Treatment of Acute Lymphoblastic Leukemia HIGH RISK BCR / ABL NEGATIVE IN ADULTS

Sponsor

PETHEMA Foundation (Other)

Overall Status

Completed

CT.gov ID

NCT01540812

Collaborator

(none)

418

Enrollment

Location

Actual Duration (Months)

4.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Trial protocol intended the optimization of induction treatment with:

Inclusion of PEG-ASP in induction and in the three blocks of consolidation.
Reduction of the dose of daunorubicin, and recent studies have shown that the use of high doses of anthracyclines has not brought higher response rates or longer duration
Replacing the poor cytological response at day 14 by the level of ER at the end of induction as a criterion to decide the further treatment (consolidation or second induction), so as to have only one criterion (the ER) throughout the study to decision making.

For another hand, reducing non-essential drugs consolidation blocks to try to reduce toxicity during it, and replace the ASP E. coli in induction and consolidation of PEG-ASP to ensure a more sustained asparagine depletion. Also, increasing the dose of methotrexate (3 to 5 g/m2) in patients with ALL-T, since there is recent evidence of a higher response rate with this strategy.

Performing an allo-HSCT early (after one cycle of consolidation) for patients with inadequate level of ER after two cycles of induction or in those patients who required two courses of induction and have obtained proper ER after the second.

Conducting studies of RD centrally by cytofluorometry following Euroflow consensus standards, to avoid bias in making treatment decisions

Condition or Disease	Intervention/Treatment	Phase
Acute Lymphoblastic Leukemia	Drug: Vincristine in induction Drug: Daunorubicin in induction Drug: Prednisone in induction Drug: Metotrexato in induction Drug: Cytarabine in induction Drug: Hydrocortisone in induction Drug: Idarubicin in induction-2 Drug: Fludarabine in induction-2 Drug: Ara-C in induction-2 Drug: G-CSF in induction-2 Drug: Dexamethasone in consolidation-1 Drug: Vincristrine in consolidation-1 Drug: Metotrexato in consolidation-1 Drug: PEG-ASP in consolidation-1 Drug: Dexamethasone in consolidation-2 Drug: ARA-C in consolidation-2 Drug: PEG-ASP in consolidation-2 Drug: Dexamethasone in consolidation-3 Drug: Vincristine in consolidation-3 Drug: Metotrexato in consolidation-3 Drug: PEG-ASP in consolidation-3 Procedure: allogeneic HSCT Procedure: Allo HSCT with reduced-intensity conditioning

Study Design

Study Type:

Observational

Actual Enrollment :

418 participants

Observational Model:

Case-Only

Time Perspective:

Prospective

Actual Study Start Date :

Feb 1, 2012

Actual Primary Completion Date :

Nov 20, 2019

Actual Study Completion Date :

Dec 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
V + Dauno+ Pred+ Metot+ Cyta+ Hc + Ida + Flud Vincristine in induction:5 mg/m2 i.v. days 1, 8, 15 and 22 in induction phase Daunorubicin in induction 45 mg/m2 i.v. days 1, 8, 15 and 22 Prednisone in induction: 60 mg/m2/ day, i.v. o p.o., days 1 to 14; 30 mg/m2/day, i.v. o p.o., days 15 to 21; 15 mg/m2/day i.v. o p.o., days 21 to 28 Metotrexato 12 mg days 1 and 22 (intrathecal) Cytarabine (ARA-C): 30 mg days 1 and 22 (intrathecal) Hydrocortisone: 20 mg days 1 and 22 (intrathecal) Idarubicin-induction 2 12 mg/m2, i.v., days 1, 3 and 5 Fludarabine in induction-2: Fludarabine 30 mg/m2, i.v., days, 1 to 5	Drug: Vincristine in induction Drug: Daunorubicin in induction Drug: Prednisone in induction Drug: Metotrexato in induction Drug: Cytarabine in induction Drug: Hydrocortisone in induction Drug: Idarubicin in induction-2 Drug: Fludarabine in induction-2 Drug: Ara-C in induction-2 Drug: G-CSF in induction-2 Drug: Dexamethasone in consolidation-1 Drug: Vincristrine in consolidation-1 Drug: Metotrexato in consolidation-1 Drug: PEG-ASP in consolidation-1 Drug: Dexamethasone in consolidation-2 Drug: ARA-C in consolidation-2 Drug: PEG-ASP in consolidation-2 Drug: Dexamethasone in consolidation-3 Drug: Vincristine in consolidation-3 Drug: Metotrexato in consolidation-3 Drug: PEG-ASP in consolidation-3 Procedure: allogeneic HSCT Procedure: Allo HSCT with reduced-intensity conditioning

