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 <i>NPM1</i> and <i>FLT3</i> Mutations
Nigel H. Russell, Charlotte S. Wilhelm-Benartzi, Jad Othman, Richard Dillon, Steven Knapper, Leona Batten, Joanna Canham, Emily L. Hinson, Sophie Betteridge, Ulrik Malthe Overgaard, Amanda Gilkes, Nicola Potter, Priyanka Mehta, Panagiotis Kottaridis, Jamie Cavenagh, Claire Hemmaway, Claire Arnold, Sylvie Freeman, Mike Dennis, Maria Kallenbach, Marianne Tang Severinsen, Mette Holm, Jan Maxwell Nørgaard, Hans Beier Ommen, Dominic Culligan, Jane Tighe, Jenny I. O. Craig, Charles Crawley, Pramila Krishnamurthy, Walid Sadik, Jeffery Smith, Ranjit Dasgupta, Leanne Berkhan, Peter Bowett, Richard Doocey, Shannon Emmett, Timothy Hawkins, Nigel Patton, Lucy Pemberton, Alison Milne, Ashok Roy, Sylwia Simpson, Claire Arnold, R Cuthbert, Damian Finnegan, Mary Francis McMullin, Victoria Pechey, Richard Lovell, Donald Milligan, Shankara Paneesha, Paul Cahalin, P. Kelsey, Sam Ackroyd, Adrian Wiliams, Roger S. Evely, David I. Marks, Priyanka Mehta, Andrew Fletcher, Maryam Al-Ani, Khalil Ahmed, Richard Lush, Adam Rye, Robert Cutting, Andrew Fletcher, Emma Welch, M.A. Wodzinski, Andrew M. Butler, Liam Fernyhough, Peter Ganly, Steve Gibbons, Mark Smith, Ruth Spearing, Andy Peniket, Faye Hatcliffe, Amit K. Patel, Kathrine Lindsay, Gillian Brearton, Salah Tuegar, S. Cowley, Adrian Copplestone, Hannah Hunter, Patrick Medd, Tim Nokes, Simon Rule, Wayne Thomas, Robert Cutting, Joe Joseph, Stuti Kaul, Youssef Sorour, Shingi Chvuka, Hilda Mangos, Annette Neylon, Katrina Farrell, Hugh Edwards, Katharine Hanlon, Tom Fail, Margaret Goodrick, Earnest Heartin, Christine Hoyle, Adam Rye
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.