Acute lymphoblastic leukemia (ALL) accounts for over three quarters of all childhood leukemias, with the majority of ALL cases being the precursor B-cell type (B-ALL).1 While >80% of pediatric patients survive the disease for 5 years or longer, the outcome drops significantly after the first relapse.2 Blinatumomab is a bi-specific T-cell engager monoclonal antibody construct that has been approved by the US Food and Drug Administration for Philadelphia chromosome-negative relapsed/refractory B-ALL in 2014.3 It was investigated in children and young adults with B-ALL who still had residual disease following induction therapy in a phase 3 trial.4 The interim analysis results were presented at the American Society of Hematology 2019 Annual Meeting.4
While allogenic hematopoietic stem cell transplant (HSCT) is considered the treatment of choice for relapsed B-ALL patients, many relapsed patients are unable to proceed to HSCT due to adverse events (AEs) from chemotherapy and/or inability to achieve minimal residual disease (MRD)-negative second remission, which is associated with the optimal HSCT outcomes.4
This phase 3 study aimed to compare disease-free survival (DFS) of high risk/intermediate risk first relapse B-ALL patients aged 1-30 years.4 208 patients were randomized following reinduction chemotherapy to receive either two intensive chemotherapy blocks (n=103), or two 4-week blocks of blinatumomab (n=105).4 After randomized therapy, patients on both arms proceeded to HSCT.4 Secondary endpoints included AEs, MRD response, overall survival (OS), and ability to proceed to HSCT.4 Median follow-up was 1.4 years.
The intent-to-treat 2-year DFS was 41.0% in the chemotherapy arm, and 59.3% in the blinatumomab arm (p=0.05), and OS was 59.2% and 79.4% respectively (p=0.005).4 Among patients with detectable MRD after receiving reinduction chemotherapy, 79% of patients receiving blinatumomab achieved undetectable MRD, as compared to 21% with intensive chemotherapy (p<0.0001).4 There was a greater likelihood of patients proceeding to HSCT if they received blinatumomab – 73% of patients receiving blinatumomab proceeded to HSCT, while only 45% did when receiving intensive chemotherapy (p<0.0001).4 The blinatumomab arm had fewer and less severe toxicities due to treatment, while the relative rates of febrile neutropenia, infection, sepsis, and mucositis were higher in the chemotherapy arm.4 Furthermore, all blinatumomab-related AEs fully resolved eventually.4
The trial was stopped early after the interim analysis, showing that a clear benefit was seen for blinatumomab, and patients receiving chemotherapy were immediately switched to the biologics.4 The combination of improved DFS, superior OS, lower toxicity, and superior MRD clearance for blinatumomab was deemed to be sufficiently compelling to establish a new standard of care in this patient population.4 Currently, patients from the trial still remain in the follow-up, and longer-term outcome results will be reported in the future.4
1. Wyatt KD, Bram RJ. Immunotherapy in pediatric B-cell acute lymphoblastic leukemia. Hum Immunol. 2019;80(6):400-408.
2. Queudeville M et al. Immunotargeting relapsed or refractory precursor B-cell acute lymphoblastic leukemia – role of blinatumomab. Onco Targets Ther. 2017;10:3567-3578.
3. Pulte ED et al. FDA Supplemental Approval: Blinatumomab for Treatment of Relapsed and Refractory Precursor B‐Cell Acute Lymphoblastic Leukemia. Oncologist. 2018;23(11):1366-1371.
4. Brown P et al. A Randomized Phase 3 Trial of Blinatumomab Vs. Chemotherapy As Post-Reinduction Therapy in High and Intermediate Risk (HR/IR) First Relapse of B-Acute Lymphoblastic Leukemia (B-ALL) in Children and Adolescents/Young Adults (AYAs) Demonstrates Superior Efficacy and Tolerability of Blinatumomab: A Report from Children’s Oncology Group Study AALL1331. In: ASH; 2019. https://ash.confex.com/ash/2019/webprogram/Paper132435.html. Accessed January 7, 2020.