Inotuzumab Ozogamicin and Post-Induction Chemotherapy in Treating Patients With High-Risk B-ALL, Mixed Phenotype Acute Leukemia, and B-LLy
Inotuzumab Ozogamicin and Post-Induction Chemotherapy in Treating Patients With High-Risk B-ALL, Mixed Phenotype Acute Leukemia, and B-LLy
This phase III trial studies whether inotuzumab ozogamicin added to post-induction
 chemotherapy for patients with High-Risk B-cell Acute Lymphoblastic Leukemia (B-ALL) improves
 outcomes. This trial also studies the outcomes of patients with mixed phenotype acute
 leukemia (MPAL), and B-lymphoblastic lymphoma (B-LLy) when treated with ALL therapy without
 inotuzumab ozogamicin. Inotuzumab ozogamicin is a monoclonal antibody, called inotuzumab,
 linked to a type of chemotherapy called calicheamicin. Inotuzumab attaches to cancer cells in
 a targeted way and delivers calicheamicin to kill them. Other drugs used in the chemotherapy
 regimen, such as cyclophosphamide, cytarabine, dexamethasone, doxorubicin, daunorubicin,
 methotrexate, leucovorin, mercaptopurine, prednisone, thioguanine, vincristine, and
 pegaspargase 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. This trial will
 also study the outcomes of patients with mixed phenotype acute leukemia (MPAL) and
 disseminated B lymphoblastic lymphoma (B-LLy) when treated with high-risk ALL chemotherapy.

 The overall goal of this study is to understand if adding inotuzumab ozogamicin to standard
 of care chemotherapy maintains or improves outcomes in High Risk B-cell Acute Lymphoblastic
 Leukemia (HR B-ALL). The first part of the study includes the first two phases of therapy:
 Induction and Consolidation. This part will collect information on the leukemia, as well as
 the effects of the initial treatment, in order to classify patients into post-consolidation
 treatment groups. On the second part of this study, patients will receive the remainder of
 the chemotherapy cycles (interim maintenance I, delayed intensification, interim maintenance
 II, maintenance), with some patients randomized to receive inotuzumab. Other aims of this
 study include investigating whether treating both males and females with the same duration of
 chemotherapy maintains outcomes for males who have previously been treated for an additional
 year compared to girls, as well as to evaluate the best ways to help patients adhere to oral
 chemotherapy regimens. Finally, this study will be the first to track the outcomes of
 subjects with disseminated B-cell Lymphoblastic Leukemia (B LLy) or Mixed Phenotype Acute
 Leukemia (MPAL) when treated with B-ALL chemotherapy.
PRIMARY OBJECTIVE:

 I. To determine in a randomized manner if the addition of 2 blocks of inotuzumab ozogamicin
 to modified Berlin-Frankfurt-Munster (mBFM) chemotherapy will improve 5-year disease-free
 survival (DFS) in children and young adults with high-risk B-cell acute lymphoblastic
 leukemia (HR B-ALL).

 SECONDARY OBJECTIVES:

 I. To describe the 5-year DFS for a favorable risk subset of National Cancer Institute (NCI)
 HR B-ALL (HR-Fav) when treated with mBFM chemotherapy with a single high-dose methotrexate
 (HD-MTX) interim maintenance (IM) phase and treatment duration of 2 years from the start of
 IM regardless of sex.

 II. To determine the toxicity and tolerability of inotuzumab ozogamicin integrated into the
 mBFM chemotherapy backbone in HR B-ALL.

 III. To describe the 5-year event-free survival (EFS) for patients with mixed phenotype acute
 leukemia (MPAL) receiving mBFM HR B-ALL therapy that includes a second IM phase with Capizzi
 escalating intravenous (IV) methotrexate (MTX) without leucovorin rescue plus pegaspargase
 (C-MTX).

 IV. To describe the 5-year EFS for patients with disseminated (Murphy stage III-IV) B-cell
 lymphoblastic lymphoma (B-LLy) receiving mBFM HR B-ALL therapy that includes a second IM
 phase with C-MTX.

