Outcomes in children with Down syndrome (DS) and B-lymphoblastic leukemia (B-ALL): A Children’s Oncology Group (COG) report.

Abstract

10510 Background: Patients with DS and B-ALL experience increased rates of relapse and toxicities. Here, we report results from 4 COG trials (2003-2018). Methods: We analyzed clinical, and outcome data for DS (n = 743) and non-DS (n = 21,703) patients age 1-30 enrolled on standard-risk (SR) trials AALL0331 and AALL0932 and high-risk (HR) trials AALL0232 and AALL1131. Initially, DS-ALL patients on AALL0232/AALL0331 experienced excess mortality, prompting enhanced supportive care and omission of induction anthracycline except for slow responders on AALL1131. Other modifications included: non-random assignment to treatment strata without investigational agents; leucovorin rescue after intrathecal methotrexate (MTX); equal maintenance length for boys and girls; every 12-week maintenance vincristine/steroid pulses; and reduced anthracycline and intravenous MTX for HR patients. Results: Across all 4 trials, DS and non-DS patients did not differ significantly in age, sex, initial WBC, or CNS status. DS-ALL patients had significantly higher end of induction (EOI) minimal residual disease (MRD) vs non-DS patients on both AALL0932 and AALL1131, but the difference persisted at end of consolidation (EOC) only on AALL1131, with fewer EOI MRD+ DS patients achieving EOC MRD < 0.01% (76.1 vs 88.0%, p = 0.001). 5-year EFS and OS were significantly poorer for DS vs non-DS across all trials (EFS 79.6+2.1% vs 86.3+0.3%, p < 0.0001; OS 86.5+1.8% vs 93.1+0.2%, p < 0.0001), as well as on each individual trial. In Cox regression analysis for all DS patients, inferior EFS was associated with several known risk factors (age > 10, EOI MRD >0.01%) but not with cytogenetics or CRLF2 status Induction death was more frequent in DS patients (3.4% vs 0.8%, p < 0.0001) as was death in remission (4.8+0.8% vs 1.8+0.1%, p < 0.0001). For death in remission, the increased frequency occurred pre-maintenance and in patients taken off protocol therapy, but not during maintenance, in contrast to prior reports. Grade >3 mucositis, infections, and hyperglycemia were significantly more frequent in DS patients on all trials. Grade >3 seizures were significantly more frequent in DS patients on HR but not SR trials (4.1% vs 1.7%. p = 0.001) and occurred in all phases pre-maintenance. Conclusions: Patients with DS and B-ALL continue to have inferior outcomes compared to non-DS, with increased relapse and toxicities. Less toxic approaches such as immunotherapies and targeted therapies hold promise to improve outcomes in both these areas.