Risk-adapted Therapy for Primary Acute Myeloid Leukemia

NCT ID: NCT04687098

Last Updated: 2023-06-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 1034 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-02-01
• Study Completion Date: 2022-11-10

Brief Summary

The AML-12 study investigates the efficacy and toxicity of standard induction chemotherapy with idarubicin and cytarabine (IC) with G-CSF priming followed by a risk-adapted post remission therapy for patients up to the age of 70 diagnosed with de novo acute myeloid leukemia (AML).

Modifications from the previous protocol AML-03 (NCT01723657) include removal of etoposide in induction, limitation of the GCSF priming to the induction phase and categorization of post remission therapy (stem cell transplant or 2 high dose cytarabine consolidations) according to diagnostic genetics as well as post-remission clearance of measurable residual disease.

The aims of these modifications are to improve the overall survival and leukemia free survival of acute myeloid leukemia patients with a risk-adapted approach.

Detailed Description

Induction chemotherapy: Idarubicin (12mg/m2/day intravenous, days 1-3), Low-dose cytarabine (200mg/m2/day, intravenous in continuous infusion, days 1-7) and G-CSF priming 150mcg/m2/day, subcutaneous from day 0 to the last day of chemotherapy if white blood cell count (WBC) <30x10E9/L.

This induction chemotherapy can be repeated twice in the case of partial response (PR) to achieve complete response (CR).

Once CR is achieved (with one or two induction cycles), all patients receive a consolidation course with high-dose cytarabine (3000mg/m2/12h days 1, 3 and 5) and pegfilgrastim 6mg on day 6.

After this, patients will be allocated to the different risk groups as follows:

• Favorable risk group [patients with t(8;21)(q22;q22)/RUNX1/RUNX1T1, inv(16)(p12;q22) or t(16;16)/CBFB/MYH11; Intermediate risk cytogenetics (MRC 2010) and NPM1 mutation with FLT3 wild type or low ratio of FLT3 internal tandem duplication (ITD)/wild type (<0.5); or CEBPA biallelic mutation]. Patients in this group will receive 2 additional courses of consolidation therapy
• Intermediate risk group [Intermediate risk cytogenetics (MRC 2010) without NPM1 mutations, FLT3-ITD, or CEBPA biallelic mutation]. Patients in this group receive an allogeneic stem cell transplant in first CR. Patients without an available donor can be autografted per center decision
• Adverse risk group [Adverse risk cytogenetics (MRC 2010), intermediate cytogenetics with FLT3-ITD without NPM1 mutation or NPM1-FLT3-ITD high ratio or MLL rearrangement; any favorable or intermediate risk patients with positive MRD following 1 (intermediate) or 2 (favorable) consolidation courses]. Intention to treat of those patients is allogeneic stem cell transplant from any source.

Conditions

Leukemia, Myeloid, Acute

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Risk-adapted postremission treatment.

Induction (idarubicin, cytarabine), first consolidation (high dose cytarabine), risk- stratification: allogeneic matched related or unrelated donor transplant vs. consolidation courses.

Group Type: OTHER

Idarubicin

Intervention Type: DRUG

12 mg/m2/day; intravenous, administration at induction phase, days 1 to 3.

Ara-C

Intervention Type: DRUG

200mg/m2/day, intravenous at induction phase; days 1-7.

• High dose during consolidation phase. In patients up to 60 years 3g/m2/12hours days 1,3,5, and patients 60 to 70 years: 1.5g/m2/12hours days 1,3,5.

G-CSF

Intervention Type: DRUG

• Administration at induction phase to remission days 1 to 7. G-CSF will not be initiated if the leukocyte count is over 30x10e9/L at diagnosis or will be interrupted if the leukocyte count during treatment arises 30x10e9/L.
• Administration at consolidation phase day 7.

Allogeneic matched or unrelated donor transplant.

Intervention Type: PROCEDURE

To be performed in patients in the intermediate or adverse risk groups.

Autologous peripheral blood stem cell transplant

Intervention Type: PROCEDURE

To be considered in patients in the intermediate risk group without an available allogeneic donor and negative measurable residual disease, per center decision.

Measurable residual disease

Intervention Type: PROCEDURE

To be performed either with molecular monitoring or, if not applicable, by flow cytometry. Pre-stablished cut-off values are defined for decision-making.

Interventions

Idarubicin

12 mg/m2/day; intravenous, administration at induction phase, days 1 to 3.

