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
Authors: Russell Nigel H. , Wilhelm-Benartzi Charlotte , Othman Jad , Dillon Richard , Knapper Steven , Batten Leona M. , Canham Joanna , 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 , Edwards David 
Published: January 2024

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.