Blinatumomab consolidation and maintenance therapy in adults with relapsed/refractory B-precursor acute lymphoblastic leukemia

Abstract

In a phase 3 clinical study of heavily pretreated adults with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL), overall survival (OS) following blinatumomab, a BiTE (bispecific T-cell engager) immunooncology therapy, was significantly improved vs chemotherapy following induction (cycles 1 to 2). Here we report the efficacy and safety of those who received additional cycles of blinatumomab. Blinatumomab was administered as a continuous IV infusion for 4 weeks in a 6-week cycle. Patients who achieved a bone marrow response (≤5% blasts) or complete remission (full, partial, or incomplete hematological recovery) during induction could receive additional cycles of blinatumomab. OS and relapse-free survival (RFS) for consolidation (cycles 3 to 5) vs no consolidation, and maintenance (cycles ≥6) vs no maintenance were analyzed using Simon-Makuch and Mantel-Byar odds ratios. Of 267 patients who received blinatumomab induction, 86 (32%) entered consolidation and 36 (13%) entered maintenance. Evidence of longer OS was demonstrated among the maintenance group compared with no-maintenance (median OS [95% confidence interval, CI]: not reached for maintenance vs 15.5 months for no maintenance). Median RFS (months; 95% CI) was numerically longer among maintenance group (14.5; 7.1 to 21.9) compared with no-maintenance (9.8; 8.5 to 11.1). A lower incidence of adverse events was seen during maintenance (72.2%) compared with induction (97.2%) and consolidation (86.1%). Adults with R/R ALL who achieved remission following blinatumomab induction had longer survival on continuation therapy than those who discontinued blinatumomab early, supporting the use of blinatumomab as long-term therapy. No new safety signals were reported. This trial was registered at www.clinicaltrials.gov as #NCT02013167.

Graphical abstract

Figure 1.

Induction, consolidation, and maintenance study design (blinatumomab group). ^aIn induction cycle 1 week 1, 9 µg per day, and 28 µg per day thereafter by continuous infusion. ^bObserved cycle 3 day 1 varied between day 85 and day 131 on study. ^cObserved maintenance day 1 varied between day 211 and day 266 on study. ^dMaintenance therapy was discontinued in the case of transition to HSCT, investigator discretion, toxicity, relapse, or use of protocol-excluded medications.

Figure 2.

Study consort diagram (blinatumomab group). ^aIntention to receive HSCT (n = 18), intention to receive treatment other than allogeneic HSCT (n = 1), relapse (n = 25), failure to achieve CR/CRh/CRi in first 2 cycles (n = 1). ^bIntention to receive HSCT (n = 5), intention to receive treatment other than allogeneic HSCT (n = 4), relapse (n = 9).

Figure 3.

Simon-Makuch plot for OS. (A) Analysis includes 115 patients alive and in CR/CRh/CRi at month 3 (from randomization), of which, 82 patients eventually received consolidation cycles (4 other consolidations patients either die or relapse before month 3 and were not included in this analysis). Median OS is 13.0 months in the no-consolidation group and 16.6 (13.6 to 19.6) months in the consolidation group. (B) Analysis includes 78 patients alive and in CR/CRh/CRi at month 7 (from randomization), of which, 36 patients eventually received maintenance cycles. Median (95% CI) is 15.5 months in the no-maintenance group and not reached in the maintenance group. OR, odds ratio.

Figure 4.

Simon-Makuch plot for RFS. (A) Analysis includes 119 patients in CR/CRh/CRi from date of first response, of which, 82 eventually received consolidation cycles (4 other consolidation patients did not achieve CR/CRh/CRi in first 2 cycles and were not included in in this analysis). Median (95% CI) is 8.8 (7.6 to 9.9) months in the no-consolidation group and 7.6 (3.7-11.6) months in the consolidation group. (B) Analysis includes 63 patients alive and in CR/CRh/CRi 5 months after first hematological response, of which, 34 eventually received maintenance cycles (2 other maintenance patients relapse before 5 months and were not included in this analysis). Median (95% CI) is 9.8 (8.5-11.1) months in the no-maintenance group and 14.5 (7.1-21.9) months in the maintenance group.