Outcomes of relapsed B-cell acute lymphoblastic leukemia after sequential treatment with blinatumomab and inotuzumab

Abstract

Novel monoclonal antibody-based therapies (mAbs) targeting CD19 and CD22, i.e. blinatumomab and inotuzumab, have demonstrated high rates of complete remission (CR) and been used as a bridging treatment to potentially curative allogeneic hematopoietic stem cell transplantation (alloHCT) in adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). However, limited data exist on the outcome of patients resistant to both mAbs as well as responses to each agent when progressed after the alternate antigen-targeted mAb. Herein, we report outcomes of 29 patients with R/R B-ALL previously treated with both blinatumomab and inotuzumab. Twenty-five patients (86.2%) received blinatumomab as first mAb (mAb1), and CD19neg/dim relapses were observed in 44% of the patients. Inotuzumab induced CR in 68% of the patients for post-blinatumomab relapse regardless of CD19 expression status. The median time between mAb1 and mAb2 was 99 days. Twelve of 19 patients (63.2%) who achieved remission after mAb2 underwent alloHCT. The median time from mAb2 to alloHCT was 37.5 days. Acute graft-versus-host disease and non-relapse mortality were observed in 58.3% (grade ≥3; 25%) and 41.7%, respectively. With a median follow-up of 16 months after mAb2, 19 patients (65.5%) relapsed and 21 patients (72.4%) have died. Overall survival (OS) was not different between alloHCT and non-alloHCT patients. In conclusion, patients with B-ALL who relapsed after blinatumomab could be successfully rescued by inotuzumab as a bridge to alloHCT, but represent an ultra-high risk group with poor OS. Further studies including novel consolidation and treatment sequence may improve outcomes of these patients.

Case report: Sequential inotuzumab, blinatumomab, and chemotherapy with concurrent donor lymphocyte infusions induce complete remission in relapsed pre‐B acute lymphoblastic leukemia

“…The absence of problematic GvHD despite moderate DLI doses is also unusual, as many cases reported high rates of severe GvHD using a chemo‐DLI approach [ 3 , 11 ]. Lastly, our timeline was tight, choosing a 15‐day InO‐Blina interval (compared to, e.g., 99 days [ 8 ]). Likewise, DLI applications mostly took place in Blina‐Cycle 3, while we applied them in Cycle 1.…”

“…Using Blina/Ino in sequence has not yet been investigated in prospective, randomized trials. But case series show a benefit of the combination [ 8 , 9 ]. Adding low‐intensity chemotherapy was successful in avoiding full‐dose antibody therapy and accompanying side effects [ 10 ].…”

Recurrent Extramedullary Relapse of Immunophenotypically Aberrant B Lymphoblastic Leukemia to Unusual Sites After Allogeneic Hematopoietic Stem Cell Transplantation: A Case Report.

“…Wang et al reported successful treatment of extramedullary relapse in Philadelphia chromosome positive B-ALL with CD19 + CAR-T although follow up is only available for 8 months 23 . Sequential treatment with inotuzumab and blinatumumab has also been studied 24 . Majority of the larger studies were conducted for patients with bone marrow relapse.…”

A Novel bispecific T-cell engager (BiTE) targeting CD22 and CD3 has both in vitro and in vivo activity and synergizes with blinatumomab in an acute lymphoblastic leukemia (ALL) tumor model

“…Additionally, they can be a treatment option for patients who no longer respond to drugs targeting those antigens. Indeed, in one trial, patients relapsed or refractory to blinatumomab who were then treated with the CD22 ADC inotuzumab experienced 68% complete response as a bridge therapy to hemopoietic stem cell treatment (HSCT) [ 25 ]. Additionally, CD22-targeted CAR-T therapies have demonstrated sustained complete responses in patients previously treated with blina or CD19 CAR-T [ 26 ].…”