Acute Myeloid Leukemia (AML)
Conditions
Keywords
Newly diagnosed, AML, Elderly, Decitabine, Transplant
Brief summary
Older patients with acute myeloid leukemia (AML) have a small (\< 10%) chance of long-term survival. Despite the treatment of elderly AML patients with intensive chemotherapy, the survival has not been improved during the last decades. The purpose of this study is to determine whether frontline therapy with a 10-day decitabine schedule provides a better survival than standard intensive combination chemotherapy in elderly AML patients (\>= 60 years).
Detailed description
* The overall survival (OS) of older AML patients has not been improved during the last decades with intensive chemotherapy based on cytarabine combined with an anthracycline (3+7). * Next generation sequencing technology reveals that mutations in genes involved in epigenetics are frequently mutated in AML (e.g. DNMT3a), suggesting an important role of epigenetics in the pathophysiology of AML. Decitabine (given in a 5-day schedule) has been shown to be superior to low-dose Ara-C. * A retrospective analysis revealed that epigenetic therapy (either azacitidine or decitabine) is associated with similar survival rates as intensive chemotherapy in older patients (n=671) with newly diagnosed AML. * The recently published encouraging phase 2 data with the 10-day decitabine schedule suggests that decitabine results in similar CR rates compared with intensive chemotherapy. Allogeneic transplantation (alloHCT) also offers the opportunity for cure among older AML patients, therefore treatment strategies should aim to allograft older AML patients. * Decitabine treatment can lead to very interesting cure rates when used as bridging to allografting. Based on the data summarized above, we hypothesize that decitabine at a daily dose of 20 mg/m² starting with the 10-day schedule followed by an alloHCT or by continuation of 5-days decitabine cycles is superior to conventional intensive chemotherapy in older AML patients.
Interventions
DRUGstandard combination chemotherapy
1. Cycle 1 1. daunorubicin (60 mg/m²) infusion (15-30 min) for 3 days 2. cytarabine (200 mg/m²) continuous infusion (24 hrs) for 7 days. 2. Cycle 2 1. daunorubicin (45 mg/m²) infusion (15-30 min) for 3 days 2. cytarabine (200 mg/m²) continuous infusion (24 hrs) for 7 days. 3. Cycle 3 (mini-ICE) 1. idarubicin (8 mg/m²) infusion (15-30 min) for 3 days 2. cytarabine (100 mg/m²) continuous infusion (24 hrs) for 5 days 3. etoposide (100 mg/m²) infusion (1 hr) for 3 days 4. Cycle 4 (mini-ICE) (optional) 1. idarubicin (8 mg/m²) infusion (15-30 min) for 3 days 2. cytarabine (100 mg/m²) continuous infusion (24 hrs) for 5 days 3. etoposide (100 mg/m²) infusion (1 hr) for 3 days
DRUGdecitabine
1. Cycle 1: decitabine (20 mg/m²) infusion (1 hr) for 10 days 2. Cycle 2 1. if bone marrow (BM) blasts \< 5%: decitabine (20 mg/m²) infusion (1 hr) for 5 days 2. if BM blasts \>= 5%: decitabine (20 mg/m²) infusion (1 hr) for 10 days 3. Cycle 3 1. if BM blasts \< 5%: decitabine (20 mg/m²) infusion (1 hr) for 5 days 2. if BM blasts \>= 5%: decitabine (20 mg/m²) infusion (1 hr) for 10 days 4. Cycle 4-6: decitabine (20 mg/m²) infusion (1 hr) for 5 days 5. Continuation therapy from Cycle 7 and until 'progression or toxicity': decitabine (20 mg/m²) infusion (1 hr) for 5 days or 3 days Note: All patients considered eligible for transplant should be consolidated with alloHCT once donor is available.
