05-001: Treatment of Acute Lymphoblastic Leukemia in Children

NCT ID: NCT00400946

Last Updated: 2026-02-13

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 800 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2005-04-30
• Study Completion Date: 2019-06-30

Brief Summary

RATIONALE: L-asparaginase is an important component of treatment for childhood acute lymphoblastic leukemia, but is also associated with notable side-effects, including hypersensitivity, pancreatitis, and thrombosis. We have previously reported that patients with acute lymphoblastic leukemia in whom asparaginase treatment was discontinued because of intolerable side-effects had survival outcomes that were inferior to those who received all or nearly all of their intended doses. Two bacterial sources of asparaginase exist: Escherichia coli (E coli) and Erwinia chrysanthemia (Erwinia). Generally, the E coli-derived enzyme has been used as front-line therapy and the Erwinia-derived preparation has been reserved for patients who develop hypersensitivity reactions. Pegylated E coli asparaginase (PEG-asparaginase) has a longer half-life and is potentially less immunogenic than native E coli L-asparaginase, and has been used as the initial asparaginase preparation in some pediatric acute lymphoblastic leukemia treatment regimens.

PURPOSE: Although the pharmacokinetics of each of these asparaginase preparations: intravenous PEG-asparaginase (IV-PEG) and intramuscular native E coli L-asparaginase (IM-EC) have been well characterized, their relative efficacy and toxicity have not been studied extensively.

Detailed Description

RISK CLASSIFICATION:

Patients received were classified into initial risk groups defined as:

High Risk (HR) High risk patients had any of the following features: age 10 years and older, a white blood cell count of 50 000 cells per μL or higher, initial spinal fluid sample with the presence of lymphoblasts and five or more white blood cells per high power field [Central Nervous System (CNS)-3], or a T-cell phenotype.

Standard Risk (SR) All other patients were classified as standard risk.

Patients who achieved complete remission (CR) after 32 days of induction therapy defined as a marrow specimen with less than 5% marrow blasts and evidence of normal haemopoiesis, absence of extramedullary disease, and recovery of peripheral blood counts were randomly assigned in a 1:1 ratio to receive IV-PEG or IM-EC. Randomization was stratified by final risk group assigned based on end-induction minimal residual disease and cytogenetics as follows:

Very High Risk (VHR)

Any initial risk group and any of the following:

• MLL gene rearrangement
• Hypodiploidy (<45 chromosomes)
• B cell-ALL (high) end-induction minimal residual disease (MRD) (>/= 0.001)

High Risk (HR)

No VHR features, plus:

HR initial risk group OR

SR initial risk group with either of the following:

• CNS-2 or CNS-3 on day 18
• CNS-2 on day 32 OR
• t(9;22) Philadelphia chromosome positive (Ph+ ALL)

Standard Risk (SR)

No VHR features, plus:

SR initial risk group AND

• CNS-1 on day 18 and 32

NOTE: CNS-1, Cerebral spinal fluid (CSF) without blasts; CNS-2, CSF with blasts and < 5 WBC per high-power field (HPF); CNS-3, CSF with blasts and ≥ 5 WBC per HPF

THERAPY:

INDUCTION

• Steroid prophase: Patients receive intrathecal (IT) cytarabine on day 1 and methylprednisolone IV every 8 hours on days 1-3. Patients then proceed to remission induction therapy.

Patients with CNS leukemia (CNS-2, CNS-3, or traumatic lumbar puncture [LP] with blasts) on initial LP receive additional IT cytarabine twice weekly beginning on days 4-6 and continuing until cerebrospinal fluid (CSF) is clear, followed by 2 additional doses. Patients with cranial nerve palsy but no leukemia blasts in CSF or leukemic eye infiltrates also receive additional IT cytarabine as above.

NOTE: Patients who received steroids within the past 7 days do not receive steroid prophase treatment; instead they proceed directly to remission induction therapy according to their risk group.

• Remission induction therapy (SR patients): Patients receive oral prednisone or prednisolone 2-3 times daily OR methylprednisolone IV every 8 hours on days 4-32; vincristine IV on days 4, 11, 18, and 25; doxorubicin hydrochloride (DOX) IV over 15 minutes on days 4 and 5; methotrexate (MTX) IV on day 6; pegasparaginase IV over 1 hour on day 7; triple intrathecal therapy (TIT) comprising methotrexate, cytarabine, and hydrocortisone on day 18; and IT MTX on day 32.
• Remission induction therapy (HR and VHR patients): Patients receive prednisone/prednisolone OR methylprednisolone; vincristine; DOX; MTX IV; pegasparaginase; TIT; and IT MTX as in the SR group. Patients also receive dexrazoxane hydrochloride IV over 15 minutes preceding the DOX infusions on days 4 and 5.

