A Remission Induction Therapy and Risk-oriented Postremission Strategy for Adult Acute Myelogenous Leukemia (AML)
- Registration Number
- NCT00495287
- Lead Sponsor
- Northern Italy Leukemia Group
- Brief Summary
The study was set up to assess:
1. Standard-dose versus high-dose remission induction therapy. A standard ICE chemotherapy vs sequential high-dose cytarabine, with appropriate supportive/prophylactic measures, followed by morphological, cytogenetic and molecular monitoring of remission.
2. A risk-oriented postremission therapy: HR patients will be electively submitted to allogeneic stem cell transplantation (allo-SCT), whenever possible (related/unrelated donor/cord blood; ablative/non-ablative conditioning according to national and local protocols and guidelines). Provided sufficient blood stem cells were previously collected (\>2x10e6/kg Cluster of Differentiation 34 cells), SR patients and HR patients excluded from allo-SCT and aged 65 years or less will be randomized to: myeloablative autologous blood stem cell transplantation vs non-myeloablative, multicycle, autologous blood stem cell-supported high-dose cytarabine-based therapy.
* HR/SR patients unable to be randomized because of inadequate blood stem cell yield will receive intermediate-dose consolidation; patients aged \>65 years will be treated with age-adapted therapy.
- Detailed Description
Adult AML is a difficult-to-treat illness because of both biological and therapeutic reasons. Most patients are aged \>50 years and/or present with comorbid conditions and/or display high-risk AML-related features (poor risk, cytogenetics, prior myelodysplasia, secondary AML). This results in unsatisfactory response to conventional first-line therapy and makes it difficult to apply the most effective post-remission consolidation options (allo-SCT in younger patients with HR features, autologous blood stem cell transplantation and high-dose cytarabine-based therapy in the remainder).
In a prior, phase II uncontrolled NILG trial (registered NCT 00400637),a two-step increasing intensity induction was adopted in order to optimize induction results. 51% of ICE-refractory cases responded to the salvage regimen, irrespective of risk class. In the same study, all HR patients had to be sent to allografting whereas SR patients (by clinico-cytogenetics criteria) were to receive up to three high-dose cytarabine-based cycles, each one supported by a fixed amount of autologous blood-stem cells (1-2x10e6/kg Cluster of Differentiation 34 cells cells), to minimize the risks of high-dose cytarabine-related myelosuppression and to increase treatment intensity by reducing intercycle delays. DFS was 41% at 5 years, 58% in SR patients aged \<55 years, 47% in SR patients aged \>55 years, and 47% in HR patients with an identifiable donor. No treatment-related death occurred during the pancytopenic phase in 118 patients receiving 299 blood stem-cell supported high-dose cytarabine cycles.
These facts led to the present trial, in which 1) high-dose induction formerly used as salvage is directly compared to standard ICE chemotherapy and 2) the blood-stem cell supported multicycle high-dose cytarabine program is directly compared to a standard autologous blood stem cell transplantation.
RANDOM 1 CYCLE 1
* Standard ICE (all drugs by IV route): idarubicin 12 mg/m2/d on dd 1-3, cytarabine 100 mg/m2/bd on dd 1-7, etoposide 100 mg/m2/d on dd 1-5, G-CSF from d 11.
* High-dose sequential (all drugs by IV route): cytarabine 2\* g/m2/bd on dd 1-2 and 8-9, idarubicin 18 mg/m2/d on dd 3 and 10, G-Colony Stimulating Factory (G-CSF) from d 11. \*1 g/m2 in frail patients aged 60-65 and in all those aged \>65 years.
CYCLE 2 (if CR achieved after cycle 1): Standard IC: idarubicin 10 mg/m2/d on dd 1-3, cytarabine 100 mg/m2/bd on dd 1-7, G-CSF.
CYCLE 3: Intermediate-dose cytarabine 1 g/m2/bd on dd 1-4 followed by G-CSF and by stem cell collection (1-2x10e6/kg CD34+ cells in three separate bags)
ALLO-SCT (Allogeneic Stem Cells Transplantation): All HR patients are eligible to allo-SCT as first therapeutic option. Allo-SCT procedure: any type according to local protocols/guidelines.
