmed Alhassani, Thubeena M., Anjum, Farahn, Chatterjee, Poulami, Stanchev, Atanas, Peters, Jayne, Lindsay-Holmes Srividhya, Sarah, Chodhouri, Senthil S., Eve, Heather, Smith, Steve, Roberts, Patrick, Rymes, Nicholas, Zhao New Oo, Rui, Ardeshna, Kirit, Blombery, Piers, Khwaja, Asim, Linch, David, Popat, Rakesh, Virchis, Andres, Yong, Kwee, McIntyre, Victoria, Horne, Gillian, Bokhari, Syed, Borg, Anton, Chapman, Oliver, Harrison, Beth, Jackson, Nicholas, Jobanputra, Shailesh, Narayanan, Mekkali, Rose, Peter, Oun, Hajer, Powell, Matthew, Gilles, Julie, Laing, Alison, Devanny, Ian, Horne, Gillian, Haskins, Lea, Micallef-Eynaud, Paul, Maclean, Peter, Alvares, Caroline, Kell, Jonathan, Knapper, Steve, Davidson, Kerri, McLintock, Lorna, Rogers, Stephen, Williamson, Peter, Corbett, Gillian, Goodman, Hugh, Islam, Shahid, Pullon, Humphrey, Johnson, Peter, Roddie, P.H., Maughan, Elizabeth, Mills, Juliet, Shafeek, Salim, Narat, Santosh, Aitchison, Robin, Pattinson, Jonathan, Bond, Lee, Munro, Laura and Edwards, David 2024. Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin with gemtuzumab ozogamicin improves event-free survival in younger patients with newly diagnosed aml and overall survival in patients with npm1 and flt3 mutations. Journal of Clinical Oncology 42 (10) , pp. 1158-1168. 10.1200/JCO.23.00943

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Abstract

Purpose To determine the optimal induction chemotherapy regimen for younger adults with newly diagnosed AML without known adverse risk cytogenetics. Patients and Methods One thousand thirty-three patients were randomly assigned to intensified (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin [FLAG-Ida]) or standard (daunorubicin and Ara-C [DA]) induction chemotherapy, with one or two doses of gemtuzumab ozogamicin (GO). The primary end point was overall survival (OS). Results There was no difference in remission rate after two courses between FLAG-Ida + GO and DA + GO (complete remission [CR] + CR with incomplete hematologic recovery 93% v 91%) or in day 60 mortality (4.3% v 4.6%). There was no difference in OS (66% v 63%; P = .41); however, the risk of relapse was lower with FLAG-Ida + GO (24% v 41%; P < .001) and 3-year event-free survival was higher (57% v 45%; P < .001). In patients with an NPM1 mutation (30%), 3-year OS was significantly higher with FLAG-Ida + GO (82% v 64%; P = .005). NPM1 measurable residual disease (MRD) clearance was also greater, with 88% versus 77% becoming MRD-negative in peripheral blood after cycle 2 (P = .02). Three-year OS was also higher in patients with a FLT3 mutation (64% v 54%; P = .047). Fewer transplants were performed in patients receiving FLAG-Ida + GO (238 v 278; P = .02). There was no difference in outcome according to the number of GO doses, although NPM1 MRD clearance was higher with two doses in the DA arm. Patients with core binding factor AML treated with DA and one dose of GO had a 3-year OS of 96% with no survival benefit from FLAG-Ida + GO. Conclusion Overall, FLAG-Ida + GO significantly reduced relapse without improving OS. However, exploratory analyses show that patients with NPM1 and FLT3 mutations had substantial improvements in OS. By contrast, in patients with core binding factor AML, outcomes were excellent with DA + GO with no FLAG-Ida benefit.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Centre for Trials Research (CNTRR)
Publisher:	American Society of Clinical Oncology
ISSN:	0732-183X
Date of First Compliant Deposit:	28 March 2024
Date of Acceptance:	20 October 2023
Last Modified:	29 Jul 2024 12:29
URI:	https://orca.cardiff.ac.uk/id/eprint/167596

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