NCT03765541

Dexamethasone in Refractory or First Relapsed Acute Myeloid Leukemia

Dexamethasone Plus Salvage Chemotherapy Versus Salvage Chemotherapy Alone in Patients With First Relapsed or Refractory Acute Myeloid Leukemia: a Randomized, Controlled, Open-label, Multicenter, Phase III Study

• Status: Terminated
• Phase: Phase 3
• Study type: Interventional
• Enrollment: 73 (actual)
• Sponsor: University Hospital, Toulouse · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

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.

Detailed description

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.

Conditions

• Relapsed or Refractory Acute Myeloid Leukemia

Interventions

Type	Name	Description
DRUG	Dexamethasone	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 \[10minutes\]).
DRUG	Amsacrine	* 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 \[3 hours\])
DRUG	Cytarabine	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
DRUG	Azacitidine	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)

Timeline

• Start date: 2020-01-13
• Primary completion: 2024-05-31
• Completion: 2024-05-31
• First posted: 2018-12-05
• Last updated: 2025-04-10

Locations

10 sites across 1 country: France