A Study to Investigate Blinatumomab in Combination With Chemotherapy in Patients With Newly Diagnosed B-Lymphoblastic Leukemia
A Study to Investigate Blinatumomab in Combination With Chemotherapy in Patients With Newly Diagnosed B-Lymphoblastic Leukemia
This phase III trial studies how well blinatumomab works in combination with chemotherapy in
 treating patients with newly diagnosed, standard risk B-lymphoblastic leukemia or
 B-lymphoblastic lymphoma with or without Down syndrome. Monoclonal antibodies, such as
 blinatumomab, may induce changes in the body's immune system and may interfere with the
 ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as vincristine,
 dexamethasone, prednisone, prednisolone, pegaspargase, methotrexate, cytarabine,
 mercaptopurine, doxorubicin, cyclophosphamide, and thioguanine, work in different ways to
 stop the growth of cancer cells, either by killing the cells, by stopping them from dividing,
 or by stopping them from spreading. Leucovorin decreases the toxic effects of methotrexate.
 Giving monoclonal antibody therapy with chemotherapy may kill more cancer cells. Giving
 blinatumomab and combination chemotherapy may work better than combination chemotherapy alone
 in treating patients with B-ALL. This trial also assigns patients into different chemotherapy
 treatment regimens based on risk (the chance of cancer returning after treatment). Treating
 patients with chemotherapy based on risk may help doctors decide which patients can best
 benefit from which chemotherapy treatment regimens.
PRIMARY OBJECTIVES:

 I. To determine in a randomized manner if the addition of 2 cycles of blinatumomab to
 standard therapy improves disease-free survival (DFS) in patients with standard risk (SR)
 B-ALL and higher risk features (SR-High), and patients with standard-risk average (SR-Avg)
 B-ALL who are negative for minimal residual disease (MRD) by flow cytometry but have
 detectable or indeterminate MRD as measured by high-throughput sequencing (HTS) at end of
 induction (EOI).

 II. To confirm that boys in the standard-risk favorable (SR-Fav) subset of B-ALL, with or
 without Down syndrome (DS), will maintain a 5-year DFS of greater than 93% when treated with
 a standard chemotherapy regimen with a treatment duration of 2 years from the start of
 interim maintenance I (IM1).

 SECONDARY OBJECTIVES:

 I. To describe the DFS for patients with SR-Avg B-ALL who are negative for MRD measured by
 flow cytometry and HTS at EOI when treated with standard chemotherapy with a treatment
 duration of 2 years from the start of IM1, regardless of sex.

 II. To describe the DFS for patients with standard-risk favorable (SR-Fav) B-ALL when treated
 with a standard chemotherapy regimen.

 III. To determine if patients with DS-High achieve a reduction of treatment-related mortality
 (TRM) after replacement of intensive elements of standard chemotherapy (omission of
 anthracyclines in induction, omission of the second month of delayed intensification [DI])
 with 3 cycles of blinatumomab.

 IV. To describe the DFS characterized by the replacement of intensive elements of standard
 chemotherapy with 3 cycles of blinatumomab in patients with DS-High B ALL.

 V. To describe the DFS for patients with localized (Murphy stage I and II) B lymphoblastic
 lymphoma (B-LLy) receiving standard risk B-ALL therapy.

 VI. To compare the change in neurocognitive functioning, as measured by the CogState
 Cognitive Composite, from baseline to end-of-therapy among patients with ALL ages 4- < 10
 years at the time of diagnosis between children from poor families (defined as presence of
 household material hardship [HMH], including either food, housing or energy insecurity) and
 non-poor families (absence of HMH).

 VII. To describe the impact of blinatumomab on caregiver burden and patient/proxy-reported
 symptoms among a subset of children enrolled in the HMH and neurocognitive outcome study.

 EXPLORATORY OBJECTIVES:

 I. To explore adaptive and innate immune functions and host genetic factors associated with
 severe infectious complications in children with DS B-ALL.

 II. To explore the impact of acute lymphoblastic leukemia (ALL) and its therapy on
 neurocognitive, functional, and quality of life outcomes in patients with DS and ALL, as
 measured by caregiver (parent/legal guardian) questionnaires.

 III. To define the prevalence of minimal marrow disease (MMD) in B-LLy and to correlate MMD
 at diagnosis with outcome in patients with B-LLy.

