Minimal Residual Disease, Long-Term Outcome, and <i>IKZF1</i> Deletions in Down Syndrome Acute Lymphoblastic Leukemia in a Matched Cohort Study

Abstract

Background: Down syndrome (DS) patients with acute lymphoblastic leukemia (ALL) are at a higher risk of treatment-related mortality and of relapse, which is influenced by a higher incidence of unfavorable genetic aberrations, such as IKZF1 deletion. We aimed to investigate the potential underlying effect of DS versus the impact of adverse cancer genetics on clinical outcome. Method: The association between DS and minimal residual disease (MRD) and clinical outcome was evaluated in a cohort of 136 DS ALL and 407 non-DS ALL pediatric patients matched for clinical risk factors and genetics, including IKZF1 deletion. Findings: The percentage of patients in the higher MRD category (≥1E-4) at the end of induction treatment did not significantly differ between DS ALL (38%) and matched non-DS ALL (39%; p=0·88). DS ALL was associated with a higher relapse risk compared with matched non-DS ALL in the IKZF1 -deleted group (cause-specific hazard ratio [HRcs], 4·3; 95% confidence interval [CI], 1·6 to 11, p=0·003), but not in the IKZF1 -wildtype group (HRcs, 1·0; 95% CI, 0·48 to 2·1; p=0·99). Our matched cohort confirmed that in addition to more induction deaths (6% versus 0·8%), DS ALL was associated with a higher risk of post-induction treatment-related mortality (HRcs, 5·0; 95% CI, 2·3 to 11; p<0·001). Interpretation: Our matched study shows that the increased relapse risk in DS ALL is not exclusively due to adverse cancer genetics, but DS itself provides an additional risk in IKZF1 -deleted cases, suggesting an interplay between the germline environment and this specific poor-risk somatic aberration. Funding Information: Stichting Kinder Oncologisch Centrum Rotterdam (SKOCR), NHMRC Australia, The Cancer Council NSW, Tour de Cure, Blood Cancer UK, UK MRC, Children with Cancer, and Swedish Society for Pediatric Cancer. Declaration of Interests: K.S: speaker and/or Advisory Board Honoraria from Jazz Pharmaceuticals and Servier; speaker fee from Amgen and Medscape; Educational grant from Servier. All other authors declare no conflict of interest. Ethics Approval Statement: The ethical review boards of each participating country or center approved treatment protocols according to local law and regulations. Written informed consent was obtained from patients, parents or guardians.