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For the FILO group, the standard of care for induction chemotherapy of elderly fit patients with AML is represented by the combination of Cytarabine, Idarubicin and Lomustine. The superiority of this combination was confirmed in a larger prospective study the LAMSA-2007. This induction treatment, followed by six courses of consolidation (Idarubicin and Cytarabine) followed then by a period of 6-month maintenance therapy, allows up to 80 % of remission, and a RFS of 46 % at 2 years.
The aim of the study is to assess the efficacy on outcome of Venetoclax combined with Cytarabine versus Idarubicin combined with Cytarabine administered as post-remission therapy to elderly patients with acute myeloid leukemia in first complete remission (CR) following induction chemotherapy.
Full description
Acute myeloid leukemia is characterized by the clonal expansion of myeloid blasts in the bone marrow, peripheral blood and extramedullary tissues which disrupts normal hematopoiesis.
It is the most common form of acute leukemia in adults with an estimated 19,950 new cases and 10,430 deaths in 2016 in the United States. The prevalence is approximately 36,000 in the US alone. The median age of diagnosis is 67 years, with 55 % of the patients diagnosed at 65 years or older, and approximately a third of them are diagnosed over the age of 75.
Due to a higher frequency of poor prognosis factors such as adverse cytogenetics, previous history of myelodysplastic syndrome (MDS) or therapy-related AML (t-AML), the prognosis of elderly AML remains dismal in patients > 60 years.
The complete remission rate achieved after induction chemotherapy is lower than in young adults, and the remission duration is seldom longer than a year. Consequently, the overall survival of these patients rarely excesses 10-15 % beyond 5 years from diagnosis. For this group of patients, improving the efficacy of post induction chemotherapy and preventing relapse, without increasing the treatment-related mortality, remain a challenge.
For the FILO group, the standard of care for induction chemotherapy of elderly fit patients with AML is represented by the combination of Cytarabine, Idarubicin and Lomustine (ICL: Idarubicin 8 mg per square meter per day, IV on days 1-5, Cytarabine 100 mg per square meter per day on days 1-7 IV continuously, Lomustine 200 mg per square meter orally at day 1). This induction treatment, followed by six courses of consolidation, consisting of reduced doses of Idarubicin 8 mg per square meter per day IV on day 1 and Cytarabine 50 mg per square meter/12h/d subcutaneously on days 1-5 followed then by a period of 6-month maintenance therapy, allows up to 80 % of remission, an improvement in 2-year Event Free Survival from 26 % to 41 %, and a 2 year relapse free survival improvement from of 33 % to 46 % for patients without unfavorable cytogenetics.
Venetoclax is a potent, selective and orally bioavailable small molecule inhibitor of BCL-2 (B-cell lymphoma 2), an anti-apoptotic protein which overexpression is associated with tumor initiation, disease progression, and drug resistance, and is thus a compelling target for anti-tumor therapy. Phse I/II studies have assessed venetoclax as single agent or in combination with low dose Cytarabine (LDAC) in upfront treatment of AML patients aged ≥ 65 years old and not eligible for standard Cytarabine and anthracycline-based induction therapy with encouraging results. The aim of the study is to assess the efficacy on outcome of Venetoclax combined with Cytarabine versus Idarubicin combined with Cytarabine administered as post-remission therapy to elderly patients with acute myeloid leukemia in first complete remission (CR) following induction chemotherapy.
Subjects will be randomized 1:1 to receive Venetoclax or Idarubicin associated to Cytarabine for 6 cycles x 28 days. Patients will be followed until progression or death or until the end of study defined by the number of relapse-free survival (RFS) events and last patient treatment period.
Enrollment
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Inclusion and exclusion criteria
Inclusion Criteria :
≥ 60 years of age.
AML de novo according to the WHO 2016 classification
AML with favorable or intermediate cytogenetics according to ELN 2017
Subjects should be eligible for intensive chemotherapy by Idarubicin, Cytarabine, and Lomustine (standard induction for FILO)
SORROR < 3 (for the protocol, calculation of Sorror excludes a history of cancer) (appendix 2)
AML secondary to MDS or chemotherapy are eligible, unless adverse cytogenetics
Eastern Cooperative Oncology Group (ECOG) < 3 (appendix 1)
Adequate baseline organ function defined by the criteria below:
Adequate cardiac function with Left Ventricular Ejection Fraction (LVEF) ≥ 50 %
Absence of any psychological, familial, sociological or geographical conditions potentially hampering compliance with the study protocol and follow-up schedule
Females must be menopausal to be pre-enrolled
Patients must be affiliated to the French Social Security (health insurance)
Signed written informed consent for the study
Exclusion Criteria:
Randomization criteria:
Subjects must have been registered at diagnosis
Subjects must have received intensive induction by Idarubicin, Cytarabine and Lomustine
Patients in Complete Response / Complete Response with incomplete hematologic recovery (CR/CRi) post induction according to ELN 2017 criteria
Randomization should be performed no more than D+60 after induction
ECOG < 3 (appendix 1)
Adequate baseline organ function defined by the criteria below:
Adequate cardiac function with LVEF ≥ 50 %
Male subjects who are sexually active must agree, from study Day 1 through at least 180 days after the last dose of study drug, to practice protocol-specified methods of contraception
Female subjects must be postmenopausal defined as with no menses for 12 or more months without an alternative medical cause
Non randomization criteria
Patient in Partial Remission (PR) or failure following one induction course by Idarubicin, Cytarabine and Lomustine (according ELN 2017 criteria)
Uncontrolled infection
Subject with cardiovascular disability status as per New York Heart Association Class > 2. Class 2 is defined as cardiac disease in which subjects are comfortable at rest but ordinary physical activity results in fatigue, palpitations, dyspnea, or angina pain. Class 3 is defined as cardiac disease in which subjects are comfortable at rest but less than ordinary activity causes fatigue, palpitation, or dyspnea. Class 4 is defined as cardiac disease in which subjects have an inability to carry on any physical activity without discomfort, symptoms of heart failure at rest, and if any physical activity is undertaken then discomfort increases.
Subject has a malabsorption syndrome or other condition that precludes enteral route of administration.
Any serious medical condition, laboratory abnormality, or psychiatric illness that would place the participant at an unacceptable risk or prevent them from giving informed consent.
Treatment with any of the following within 7 days prior to the first dose of study drug :
Subject having consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Star fruit within 3 days prior to the initiation of study treatment.
Subject having chronic respiratory disease that requires continuous oxygen, or a significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, any other medical condition that in the opinion of the investigator would adversely affect his/her participating in this study.
Previous treatment with Venetoclax and/or current participation in any other research study with investigational products.
Known hypersensitivity to the study medication
Primary purpose
Allocation
Interventional model
Masking
134 participants in 2 patient groups
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Central trial contact
Ariane MINEUR
Data sourced from clinicaltrials.gov
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