NOTE: Patients who do not receive steroid prophase treatment also receive IT cytarabine on day 4.

NOTE: Patients who are in CR on day 32 proceed to consolidation I. Patients who do not meet protocol definition of CR on day 32 but have no evidence of persistent disease receive vincristine IV weekly until CR is achieved. Patients with persistent marrow disease (greater than 5% leukemic blasts) and/or persistent extramedullary disease or those who do not achieve CR by day 53 are removed from the study.

NOTE: Patients with Ph+ ALL received imatinib (340 mg/m2 PO maximum 600 mg daily starting day 18) in combination with HR chemotherapy until they proceeded to stem cell transplant. Patients with Ph+ ALL patients did not participate in asparaginase randomization but were directly assigned to receive IM-EC during post-induction therapy.

CONSOLIDATION I

• Consolidation I (SR patients): Patients receive vincristine IV and IT MTX on day 1 and oral mercaptopurine once daily on days 1-14. Patients also receive high-dose MTX (HDM) IV continuously over 24 hours on day 1 and leucovorin calcium IV every 6 hours beginning 36 hours after the start of the HDM infusion and continuing until MTX levels are undetectable. Patients proceed to CNS therapy after day 21.
• Consolidation I (HR patients): Patients receive vincristine, IT MTX, and mercaptopurine as in the SR group. Patients also receive dexrazoxane hydrochloride IV over 15 minutes followed by DOX IV over 15 minutes on day 1 and HDM with leucovorin calcium support as in the SR group beginning 8-24 hours after the completion of the DOX infusion. Patients proceed to CNS therapy after day 21.
• Consolidation I (VHR patients): Patients receive consolidation therapy in 3 stages.

• IA: Patients receive vincristine, IT MTX, and mercaptopurine as in the SR group. Patients also receive dexrazoxane hydrochloride, DOX, HDM, and leucovorin calcium as in the HR group.
• IB: Patients receive cyclophosphamide IV over 1 hour and IT MTX on day 22; oral mercaptopurine once daily on days 22-35; and cytarabine IV on days 23-26 and 30-33.
• IC: Patients receive high-dose cytarabine IV over 3 hours every 12 hours on days 43 and 44; etoposide IV over 1 hour on days 45-47; and oral dexamethasone twice daily on days 43-47. Patients also receive IM-EC weekly beginning on day 48 and continuing for up to 30 weeks OR IV-PEG over 1 hour every 2 weeks beginning on day 48 and continuing for up to 30 weeks. Patients proceed to CNS therapy after day 49.

KEY RANDOMIZATION: Patients are randomized 1:1 to receive either IV-PEG or IM-EC post-induction. Those who achieved a complete remission after induction therapy were assigned a final risk group and were eligible to participate in the randomization. The randomization was stratified by final risk group.

NOTE: Ph+ ALL patients did not participate in asparaginase randomization but were directly assigned to receive IM-EC during post-induction therapy. Patients who were eligible but declined randomization were also directly assigned to receive IM-EC. Patients who developed severe pancreatitis (defined as symptoms persisting for >72 h) during induction were not eligible for randomization and received no further doses of asparaginase. Patients who had hypersensitivity to IV-PEG during induction were also ineligible for randomization, but received twice-weekly IM-EC (25 000 IU/m2) during the post-induction treatment phases.

CNS

• CNS therapy (SR patients): Patients receive vincristine IV on day 1; oral mercaptopurine once daily on days 1-14; oral dexamethasone twice daily on days 1-5; and TIT twice weekly for 2 weeks. Patients also receive IV-PEG OR IM-EC as above beginning on day 1 and continuing for up to 30 weeks. Patients proceed to consolidation II after day 21.
• CNS therapy (HR and VHR patients): Patients receive vincristine, mercaptopurine, dexamethasone, and TIT as in the SR group. Patients also receive dexrazoxane hydrochloride IV over 15 minutes followed by DOX IV over 15 minutes on day 1. HR patients also receive IV-PEG OR IM-EC as above beginning on day 1 and continuing for up to 30 weeks. VHR patients continue to receive IV-PEG OR IM-EC as per consolidation I treatment. Patients proceed to consolidation II after day 21.

