A randomised comparison of CPX-351 and FLAG-Ida in adverse karyotype AML and high-risk MDS: the UK NCRI AML19 trial

Othman, Jad, Wilhelm-Benartzi, Charlotte S. ORCID: https://orcid.org/0000-0003-4927-6158, Dillon, Richard, Knapper, Steven ORCID: https://orcid.org/0000-0002-6405-4441, Freeman, Sylvie D., Batten, Leona M., Canham, Joanna ORCID: https://orcid.org/0000-0003-3482-0990, Hinson, Emily L., Wych, Julie, Betteridge, Sophie, Villiers, William, Kleeman, Michelle, Gilkes, Amanda Frances, Potter, Nicola, Overgaard, Ulrik, Mehta, Priyanka, Kottaridis, Panagiotis, Cavenagh, Jamie, Hemmaway, Claire Jane, Arnold, Claire, Dennis, Mike and Russell, Nigel H. 2023. A randomised comparison of CPX-351 and FLAG-Ida in adverse karyotype AML and high-risk MDS: the UK NCRI AML19 trial. Blood Advances 7 (16) , pp. 4539-4549. 10.1182/bloodadvances.2023010276

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Abstract

Liposomal daunorubicin and cytarabine (CPX-351) improves overall survival (OS) compared to 7+3 chemotherapy in older patients with secondary acute myeloid leukaemia (AML); to date there have been no randomized studies in younger patients. The high-risk cohort of the UK NCRI AML19 trial (ISRCTN78449203) compared CPX-351 with FLAG-Ida in younger adults with newly-diagnosed adverse cytogenetic AML or high-risk myelodysplastic syndromes (MDS). 189 patients were randomized (median age 56y). By clinical criteria 49% had de novo AML, 20% secondary AML and 30% high risk MDS. MDS-related cytogenetics were present in 73% of patients, with complex karyotype in 49%. TP53 was the most commonly mutated gene, in 43%. Myelodysplasia-related gene mutations were present in 75 patients (44%). The overall response rate (CR + CRi) after course two was 64% and 76% for CPX-351 and FLAG-Ida (OR:0.54, 95%CI 0.28-1.04, p=0.06). There was no difference in OS (13.3 months vs 11.4 months, HR:0.78, 95%CI 0.55-1.12, p=0.17) or event-free survival (HR:0.90, 95%CI 0.64-1.27, p=0.55) in multivariable analyses. However, relapse-free survival was significantly longer with CPX-351 (median 22.1 vs 8.35 months, HR:0.58, 95% CI 0.36-0.95, p=0.03). There was no difference between the treatment arms in patients with clinically defined secondary AML (HR:1.1, 95%CI 0.52-2.30) or those with MDS-related cytogenetic abnormalities (HR:0.94, 95%CI 0.63-1.40), however an exploratory sub-group of patients with MDS-related gene mutations had significantly longer OS with CPX-351 (median 38.4 vs 16.3 months, HR:0.42, 95%CI 0.21-0.84, heterogeneity p=0.05). In conclusion, OS in younger patients with adverse risk AML/MDS was not significantly different between CPX-351 and FLAG-Ida.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Centre for Trials Research (CNTRR)
Publisher:	American Society of Hematology
ISSN:	2473-9529
Funders:	Cancer Research UK
Date of First Compliant Deposit:	11 July 2023
Date of Acceptance:	2 May 2023
Last Modified:	06 Jan 2024 03:07
URI:	https://orca.cardiff.ac.uk/id/eprint/160945

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