 OUTLINE: All patients are assigned to, and complete an INDUCTION treatment regimen. Patients
 are then assigned to a CONSOLIDATION treatment regimen. Finally, following CONSOLIDATION,
 patients are either assigned or randomized to 1 of 7 arms.

 NON-DS SR B-ALL INDUCTION: Patients receive cytarabine intrathecally (IT) on day 1,
 vincristine intravenous (IV) push over 1 minute on days 1, 8, 15, and 22, dexamethasone
 orally (PO) or IV twice daily (BID) on days 1-28, pegaspargase IV over 1-2 hours or
 intramuscularly (IM) on day 4, and methotrexate IT on days 8 and 29. CNS2 patients also
 receive cytarabine IT twice weekly except during weeks when days 8 and 29 methotrexate is
 administered. Treatment continues for 35 days in the absence of disease progression or
 unacceptable toxicity.

 * After Non-DS SR B-ALL INDUCTION, SR-Fav and SR-Avg patients complete SR CONSOLIDATION,
 while patients with SR-High complete high-risk (HR) CONSOLIDATION.

 DS B-ALL INDUCTION: Patients receive cytarabine IT on day 1, vincristine IV push over 1
 minute on days 1, 8, 15, and 22, pegaspargase IV over 1-2 hours or IM on day 4, methotrexate
 IT on days 8 and 29, and leucovorin PO or IV every 6 hours for 2 doses on days 9 and 30.
 Additionally, patients under 10 years of age receive dexamethasone PO or IV BID on days 1-28,
 and patients 10 years of age or older receive prednisone or prednisolone PO or IV BID on days
 1-28. CNS2 patients also receive cytarabine IT twice weekly except during weeks when days 8
 and 29 IT methotrexate is administered. CNS3 patients also receive methotrexate IT on days 15
 and 22, and leucovorin PO or IV every 6 hours for 2 doses on days 16 and 23. Treatment
 continues for 35 days in the absence of disease progression or unacceptable toxicity.

 * After DS B-ALL INDUCTION, patients without high risk features and MRD < 0.01 % complete SR
 CONSOLIDATION. Patients without high risk features and MRD >= 0.01%, OR with high risk
 features and any MRD complete HR CONSOLIDATION.

 NON-DS B-LLy INDUCTION: Patients receive cytarabine IT on day 1 and twice weekly if CNS2,
 vincristine IV push over 1 minute on days 1, 8, 15, and 22, dexamethasone PO or IV BID on
 days 1-28, pegaspargase IV over 1-2 hours or IM on day 4, and methotrexate IT on days 8 and
 29. Treatment continues for 35 days in the absence of disease progression or unacceptable
 toxicity.

 * After NON-DS B-LLy INDUCTION, all B-LLy patients then complete SR CONSOLIDATION.

 DS B-LLY INDUCTION: Patients receive cytarabine IT on day 1, vincristine IV push over 1
 minute on days 1, 8, 15, and 22, pegaspargase IV over 1-2 hours or IM on day 4, methotrexate
 IT on days 8 and 29, and leucovorin PO or IV every 6 hours for 2 doses on days 9 and 30.
 Additionally, patients under 10 years of age receive dexamethasone PO or IV BID on days 1-28,
 and patients 10 years of age or older receive PO or IV prednisone or methylprednisolone on
 days 1-28. Treatment continues for 35 days in the absence of disease progression or
 unacceptable toxicity.

 * After DS B-LLy INDUCTION, patients then complete SR CONSOLIDATION.

 SR CONSOLIDATION: Patients receive vincristine IV push over 1 minute on day 1, mercaptopurine
 PO on days 1-28, and methotrexate IT on days 1, 8, and 15. DS patients also receive
 leucovorin PO or IV every 6 hours for 2 doses on days 2, 9, and 16. Treatment continues for
 28 days in the absence of disease progression or unacceptable toxicity.

 * After SR CONSOLIDATION, patients with MRD undetectable are assigned to ARM A, and patients
 with MRD detectable/indeterminate/unavailable are randomized to ARM A or B. Patients with
 SR-Fav and all B-LLy patients are assigned to treatments identical to that in ARM A.