NOTE: Patients with WBC > 100,000/mm³, T-cell disease, and/or CNS-3 at diagnosis or CNS-2 at end of remission induction therapy also undergo cranial radiation therapy daily for 8 or 10 days.

CONSOLIDATION II

• Consolidation II (SR patients): Patients receive vincristine IV on day 1; oral dexamethasone twice daily on days 1-5; and oral mercaptopurine once daily on days 1-14. Treatment repeats every 21 days until IV-PEG OR IM-EC is completed. Patients also receive MTX IV or IM 1 day after each IV-PEG OR IM-EC dose and TIT every 9 weeks for 6 doses and then every 18 weeks thereafter.
• Consolidation II (HR and VHR patients): Patients receive vincristine, dexamethasone, and mercaptopurine as in the SR group. Patients also receive dexrazoxane hydrochloride IV over 15 minutes followed by DOX IV over 15 minutes on day 1. Treatment repeats every 21 days until IV-PEG OR IM-EC is completed. Patients also receive MTX IV or IM as in the SR group and TIT every 9 weeks for 6 doses and then every 18 weeks thereafter OR TIT every 18 weeks.

CONTINUATION

• Continuation therapy: After completion of all consolidation therapy, all patients receive vincristine IV on day 1; oral dexamethasone twice daily on days 1-5; oral mercaptopurine once daily on days 1-14; and MTX IV or IM on days 1, 8, and 15. Treatment repeats every 21 days for up to 24 months (102 weeks) after achieving CR. Patients continue to receive TIT as in consolidation II until completion of therapy.

OBJECTIVES:

Primary

• To determine the relative toxicity of IV PEG asparaginase and IM E.coli asparaginase in children with acute lymphoblastic leukemia (ALL)

Secondary (reported)

• To explore the relative efficacy of IV PEG asparaginase and IM E.coliasparaginase
• To determine the rate of infections (episodes of bacteremia and disseminated fungal infections) during the remission induction phase
• To compare trough serum asparaginase enzyme levels, asparagine levels and antiasparaginase antibody levels
• To evaluate the outcome of patients based upon MRD status after 28 days of multiagent chemotherapy within the context of a regimen which intensifies treatment for B-lineage patients with MRD levels >0.001 at the end of remission induction (day 32 MRD status used)
• To evaluate the outcome of patients based upon bone marrow morphology after 14 days of multiagent chemotherapy (day 18 marrow morphology status used)
• To determine the efficacy of CNS-directed treatments

Secondary (not reported)

• To compare antiasparaginase antibody levels (not available due to problems with the assay)
• To correlate trough enzyme levels with outcome (toxicity, relapse)
• To determine CNS-related toxicity of CNS-directed treatments (data is not mature on late neurocognitive impairments in long-term survivors)
• To determine the efficacy and CNS-related toxicity (acute and long-term) of the HR regimen in which a subset of HR patients (B-lineage, CNS-1 or CNS-2, WBC <100,000/m3) are treated with intensive intrathecal chemotherapy and the remainder are treated with 12 Gy cranial radiation (with intrathecal chemotherapy)
• To determine the efficacy and CNS-related toxicity (acute and long-term) of intensive intrathecal therapy in SR patients
• To determine the prognostic significance of asparaginase antibody formation
• To compare randomized treatment groups using health-related quality-of-life analysis (connected with a separate protocol 06-373)
• To investigate the association of dietary antioxidant micronutrient intake with the rate of infections (episodes of bacteremia and disseminated fungal infections) during remission induction therapy and the Consolidation IA phase
• To determine the relationship of dietary calcium intake with risk for development of fractures during the continuation phase of therapy
• To evaluate the association of dietary intake of specific nutrients with treatment-related toxicities during treatment
• To evaluate the outcome of patients based upon MRD status after 14 days of multiagent chemotherapy and at various other timepoints while on treatment every 18 weeks after achieving complete remission and at the completion of all chemotherapy
• To determine the prognostic significance of response to remission induction chemotherapy as measured by morphologic and minimal residual disease (MRD) measures within the context of DFCI ALL Consortium protocol therapy (data limited due to response outcomes)
• To compare rate of infection during remission induction in patients treated with a less intensive induction regimen on Protocol 05-01 (low-dose instead of high-dose methotrexate) with that of patients treated on prior DFCI ALL Consortium Protocol 00-01 (induction regimen included high-dose methotrexate)
• To determine the concordance of MRD quantification using multi-parameter flow cytometry and PCR techniques
• To determine the prognostic significance of gene expression programs in childhood ALL and identify new targets for specific therapies
• To identify clinically relevant gene expression signatures in leukemia cells
• To identify gene expression signature in leukemia cells at diagnosis that predicts peripheral blood response to the steroid prophase
• To identify gene expression changes in leukemia cells induced by steroid treatment
• To determine the frequency and type of tyrosine kinase mutations in childhood ALL and identify new targets for specific therapies
• To explore the potential relationship between abnormal glucose homeostasis during therapy and the development of obesity, as well as the potential relationship between obesity and the age of pubertal onset (assessed in patients treated at DFCI/CHB only)
• To characterize the degree of hyperglycemia and insulin resistance in patients receiving therapy for childhood ALL
• To characterize the degree of insulin resistance and obesity after the completion of therapy for childhood ALL

