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Remission induction arm A is with conventional chemotherapy cycle ("ICE": idarubicin, standard-dose cytarabine, etoposide)

Remission induction therapy with high-dose cytarabine sequential regimen (HD-Ara-C, idarubicin)

Arm A: use of standard-dose cytosine arabinoside (100 mg/m2/bd iv. on days 1-7) in association with idarubicin and etoposide.

Arm B: use of high-dose cytosine arabinoside (1000-2000 mg/m2/bd according to age +/-65 years iv. on days 1-2 and 8-9) in association with idarubicin.

cytosine arabinoside

Renato Bassan, MD

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.

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.

A Remission Induction Therapy and Risk-oriented Postremission Strategy for Adult Acute Myelogenous Leukemia (AML)

Phase III Trial in AML Comparing Standard-dose vs High-dose Remission Induction and, Within a Risk-oriented Postremission Strategy, Autologous Blood Stem Cell Transplantation vs Blood Stem Cell-supported Multicycle High-dose Program

Northern Italy Leukemia Group

Medical Doctor

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)

Two-step remission induction and risk-oriented consolidation

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.

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).

A Risk-Oriented Therapeutic Strategy for Adult Acute Myelogenous Leukemia

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

Percent of patients who are disease-free 5 years from start of therapy

Percent of patients who achieve complete remission within two months from start of therapy (i.e. after two chemotherapy cycles)

Percent of patients who are alive 5 years after diagnosis

Percent of patients who suffer from leukemia relapse at 5 years from date of remission

Percent of patients who die of treatment-related complications (in different prognostic/treatment groups)until 5 years from start of therapy

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Remission Induction Therapy and Risk-oriented Postremission Strategy for Adult Acute Myelogenous Leukemia (AML)	NCT00495287	Acute Myelogeno...	cytosine arabin...	16 Years - 65 Years	Northern Italy Leukemia Group
A Risk-Oriented Therapeutic Strategy for Adult Acute Myelogenous Leukemia	NCT00400673	Acute Myelogeno...	Two-step remiss...	15 Years - 65 Years	Northern Italy Leukemia Group

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