In a phase II trial reported in The New England Journal of Medicine, van der Sluis et al found that the addition of blinatumomab—a bispecific T-cell engager molecule targeting CD19—to standard chemotherapy appeared to result in marked improvements in outcome among infants with KMT2A-rearranged acute lymphoblastic leukemia (ALL) compared with historical controls.
As stated by the investigators, “KMT2A-rearranged ALL in infants is an aggressive disease with a 3-year event-free survival of below 40%. Most relapses occur during treatment, with two-thirds occurring within 1 year and 90% within 2 years of diagnosis. Outcomes have not improved in recent decades despite intensification of chemotherapy.”
Study Details
In the trial, 30 patients aged < 1 year enrolled at sites in nine countries between July 2018 and July 2021 received 1 month of induction chemotherapy used in the Interfant-06 trial, followed by one postinduction course of blinatumomab at 15 μg/m2 per day via 28-day continuous infusion. Following blinatumomab, patients continued treatment in accordance with the Interfant-06 protocol, with consecutive courses of protocol IB (cyclophosphamide, cytarabine, and mercaptopurine), MARMA (high-dose cytarabine, high-dose methotrexate, mercaptopurine, and asparaginase), OCTADAD (vincristine, dexamethasone, asparaginase, daunorubicin, thioguanine, cytarabine, and cyclophosphamide), and maintenance therapy (mercaptopurine and methotrexate).
The primary endpoint was clinically relevant toxic effects, defined as any toxic effect that was possibly or definitely attributable to blinatumomab and resulted in permanent discontinuation of blinatumomab or death. Outcome data were compared with historical control data from the Interfant-06 trial.
KEY POINTS
- No adverse event considered possibly or definitely attributable to blinatumomab resulted in permanent discontinuation of blinatumomab or death.
- When comparing the blinatumomab regimen with historical controls in Interfant-06, 2-year disease-free survival was 81.6% vs 49.4% and 2-year overall survival was 93.3% vs 65.8%.
Safety Outcomes
Median follow-up was 26.3 months (range = 3.9–48.2 months). All 30 patients received the full course of blinatumomab. No toxic effects meeting the definition of the primary endpoint occurred. From the start of the blinatumomab treatment period to the next chemotherapy block, 10 serious adverse events were reported in nine patients (fever in four, infection in four, hypertension in one, and vomiting in one). No fatal adverse events occurred, and no neurologic adverse events were reported. The most common grade 3 or 4 adverse events were anemia (17%), febrile neutropenia (7%), neutropenia (7%), and elevated γ-glutamyltransferase (7%).
Responses and Survival Outcomes
After blinatumomab infusion, 28 patients (93%) were measurable residual disease (MRD)-negative (n = 16) or had low levels of MRD (< 5×10−4; ie, < 5 leukemic cells per 10,000 normal cells; n = 12). All patients who continued chemotherapy became MRD-negative during treatment.
Disease-free survival at 2 years was 81.6% (95% confidence interval [CI] = 60.8%–92.0%) in the current study, compared with 49.4% (95% CI = 42.5%–56.0%) in the Interfant-06 trial. Overall survival at 2 years was 93.3% (95% CI = 75.9%–98.3%) compared with 65.8% (95% CI = 58.9%–71.8%).
The investigators concluded, “Blinatumomab added to Interfant-06 chemotherapy appeared to be safe and had a high level of efficacy in infants with newly diagnosed KMT2A-rearranged ALL as compared with historical controls from the Interfant-06 trial.”
Inge M. van der Sluis, MD, PhD, of the Princess Maxima Center for Pediatric Oncology, Utrecht, the Netherlands, is the corresponding author for The New England Journal of Medicine article.
Disclosure: The study was funded by the Princess Maxima Center Foundation and others. For full disclosures of the study authors, visit nejm.org.
