Safety and Feasibility of Blinatumomab As Frontline Therapy for Pediatric Patients with B-Acute Lymphoblastic Leukemia and Lymphoma: St. Jude Total Therapy Study XVII
Authors: Duffy Caitlyn , Dang Elizabeth , Yinmei Zhou , Bell Jessica , Bhakta Nickhill , Henry Meret , Heym Kenneth Matthew , Jeha Sima , Lacayo Norman J. , Karol Seth E. , Khaw Seong Lin , Ribeiro Raul C. , Schiff Deborah E. , Mullighan Charles G. , Yang Jun J. , Cheng Cheng , Pui Ching-Hon , Inaba Hiroto 
Published: December 2024

Background
Total Therapy Studies XV and XVI demonstrated that, for children with acute lymphoblastic leukemia (ALL), minimal residual disease (MRD) ≥ 0.01% at the end of induction (EOI) and/or high-risk (HR) genetic subtypes were associated with poorer outcomes. In Total Therapy Study XVII, children with ALL and lymphoblastic lymphoma (LLy) were treated with a precision medicine approach using flow cytometry-based MRD detection and next-generation sequencing-based genetic characterization. Blinatumomab, a bispecific T-cell engager, is indicated for treating B-ALL. This study evaluated the safety of blinatumomab in pediatric patients with B-ALL/LLy who had HR features or were intolerant of conventional chemotherapy.
Methods
Between 2017-2023, children aged 1-18 years at diagnosis received blinatumomab in St. Jude Total Therapy Study XVII. Per protocol, up to 2 consecutive cycles of blinatumomab were administered after consolidation therapy to patients with EOI MRD of 0.01%-1% and/or HR genetic subtypes (BCR::ABL1, BCR::ABL-like [with JAK-STAT activating mutations or ABL1-class fusions], iAMP21, hypodiploidy, MEF2D fusions, ETV6::RUNX1-like, TCF3::HLF, BCL2/MYC) or Down syndrome (DS) (protocol-defined patients). Blinatumomab was also administered as interim therapy to patients who were intolerant of conventional chemotherapy (interim therapy patients). Safety and feasibility of blinatumomab were assessed by evaluating adverse events (AEs) (CTCAE version 4.0) and number and etiology of cycle interruptions and discontinuations.
Results
Of 621 patients (612 B-ALL, 9 B-LLy) enrolled in Total Therapy Study XVII, 147 patients (144 B-ALL, 3 B-LLy) (median age: 8.1 years [range: 1.0-18.1 years]) received blinatumomab. Of these, 116 (17 MRD only, 77 HR genetic subtypes, 6 DS, 15 both MRD and genetic criteria, and 1 both MRD and DS) received 223 cycles per protocol indications. Thirty-one received 56 cycles as part of interim therapy with common indications including pancreatitis (n=7, 22.6%), fungal infection (n=7, 22.6%), physician preference (n=4, 12.9%), and pegaspargase allergy (n=3, 9.7%).
In protocol-defined patients, 10 events (9 patients) of cytokine release syndrome (CRS) (8 events in cycle 1, 3 grade ≥3) were observed, and 4 events (4 patients) of neurotoxicity (NT) (4 in cycle 1, 1 grade ≥3) including 3 seizures, 30 events (25 patients) of fever (19 in cycle 1, 29 grade ≥3, median time to onset: 2 days), 7 events (6 patients) of febrile neutropenia (6 in cycle 1, 7 grade ≥3, median time to onset: 2 days), 31 events (27 patients) of infection (17 in cycle 2, 14 grade ≥3). Upper respiratory viral infection was most common and observed in 21 events (18 patients) (11 in cycle 2, 12 grade ≥3). In patients who received interim therapy, 1 event of CRS (0 grade ≥3) was observed in cycle 2, and 3 events (2 patients) of NT (2 in cycle 2, 2 grade ≥3), 2 events (2 patients) of fever (1 in cycle 1, 1 in cycle 2, 2 grade ≥3, median time to onset: 6 days), 0 events of febrile neutropenia, 3 events (3 patients) of infection (2 in cycle 2, 3 grade ≥3) including 1 event of upper respiratory viral infection.
Among total 279 cycles, 57 interruptions occurred in 46 cycles (16.5%, 43 patients) (median 7 days from infusion initiation [range: 1-28 days] for 43 interruptions during cycle 1; median 9 days from initiation [range: 0-27 days] for 14 interruptions during cycle 2). Thirty-nine interruptions (68.4%) lasted &gt;4 hours, and 19 (33.3% of interruptions, 42.2% of cycles) resulted in permanent discontinuation (median 5.5 days from infusion initiation [range: 2-15 days] for 6 discontinuations during cycle 1; median 15 days from initiation [range: 0-27 days] for 13 discontinuations during cycle 2). Interruptions were attributed to equipment issues (n=21, 36.8%), physician or family preference (n=11, 19.3%), or AEs (n=25, 43.9%). The most common AEs requiring interruptions were NT (n=12, 21.1%; 5 seizures) and CRS (n=6, 10.5%). For discontinuation, common reasons were NT (n=6, 31.6%; 2 seizures), arrhythmia (n=2, 10.5%), and family preference (n=2, 10.5%).
Conclusion
Our results show blinatumomab is a feasible and well-tolerated frontline therapy for pediatric patients with B-ALL/LLy, including those who are intolerant of conventional therapy with expected AE profiles. Management to prevent interruptions, especially due to equipment issues, should improve tolerability.