Clinical Benefits and Safety of Gemtuzumab Ozogamicin in Treating Acute Myeloid Leukemia in Various Subgroups: An Updated Systematic Review, Meta-Analysis, and Network Meta-Analysis

Abstract

Background: Previous trials demonstrated evidence involving the total effects of gemtuzumab ozogamicin (GO), an anti-CD33 humanized antibody, on treating acute myeloid leukemia (AML). In this updated systematic review, meta-analysis, and network meta-analysis (NMA), we aimed to comprehensively explore the clinical benefits and safety of GO in various subtypes of AML.

Methods: PubMed, Embase, Cochrane, and Chinese databases were filtered to search randomized controlled trials (RCTs) and retrospective cohort studies that compared clinical efficiency and toxicity of GO with non-GO groups in AML. Random-effects models were used to calculate pooled effect sizes and 95% confidence intervals (CIs). Relative risk (RR) was used for estimating complete remission (CR), early death, and toxicity. Hazard risk (HR) was accomplished to evaluate survival.

Results: Fifteen RCTs and 15 retrospective cohort studies were identified (GO: 4,768; Control: 6,466). GO tended to improve CR (RR 0.95, p = 0.084), followed by significantly improved survival (overall survival: HR 0.86, p = 0.003; event-free survival: HR 0.86, p = 0.015; relapse-free survival: HR 0.83, p = 0.001; cumulative incidence of relapse: HR 0.82, p < 0.001). GO benefits of CR and survival were evident in favorable- and intermediate-risk karyotypes (p ≤ 0.023). GO advantages were also associated with nucleophosmin 1 mutations (p ≤ 0.04), wild-type FMS-like tyrosine kinase 3 internal tandem duplication gene (p ≤ 0.03), age of <70 years (p < 0.05), de novo AML (p ≤ 0.017), and CD33(+) (p ≤ 0.021). Both adding GO into induction therapy (p ≤ 0.011) and a lower (<6 mg/m²) dose of GO (p ≤ 0.03) enhanced survival. Prognosis of combined regimens with GO was heterogeneous in both meta-analysis and NMA, with several binding strategies showing improved prognosis. Additionally, GO was related to increased risk of early death at a higher dose (≥6 mg/m²) (RR 2.01, p = 0.005), hepatic-related adverse effects (RR 1.29, p = 0.02), and a tendency of higher risk for hepatic veno-occlusive disease or sinusoidal obstruction syndrome (RR 1.56, p = 0.072).

Conclusions: These data indicated therapeutic benefits and safety of GO in AML, especially in some subtypes, for which further head-to-head RCTs are warranted.

Systematic review registration: [PROSPERO: https://www.crd.york.ac.uk/prospero/], identifier [CRD42020158540].

Keywords: acute myeloid leukemia; gemtuzumab ozogamicin; meta-analysis; network meta-analysis; response; survival; toxicity.

Figure 1

Pooled prognosis between GO and non-GO groups with AML. (A) Pooled CR. (B) Pooled OS. (C) Pooled EFS. (D) Pooled RFS. (E) Pooled CIR. (F) Pooled CIR after sensitivity analyses. The diamonds represent the overall summary RR and HR estimates with 95% CI. GO, gemtuzumab ozogamicin; AML, acute myeloid leukemia; CR, complete remission; OS, overall survival; EFS, event-free survival; RFS, relapse-free survival; CIR, cumulative incidence of relapse; RR, relative risk; HR, hazard ratio; 95% CI, 95% confidence interval.

Figure 2

Prognostic subgroup analyses regarding karyotype stratifications of AML. (A) CR. (B) OS. (C) EFS. (D) RFS. (E) CIR. The diamonds represent the overall summary RR and HR estimates with 95% CI. GO, gemtuzumab ozogamicin; AML, acute myeloid leukemia; CR, complete remission; OS, overall survival; EFS, event-free survival; RFS, relapse-free survival; CIR, cumulative incidence of relapse; RR, relative risk; HR, hazard ratio; 95% CI, 95% confidence interval.

Figure 3

Prognostic subgroup analyses regarding NPM1 and FLT3-ITD mutations. (A) OS subgrouped by NPM1 mutational status. (B) RFS subgrouped by NPM1 mutational status. (C) CIR subgrouped by NPM1 mutational status. (D) CR subgrouped by FLT3-ITD mutational status. (E) OS subgrouped by FLT3-ITD mutational status. (F) EFS subgrouped by FLT3-ITD mutational status. (G) CIR subgrouped by FLT3-ITD mutational status. The diamonds represent the overall summary RR and HR estimates with 95% CI. GO, gemtuzumab ozogamicin; CR, complete remission; OS, overall survival; EFS, event-free survival; RFS, relapse-free survival; CIR, cumulative incidence of relapse; RR, relative risk; HR, hazard ratio; 95% CI, 95% confidence interval; NPM1, nucleophosmin 1; FLT3-ITD, FMS-like tyrosine kinase 3 internal tandem duplication.

Figure 4

Prognostic subgroup analyses regarding age stratifications and gender. (A) OS subgrouped by age (60 years old). (B) OS subgrouped by age (70 years old). (C) RFS subgrouped by age (60 years old). (D) CIR subgrouped by age (60 years old). (E) CIR subgrouped by age (70 years old). (F) OS subgrouped by gender. (G) EFS subgrouped by gender. (H) CIR subgrouped by gender. The diamonds represent the overall summary HR estimates with 95% CI. GO, gemtuzumab ozogamicin; OS, overall survival; EFS, event-free survival; RFS, relapse-free survival; CIR, cumulative incidence of relapse; HR, hazard ratio; 95% CI, 95% confidence interval.

Figure 5

Prognostic subgroup analyses regarding AML types and CD33 expression status. (A) OS subgrouped by AML types. (B) EFS subgrouped by AML types. (C) RFS subgrouped by AML types. (D) CIR subgrouped by AML types. (E) RFS subgrouped by CD33 expression status. (F) CIR subgrouped by CD33 expression status. The diamonds represent the overall summary HR estimates with 95% CI. GO, gemtuzumab ozogamicin; AML, acute myeloid leukemia; OS, overall survival; EFS, event-free survival; RFS, relapse-free survival; CIR, cumulative incidence of relapse; HR, hazard ratio; 95% CI, 95% confidence interval.

Figure 6

Prognostic subgroup analyses regarding treatment stages and doses of GO. (A) OS subgrouped by treatment stages. (B) RFS subgrouped by treatment stages. (C) CIR subgrouped by treatment stages. (D) OS subgrouped by GO doses. (E) EFS subgrouped by GO doses. (F) RFS subgrouped by GO doses. (G) CIR subgrouped by GO doses. The diamonds represent the overall summary HR estimates with 95% CI. GO, gemtuzumab ozogamicin; OS, overall survival; EFS, event-free survival; RFS, relapse-free survival; CIR, cumulative incidence of relapse; HR, hazard ratio; 95% CI, 95% confidence interval.

Figure 7

Prognostic subgroup analyses regarding combined regimens of GO. (A) CR. (B) OS. (C) RFS. (D) CIR. The diamonds represent the overall summary RR and HR estimates with 95% CI. GO, gemtuzumab ozogamicin; CR, complete remission; OS, overall survival; RFS, relapse-free survival; CIR, cumulative incidence of relapse; RR, relative risk; HR, hazard ratio; 95% CI, 95% confidence interval; DA, daunorubicin plus cytarabine; Ara-C, cytarabine; FLAG, fludarabine, Ara-C, and granulocyte colony-stimulating factor.