Superior Event-Free Survival with Blinatumomab Versus Chemotherapy in Children with High-Risk First Relapse of B-Cell Precursor Acute Lymphoblastic Leukemia: A Randomized, Controlled Phase 3 Trial

Background: Children with high-risk (HR) first-relapse B-cell precursor acute lymphoblastic leukemia (BCP-ALL) are candidates for allogeneic hematopoietic stem cell transplant (alloHSCT) when a second complete morphological remission (CR2, M1 marrow) is achieved. Immuno-oncotherapy with blinatumomab, a bispecific T-cell engager (BiTE^®) molecule, is efficacious in children with relapsed/refractory BCP-ALL. We conducted an open-label randomized, controlled phase 3 trial comparing blinatumomab with high-risk consolidation (HC) 3 chemotherapy as pretransplant consolidation therapy for children with HR first-relapse BCP-ALL.

Methods: Children with M1 (< 5% blasts) or M2 (< 25% and ≥ 5% blasts) marrow were randomized 1:1 after induction therapy and cycles of HC1 and HC2 chemotherapy, administered according to the IntReALL HR 2010, ALL-REZ BFM 2002, ALL R3, COOPRALL, and AIEOP ALL REC 2003 protocols, to receive a third consolidation course with blinatumomab (15 µg/m²/day for 4 weeks) or HC3 (dexamethasone, vincristine, daunorubicin, methotrexate, ifosfamide, PEG-asparaginase); intrathecal chemotherapy (methotrexate/cytarabine/prednisolone) was administered before treatment. Stratification variables included age, marrow status at end of HC2, and minimal residual disease (MRD) after induction (evaluated in a local laboratory). Patients with CR2 (M1 marrow) after blinatumomab or HC3 proceeded to alloHSCT. The primary endpoint was event-free survival (EFS; from randomization until relapse date or M2 marrow after a CR, failure to achieve CR at end of treatment, second malignancy, or death from any cause). Secondary endpoints included overall survival (OS), cumulative incidence of relapse, MRD status (evaluated in a central laboratory by polymerase chain reaction), and incidence of adverse events (AEs). Two interim analyses were planned at approximately 50% and 75% of total EFS events.

Results: Enrollment was terminated for benefit (blinatumomab group) based on a predefined efficacy threshold at the 50% EFS events interim analysis. From November 10, 2015, to July 17, 2019 (data as-is snapshot), 108 patients were enrolled and randomized; 54 (50%) to blinatumomab and 54 (50%) to HC3. Patient baseline characteristics were comparable between treatment groups; most patients had completed treatment (blinatumomab, 91%; HC3, 89%). Events were reported for 18/54 (33.3%) and 31/54 (57.4%) blinatumomab- and HC3‑randomized patients, with a median EFS of “not reached” and 7.4 months, respectively (Figure). Blinatumomab reduced the risk of relapse by 64% vs HC3 (hazard ratio 0.36, 95% confidence interval [CI] 0.19-0.66, p < 0.001). In addition, OS favored blinatumomab vs HC3 (hazard ratio 0.43, 95% CI 0.18-1.01) (Figure). MRD remission (MRD < 10^-4) was seen in 43/46 (93.5%) blinatumomab-randomized and 25/46 (54.3%) HC3-randomized patients. Grade ≥ 3 treatment-emergent AEs were reported by 30/53 (57%) and 41/51 (80%) patients in the blinatumomab and HC3 groups, respectively. As expected, grade ≥ 3 neurologic events occurred more frequently with blinatumomab than with HC3; no grade ≥ 3 cytokine release syndrome events were reported. Types of alloHSCT conditioning regimens received by patients as well as types of donors were balanced between groups.

Conclusions: Blinatumomab monotherapy as consolidation therapy before alloHSCT in children with HR first-relapse BCP-ALL leads to significantly better EFS, lower risk of recurrence, and fewer grade ≥ 3 treatment-emergent AEs vs HC3, suggesting a new standard‑of-care treatment for these patients.