 EXPLORATORY OBJECTIVES:

 I. To describe the therapy administered, disease response, and survival outcomes of patients
 with MPAL who come off protocol therapy due to poor disease response to ALL therapy either
 during Induction, at end of induction (EOI), or at end of consolidation (EOC).

 II. To define the prevalence and significance of minimal marrow disease (MMD) at diagnosis
 and bone marrow minimal residual disease (MRD) at EOI in disseminated B-LLy.

 III. To determine the impact of proposed adherence-enhancing interventions on adherence to
 oral 6-mercaptopurine in patients with ALL.

 OUTLINE: All patients receive the same Induction and Consolidation chemotherapy. Patients
 with HR-Fav B-ALL are assigned to Arm I. Patients with HR B-ALL are randomized to Arm II or
 III. Patients with MPAL are assigned to Arm IV, and patients with B-LLy are assigned to Arm
 V.

 All patients with B-ALL receive Induction and Consolidation therapy:

 INDUCTION: Patients receive cytarabine intrathecally (IT) on day 1 and central nervous system
 (CNS)2 patients also receive cytarabine IT on days 4, 5 or 6 and 11 or 12. Patients also
 receive vincristine intravenously (IV) or IV push over 1 minute on days 1, 8, 15, and 22,
 daunorubicin IV over 1-15 minutes days 1, 8, 15, and 22, pegaspargase intramuscularly (IM) or
 IV over 1-2 hours on day 4, and methotrexate IT on days 8 and 29 (and on days 15 and 22 for
 CNS3 patients). Patients < 10 years old receive dexamethasone orally (PO) twice daily (BID)
 or IV on days 1-14; patients >= 10 years old receive prednis(ol)one PO BID or IV on days
 1-28. Treatment continues for 5 weeks in the absence of disease progression or unacceptable
 toxicity.

 CONSOLIDATION: Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29,
 cytarabine IV over 1-30 minutes or subcutaneously (SC) on days 1-4, 8-11, 29-32, and 36-39,
 mercaptopurine PO once daily (QD) on days 1-14 and 29-42, and methotrexate IT on days 1, 8,
 15, and 22 (CNS3 patients receive methotrexate IT on days 1 and 8). Patients also receive
 vincristine IV or IV push over 1 minute on days 15, 22, 43, and 50, and pegaspargase IV over
 1-2 hours or IM on days 15 and 43. Treatment continues for 8 weeks in the absence of disease
 progression or unacceptable toxicity. Additionally, patients with testicular disease at
 diagnosis that does not resolve by the end of induction will undergo radiation therapy over
 12 once daily fractions.

 POST-CONSOLIDATION THERAPY: After Consolidation, based on clinical features and response,
 patients with B-ALL are designated as HR-Fav or HR B-ALL. Patients with HR-Fav B-ALL are
 assigned to Arm I. Patients with HR B-ALL are randomized to Arm II or III. Patients with MPAL
 and B-LLy are assigned to therapy arms (Arms IV and V) that are identical to Arm II. Patients
 that are < 10 years, have CNS1, no testicular leukemia, with favorable cytogenetics (ETV6
 RUNX1 fusion or double trisomies [4 and 10]), =< 24 hours of steroids in the two weeks prior
 to diagnosis, and EOI MRD < 0.01% are assigned to Arm I. Patients with HR B-ALL who are
 surface CD22 positive at diagnosis and have MRD < 0.01% by the end of Consolidation, are
 randomized to either Arm II or III.

 ARM I: HR-FAV B-ALL (Patients that are < 10 years, have CNS1 status, no testicular leukemia,
 with favorable cytogenetics (ETV6 RUNX1 fusion or double trisomies [4 and 10]), =< 24 hours
 of steroids in the two weeks prior to diagnosis, and EOI MRD < 0.01%)

 INTERIM MAINTENANCE: Patients receive vincristine IV or IV push over 1 minute on days 1, 15,
 29, and 43, high dose methotrexate IV over 24 hours on days 1, 15, 29, and 43, leucovorin PO
 or IV on days 3-4, 17-18, 31-32, and 45-46, mercaptopurine PO QD on days 1-14, 15-28, 29-42,
 and 43-56, and methotrexate IT on days 1 and 29. Treatment continues for 9 weeks in the
 absence of disease progression or unacceptable toxicity.

