Inotuzumab Ozogamicin and Post-Induction Chemotherapy in Treating Patients With High-Risk B-ALL, Mixed Phenotype Acute Leukemia, and B-LLy

PRIMARY OBJECTIVE:

I. To compare in a randomized manner the post-induction 5-year event-free survival (EFS) for children and young adults with High Risk (HR) B-cell acute lymphoblastic leukemia (B-ALL) treated with a modified Berlin-Frankfurt-Münster (mBFM) chemo-immunotherapy backbone that includes blinatumomab and replaces Consolidation Part 2 and Delayed Intensification (DI) Part 2 with two blocks of inotuzumab ozogamicin, versus those treated with a full mBFM chemo-immunotherapy backbone that includes blinatumomab and retains Consolidation Part 2 and DI Part 2 without the addition of inotuzumab ozogamicin.

SECONDARY OBJECTIVES:

I. To describe the 5-year disease-free survival (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. (Pre-Amendment #7B) II. To determine the toxicity and tolerability of inotuzumab ozogamicin integrated into the mBFM chemotherapy backbone in HR B-ALL, including toxicity experienced during phases of therapy subsequent to inotuzumab ozogamicin.

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 intravenous (IV) methotrexate without leucovorin rescue plus pegaspargase or calaspargase pegol (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.

V. To compare health-related quality of life (HRQoL) for randomized HR B-ALL patients by study arm at two defined time points: Consolidation Part 2 Day 43 (Arm D)/inotuzumab ozogamicin Block 1 Day 15 (Arm E) and day 1 of IM2 (Arms D and E).

VI. To compare symptomatic adverse events (AEs) for patients with HR B-ALL by study arm using Patient Reported Outcome (PRO) Measures.

EXPLORATORY OBJECTIVES:

I. To describe the 5-year overall survival (OS) and cumulative incidence of relapse (CIR) for randomized patients with HR B-ALL.

II. 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).

III. 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.

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

V. To characterize the pharmacokinetics (PK) of inotuzumab ozogamicin when administered in the setting of first remission in pediatric and young adult patients with HR B-ALL.

VI. To explore associations between family-reported social determinants of health and survival outcomes, toxicities, and blinatumomab patterns of delivery.

VII. To describe both the short- and long-term impact of chemo-immunotherapy on measures of immune function and infectious toxicities.

OUTLINE:

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

INDUCTION: Patients receive cytarabine intrathecally (IT) on day 1. Patients also receive vincristine intravenously (IV) on days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes days 1, 8, 15, and 22, pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase intramuscularly (IM) on day 4, and methotrexate IT on days 8 and 29 (and on days 15 and 22 for central nervous system [CNS]3 patients). Patients < 10 years old receive dexamethasone orally (PO) twice daily (BID) or IV on days 1-14; patients >= 10 years old receive prednisone or prednisolone PO BID or IV on days 1-28. Treatment continues for 5 weeks in the absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of age.

After completion of Induction treatment, patients with HR Fav B-ALL discontinue study, and patients with HR B-ALL and CD22 positive at diagnosis are randomized to Arm D or Arm E.

