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.
Inclusion Criteria:
1. At least 18 years of age or older
2. 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 µmol/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:
1. Acute promyelocytic leukemia (M3 subtype of acute myeloid leukemia).
2. More than 2 cycles of first line induction chemotherapy.
3. Acute myeloid leukemia with Philadelphia chromosome or BCR-ABL1 or blast crisis stage
of chronic myeloid leukemia.
4. Known or suspected central nervous system leukemia.
5. 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.
6. Use of any experimental, cytotoxic, or targeted, anti-leukemic therapy within 14 days
prior to randomization, with the exception of hydroxyurea.
7. Formal contraindication to glucocorticoids.
8. Non-acute myeloid leukemia-associated organic or psychiatric severe disease that
contraindicates use of study treatment.
9. Patient who may not be followed regularly in consultation because of psychological,
family, social, or geographical reasons.
10. History of uncontrolled other malignancy for at least two years, with the exception of
basal cell carcinoma and in situ cervix carcinoma.
11. Severe uncontrolled infection at time of inclusion.
12. 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.
13. Pregnant (beta gonadotropic chorionic hormon positive) or breastfeeding woman.
14. Incapable patient of age, under guardianship, under curators or safeguard of justice.
15. Patient under State Medical Assistance.
