Combination Chemotherapy in Treating Young Patients With Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia or T-cell Lymphoblastic Lymphoma
Combination Chemotherapy in Treating Young Patients With Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia or T-cell Lymphoblastic Lymphoma
This randomized phase III trial is studying different combination chemotherapy regimens and
 their side effects and comparing how well they work in treating young patients with newly
 diagnosed T-cell acute lymphoblastic leukemia or T-cell lymphoblastic lymphoma. 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. It is not yet known which combination chemotherapy regimen is
 more effective in treating T-cell acute lymphoblastic leukemia or T-cell lymphoblastic
 lymphoma. After a common induction therapy, patients were risk assigned and eligible for one
 or both post-induction randomizations: Escalating dose Methotrexate versus High Dose
 Methotrexate in Interim Maintenance therapy, No Nelarabine versus Nelarabine in Consolidation
 therapy. T-ALL patients are risk assigned as Low Risk, Intermediate Risk or High Risk. Low
 Risk patients are not eligible for the Nelarabine randomization, Patients with CNS disease at
 diagnosis were assgined to receive High Dose Methotrexate, patients who failed induction
 therapy were assigned to receive Nelarabine and High Dose Methotrexate. T-LLy patients were
 all assigned to escalating dose Methotrexate and were risk assigned as Standard Risk, High
 Risk and induction failures. Standard risk patients did not receive nelarabine, High risk
 T-LLy patients were randomized to No Nelarabine versus Nelarabine, and Induction failures
 were assigned to receive Nelarabine.
PRIMARY OBJECTIVES:

 I. To determine, through randomization, the relative safety and efficacy of the addition of
 nelarabine (Compound 506U78) to augmented Berlin-Frankfurt-Münster (BFM) therapy (Regimen C,
 Children's Cancer Group [CCG]-1961).

 II. To determine the relative safety and efficacy of high dose methotrexate (5 g/m^2) with
 leucovorin (leucovorin calcium) rescue compared to escalating methotrexate without leucovorin
 rescue plus pegaspargase (Capizzi I) delivered during interim maintenance.

 III. To gain preliminary data on the use of nelarabine in patients with high risk T-cell
 lymphoblastic lymphoma and its effect on long-term survival.

 SECONDARY OBJECTIVES:

 I. To determine the relative safety and efficacy of withholding radiation in patients with
 low risk T-cell acute lymphoblastic leukemia (T-ALL), while treating Intermediate and high
 risk patients with 1200 cGy of prophylactic cranial radiation.

 OUTLINE: This is a randomized, controlled, factorial-group, multicenter study.

 GROUP 0 (INDUCTION THERAPY): All patients (T-ALL and T-LLy) receive cytarabine intrathecally
 (IT) on day 1; vincristine sulfate intravenously (IV) on days 1, 8, 15, and 22; prednisone IV
 or orally (PO) twice daily (BID) on days 1-28; pegaspargase intramuscularly (IM) (may give IV
 over 1 to 2 hours) on day 4, 5, or 6; duanorubicin IV on days 1, 8, 15 and 22; and
 methotrexate IT on days 8 and 29 (and days 15 and 22 for patients with CNS3 disease).

 GROUP I ARM I COMBINATION CHEMOTHERAPY (CONSOLIDATION CHEMOTHERAPY): Patients receive
 methotrexate IT on days 1, 8, 15, and 22; cyclophosphamide IV over 30 minutes on days 1 and
 29; cytarabine IV over 15-30 minutes or subcutaneously (SC) on days 1-4, 8-11, 29-32, and
 36-39; mercaptopurine PO on days 1-14 and 29-42; vincristine sulfate IV on days 15, 22, 43
 and 50; and pegaspargase IM or IV over 1-2 hours on days 15 and 43. Patients with DS also
 receive leucovorin calcium PO at 48 and 60 hours after each methotrexate dose. Patients with
 persistent testicular disease or with DS and testicular disease undergo testicular
 radiotherapy on days 11-12, 15-19, and 22-26. (DS patients excluded as of 09/29/10.) Patients
 with intermediate-risk or high-risk disease (CNS1 or CNS2) undergo prophylactic CRT (1,200
 cGy/dose) QD on days 15-21 and 22-28. Patients with low-risk disease do not undergo conformal
 radiation therapy (CRT). Patients with standard risk T-LLy received Arm I, and those with
 high risk T-LLy were randomized between Arm I and Arm II combination chemotherapy.

