Characteristics and Outcomes Of Patients With Down Syndrome Associated Acute Lymphoblastic Leukaemia Treated On UKALL 2003

Children with Down Syndrome (DS) are at significantly increased risk of developing acute leukaemia, both AML and ALL. Whilst outcomes for AML are excellent, ALL associated with DS (DS-ALL) confers an inferior survival due to a combination of increased relapse risk and high treatment related mortality (TRM). We report the outcome for children and young adults with DS-ALL treated on a modern, intensive, minimal residual disease (MRD) directed protocol, UKALL2003.

Treatment was not modified for DS-ALL patients at the start of the trial. NCI standard risk patients received a 3 drug induction with dexamethasone, vincristine and pegylated asparaginase. NCI high risk patients also received daunorubicin. MRD was measured at day 29 and MRD negative patients were randomised to standard or reduced intensity therapy. MRD high risk patients were randomised to standard therapy or an intensified regime consisting of augmented BFM consolidation, escalating Capizzi methotrexate and 2 delayed intensifications. Six years after the trial opened, an unacceptably high TRM in DS patients, (10 deaths out of 46 patients), prompted modifications to their treatment. DS patients were excluded from randomisations and, regardless of NCI risk, received a three drug induction with the addition of daunorubicin at day 15 for those with a slow morphological marrow response (>25% blasts). Patients with positive MRD at day 29 or those with a slow day 15 morphological response were treated with augmented therapy described above, in the absence of established significant comorbidity. All patients received only one delayed intensification and maintenance was shortened to 2 years for boys (standard duration 3 years).Strict supportive care measures during intensive phases of treatment were mandated.

Of 3126 eligible patients in the trial, 85 (2.7%) had DS with median age 4 years (range 1-23 years). DS-ALL patients were more likely than non-DS-ALL patients to be male (68% vs 56%, p=0.03) and were almost exclusively B-cell precursor ALL (99 % vs 87%, p=0.001), but there were no significant differences by age, WBC or NCI risk. Nine of 80 DS-ALL patients from whom data on cytogenetic abnormalities was available had high hyperdiploidy (11% vs 30% in non-DS-ALL, p=0.0003), and 13 had an ETV6/RUNX1 fusion (16% vs 25%, p=0.06).

With a median follow-up of 4 years 10 months, patients with DS-ALL had an inferior EFS compared to non-DS-ALL patients (65.3% (95% CI 54.5-76.1%) at 5 years vs. 87.8% (86.4-89.2%); OR=8.90 (95% CI: 4.53-17.48) p<0.00005). Of the 85 DS-ALL patients, 25 have died, 7 due to relapsed disease, 2 due to induction failure and death with active disease and 16 due to TRM during first line therapy. TRM deaths occurred throughout treatment (induction = 5, CR = 11) and were not confined to the most intensive phases. In all cases, deaths were due to infection, most commonly bacterial sepsis (75%) and viral pneumonitis (25%). The excess TRM was primarily responsible for the worse EFS for DS patients, as their risk of relapse (16.4% at 5 years ) was not significantly worse (p=0.1) than for non-DS patients (8.8%).

In contrast to other recently reported studies, we report excess TRM as the main cause of treatment failure in DS-ALL, possibly due to the intensity of our treatment protocol which included dexamethasone and pegylated asparaginase for all patients. There have been fewer treatment related deaths in induction after introducing the treatment modifications in 2009 (4/46 vs 1/41) without an apparent increase in relapse risk. Improvements in outcome for this vulnerable group of patients will require such risk stratified treatment modifications, better supportive care and innovative agents that can replace the more intensive elements of current treatment schedules.