Initial Results from a Phase 2 Study of Blinatumomab in Pediatric Patients with Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia

Introduction: Acute lymphoblastic leukemia (ALL) is the most common malignant disease in childhood. Patients (pts) with relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT) and/or multiple prior salvage therapies and/or refractory disease have a particularly poor prognosis. Blinatumomab is an investigational bispecific T-cell engager (BiTE^®) antibody construct that redirects T cells to CD19⁺ B cells resulting in serial lysis. In phase 2 clinical studies, blinatumomab has demonstrated antitumor activity in adults with relapsed/refractory non-Hodgkin lymphoma and ALL. We evaluated efficacy and toxicity of blinatumomab in pediatric pts with relapsed/refractory ALL who have a particularly poor prognosis.

Methods: Eligible pts were 2-18 years of age and had B-cell precursor ALL that was refractory, in ≥2^nd bone marrow relapse, or in any marrow relapse after alloHSCT. This was a multicenter, open-label study using a Simon 2-stage design with a phase 1 and a phase 2 part. In the phase 1 part, a stepwise dose of 5→15 µg/m²/day was established as the recommended phase 2 dose (von Stackelberg et al. Blood. 2013;122:70). Blinatumomab was given by continuous intravenous infusion for 4 weeks (5 µg/m²/day for the first week and 15 µg/m²/day thereafter), followed by two treatment-free weeks (one cycle) for up to five cycles. The primary endpoint for the phase 2 part of the study was rate of complete remission (CR) within the first two cycles of treatment, including CR with incomplete hematologic recovery. Secondary endpoints included relapse-free survival (RFS), rate of advancement to alloHSCT, overall survival (OS), and incidence and severity of adverse events (AEs). Minimal residual disease (MRD) response (<10^-4 leukemic cells by PCR or flow cytometry) was an exploratory endpoint. We present 39 pts who were treated at the phase 2 dose (5→15 µg/m²/day), including 18 pts from the dose expansion cohort of the phase 1 part and 21 pts from the phase 2 part of the study.

Results: 39 pts received blinatumomab at a dose of 5→15 µg/m²/day. The median (range) age was 9 (2–16) years; 62% of pts were male. Sixteen (41%) pts had one and 16 (41%) pts had two or more prior salvage therapies, respectively; seven (18%) were either primary refractory or had refractory relapse. Twenty-five (64%) pts had received prior alloHSCT; of those, six (16%) had one relapse and 19 (50%) had two or more relapses. Of the 39 pts, 34 (87%) had relapsed within 6 months prior to study entry. The median (range) time from last prior relapse to the relapse at study entry was 2.1 (0–13.7) months. 69% of pts had bone marrow blast infiltration of ≥50%. 19 (49%) pts started and completed one cycle of blinatumomab treatment (two cycles, 4 [10%] pts; three cycles, 2 [5%] pts). During the first two treatment cycles, 12 pts achieved CR, (31%; 95% CI, 17%–48%), mainly during the first cycle. Two additional pts (5%) had blast-free hypoplastic or aplastic bone marrow. Among pts with CR in the first two cycles, five (42%) had complete MRD response. Median RFS for CR responders was 5.6 (95% CI, 2.6–12.1) months. Among all 39 pts, median OS was 4.3 (95% CI, 3.6–8.1) months with 6 months of study follow-up time. Six (50%) of the 12 pts with CR proceeded to alloHSCT. An additional five pts who did not respond to blinatumomab received alloHSCT after blinatumomab treatment was stopped. All pts experienced AEs, mostly flu-like symptoms consistent with the mechanism of action of blinatumomab. AEs regardless of causality occurring in >20% of pts were pyrexia (74%), anemia (33%), nausea (31%), headache (28%), hypertension (26%), increased alanine aminotransferase (23%), and cough (21%). The most common grade ≥3 AEs included anemia (26%), pyrexia (21%), increased alanine aminotransferase (18%), increased aspartate aminotransferase (18%), and febrile neutropenia (15%). Cytokine-release syndrome occurred in three (8%) pts, two of whom (5%) had grade 3 events.

Conclusions: Blinatumomab showed promising antileukemia activity in heavily pretreated pediatric relapsed/refractory B-cell precursor ALL pts, with a median time from last relapse of 2.1 months. Half of the pts who responded within the first two cycles were able to receive alloHSCT following blinatumomab-induced remission, suggesting that blinatumomab may open a window for alloHSCT in those pts who are resistant to salvage chemotherapy.