• Pharmacodynamics of EZN-2285 compared to pegaspargase during induction and consolidation therapy [ Designated as safety issue: No ]
• Response rate [ Designated as safety issue: No ]
• Event-free survival [ Designated as safety issue: No ]
• Minimal residual disease at day 29 of induction therapy [ Designated as safety issue: No ]
• Complete remission rates [ Designated as safety issue: No ]
• Immunogenicity of EZN-2285 compared to pegaspargase [ Designated as safety issue: No ]
• Toxicities [ Designated as safety issue: Yes ]

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells.

PURPOSE: This randomized clinical trial is studying giving EZN-2285 together with combination chemotherapy to see how well it works compared with giving pegaspargase together with combination chemotherapy in treating younger patients with newly diagnosed high-risk acute lymphoblastic leukemia.

OBJECTIVES:

Primary

• Determine the pharmacokinetic (PK) comparability of SC-PEG E. coli L-asparaginase (EZN-2285) to pegaspargase given intravenously during induction and consolidation in patients with high-risk acute lymphoblastic leukemia (ALL) receiving augmented Berlin-Frankfurt-Munster (BFM) therapy.

Secondary

• Describe the pharmacodynamics of EZN-2285 compared to pegaspargase in these patients.
• Determine, at end of induction therapy by day 29, minimal residual disease for patients randomized to the EZN-2285-containing regimen compared to the pegaspargase-containing regimen.
• Determine the complete remission rates for patients receiving EZN-2285, by day 29 of induction, compared to pegaspargase.
• Assess event-free survival associated with the administration of EZN-2285 compared to pegaspargase given during augmented post-induction intensification therapy in patients with high-risk ALL.
• Determine the proportion of patients with an asparaginase level of at least 0.1 IU/mL and the proportion of patients with that of at least 0.4 IU/mL on days 4, 15, 22, and 29 of induction in both arms.
• Determine the serum and cerebrospinal fluid concentrations of asparagine after administration of EZN-2285 compared to pegaspargase.
• Assess the immunogenicity of EZN-2285, including the detection of binding and neutralizing antibodies, compared to pegaspargase.
• Assess the tolerability and toxicities associated with the administration of EZN-2285 compared to pegaspargase given during augmented post induction intensification therapy in patients with high-risk ALL .
• Explore the relationship between the terminal PKs of EZN-2285 and the presence of antibodies.

OUTLINE: This is a multicenter study. Patients are stratified according to response to induction therapy (slow early responders [SER] vs rapid early responders [RER]. Patients are randomized to 1 of 2 treatment arms in 2:1 ratio (arm I:arm II) (patients randomized to arm I receive study drug SC-PEG E. coli L-asparaginase [EZN-2285]; patients randomized to arm II receive study drug pegaspargase).

• Induction therapy (all patients): Patients receive cytarabine intrathecally (IT) on day 1; vincristine IV and daunorubicin hydrochloride IV over 15 minutes on days 1, 8, 15, and 22; prednisone orally or IV twice a day on days 1-28; study drug IV over 1 hour on day 4; and methotrexate IT on days 8, 15*, 22*, and 29.

Patients are assessed for response on day 8 and/or day 15 and day 29. Patients who achieve M1 marrow on day 8 or 15 and negative minimum residual disease (MRD) (i.e., < 0.1%) on day 29 are considered RER. Patients who achieve M2 or M3 marrow on day 15 OR MRD ≥ 0.1% but < 1% on day 29 are considered SER. Patients with M3 bone marrow are removed from the study. RER and SER proceed to consolidation therapy. Patients with M2 marrow or M1 marrow with ≥ 1% MRD receive extended induction therapy.

NOTE: *For patients with CNS3 disease only.

• Extended induction therapy: Patients receive vincristine IV on days 1 and 8; prednisone orally or IV twice a day on days 1-14; daunorubicin hydrochloride IV over 15 minutes on day 1; and study drug IV over 1 hour on day 4.

Patients are assessed for response on day 43. Patients who achieve M1 and MRD < 1% are treated as SER (proceed to consolidation therapy). All other patients are removed from study.

