Inclusion Criteria:

• Subjects or their legally authorized representative(if permitted per local regulations) must voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures.
• Adult male or female, at least 18 years old, suitable for oral administration of study drugs.
• Laboratory values meeting the following criteria within the screening period prior to the first dose of study drug:
  • alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ 3 × the upper limit of normal (ULN);
  • adequate liver function as indicated by a total bilirubin ≤ 1.5 × ULN (subjects with documented Gilbert's syndrome may have bilirubin > 1.5 × ULN);
  • absolute neutrophil count (ANC) > 1000/µL (growth factor support is allowed to achieve eligibility criteria);
  • platelet count > 50,000/µL (platelet transfusion is allowed if the cytopenia is due to infiltration of the leukemia in the bone marrow);
  • creatinine clearance (CrCL) ≥ 50 mL/minute (calculated according to the modified formula of Cockcroft and Gault
  • Men: ([140 – age (years)] × bodyweight [kg])/(72 × creatinine [mg/dL]);
  • Women: (modified Cockcroft and Gault formula) for men × 0.85] or directly measured with a 24-hour urine collection);
  • hemoglobin > 8 g/dL (red blood cell transfusion is allowed if the cytopenia is due to infiltration of the leukemia in the bone marrow).
• Willingness or ability to comply with procedures required in this protocol.
• Diagnosis of T-cell prolymphocytic leukemia (T-PLL) that requires treatment.
• Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2.
• Negative for human T-cell lymphotropic virus, type 1.
• Received prior alemtuzumab (unless unsuitable or unavailable).
• Has no malignancies other than T-PLL that:
  • currently require systemic therapies;
  • were not previously treated with curative intention (unless the malignant disease is in a stable remission due to the discretion of the treating physician); or
  • developed signs of progression after curative treatment.
• Subject must not have received any live or attenuated live vaccine within 28 days prior to the first dose of ibrutinib or venetoclax. Seasonal flu vaccines that do not contain a live virus are permitted.
• A negative serum pregnancy test for all women of childbearing potential at the screening visit and a negative urine pregnancy test at baseline prior to the first dose of study drug.
• If female, subject must be either postmenopausal OR permanently surgically sterile OR, for women of childbearing potential, practicing at least 1 protocol-specified method of birth control that is effective from study Day 1 through at least 30 days after the last dose of venetoclax or 3 months after the last dose of ibrutinib, whichever is later.
• Female who is not pregnant, breastfeeding, or considering becoming pregnant during the study or for approximately 30 days after the last dose of venetoclax or 3 months after the last dose of ibrutinib, whichever is later.
• If male, and subject is sexually active with female partner(s) of childbearing potential, he must agree, from Study Day 1 through 30 days after the last dose of venetoclax and 90 days after the last dose of ibrutinib, to practice the protocol-specified contraception.
• Male who is not considering fathering a child or donating sperm during the study or for approximately 30 days after the last dose of venetoclax and 90 days after the last dose of ibrutinib.
• Male subjects who are sexually active with a woman of childbearing potential must agree to use condoms, even if the male subject has undergone a successful vasectomy, from Study Day 1 through at least 30 days after the last dose of venetoclax and at least 90 days after the last dose of ibrutinib. His female partner(s) must also use at least one of the following methods of birth control:
  • combined (estrogen- and progestogen-containing) hormonal birth control (oral, intravaginal, transdermal, injectable) associated with inhibition of ovulation initiated at least 30 days prior to study Day 1;
  • progestogen-only hormonal birth control (oral, injectable, implantable) associated with inhibition of ovulation initiated at least 1 month prior to study Day 1;
  • bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a hysterosalpingogram confirms success of the procedure);
  • intrauterine device;
  • intrauterine hormone-releasing system.
• During the study drug dosing period, a subject with confirmed (viral test positive) or suspected COVID-19 infection can only be dosed with study drug if the following COVID-19 viral clearance criteria are met:
  • Symptomatic subjects: At least 2 negative viral tests in a row, ≥ 24 hours apart after at least 10 days have passed since recovery, defined as resolution of fever without use of antipyretics and improvement in respiratory symptoms (e.g., cough, shortness of breath);
  • Asymptomatic subjects: At least 2 negative viral tests in a row, ≥ 24 hours apart after at least 10 days have passed since prior positive result.
  • Note: subjects who develop symptoms will follow guidance above for symptomatic subjects.

Exclusion Criteria:

• History of or current decompensated cirrhosis including Child-Pugh class B or C, ascites, hepatic encephalopathy, or variceal bleeding.
• Has human T-cell lymphotropic virus, type 1.
• Prior allogeneic stem cell transplant within 6 months of study drug administration and requirement for graft versus host therapy.
• Has an uncontrolled or active infection.
• Previously treated with a B-cell lymphoma (BCL)-2 inhibitor.
• Received a prohibited therapy within the specified time frame as described in the protocol.