Conditions

Drug/Agent Toxicity by Tissue/Organ; Leukemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Intramuscular native E coli L-asparaginase (IM-EC)

Patients in this arm were randomized to intramuscular native E coli L-asparaginase 25 000 IU/m2 weekly for 30 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.

Group Type: ACTIVE_COMPARATOR

asparaginase

Intervention Type: DRUG

cyclophosphamide

Intervention Type: DRUG

cytarabine

Intervention Type: DRUG

dexamethasone

Intervention Type: DRUG

dexrazoxane hydrochloride

Intervention Type: DRUG

doxorubicin hydrochloride

Intervention Type: DRUG

etoposide

Intervention Type: DRUG

Given IV

leucovorin calcium

Intervention Type: DRUG

mercaptopurine

Intervention Type: DRUG

Given orally

methotrexate

Intervention Type: DRUG

methylprednisolone

Intervention Type: DRUG

prednisolone

Intervention Type: DRUG

therapeutic hydrocortisone

Intervention Type: DRUG

vincristine sulfate

Intervention Type: DRUG

radiation therapy

Intervention Type: RADIATION

Intravenous PEG-asparaginase (IV-PEG)

Patients in this arm were randomized to intravenous PEG-asparaginase 2500 IU/m2 every 2 weeks for 15 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.

Group Type: EXPERIMENTAL

cyclophosphamide

Intervention Type: DRUG

cytarabine

Intervention Type: DRUG

dexamethasone

Intervention Type: DRUG

dexrazoxane hydrochloride

Intervention Type: DRUG

doxorubicin hydrochloride

Intervention Type: DRUG

etoposide

Intervention Type: DRUG

Given IV

leucovorin calcium

Intervention Type: DRUG

mercaptopurine

Intervention Type: DRUG

Given orally

methotrexate

Intervention Type: DRUG

methylprednisolone

Intervention Type: DRUG

pegaspargase

Intervention Type: DRUG

Given IV

prednisolone

Intervention Type: DRUG

therapeutic hydrocortisone

Intervention Type: DRUG

vincristine sulfate

Intervention Type: DRUG

radiation therapy

Intervention Type: RADIATION

Interventions

asparaginase

Intervention Type: DRUG

cyclophosphamide

Intervention Type: DRUG

cytarabine

Intervention Type: DRUG

dexamethasone

Intervention Type: DRUG

dexrazoxane hydrochloride

Intervention Type: DRUG

doxorubicin hydrochloride

Intervention Type: DRUG

etoposide

Given IV

Intervention Type: DRUG

leucovorin calcium

Intervention Type: DRUG

mercaptopurine

Given orally

Intervention Type: DRUG

methotrexate

Intervention Type: DRUG

methylprednisolone

Intervention Type: DRUG

pegaspargase

Given IV

Intervention Type: DRUG

prednisolone

Intervention Type: DRUG

therapeutic hydrocortisone

Intervention Type: DRUG

vincristine sulfate

Intervention Type: DRUG

radiation therapy

Intervention Type: RADIATION

Eligibility Criteria

Inclusion Criteria

DISEASE CHARACTERISTICS:

• Diagnosis of acute lymphoblastic leukemia (ALL)

• No known mature B-cell ALL, defined by the presence of any of the following:

• Surface immunoglobulin
• L3 morphology
• t(8;14)(q24;q32)
• t(8;22)
• t(2;8)
• T-cell surface markers and t(8;14)(q24;q11) allowed
• No secondary ALL

