Early Mortality In Hyperleukocytosis In Patients With Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis

Hyperleukocytosis in acute myeloid leukemia (AML) is associated with early deaths, typically related to respiratory failure and intracranial ischemia/hemorrhage. Various interventions for leukoreduction including leukapheresis, low-dose chemotherapy and hydroxyurea have been used in an attempt to decrease mortality. However, there are no randomized trials and observational trials are biased. We undertook a systematic review and meta-analysis to evaluate the effect of these interventions using an “intent-to-treat” approach and classifying studies as always, sometimes and never using these interventions.

The primary objective was to describe the proportion of early deaths in patients with AML with an initial WBC ≥ 100,000x10⁹/L stratified by the approach to leukapheresis and hydroxyurea/low dose chemotherapy (universal, sometimes or never). The secondary objective was to compare the proportion of early deaths in patients who did and did not receive leukapheresis.

Electronic searches of Ovid Medline from 1980 to July 12, 2013, EMBASE from 1980 to July 12, 2013 and Cochrane Central Register of Controlled Trials until June 2013 were conducted. Studies were included if: (1) Population included patients with AML; and (2) Either described the proportion of patients with early deaths in patients with an initial WBC ≥ 100,000x10⁹/L or compared the proportion of early deaths by receipt of leukapheresis in patients using the same initial WBC threshold. Studies including solely acute promyelocytic leukemia (APML) patients were excluded. The pre-specified subgroups in the evaluation of early death proportions were whether leukapheresis and low-dose chemotherapy/hydroxyurea were intended to be applied universally, sometimes or never in hyperleukocytosis. These subgroups were defined based on the study’s stated policy independent of the number of patients actually receiving the intervention. Two investigators assessed the quality of the included studies for selection and confounding bias using the Hayden framework. Synthesis of proportions was conducted using RevMan. Meta-regression was conducted in which the natural log of the proportion of early deaths was modelled. Heterogeneity was assessed by visual inspection and I².

Twenty studies representing 1427 patients were included in the final meta-analysis. Overall, the proportion of early deaths (19 studies, 1281 patients) was 19.9% (95% CI: 14.7-25.1). Table 1 illustrates that neither leukapheresis strategy nor hydroxyurea/low dose chemotherapy influenced the early death rate. Meta-regression evaluating the percent of patients receiving leukapheresis showed no relationship with early death rate (odds ratio 1.01, 95% CI: 0.99-1.02; P=0.249). Evaluation of leukapheresis within studies included 7 studies of which 6 were at high risk of confounding bias and sufficiently heterogeneous to not permit synthesis.

Early mortality related to hyperleukocytosis is high and is not influenced by universal or selected use of leukapheresis or low-dose chemotherapy/hydroxyurea. This meta-analysis does not support these interventions for patients with AML and hyperleukocytosis. Novel approaches are required to decrease mortality.

Lehrnbecher:Gilead: Honoraria; MSD: Honoraria; Pfizer: Honoraria; Astellas: Honoraria.