 HR CONSOLIDATION: Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29,
 cytarabine IV over 1-30 minutes or SC on days 1-4, 8-11, 29-32, and 36-39, vincristine IV
 push over 1 minute on days 15, 22, 43, and 50, mercaptopurine PO on days 1-14 and 29-42,
 methotrexate IT on days 1, 8, 15, and 22 , and pegaspargase IV over 1-2 hours or IM on days
 15 and 43. DS patients also receive leucovorin PO or IV every 6 hours for 2 doses on days 2,
 9, 16, and 23 (on days 2 and 9 only for DS CNS3 patients). Treatment continues for 56 days in
 the absence of disease progression or unacceptable toxicity. Patients with continued clinical
 evidence of DS or testicular leukemia (from diagnosis through the end of Induction) undergo
 testicular radiation therapy over 12 fractions once daily (QD).

 * After HR CONSOLIDATION, patients are randomized to ARM C or D. DS B-ALL patients with MRD <
 1% are assigned to an arm including three blocks of blinatumomab.

 ARM A:

 -  INTERIM MAINTENANCE I: Patients receive vincristine IV push over 1 minute on days 1, 11,
 21, 31, and 41, methotrexate IV over 2-5 minutes (undiluted) or 10-15 minutes (diluted)
 on days 1, 11, 21, 31, and 41, and methotrexate IT on day 31. DS patients also receive
 leucovorin PO or IV every 6 hours for 2 doses on day 32. Treatment continues for 56 days
 in the absence of disease progression or unacceptable toxicity.

 -  DELAYED INTENSIFICATION: Patients receive methotrexate IT on day 1 and 29, dexamethasone
 PO BID or IV on days 1-7 and 15-21, vincristine IV push over 1 minute on days 1, 8, and
 15, doxorubicin IV push/infusion over 1-15 minutes on days 1, 8, and 15, pegaspargase IV
 over 1-2 hours or IM on day 4, cyclophosphamide IV over 30-60 minutes on day 29,
 thioguanine PO on days 29-42, and cytarabine IV over 1-30 minutes or subcutaneously (SC)
 on days 29-32 and 36-39. DS patients receive leucovorin PO or IV every 6 hours for 2
 doses on days 2 and 30. Treatment continues for 56 days in the absence of disease
 progression or unacceptable toxicity.

 -  INTERIM MAINTENANCE II: Patients receive vincristine IV push over 1 minute on days 1,
 11, 21, 31, and 41, methotrexate IV over 2-5 minutes undiluted or 10-15 minutes diluted
 on days 1, 11, 21, 31, and 41, and methotrexate IT on days 1 and 31. DS patients receive
 leucovorin PO or IV every 6 hours for 2 doses on days 2 and 32. Treatment continues for
 56 days in the absence of disease progression or unacceptable toxicity.

 -  MAINTENANCE: Non-DS patients receive methotrexate IT on day 1, vincristine IV push over
 1 minute on day 1, dexamethasone PO on days 1-5, mercaptopurine PO on days 1-84, and
 methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. DS patients
 receive vincristine IV push over 1 minute on day 1, methotrexate IT on day 1,
 dexamethasone PO on days 1-5, mercaptopurine PO on days 1-84, and methotrexate PO on
 days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78, and leucovorin IV or PO on day 2 if
 DS. Treatment repeats every 84 days until a total duration of therapy of 2 years from
 start of INTERIM MAINTENANCE I is reached in the absence of disease progression or
 unacceptable toxicity.

 ARM B:

 -  BLINATUMOMAB BLOCK I: Patients receive dexamethasone IV or PO on day 1, methotrexate IT
 on day 1, and blinatumomab IV continuously on days 1-28. DS patients also receive
 leucovorin IV or PO every 6 hours for 2 doses on day 2. Treatment continues for 35 days
 in the absence of disease progression or unacceptable toxicity.

 -  INTERIM MAINTENANCE I: Patients receive vincristine IV push over 1 minute on days 1, 11,
 21, 31, and 41, methotrexate IV over 2-5 minutes (undiluted) or 10-15 minutes (diluted)
 on days 1, 11, 21, 31, and 41, and methotrexate IT on day 31. DS patients also receive
 leucovorin PO or IV every 6 hours for 2 doses on day 32. Treatment continues for 56 days
 in the absence of disease progression or unacceptable toxicity.

