Exposure-response analysis of blinatumomab in patients with relapsed/refractory acute lymphoblastic leukaemia and comparison with standard of care chemotherapy.

AIMS: The relationship between blinatumomab exposure and efficacy endpoints (occurrence of complete remission [CR] and duration of overall survival [OS]) or adverse events (occurrence of cytokine release syndrome [CRS] and neurologic events) were investigated in adult patients with relapsed/refractory acute lymphoblastic leukaemia (r/r ALL) receiving blinatumomab or standard of care (SOC) chemotherapy to evaluate appropriateness of the blinatumomab dosing regimen.

METHODS: Exposure, efficacy, and safety data from adult patients (n=646) with r/r ALL receiving stepwise (9 then 28 μg day-1 , 4-week cycle) continuous intravenous infusion (n=537) of blinatumomab or SOC (n=109) chemotherapy were pooled from phase 2 and 3 studies. The occurrence of CR, neurologic and CRS events, and duration of OS were analysed using Cox proportional hazards models or logistic regression, as appropriate. Confounding factors were tested multivariately as needed.

RESULTS: Blinatumomab steady-state concentration (Css ) following 28 μg day-1 dosing was associated with the probability of achieving CR (odds ratio and 95% confidence interval [CI]: 1.073 [1.033-1.114]), and a longer duration of OS compared to SOC (hazard ratio and 95% CI: 0.954 [0.936-0.973], P<0.05) in multivariate analyses. The exposure-safety analyses indicated that blinatumomab Css following the 9 or 28 μg day-1 dose was not associated with increased probability of CRS or neurologic events, after accounting for blinatumomab treatment effect (P>0.05).

CONCLUSIONS: Blinatumomab step-dosing regimen of 9/28 μg day-1 provided treatment benefit in achieving CR and increasing the duration of OS over SOC and was appropriate in management of CRS and neurologic events in patients with r/r ALL.