Pegaspargase and Combination Chemotherapy in Treating Younger Patients With Newly Diagnosed High-Risk Acute Lymphoblastic Leukemia (Closed to Accrual 4-22-2011)

RATIONALE: Pegaspargase may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. 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) together with pegaspargase may kill more cancer cells.

PURPOSE: This clinical trial is studying the side effects of giving pegaspargase together with combination chemotherapy and to see how well it works in treating patients with newly diagnosed high-risk acute lymphoblastic leukemia.

OBJECTIVES:

Primary

• To demonstrate that biweekly intravenous pegaspargase in combination with consolidation, interim maintenance, delayed intensification, and maintenance therapies is feasible and safe in younger patients with newly diagnosed high-risk acute lymphoblastic leukemia. (closed to accrual 4-22-2011)

OUTLINE: This is a multicenter study (closed to accrual 4-22-2011). Patients are stratified according to risk assignment (high-risk [HR]-average [day 29 minimal residual disease (MRD) < 0.01%] vs HR-high [MRD ≥ 0.01%, presence of CNS3 leukemia, testicular disease, MLL rearrangement, hypodiploidy, or steroid therapy within the past month]). Patients are assigned to 1 of 2 treatment groups.*

NOTE: *Amendment 2 (4-22-2011) requires changes in the regimens. See the changes below, after Maintenance therapy.

• Induction therapy: All patients receive cytarabine intrathecally (IT) on day 1; vincristine sulfate IV on days 1, 8, 15, and 22; prednisone IV or orally twice daily on days 1-28; daunorubicin hydrochloride IV over 15 minutes on days 1, 8, 15, and 22; methotrexate IT on days 8 and 29*; and pegaspargase IV over 1-2 hours on day 4.

Patients with M3 (< 25% lymphoblasts) or Philadelphia chromosome-positive (Ph+) disease at day 29 are removed from study.

NOTE: *Patients with CNS3 disease (WBC ≥ 5/μL and positive for blasts on cytospin) also receive methotrexate IT on days 15 and 22.

• Consolidation therapy (begins on day 36 of induction therapy):

  • Group A (HR-average): Patients receive cyclophosphamide IV over 1 hour on days 1 and 29; cytarabine IV over 15 minutes or subcutaneously (SC) on days 1-4, 8-11, 29-32, and 36-39; oral mercaptopurine once daily on days 1-14 and 29-42; vincristine sulfate IV on days 15, 22, 43, and 50; methotrexate IT on days 1, 8, 15*, and 22*; and pegaspargase IV over 1-2 hours on days 15 and 43.
  • Group B (HR-high): Patients receive cyclophosphamide, cytarabine, mercaptopurine, vincristine sulfate, and methotrexate as in group A. Beginning on day 1, patients also receive pegaspargase IV over 1-2 hours every 2 weeks. Patients with CNS3 disease undergo cranial radiotherapy once daily for 10 days and patients with testicular disease undergo testicular radiotherapy once daily for 12 days, beginning on day 1 of consolidation.

NOTE: *Patients with CNS3 disease (WBC ≥ 5/μL and positive for blasts on cytospin) do not receive methotrexate IT on days 15 and 22.

• Interim maintenance (IM) therapy (begins on day 57 of consolidation):

  • Group A: Patients receive vincristine sulfate IV on days 1, 11, 21, 31, and 41; methotrexate IV over 10-15 minutes on days 1, 11, 21, 31, and 41; methotrexate IT on days 1 and 31; and pegaspargase IV over 1-2 hours on days 2 and 22.
  • Group B: Patients receive vincristine sulfate and methotrexate as in group A. Beginning on day 1, patients also receive pegaspargase IV over 1-2 hours every 2 weeks.

• Delayed intensification (DI) therapy (begins on day 57 of IM):

  • Group A: Patients receive vincristine sulfate IV on days 1, 8, 15, 43, and 50; dexamethasone IV or orally twice daily on days 1-7 and 15-21; doxorubicin hydrochloride IV over 15 minutes on days 1, 8, and 15; cyclophosphamide IV over 1 hour on day 29; cytarabine IV over 15 minutes or SC on days 29-32 and 36-39; oral thioguanine on days 29-42; methotrexate IT on days 1, 29, and 36; and pegaspargase IV over 1-2 hours on days 4 and 43.
  • Group B: Patients receive vincristine sulfate, dexamethasone, doxorubicin hydrochloride, cyclophosphamide, cytarabine, thioguanine, and methotrexate as in group A. Beginning on day 1, patients also receive pegaspargase IV over 1-2 hours every 2 weeks.
• Maintenance therapy (MT; begins on day 57 of DI): All patients receive vincristine sulfate IV on days 1, 29, and 57; oral prednisone on days 1-5, 29-33, and 57-61; oral mercaptopurine on days 1-84; methotrexate IT on day 1; and oral methotrexate on days 8, 15, 22, 29*, 36, 43, 50, 57, 64, 71, and 78.