ARM D

• 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 QD on days 1-14 and 29-42, methotrexate IT on days 1, 8, 15, and 22 (also days 29 and 43 for CNS3 patients), vincristine IV on days 15, 22, 43, and 50, pegaspargase IM or IV over 1-2 hours OR calaspargase pegol (< 22 years of age only) IV over 1-2 hours on days 15 and 43. Consolidation treatment continues for 57 days in the absence of disease progression or unacceptable toxicity. Patients with testicular disease at diagnosis also receive radiation therapy (RT) to the testes once daily (QD) over 12 treatment fractions. After completion of Consolidation treatment, patients with MRD ≥ 25% discontinue study treatment.
• BLINATUMOMAB (BLINA) BLOCK 1: Patients receive dexamethasone PO or IV on day 1 (and day 8 for patients with MRD ≥ 5% - <25% at end of Consolidation [EOC]), blinatumomab IV continuously on days 1-28, and methotrexate IT on day 1. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity. After completion of Blina Block 1 treatment, patients with MRD ≥ 0.01% discontinue study treatment.
• INTERIM MAINTENANCE 1: Patients receive vincristine IV 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 63 days in the absence of disease progression or unacceptable toxicity.
• BLINA BLOCK 2: Patients receive blinatumomab IV continuously 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 PART 1: Patients receive methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine IV on days 1, 8, and 15, doxorubicin IV over 3-15 minutes or up to 1 hour on days 1, 8, and 15, and pegaspargase IM or IV over 1-2 hours OR calaspargase pegol (< 22 years of age only) IV over 1-2 hours on day 4 in the absence of disease progression or unacceptable toxicity. Patients then proceed to Delayed Intensification Part 2.
• DELAYED INTENSIFICATION PART 2: Patients receive cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO QD 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 on days 43 and 50, and pegaspargase IM or IV over 1-2 hours OR calaspargase pegol (< 22 years of age only) IV over 1-2 hours on day 43. Delayed Intensification Part 1 and 2 treatment continues for 63 days in the absence of disease progression or unacceptable toxicity.
• INTERIM MAINTENANCE 2: Patients receive vincristine IV on days 1, 11, 21, 31 and 41, methotrexate IV over 2-5 or 10-15 minutes on days 1, 11, 21, 31 and 41, methotrexate IT on days 1 and 31, and pegaspargase IM or IV over 1-2 hours on days 2 and 22 OR calaspargase pegol (< 22 years of age only) IV over 1-2 hours on days 2 and 23. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity.
• MAINTENANCE: Patients receive vincristine IV on day 1 of each cycle, prednisone or prednisolone PO BID or IV on days 1-5 of each cycle, mercaptopurine PO QD on days 1-84 of each cycle, methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 of each cycle, and methotrexate IT on day 1 of each cycle. Patients with CNS3 at diagnosis also receive cranial RT over 10 treatment fractions QD, 5 days per week, during the first 4 weeks of Maintenance treatment. Cycles repeat every 84 days until 2 years from start of Blina Block 1 treatment in the absence of disease progression or unacceptable toxicity.

ARM E:

• CONSOLIDATION PART 1: Patients receive cyclophosphamide IV over 30-60 minutes on day 1, cytarabine IV over 1-30 minutes or SC on days 1-4 and 8-11, mercaptopurine PO QD on days 1-14, methotrexate IT on days 1, 8, 15, and 22 (NOTE: Patients with CNS3 omit days 15 and 22), vincristine IV on days 15 and 22, and pegaspargase IM or IV over 1-2 hours OR calaspargase pegol (< 22 years of age only) IV over 1-2 hours on day 15. Treatment continues for 29 days in the absence of disease progression or unacceptable toxicity. Patients with testicular disease at diagnosis also receive RT to the testes QD over 12 treatment fractions.
• 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 (and day 15 for patients with CNS3). Treatment continues for 28 days in the absence of disease progression or unacceptable toxicity. After completion of InO Block 1 treatment, patients with MRD ≥ 25% discontinue study treatment.
• BLINA BLOCK 1: Patients receive dexamethasone PO or IV on day 1 (and day 8 for patients with MRD ≥ 5% - <25% at end of InO Block 1), blinatumomab IV continuously on days 1-28, and methotrexate IT on day 1. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity. After completion of Blina Block 1 treatment, patients with MRD ≥ 0.01% discontinue study treatment.
• INTERIM MAINTENANCE 1: Patients receive vincristine IV 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 63 days in the absence of disease progression or unacceptable toxicity.
• BLINA BLOCK 2: Patients receive blinatumomab IV continuously 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 PART 1: Patients receive methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine IV on days 1, 8, and 15, doxorubicin IV over 3-15 minutes or up to 1 hour on days 1, 8, and 15, and pegaspargase IM or IV over 1-2 hours OR calaspargase pegol (< 22 years of age only) IV over 1-2 hours on day 4 in the absence of disease progression or unacceptable toxicity. Patients then proceed to Delayed Intensification Part 2.
• InO BLOCK 2: Patients receive inotuzumab ozogamicin IV over 60 minutes on days 1, 8, and 15 and methotrexate IT on day 1. Treatment continues for 28 days in the absence of disease progression or unacceptable toxicity.
• INTERIM MAINTENANCE 2: Patients receive vincristine IV on days 1, 11, 21, 31 and 41, methotrexate IV over 2-5 or 10-15 minutes on days 1, 11, 21, 31 and 41, methotrexate IT on days 1 and 31, and pegaspargase IM or IV over 1-2 hours on days 2 and 22 OR calaspargase pegol (< 22 years of age only) IV over 1-2 hours on days 2 and 23. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity.
• MAINTENANCE: Patients receive vincristine IV on day 1 of each cycle, prednisone or prednisolone PO BID or IV on days 1-5 of each cycle, mercaptopurine PO QD on days 1-84 of each cycle, methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 of each cycle, and methotrexate IT on day 1 of each cycle. Patients with CNS3 at diagnosis also receive cranial RT over 10 treatment fractions QD, 5 days per week, during the first 4 weeks of Maintenance treatment. Cycles repeat every 84 days for 2 years in the absence of disease progression or unacceptable toxicity.