 DELAYED INTENSIFICATION (PART I): Patients receive methotrexate IT on day 1, dexamethasone PO
 BID or IV on days 1-7 and 15-21, vincristine IV or IV push over 1 minute on days 1, 8, and
 15, doxorubicin IV over 1-15 minutes or up to 1 hour on days 1, 8, and 15, and pegaspargase
 IV over 1-2 hours or IM on day 4. Treatment (Parts I and II of Delayed Intensification)
 continues for 8 weeks in the absence of disease progression or unacceptable toxicity.

 DELAYED INTENSIFICATION (PART II): Patients receive cyclophosphamide IV over 30-60 minutes on
 day 29, thioguanine PO on days 29-42, cytarabine IV over 1-30 minutes or SC on days 29-32 and
 36-39, methotrexate IT on days 29 and 36, vincristine IV or IV push over 1 minute on days 43
 and 50, and pegaspargase IV over 1-2 hours or IM on day 43. Treatment (Parts I and II of
 Delayed Intensification) continues for 8 weeks in the absence of disease progression or
 unacceptable toxicity.

 MAINTENANCE: Patients receive methotrexate IT on days 1 and 29 for cycles 1-4, and day 1 for
 subsequent cycles. Patients also receive vincristine IV or IV push over 1 minute on day 1,
 prednisolone PO BID or IV on days 1-5, mercaptopurine PO QD on days 1-84, and methotrexate PO
 on days 8, 15, 22, (29 excluded in cycles 1-4), 36, 43, 50, 57, 64, 71, and 78. Cycles repeat
 every 12 weeks for up to 2 years in the absence of disease progression or unacceptable
 toxicity.

 Patients with HR B-ALL who have MRD < 0.01% by the end of Consolidation, and leukemic blasts
 positive for surface CD22 at diagnosis are randomized to Arm II or Arm III.

 ARM II: HR B-ALL (CONTROL) INTERIM MAINTENANCE I: Patients receive vincristine IV or IV push
 over 1 minute on days 1, 15, 29 and 43, high dose methotrexate IV over 24 hours on days 1,
 15, 29 and 43, leucovorin PO or IV on days 3-4, 17-18, 31-32, 45-46, mercaptopurine PO QD on
 days 1-14, 15-28, 29-42, and 43-56, and methotrexate IT on days 1 and 29. Treatment continues
 for 9 weeks in the absence of disease progression or unacceptable toxicity.

 DELAYED INTENSIFICATION (PART I): Patients receive methotrexate IT on day 1, dexamethasone PO
 BID or IV on days 1-7 and 15-21, vincristine IV or IV push over 1 minute on days 1, 8, and
 15, doxorubicin IV over 1-15 minutes or up to 1 hour on days 1, 8, and 15, and pegaspargase
 IV over 1-2 hours or IM on day 4. Treatment (Parts I and II of Delayed Intensification)
 continues for 8 weeks in the absence of disease progression or unacceptable toxicity.

 DELAYED INTENSIFICATION (PART II): Patients receive cyclophosphamide IV over 30-60 minutes on
 day 29, thioguanine PO on days 29-42, cytarabine IV over 1-30 minutes or SC on days 29-32 and
 36-39, methotrexate IT on days 29 and 36, vincristine IV or IV push over 1 minute on days 43
 and 50, and pegaspargase IV over 1-2 hours or IM on day 43. Treatment (Parts I and II of
 Delayed Intensification) continues for 8 weeks in the absence of disease progression or
 unacceptable toxicity.

