Single-Agent Subcutaneous Blinatumomab for Advanced B-Cell Acute Lymphoblastic Leukemia: Long-Term Follow-up from a Phase 1b Dose Expansion Cohort
Authors: Jabbour Elias , Zugmaier Gerhard , Martinez Sanchez Pilar , Rifon Jose J. , Agrawal Vaibhav , Cassaday Ryan D , Cluzeau Thomas , Huguet Françoise , Vucinic Vladan , Böll Boris , Rijneveld Anita W. , Tormo Mar , Abdul-Hay Maher , Gordon Paul R , Rambaldi Alessandro , Kantarjian Hagop M. 
Published: December 2024

Background: Blinatumomab, a BiTE® (bispecific T-cell engager) molecule, has demonstrated efficacy for patients (pts) with B-cell acute lymphoblastic leukemia (B-ALL) when administered as a 28-day continuous intravenous infusion (cIV). We previously reported from the dose expansion of a phase 1b trial (NCT04521231) that subcutaneous (SC) blinatumomab monotherapy can provide high efficacy, acceptable safety profile, and is well tolerated in adults with advanced relapsed or refractory (R/R) B-ALL. (Jabbour 2024) Here, we provide long-term follow-up.

Methods: Pts with R/R B-ALL could receive 1‒5 cycles of SC blinatumomab as monotherapy. Transplantation after the end of the 1st cycle was permitted. Each cycle included a 26-day treatment period and a 1-week treatment-free interval. Blinatumomab was given at two doses, either 1) 250μg once-daily (QD) for week 1 and 500μg three times weekly (TIW) thereafter (250μg/500μg) or 2) 500μg QD for week 1 and 1000μg TIW thereafter (500μg/1000μg). The primary efficacy end point was complete remission (CR) or CR with partial hematologic recovery (CRh) within two cycles. Pts with incomplete hematology recovery (CRi) were included in the analysis. Duration of CR/CRh/CRi was defined from initial remission until relapse or latest disease assessment.

Results: At the data cut-off on May 9, 2024, 27 pts were treated with SC blinatumomab and had opportunity to be observed in long term follow up; 14 at 250µg/500µg and 13 at 500µg/1000µg. Sixteen pts (59%) were male, median age was 52 years (range, 19‒78) with 12 pts (44%) ≥ 55 years. For race/ethnicity, 19 pts were white, 1 pt was Asian, 0 pts were Black, 7 pts reported other race, and 13 pts reported Hispanic ethnicity. Pts had received a median of 2 (range, 1‒5) prior lines of therapy. Of these, 9 pts (33%) were primary refractory, 8 pts (30%) had relapsed after prior HSCT, 4 pts (15%) had relapsed after prior CD19 CAR T-cell therapy, 7 pts (26%) had prior inotuzumab ozogamycin, and 5 pts (19%) had previously received cIV blinatumomab. Median bone marrow blast percentage was 74% (range, 5%‒98%). Median number of SC blinatumomab cycles received was 2 (range, 1‒5).

Of the 27 pts, 24 (89%) achieved a remission (CR/CRh/CRi) within 2 cycles; 12 of 14 (86%) at 250μg/500μg and 12 of 13 (92%) at 500μg/1000μg. Ten (83%) and 12 (100%) responders in 250µg/500µg and 500µg/1000µg, respectively, were negative for measurable residual disease (MRD; &lt;10-4). Three pts did not have response evaluation - 2 due to fatal adverse events, unrelated to SC blinatumomab, and 1 pt requested to discontinue treatment. Median duration of remission was not reached for either dose. The median (range) follow-up was 5.0 (0.49-10.9) months overall, and 4.2 (0.66-10.6) and 5.8 (0.49-10.9) months for 250μg/500μg and 500μg/1000μg, respectively. Of the 24 pts in remission, 21 (88%) have not relapsed. Median (range) of follow-up in CR without relapse (n = 16) was 5.2 (0.66-10.9) months overall, and 4.4 (0.66-10.6) and 5.8 (0.49-10.9) months for 250μg/500μg and 500μg/1000μg, respectively. Three pts relapsed (2 in 500μg/1000μg had CD19 negative relapse [1 each after cycle 2 and HSCT] and 1 pt in 250μg/500μg after early discontinuation) with a median duration of CR/CRh/CRi of 3.8 (range, 1.8-8.4) months.

At data cut off, 19 pts were alive with median (range) follow-up for overall survival (OS) of 9.8 (6.5-14.3) months - dose groups follow-up was 9.8 (6.5-13.8) months for 250μg/500μg and 9.8 (8.0 - 14.3) months for 500μg/1000μg. Five pts died, all in the 250μg/500μg group, one of which had relapsed, with a median time to death of 6.3 (range, 4.7-14.5) months. Eleven (46%) pts received HSCT after responding to SC blinatumomab; 5 (42%) and 6 (50%) for 250μg/500μg and 500μg/1000μg, respectively. Nine remain alive (3 and 6 in 250μg/500μg and 500μg/1000μg, respectively), with 2 pts in 500μg/1000μg receiving HSCT and experiencing relapse. Two pts from 250μg/500μg died in CR after HSCT. Six of 12 responders (median OS of 9.8 months [range, 8.0 - 14.3]) treated with 500μg/1000μg received SC blinatumomab without proceeding to HSCT; 5 completed ≥4 cycles of SC blinatumomab. All 6 are alive and in CR.

Conclusion: Treatment with SC blinatumomab in heavily pretreated pts with R/R B-ALL resulted in high response rates, demonstrated deep and durable remission, and OS. The trial continues to accrue. These results warrant further evaluation of SC blinatumomab.

Jabbour et al. Am J Hematol. 2024: 99(4):586-595.