A Risk-Oriented Therapeutic Strategy for Adult Acute Myelogenous Leukemia
Study Details
Study Description
Brief Summary
The study was set up to assess:
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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.
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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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
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:
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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.
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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.
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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
- 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).
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Other: Chemotherapy 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
|
Outcome Measures
Primary Outcome Measures
- Disease-free survival [5-years]
Percent of patients who are disease-free 5 years from start of therapy
Secondary Outcome Measures
- Complete remission [Two months]
Percent of patients who achieve complete remission within two months from start of therapy (i.e. after two chemotherapy cycles)
- Overall survival [5 years]
Percent of patients who are alive 5 years after diagnosis
- Cumulative incidence of relapse [5 years]
Percent of patients who suffer from leukemia relapse at 5 years from date of remission
- Toxicity [5 years]
Percent of patients who die of treatment-related complications (in different prognostic/treatment groups)until 5 years from start of therapy
Eligibility Criteria
Criteria
Inclusion Criteria:
- age 15-65 years,untreated AML (de novo, secondary, myelodysplasia-related, granulocytic sarcoma),untreated high-risk myelodysplasia (RAEB, RAEB-T), informed consent
Exclusion Criteria:
- acute promyelocytic leukemia, comorbidity precluding intensive chemotherapy approaches
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | USC Ematologia Ospedali Riuniti di Bergamo | Bergamo | BG | Italy | 24128 |
| 2 | Divisione Ematologia Spedali Civili di Brescia | Brescia | BS | Italy | 25123 |
| 3 | Divisione di Ematologia e TMO Ospedale San Maurizio | Bolzano | BZ | Italy | 39100 |
| 4 | Ematologia Azienda Ospedaliera S. Croce e Carle | Cuneo | CN | Italy | 12100 |
| 5 | Ematologia e TMO Ospedale San Raffaele | Milano | MI | Italy | 20132 |
| 6 | Ematologia e TMO Istituto Nazionale dei Tumori | Milano | MI | Italy | 20133 |
| 7 | Ematologia-TMO Ospedale San Gerardo | Monza | MI | Italy | 20052 |
| 8 | Oncoematologia e TMO Dipartimento Oncologico | Palermo | PA | Italy | 90146 |
| 9 | Ematologia 2 Ospedale San Giovanni Battista | Torino | TO | Italy | 10126 |
| 10 | Medicina Interna I Ospedale di Circolo | Varese | VA | Italy | 21100 |
| 11 | Divisione Ematologia Ospedale Umberto I Mestre | Mestre | VE | Italy | 30172 |
| 12 | Dipartimento di Oncologia e di Ematologia Oncologica Regione Veneto ULSS n.13- Presidi Ospedalieri di Noale, Dolo, Mirano | Noale | VE | Italy | 30033 |
Sponsors and Collaborators
- Northern Italy Leukemia Group
Investigators
- Principal Investigator: Renato Bassan, MD, Ospedali Riuniti di Bergamo USC Ematologia
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- NILG-AML 01/00