 INTERIM MAINTENANCE II: Patients receive vincristine IV or IV push over 1 minute on days 1,
 11, 21, 31 and 41, methotrexate IV over 2-15 minutes or 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 or IM on days 2
 and 22. Treatment continues for 8 weeks in the absence of disease progression or unacceptable
 toxicity.

 ARM III: HR B-ALL (EXPERIMENTAL) INOTUZUMAB OZOGAMICIN (InO) BLOCK 1: Patients receive
 inotuzumab ozogamicin IV over 60 minutes on days 1, 8, and 15 and methotrexate IT on day 1.
 Treatment continues for 4 weeks in the absence of disease progression or unacceptable
 toxicity.

 INTERIM MAINTENANCE I: Patients receive vincristine IV or IV push over 1 minute on days 1,
 15, 29 and 43, high dose methotrexate IV over 24 hours on days 1, 15, 29, and 43, leucovorin
 PO or IV on days 3-4, 17-18, 31-32, and 45-46, mercaptopurine PO on days 1-14, 15-28, 29-42,
 and 43-56, and methotrexate IT on days 1 and 29. Treatment continues for 9 weeks in the
 absence of disease progression or unacceptable toxicity.

 InO BLOCK 2: Patients receive inotuzumab ozogamicin IV over 60 minutes on days 1, 8, and 15.
 Treatment continues for 4 weeks in the absence of disease progression or unacceptable
 toxicity.

 DELAYED INTENSIFICATION (PART I): Patients receive methotrexate IT on day 1, dexamethasone PO
 BID or IV on days 1-7 and 15-21, vincristine IV or IV push over 1 minute on days 1, 8, and
 15, doxorubicin IV over 1-15 minutes or up to 1 hour on days 1, 8, and 15, and pegaspargase
 IV over 1-2 hours or IM on day 4. Treatment (Parts I and II of Delayed Intensification)
 continues for 8 weeks in the absence of disease progression or unacceptable toxicity.

 DELAYED INTENSIFICATION (PART II): Patients receive cyclophosphamide IV over 30-60 minutes on
 day 29, thioguanine PO on days 29-42, cytarabine IV over 1-30 minutes or SC on days 29-32 and
 36-39, methotrexate IT on days 29 and 36, vincristine IV or IV push over 1 minute on days 43
 and 50, and pegaspargase IV over 1-2 hours or IM on day 43. Treatment (Parts I and II of
 Delayed Intensification) continues for 8 weeks in the absence of disease progression or
 unacceptable toxicity.

 INTERIM MAINTENANCE II: Patients receive vincristine IV or IV push over 1 minute on days 1,
 11, 21, 31, and 41, methotrexate IV 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 8
 weeks in the absence of disease progression or unacceptable toxicity.

 ARMS II AND III: HR B-ALL MAINTENANCE: Patients receive vincristine IV or IV push over 1
 minute on day 1, prednisolone PO BID or IV on days 1-5, mercaptopurine PO on days 1-84,
 methotrexate PO on days 8, 15, 22, 29 (excluded in cycles 1 and 2), 36, 43, 50, 57, 64, 71
 and 78, and methotrexate IT on days 1 (and 29 of cycles 1-2 for patients who do not receive
 cranial radiation). Cycles repeat every 12 weeks for up to 2 years in the absence of disease
 progression or unacceptable toxicity. Patients with CNS3 disease undergo cranial radiation
 therapy over 10 fractions during the first 4 weeks.

 ARM IV: MPAL INDUCTION: Patients receive cytarabine IT on day 1 and CNS2 patients also
 receive cytarabine IT on days 4, 5 or 6 and 11 or 12. Patients also receive vincristine IV or
 IV push over 1 minute on days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes days 1, 8,
 15, and 22, pegaspargase IM or IV over 1-2 hours on day 4, and methotrexate IT on days 8 and
 29 (and on days 15 and 22 for CNS3 patients). Patients < 10 years old receive dexamethasone
 PO BID or IV on days 1-14; patients >= 10 years old receive prednisolone PO BID or IV on days
 1-28. Treatment continues for 5 weeks in the absence of disease progression or unacceptable
 toxicity.