 -  BLINATUMOMAB BLOCK II: Patients receive methotrexate IT on day 1, and blinatumomab IV
 continuously on days 1-28. DS patients also receive leucovorin PO or IV every 6 hours
 for 2 doses on day 2. Treatment continues for 35 days in the absence of disease
 progression or unacceptable toxicity.

 -  DELAYED INTENSIFICATION: Patients receive methotrexate IT on day 1 and 29, dexamethasone
 PO or IV on days 1-7 and 15-21, vincristine IV push over 1 minute on days 1, 8, and 15,
 doxorubicin IV push/infusion over 1-15 minutes on days 1, 8, and 15, pegaspargase IV
 over 1-2 hours or IM on day 4, cyclophosphamide IV over 30-60 minutes on day 29,
 thioguanine PO on days 29-42, and cytarabine IV over 1-30 minutes or SC on days 29-32
 and 36-39. DS patients receive leucovorin PO or IV every 6 hours for 2 doses on days 2
 and 30. Treatment continues for 56 days in the absence of disease progression or
 unacceptable toxicity.

 -  INTERIM MAINTENANCE II: Patients receive vincristine IV push over 1 minute on days 1,
 11, 21, 31, and 41, methotrexate IV over 2-5 minutes (undiluted) or 10-15 minutes
 (diluted) on days 1, 11, 21, 31, and 41, and methotrexate IT on days 1 and 31. DS
 patients also receive leucovorin PO or IV every 6 hours for 2 doses on days 2 and 32.
 Treatment continues for 56 days in the absence of disease progression or unacceptable
 toxicity.

 -  MAINTENANCE: Non-DS patients receive methotrexate IT on day 1 (omit on final 2 cycles),
 vincristine IV push over 1 minute on day 1, dexamethasone PO on days 1-5, mercaptopurine
 PO on days 1-84, and methotrexate PO on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71,
 and 78 (omit day 1 on final 2 cycles). DS patients receive methotrexate IT on day 1
 (omit on final 2 cycles), dexamethasone PO on days 1-5, mercaptopurine PO on days 1-84,
 and methotrexate PO on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 (omit day 1
 except for final 2 cycles), for DS patients and leucovorin IV or PO every 6 hours for 2
 doses on day 2 (omit on final 2 cycles). Treatment repeats every 84 days until a total
 duration of therapy of 2 years from start of INTERIM MAINTENANCE I is reached in the
 absence of disease progression or unacceptable toxicity.

 ARM C:

 -  INTERIM MAINTENANCE I: Patients receive vincristine IV push over 1 minute on days 1, 15,
 29, and 43, high dose methotrexate IV on days 1, 15, 29, and 43, mercaptopurine PO on
 days 1-14, 15-28, 29-42, and 43-56, methotrexate IT on day 1 and 29, and leucovorin PO
 or IV on days 3-4, 17-18, 31-32, and 45-46. Treatment continues for 56 days in the
 absence of disease progression or unacceptable toxicity.

 -  DELAYED INTENSIFICATION: Patients receive methotrexate IT on day 1, dexamethasone PO BID
 or IV on days 1-7 and 15-21, vincristine IV over 1 minute on days 1, 8, 15, 43, and 50,
 doxorubicin IV over 1-15 minutes on days 1, 8, and 15, pegaspargase IV over 1-2 hours or
 IM on days 4 and 43, cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on
 days 29-42, and cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39. Treatment
 continues for 56 days in the absence of disease progression or unacceptable toxicity.

 -  INTERIM MAINTENANCE II: Patients receive vincristine IV over 1 minute on days 1, 11, 21,
 31, and 41, Capizzi style methotrexate IV over 2-5 minutes (undiluted) or over 10-15
 minutes (diluted) on days 1, 11, 21, 31, and 41, methotrexate IT on days 1 and 31, and
 pegaspargase IV over 1-2 hours or IM on days 2 and 22. Treatment continues for 56 days
 in the absence of disease progression or unacceptable toxicity.

 -  MAINTENANCE: Patients receive vincristine IV over 1 minute on day 1, prednisone or
 prednisolone or methylprednisolone PO or IV on days 1-5, mercaptopurine PO on days 1-84,
 methotrexate IT on days 1 and 29 of cycles 1-2 and on day 1 of subsequent cycles,
 methotrexate PO on days 8, 15, 22, 29 (for cycle 3 and later only), 36, 43, 50, 57, 64,
 71, and 78. Treatment repeats every 84 days until a total duration of therapy of 2 years
 from start of interim maintenance I is reached in the absence of disease progression or
 unacceptable toxicity.

