Clinical Trials

Inclusion Criteria: 

PRE-REGISTRATION ELIGIBILITY CRITERIA (STEP 0)

• Patients must have been diagnosed with CLL and have > 5000 B-cells per uL of peripheral blood at any point during the course of their disease.
• This blood submission is mandatory prior to registration/randomization to perform FISH centrally that will be used for stratification. It should be obtained as soon after preregistration as possible.

REGISTRATION ELIGIBILITY CRITERIA (STEP 1) 

• Patients must be diagnosed with CLL in accordance with 2018 IWCLL criteria [28] that includes all of the following:
  • ≥ 5 x10^9 B lymphocytes (5000/μL) in the peripheral blood measured by flow cytometry at any point in the course of the disease;
  • On local morphologic review, the leukemic cells must be small mature lymphocytes, and prolymphocytes must not exceed 55% of the blood lymphocytes;
  • CLL cells on immunophenotype (performed locally) must reveal a clonal B-cell population, which express the B cell surface markers of CD19 and CD20, as well as the T-cell antigen CD5. Patients with bright surface immunoglobulin expression or lack of CD23 expression in >10% of cells must lack t(11;14) translocation by interphase cytogenetics.
• Patients must be intermediate or high-risk Rai stage CLL.
  • Intermediate risk (formerly Rai stage I/II) is defined by lymphocytosis plus any of the following: enlarged lymph nodes, hepatomegaly, or splenomegaly'
  • High risk (formerly Rai stage III/IV) is defined by lymphocytosis with or without enlarged nodes and spleen plus disease-related anemia (hemoglobin < 11 g/dL) or thrombocytopenia (platelet count < 100 x 10^9/L) that is not attributable to autoimmune hemolytic anemia or thrombocytopenia.
• Patients must meet criteria for treatment as defined by 2018 IWCLL guidelines which includes at least one of the following criteria:
  • Evidence of marrow failure as manifested by the development or worsening of anemia or thrombocytopenia (not attributable to autoimmune hemolytic anemia or thrombocytopenia);
  • Massive (≥ 6 cm below the costal margin), progressive or symptomatic splenomegaly;
  • Massive nodes (≥ 10 cm) or progressive or symptomatic lymphadenopathy;
  • Progressive lymphocytosis with a lymphocyte doubling time < 6 months or an increase of ≥ 50% over a 2 month period;
  • Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy;
  • Symptomatic or functional extranodal involvement (e.g., skin, kidney, lung, spine);
  • Constitutional symptoms, which include any of the following:
    • Unintentional weight loss of 10% or more within 6 months;
    • Significant fatigue;
    • Fevers >100.5 degrees F for 2 weeks or more without evidence of infection;
    • Night sweats ≥1 month without evidence of infection.
• Patients must not have had prior therapy for CLL (except palliative steroids or treatment of autoimmune complications of CLL with rituximab or steroids).
• Treatment with rituximab and/or high dose corticosteroids for autoimmune complications of CLL must be complete at least 4 weeks prior to enrollment. Palliative steroids must be at a dose not higher than 20 mg/day of prednisone or equivalent corticosteroid at the time of registration.
• Age ≥ 65 years.
• ECOG performance status 0-2.
• Required initial laboratory values.
• Absolute Neutrophil Count (ANC) ≥ 1,000/mm^3 except if due to bone marrow involvement.
• Platelet Count (untransfused) ≥ 30,000/mm^3.
• Calc. Creatinine Clearance ≥ 40 mL/min (by Cockcroft-Gault).
• Bilirubin ≤ 1.5 x upper limit of normal (ULN) except if due to liver involvement, hemolysis, or Gilbert’s disease.
• AST / ALT ≤ 2.5 x upper limit of normal (ULN) except if due to liver involvement.
• Patients must not have any history of Richter’s transformation or prolymphocytic leukemia (prolymphocytes in blood > 55%).
• If evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be undetectable on suppressive therapy if indicated.
  • Please note: IVIG can cause a false positive hepatitis B serology. If patients receiving routine IVIG have core antibody or surface antigen positivity without evidence of active viremia (negative hepatitis B DNA) they may still participate in the study, must have hepatitis serologies and hepatitis B DNA monitored periodically by the treating physician.
• If history of hepatitis C virus (HCV) infection, must be treated with undetectable HCV viral load.
• Patients with Class III or Class IV heart failure by New York Heart Association, those with unstable angina, and those with uncontrolled arrhythmia are not eligible.
• Patients who have had a myocardial infarction, intracranial bleed, or stroke within the past 6 months are not eligible.
• Human immunodeficiency virus (HIV)-infected patients on effective antiretroviral therapy with undetectable viral load within 6 months are eligible for this trial
• Patients must not be receiving active systemic anticoagulation with heparin or warfarin. Patients on warfarin must discontinue the drug for at least 10 days prior to registration on the study.
• Chronic concomitant treatment with strong inhibitors of CYP3A4/5 is not allowed on this study. Patients on strong CYP3A inhibitors must discontinue the drug for 14 days prior to registration on the study. 
• Chronic concomitant treatment with strong CYP3A4/5 inducers is not allowed.
• Patients must discontinue the drug 14 days prior to registration on the study.
• Patients must not require more than 20 mg prednisone or equivalent corticosteroid daily.
• Patients must not have uncontrolled active systemic infection requiring intravenous antibiotics.
• Central FISH blood results are mandatory prior to registration/randomization for it will be used for stratification.
• Patients must be able to swallow capsules and not have the following conditions:  disease significantly affecting gastrointestinal absorption, resection of the stomach or small bowel, partial or complete bowel obstruction.
• Patients must not have a known allergy to mannitol.
• Patients must not have prior significant hypersensitivity to rituximab (not including infusion reactions).
• Patients may not have had major surgery within 10 days prior to registration, or minor surgery within 7 days prior to registration. Examples of minor surgery include dental surgery, insertion of a venous access device, skin biopsy, or aspiration for a joint. The decision about whether a surgery is major or minor can be made at the discretion of the treating physician.
• Patients must be able to receive either a xanthine oxidase inhibitor or rasburicase for prophylaxis/treatment of TLS.

RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2)

• Completion of treatment through Cycle 14 Day 28, and remain on ibrutinib therapy.
• Receipt of central BM MRD results.
• Response assessment completed per Section 5.0 with CR determination.

Eligibility last updated 1/17/22. Questions regarding updates should be directed to the study team contact.