Risk-adapted Therapy for Primary Acute Myeloid Leukemia

Sponsor

Grupo Cooperativo de Estudio y Tratamiento de las Leucemias Agudas y Mielodisplasias (Other)

Overall Status

Recruiting

CT.gov ID

NCT04687098

Collaborator

(none)

1,000

Enrollment

Locations

Arm

116

Anticipated Duration (Months)

66.7

Patients Per Site

0.6

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Leukemia, Myeloid, Acute	Drug: Idarubicin Drug: Ara-C Drug: G-CSF Procedure: Allogeneic matched or unrelated donor transplant. Procedure: Autologous peripheral blood stem cell transplant Procedure: Measurable residual disease	N/A

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

1000 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Risk-adapted Therapy for Primary Acute Myeloid Leukemia (AML) in Adult Patients up to 70 Years Old

Actual Study Start Date :

Feb 1, 2012

Anticipated Primary Completion Date :

Oct 1, 2021

Anticipated Study Completion Date :

Oct 1, 2021

Arms and Interventions

Arm	Intervention/Treatment
Other: Risk-adapted postremission treatment. Induction (idarubicin, cytarabine), first consolidation (high dose cytarabine), risk- stratification: allogeneic matched related or unrelated donor transplant vs. consolidation courses.	Drug: Idarubicin 12 mg/m2/day; intravenous, administration at induction phase, days 1 to 3. Other Names: Ida 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. Other Names: HDAC 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. Other Names: Pegfilgrastim Procedure: Allogeneic matched or unrelated donor transplant. To be performed in patients in the intermediate or adverse risk groups. 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. 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. Other Names: MRD

Arm

Intervention/Treatment

Other: Risk-adapted postremission treatment.

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

Drug: Idarubicin

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

Other Names:

Ida

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.

Other Names:

HDAC

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.

Other Names:

Pegfilgrastim

Procedure: Allogeneic matched or unrelated donor transplant.

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

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.

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.

Other Names:

MRD

Outcome Measures

Primary Outcome Measures

Complete remission rate (CRR) [2 months]
Analyze the efficacy and toxicity of the current doses of IC (Idarubicin and cytarabine) with G-CSF priming to achieve complete remission in patients tih AML up to 70yo.
Disease free survival (DFS) [4 years]
Analyze the disease free survival in the whole cohort of AML patients.
Relapse rate (RR) [4 years]
Analyze the relapse rate of all patients achieving remission with intensive induction followed by risk-adapted consolidation strategies.

Secondary Outcome Measures

Feasibility of treatment completion [4 years]
Increase the number of patients who complete all treatment phases
Survival outcome analysis of the 3 risk-adapted categories (favourable, intermediate and adverse) [4 years]
Evaluate the feasibility of the consolidation treatments in the different risk groups by comparison of overall survival (OS), RR and DFS.
Feasibility of centralized monitoring of measurable residual disease (MRD) [4 years]
Survival outcomes in positive vs negative MRD patients. Number of patients with modified risk due to positive MRD.
Comparison of global outcomes with previous protocol (AML-03) and other published protocols. [4 years]
Comparison of CRR, OS, RR and DFS

Eligibility Criteria

Criteria

Ages Eligible for Study:

17 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	ICO Badalona-Hospital Universitari Germans Trias i Pujol	Badalona	Barcelona	Spain	08916
2	ICO Hospital Universitari de Bellvitge	Hospitalet de Llobregat	Barcelona	Spain	08907
3	Hospital Universitari Son Espases	Palma de Mallorca	Mallorca	Spain	07198
4	Hospital Universitari Son Llatzer	Palma de Mallorca	Mallorca	Spain
5	Hospital Verge de la Cinta	Tortosa	Tarragona	Spain	43517
6	Hospital del Mar	Barcelona		Spain	08003
7	Hospital de la Santa Creu i Sant Pau	Barcelona		Spain	08025
8	Hospital Vall d'Hebron	Barcelona		Spain	08035
9	Hospital Clinic Barcelona	Barcelona		Spain	08036
10	ICO-Girona Hopital Universitari de Girona Dr. Josep Trueta	Girona		Spain	17007
11	Hospital Universitari Arnau de Vilanova	Lleida		Spain	25006
12	Hospital Universitario Virgen de la Victoria	Malaga		Spain	29010
13	ICO Tarragona-Hospital Universitari Joan XXIII	Tarragona		Spain	43007
14	Mutua de Terrassa	Terrassa		Spain	08225
15	Hospital Clínico Universitario de Valencia	Valencia		Spain	496010

Sponsors and Collaborators

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

Investigators

Principal Investigator: Jorge Sierra, Prof, MD, Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau
Principal Investigator: Jordi Esteve, MD, PhD, Hospital Clinic of Barcelona