Leukapheresis and low-dose chemotherapy do not reduce early mortality in acute myeloid leukemia hyperleukocytosis: A systematic review and meta-analysis
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.
Section snippets
Data sources and searches
We performed 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. The search strategy included the Medical Subject Heading terms and text words leukemia, leukapheresis and hyperleukocytosis (see Supplemental File for the complete search strategy). As this study was a systematic review of primary studies, no ethical approval was required.
Study selection
Inclusion and exclusion criteria were defined a
Results
A total of 4876 titles and abstracts were reviewed; 42 articles were retrieved for detailed evaluation. Twenty-one satisfied eligibility criteria and were included in the final meta-analysis. Of the 21 included studies, 20 met eligibility criteria for the primary objective of describing 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. One study [14] was only eligible for the
Discussion
We found that the early mortality rate associated with hyperleukocytosis in patients with AML has remained high over the last three decades. Universal or selected approaches to leukapheresis and hydroxyurea/low-dose chemotherapy did not have an impact on the early death rate. These findings do not support the routine use of these interventions in AML patients with hyperleukocytosis.
The optimal management of hyperleukocytosis is uncertain and although some authors advocate the use of
Financial disclosure statement
Authors have no financial relationships relevant to this article to disclose.
Conflict of interest statement
The authors declare no competing financial interests.
Acknowledgements
We wish to thank Elizabeth Uleryk for her tremendous support in conducting the literature search. LS is supported by a New Investigator Award by the Canadian Institutes of Health Research.
Contributors: LS conceptualized and designed the study; LS, SO, and MCE collected the data; LS, SO and JB analyzed the data; LS and SO wrote the manuscript; and all authors critically revised the manuscript for important content. All authors approve the final version of the manuscript.
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