Minimal Residual Disease and IKZF1 As Predictors of Relapse, and Increased Treatment Related Mortality in Down Syndrome Acute Lymphoblastic Leukemia: A Unique and Large International Matched Case-Control Study

INTRODUCTION Down syndrome patients with acute lymphoblastic leukemia (DS ALL) are less likely to have a favorable (cyto)genetic subtype and are at higher risk of relapse and treatment-related mortality (TRM) than non-DS ALL (Buitenkamp et al., Blood 2014). At present, the independent predictive value of minimal residual disease (MRD) is unclear and may be biased by an unequal distribution of (cyto)genetic risk groups among DS ALL and non-DS ALL patients. This study was aimed to decipher the prognostic implications of MRD and IKZF1 deletions and the frequency of TRM in a matched cohort of DS ALL cases and non-DS ALL controls. METHODS Each DS ALL patient was matched to 3 non-DS ALL patients based on treatment protocol, induction treatment, cytogenetic subtype, IKZF1 status, age (cutoff at 10 years), and white blood cell count (cutoff at 50,000 cells/µl). For MRD analysis, matching was only on induction treatment and excluded the MRD-guided treatment arm; for survival analyses, matching included the MRD-guided treatment arm, thus resulting in two separately matched cohorts. Patients who died during induction were excluded from matching. Absolute MRD levels were measured with RQ-PCR, log-transformed and analyzed with a multilevel mixed-effects linear regression model. Matched Cox proportional hazard regression models were used to analyze event-free survival (EFS), overall-survival (OS), relapse-free survival (RFS) and mortality in remission as surrogate for TRM. RESULTS Patients treated between 2002 and 2018 on Dutch DCOG-ALL10/11 trials, Australian ANZCHOG-ALL8 and AIEOP-BFM-ALL2009 trials, and UKALL2003 trial were included, resulting in 160 DS ALL and 5313 non-DS ALL patients. Out of these 160 DS ALL patients, 13 died during induction versus 42/5313 non-DS ALL patients (8.1% versus 0.8%, p