Testing the Combination of Inotuzumab Ozogamicin and Lower Dose Chemotherapy Compared to Usual Chemotherapy for Adults With B-Cell Acute Lymphoblastic Leukemia or B-Cell Lymphoblastic Lymphoma

This phase II trial compares the combination of inotuzumab ozogamicin and chemotherapy to the usual chemotherapy in treating patients with B-cell acute lymphoblastic leukemia or B-cell lymphoblastic lymphoma. Inotuzumab ozogamicin is a monoclonal antibody, called inotuzumab, linked to a drug, called CalichDMH. Inotuzumab is a form of targeted therapy because it attaches to specific molecules (receptors) on the surface of cancer cells, known as CD22 receptors, and delivers CalichDMH to kill them. Chemotherapy drugs 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. Giving inotuzumab ozogamicin with chemotherapy may help shrink the cancer and stop it from returning.

PRIMARY OBJECTIVE:

I. To compare undetectable measurable residual disease (MRD) event-free survival (EFS) rate of the experimental arm (A) to standard arm (B) with EFS defined as time from randomization to occurrence of an event.

SECONDARY OBJECTIVES:

I. To determine overall response rate (complete response \[CR\], CR + complete remission with incomplete platelet counts \[CRp\], CR + complete remission with partial hematologic recovery \[CRh\], CR + complete remission with incomplete blood count recovery \[CRi\]) at designated time points (after cycle 1, after cycle 2, end of intensive phase) in each treatment arm.

II. To determine rate of flow cytometry MRD-negativity (undetectable or detectable \< 10\^-4) at designated time points (after cycle 1, after cycle 2, end of intensive phase) in each treatment arm.

III. To compare MRD response by central aspirate multiparameter flow cytometry (Wood lab) to next generation sequencing MRD assessment (clonoSEQ, Adaptive) of blood and bone marrow at designated time points (after cycle 1, after cycle 2, and end of intensive phase) and to determine association with outcome, in each treatment arm.

IV. To determine the event-free survival (EFS) standard-definition (event defined as failure to achieve morphologic remission by cycle 2, hematologic relapse, death), disease-free survival (DFS), overall survival (OS) of each arm (median, 6-month, 1-year, 2-year, 3-year) in each treatment arm.

V. To determine proportion of patients who proceed to allogeneic transplant after initial response (without intervening salvage therapy) in each treatment arm.

VI. To determine rate of liver toxicity (grade 3-5 alanine aminotransferase \[ALT\] increase, aspartate aminotransferase \[AST\] increase, bilirubin increase, alkaline phosphatase increase).

VII. To describe the safety and tolerability of each arm including rate of grade 3-5 non-hematologic toxicity and treatment-related mortality (grade 5 toxicity VIII. To determine rate of delays in intensive-phase chemotherapy due to neutropenia and thrombocytopenia (in responding patients).

IX. To assess the baseline variations in comorbidity burden, physical, nutritional, and cognitive function of the study participants, and explore the association between comorbidity burden, physical, nutritional, and cognitive function, and the outcomes of therapy (grade 3-5 non-hematological toxicities, and OS).

X. To explore the longitudinal changes in physical, nutritional, and cognitive function among the experimental and control groups.

XI. To compare the burden of patient-reported symptomatic adverse events between treatment arms using the Patient Reported Outcomes - Common Terminology Criteria for Adverse Events (PRO-CTCAE).

XII. To correlate specific karyotype groups (normal or various primary and secondary chromosomal abnormalities) with clinical and laboratory parameters.

XIII. To correlate specific karyotype groups with response rates, response duration, MRD, and survival in patients treated on this study.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A:

INDUCTION: Patients receive cyclophosphamide intravenously (IV) over 3 hours every 12 hours (Q12H) on days 1-3 of cycles 1, 3, 5, and 7, vincristine IV on days 1 and 8 of cycle 1, 3, 5, and 7, dexamethasone IV or orally (PO) on days 1-4 and 11-14 of cycles 1, 3, 5, and 7, inotuzumab ozogamicin IV over 1 hour on days 2 and 8 of cycles 1-4, methotrexate IV over 24 hours on day 1 of cycles 2, 4, 6, and 8, cytarabine IV over 3 hours Q12H on days 2-3 of cycles 2, 4, 6, and 8, and methylprednisolone IV over 2 hours Q12H on days 1-3. Patients with leukemic blasts expressing CD20 also receive rituximab IV on days 2 and 8 of cycles 1-4. For patients \>= 70 years of age, treatment repeats every 28 days for 2 cycles (an additional 2 cycles may be given at the discretion of the principal investigator \[PI\]) in the absence of disease progression or unacceptable toxicity. For patients \< 70 years of age, treatment repeats every 28 days for 8 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients receive vincristine IV on day 1, prednisone PO daily on days 1-5, mercaptopurine PO twice daily (BID) on days 1-28, and methotrexate PO weekly. Treatment repeats every 28 days for up to 24 cycles or 2 years, whichever comes first, in the absence of disease progression or unacceptable toxicity.

