Differentiation syndrome (DS) is the life-threatening adverse event that occurs in approximately 20–25% of acute promyelocytic leukemia (APL) patients undergoing induction therapy with all-trans retinoic acid (ATRA). During the APL-DS, changes in seric levels of cytokines [1], and in cellular adhesion/migration properties [2, 3, 4], as well as endothelial damage [5] have been reported to be related to ATRA-driven DS. Most of the cases manifest with dyspnea, pulmonary infiltrates, unexplained fever, more than 5 Kg weight gain, pleural and/or pericardial effusion, hypotension, and renal failure [4, 6].
ATRA therapy appears to alter the interaction between endothelial cells and leukocytes by inducing the production of specific cytokines and expression of adhesion molecules which may play a role in the APL-DS. The in vitro release of pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor-α (TNF-α) have been reported to coincide with ATRA-induced differentiation of APL blasts, which may lead in vivo to a systemic inflammatory response syndrome (SIRS) [1, 7]. Moreover, the ATRA-differentiating APL cells have increased ability to migrate from the blood flow into the tissues by upregulating molecules involved in cell adhesion (VLA-4: Very Late Antigen-4, LFA-1: Lymphocyte function-associated antigen-1, Mac-1: Macrophage-1 antigen and ICAM: Intercellular Adhesion Molecule-1 and 2) and migration (E-selectin and β2-integrin) [3, 8]. It suggests that both events may be important in the development of APL-DS once the systemic inflammatory response supports the infiltration of differentiating APL cells that have been implicated in tissue injuries.
The lung is the most clinically relevant target organ in APL-DS patients, which can develop distinct pulmonary complications [9]. Accordingly, it was experimentally demonstrated that the in vivo increased expression of ICAM-1 on the lung of NOD/scid mice after the differentiation therapy with ATRA is important for the pulmonary infiltration of APL cells [10]. The treatment with ATRA of CD54 and CD18 knockout mice inoculated with NB4 cells failed to increase MPO activity in the lungs in contrast with wild-type control mice suggesting that both leukocytic and endothelial adhesion molecules are essential for DS development [4]. Moreover, the IL-8 secretion by A549 alveolar epithelial cells support the chemotactic transmigration of ATRA-treated NB4 APL cells toward A549 cells [11].
In fact, IL-8 plays a important role in acute inflammation by activating and chemoattracting neutrophils [12]. In acute myeloid leukemia (AML) samples, the constitutive expression of IL-8 is well known [13, 14, 15]. Kornblau et al. (2010) described that recurrent patterns of cytokine and chemokine signatures have prognostic impact in patients with AML [14]. Among them, AML patients that expressed lower levels of IL-8 had better survival outcomes [14]. Accordingly, the IL-8 receptor CXCR2 is an adverse prognostic factor in AML and its inhibition decreases the proliferation of AML cell lines and primary samples [16]. More precisely, Kuett et al. found lowest expression of IL-8 mRNA in APL and the highest expression in AML with FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation, suggesting that these differences might explain prognostic differences associated with IL-8 expression [15].
Despite the lack of biomarkers that predict development of DS, Shibakura et al. observed that serum levels of IL-8 were increased during the course of ATRA treatment in two patients who developed APL-DS [17]. To support these in vivo findings, the same authors confirmed that the in vitro IL-8 expression was also up-regulated in leukemic primary cells from both APL patients after incubation with ATRA [17]. Nevertheless, no previous study has investigated and compared the IL-8 plasma levels in the plasma of DS and non-DS APL patients during the treatment with ATRA to determine whether this cytokine has the potential to predict the development of the APL-DS.