 GROUP I ARM I COMBINATION CHEMOTHERAPY (DELAYED INTENSIFICATION CHEMOTHERAPY): Patients
 receive vincristine sulfate IV on days 1, 8, 15, 43, and 50; dexamethasone IV or PO BID on
 days 1-21 (for patients < 10 years of age) OR on days 1-7 and 15-21 (for patients >= 10 years
 of age and for patients with DS); doxorubicin hydrochloride IV on days 1, 8, and 15;
 pegaspargase IM or IV over 1-2 hours on day 4, 5, OR 6, AND day 43; methotrexate IT on days
 1, 29, and 36; cyclophosphamide IV over 30 minutes on day 29; cytarabine IV over 15-30
 minutes or SC on days 29-32 and 36-39; and thioguanine PO on days 29-42. Patients with DS
 also receive leucovorin calcium PO at 48 and 60 hours after each methotrexate dose (DS
 patients excluded as of 09/29/10). Standard risk T-LLy patients were assigned to Arm I and
 those with high risk were randomized between Arm I and Arm II.

 GROUP I ARM I COMBINATION CHEMOTHERAPY (INTERIM MAINTENANCE CHEMOTHERAPY): Patients receive
 vincristine sulfate IV and escalating doses of methotrexate IV on days 1, 11, 21, 31, and 41;
 pegaspargase* IM or IV over 1-2 hours on days 2 and 22; and methotrexate IT on days 1 and 31.
 Patients with DS also receive leucovorin calcium PO 48 and 60 hours after each methotrexate
 IT dose (DS patients excluded as of 09/29/10).

 Note: *Patients with an allergy to pegaspargase receive Erwinia asparaginase on days 2, 4, 6,
 8, 10, 12, 22, 24, 26, 28, 30, and 32.

 GROUP I ARM I COMBINATION CHEMOTHERAPY (MAINTENANCE CHEMOTHERAPY): Patients receive
 vincristine sulfate IV on days 1, 29, and 57; prednisone PO BID on days 1-5, 29-33, and
 57-61; mercaptopurine PO QD on days 1-84; methotrexate PO on days 8, 15, 22, 29, 36, 43, 50,
 57, 64, 71, and 78; and methotrexate IT on day 1. Treatment repeats every 84 days until the
 total duration of study treatment is 2 years from the start of interim maintenance therapy
 (approximately week 119) (for girls with T-ALL), all patients with T-LLy, and 3 years from
 the start of interim maintenance therapy (approximately week 171) (for boys with T-ALL).

 GROUP I ARM II COMBINATION CHEMOTHERAPY (CONSOLIDATION CHEMOTHERAPY): Patients receive
 nelarabine IV over 60 minutes on days 1-5 and 43-47; methotrexate IT on days 15, 22, 57, and
 64; cyclophosphamide IV over 30 minutes on days 8 and 50; cytarabine IV over 15-30 minutes or
 SC on days 8-11, 15-18, 50-53 and 57-60; mercaptopurine PO on days 8-21 and 50-63;
 vincristine sulfate IV on days 22, 29, 64, and 71; and pegaspargase IM or IV over 1-2 hours
 on days 22 and 64. Patients with persistent testicular disease or with DS and testicular
 disease undergo testicular radiotherapy on days 15, 22-26, and 29-33 (DS patients excluded as
 of 09/29/10). (Patients with intermediate-risk or high-risk disease (CNS1 or CNS2) undergo
 prophylactic CRT QD on days 22-28 and 29-35. Patients with high risk T-LLy were either
 randomized to Arm I or Arm II. Patients with T-LLy who failed induction therapy were assigned
 to Arm II.

