Dexamethasone in hyperleukocytic acute myeloid leukemia

Abstract

Patients with acute myeloid leukemia and a high white blood cell count are at increased risk of early death and relapse. Because mediators of inflammation contribute to leukostasis and chemoresistance, dexamethasone added to chemotherapy could improve outcomes. This retrospective study evaluated the impact of adding or not adding dexamethasone to chemotherapy in a cohort of 160 patients with at least 50×109 white blood cells. In silico studies, primary samples, leukemic cell lines, and xenograft mouse models were used to explore the antileukemic activity of dexamethasone. There was no difference with respect to induction death rate, response, and infections between the 60 patients in the dexamethasone group and the 100 patients in the no dexamethasone group. Multivariate analysis showed that dexamethasone was significantly associated with improved relapse incidence (adjusted sub-HR: 0.30; 95% CI: 0.14–0.62; P=0.001), disease-free survival (adjusted HR: 0.50; 95% CI: 0.29–0.84; P=0.010), event-free survival (adjusted HR: 0.35; 95% CI: 0.21–0.58; P<0.001), and overall survival (adjusted HR: 0.41; 95% CI: 0.22–0.79; P=0.007). In a co-culture system, dexamethasone reduced the frequency of leukemic long-term culture initiating cells by 38% and enhanced the cytotoxicity of doxorubicin and cytarabine. In a patient-derived xenograft model treated with cytarabine, chemoresistant cells were enriched in genes of the inflammatory response modulated by dexamethasone. Dexamethasone also demonstrated antileukemic activity in NPM1-mutated samples. Dexamethasone may improve the outcome of acute myeloid leukemia patients receiving intensive chemotherapy. This effect could be due to the modulation of inflammatory chemoresistance pathways and to a specific activity in acute myeloid leukemia with NPM1 mutation.

Ferritin heavy/light chain (FTH1/FTL) expression, serum ferritin levels, and their functional as well as prognostic roles in acute myeloid leukemia

“…Having shown that AML cells express higher ferritin levels than their normal counterparts, we sought to determine whether chemotherapy could induce higher levels of inflammatory markers including serum ferritin and if so, whether dexamethasone, used in hyperleukocytic AML patients, could limit this chemotherapy‐induced inflammatory response . We thus collected serum ferritin, CRP, and albumin values on days 1 and 8 of induction chemotherapy in an independent exploratory cohort of 234 AML patients from TUH: 134 patients with WBC < 20 G/L, 49 patients with WBC > 50 G/L not treated by dexamethasone, and 51 patients with WBC > 50 G/L treated by dexamethasone in combination with intensive chemotherapy . Serum ferritin, CRP, and albumin levels were significantly altered at day 8 indicating that intensive chemotherapy induces an inflammatory response in AML patients (Table ).…”

“…15,47 Interestingly, we show that the anti-inflammatory drug dexamethasone that we used in patients with high WBC blocks the increase of serum ferritin indicating that it can target inflammatory dysregulations and ferritin production in these conditions. 23 It has been previously shown that a short course of high-dose methylprednisolone could reduce the duration of neutropenia following consolidation chemotherapy in children with AML. 48 Altogether, these observations deserve prospective clinical trials assessing the impact of glucocorticoids and other agents modulating ferritin expression in adult AML patients.…”

“…In AML patients, this increase in ferritin levels is likely further worsened during chemotherapy‐induced aplasia by the massive red blood cell transfusion and infectious events creating conditions for prolonged deleterious effects of ferritin . Interestingly, we show that the anti‐inflammatory drug dexamethasone that we used in patients with high WBC blocks the increase of serum ferritin indicating that it can target inflammatory dysregulations and ferritin production in these conditions . It has been previously shown that a short course of high‐dose methylprednisolone could reduce the duration of neutropenia following consolidation chemotherapy in children with AML .…”

“…Having shown that AML cells express higher ferritin levels than their normal counterparts, we sought to determine whether chemotherapy could induce higher levels of inflammatory markers including serum ferritin and if so, whether dexamethasone, used in hyperleukocytic AML patients, could limit this chemotherapy-induced inflammatory response. 21 We thus collected serum ferritin, CRP, and albumin values on days 1 and 8 of induction chemotherapy in an 23 Serum ferritin, CRP, and albumin levels were significantly altered at day 8 indicating that intensive chemotherapy induces an inflammatory response in AML patients (Table 4). There were no differences between males and females regarding CRP and albumin levels either at day 1 and 8.…”

Association between intraoperative administration of dexamethasone and survival after curative resection for non-small cell lung cancer (NSCLC): A propensity score matching analysis

“…Glucocorticoids (GCs), such as dexamethasone, can arrest growth or induce apoptosis in lymphocytes [22]. In leukemia and lymphoma, dexamethasone is the cornerstone of treatment for all lymphatic cancers and hematopoietic malignancies [23]. Moreover, dexamethasone performs a variety of functions, including preventing postoperative nausea and vomiting, reducing postoperative pain, antiin ammation, antianaphylaxis, immunosuppression and so on [12,24,25].…”