Management of toxicities associated with novel immunotherapy agents in acute lymphoblastic leukemia

Abstract

The advent of novel immunotherapies, such as blinatumomab, inotuzumab, and chimeric antigen receptor (CAR) T cell therapy, has revolutionized the therapeutic landscape in the treatment of relapsed/refractory B cell acute lymphoblastic leukemia, but can be associated with specific toxicities. We review unique toxicities of each of these in this article. Blinatumomab, a bispecific T cell engager, has been associated with cytokine release syndrome (CRS) and neurological toxicities, both of which can be prevented and managed with corticosteroids. Inotuzumab is a calicheamicin-conjugated CD22 targeting antibody. The calicheamicin component of the drug is likely associated with the hepatotoxicity seen with inotuzumab, especially sinusoidal obstruction syndrome, which can happen both in the context of the drug alone, and also with allogeneic stem cell transplantation. QT prolongation has also been noted with inotuzumab. CAR T therapy uses genetically modified autologous T cells directed against CD19, a known target on B cells. CRS and neurological symptoms, formally termed as immune-effector-cell-associated neurological syndrome, have been described along with hypogammaglobulinemia, cytopenias, and infections.

Side-effect management of chimeric antigen receptor (CAR) T-cell therapy

“…65 Preemptive use of tocilizumab has not been addressed in current CRS management algorithms and is therefore not recommended. 51,53,66 Tocilizumab exerts anti-CRS effects by inhibition of the IL-6 receptor. IL-6 can act via three signaling mechanisms: classic cis and trans-signaling as well as trans-presentation.…”

Secondary Dysgammaglobulinemia in Children with Hematological Malignancies Treated with Targeted Therapies

“…The depletion of CD19 B cells via activation of CD3 T cells results in a decrease in the number of B cells and plasma cells and in a decline of serum IG levels that recover after the regeneration of both naïve and memory B cells [27,28]. The main adverse events related to its use in both children and adults include cytokine-release syndrome (CRS), neurotoxicity, increased risk of infections, hepatotoxicity, tumor lysis syndrome, and hypogammaglobulinemia [29][30][31][32]. In a multicenter phase III trial that evaluated the efficacy and safety of blinatumomab in 405 adult patients who were randomly assigned to receive blinatumomab (271 patients) or chemotherapy (134 patients), hypogammaglobulinemia was reported in 2.7% of patients receiving blinatumomab arm versus 0% of those treated with conventional chemotherapy [33].…”

“…The FDA has approved Besponsa® for the treatment of adults with relapsed or refractory B-cell precursor ALL [20]. The main adverse events related to its use are hepatotoxicity and cardiotoxicity (QTc prolongation) [29]. According to the mechanism of action of inotuzumab ozogamicin on B cells and data on the reduction of the number of CD22+ B cells, an increased risk of infection and a decrease in the number of plasma cells and serum IG levels should be considered [42][43][44].…”

How we infuse blinatumomab

“…There are many detailed reviews of the expected toxicities of blinatumomab and how to treat them, 1,5‐9 so it is only discussed briefly below. If patients are enrolled on clinical trials, the guidelines surrounding holding an infusion, emergency medications, and dose modifications should be followed closely.…”