Low-Intensity Chemotherapy and Venetoclax in Treating Patients With Relapsed or Refractory B- or T-Cell Acute Lymphoblastic Leukemia

Inclusion Criteria:

1. Diagnosis of one of the following

2. Patients ≥ 18 years of age with relapsed/refractory B- or T-cell ALL (for phaseII only)

3. Patients ≥ 60 years of age with previously untreated B- or T-cell ALL. Patients <60 years of age may be enrolled if they are considered unfit for intensivechemotherapy

4. Patients ≥ 60 years of age with previously treated B- or T-cell ALL whoreceived 1-2 courses of any frontline chemotherapy. Patients <60 years of agemay be enrolled if they are considered unfit for intensive chemotherapy

• If they achieved CR/CRi, they are assessable only for event-free andoverall survival
• If they failed to achieve CR/CRi, they are assessable for response,event-free, and overall survival

2. Performance status ≤ 3 (Eastern Cooperative Oncology Group [ECOG] Scale)

3. Adequate liver and renal function as defined by the following criteria:

• Total serum bilirubin ≤ 1.5 x upper limit of normal (ULN)

• Alanine aminotransferase (ALT) ≤ 3 x ULN, unless due to disease involvement ofthe liver or hemolysis, in which case an ALT ≤ 10 x ULN is acceptable

• Aspartate aminotransferase (AST) ≤ 3 x ULN, unless due to disease involvementof the liver or hemolysis, in which case an ALT ≤ 10 x ULN is acceptable

• Creatinine clearance ≥ 30 mL/min

• INR ≤ 1.5 x ULN and aPTT . 1.5 x ULN

4. For females of childbearing potential, a negative pregnancy test must be documentedwithin 1 week of starting treatment

5. Female and male patients who are fertile must agree to use an effective form ofcontraception (birth control methods while on study, such as birth control pills orinjections, intrauterine devices [IUDs]), or double-barrier methods (for example, acondom in combination with spermicide) with their sexual partners for 4 months afterthe end of treatment

6. Signed informed consent

Exclusion Criteria:

1. Patients with Philadelphia chromosome-positive ALL or Burkitt leukemia

2. Patients who are willing and eligible to receive intensive chemotherapy (only forpatients enrolling in frontline cohort)

3. Active serious infection not controlled by oral or intravenous antibiotics

4. Known CNS leukemia requiring radiation

5. Active GVHD

6. Active secondary malignancy other than skin cancer (e.g., basal cell carcinoma orsquamous cell carcinoma) that in the investigator's opinion will shorten survival toless than 1 year

7. Known hepatitis B or C infection, or known seropositivity for human immunodeficiencyvirus (HIV)

8. Active grade III-V cardiac failure as defined by the New York Heart AssociationCriteria

9. Patients with a cardiac ejection fraction (as measured by either multigatedacquisition [MUGA] or echocardiogram) < 40%

10. Received moderate or strong CYP3A inhibitors or strong CYP3A inducers within 7 daysof starting venetoclax

11. Received medication that interferes with coagulation or platelet function within 7days prior to the first dose of study drug or during the study treatment period

12. Consumed grapefruit, grapefruit products, Seville oranges, or star fruit within 3days prior to starting venetoclax

13. Prior history of treatment with navitoclax.

14. Treatment with any investigational antileukemic agents or chemotherapy agents in thelast 7 days before study entry, unless full recovery from side effects has occurredor patient has rapidly progressive disease judged to be life-threatening by theinvestigator. Exception: Treatment with hydroxyurea and/or dexamethasone are allowedprior to study treatment, without window of exclusion

15. Pregnant and lactating women will not be eligible; women of childbearing potentialshould have a negative pregnancy test prior to entering on the study and be willingto practice methods of contraception. Women do not have childbearing potential ifthey have had a hysterectomy or are postmenopausal without menses for 12 months. Inaddition, men enrolled on this study should understand the risks to any sexualpartner of childbearing potential and should practice an effective method of birthcontrol

16. History of significant bleeding disorder unrelated to cancer, including: diagnosedcongenital bleeding disorders (e.g., von Willebrand's disease); diagnosed acquiredbleeding disorder within one year (e.g., acquired anti-factor VIII antibodies)

17. Patient with total serum bilirubin > 1.5 x upper limit of normal (ULN).