Leukapheresis and low-dose chemotherapy do not reduce early mortality in acute myeloid leukemia hyperleukocytosis: A systematic review and meta-analysis

Abstract

The role of leukapheresis and low-dose chemotherapy is unclear in decreasing early mortality in acute myeloid leukemia (AML) patients with hyperleukocytosis. This systematic review was conducted to describe early mortality (deaths during first induction) in patients with AML with an initial white blood count ≥ 100 × 10⁹ L⁻¹ stratified by the approach to leukapheresis and hydroxyurea/low-dose chemotherapy. Twenty-one studies were included. Weighted mean early deaths rate (20 studies, 1354 patients) was 20.1% (95% confidence interval 15.0–25.1). Neither leukapheresis strategy (p = 0.67) nor hydroxyurea/low-dose chemotherapy (p = 0.23) influenced the early death rate. Early mortality related to hyperleukocytosis in AML is not influenced by universal or selected use of leukapheresis or hydroxyurea/low-dose chemotherapy.

Introduction

The management of hyperleukocytosis in patients with acute myeloid leukemia (AML) is controversial. Hyperleukocytosis is commonly defined as a white blood count (WBC) > 100 × 10⁹ L⁻¹ [1], [2]. Approximately 12–22% patients with AML have hyperleukocytosis at diagnosis or at relapse [3], [4], [5], [6], [7], [8]. These patients are at high risk of early morbidity and mortality primarily related to leukostasis and tumor lysis syndrome [6], [7], [8], [9]. Myeloblast leukostasis in the microcirculation of vital organs leads to tissue hypoxia, thrombosis or hemorrhage [10], [11], [12]. Leukostasis is thought to be relatively more common in AML compared to acute lymphobastic leukemia due to increased adhesiveness and larger size of myeloblasts [10]. Respiratory failure, intracranial hemorrhage and/or ischemia and coagulopathy are the typical manifestations of leukostasis [2], [7], [9], [10].

Various interventions have been implemented in an attempt to improve outcomes in patients with hyperleukocytosis. Interventions for which there is more universal support include optimization of coagulation, hyperhydration, urate oxidase administration and avoidance of packed red blood cell transfusions which may increase blood viscosity [10], [13]. However, other interventions are more controversial including initial therapy with hydroxyurea or low-dose chemotherapy, and exchange transfusion or leukapheresis [5], [8], [14], [15], [16]. Hydroxyurea and low-dose chemotherapy with cytarabine, etoposide and 6-thioguinine have been used in an attempt to achieve more gradual cytoreduction [4], [15], [16], [17], [18]. In contrast, leukapheresis has been used to achieve more rapid cytoreduction with the potential to decrease tumor lysis syndrome [5], [8], [14], [19], [20].

To decide whether these interventions should be implemented, studies in which these interventions were rigorously evaluated would be optimal. However, there are no randomized trials in this setting and it is unlikely that trials will ever be feasible given the rarity of the condition, urgency for decision making and strong physician preferences. In some centers, decision making for each patient is individualized based on patient characteristics and physician preferences. However, these studies suffer from confounding by indication with important differences in patient characteristics among those who do and do not receive the intervention. For example, with leukapheresis, patients who die very quickly or who have severe comorbidities may not receive the intervention. Conversely, leukapheresis may be reserved for the sickest patients or those who are symptomatic. This issue makes inferences based on “as treated” analyses highly problematic.

One way to address this bias is to evaluate a study's or institution's policy toward these interventions to obtain an “intent-to-treat” approach measure. In this analysis, we categorized studies as “universal”, “sometimes” or “never” using the specific intervention by review of each study's methods section. Our primary objective was to describe the proportion of early deaths in patients with AML and an initial WBC ≥ 100 × 10⁹ L⁻¹ 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 do and do not receive leukapheresis.