Recent preclinical and retrospective clinical data have suggested that dexamethasone might sensitize leukemic cells to chemotherapy-induced cell death and thus limit the risk of leukemic regrowth and relapse. Moreover, it has been experimentally shown that leukemic cells in acute myeloid leukemia patients who relapse become sensitive to glucocorticoids treatment highlighting a novel potential role for dexamethasone in relapsed or refractory acute myeloid leukemia (R/R). This study was designed to determine whether adding dexamethasone to standard salvage therapy in the treatment of relapsed/refractory acute myeloid leukemia in adult patients (intensive chemotherapy amsacrine-cytarabine or azacitidine according to investigator's willingness) results in a significant improvement of the overall survival.
The prognosis for patients with relapsed or refractory acute myeloid leukemia is poor ; median survival is less than 1 year. High-dose cytarabine monotherapy or cytarabine-based combination regimens are often used as salvage therapy with limited efficacy. A recent retrospective study has shown that the addition of dexamethasone to intensive chemotherapy was significantly associated with better disease-free and overall survival in hyperleukocytic acute myeloid leukemia patients. The gene signatures of some molecular subgroups of acute myeloid leukemia were highly enriched in genes responsive to dexamethasone, including acute myeloid leukemia with NPM1 mutations which were particularly sensitive to the antileukemic activity of dexamethasone both in vitro and in vivo. Moreover, three recent preclinical studies have shown that cytarabine-resistant or RUNX1-mutated acute myeloid leukemia cells acquired sensitivity to glucocorticoids. Therefore, dexamethasone might sensitize leukemic stem cells to chemotherapy-induced cell death and thus limit the risk of relapse. This study consists of a screening period, a treatment period, and a post-treatment follow-up period. Adult patients with relapsed/refractory acute myeloid leukemia are randomly assigned in a 1:1 ratio to receive either standard salvage therapy in combination with dexamethasone or standard salvage therapy alone. Standard salvage therapy is intensive chemotherapy (amsacrine-cytarabine) or azacitidine according to the investigator's willingness. For those patients with intensive chemotherapy amsacrine-cytarabine, the study treatment period includes 1 induction cycle and up to 3 consolidation cycles. For those patients with azacitidine, the study treatment period includes 3 cycles prior to the evaluation of the complete remission and thereafter lasts until progression. Of note, any patients in the study can undergo allogeneic hematopoietic stem cell transplantation providing his/her disease is controlled. After discontinuing the study treatment all patients must further carry out post-treatment follow-up visits every 3 months during the first and second year, and every 6 months thereafter until death, withdrawal of consent, loss to follow-up, or the end of the study, whichever occurs first. The end of the study is planned 5 years after the randomization of the first patient. The primary endpoint is the overall survival.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
73
In combination with intensive chemotherapy amsacrine-cytarabine: * Induction (1 cycle): 10 mg/12h from Day 1 to Day 3 of cycle (2 infusions/24h, slow IV \[10 minutes\]) * Consolidation (3 cycles): 10 mg/12h from Day 1 to Day 3 of each cycle (2 infusions/24h, slow IV \[10 minutes\]) In combination with azacitidine: * Cycle 1: 20 mg/24h from Day 1 to Day 3 of cycle (1 infusion/24h, slow IV \[10 minutes\]). * Subsequent cycles: 20 mg/24h on Day 1 of each cycle (1 infusion/24h, slow IV \[10minutes\]).
* Induction (1 cycle): 200 mg/m2/24h from Day 1 to Day 3 of cycle (slow IV \[3 hours\]) * Consolidation (3 cycles): 200 mg/m2/24h on Day 1 of each cycle (slow IV \[3 hours\])
Patients \< 60 years of age: * Induction (1 cycle): 3 g/m2/12h from Day 1 to Day 4 of cycle (2 infusions/24h, slow IV \[2 hours\]) * Consolidation (3 cycles): 3 g/m2/12h from Day 1 to Day 3 of each cycle (2 infusions/24h, slow IV \[2 hours\]) Note: If the investigators believe that there is an undue risk for the safety of a patient under 60 years of age with comorbidity in receiving a dose level of 3 g/m2/12h, the dose may be reduced to 1 g/m2/12h
75 mg/m2/24h from Day 1 to Day 7 of each cycle \[or from Day 1 to Day 5 and from Day 8 to Day 9 of each cycle\] (SC)
CH de la Côte Basque
Bayonne, France, France
CHU de la Réunion
Saint-Pierre, France, France
CHU de Grenoble
Grenoble, France
CHU de Limoges
Limoges, France
Institut Paoli Calmettes
Marseille, France
CHU de Montpellier
Montpellier, France
CHU de Nantes
Nantes, France
CHU de Nîmes
Nîmes, France
CHU de Bordeaux
Pessac, France
CHU de Poitiers
Poitiers, France
Overall survival
Time from the date of randomization to the date of death from any cause
Time frame: Up to 60 months
Response to therapy
Best response of complete remission or complete remission with incomplete recovery as assessed by the investigators according to the 2010 European Leukemia Net recommendations for diagnosis and management of acute myeloid leukemia in adults
Time frame: Up to 60 months
Minimal residual disease positivity
Quantitative assessment by either quantitative polymerase chain reaction or multiparameter flow cytometry of any tumor cells greater than pre-specified sensitivity thresholds of detection
Time frame: Up to 60 months
Number of patient who realize allogeneic hematopoietic stem cell transplantation
Undergoing allogeneic hematopoietic stem cell transplantation
Time frame: Up to 60 months
Duration of remission
Time from the date of first complete remission or complete remission with incomplete recovery to the date of relapse, where complete remission, complete remission with incomplete recovery, and relapse as assessed by the investigators according to the 2010 European Leukemia Net recommendations for diagnosis and management of acute myeloid leukemia in adults
Time frame: Up to 60 months
Relapse-free survival
Time from the date of first complete remission or complete remission with incomplete recovery to the date of relapse or death from any cause, whichever occurs first, where complete remission, complete remission with incomplete recovery, and relapse as assessed by the investigators according to the 2010 European Leukemia Net recommendations for diagnosis and management of acute myeloid leukemia in adults
Time frame: Up to 60 months
Event-free survival
Time from the date of randomization to the date of treatment failure, or relapse from complete remission or complete remission with incomplete recovery, or death from any cause, whichever occurs first, where treatment failure, complete remission, complete remission with incomplete recovery, and relapse as assessed by the investigators according to the 2010 European Leukemia Net recommendations for diagnosis and management of acute myeloid leukemia in adults
Time frame: Up to 60 months
Quality of life with leukemia questionnaire
Scoring of functional assessment of cancer therapy - Leukemia questionnaire
Time frame: At baseline, through complete remission, on Day 1 before dosing of each post-remission cycle, at 60 months
Adverse events
Adverse events reported according to the descriptions and grading scale found in the version 4.03 of the National Cancer Institute - Common Terminology Criteria for Adverse Events
Time frame: During 60 months
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