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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

Phase 3
16 Years
65 Years
Open (Enrolling)
Acute Myelogenous Leukemia

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Trial Information

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

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 stenm 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
CD34+ 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.


- 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-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: All HR patients are eligible to allo-SCT as first therapeutic option. Allo-SCT
procedure: any type according to local protocols/guidelines.


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

- 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, MDS-associated AML, hepatosplenomegaly, FLT3 mutation, CR) not achieved with
cycle, persistent cytogenetic abnormality at CR), or other/unknown cytogenetics.

Inclusion Criteria

Inclusion criteria (Random 1):

- Age 16+ years

- Diagnosis of untreated (or only hydroxyurea/cyclophosphamide) acute myelogenous
leukemia (AML, including myeloid sarcoma) or high-risk myelodysplasia (RAEB-2),
either de novo or following an antecedent hematological disorder, or secondary to
chemo-radiotherapy for other cancer

- Signed informed consent

- Adequate sampling for full cytological, cytochemical, cytogenetic and
immunobiological disease characterization by revised FAB, EGIL and WHO criteria

- ECOG performance status 0-2 or reversible ECOG 3 score following intensive care of

Exclusion criteria:

- Diagnosis of acute promyelocytic leukemia

- Pre-existing, uncontrolled pathology such as cardiac disease (congestive/ischemic,
acute myocardial infarction within the past 3 months, untreatable arrythmias, NYHA
classes III and IV), severe liver disease with serum bilirubin >3 mg/dL and/or ALT >3
x upper normal limit (unless attributable to AML), kidney function impairment with
serum creatinine >2 mg/dL (unless attributable to AML), and severe neuropsychiatric
disorder that impairs the patient's ability to understand and sign the informed
consent, or to cope with the intended treatment plan

- Known HIV positive serology

- Other active hematological or non-hematological cancers with life expectancy <1 year

- Pregnancy (fertile women will be advised not to become pregnant while on treatment;
and male patients to adopt contraceptive methods)

Type of Study:


Study Design:

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

Outcome Measure:

Remission induction (R1): Complete remission (CR) rate after cycle 1

Outcome Time Frame:

30 days after beginning chemotherapy.

Safety Issue:


Principal Investigator

Renato Bassan, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Ospedali Riuniti di Bergamo USC Ematologia


Italy: Ministry of Health

Study ID:

NILG-AML 02/06



Start Date:

November 2006

Completion Date:

December 2011

Related Keywords:

  • Acute Myelogenous Leukemia
  • Acute myelogenous leukemia
  • Adult patients
  • Cytogenetic risk class
  • Clinico-cytogenetic risk model
  • Risk-oriented therapy
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid