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Dexamethasone in AML
gene signature was observed in 45-60% of AML patients (Online Supplementary Figure S4B).
All together, these results demonstrate that dexametha- sone has significant activity against NPM1-mutated AML cells, corresponding to ~65% of the patients treated by dexamethasone in the clinical study.
Discussion
Three very recent pre-clinical studies have demonstrat- ed that glucocorticoids could be of real interest in AML. Malani et al. and Kurata et al. have shown that the devel- opment of cytarabine resistance in AML cells is associated with increased sensitivity to glucocorticoids.17,18 Using a chemogenomic approach, Simon et al. demonstrated that AML samples bearing inactivating RUNX1 mutations are particularly sensitive to glucocorticoids.21 Our study is the first to detect a significant clinical correlation between dexamethasone treatment and outcome in adult patients with AML. Indeed, we showed that the addition of dex- amethasone to intensive chemotherapy was associated with significantly better disease-free and overall survival in hyperleukocytic AML patients. We must, however, acknowledge that Turkish investigators previously report- ed their long-lasting experience on the potential impact of high-dose methylprednisolone in pediatric AML.25
The strong and unexpected impact of dexamethasone in preventing relapses prompted us to undertake in silico, in vitro, and in vivo exploratory analyses. The gene signatures of some molecular subgroups of AML were highly enriched in genes responsive to dexamethasone, including AML with NPM1 mutations, which were particularly sen- sitive to the antileukemic activity of dexamethasone both in vitro and in vivo. Moreover, using a xenotransplantation model of chemoresistance, we demonstrated that the transcriptome of viable AML cells in xenograft NSG mice following cytarabine exposure is highly enriched in inflammatory response genes as well as in genes respon- sive to dexamethasone.19 Although inflammation is a hall- mark of cancer, its role has been neglected in AML in which other oncogenic pathways, including transcription- al dysregulation, sustained proliferative signaling, epige- netic or metabolic alterations, as well as deregulated splic- ing have been more deeply assessed. Yet, several aspects of inflammation could be explored to increase our knowl- edge of AML pathophysiology and to expand therapeutic opportunities or prognostic markers.26 The results of our study led us to speculate that dexamethasone, by affecting specific transcriptomic programs and/or by modulating the early inflammatory response which is associated with chemoresistance, might sensitize AML cells to chemother- apy-induced cell death and thereby limit the risk of leukemic regrowth and relapse. Thus, although there was only a trend for a higher complete response rate in the dexamethasone group, this effect was translated in our study into a reduction of cumulative incidence of relapse, which is a better end point than the complete response rate for assessing the quality of response and impact on chemoresistant disease. Our findings also suggest that dexamethasone, used as a chemosensitizer in combina- tion with intensive chemotherapy, should be assessed in prospective trials regardless of the WBC count.
Dexamethasone has both cytoplasmic and nuclear activities that interfere with signal transducers or tran-
scription factors such as PI3-kinase, activating protein-1, and nuclear factor-κB, which are both involved in leukemic stem-cell biology.8,27 Inflammatory cytokines can induce both nuclear factor-κB and activating protein-1 to support leukemic stem-cell survival in a synergistic man- ner.28 Thus, by suppressing cytokine release and targeting specific intracellular pathways, dexamethasone could make leukemic stem cells more susceptible to chemother- apy-induced cell death. The mechanisms of action under- pinning dexamethasone activity in AML are likely to be multiple as leukemic stem cells are subject to different lev- els of regulation which are either cell autonomous or driv- en by interactions with the microenvironment.29,30
In most studies that have focused on hyperleukocytosis in AML, the early mortality rate is about 20–30%, which is similar to that in the no dexamethasone group in our study.31 Early mortality has remained very high compared to that of patients without hyperleukocytosis even in recent series, and therapeutic strategies, aimed at reduc- ing leukocytosis through the use of leukapheresis or low- dose chemotherapy, failed to demonstrate any benefit.2,31 Our results show that dexamethasone treatment was associated with a lower rate of early mortality following induction chemotherapy despite a higher rate of admis- sion to the intensive care unit. There was, however, no significant difference compared to patients in the no dex- amethasone group, which may reflect the low number of events. The criteria for intensive care unit admission in our center changed in 2015 when AML patients with a WBC count >100x109/L or leukostasis were admitted directly into the unit. However, we analyzed the 2004- 2013 period and found the same difference with more intensive care unit admissions in the dexamethasone group (31% vs. 15%; P=0.028). Thus, it is likely that this difference is related to the selection criteria for giving dexamethasone, including higher WBC count and leukostasis syndrome, which are the main risk factors for transfer into the intensive care unit. Furthermore, although many physicians may be reluctant to use steroids in AML because of the potential risk of invasive fungal infections, we did not identify such adverse effects in dexamethasone-treated patients who also received antifungal prophylaxis.
Because this study is retrospective and included only a relatively low number of patients, there are some limita- tions. However, it also reflects some real-life aspects of the care of AML patients with a high WBC count, a difficult- to-treat population requiring immediate medical treat- ment, which means that these patients are often excluded from prospective trials. In our study, the impact of dexam- ethasone was adjusted for several clinical and biological factors to limit the potential biases inherent to non-ran- domized studies, and a biological rationale was further provided to strengthen the clinical findings. Although prospective randomized clinical trials are needed to con- firm the results of this study, our findings argue for a repo- sitioning of dexamethasone use within the backbone of intensive chemotherapy in AML patients.
Acknowledgments
This work was supported by grants from the French govern- ment under the "Investissement d'Avenir" program (ANR-11- PHUC-001), the Institut National du Cancer (PLBIO 2015- 143), the InnaBioSanté Foundation (RESISTAML project), the Toulouse Cancer Santé Foundation, the Laboratoire d'Excellence
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