Dexamethasone in Refractory or First Relapsed Acute Myeloid Leukemia

  • STATUS
    Recruiting
  • End date
    Sep 25, 2024
  • participants needed
    142
  • sponsor
    University Hospital, Toulouse
Updated on 25 January 2021

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.

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.

Details
Condition Relapsed or Refractory Acute Myeloid Leukemia
Treatment cytarabine, Dexamethasone, Azacitidine, Amsacrine
Clinical Study IdentifierNCT03765541
SponsorUniversity Hospital, Toulouse
Last Modified on25 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

At least 18 years of age or older
Diagnosis of acute myeloid leukemia by World Health Organization classification
First relapsed or refractory acute myeloid leukemia with at least 5% blasts by
bone marrow biopsy or aspirate, or at least 1% blasts in peripheral blood, and
meeting the following criteria
First relapsed acute myeloid leukemia
First relapse occurred at least 90 days to 24 months after the first complete remission or complete remission with incomplete recovery
The first complete remission or complete remission with incomplete recovery had to result from no more than 2 cycles of cytotoxic chemotherapy. At least 1 induction cycle must have consisted of an anthracycline and cytarabine combination with a reasonable schedule/dose of anthracycline in the judgment of the investigator
The re-emergence of at least 5% leukemic blasts in bone marrow is not attributable to other causes, regardless of new or recurrent dysplastic changes or extramedullary disease, or the re-emergence of at least 1% blasts in the peripheral blood is not attributable to other causes such as regenerating marrow
Refractory acute myeloid leukemia
Persistent acute myeloid leukemia was documented by bone marrow biopsy or aspirate at least 28 days after day 1 of the first induction cycle of 1 or 2 cycles of cytotoxic chemotherapy
Re-emergence of at least 5% leukemic blasts in bone marrow or at least 1% blasts in peripheral blood is not attributable to other causes such as regenerating marrow, and was less than 90 days after the first complete remission or complete remission with incomplete recovery
Prior induction therapy had to include no more than 2 cycles of cytotoxic chemotherapy. At least 1 induction cycle must have consisted of an anthracycline and cytarabine combination with a reasonable schedule/dose of anthracycline in the judgment of the investigator. 3. Eastern Cooperative Oncology Group performance status 2. 4. Left ventricular ejection fraction 50% by echocardiogram or multi-gated acquisition scan ; only applicable for patients who will receive intensive chemotherapy. 5. Serum creatinine 150 mol/L and/or total bilirubin 1.5 the upper limit of normal and/or, aspartate aminotransferase 2.5 the upper limit of normal, and/or alanine aminotransferase 2.5 the upper limit of normal (unless related to acute myeloid leukemia) 6. Any clinically significant non-hematological toxicity after prior chemotherapy must be resolved or of grade 1 as per Common Terminology Criteria for Adverse Events version 4.03. 7. Women must be surgically or biologically sterile, or in post-menopause (amenorrheic for at least 12 months), or if of childbearing potential, must have a negative urine or serum pregnancy test within 14 days prior to the randomization and agree to use a highly effective method of contraception throughout the entire duration of the study treatment (including dose interruptions) and until 3 months after the last study treatment administration. Men must be surgically or biologically sterile, or agree to use a highly effective method of contraception throughout the entire duration of the study treatment (including dose interruptions) and until 6 months after the last study treatment administration. 8. Registered to, or beneficiary of, social security insurance or equivalent. 9. Signed written informed consent by both the patient and the investigator prior to perform any study-relayed procedure not part of normal medical care

Exclusion Criteria

Acute promyelocytic leukemia (M3 subtype of acute myeloid leukemia)
More than 2 cycles of first line induction chemotherapy
Acute myeloid leukemia with Philadelphia chromosome or BCR-ABL1 or blast crisis stage of chronic myeloid leukemia
Known or suspected central nervous system leukemia
Undergoing allogeneic hematopoietic stem cell transplantation within 90 days prior to randomization, or being on immunosuppressive therapy for prophylaxis of graft-versus-host disease, or experiencing graft-versus-host disease within 2 weeks prior to randomization
Use of any experimental, cytotoxic, or targeted, anti-leukemic therapy within 14 days prior to randomization, with the exception of hydroxyurea
Formal contraindication to glucocorticoids
Non-acute myeloid leukemia-associated organic or psychiatric severe disease that contraindicates use of study treatment
Patient who may not be followed regularly in consultation because of psychological, family, social, or geographical reasons
History of uncontrolled other malignancy for at least two years, with the exception of basal cell carcinoma and in situ cervix carcinoma
Severe uncontrolled infection at time of inclusion
Positive serology for human immunodeficiency virus-1 or 2, and/or Human T-Cell lymphotropic viruses-1 or 2, and/or active viral infection with hepatitis B virus and/or hepatitis C virus
Pregnant (beta gonadotropic chorionic hormon positive) or breastfeeding woman
Incapable patient of age, under guardianship, under curators or safeguard of justice
Patient under State Medical Assistance
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