Clinical trial NCT00400673: A Risk-Oriented Therapeutic Strategy for Adult Acute Myelogenous Leukemia
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Myelogenous Leukemia
Keywords: Acute myelogenous leukemia
Adult patients
Cytogenetic risk class
Clinico-cytogenetic risk model
Risk-oriented therapy
Lead sponsor: Northern Italy Leukemia Group
Sponsor class: OTHER
First posted: 2006-11-17
Enrollment: 581
Sex: ALL
Minimum age (years): 15
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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:

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).

Eligibility 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

Primary outcomes:
measure: Disease-free survival
timeFrame: 5-years
Secondary outcomes:
measure: Complete remission
timeFrame: Two months
measure: Overall survival
timeFrame: 5 years
measure: Cumulative incidence of relapse
timeFrame: 5 years
measure: Toxicity
timeFrame: 5 years
Other outcomes:
Locations:
city: Bergamo
country: Italy
facility: USC Ematologia Ospedali Riuniti di Bergamo
state: BG
city: Brescia
country: Italy
facility: Divisione Ematologia Spedali Civili di Brescia
state: BS
city: Bolzano
country: Italy
facility: Divisione di Ematologia e TMO Ospedale San Maurizio
state: BZ
city: Cuneo
country: Italy
facility: Ematologia Azienda Ospedaliera S. Croce e Carle
state: CN
city: Milano
country: Italy
facility: Ematologia e TMO Ospedale San Raffaele
state: MI
city: Milano
country: Italy
facility: Ematologia e TMO Istituto Nazionale dei Tumori
state: MI
city: Monza
country: Italy
facility: Ematologia-TMO Ospedale San Gerardo
state: MI
city: Palermo
country: Italy
facility: Oncoematologia e TMO Dipartimento Oncologico
state: PA
city: Torino
country: Italy
facility: Ematologia 2 Ospedale San Giovanni Battista
state: TO
city: Varese
country: Italy
facility: Medicina Interna I Ospedale di Circolo
state: VA
city: Mestre
country: Italy
facility: Divisione Ematologia Ospedale Umberto I Mestre
state: VE
city: Noale
country: Italy
facility: Dipartimento di Oncologia e di Ematologia Oncologica Regione Veneto ULSS n.13- Presidi Ospedalieri di Noale, Dolo, Mirano
state: VE
Study officials:
affiliation: Ospedali Riuniti di Bergamo USC Ematologia
name: Renato Bassan, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Borlenghi E, Cattaneo C, Bertoli D, Cerqui E, Archetti S, Passi A, Oberti M, Zollner T, Giupponi C, Pagani C, Bianchetti N, Bottelli C, Bagnasco S, Sciume M, Tucci A, Rossi G. Prognostic Relevance of NPM1 and FLT3 Mutations in Acute Myeloid Leukaemia, Longterm Follow-Up-A Single Center Experience. Cancers (Basel). 2022 Sep 28;14(19):4716. doi: 10.3390/cancers14194716.