Blinatumomab May Be an Effective Alternative to Consolidation Chemotherapy in Down Syndrome B-ALL

Treatment with first-line blinatumomab (Blincyto) in lieu of consolidation chemotherapy could address a critical need for less toxic regimens among children with Down syndrome and intermediate- to high-risk acute lymphoblastic leukemia (ALL), who historically experience poor survival outcomes due to high treatment-related mortality and disease resistance, according to Sujith Samarasinghe, BSc, MBBS, MRCPCH, FRCPath, PhD.¹

Initial data from the phase 2 ALLTogether1 DS study (NCT043067576) presented at the 2024 EHA Congress showed improved clearance rates of minimal residual disease (MRD) with first-line blinatumomab compared with chemotherapy blocks in this patient population, meeting the study’s primary end point. Undetectable MRD rates in evaluable patients at the end of cycle 1 were 91% (95% CI, 79.8%-99.3%) with blinatumomab (n = 33), and 61% among patients in a historical control arm treated with chemotherapy in the UKALL 2011 study (EudraCT/CTIS: 2010-020924-22; n = 22). Moreover, at a median follow-up of 15 months (interquartile range, 6.4-22.1) the event-free survival and overall survival rates were both 100% in the overall cohort.

Regarding safety, 77.3% of patients in the historical control arm experienced a grade 3/4 adverse effect (AE) vs 39.4% of those given blinatumomab (P = .0057). Notably, a trend for a higher rate of seizures with blinatumomab was observed in patients over 10 years of age, at 18.2% vs 4.5% in the blinatumomab and historical chemotherapy arms, respectively, (P = .14).

“The data in terms of MRD clearance were stunning,” Samarasinghe, who serves as a consultant in pediatric hematology and the Hematology Specialty Lead at Great Ormand Street Hospital in London, United Kingdom, stated during an interview with OncLive®. “For patients both with and without Down syndrome [who have] ALL, this [drug] is a game changer.”

In the interview, Samarasinghe explained how replacing chemotherapy with blinatumomab in the front line could address the unique challenges experienced by children with Down syndrome ALL; discussed key efficacy and safety results with this approach from the ALLTogether1 DS study; and outlined plans to introduce blinatumomab earlier in the treatment course to potentially reduce early mortality.

OncLive: What was the rationale for evaluating blinatumomab as a replacement for consolidation chemotherapy in the first-line management of Down syndrome ALL?

Samarasinghe:Children and young people with Down syndrome have a much higher risk of developing ALL. However, they are characterized by a much higher treatment-related mortality [rate] and high rates of disease resistance. Survival outcomes for children with Down syndrome and ALL are approximately 20% lower than [those for] children who don’t have [Down syndrome] ALL. Accordingly, there’s a real unmet need [in this patient population] for new, innovative treatments that are less toxic. One idea we came up with was to use blinatumomab in the front line as a replacement for toxic consolidation chemotherapy.

What baseline characteristics from the study population should be noted?

Patients had to have Down syndrome and CD19-positive [ALL], but they also had to be MRD-positive at the end of induction because the primary end point was an MRD-based end point. However, patients who had MRD of 25% or more were not eligible for the study.

How did the MRD clearance rates for patients treated with blinatumomab compare with those of patients in the historical control arm treated with chemotherapy?

We recruited 33 patients into the study, and in cycle 1, 2 patients had to come off [treatment] and couldn’t complete cycle 1 due to seizures. That left 31 patients who completed cycle 1. When we evaluated MRD clearance rates, all patients had a complete MRD response rate of 91%, which was significantly better than [the MRD response rate seen among patients in the] historical control arm treated with chemotherapy [in the UKALL 2011 study], which was 61%.

What were the differences in toxicities between the blinatumomab and historical control arms, and how did the study address the higher rate of seizures observed with blinatumomab?

First, we looked at [the rates of] grade 3/4 AEs in the blinatumomab cycle and compared those with the [AEs observed at] equivalent time points in the historical control [patients who received] chemotherapy. We found that 77.3% of patients in the historical control arm experienced a grade 3/4 AE; in [our] study, [this rate] was 39.4%, so [the incidence was] significantly lower. However, there was a trend [for a] higher rate of seizures in the Down Syndrome blinatumomab arm, at 18.2% vs 4.5% in the historical control [arm].

We’ve brought in new measures to reduce the rate of seizures. We’re starting prophylactic levetiracetam 1 week before we administer blinatumomab. That means [patients experience] therapeutic levels [of this prophylaxis] before we start [treatment] with the agent. We also dose escalate the levetiracetam 2 weeks into treatment, so we’ll get optimal dosing.

What next steps are planned for this research?

In the next iteration [of this research, we aim to] bring blinatumomab earlier [in the treatment course]. We found that we were losing 1 in 10 children in the induction [phase] before they could benefit from blinatumomab. The idea is to give blinatumomab at day 15, once we’ve debulked the blast percentage to below 55%.

[Ultimately,] blinatumomab has generated stunning results in terms of efficacy for the whole population, including patients who don’t have Down syndrome, and has [been shown to] reduce AEs as well.

Reference

Hodder A, Kirkwood A, van der Sluis I, 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. HemaSphere. 2024;8(suppl 1):S111