Frontline Blinatumomab Demonstrates “Impressive” Activity in Down Syndrome B-ALL

Sujith Samarasinghe, BSc, MBBS,
MRCPCH, FRCPath, PhD

Blinatumomab (Blincyto) consolidation led to improved minimal residual disease (MRD) clearance rates compared with chemotherapy blocks in patients with Down syndrome (DS) B-precursor acute lymphoblastic leukemia (B-ALL), according to data from the ALLTogether1 DS study (NCT043067576) presented during the 2024 European Hematology Association (EHA) Congress.¹

At the end of cycle 1, the undetectable MRD rate with blinatumomab was 91% (95% CI, 79.8%-99.3%) in evaluable patients (n = 33), which proved to be significantly higher than the 61% observed in historical controls treated with chemotherapy in the UKALL 2011 study (EudraCT/CTIS: 2010-020924-22; n = 22),2 meeting the trial’s primary end point.

With regard to secondary end points, at a median follow-up of 15 months (IQR, 6.4-22.1) 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%.

Moreover, a lower rate of adverse effects (AEs) has been reported with blinatumomab vs historical controls who received chemotherapy in the same period. Of the 22 controls treated with 2 cycles of chemotherapy consolidation, 77.3% experienced a grade 3/4 AE vs 39.4% of those given blinatumomab (P = .0057). However, a trend for a higher rate of seizures was observed in patients over 10 years of age, at 18.2% in the blinatumomab arm and 4.5% in the historical chemotherapy arm (P = .14).

“Our data show that blinatumomab has shown really impressive activity,” Sujith Samarasinghe, BSc, MBBS, MRCPCH, FRCPath, PhD, a consultant in pediatric hematology and Haematology Specialty Lead at Great Ormand Street Hospital in London, United Kingdom, said in a presentation of the data. “We have [also] shown a high rate of seizures in the over 10 [year olds], but not in the under 10 [year olds]. We have met the primary end point [in that] we have shown that blinatumomab has shown enhanced MRD clearance, over 90%.”

Those with Down syndrome have a higher risk of developing ALL, although it is rare—accounting for approximately 2% to 3% of all pediatric ALL cases, Samarasinghe said. “It’s nearly always exclusively B precursor [though, which] is a really high-risk cohort. It’s characterized by higher disease resistance, but also, worse outcomes due to high treatment-related mortality.”

He cited that a Ponte di Legno retrospective study3 previously demonstrated that in patients with Down syndrome enrolled across 16 trials from 1995 to 2004 (n = 653), outcomes were “suboptimal.” The 8-year EFS rate reported in these patients was 64%, the OS rate was 74%, and the treatment-related mortality rate was 7%. Another study,4 conducted more recently, showed that outcomes remain suboptimal, even with enhanced supportive care and reduced chemotherapy intensity. The 5-year EFS and OS rates were 69% and 83%, respectively. “If you were MRD persistently positive at the end of consolidation, outcomes are really poor, with a 26% EFS rate,” he added. “Therefore, we desperately need new innovative approaches.”

Investigators hypothesized that replacing chemotherapy consolidation with blinatumomab could lead to increased efficacy with greater MRD clearance and increased safety with reduced treatment-related mortality. To examine this further, they launched the single-arm, international, phase 2 ALLTogether1 DS study. They compared outcomes with those of patients with Down Syndrome enrolled on the UKALL 2011 trial.

To be eligible, patients needed to be treated and registered according to the trial protocol. They needed to be between the ages of 0 and 45 years, have newly diagnosed, CD19-positive B-ALL, and Down syndrome. “One of the primary end points was based upon MRD. Therefore, one of the key inclusion criteria was, you had to be MRD positive at the end of induction. However, patients who had an MRD level of 25% or more were excluded,” Samarasinghe noted. Because these patients had Down syndrome and had detectable MRD at the end of induction, they were classified as intermediate or high risk. “But as I mentioned to you, this is really a high-risk cohort,” he said.

Those included in the standard-of-care arm received induction treatment, followed by 2 cycles of chemotherapy consolidation. They then received delayed intensification and subsequent maintenance treatment. Those in the experimental arm received induction treatment, followed by 2 cycles of blinatumomab consolidation, and then delayed intensification and maintenance.

MRD assessments were done at the end of induction, day 15 of cycle 1 of consolidation, end of cycle 1 of consolidation, and end of cycle 2 of consolidation, among other time points. “We did our MRD assessments, and if they met their relevant thresholds, they could then carry on with delayed intensification [and] maintenance,” Samarasinghe explained. “If they didn’t meet their relevant thresholds, then that was classified as therapy failure, and they received more intensive chemotherapy.”

