Children with Down Syndrome have a much higher risk of acute lymphoblastic leukaemia (ALL) and generally have a worse treatment outcome. Initial findings from the ALLTogether DS trial demonstrated that blinatumomab for first-line treatment of intermediate and high risk Down Syndrome B-cell ALL showed impressive activity, with high minimal residual disease clearance rates. Although there was an improved overall toxicity profile compared to UKALL 2011 consolidation, an increased rate of seizures in patients older than ten years was reported.
own syndrome leads to a 10-20 fold increased risk of acute lymphoblastic leukaemia (ALL), accounting for 2-3% of all paediatric cases. These patients generally have a worse outcome due to higher treatment-related mortality and disease resistance. Blinatumomab, a CD3-/CD19-directed bispecific T-cell engager, improves outcomes in relapsed/refractory B precursor ALL (B-ALL), and has shown promise in a frontline setting for both children and adults. Samarsinghe et al. hypothesised that blinatumomab can successfully replace chemotherapy consolidation in children with Down Syndrome ALL.
Eligible patients were those with Down Syndrome enrolled on the ALLTogether1 protocol, aged 0-45 years, with newly diagnosed CD19 positive B-ALL who were minimal residual disease (MRD) positive at the end of induction (EOI) by flow cytometry or Ig/TCR molecular techniques. Patients had consolidation chemotherapy replaced with two 28-day (D) blocks of blinatumomab, with response assessed by flow/molecular techniques at D15/D28 cycle 1, and D28 cycle 2. Outcomes were compared to Down Syndrome B-ALL patients from the UKALL 2011 trial who were MRD positive at EOI (efficacy cohort, N= 33), and those with toxicity data who received chemotherapy regimens approximate to what patients would have received on UKALL 2011 instead of blinatumomab (regimen B/C, toxicity cohort, N= 22). Primary endpoint of the study was the fraction of MRD undetectable patients at end of blinatumomab cycle 1. Secondary endpoint were the rate of adverse events and improved leukaemia specific outcomes.
The induction backbone was based on what was used in UKALL 2011 (dexamethasone, asparaginase, and vincristine or daunorubicin), of which daunorubicin was added for slow early responders on day 15. Following induction death in May 2021, the use of daunorubicin was stopped. Following further induction deaths, researchers switched since February 2023 from dexamethasone to prednisolone. Since then, no further induction deaths occurred.
In total, 53 patients rolled on to the study but 20 were not eligible, predominantly because they were MRD undetectable. Of the 33 patients who were treated with cycle 1, two could not complete cycle 1 because of neurotoxicity. Both, however, became MRD undetectable. All remaining 31 patients had undetectable MRD (MRD undetectable rate: 31/33= 91%), which proved to be significantly higher than the 61% observed in historical controls treated with chemotherapy in the UKALL 2011 study. All 31 patients went on to receive cycle 2 but a further three patients had to stop treatment because of seizures (N= 2) or viral pneumonitis (N= 1). After a median follow-up of 15 months, in the entire cohort, no deaths, relapses, or secondary cancers have been observed; as such, the event-free survival (EFS) and overall survival (OS) rates are at 100%.
Adverse events (AEs) were reported in 77.3% of patients in de UKALL 2011 study and in 39.4% of patients in the ALLTogether-DS study. Seizures were reported in 18.2% of patients in the ALLTogether-DS study, despite the majority (29/33) receiving prophylactic levetiracetam. However, all cases resolved and all patients had undetectable MRD. Seizures were significantly more present in patients >10 years old as compared to the younger patients (56.6% vs. 4.2%, p= 0.003). Based on these data, the prophylaxis against epileptic seizures has been adjusted. It is recommended to start levetiracetam one week before the first cycle of blinatumomab (10 mg/kg twice daily for two weeks and 15 mg/kg from week 3) until the end of the second cycle of blinatumomab. More patients and a longer follow-up are needed to assess whether these favourable results will translate into better survival.
The replacement of consolidation chemotherapy blocks with blinatumomab for children with Down Syndrome B-ALL showed impressive activity, with MRD clearance rates of 91%. Although there was an improved overall toxicity profile compared to UKALL 2011 consolidation, there was a high rate of seizures in patients >10 years.
Reference
Samarasinghe S, et al. Blinatumomab for first line treatment in intermediate and high risk down syndrome B-cell Acute lymphoblastic leukaemia: initial findings from the ALLTogether1 DS trial. Presented at EHA 2024; Abstract S111.
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