A Risk-Oriented Therapeutic Strategy for Adult Acute Myelogenous Leukemia

Acute Myelogenous Leukemia Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00400673
• Other study ID #: NILG-AML 01/00
• Status: Completed
• Phase: Phase 2
• First received: November 16, 2006
• Last updated: March 31, 2011
• Start date: May 2000
• Est. completion date: October 2007

Study information

• Verified date: March 2011
• Source: Northern Italy Leukemia Group
• Contact: n/a
• Is FDA regulated: No
• Health authority: Italy: Ministry of Health
• Study type: Interventional

Clinical Trial Summary

The study was set up to assess:

1. 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.

2. 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.

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:

1. 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.

2. 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.

3. 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 581
• Est. completion date: October 2007
• Est. primary completion date: October 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 15 Years to 65 Years

Eligibility

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

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acute Myelogenous Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Behavioral:
• Two-step remission induction and risk-oriented consolidation

Locations

Country	Name	City	State
Italy	USC Ematologia Ospedali Riuniti di Bergamo	Bergamo	BG
Italy	Divisione di Ematologia e TMO Ospedale San Maurizio	Bolzano	BZ
Italy	Divisione Ematologia Spedali Civili di Brescia	Brescia	BS
Italy	Ematologia Azienda Ospedaliera S. Croce e Carle	Cuneo	CN
Italy	Divisione Ematologia Ospedale Umberto I Mestre	Mestre	VE
Italy	Ematologia e TMO Istituto Nazionale dei Tumori	Milano	MI
Italy	Ematologia e TMO Ospedale San Raffaele	Milano	MI
Italy	Ematologia-TMO Ospedale San Gerardo	Monza	MI
Italy	Dipartimento di Oncologia e di Ematologia Oncologica Regione Veneto ULSS n.13- Presidi Ospedalieri di Noale, Dolo, Mirano	Noale	VE
Italy	Oncoematologia e TMO Dipartimento Oncologico	Palermo	PA
Italy	Ematologia 2 Ospedale San Giovanni Battista	Torino	TO
Italy	Medicina Interna I Ospedale di Circolo	Varese	VA

Sponsors (1)

Lead Sponsor	Collaborator
Northern Italy Leukemia Group

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Disease-free survival	Percent of patients who are disease-free 5 years from start of therapy	5-years	No
Secondary	Complete remission	Percent of patients who achieve complete remission within two months from start of therapy (i.e. after two chemotherapy cycles)	Two months	No
Secondary	Overall survival	Percent of patients who are alive 5 years after diagnosis	5 years	No
Secondary	Cumulative incidence of relapse	Percent of patients who suffer from leukemia relapse at 5 years from date of remission	5 years	No
Secondary	Toxicity	Percent of patients who die of treatment-related complications (in different prognostic/treatment groups)until 5 years from start of therapy	5 years	Yes