The primary end point was the proportion of MRD undetectable patients at the end of 1 cycle of blinatumomab. Based on prior research, they assumed 80% of patients would become MRD undetectable with blinatumomab, and they calculated that 50 patients would need to be recruited to the study. Secondary end points included grade 3/4 AE rates vs controls on UKALL 2011 and improved leukemia-specific outcomes, specifically incidences of protocol therapy failure and relapsed and death in complete remission.

The induction backbone was based on what was used in UKALL 2011, Samarasinghe said, which was dexamethasone, asparaginase, and vincristine or daunorubicin, which was added for slow early responders on day 15. However, after induction deaths, daunorubicin was omitted in May 2021. “Following further induction deaths, we have now switched [since] February 2023 from dexamethasone to prednisolone, and since then, we haven’t seen any further induction deaths,” he added. After blinatumomab, patients received delayed intensification and maintenance with monthly pulses. “Two years of maintenance [were given] for boys and girls,” he said.

A total of 53 patients were enrolled in the ALLTogether1 DS study but 20 patients were not eligible due to induction death (n = 4), death in first complete remission (n = 1), and MRD undetectability (n = 15). There was also a high induction death rate of 9.4%, Samarasinghe added. The remaining 33 patients were included in the analysis. The population included patients between the ages of 1 and 5 years (n = 16), 6 and 10 years (n = 8), and 11 and 25 years (n = 9). Most patients were male (n = 19). Genetic subtypes included B-other (n = 2), high hyperdiploid (n = 3), ETV6::RUNX1 (n = 1), iAMP21 (n = 1), and low hypodiploid (n = 1).

All 33 patients received 1 cycle of treatment, with 2 patients stopping because of neurotoxicity; both of these patients achieved undetectable MRD off study. All remaining 31 patients had undetectable MRD and went on to receive cycle 2 of treatment. Three additional patients stopped treatment due to neurotoxicity (n = 2) and viral pneumonitis (n = 1). “All 33 have rejoined the study,” Samarasinghe said.

Additional data indicated that the rate of seizures in those above 10 years was 56.6% on the AllTogether1 DS study vs 4.2% in those 10 years and younger (P = .003). “The only predictive marker for seizures that we could identify was age [and the rate of seizures was] significantly higher with the older patients,” Samarasinghe said.

Notably, 18.2% of patients developed seizures despite most (n = 29) of them receiving prophylactic treatment with levetiracetam. “Looking at the timeline for seizures, you can see in cycle 1 and cycle 2, they’re all teenagers except for one,” he noted. Four of 6 patients experienced their first seizure event in cycle 1, 5 of 6 patients were rechallenged, and 3 of 5 experienced a second event and stopped. He added that “Four were grade 2, one was grade 3, and one was grade 4.”

After the updated data, investigators changed their supportive care for seizure prophylaxis. The new recommendation is to begin levetiracetam 1 week before to achieve therapeutic levels prior to initiating blinatumomab. “We also dose escalated levetiracetam 2 weeks after starting,” he added. “For patients who had seizures that are grade 2 or lower and you plan to restart, in addition to giving levetiracetam, given them phenytoin and restart the blinatumomab at a lower dose.”

Samarasinghe concluded by saying further follow-up is needed for additional assessment.

Disclosures: Dr Samarasinghe disclosed that blinatumomab was supplied by Amgen and educational honoraria was received by Amgen.

References

1. 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.
2. Ghorashian S, Samarasinghe S, Kirkwood AA, et al. Preliminary outcomes of children and young adults with acute lymphoblastic leukaemia and Down Syndrome (DS-ALL) on UKALL 2011. Reduction in treatment-related mortality with de-escalated therapy. Blood. 2018;32(suppl 1):656. doi:10.1182/blood-2018-99-118426
3. Buitenkamp TD, Izraeli S, Zimmermann M, et al. Acute lymphoblastic leukemia in children with Down syndrome: a retrospective analysis from the Pontre di Legno study group. Blood. 2014;123(1):70-77. doi:10.1182/blood-2013-06-509463
4. Rabin KR, Devidas M, Chen Z, et al. Outcomes in children, adolescents, and young adults with Down Syndrome and ALL: a report from the Children’s Oncology Group. J Clin Oncol. 2023;42(2). doi:10.1200/JCO.23.00389