RANDOM 2
All SR patients and HR ones excluded from allo-SCT:
* Autologous blood stem cell transplantation after BU-CY2 regimen (Busulfan 0.8 mg/kg IV on dd -8 to -5, Cy 60 mg/kg/d on dd -4 to -3, autograft on d 0 (2-6x10e6/kg CD34+ cells) and G-CSF from d +1.
* Autologous blood stem cell supported multicycle therapy (x3, monthly) with cytarabine 2 g/m2/bd on dd 1-5, idarubicin 8 mg/m2/d on dd 1-2, autograft on d 6 (1-2x10e6/kg CD34+ cells) and G-CSF from d 8.
Patients excluded from Random 2 as well as from allo-SCT receive attenuated, unsupported consolidation with 1-2 intermediate-dose cytarabine cycles. Patients aged \>65 years are excluded from Random 2.
RISK CLASSIFICATION Cytogenetic risk classification is based on MRC/ECOG-SWOG/CALGB criteria (cytogenetic risk classes: favorable, normal/intermediate, unfavorable, other, unknown); clinical risk classification is based on selected diagnostic criteria and response to chemotherapy cycle 1. The final risk model integrates cytogenetic and clinical risk to encompass two broad risk classes (SR and HR).
* Standard risk (SR): favorable cytogenetics, CR achieved after cycle 1; or normal/intermediate cytogenetics, CR achieved after cycle 1, lack of high-risk characteristics.
* High risk (HR): unfavorable cytogenetics; or normal/intermediate cytogenetics with any high-risk characteristic (WBC \>50x10e9/l,FAB M0,6,7 or corresponding WHO, secondary AML, Myelodysplastic Syndrome (MDS)-associated AML, hepatosplenomegaly, FLT3 mutation, CR) not achieved with cycle, persistent cytogenetic abnormality at CR), or other/unknown cytogenetics.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 573
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description A cytosine arabinoside Remission induction arm A is with conventional chemotherapy cycle ("ICE": idarubicin, standard-dose cytarabine, etoposide) B cytosine arabinoside Remission induction therapy with high-dose cytarabine sequential regimen (HD-Ara-C, idarubicin)
- Primary Outcome Measures
Name Time Method Remission induction (R1): Complete remission (CR) rate after cycle 1 30 days after beginning chemotherapy. Remission consolidation (R2): Length of remission (DFS, disease-free survival) 5 years
- Secondary Outcome Measures
Name Time Method R1: Treatment-related death (TRD) 2 months Treatment-related death 5 years R1: CR with incomplete hematological recovery 30 days after beginning chemotherapy R2: Overall survival (OS) 5 years Remission duration and cumulative incidence of relapse 5 years Quality of Life 1 year and 3 years R1:Complete cytogenetic remission 30 days after beginning chemotherapy
Trial Locations
- Locations (17)
Istituti Ospitalieri
🇮🇹Cremona, Italy
S.C. Ematologia - Azienda Ospedaliera S.Croce e Carle
🇮🇹Cuneo, CN, Italy
Ematologia - AOU Careggi
🇮🇹Firenze, FI, Italy
Istituto Clinico Humanitas
🇮🇹Rozzano, Milano, Italy
Ematologia - TMO - Ospedale San Gerardo
🇮🇹Monza, MI, Italy
Ospedale dell'Angelo
🇮🇹Mestre, Venezia, Italy
Ematologia Centro TMO - Fondazione IRCSS Ospedale Maggiore
🇮🇹Milano, MI, Italy
USC Ematologia Azienda Papa Giovanni XXIII
🇮🇹Bergamo, BG, Italy
Ospedale Generale di Bolzano
🇮🇹Bolzano, Bz, Italy
Ospedale Spedali Civili di Brescia
🇮🇹Brescia, Italy
Ospedale di Circolo di Varese
🇮🇹Varese, Italy
Istituto Nazionale Dei Tumori
🇮🇹Milano, MI, Italy
Ospedale Mauriziano
🇮🇹Torino, TO, Italy
Dipartimento di Ematologia e Medicina Trasfusionale - Azienda Osp. Nazionale Santi Antonio e Biagio e Cesare Arrigo
🇮🇹Alessandria, AL, Italy
Ematologia e TMO - Ospedale San Raffaele
🇮🇹Milano, MI, Italy
A.O.U San Giovanni Battista-Divisione Ematologica dell'Università
🇮🇹Torino, TO, Italy
Ematologia 2 - Osp. Molinette San Giovanni Battista
🇮🇹Torino, TO, Italy