• Participants must have histologically confirmed CD22+ B-ALL or B-LBL.

‣ Note: CD22 must be detected on ≥ 20% of lymphoblasts by flow cytometry of peripheral blood, flow cytometry of bone marrow aspirate or tissue biopsy, or immunohistochemistry of the bone marrow or tissue biopsy.

⁃ Note: for R/R disease: ≥ 5% lymphoblasts must be documented in the diagnostic sample (blood, marrow, or tissue biopsy).

⁃ Note: Participants with B-LBL (confirmed CD22-positive extramedullary disease, but none or minimal marrow involvement) are eligible if eligibility criteria otherwise met.

⁃ Note: Participants with Philadelphia-chromosome positive B-ALL are eligible but must be refractory to 2 or more tyrosine kinase inhibitors (TKIs), refractory to ponatinib, or ineligible to receive all available TKIs.

⁃ Note: Participants with chronic myeloid leukemia (CML) in lymphoid blast crisis are eligible but must be refractory to 2 or more TKIs, refractory to ponatinib, or ineligible to receive all available TKIs.

• Participants must have disease that is relapsed or refractory (R/R) to 1 or more cycles of cytotoxic chemotherapy.

‣ Note: There is no limit to number or type of prior therapies (prior inotuzumab ozogamicin is not permitted).

⁃ Note: Philadelphia-chromosome positive B-ALL patients previously treated with TKI are eligible without receiving cytotoxic chemotherapy if they are unsuitable for standard cytotoxic chemotherapy.

• Participants be aged ≥ 18 years.

• ECOG performance status of 0-3.

• Adequate organ function.

‣ Serum total bilirubin ≤ 1.5x upper limit of normal (ULN), unless due to Gilbert's syndrome or of non-hepatic origin (i.e. hemolysis).

⁃ ALT and AST ≤ 2.5x ULN, unless clearly due to disease, in which case ≤ 5x ULN is permissible.

⁃ Creatinine clearance of ≥ 30 mL/min calculated using Cockcroft-Gault formula or measured by 24-hour urine collection.

• Women of childbearing potential must have a negative serum or urine beta human chorionic gonadotropin (β-hCG) pregnancy test result within 14 days prior to the first dose of study drugs. Women of non-childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy. The effects of venetoclax and inotuzumab ozogamicin on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, during treatment, and for at least 8 and 5 months after the last dose, respectively. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.

• Human immunodeficiency virus (HIV)-infected participants on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. Medication list must be carefully reviewed to ensure no contra-indicated drug-drug interactions.

• For participants with known evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be confirmed to be undetectable (and appropriate suppressive therapy must be initiated in consultation with an infectious disease expert, if indicated).

• Participants with a known history of hepatitis C virus (HCV) infection must have an undetectable HCV viral load confirmed.

• Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. The treating investigator must review such cases with the overall PI prior to confirming eligibility.

• Participants with prior HSCT or chimeric antigen receptor T-cell (CAR-T) therapy (autologous or allogeneic) are eligible if they are day +60 from cell infusion and do not have active Glucksberg grade 2 or higher graft versus host disease (GVHD). Patient must be off calcineurin inhibitor for 2 weeks.

• Ability to understand and the willingness to sign and date written informed consent document.