 GROUP I ARM II COMBINATION CHEMOTHERAPY (DELAYED INTENSIFICATION CHEMOTHERAPY): Patients
 receive vincristine sulfate IV on days 1, 8, 15, and 50; dexamethasone IV or PO BID on days
 1-21 (for patients < 10 years of age) OR on days 1-7 and 15-21 (for patients >= 10 years of
 age); doxorubicin hydrochloride IV on days 1, 8, and 15; pegaspargase IM or IV over 1-2 hours
 on day 4, 5, OR 6 AND day 50; methotrexate IT on days 1, 36, and 43; nelarabine IV over 60
 minutes on days 29-33; cyclophosphamide IV over 30 minutes on day 36; cytarabine IV over
 15-30 minutes or SC on days 36-39 and 43-46; and thioguanine PO on days 36-49.

 GROUP I ARM II COMBINATION CHEMOTHERAPY (INTERIM MAINTENANCE CHEMOTHERAPY): Patients receive
 vincristine sulfate IV and escalating doses of methotrexate IV on days 1, 11, 21, 31, and 41;
 pegaspargase* IM or IV over 1-2 hours on days 2 and 22; and methotrexate IT on days 1 and 31.

 Note: *Patients with an allergy to pegaspargase receive Erwinia asparaginase on Monday,
 Wednesday and Friday for two consecutive weeks starting the day of asparaginase substitution.

 GROUP I ARM II COMBINATION CHEMOTHERAPY (MAINTENANCE CHEMOTHERAPY): Patients receive
 vincristine sulfate, prednisone, mercaptopurine, methotrexate PO, methotrexate IT, and
 nelarabine in Cycles 1, 2 and 3. Patients then receive treatment (without nelarabine) as
 follows: vincristine sulfate, prednisone, mercaptopurine, methotrexate PO, and methotrexate
 IT as in arm II. Treatment (without nelarabine) repeats every 84 days until the total
 duration of study treatment is 2 years from the start of interim maintenance therapy
 (approximately week 121) (for girls with T-ALL), and for those with T-LLY, and 3 years from
 the start of interim maintenance therapy (approximately week 173) (for boys with T-ALL).

 GROUP I ARM III COMBINATION CHEMOTHERAPY (CONSOLIDATION CHEMOTHERAPY): Patients receive
 methotrexate IT on days 1, 8, 15, and 22; cyclophosphamide IV over 30 minutes on days 1 and
 29; cytarabine IV over 15-30 minutes or SC on days 1-4, 8-11, 29-32, and 36-39;
 mercaptopurine PO on days 1-14 and 29-42; vincristine sulfate IV on days 15, 22, 43 and 50;
 and pegaspargase IM or IV over 1-2 hours on days 15 and 43. Patients with DS also receive
 leucovorin calcium PO at 48 and 60 hours after each methotrexate dose. Patients with
 persistent testicular disease or with DS and testicular disease undergo testicular
 radiotherapy on days 11-12, 15-19, and 22-26. (DS patients excluded as of 09/29/10.) Patients
 with intermediate-risk or high-risk disease (CNS1 or CNS2) undergo prophylactic CRT (1,200
 cGy/dose) QD on days 15-21 and 22-28. Patients with low-risk disease do not undergo CRT.

 GROUP I ARM III COMBINATION CHEMOTHERAPY (DELAYED INTENSIFICATION CHEMOTHERAPY): Patients
 receive vincristine sulfate IV on days 1, 8, 15, 43, and 50; dexamethasone IV or PO BID on
 days 1-21 (for patients < 10 years of age) OR on days 1-7 and 15-21 (for patients >= 10 years
 of age and for patients with DS); doxorubicin hydrochloride IV on days 1, 8, and 15;
 pegaspargase IM or IV over 1-2 hours on day 4, 5, OR 6, AND day 43; methotrexate IT on days
 1, 29, and 36; cyclophosphamide IV over 30 minutes on day 29; cytarabine IV over 15-30
 minutes or SC on days 29-32 and 36-39; and thioguanine PO on days 29-42. Patients with DS
 also receive leucovorin calcium PO at 48 and 60 hours after each methotrexate dose (DS
 patients excluded as of 09/29/10).

