<p>Evaluating Blinatumomab for the Treatment of Relapsed/Refractory ALL: Design, Development, and Place in Therapy</p>

Abstract

Although adults with B-cell acute lymphoblastic leukemia (B-ALL) achieve high complete remission (CR) rates following treatment with intensive multi-agent chemotherapy regimens, up to two-thirds of these patients eventually relapse. Unfortunately, adults with relapsed or refractory (R/R) B-ALL have a poor prognosis, with variable responses to salvage chemotherapy regimens and allogeneic stem cell transplant. As such, the need to develop effective and well-tolerated treatments for this patient population has been of paramount importance over the past decade. In this regard, treatment options for R/R B-ALL patients have expanded considerably over a relatively short period of time, with the approvals of blinatumomab, inotuzumab ozogamicin and tisagenlecleucel occurring within only the past six years. Blinatumomab, a CD19 x CD3 bispecific T-cell engager (BiTE) was the first of these immune therapies to receive approval, and for many patients, is used as first-line salvage therapy. A number of large clinical trials have demonstrated improved progression-free survival and overall survival for R/R B-ALL patients receiving blinatumomab as compared to those receiving conventional salvage chemotherapy. In addition to being approved for both Philadelphia chromosome-negative and Philadelphia chromosome-positive R/R B-ALL, blinatumomab is also the only ALL therapy that carries approval for the treatment of measurable residual disease (MRD). Although blinatumomab has changed the therapeutic landscape for adults with R/R B-ALL, a number of important clinical considerations and questions remain, including the potential role of blinatumomab in the frontline setting, mechanisms of resistance, optimal goal MRD level, the role of transplant following MRD clearance, the optimal place for blinatumomab in the context of other recently approved immune-mediated therapies, and real world outcomes for patients treated outside the context of clinical trials. These issues are the focus of ongoing studies, which will hopefully inform future clinical practice regarding the utility of blinatumomab in the treatment of B-ALL patients.

Bispecific Antibodies: From Research to Clinical Application

“…Patients with ALL who are cured always have some measurable residual disease (MRD), which often causes a relapse (180,181). After blinatumomab treatment, a certain degree of complete remission (CR) can be achieved (182)(183)(184). The main side effects of blinatumomab are fever, headache, edema, nausea, tremor, neutropenia, thrombocytopenia, and elevated transaminase (168,185).…”

The diverse landscape of dermatologic toxicities of non‐immune checkpoint inhibitor monoclonal antibody‐based cancer therapy

“…Blinatumomab, a CD19‐directed CD3 + T‐cell engager that facilitates cytolytic synapses between CD19 + B‐cells and CD3 + T‐cells, 297 has shown promise in treatment of relapsed and refractory precursor B‐cell acute lymphoblastic leukemia 298 . The most common adverse cutaneous event with blinatumomab use is a low‐grade maculopapular cAE 132,138,139 . Histopathologic features may include a dermal hypersensitivity reaction with perivascular lymphocytic inflammation (Figure 5).…”

Targeting the lncRNA DUXAP8/miR-29a/PIK3CA Network Restores Doxorubicin Chemosensitivity via PI3K-AKT-mTOR Signaling and Synergizes With Inotuzumab Ozogamicin in Chemotherapy-Resistant B-Cell Acute Lymphoblastic Leukemia

“…For chemotherapy-refractory or relapsed B-ALL patients, salvage treatment options are lacking and urgently need investigation. Currently, inotuzumab ozogamicin, an anti-CD22 antibody–drug conjugate, achieves encouraging efficacy and acceptable tolerance as a salvage treatment regimen in refractory or relapsed B-ALL patients ( 46 – 50 ). In the current study, it was further discovered that targeting lncRNA DUXAP8 and inotuzumab ozogamicin had synergistic effects in killing chemoresistant B-ALL cells.…”