• Consolidation therapy (all patients): Beginning on day 36 (after completion of induction therapy) or after completion of extended induction therapy, patients (RER and SER) receive cyclophosphamide IV over 30 minutes on days 1 and 29; cytarabine IV or SC on days 1-4, 8-11, 29-32, and 36-39; oral mercaptopurine on days 1-14 and 29-42; vincristine IV on days 15, 22, 43, and 50; study drug IV over 1 hour on days 15 and 43; and methotrexate IT on days 1, 8, 15*, and 22*. Patients who were initially diagnosed with CNS3 disease receive cranial radiotherapy on days 1-5 and 8-12. Patients then proceed to interim maintenance I therapy.

NOTE: *Omit doses for patients with CNS3 disease.

• Interim maintenance I (all patients): Patients receive vincristine IV and methotrexate IV on days 1, 11, 21, 31, and 41; study drug IV over 1 hour on days 2 and 22; and methotrexate IT on days 1 and 31. Patients then proceed to delayed intensification I therapy.
• Delayed intensification I (all patients): Patients receive vincristine IV on days 1, 8, 15, 43, and 50; dexamethasone orally or IV twice a day on days 1-21 for patients age 1-9, or on days 1-7 and 15-21 for patients age ≥ 10; doxorubicin hydrochloride IV over 15 minutes on days 1, 8, and 15; study drug IV over 1 hour on days 4 and 43; cyclophosphamide IV over 30 minutes on day 29; cytarabine IV or subcutaneously (SC) on days 29-32 and 36-39; oral thioguanine on days 29-42; and methotrexate IT on days 1, 29, and 36.

Patients treated as RER proceed to maintenance therapy. Patients treated as SER (i.e., patients with CNS3 disease at diagnosis, or pre-treated with steroids, or who are RERs with mixed lineage leukemia [MLL] gene rearrangements) proceed to interim maintenance II followed by delayed intensification II.

• Interim maintenance II (SER only): Patients receive vincristine IV, methotrexate IV, study drug IV, and methotrexate IT as in interim maintenance I.
• Delayed intensification II (SER only): Beginning on day 29, patients (except patients with CNS3 disease) receive 8 daily fractions of cranial radiotherapy. All patients then receive vincristine IV, dexamethasone orally or IV, doxorubicin hydrochloride IV, study drug IV, cyclophosphamide IV, cytarabine IV or SC, oral thioguanine, and methotrexate IT as in delayed intensification I. Patients then proceed to maintenance therapy.
• Maintenance therapy (all patients): Patients receive vincristine IV on days 1, 29, and 57; oral dexamethasone on days 1-5, 29-33, and 57-61; oral mercaptopurine on days 1-84; methotrexate IT on day 29; and oral methotrexate on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. Treatment repeats every 12 weeks for up to 2 years (for female patients) or up to 3 years (for male patients) from the start of interim maintenance I.

Blood and cerebrospinal fluid samples are collected periodically for correlative studies, including immunogenicity, pharmacokinetic, and pharmacodynamic studies.

After completion of study therapy, patients are followed every 2 months for 2 years, every 3 months for 1 year, and then every 6-12 months for 2 years.

• Drug: SC-PEG E. coli L-asparaginase
• Drug: cyclophosphamide
• Drug: cytarabine
• Drug: daunorubicin hydrochloride
• Drug: dexamethasone
• Drug: doxorubicin hydrochloride
• Drug: methotrexate
• Drug: pegaspargase
• Drug: prednisone
• Drug: vincristine sulfate
• Radiation: radiation therapy

• Experimental: Patients receive SC-PEG E. coli L-asparaginase (EZN-2285) together with combination chemotherapy. Patients receive chemotherapy by mouth, infusion, injection, and intrathecally. Some patients also undergo radiation therapy to the head. Treatment may continue for up to 4 years.
• Active Comparator: Patients receive pegaspargase together with combination chemotherapy. Patients receive chemotherapy by mouth, infusion, injection, and intrathecally. Some patients also undergo radiation therapy to the head. Treatment may continue for up to 4 years.

DISEASE CHARACTERISTICS:

• Newly diagnosed high-risk B-precursor acute lymphoblastic leukemia
• No Down syndrome
• No testicular leukemia
• Enrolled on COG-AALL03B1 study or the successor classification study

PATIENT CHARACTERISTICS:

• WBC ≥ 50,000/μL for patients age 1-9 OR any WBC count for patients age 10-30 or for patients treated with prior steroids
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

• No prior cytotoxic chemotherapy except for steroid therapy or intrathecal cytarabine