A Risk-Oriented Therapeutic Strategy for Adult Acute Myelogenous Leukemia
The study was set up to assess:
- A two-step, increasing-intensity remission induction phase. A conventional chemotherapy course (ICE, plus G-CSF) was followed, in unresponsive patients, by sequential high-dose cytarabine (plus G-CSF), aiming to provide an early effective rescue to as many refractory cases as possible.
- A risk-oriented postremission consolidation phase. The objective was to adopt allogeneic stem cell transplantation (alloSCT) in high-risk (HR) cases, while standard-risk (SR) ones were consolidated with a multicycle high-dose cytarabine-containing program, which included the use of autologous stem cells plus G-CSF to limit drug-related toxicity and intercycle treatment delays.
|Acute Myelogenous Leukemia||Behavioral: Two-step remission induction and risk-oriented consolidation||Phase 2|
|Study Design:||Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Official Title:||Two-Step Remission Induction With Risk-Oriented Consolidation (High-Risk: Allogeneic Stem Cell Transplant; Standard-Risk: Multicycle High-Dose Cytarabine With Autologous Blood Stem Cell Support) for Adult Acute Myelogenous Leukemia|
- Disease-free survival [ Time Frame: 5-years ]Percent of patients who are disease-free 5 years from start of therapy
- Complete remission [ Time Frame: Two months ]Percent of patients who achieve complete remission within two months from start of therapy (i.e. after two chemotherapy cycles)
- Overall survival [ Time Frame: 5 years ]Percent of patients who are alive 5 years after diagnosis
- Cumulative incidence of relapse [ Time Frame: 5 years ]Percent of patients who suffer from leukemia relapse at 5 years from date of remission
- Toxicity [ Time Frame: 5 years ]Percent of patients who die of treatment-related complications (in different prognostic/treatment groups)until 5 years from start of therapy
|Study Start Date:||May 2000|
|Study Completion Date:||October 2007|
|Primary Completion Date:||October 2007 (Final data collection date for primary outcome measure)|
Risk-oriented chemotherapy for remission induction (application of sequential high-dose cytarabine course to patients unresponsive to standard chemotherapy course 1) and postremission consiolidation(standard risk: blood stem cell supported high-dose cytarabine course [x3]; high risk: allogeneic SCT)
|Behavioral: Two-step remission induction and risk-oriented consolidation|
Adult AML is a difficult-to-treat illness because of both biological and therapeutic reasons.
As to the first point, many patients are aged >50 years and/or present with significant comorbidity and/or AML-related risk features (poor risk cytogenetics, prior myelodysplasia, secondary AML).
As to the second point, standard-type remission induction therapy is ineffective in 20% or more of the patients, whereas the application of the more effective postremission consolidation options (alloSCT, high-dose cytarabine courses) is often flawed by high-grade toxicity which can offset expected benefits, particularly in older age groups (>50-55 years), where therapy-related death rates are seen in 5%-10% of the cases (chemotherapy) or more (transplants).
Against this background an explorative study was developed in which:
- All patients aged 16-65 years were considered eligible (acute promyelocytic leukemia excluded), including those with an antecedent diagnosis of myelodysplasia/hematological disorder and/or secondary AML. Both age and disease subtype selection criteria are broader than in most studies on adult AML, adhering more closely to the reported epidemiology of the disease.
- Remission induction was attempted with a two-step regimen, consisting of conventional chemotherapy (ICE: idarubicin/cytarabine/etoposide +G-CSF) followed, only in the case of failure to respond, by a sequential high dose-cytarabine cycle (cytarabine 3 g/m2/bd on days 1,2,8,9; idarubicin on days 3 and 10; G-GSF; cytarabine dosing 2 g/m2 in patients aged >55 years). It was hoped that this choice would optimize salvage rates (hence overall response rates), by allowing more patients (and more fit, uncomplicated ones) to reach the salvage phase, compared to a policy where salvage is usually given after two failed induction courses.
- Remission consolidation was risk-oriented, the risk being defined through a mixed clinico-cytogenetic model. Thus all patients entering CR after one/two cycles were stratified as HR or SR according to what is reported below. Once defined the risk class, therapy consisted of an alloSCT for HR patients, and of 3 consecutive monthly cytarabine-based cycles (2 g/m2/bd on days 1-5; idarubicin on days 1,2) in SR patients, each cycle being followed by the reinfusion of a limited amount of autologous blood stem cells (1-2x10e6/kg CD34+ cells) and G-CSF. Blood stem cells were collected following an early consolidation cycle with intermediate-dose cytarabine plus G-CSF. HR patients unable/unfit to proceed to alloSCT were offered instead the SR-type multicycle cytarabine consolidation, whereas all patients unable to mobilize autologous stem cells were treated with one/two intermediate-dose cytarabine course(s).
HR: high-risk cytogenetics or intermediate-risk/normal cytogenetics with FLT3 mutation and/or any one or more additional clinical risk factor(s), i.e. total WBC >50x10e9/l, FAB subtype M0, M6 or M7, prior myelodysplasia or secondary AML,hepatosplenomegaly, late CR (cycle 2), or favorable cytogenetics with late CR (cycle 2).
SR: favorable cytogenetics (without associated high-risk abnormalities and in CR after cycle 1) or intermediate-risk/normal cytogenetics without FLT3 mutation and/or without any one additional clinical risk factor(s), i.e. total WBC >50x10e9/l, FAB subtype M0, M6 or M7, prior myelodysplasia or secondary AML,hepatosplenomegaly, late CR (cycle 2).
Please refer to this study by its ClinicalTrials.gov identifier: NCT00400673
|USC Ematologia Ospedali Riuniti di Bergamo|
|Bergamo, BG, Italy, 24128|
|Divisione Ematologia Spedali Civili di Brescia|
|Brescia, BS, Italy, 25123|
|Divisione di Ematologia e TMO Ospedale San Maurizio|
|Bolzano, BZ, Italy, 39100|
|Ematologia Azienda Ospedaliera S. Croce e Carle|
|Cuneo, CN, Italy, 12100|
|Ematologia e TMO Ospedale San Raffaele|
|Milano, MI, Italy, 20132|
|Ematologia e TMO Istituto Nazionale dei Tumori|
|Milano, MI, Italy, 20133|
|Ematologia-TMO Ospedale San Gerardo|
|Monza, MI, Italy, 20052|
|Oncoematologia e TMO Dipartimento Oncologico|
|Palermo, PA, Italy, 90146|
|Ematologia 2 Ospedale San Giovanni Battista|
|Torino, TO, Italy, 10126|
|Medicina Interna I Ospedale di Circolo|
|Varese, VA, Italy, 21100|
|Divisione Ematologia Ospedale Umberto I Mestre|
|Mestre, VE, Italy, 30172|
|Dipartimento di Oncologia e di Ematologia Oncologica Regione Veneto ULSS n.13- Presidi Ospedalieri di Noale, Dolo, Mirano|
|Noale, VE, Italy, 30033|
|Principal Investigator:||Renato Bassan, MD||Ospedali Riuniti di Bergamo USC Ematologia|