 GROUP I ARM III COMBINATION CHEMOTHERAPY (INTERIM MAINTENANCE CHEMOTHERAPY): Patients receive
 high dose methotrexate (HDMTX) IV over 24 hours and vincristine sulfate IV on days 1, 15, 29,
 and 43; mercaptopurine PO on days 1-56; and methotrexate IT on days 1 and 29. Beginning 42
 hours after the start of HDMTX, patients also receive leucovorin calcium IV or PO once every
 6 hours for 3 doses.

 GROUP I ARM III COMBINATION CHEMOTHERAPY (MAINTENANCE CHEMOTHERAPY): Patients receive
 vincristine sulfate IV on days 1, 29, and 57; prednisone PO BID on days 1-5, 29-33, and
 57-61; mercaptopurine PO QD on days 1-84; methotrexate PO on days 8, 15, 22, 29, 36, 43, 50,
 57, 64, 71, and 78; and methotrexate IT on day 1. Treatment repeats every 84 days until the
 total duration of study treatment is 2 years from the start of interim maintenance therapy
 (approximately week 119) (for girls with T-ALL) and all patients with T-LLy, and 3 years from
 the start of interim maintenance therapy (approximately week 171) (for boys with T-ALL).

 GROUP I ARM IV COMBINATION CHEMOTHERAPY (CONSOLIDATION CHEMOTHERAPY): Patients receive
 nelarabine IV over 60 minutes on days 1-5 and 43-47; methotrexate IT on days 15, 22, 57, and
 64; cyclophosphamide IV over 30 minutes on days 8 and 50; cytarabine IV over 15-30 minutes or
 SC on days 8-11, 15-18, 50-53 and 57-60; mercaptopurine PO on days 8-21 and 50-63;
 vincristine sulfate IV on days 22, 29, 64, and 71; and pegaspargase IM or IV over 1-2 hours
 on days 22 and 64. (DS patients excluded as of 09/29/10). (Patients with intermediate-risk or
 high-risk disease (CNS1 or CNS2) undergo prophylactic CRT QD on days 22-28 and 29-35.

 GROUP I ARM IV COMBINATION CHEMOTHERAPY (DELAYED INTENSIFICATION CHEMOTHERAPY): Patients
 receive vincristine sulfate IV on days 1, 8, 15, and 50; dexamethasone IV or PO BID on days
 1-21 (for patients < 10 years of age) OR on days 1-7 and 15-21 (for patients >= 10 years of
 age); doxorubicin hydrochloride IV on days 1, 8, and 15; pegaspargase IM or IV over 1-2 hours
 on day 4, 5, OR 6 AND day 50; methotrexate IT on days 1, 36, and 43; nelarabine IV over 60
 minutes on days 29-33; cyclophosphamide IV over 30 minutes on day 36; cytarabine IV over
 15-30 minutes or SC on days 36-39 and 43-46; and thioguanine PO on days 36-49.

 GROUP I ARM IV COMBINATION CHEMOTHERAPY (INTERIM MAINTENANCE CHEMOTHERAPY): Patients receive
 HDMTX IV over 24 hours and vincristine sulfate IV on days 1, 15, 29, and 43; mercaptopurine
 PO on days 1-56; and methotrexate IT on days 1 and 29. Beginning 42 hours after the start of
 HDMTX, patients also receive leucovorin calcium IV or PO once every 6 hours for 3 doses.

 GROUP I ARM IV COMBINATION CHEMOTHERAPY (MAINTENANCE CHEMOTHERAPY): Patients receive
 vincristine sulfate, prednisone, mercaptopurine, methotrexate PO, methotrexate IT, and
 nelarabine in Cycles 1, 2 and 3. Patients then receive treatment (without nelarabine) as
 follows: vincristine sulfate, prednisone, mercaptopurine, methotrexate PO, and methotrexate
 IT as in arm II. Treatment (without nelarabine) repeats every 84 days until the total
 duration of study treatment is 2 years from the start of interim maintenance therapy
 (approximately week 121) (for girls with T-ALL), and for those with T-LLY, and 3 years from
 the start of interim maintenance therapy (approximately week 173) (for boys with T-ALL).