 ARM D:

 -  BLINATUMOMAB BLOCK I: Patients receive dexamethasone PO or IV on day 1, methotrexate IT
 on day 1, and blinatumomab IV continuously on days 1-28. Treatment continues for 35 days
 in the absence of disease progression or unacceptable toxicity.

 -  INTERIM MAINTENANCE I: Patients receive vincristine IV over 1 minute on days 1, 15, 29,
 and 43, high dose methotrexate IV on days 1, 15, 29, and 43, mercaptopurine PO on days
 1-14, 15-28, 29-42, and 43-56, methotrexate IT on days 1 and 29, and leucovorin PO or IV
 on days 3-4, 17-18, 31-32, and 45-46. Treatment continues for 56 days in the absence of
 disease progression or unacceptable toxicity.

 -  BLINATUMOMAB BLOCK II: Patients receive blinatumomab IV on days 1-28 and methotrexate IT
 on day 1. Treatment continues for 35 days in the absence of disease progression or
 unacceptable toxicity.

 -  DELAYED INTENSIFICATION: Patients receive methotrexate IT on day 1, dexamethasone PO or
 IV on days 1-7 and 15-21, vincristine IV over 1 minute on days 1, 8, 15, 43, and 50,
 doxorubicin IV over 1-15 minutes on days 1, 8, and 15, pegaspargase IV over 1-2 hours or
 IM on days 4 and 43, cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on
 days 29-42, and cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39. Treatment
 continues for 56 days in the absence of disease progression or unacceptable toxicity.

 -  INTERIM MAINTENANCE II: Patients receive vincristine IV over 1 minute on days 1, 11, 21,
 31, and 41, Capizzi style methotrexate IV over 2-5 minutes (undiluted) or over 10-15
 minutes (diluted) on days 1, 11, 21, 31, and 41, methotrexate IT on days 1 and 31, and
 pegaspargase IV over 1-2 hours or IM on days 2 and 22. Treatment continues for 56 days
 in the absence of disease progression or unacceptable toxicity.

 -  MAINTENANCE: Patients receive methotrexate IT on day 1, vincristine IV over 1 minute on
 day 1, prednisone, prednisolone or methylprednisolone PO or IV on days 1-5,
 mercaptopurine PO on days 1-84, and methotrexate PO on days 8, 15, 22, 29, 36, 43, 50,
 57, 64, 71, and 78. Treatment repeats every 84 days until a total duration of therapy of
 2 years from start of interim maintenance I is reached in the absence of disease
 progression or unacceptable toxicity.

 DS-HIGH B-ALL:

 -  BLINATUMOMAB BLOCK I: Patients receive dexamethasone PO or IV on day 1, blinatumomab IV
 continuously on days 1-28, methotrexate IT on day 1 (or on day 56 of Consolidation), and
 leucovorin PO or IV every 6 hours for 2 doses on day 2. Treatment continues for 35 days
 in the absence of disease progression or unacceptable toxicity.

 -  INTERIM MAINTENANCE: Patients receive vincristine IV push over 1 minute on days 1, 15,
 29, and 43, intermediate dose methotrexate IV over 24 hours on days 1, 15, 29, and 43,
 mercaptopurine PO on days 1-14, 15-28, 29-42, and 43-46, methotrexate IT on days 1 and
 29, and leucovorin PO or IV every 6 hours for 2 doses on days 2-4, 16-18, 30-32, and
 44-46. Treatment continues for 63 days in the absence of disease progression or
 unacceptable toxicity.

 -  BLINATUMOMAB BLOCK II: Patients receive blinatumomab IV on days 1-28, methotrexate IT on
 day 1, and leucovorin PO or IV every 6 hours for 2 doses on day 2. Treatment continues
 for 35 days in the absence of disease progression or unacceptable toxicity.

 -  DELAYED INTENSIFICATION: Patients receive vincristine IV over 1 minute on days 1, 8, and
 15, doxorubicin IV over 1-15 minutes on days 1, 8, and 15, dexamethasone PO or IV on
 days 1-7 and 15-21, methotrexate IT on day 1, leucovorin PO or IV every 6 hours for 2
 doses on day 2, and pegaspargase IV over 1-2 hours or IM on day 4. Treatment continues
 for 28 days in the absence of disease progression or unacceptable toxicity.

