Inclusion Criteria:

• Patients must have B-ALL with ≥5% (M2 or M3) bone marrow blasts with or without extramedullary disease
• Leukemic blasts must demonstrate surface expression of CD22 at the time of relapse by local/institutional flow cytometry of a bone marrow aspirate sample; (assessment of CD22 using a phycoerythrin [PE] fluorophore is strongly recommended)
  • In the case of an inadequate aspirate sample (dry tap), flow cytometry of peripheral blood specimen may be substituted if the patient has at least 1000/uL circulating blasts; alternatively, CD22 expression may be documented by immunohistochemistry of a bone marrow biopsy specimen
• Patient must have one of the following:
  • Second or greater relapse
  • Primary refractory disease with at least 2 prior induction attempts;
  • First or greater relapse refractory to at least one prior re-induction attempt
• Relapsed patients previously diagnosed with B-lymphoblastic lymphoma are eligible if they have an M2 or M3 marrow at the time of enrollment on this study
• Patients with Philadelphia chromosome (Ph)+ ALL must have had two prior therapy attempts including two different tyrosine kinase inhibitors (TKIs)
• Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy, defined as resolution of all such toxicities to ≤ grade 2 or lower per the inclusion/exclusion criteria prior to entering this study
  • Myelosuppressive chemotherapy:
    • Patients who relapse while receiving standard maintenance therapy will not be required to have a waiting period prior to enrollment onto this study; otherwise, at least 14 days must have elapsed since the completion of cytotoxic therapy, with the exceptions of hydroxyurea or corticosteroids used for cytoreduction
    • Intrathecal cytotoxic therapy: No waiting period is required for patients having received intrathecal cytarabine, methotrexate, and/or hydrocortisone; intrathecal chemotherapy given at the time of diagnostic lumbar puncture (LP) to evaluate for relapse prior to study enrollment is allowed
  • At least 7 days must have elapsed since the completion of therapy with a growth factor; at least 14 days must have elapsed after receiving pegfilgrastim
  • At least 7 days must have elapsed since completion of therapy with a biologic agent; for agents that have known adverse events occurring beyond 7 days after administration, this period prior to enrollment must be extended beyond the time during which adverse events are known to occur
  • At least 3 half-lives must have elapsed since prior therapy that included a monoclonal antibody with the exception of blinatumomab; patients must have been off blinatumomab infusion for at least 7 days and all drug related toxicity must have resolved to grade 2 or lower as outlined in the inclusion/exclusion criteria
  • ≥ 2 weeks must have elapsed since local palliative radiation therapy (XRT) (small port); ≥ 3 months must have elapsed if prior cranial or craniospinal XRT was received, if ≥ 50% of the pelvis was irradiated, or if total-body irradiation (TBI) was received; ≥ 6 weeks must have elapsed if other substantial bone marrow irradiation was given
  • At least 90 days must have elapsed since stem cell transplant; patient must have had no more than one previous HSCT and currently have no evidence of active graft versus (vs.) host disease (GVHD)
  • At least 42 days must have elapsed since chimeric antigen receptor (CAR)-T cell therapy
• Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2; use Karnofsky for patients > 16 years of age and Lansky for patients ≤ 16 years of age; patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 70 mL/min/1.73 m^2 or
• A serum creatinine based on age/gender as follows:
  • 1 to < 2 years: maximum serum creatinine 0.6 mg/dL (both male and female)
  • 2 to < 6 years: maximum serum creatinine 0.8 mg/dL (both male and female)
  • 6 to < 10 years: maximum serum creatinine 1 mg/dL (both male and female)
  • 10 to < 13 years: maximum serum creatinine 1.2 mg/dL (both male and female)
  • 13 to < 16 years: maximum serum creatinine 1.5 mg/dL (male), 1.4 mg/dL (female)
  • ≥ 16 years: maximum serum creatinine 1.7 mg/dL (male), 1.4 mg/dL (female)
• Direct bilirubin ≤ 1.5 x upper limit of normal (ULN) for age, and
• Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) ≤ 3 x ULN for age

Exclusion Criteria:

• Patients with any prior history of SOS/VOD irrespective of severity
• Patients with isolated central nervous system (CNS), testicular, or other extramedullary site of relapse
• Patients who have been previously treated with InO
• Patients with active optic nerve and/or retinal involvement that would require urgent radiation therapy concurrent with protocol therapy; patients who are presenting with visual disturbances should have an ophthalmologic exam and, if indicated, a magnetic resonance imaging (MRI) to assess optic nerve or retinal involvement
• Patients who are currently receiving another investigational drug
• Patients who are currently receiving or plan to receive other anti-cancer agents (except hydroxyurea, which may be continued until 24 hours prior to start of protocol therapy and intrathecal chemotherapy)
• Anti-GVHD or agents to prevent organ rejection post-transplant; patients who are receiving cyclosporine, tacrolimus, or other agents to prevent either graft-versus-host disease post bone marrow transplant or organ rejection post-transplant are not eligible for this trial; at least 3 half-lives must have elapsed after the last dose of GVHD medications (meds)
• Patients who are currently receiving or plan to receive corticosteroids except as described below
  • Systemic corticosteroids may be administered for cytoreduction up to 24 hours prior to the start of protocol therapy, as a premedication for InO and as treatment for allergic reactions or for physiologic replacement/stress dosing of hydrocortisone for documented adrenal insufficiency; corticosteroids are not allowed for other indications
• Patients who have an active uncontrolled infection defined as:
  • Positive bacterial blood culture within 48 hours of study enrollment;
  • Fever above 38.2 degree Celsius (C) within 48 hours of study enrollment with clinical signs of infection; fever that is determined to be due to tumor burden is allowed if patients have documented negative blood cultures for at least 48 hours prior to enrollment and no concurrent signs or symptoms of active infection or hemodynamic instability
  • A positive fungal culture within 30 days of study enrollment or active therapy for presumed invasive fungal infection
  • Patients may be receiving IV or oral antibiotics to complete a course of therapy for a prior documented infection as long as cultures have been negative for at least 48 hours and signs or symptoms of active infection have resolved; for patients with clostridium (c.) difficile diarrhea, at least 72 hours of antibacterial therapy must have elapsed and stools must have normalized to baseline
  • Active viral or protozoal infection requiring IV treatment
• Patients with known human immunodeficiency virus (HIV), hepatitis B or C infections; testing to prove negative status is not required for enrollment unless it is deemed necessary for usual medical care of the patient
• Patients known to have one of the following concomitant genetic syndromes: Bloom syndrome, ataxia-telangiectasia, Fanconi anemia, Kostmann syndrome, Shwachman syndrome, or any other known bone marrow failure syndrome
• Women of childbearing potential should be advised to avoid becoming pregnant while receiving InO; women should not breast-feed during treatment with InO and for at least 3 months after the final dose
  • Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained within 7 days of starting protocol therapy
  • Female patients who are sexually active and of reproductive potential are not eligible unless they agree to use an effective contraceptive method for the duration of their study participation and for 8 months after the last dose of InO
  • Men with female partners of childbearing potential should use effective contraception during treatment with InO and for at least 5 months after the last dose of InO
  • Lactating females are not eligible unless they agree not to breastfeed their infants
• Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study