PATIENT CHARACTERISTICS:

• No known HIV positivity
• Not pregnant or nursing
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

• No prior therapy except steroids of ≤ 1 week in duration and/or emergent radiation therapy to the mediastinum

• Patients treated with steroids within the past 7 days will not receive steroid prophase during study treatment

• Minimum Eligible Age: 1 Year
• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Dana-Farber Cancer Institute

OTHER

Sponsor Role: lead

Responsible Party

Lynda Vrooman, MD

Lynda Vroom, MD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Lynda Vrooman, MD

Role: PRINCIPAL_INVESTIGATOR

Dana-Farber Cancer Institute

Locations

Dana Farber Cancer Institute

Boston, Massachusetts, United States

Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center

New York, New York, United States

James P. Wilmot Cancer Center at University of Rochester Medical Center

Rochester, New York, United States

Albert Einstein Cancer Center at Albert Einstein College of Medicine

The Bronx, New York, United States

Hasbro Children's Hospital

Providence, Rhode Island, United States

McMaster Children's Hospital at Hamilton Health Sciences

Hamilton, Ontario, Canada

Hopital Sainte Justine

Montreal, Quebec, Canada

Centre de Recherche du Centre Hospitalier de l'Universite Laval

Sainte-Foy, Quebec, Canada

Countries

United States; Canada

References

Silverman LB, Supko JG, Stevenson KE, Woodward C, Vrooman LM, Neuberg DS, Asselin BL, Athale UH, Clavell L, Cole PD, Kelly KM, Laverdiere C, Michon B, Schorin M, Schwartz CL, O'Brien JE, Cohen HJ, Sallan SE. Intravenous PEG-asparaginase during remission induction in children and adolescents with newly diagnosed acute lymphoblastic leukemia. Blood. 2010 Feb 18;115(7):1351-3. doi: 10.1182/blood-2009-09-245951. Epub 2009 Dec 10.

Reference Type: RESULT

PMID: 20007809 (View on PubMed)

Place AE, Stevenson KE, Vrooman LM, Harris MH, Hunt SK, O'Brien JE, Supko JG, Asselin BL, Athale UH, Clavell LA, Cole PD, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Schorin MA, Welch JJ, Lipshultz SE, Kutok JL, Blonquist TM, Neuberg DS, Sallan SE, Silverman LB. Intravenous pegylated asparaginase versus intramuscular native Escherichia coli L-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): a randomised, open-label phase 3 trial. Lancet Oncol. 2015 Dec;16(16):1677-90. doi: 10.1016/S1470-2045(15)00363-0. Epub 2015 Nov 6.

Reference Type: RESULT

PMID: 26549586 (View on PubMed)

Vrooman LM, Blonquist TM, Harris MH, Stevenson KE, Place AE, Hunt SK, O'Brien JE, Asselin BL, Athale UH, Clavell LA, Cole PD, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Schorin MA, Sulis ML, Welch JJG, Neuberg DS, Sallan SE, Silverman LB. Refining risk classification in childhood B acute lymphoblastic leukemia: results of DFCI ALL Consortium Protocol 05-001. Blood Adv. 2018 Jun 26;2(12):1449-1458. doi: 10.1182/bloodadvances.2018016584.

Reference Type: DERIVED

PMID: 29941458 (View on PubMed)

Kahn JM, Cole PD, Blonquist TM, Stevenson K, Jin Z, Barrera S, Davila R, Roberts E, Neuberg DS, Athale UH, Clavell LA, Laverdiere C, Leclerc JM, Michon B, Schorin MA, Welch JJG, Sallan SE, Silverman LB, Kelly KM. An investigation of toxicities and survival in Hispanic children and adolescents with ALL: Results from the Dana-Farber Cancer Institute ALL Consortium protocol 05-001. Pediatr Blood Cancer. 2018 Mar;65(3):10.1002/pbc.26871. doi: 10.1002/pbc.26871. Epub 2017 Nov 1.

Reference Type: DERIVED

PMID: 29090520 (View on PubMed)

Other Identifiers

P01CA068484

Identifier Type: NIH

Identifier Source: secondary_id

View Link

P30CA006516

Identifier Type: NIH

Identifier Source: secondary_id

View Link

DFCI-05001

Identifier Type: OTHER

Identifier Source: secondary_id

05-001 / CDR0000513019

Identifier Type: -

Identifier Source: org_study_id

NCT00165165

Identifier Type: -

Identifier Source: nct_alias