Adverse effects in hematologic malignancies treated with chimeric antigen receptor (CAR) T cell therapy: a systematic review and Meta-analysis

Abstract

Background Recently, chimeric antigen receptor-modified (CAR) T cell therapy for hematological malignancies has shown clinical efficacy. Hundreds of clinical trials have been registered and lots of studies have shown hematologic toxic effects were very common. The main purpose of this review is to systematically analyze hematologic toxicity in hematologic malignancies treated with CAR-T cell therapy. Methods We searched databases including PubMed, Web of Science, Embase and Cochrane up to January 2021. For safety analysis of overall hematologic toxicity, the rate of neutrophil, thrombocytopenia and anemia were calculated. Subgroup analysis was performed for age, pathological type, target antigen, co-stimulatory molecule, history of hematopoietic stem cell transplantation (HSCT) and prior therapy lines. The incidence rate of aspartate transferase (AST) increased, alanine transaminase (ALT) increased, serum creatine increased, APTT prolonged and fibrinogen decreased were also calculated. Results Overall, 52 studies involving 2004 patients were included in this meta-analysis. The incidence of any grade neutropenia, thrombocytopenia and anemia was 80% (95% CI: 68–89%), 61% (95% CI: 49–73%), and 68% (95%CI: 54–80%) respectively. The incidences of grade ≥ 3 neutropenia, thrombocytopenia and anemia were 60% (95% CI: 49–70%), 33% (95% CI: 27–40%), and 32% (95%CI: 25–40%) respectively. According to subgroup analysis and the corresponding Z test, hematological toxicity was more frequent in younger patients, in patients with ≥4 median lines of prior therapy and in anti-CD19 cases. The subgroup analysis of CD19 CAR-T cell constructs showed that 41BB resulted in less hematological toxicity than CD28. Conclusion CAR-T cell therapy has dramatical efficacy in hematological malignancies, but the relevant adverse effects remain its obstacle. The most common ≥3 grade side effect is hematological toxicity, and some cases die from infections or severe hemorrhage in early period. In long-term follow-up, hematological toxicity is less life-threatening generally and most suffered patients recover to adequate levels after 3 months. To prevent life-threatening infections or bleeding events, clinicians should pay attention to intervention of hematological toxicity in the early process of CAR-T cell therapy.

CAR-T cell therapy for hematological malignancies: Limitations and optimization strategies

“…Therefore, the use of CD28-based or 4-1BB-based CARs needs to be evaluated with caution. It is notable that 4-1BB-based CAR-T cells appear to be less hematological toxic than CD28-based CAR-T cells ( 110 ), which is perhaps due to their lower activation capacity. Other than 4-1BB, integration of costimulatory domains, ICOS and CD27, can promote CAR-T cell fitness as well ( 111 , 112 ), although further investigations are required to validate these constructs.…”

Role of CAR T Cell Metabolism for Therapeutic Efficacy

“…Unlike CRS, IL-6 does not play a prominent role and first line treatment consists of steroids. The situation is similar for hematotoxicity, where therapy is symptomatic with, e.g., transfusions, autologous stem cell boost, and use of thrombopoietin receptor agonists [ 19 , 20 , 21 ]. For instance, it has been shown that CD28 CAR T cells induce more severe adverse effects than 4-1BB CAR T cells, including higher frequency of grade III-IV CRS, grade I-II neurotoxicity and episodes of severe ICANS [ 22 ].…”

“…Countermeasures include the development of multi-specific CARs (e.g., dual or tandem CARs) that target more than one tumor antigen. Signals from clinical trials are encouraging [ 20 , 21 ].…”

Allogeneic CD34+ Selected Hematopoietic Stem Cell Boost Following CAR T-cell Therapy in a Patient with Prolonged Cytopenia and Active Infection

“…While eventual recovery from hematotoxicity may be possible, patients are at high risk of succumbing to infections (8). CD34+ HSCB can be a useful therapeutic intervention to shorten the duration of pancytopenia.…”