 After completion of study therapy, patients are followed periodically for at least 10 years.
Inclusion Criteria:

 -  T-ALL patients must be enrolled on AALL08B1 prior to treatment and enrollment on
 AALL0434

 -  Patients must have newly diagnosed T-ALL or T-lineage lymphoblastic lymphoma (T-NHL)
 stage II-IV; B-lineage lymphoblastic lymphoma will not be eligible for this study; a
 diagnosis of T-ALL is established when leukemic blasts lack myeloperoxidase or
 evidence of B-lineage derivation (cluster of differentiation [CD]19/CD22/CD20), and
 express either surface or cytoplasmic CD3 or two or more of the antigens CD8, CD7,
 CD5, CD4, CD2 or CD1a; if surface CD3 is expressed on all leukemic cells, additional
 markers of immaturity, including transmission disequilibrium test (TdT), CD34 or CD99
 will be assessed for expression; cases with uncertain expression will receive
 additional review within the appropriate Children's Oncology Group (COG) reference
 laboratory

 -  T-NHL PATIENTS:

 -  For T-NHL patients with tissue available for flow cytometry, the criterion for
 diagnosis should be analogous to T-ALL; for tissue processed by other means (i.e.
 paraffin blocks), the methodology and criteria for immunophenotypic analysis to
 establish the diagnosis of T-NHL defined by the submitting institution will be
 accepted

 -  Prior therapy restrictions

 -  Patients shall have had no prior cytotoxic chemotherapy with the exception of
 steroids and/or IT cytarabine

 -  IT chemotherapy with cytarabine is allowed prior to registration for patient
 convenience; this is usually done at the time of the diagnostic bone marrow or
 venous line placement to avoid a second lumbar puncture; (Note: the CNS status
 must be determined based on a sample obtained prior to administration of any
 systemic or intrathecal chemotherapy, except for steroid pretreatment); systemic
 chemotherapy must begin within 72 hours of this IT therapy

 -  Patients diagnosed as having T-NHL or T-ALL with respiratory distress or
 hyperleukocytosis may require steroids prior to the initiation of additional
 systemic therapy; they are eligible for AALL0434 and will be stratified, based on
 the initial complete blood count (CBC); steroid pretreatment may alter the risk
 group assessment; if the T-ALL patient's clinical status precludes a lumbar
 puncture within 48 hours of the initiation of steroid therapy, T-ALL patients
 CANNOT be classified as low risk and will be Intermediate or high risk based on
 the results of the day 29 marrow as above; patients with T-NHL who receive
 steroid pre-treatment will be classified as high risk; the dose and duration of
 previous steroid therapy should be carefully documented

 -  For the management of airway compromise, patients who have received emergent
 chest irradiation up to 600 cGy will be eligible for this study

 -  Patients with a prior seizure disorder requiring anti-convulsant therapy are not
 eligible to receive nelarabine; in addition, patients with pre-existing grade 2 (or
 greater) peripheral neurotoxicity, as determined prior to Induction treatment by the
 treating physician or a neurologist, are not eligible to receive nelarabine; these
 restrictions in eligibility are designed to prevent excessive nelarabine-induced
 central and peripheral neurotoxicity in at-risk patients; for the purposes of this
 study, this includes any patient that has received anticonvulsant therapy to
 prevent/treat seizures in the prior two years

 Exclusion Criteria:

 -  Pregnant or lactating females are ineligible

 -  Patients with Down syndrome are ineligible to enroll onto this study

 -  For T-NHL patients the following additional exclusion criteria apply:

 -  B-precursor lymphoblastic lymphoma

 -  Morphologically unclassifiable lymphoma

 -  Absence of both B-cell and T-cell phenotype markers in a case submitted as
 lymphoblastic lymphoma

 -  CNS3-positive or testicular involvement