Sponsors
Janssen Pharmaceuticals
Gruppo Italiano Malattie EMatologiche dell'Adulto
European Organisation for Research and Treatment of Cancer - EORTC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥ 60 years 2. WHO Performance status ≤ 2 3. Eligible for standard intensive chemotherapy 4. Newly diagnosed AML cytopathologically confirmed to the WHO classification (up to 2 months prior to randomization) 5. De novo or secondary AML is allowed 6. White blood cell (WBC) count is ≤ 30x10E9/L (measured within 72 hours prior to randomization). 7. Laboratory assessments (measured prior to randomization): 1. serum glutamate oxaloacetate transaminase (SGOT / ASAT) and serum glutamate pyruvate transaminase (SGPT / ALAT) \< 2.5 x the upper limit of normal range unless considered AML-related 2. Total serum bilirubin \< 2.5 x the upper limit of normal range unless considered AML-related or due to Gilbert's syndrome 3. Serum creatinine \< 2.5 x the upper limit of normal range unless considered AML-related 8. Patients of reproductive potential should use adequate birth control measures, as defined by investigator, during the study treatment period and for at least 3 months after the last study treatment. 9. Before patient registration/randomization, written informed consent must be given according to the International Conference of Harmonization good clinical practice (ICH GCP) and national/local regulations
Exclusion criteria
1. Presence of acute promyelocytic leukemia (APL, i.e. AML-M3 with t(15;17)(q22;q12); promyelocytic leukemia - retinoic acid receptor-alpha (PML-RARA) fusion gene and cytogenetic variants) 2. Presence of blast crisis of chronic myeloid leukemia 3. Presence of active central nervous system (CNS) leukemia 4. Patients did not receive any prior treatment for AML (relapsed AML is not allowed), such as any antileukemic therapy including investigational agents and hypomethylating agents (decitabine, 5-azacytidine). Treatment with hydroxyurea (HU) is allowed to control the leukocytosis if given preferably for less than 5 days and is stopped at least two days prior to the start of any of the protocol regimens 5. Patients received any prior treatment for myelodysplastic syndrome (MDS) or myeloproliferative neoplasms (MPN) with: 1. hypomethylating agents (decitabine, 5-azacytidine), OR 2. with intensive chemotherapy or transplantation within the last three years 3. NOTE: The following treatments for previous MDS or MPN are allowed (up to one month before inclusion): * Growth factors, thrombomimetics, immunosuppression (cyclosporin A, steroids, antithymocyte globulin etc.), chelation, interferons, anagrelide * Lenalidomide, low-dose chemotherapy (low-dose melphalan, HU, low-dose cytarabine etc.), tyrosine-kinase inhibitors, histone deacetylase inhibitors (e.g. valproic acid, panobinostat etc.), mammalian target of rapamycin (mTOR) inhibitors, other experimental treatment that is not based on inhibition of deoxyribonucleic acid (DNA) methyltransferase 6. Presence of concomitant severe cardiovascular disease which would make intensive chemotherapy impossible, i.e. uncontrolled arrhythmias requiring chronic treatment, congestive heart failure or symptomatic ischemic heart disease, reduced left ventricular function assessed by multigated acquisition (MUGA) scan or echocardiogram 7. Presence of any malignancy (except basal and squamous cell carcinoma of the skin) for which the patient received systemic anticancer treatment within 6 months prior to randomization NOTE: Diagnosis of any previous or concomitant malignancy is thus not an exclusion criterion. 8. Presence of active uncontrolled infection 9. Presence of any psychological, familial, sociological or geographical condition in the opinion of the investigator potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Overall survival (OS) | 4.9 years from first patient in |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free survival (PFS) from randomization to the date of either first progression, first relapse or death, whichever occurs first | 4.9 years from first patient in | — |
| Transplantation feasibility | 4.9 years from first patient in | Percentage of patients transplanted |
| Outcome post-transplantation | 4.9 years from first patient in | PFS, incidence of relapse or progression, and incidence of non-relapse or progression related mortality |
| Health economics impact of each treatment arm | 4.9 years from first patient in | At the end of each cycle, duration of hospitalization and number of visits (planned or related to event), number of transfusions, growth factor support and intravenous anti-infective are collected |
| Occurrence of adverse events (AEs) | 4.9 years from first patient in | The events are graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 |
| Prognostic value of baseline physical and functional conditions on treatment outcome using geriatric assessment tools | 4.9 years from first patient in | Short physical performance battery (SPPB) and activities of daily living (ADL) |
| complete response (CR/CRi) rate | 4.9 years from first patient in | All patients who reached complete response (CR) or complete response with incomplete marrow recovery (CRi) after the administration of protocol treatment (3+7 or decitabine) |
| Overall CR/CRi rate | 4.9 years from first patient in | All patients who reached CR or CRi, after administration of the protocol treatment (3+7 or decitabine) or following another salvage/new treatment for AML (other than transplant) |
| Disease-free survival (DFS) from CR or CRi | 4.9 years from first patient in | The time between the date of CR or CRi and the date of first relapse or death (whatever the cause), whichever occurs first |
| Health Related Quality of Life (HRQoL) questionnaires | 4.9 years from first patient in | EORTC Quality of Life Questionnaire (QLQ-C30) Elderly module (ELD14) |
Countries
Belgium, Bulgaria, Croatia, France, Germany, Italy, Lithuania, Netherlands, Portugal
Outcome results
None listed