ARM B:

INDUCTION: Patients receive cyclophosphamide IV over 3 hours Q12H on days 1-3 of cycle 1, 3, 5, and 7, vincristine IV on days 1 and 8 of cycles 1, 3, 5, and 7, dexamethasone IV or PO on days 1-4 and 11-14 of cycle 1, 3, 5, and 7, doxorubicin IV over 24 hours on day 4 of cycles 1, 3, 5, and 7, methotrexate IV over 24 hours on day 1 of cycles 2, 4, 6, and 8, cytarabine IV over 3 hours Q12H on days 2-3 of cycles 2, 4, 6, and 8, and methylprednisolone IV over 2 hours Q12H on days 1-3 of cycles 2, 4, 6, and 8. Patients with leukemic blasts expressing CD20 also receive rituximab IV on days 2 and 8 of cycles 1-4. For patients \>= 70 years of age, treatment repeats every 28 days for 2 cycles (an additional 2 cycles may be given at the discretion of the PI) in absence of disease progression or unacceptable toxicity. For patients \< 70 years of age, treatment repeats every 28 days for 8 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients receive vincristine IV on day 1, prednisone PO daily on days 1-5, mercaptopurine PO BID on days 1-28, and methotrexate PO weekly. Treatment repeats every 28 days for up to 24 cycles or 2 years, whichever comes first, in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 2 months until 1 year after completion of therapy, every 3 months until 2 years after completion of therapy, and then every 6 months until 5 years from study registration.

Eligibility Criteria:
Inclusion Criteria:

* PRE-REGISTRATION ELIGIBILITY CRITERIA (STEP 0)
* Research bone marrow or peripheral blood submission

  \* This bone marrow or peripheral blood submission is mandatory prior to registration/randomization as baseline for real-time MRD analysis. The bone marrow sample should be from the first aspiration (i.e., first pull). Aspirate needle should be redirected if needed to get first pull bone marrow aspirate. It should be obtained as soon after pre-registration as possible
* REGISTRATION INCLUSION CRITERIA (STEP 1)
* Diagnosis of B-cell acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL) per World Health Organization (WHO) 2016 criteria. Patients must have \>= 5% blasts in the bone marrow or blood. Patients with lymphoblastic lymphoma (LBL) without measurable marrow involvement (\>= 5% blasts) are not eligible

  \* T-cell ALL/LBL, Philadelphia-chromosome positive B-cell (as determined by fluorescence in situ hybridization \[FISH\], cytogenetics, or reverse transcriptase polymerase chain reaction \[RT-PCR\]), and Burkitt's like leukemia/lymphoma (mature B-ALL) are not eligible
* Must be CD22 positive by local assessment (\>= 20% by immunohistochemistry or flow cytometry). Patients are eligible regardless of CD20 status but CD20 expression should be assessed at diagnosis by flow cytometry or immunohistochemistry
* Patients must have \>= 5% blasts in the bone marrow or blood. Patients with lymphoblastic lymphoma (LBL) without marrow involvement (\>= 5% blasts) are not eligible
* No prior chemotherapy for ALL except for hydroxyurea (no limit), steroids limited to 7 days, ATRA (no limit), vincristine (single dose), and/or intra-thecal chemotherapy. Leukapheresis is permitted. Palliative radiation to doses 24 Gy or less is permitted. Patients being treated with chronic steroids for other reasons (autoimmune disorder, etc.) are eligible
* Age \>= 50 years
* Eastern Cooperative Oncology Group (ECOG) performance status =\< 2. ECOG 3 permitted if related to disease
* Creatinine =\< 2.0 g/dL
* Total bilirubin =\< 1.5 x upper limit of normal (ULN)

  \* Except in the event of: 1) Gilbert disease, in which case total bilirubin must be =\< 2 x ULN, or 2) elevated bilirubin believed by investigator to be due to leukemic infiltration, in which case total bilirubin must be =\< 2 x ULN
* AST / ALT =\< 2.5 x upper limit of normal (ULN)
* Cardiac ejection fraction (as measured by multigated acquisition scan \[MUGA\] or echocardiogram) \> 40%
* No clinically relevant liver disease (such as cirrhosis, active hepatitis, or alcohol use disorder), which in the opinion of the treating physician would make this protocol unreasonably hazardous

  * Patients with known hepatitis B virus (HBV) infection are eligible if they are on effective HBV suppressive therapy with undetectable HBV viral load and there is no clinically relevant liver disease present (related or unrelated to HBV-related liver damage)
  * Patients with known history of hepatitis C virus (HCV) infection are eligible if they have cleared the infection spontaneously or via eradication therapy (HCV viral load undetectable) and there is no clinically relevant liver disease present (related or unrelated to HCV-related liver damage)
* Women and men of reproductive potential should agree to use an appropriate method of birth control throughout their participation in this study due to the teratogenic potential of the therapy utilized in this trial. Include as applicable: Appropriate methods of birth control include abstinence, oral contraceptives, implantable hormonal contraceptives, or double barrier method (diaphragm plus condom)

Exclusion Criteria:

* Physicians should consider whether any of the following may render the patient inappropriate for this protocol:

  * Medical condition such as uncontrolled diabetes mellitus, uncontrolled cardiac disease, and uncontrolled pulmonary disease.
  * Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
  * Patients with a "currently active" second malignancy other than non-melanoma skin cancers, early stage prostate cancer, cervical carcinoma in situ, or other cancer for which standard of care would be observation (not requiring treatment). Patients are not considered to have a "currently active" malignancy if they have completed therapy and are free of disease for \>= 1 year, or if the cancer has been surgically resected and considered cured. Patients with a history of multiple myeloma with absence of serum paraprotein for \>= 1 year are not considered to have a "currently active" malignancy.
* REGISTRATION EXCLUSION CRITERIA (STEP 1)
* Patients with symptomatic central nervous system (CNS) disease are not eligible. CNS assessment is not required for eligibility determination if asymptomatic