ARM I: MPAL

• INDUCTION: Patients receive cytarabine IT on day 1, vincristine IV on days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes days 1, 8, 15, and 22, pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase IM 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 prednisone or prednisolone PO BID or IV on days 1-28. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of age. Patients with MRD ≥ 5% at EOI discontinue study treatment.
• 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 on days 15, 22, 43, and 50, and pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase IM on days 15 and 43. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity. Patients with testicular disease at diagnosis that does not resolve by EOC and continued evidence of testicular disease at end of induction (EOI) undergo testicular RT over 12 once-daily fractions. Calaspargase pegol can only be given to patients less than 22 years of age. Patients with MRD ≥ 0.01% at EOC discontinue study treatment.

ARM II: B-LLY

• INDUCTION: Patients receive cytarabine IT on day 1, vincristine IV on days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes days 1, 8, 15, and 22, pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase IM 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 prednisone or prednisolone PO BID or IV on days 1-28. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of age.
• 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 on days 15, 22, 43, and 50, and pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase IM on days 15 and 43. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity. Patients with testicular disease at diagnosis that does not resolve by the EOI will and continued evidence of testicular disease at EOI undergo testicular RT over 12 once-daily fractions. Calaspargase pegol can only be given to patients less than 22 years of age. Patients without complete response (CR) at EOC discontinue study treatment.

ARM I AND II: MPAL AND B-LLY (POST-CONSOLIDATION THERAPY)

• INTERIM MAINTENANCE 1: Patients receive vincristine IV 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 63 days in the absence of disease progression or unacceptable toxicity.
• DELAYED INTENSIFICATION (PART 1): Patients receive methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine IV on days 1, 8, and 15, doxorubicin IV over 3-15 minutes or up to 1 hour on days 1, 8, and 15, and pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase IM on day 4. Treatment (Parts 1 and 2 of Delayed Intensification) continues for 63 days in the absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of age.
• DELAYED INTENSIFICATION (PART 2): 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 or calaspargase pegol IV over 1-2 hours or pegaspargase IM on day 43. Treatment (Parts 1 and 2 of Delayed Intensification) continues for 63 days in the absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of age.
• INTERIM MAINTENANCE 2: Patients receive vincristine IV 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 or calaspargase pegol IV over 1-2 hours on days 2 and 22 (pegaspargase) or (calaspargase) 23 or pegaspargase IM on days 2 and 22. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of age.
• MAINTENANCE: Patients receive vincristine IV on days 1, prednisone or 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.

Patients undergo blood sample collection and bone marrow aspiration and biopsy on study. B-LLy patients undergo computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and/or bone scan on study.

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 22 days of enrollment for suspected 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.
• Patients must be > 365 days and < 25 years of age
• Initial 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 one or more of the following:

• Testicular leukemia
• CNS leukemia (CNS3)
• Steroid pretreatment.
• Initial 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 NOTE: Patients enrolled as suspected MPAL but found on central confirmatory testing to have B-ALL must meet the B-ALL criteria above (age, WBC, extramedullary disease, steroid pretreatment) to switch to the B-ALL stratum before the end of induction.
• 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.
• Central nervous system (CNS) status must be determined prior to enrollment based on a sample obtained prior to administration of any systemic or intrathecal chemotherapy, except for steroid pretreatment and cytoreduction. Note that once cerebrospinal fluid (CSF) has been collected, protocol therapy can be initiated while final determination of CNS status is pending. It is recommended that intrathecal cytarabine be administered at the time of the diagnostic lumbar puncture. This is usually done at the time of the diagnostic bone marrow or venous line placement to avoid a second lumbar puncture. This is allowed prior to enrollment. Systemic chemotherapy must begin within 72 hours of this intrathecal therapy.
• Direct bilirubin < 2.0 mg/dL (34 micromoles/L)
• Alanine aminotransferase (ALT) ≤ 10x upper limit of normal (ULN). For the purposes of this study, the ULN for ALT is defined as 45 U/L
• Exceptions to this include patients with known Gilbert's Syndrome, or those with hepatic involvement from leukemic or lymphomatous infiltration
• 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
• With the exception of steroid pretreatment and steroid cytoreduction 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.