 -  BLINATUMOMAB BLOCK III: Patients receive blinatumomab IV on days 1-28, methotrexate IT
 on day 1, and leucovorin PO or IV every 6 hours for 2 doses on day 2. Treatment
 continues for 35 days in the absence of disease progression or unacceptable toxicity.

 -  MAINTENANCE: Patients receive vincristine IV push over 1 minute on day 1, prednisone,
 prednisolone or methylprednisolone PO or IV BID on days 1-5, mercaptopurine PO on days
 1-84, methotrexate IT on day 1, methotrexate PO on days 8, 15, 22, 29 (omit day 29 for
 first 3 cycles for patients who do not receive cranial radiotherapy), 36, 43, 50, 57,
 64, 71, and 78, and leucovorin PO on days 2 and 30 (day 30 dose is for cycles 1-3 and
 for patients who do not receive cranial radiotherapy). CNS3 patients receive cranial
 radiotherapy during first 4 weeks of cycle 1. Treatment repeats every 84 days until a
 total duration of therapy of 2 years from start of interim maintenance I is reached in
 the absence of disease progression or unacceptable toxicity.

 All B-LLy patients:

 -  INTERIM MAINTENANCE I: Patients receive vincristine IV push over 1 minute on days 1, 11,
 21, 31, and 41, methotrexate IV over 2-5 minutes (undiluted) or 10-15 (diluted) on days
 1, 11, 21, 31, and 41, and methotrexate IT on day 31. DS patients also receive
 leucovorin PO or IV every 6 hours for 2 doses on day 32. Treatment continues for 56 days
 in the absence of disease progression or unacceptable toxicity.

 -  DELAYED INTENSIFICATION: Patients receive vincristine IV push over 1 minute on days 1, 8
 and 15, doxorubicin IV over 1-15 minutes on days 1, 8, and 15, dexamethasone PO or IV on
 days 1-7 and 15-21, methotrexate IT on days 1 and 29, pegaspargase IV over 1-2 hours or
 IM on day 4, cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on days
 29-42, and cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39. DS patients
 additionally receive leucovorin PO or IV every 6 hours for 2 doses on days 2 and 30.
 Treatment continues for 56 days in the absence of disease progression or unacceptable
 toxicity.

 -  INTERIM MAINTENANCE II: Patients receive vincristine IV push over 1 minute on days 1,
 11, 21, 31, and 41, methotrexate IV over 2-5 minutes (undiluted) or 10-15 minutes
 (diluted) on days 1, 11, 21, 31, and 41, and methotrexate IT on days 1 and 31. DS
 patients also receive leucovorin PO or IV every 6 hours for 2 doses on days 2 and 32.
 Treatment continues for 56 days in the absence of disease progression or unacceptable
 toxicity.

 -  MAINTENANCE: Patients receive vincristine IV push over 1 minute on day 1, dexamethasone
 PO on days 1-5, mercaptopurine PO on days 1-84, methotrexate IT on day 1, and
 methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. DS patients also
 receive leucovorin PO or IV every 6 hours for 2 doses on day 2. Treatment repeats every
 84 days until a total duration of therapy of 2 years from start of interim maintenance I
 is reached in the absence of disease progression or unacceptable toxicity.

 After completion of study treatment, patients are followed up every 4 weeks until complete
 blood count(CBC)/differential/platelet count recovery, then every 3 months for the first 2
 years, then every 4-6 months for the 3rd year, and every 6-12 months for the 4th and 5th
 years.
Inclusion Criteria:

 -  All B-ALL patients must be enrolled on APEC14B1 and consented to Eligibility Screening
 (Part A) prior to treatment and enrollment on AALL1731. APEC 14B1 is not a requirement
 for B-LLy patients. B-LLy patients may directly enroll on AALL1731.

 -  Age at diagnosis:

 -  Patients must be >= 365 days and < 10 years of age (B-ALL patients without DS).

 -  Patients must be >= 365 days and =< 31 years of age (B-ALL patients with DS).

 -  Patients must be >= 365 days and =< 31 years of age (B-LLy patients with or
 without DS).

