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Dexamethasone in AML
Introduction
Acute myeloid leukemias (AML) are myeloid malignan- cies induced by the oncogenic transformation of hematopoietic progenitors in the bone marrow leading to the destruction of blood tissue and, therefore, to profound pancytopenia, severe bleeding, and infection.1 Approximately 20% of patients present at diagnosis with high white blood cell (WBC) counts (i.e. >50x109/L).2 In this high-risk situation, the probability of severe complica- tions is increased because of leukemic organ infiltration, severe hemorrhage, or metabolic disorders, including tumor lysis syndrome, renal failure, and disseminated intravascular coagulopathy, which is further worsened by the induction of antileukemic treatment. Hyperleukocytosis is also associated with leukostasis syn- drome within the lung or brain, which can potentially lead to acute respiratory distress syndrome or stroke. Thus, patients with a high WBC count share an increased risk of death during the initial phase of the disease. Hyperleukocytosis is also independently associated with shorter relapse-free survival in patients treated by inten- sive chemotherapy, indicating a potential link with chemoresistance.2
Dexamethasone is an anti-inflammatory drug widely used in acute lymphoblastic leukemia and other lymphoid malignancies.3 Much less frequently used in myeloid dis- orders, this drug is often offered to prevent or treat a severe inflammatory status, so-called differentiation syn- drome in patients with acute promyelocytic leukemia treated with all trans-retinoic acid and/or arsenic triox- ide.4,5 Mediators of inflammation induced by leukemic blasts and endothelial cells contribute to the pathogenesis of leukostasis.6 Studies on the molecular mechanisms of leukostasis and leukemic cell invasion have shown that leukemic blasts use integrins and selectins to attach to cytokine-activated endothelium and directly activate endothelial cells by secreting inflammatory cytokines, such as tumor necrosis factor-α, interleukin-1β, and inter- leukin-6, which induce the conditions necessary for their adhesion to vascular endothelium, migration to tissues, proliferation, and chemoresistance.6,7 The central role of the inflammatory response prompted us to assess the impact of dexamethasone in this setting because this drug exerts a potent inhibitory effect on cytokine production.8 We hypothesized that introducing a short course of dex- amethasone into routine practice during the early phase of induction chemotherapy would improve the outcome of hyperleukocytic AML patients.
Methods
Patients
Between January 2004 and December 2015, 802 patients aged between 18 and 75 years with cytologically confirmed AML were consecutively treated with intensive chemotherapy at Toulouse University Hospital. Patients with acute promyelocytic leukemia were not considered. Patients were classified into three prognostic categories based on cytogenetics.9 FLT3-ITD and NPM1 mutations were assessed in patients with intermediate-risk cytogenetics. Data were collected from the patients' files and certified by the Data Management Committee of the AML database of Toulouse University Hospital registered at the Commission Nationale de l’Informatique et des Libertés (CNIL, #1778920).10 In accordance
with the Declaration of Helsinki, the study was reviewed and approved by the research ethics committee at Toulouse University Hospital.
Treatment
Study patients received induction chemotherapy that included daunorubicin at a daily dose of 60–90 mg/m2 of body surface area daily for 3 days, or idarubicin at a daily dose of 8-9 mg/m2 daily for 5 days, together with a continuous intravenous infusion of cytarabine at a daily dose of 100–200 mg/m2 daily for 7 days.10 No patient received an FLT3 inhibitor in combination with chemotherapy during first-line induction. Lomustine was added in patients aged over 60 years.11 Hydroxyurea could be started promptly at diagnosis for leukocytic reduction. Leukapheresis was not performed. Starting in January 2010, dexamethasone (10 mg b.i.d. given for 3 days) was systematically added to induction chemotherapy in all patients who had a WBC count of at least 100 x 109/L or in patients with a WBC count over 50 x 109/L and clini- cal symptoms of leukostasis. This dexamethasone schema was used based on our previous experience in patients with acute promyelocytic leukemia.4 Supportive care, which included pre- vention of invasive fungal infections with voriconazole from 2004 to 2008 then posaconazole, treatment of febrile neutropenia and disseminated intravascular coagulopathy, and blood-product transfusions were given according to standard guidelines that did not change over the study period.12,13 Patients who achieved com- plete remission proceeded to subsequent treatment steps. Post- remission therapy was based on relapse risk and whether an HLA- identical donor had been identified or not. Patients at low risk of relapse (i.e. patients with a core-binding factor AML, NPM1, or CEBPA mutation without FLT3-ITD) received only chemotherapy as post-remission therapy. All other patients with an HLA- matched donor underwent allogeneic stem-cell transplantation, whereas those without such a donor received chemotherapy.
Response criteria and end points
Complete response was defined according to standard criteria.14 Relapse was defined as leukemia recurrence after a first complete remission. Disease-free survival was measured from the time of complete remission evaluation to the date of relapse or death, whatever the cause. Event-free survival was measured from the date of diagnosis to the date of failure to enter complete remission, relapse, or death, whichever came first. Overall survival was defined as the time interval from diagnosis until death, whatever the cause.
The statistical analyses and exploratory analyses are described in the Online Supplementary Appendix.
Results
Study population
The flowchart of the 160 patients with a WBC count of at least 50 x 109/L included in this retrospective study is shown in Figure 1 and the patients’ characteristics are summarized in Table 1. The median follow-up period of patients still alive at the date of last contact was 52.2 months [inter-quartile range (IQR); 23.7-72.9 months]; the median periods in the dexamethasone and the no dexam- ethasone groups were 44.1 months (IQR; 19.6-55.8) and 65.7 months (IQR 52.0-79.7), respectively. The median age of the patients was 60.1 years (IQR: 49.2-67.3); 50% of patients were aged ≥60 years. Compared to the 100 patients in the no dexamethasone group, the 60 patients in the dexamethasone group were more likely to have a poor
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