 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, mercaptopurine PO
 on days 1-14 and 29-42, methotrexate IT on days 1, 8, 15, and 22 (excluded on days 15 and 22
 for CNS3 patients), vincristine IV or IV push over 1 minute on days 15, 22, 43, and 50, and
 pegaspargase IV over 1-2 hours or IM on days 15 and 43. Treatment continues for 8 weeks in
 the absence of disease progression or unacceptable toxicity. Patients with testicular disease
 at diagnosis that does not resolve by the end of induction will and continued evidence of
 testicular disease at end of induction undergo testicular radiation over 12 once-daily
 fractions.

 ARM V: B-LLY INDUCTION: Patients receive cytarabine IT on day 1 and CNS2 patients also
 receive cytarabine IT on days 4, 5 or 6 and 11 or 12. Patients also receive vincristine IV or
 IV push over 1 minute on days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes days 1, 8,
 15, and 22, pegaspargase IM or IV over 1-2 hours on day 4, and methotrexate IT on days 8 and
 29 (and on days 15 and 22 for CNS3 patients). Patients < 10 years old receive dexamethasone
 PO BID or IV on days 1-14; patients >= 10 years old receive prednisolone PO BID or IV on days
 1-28. Treatment continues for 5 weeks in the absence of disease progression or unacceptable
 toxicity.

 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, mercaptopurine PO
 on days 1-14 and 29-42, methotrexate IT on days 1, 8, 15, and 22 (excluded on days 15 and 22
 CNS3 patients), vincristine IV or IV push over 1 minute on days 15, 22, 43, and 50, and
 pegaspargase IV over 1-2 hours or IM on days 15 and 43. Treatment continues for 8 weeks in
 the absence of disease progression or unacceptable toxicity. Patients with testicular disease
 at diagnosis that does not resolve by the end of induction will and continued evidence of
 testicular disease at end of induction undergo testicular radiation therapy over 12
 once-daily fractions.

 ARM IV AND V: MPAL AND B-LLY (Post-Consolidation Therapy) INTERIM MAINTENANCE I: Patients
 receive vincristine IV or IV push over 1 minute on days 1, 15, 29, and 43, high dose
 methotrexate IV over 24 hours on days 1, 15, 29, and 43, leucovorin PO or IV on days 3-4,
 17-18, 31-32, and 45-46, methotrexate IT on days 1 and 29 and mercaptopurine PO QD on days
 1-14, 15-28, 29-42, and 43-56. Treatment continues for 9 weeks in the absence of disease
 progression or unacceptable toxicity.

 DELAYED INTENSIFICATION (PART I): Patients receive methotrexate IT on day 1, dexamethasone PO
 BID or IV on days 1-7 and 15-21, vincristine IV or IV push over 1 minute on days 1, 8, and
 15, doxorubicin IV over 1-15 minutes or up to 1 hour on days 1, 8, and 15, and pegaspargase
 IV over 1-2 hours or IM on day 4. Treatment (Parts I and II of Delayed Intensification)
 continues for 8 weeks in the absence of disease progression or unacceptable toxicity.

 DELAYED INTENSIFICATION (PART II): Patients receive cyclophosphamide IV over 30-60 minutes on
 day 29, thioguanine PO on days 29-42, cytarabine IV over 1-30 minutes or SC on days 29-32 and
 36-39, methotrexate IT on days 29 and 36, vincristine IV or IV push over 1 minute on days 43
 and 50, and pegaspargase IV over 1-2 hours or IM on day 43. Treatment (Parts I and II of
 Delayed Intensification) continues for 8 weeks in the absence of disease progression or
 unacceptable toxicity.

 INTERIM MAINTENANCE II: Patients receive vincristine IV or IV push over 1 minute on days 1,
 11, 21, 31, and 41, methotrexate IV or infusion over 2-15 minutes or 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 or
 IM on days 2 and 22. Treatment continues for 8 weeks in the absence of disease progression or
 unacceptable toxicity.