In both groups, MT repeats every 12 weeks until total duration of therapy is 2 years from the start of IM for female patients and 3 years from the start of IM for male patients. Patients in group B who did not undergo radiotherapy to the brain during consolidation therapy undergo prophylactic cranial radiotherapy (CR) daily for 8 days.

NOTE: *Patients in group A also receive methotrexate IT on day 29 of courses 1-4 (no oral methotrexate).

• Revised MT (RMT): The regimen is the same as standard MT, but 2 of the doses of IT methotrexate are omitted (day 29 of courses 3 and 4).

Amendment 2 (4-22-2011) requires changes to the regimens as follows:

• Group A (HR-Avg):

  • Patients who have not started IM therapy receive high-dose (HD) methotrexate instead of Capizzi methotrexate. The rest of the IM therapy remains the same.
  • Patients currently in IM or DI therapy receive the same regimens, but also receive and additional block of therapy (IM-HD) and then proceed to RMT.
  • If patient is currently receiving MT, then stop the regimen. After 1 week, patients receive IM-HD therapy, then RMT.

• Group B (HR-high):

  • Patients who have not started IM therapy (except those who are CNS3) receive IM-HD, then revised DI (pegaspargase IV resumes every other week on days 4, 18, 32, and 46 of DI), and then receive standard MT.
  • Patients who are currently in IM or DI (except those who are CNS3) complete the standard regimens, then receive IM-HD and MT.
  • Patients who are currently receiving the first course of MT (except those who are CNS3) stop MT therapy. After 1 week, patients receive IM-HD therapy. MT then begins with course 1 starting with the next prednisoe pulse (day 1, 29, or 57) and undergo CR in the first 4 weeks of that course.

• Patients with CNS3 disease:

  • Patients who have received CR continue protocol with no modifications.
  • Patients in consolidation therapy who have NOT undergone CR finish the consolidation therapy and then receive IM-HD, revised DI, and then CR during the first 4 weeks of MT.
• Patients less than 10 years old who have not received day 8 of IM therapy stop receiving prednisone and receive a 14-day course of dexamethasone instead.
• The total number of lumbar punctures performed with IT chemotherapy is capped at 23 for females and 27 for men in group A and 19 for females and 23 for males in group B.

After completion of study treatment, patients are followed periodically for 5 years.

• Drug: cyclophosphamide
• Drug: cytarabine
• Drug: daunorubicin hydrochloride
• Drug: dexamethasone
• Drug: doxorubicin hydrochloride
• Drug: mercaptopurine
• Drug: methotrexate
• Drug: pegaspargase
• Drug: prednisone
• Drug: thioguanine
• Drug: vincristine sulfate
• Radiation: prophylactic cranial irradiation

DISEASE CHARACTERISTICS:

• Newly diagnosed high-risk B-precursor acute lymphoblastic leukemia as defined by 1 of the following criteria:

  • WBC ≥ 50,000/μL (for patients 1-10 years of age)
  • Any WBC (for patients 10-30 years of age)
  • Any WBC AND have received prior steroid therapy
  • Any WBC with biopsy proven testicular leukemia disease
• Enrolled on clinical trial COG-AALL03B1 or the successor classification study

• No Philadelphia chromosome-positive (Ph+) disease, as defined by the following:

  • BCR-ABL fusion transcript determined by FISH or RT-PCR
  • t(9;22)(q34;q11) determined by cytogenetics

PATIENT CHARACTERISTICS:

• See Disease Characteristics
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No Down syndrome

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No concurrent intensity-modulated radiotherapy

• No prior cytotoxic chemotherapy except steroids and intrathecal cytarabine

  • Systemic chemotherapy must begin within 72 hours of intrathecal cytarabine
  • Inhalational steroids not considered as pretreatment