Intervention Type: DRUG

Ara-C

200mg/m2/day, intravenous at induction phase; days 1-7.

• High dose during consolidation phase. In patients up to 60 years 3g/m2/12hours days 1,3,5, and patients 60 to 70 years: 1.5g/m2/12hours days 1,3,5.

Intervention Type: DRUG

G-CSF

• Administration at induction phase to remission days 1 to 7. G-CSF will not be initiated if the leukocyte count is over 30x10e9/L at diagnosis or will be interrupted if the leukocyte count during treatment arises 30x10e9/L.
• Administration at consolidation phase day 7.

Intervention Type: DRUG

Allogeneic matched or unrelated donor transplant.

To be performed in patients in the intermediate or adverse risk groups.

Intervention Type: PROCEDURE

Autologous peripheral blood stem cell transplant

To be considered in patients in the intermediate risk group without an available allogeneic donor and negative measurable residual disease, per center decision.

Intervention Type: PROCEDURE

Measurable residual disease

To be performed either with molecular monitoring or, if not applicable, by flow cytometry. Pre-stablished cut-off values are defined for decision-making.

Intervention Type: PROCEDURE

Other Intervention Names

Ida; HDAC; Pegfilgrastim; MRD

Eligibility Criteria

Inclusion Criteria

• Patients with newly diagnosed AML, classified using the World Health Organization (WHO) 2017 criteria.
• Patients with 70 years old or younger.

Exclusion Criteria

• Patients previously treated for the AML with chemotherapy different from hydroxyurea.
• Acute promyelocytic leukemia with t(15;17).
• Chronic myeloid leukemia in blastic phase.
• Secondary AML or therapy related AML.
• Presence of concomitant active neoplastic disease.
• Abnormal renal and hepatic functions with creatinin and/or bilirubin 2 times higher than the normal threshold, except when the alteration should be attributed to the leukemia.
• Patients with a cardiac ejection fraction below 45%, symptomatic cardiac deficiency or both.
• Patients with neurological or concomitant psychiatric disease.
• HIV infection.

• Minimum Eligible Age: 17 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Grupo Cooperativo de Estudio y Tratamiento de las Leucemias Agudas y Mielodisplasias

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jorge Sierra, Prof, MD

Role: PRINCIPAL_INVESTIGATOR

Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau

Jordi Esteve, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Hospital Clinic of Barcelona

Locations

ICO Badalona-Hospital Universitari Germans Trias i Pujol

Badalona, Barcelona, Spain

ICO Hospital Universitari de Bellvitge

L'Hospitalet de Llobregat, Barcelona, Spain

Hospital Universitari Son Espases

Palma de Mallorca, Mallorca, Spain

Hospital Universitari Son Llatzer

Palma de Mallorca, Mallorca, Spain

Hospital Verge de la Cinta

Tortosa, Tarragona, Spain

Hospital del Mar

Barcelona, , Spain

Hospital de la Santa Creu i Sant Pau

Barcelona, , Spain

Hospital Vall d'Hebron

Barcelona, , Spain

Hospital Clinic Barcelona

Barcelona, , Spain

ICO-Girona Hopital Universitari de Girona Dr. Josep Trueta

Girona, , Spain

Hospital Universitari Arnau de Vilanova

Lleida, , Spain

Hospital Universitario Virgen de la Victoria

Málaga, , Spain

ICO Tarragona-Hospital Universitari Joan XXIII

Tarragona, , Spain

Mutua de Terrassa

Terrassa, , Spain

Hospital Clínico Universitario de Valencia

Valencia, , Spain

Countries

Spain

References

Onate G, Pratcorona M, Garrido A, Artigas-Baleri A, Bataller A, Tormo M, Arnan M, Vives S, Coll R, Salamero O, Vall-Llovera F, Sampol A, Garcia A, Cervera M, Avila SG, Bargay J, Ortin X, Nomdedeu JF, Esteve J, Sierra J; Spanish Cooperative Group for the Study and Treatment of Acute Leukemias and Myelodysplasias (CETLAM). Survival improvement of patients with FLT3 mutated acute myeloid leukemia: results from a prospective 9 years cohort. Blood Cancer J. 2023 May 5;13(1):69. doi: 10.1038/s41408-023-00839-1.

Reference Type: DERIVED

PMID: 37147301 (View on PubMed)

Other Identifiers

AML-12

Identifier Type: -

Identifier Source: org_study_id