 -  B-ALL patients without DS must have an initial white blood cell count < 50,000/uL
 (performed within 7 days prior to enrollment).

 -  B-ALL patients with DS are eligible regardless of the presenting white blood cell
 count (WBC) (performed within 7 days prior to enrollment).

 -  Patient has newly diagnosed B-cell ALL, with or without Down syndrome: > 25% blasts on
 a bone marrow (BM) aspirate;

 -  OR if a BM aspirate is not obtained or is not diagnostic of B-ALL, the diagnosis
 can be established by a pathologic diagnosis of B-ALL on a BM biopsy;

 -  OR a complete blood count (CBC) documenting the presence of at least 1,000/uL
 circulating leukemic cells;

 -  OR patient has newly diagnosed B-cell LLy Murphy stages I or II, with or without
 Down syndrome.

 -  Note: For B-LLy patients with tissue available for flow cytometry, the criterion
 for diagnosis should be analogous to B-ALL. For tissue processed by other means
 (i.e., paraffin blocks), the methodology and criteria for immunophenotypic
 analysis to establish the diagnosis of B-LLy defined by the submitting
 institution will be accepted (diagnostic biopsy for B-LLy must be performed
 within 14 days prior to enrollment).

 -  All institutional, Food and Drug Administration (FDA), and National Cancer Institute
 (NCI) requirements for human studies must be met.

 -  All patients and/or their parents or legal guardians must sign a written informed
 consent.

 Exclusion Criteria:

 -  Patient must not have secondary ALL that developed after treatment of a prior
 malignancy with cytotoxic chemotherapy. Note: patients with Down syndrome with a prior
 history of transient myeloproliferative disease (TMD) are not considered to have had a
 prior malignancy. They would therefore be eligible whether or not the TMD was treated
 with cytarabine.

 -  With the exception of steroid pretreatment or the administration of intrathecal
 cytarabine, patients must not have received any prior cytotoxic chemotherapy for
 either the current diagnosis of B ALL or B LLy or for any cancer diagnosed prior to
 initiation of protocol therapy on AALL1731.

 -  For patients receiving steroid pretreatment, the following additional exclusion
 criteria apply:

 -  Non-DS B-ALL patients must not have received steroids for more than 24 hours in
 the 2 weeks prior to diagnosis without a CBC obtained within 3 days prior to
 initiation of the steroids.

 -  DS and non-DS B-LLy patients must not have received > 48 hours of oral or IV
 steroids within 4 weeks of diagnosis.

 -  Patients who have received > 72 hours of hydroxyurea.

 -  B-ALL patients who do not have sufficient diagnostic bone marrow submitted for
 APEC14B1 diagnostic testing and who do not have a peripheral blood sample submitted
 containing > 1,000/uL circulating leukemia cells.

 -  Patient must not have acute undifferentiated leukemia (AUL).

 -  Non-DS B-ALL patients with central nervous system [CNS]3 leukemia (CNS status must be
 known prior to enrollment).

 -  Note: DS patients with CNS3 disease are eligible but will be assigned to the
 DS-High B-ALL arm. CNS status must be determined based on a sample obtained prior
 to administration of any systemic or intrathecal chemotherapy, except for steroid
 pretreatment.

 -  Non-DS B-ALL patients with testicular leukemia. (Note: DS patients with testicular
 disease are eligible but will be assigned to the DS-High B-ALL arm).

 -  For LLy patients, the following additional exclusion criteria apply:

 -  T-Lymphoblastic Lymphoma.

 -  Morphologically unclassifiable lymphoma.

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

 -  CNS positive disease or testicular involvement.

 -  M2 (5% - 25% blasts) or M3 (> 25% blasts) marrow.

 -  Patients with known Charcot-Marie-Tooth disease.

 -  Patients with known MYC translocation associated with mature (Burkitt) B-cell ALL,
 regardless of blast immunophenotype.

 -  Patients requiring radiation at diagnosis.

 -  Female patients who are pregnant since fetal toxicities and teratogenic effects have
 been noted for several of the study drugs. A pregnancy test is required for female
 patients of childbearing potential.

 -  Lactating females who plan to breastfeed their infants.

 -  Sexually active patients of reproductive potential who have not agreed to use an
 effective contraceptive method for the duration of their study participation.