 MAINTENANCE: Patients receive vincristine IV or IV push over 1 minute on days 1, prednisolone
 PO BID or IV on days 1-5, mercaptopurine PO on days 1-84, methotrexate PO on days 8, 15, 22,
 29 (excluded in cycles 1 and 2), 36, 43, 50, 57, 64, 71, and 78, and methotrexate IT on days
 1 (and 29 of cycles 1-2 for patients who do not receive cranial radiation). Cycles repeat
 every 12 weeks for up to 2 years in the absence of disease progression or unacceptable
 toxicity. Patients with CNS3 disease at diagnosis undergo cranial radiation therapy for 10
 fractions over 4 weeks.

 After completion of study treatment, patients are followed up at 4 weeks, then every 3 months
 for 2 years, every 4-6 months for the third year, then every 6-12 months for years 4-5.
Inclusion Criteria:

 -  B-ALL and MPAL patients must be enrolled on APEC14B1 and consented to eligibility
 studies (Part A) prior to treatment and enrollment on AALL1732. Note that central
 confirmation of MPAL diagnosis must occur within 7 business days after enrollment for
 MPAL patients. If not performed within this time frame, patients will be taken off
 protocol.

 -  APEC14B1 is not a requirement for B-LLy patients but for institutional compliance
 every patient should be offered participation in APEC14B1. B-LLy patients may directly
 enroll on AALL1732.

 -  White blood cell count (WBC) criteria for patients with B-ALL (within 7 days prior to
 the start of protocol-directed systemic therapy):

 -  Age 1-9.99 years: WBC >= 50,000/uL

 -  Age 10-24.99 years: Any WBC

 -  Age 1-9.99 years: WBC < 50,000/uL with:

 -  Testicular leukemia

 -  CNS leukemia (CNS3)

 -  Steroid pretreatment.

 -  White blood cell count (WBC) criteria for patients with MPAL (within 7 days prior to
 the start of protocol-directed systemic therapy):

 -  Age 1-24.99 years: any WBC.

 -  Patient has newly diagnosed B-ALL or MPAL (by World Health Organization [WHO] 2016
 criteria) with > 25% blasts on a bone marrow (BM) aspirate;

 -  OR If a BM aspirate is not obtained or is not diagnostic of acute leukemia, the
 diagnosis can be established by a pathologic diagnosis of acute leukemia on a BM
 biopsy;

 -  OR A complete blood count (CBC) documenting the presence of at least 1,000/uL
 circulating leukemic cells if a bone marrow aspirate or biopsy cannot be
 performed.

 -  Patient has newly diagnosed B-LLy Murphy stages III or IV.

 -  Patient has newly diagnosed B-LLy Murphy stages I or II with steroid pretreatment.

 -  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.

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

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

 Exclusion Criteria:

 -  Patients with Down syndrome are not eligible (patients with Down syndrome and B-ALL
 are eligible for AALL1731, regardless of NCI risk group).

 -  With the exception of steroid pretreatment or the administration of intrathecal
 cytarabine, patients must not have received any prior cytotoxic chemotherapy for the
 current diagnosis of B-ALL, MPAL, or B-LLy or for any cancer diagnosed prior to
 initiation of protocol therapy on AALL1732.

 -  Patients who have received > 72 hours of hydroxyurea within one week prior to start of
 systemic protocol therapy.

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

 -  Patients with acute undifferentiated leukemia (AUL) are not eligible.

 -  For Murphy stage III/IV B-LLy patients, or stage I/II patients with steroid
 pretreatment, 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.

 -  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 women who plan to breastfeed their infants while on study and for 2 months
 after the last dose of inotuzumab ozogamicin.

 -  Sexually active patients of reproductive potential who have not agreed to use an
 effective contraceptive method for the duration of study participation. For those
 patients randomized to inotuzumab ozogamicin, there is a minimum of 8 months after the
 last dose of inotuzumab ozogamicin for females and 5 months after the last dose of
 inotuzumab ozogamicin for males.