Improved multistate survival in younger AML patients over time

Over the last three decades, HOVON-SAKK has performed six randomized controlled trials (RCTs) in newly diagnosed younger adults with acute myeloid leukemia (AML). While overall survival (OS) improved over time, no OS benefit was apparent in individual RCTs. We investigated whether complete remission (CR) rates, postremission treatment (PRT), and/or a reduction of early mortality might have accounted for improved OS. Two multistate models, from the start of induction treatment until the date of death or last contact, were developed. These models included (1) CR ≤ 2 cycles and (2) CR followed by type of PRT as intermediate states and overall mortality as an end state. Patients were categorized by decade of diagnosis. Transition probabilities were adjusted for age and European LeukemiaNet (ELN) 2017 risk classification. Multistate survival (MS) was defined by the probability of obtaining CR with the intention or actual receipt of PRT and surviving thereafter. A total of 924, 1896, and 2253 patients were enrolled between 1987-1996, 1997-2006, and 2007-2017, respectively. OS at 5 years increased from 33 ± 2% to 47 ± 1% in the most recent cohort. CR rates increased from 77.5% to 83.9%. Sixty-day mortality decreased from 9.9% to 7.8%. The proportion of alloHSCT as PRT increased from 16.6% to 48.3%. MS at 5 years increased from 28.8% to 47.4% and from 11.3% to 26.1% for ELN17 intermediate and adverse risk patients, which was largely due to improved OS in CR patients proceeding to alloHSCT. Increased CR rates and an increased application of alloHSCT mainly accounted for improved MS and OS. MS, as a novel endpoint, effectively captures favorable treatment outcome, while allowing quantification of the survival gain of pivotal, subsequent intermediate states.