BACKGROUND

Two doses of subcutaneous blinatumomab in patients with relapsed or refractory B-cell acute lymphoblastic leukaemia were identified as preliminary recommended phase 2 doses, based on the dose-escalation phase of this multicentre single-arm, phase 1/2 trial. Here, we aim to further study the safety, activity, and pharmacokinetics of these doses in all participants who have received them, including those treated in the completed phase 1b expansion part of the study.

METHODS

We did a post-hoc analysis of data from patients enrolled in the dose-escalation and dose-expansion phases and in the pharmacokinetic evaluation cohort of this multicentre, single-arm, phase 1/2 study. Patients were recruited from 44 hospitals in 11 countries. Eligible participants were aged 18 years or older with relapsed or refractory B-cell acute lymphoblastic leukaemia, at least 5% of blasts in the bone marrow, and an Eastern Cooperative Oncology Group performance status of 2 or lower. Patients received either 250 μg subcutaneous blinatumomab once daily in week 1 of cycle 1 and then 500 μg three times weekly thereafter (250 μg/500 μg group), or 500 μg and then 1000 μg subcutaneous blinatumomab on the same schedule (500 μg/1000 μg group), previously identified as the preliminary recommended phase 2 doses. Each treatment cycle included a 4-week treatment period and a 1-week treatment-free interval. Patients received between two and five cycles. The primary endpoint for the dose-expansion phase was complete remission or complete remission with partial haematological recovery within the first two cycles, which was used as the primary outcome for this study. Data were pooled from all cohorts of the same dose level to form two dose groups. The response rates, adverse event incidence, and pharmacokinetics were summarised in each dose group separately and compared descriptively. Response was calculated with two-sided exact 80% CIs (Clopper-Pearson method). This study is registered with ClinicalTrials.gov, NCT04521231; phase 1 is complete, and phase 2 is active but not recruiting.

FINDINGS

Participants were recruited from Oct 18, 2021, to Sept 23, 2024, and median follow-up for the analyses was 5 months (IQR 3-9). Of the 88 patients included in the analysis at the data cutoff of Nov 28, 2024, 36 (41%) were treated with the 250 μg/500 μg regimen and 52 (59%) with the 500 μg/1000 μg regimen. The enrolled population comprised 55 (63%) male and 33 (38%) female participants; 56 (64%) were White, six (7%) Asian, three (3%) Black or African American, two (2%) American Indian or Alaska Native, and 20 (23%) other. Hispanic or Latino ethnicity was reported for 33 (38%) patients. 27 (75%) of 36 patients in the 250 μg/500 μg group and 41 (79%) of 52 in the 500 μg/1000 μg group showed complete remission or complete remission with partial haematological recovery. The most common grade 3-4 adverse events were neutropenia (19 [22%] patients), cytokine release syndrome (CRS; 18 [20%] patients), and immune effector cell-associated neurotoxicity syndrome (ICANS; 15 [17%] patients). Serious adverse events occurred in 70 (80%) of 88 patients and included CRS (33 [38%] patients), ICANS (20 [23%] patients), and neurotoxicity (six [7%] patients). No treatment-related deaths were reported. Consistent pharmacokinetics with dose-proportional exposures was observed following subcutaneous administration. Based on the totality of data, including efficacy, safety, and pharmacokinetic data, the subcutaneous blinatumomab dose regimen of 250 μg/500 μg was selected as the recommended phase 2 dose.

INTERPRETATION

Treatment with subcutaneous blinatumomab at the two dose regimens of 250 μg/500 μg and 500 μg/1000 μg resulted in promising preliminary activity and a manageable safety profile in adults with relapsed or refractory B-cell acute lymphoblastic leukaemia. The phase 2 part of the trial is ongoing to further evaluate subcutaneous blinatumomab activity and duration of response.

FUNDING

Amgen.