Arm

Intervention/Treatment

V + Dauno+ Pred+ Metot+ Cyta+ Hc + Ida + Flud

Vincristine in induction:5 mg/m2 i.v. days 1, 8, 15 and 22 in induction phase Daunorubicin in induction 45 mg/m2 i.v. days 1, 8, 15 and 22 Prednisone in induction: 60 mg/m2/ day, i.v. o p.o., days 1 to 14; 30 mg/m2/day, i.v. o p.o., days 15 to 21; 15 mg/m2/day i.v. o p.o., days 21 to 28 Metotrexato 12 mg days 1 and 22 (intrathecal) Cytarabine (ARA-C): 30 mg days 1 and 22 (intrathecal) Hydrocortisone: 20 mg days 1 and 22 (intrathecal) Idarubicin-induction 2 12 mg/m2, i.v., days 1, 3 and 5 Fludarabine in induction-2: Fludarabine 30 mg/m2, i.v., days, 1 to 5

Drug: Vincristine in induction

Drug: Daunorubicin in induction

Drug: Prednisone in induction

Drug: Metotrexato in induction

Drug: Cytarabine in induction

Drug: Hydrocortisone in induction

Drug: Idarubicin in induction-2

Drug: Fludarabine in induction-2

Drug: Ara-C in induction-2

Drug: G-CSF in induction-2

Drug: Dexamethasone in consolidation-1

Drug: Vincristrine in consolidation-1

Drug: Metotrexato in consolidation-1

Drug: PEG-ASP in consolidation-1

Drug: Dexamethasone in consolidation-2

Drug: ARA-C in consolidation-2

Drug: PEG-ASP in consolidation-2

Drug: Dexamethasone in consolidation-3

Drug: Vincristine in consolidation-3

Drug: Metotrexato in consolidation-3

Drug: PEG-ASP in consolidation-3

Procedure: allogeneic HSCT

Procedure: Allo HSCT with reduced-intensity conditioning

Outcome Measures

Primary Outcome Measures

Overall response rate [2 years]
Improve the results of the protocol ALL-AR-03 with modifications in the study methodology of residual disease: centralized, Biomed protocols and the cut-off - <0.01% - internationally accepted and changes in the induction and consolidation treatment, without altering the overall design

Secondary Outcome Measures

Evaluate CR rate with addition of PEG-ASP in the induction phase [2 years]
Standarization of minimal residual disease [2 years]
Determination of minimal residual disease in a central laboratory trying to homogenice the results
To assess the toxic mortality [2 years]
To assess whether the reduction of daunorubicin in induction and changes in the consolidation drugs reduce toxic mortality in patients in complete remission
Assess the proportion of non-responders or slow responders [2 years]
Overall survival [5 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

15 Years to 60 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

ALL de novo high-risk criteria
Age 15-55 years (55-60 years patients will be included at the discretion of the medical team that will attend)
No prior treatment, except Emergency leukapheresis Emergency treatment of hyperleukocytosis with hydroxyurea Urgent cranial irradiation (one dose) for CNS leukostasis Mediastinal irradiation for urgent superior vena cava syndrome
General condition suitable scale (ECOG 0-2), or> 2 if due to ALL
Negative pregnancy test for women of childbearing age
Written informed consent because, although the protocol does not include the use of investigational drugs, biological samples sent there for them

Exclusion Criteria:

L3 type ALL or mature phenotype B (sIg +) or cytogenetic abnormalities characteristic of mature B-ALL (t (8; 14), t (2, 8), t (8; 22)). For these patients is available BURKIMAB protocol.
LAL Ph (BCR-ABL) positive. For these patients have the protocol ALL-Ph-08 (if under

or LALOPh (if over 55).

Lymphoid blast crisis of chronic myeloid leukemia
Biphenotypic acute leukemia or bilinear according to the criteria of EGIL group
Undifferentiated acute leukemias
Patients with a history of coronary artery disease, valvular or hypertensive heart disease, contraindicating the use of anthracyclines
Patients with chronic phase of activity
Patients with severe chronic respiratory failure
Kidney failure due to ALL
Serious neurological disorder not due to the LAL
History of pancreatitis
Pregnancy or breastfeeding
Mental or psychiatric illness preventing informed consent is given for sending samples or properly follow the study
General condition affected, not attributable to the ALL