Survival after blinatumomab treatment in pediatric patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia
2018-08-22

Acute lymphoblastic leukemia (ALL) is the most common cancer in children 1 .Pediatric patients with disease refractory to last chemotherapy, relapse after allogeneic hematopoietic stem-cell transplantation (alloHSCT), or second or further relapse have a particularly poor prognosis 2 .Intensive chemotherapy followed by alloHSCT after achieving remission can result in cure for some patients.However, survival is still low with this approach 3 .Thus, additional treatment modalities with acceptable toxicity are needed to improve long-term survival.Blinatumomab is a bispecific T-cell engager (BiTE) antibody construct that directs CD3-positive effector memory T-cells to CD19-positive target leukemia cells.We previously reported the primary results of a phase 1-2 study of blinatumomab treatment in pediatric patients with relapsed/refractory B-cell precursor ALL (BCP-ALL) 4 .In that report, of the 70 patients who received the recommended phase 2 dose in either phase, 27 patients (39%; 95% confidence interval [CI], 27 to 51%) achieved complete remission (CR) within the first two cycles; of these, 52% attained negative minimal residual disease (MRD).Adverse events of interest included neurologic events (24%), cytokine release syndrome (11%), and transient, clinically non-significant elevation of alanine aminotransferase (19%), aspartate aminotransferase (14%), or bilirubin (6%).The objective of this follow-up analysis is to examine the final results for remission and survival 24 months after blinatumomab treatment.Full study methods have been reported previously 4 .In brief, this open-label, single-arm phase 1-2 study enrolled patients ≤ 18 years of age with relapsed/refractory BCP-ALL and > 25% bone marrow blasts if disease was primary refractory or in refractory first relapse after full standard induction regimen, in second or further relapse, or in any relapse after alloHSCT.Patients in nonrefractory first relapse without prior alloHSCT were not permitted in the study.All patients received blinatumomab as a 4-week continuous intravenous infusion, with a 2-week treatment-free interval after each cycle.On the basis of phase 1 results, the recommended phase 2 dose was 5 μg/m 2 /day for the first week of cycle 1, followed by 15 μg/m 2 /day for the remaining 3 weeks of cycle 1 and for all 4 weeks of the following cycles.Infusions were administered in the hospital during the first week of cycle 1 and the first 2 days of cycle 2, then in an outpatient setting whenever clinically appropriate for a given patient's condition.Bone marrow aspirate for response assessment (or biopsy if aspirate could not be obtained) was performed during screening, on day 15 of cycle 1, and on day 29 of each cycle.Patients achieving hematologic CR within the first 2 cycles could receive up to three additional cycles and/or consolidation chemotherapy and/or alloHSCT at any time per investigator's choice.Central nervous system prophylaxis according to institutional/national standards was administered at ageadjusted doses when bone marrow assessment was performed.Patients who experienced neurologic adverse events requiring medical intervention were given