Ibrutinib lead-in Followed by Venetoclax Plus Ibrutinib in Patients With RR CLL

Inclusion Criteria: * Written informed consent according to Swiss law and ICH/GCP regulations before registration and prior to any trial specific procedures * Cytologically and immunophenotypically confirmed relapsed/refractory CLL (irrespective of the 17p deletion and/or TP53 mutation status and the duration of remission from last prior therapy) * Patients in need of systemic treatment as defined by international workshop on chronic lymphocytic leukemia (iwCLL) criteria (at least one of the following indications must be fulfilled): * Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia. Cut-off levels of Hb \< 100 g/L or platelet counts of \< 100x109/L * Massive (i.e., ≥ 6 cm below the left costal margin) or progressive or symptomatic splenomegaly * Massive nodes (i.e., ≥ 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy * Progressive lymphocytosis with an increase of ≥ 50% over a 2-month period, or lymphocyte doubling time of less than 6 months * Disease-related symptoms as defined by any of the following: (a) Unintentional weight loss ≥ 10% within the previous 6 months. (b) Significant fatigue (i.e., ECOG PS 2 or worse; cannot work or unable to perform usual activities). (c) Fevers ≥38.0° C for 2 or more weeks without evidence of infection. (d) Night sweats for ≥ 1 month without evidence of infection * Age at least 18 years * WHO performance status 0-2 * Hematological function: * Absolute neutrophil count (ANC) ≥ 1 x 109/L or ANC \< 1 x 109/L, if attributable to the underlying CLL (growth factor support may be administered after screening) * Platelet count ≥ 30 x 109/L * Hepatic function: * Bilirubin ≤ 1.5 x ULN (except for patients with Gilbert's disease ≤ 3.0 x ULN) * ALT and AST ≤ 3.0 x ULN * Renal function: Creatinine clearance \> 30 mL/min (calculated according to institutional standards or using Cockcroft-Gault formula * Adequate coagulation parameters per local laboratory reference range as follows: activated partial thromboplastin time (aPTT) and international normalized ratio (INR) ≤ 1.5 × ULN * Women with child-bearing potential are using effective contraception, are not pregnant or lactating and agree not to become pregnant during trial treatment and during the 30 days thereafter. A negative pregnancy test before inclusion into the trial is required for all women with child-bearing potential * Men agree not to father a child during trial treatment and during 3 months thereafter * Patient is able and willing to swallow trial drugs as whole tablet/capsule * Patient is willing to participate in translational research Exclusion Criteria: Any potential patient who meets any of the following criteria has to be excluded from entering the trial. * Transformation of CLL (i.e. Richter's transformation, prolymphocyctic leukemia) * Patients with a prior malignancy and treated with curative intention are eligible if all treatment of that malignancy was completed at least 2 years before registration and the patient has no evidence of disease at registration. Less than 2 years is acceptable for malignancies with low-risk of recurrence and/or no late recurrence * Prior treatment with venetoclax and/or ibrutinib * Major surgery and any systemic anti-cancer treatment within 3 weeks prior to registration * Steroid therapy for anti-neoplastic intent; strong and moderate CYP3A inhibitors; strong and moderate CYP3A inducers must be stopped at least 7 days prior to the first dose of trial drug (see http://medicine.iupui.edu/ and useful tools for examples) * Severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV), unstable angina pectoris, history of myocardial infarction within the last six months, serious arrhythmias requiring medication (with exception of atrial fibrillation or paroxysmal supraventricular tachycardia on direct oral anticoagulants (DOAC), Aspirin or low molecular weight heparins (LMWH) but not on Vitamin K antagonist), significant QT-prolongation, uncontrolled hypertension * History of cerebrovascular accident or intracranial hemorrhage within 6 months prior to registration and known bleeding disorders (e.g., von Willebrand's disease or hemophilia) * Patients with a history of confirmed progressive multifocal leukoencephalopathy (PML) * Concomitant diseases that require anticoagulant therapy with warfarin or phenoprocoumon or other vitamin K antagonists. Patients being treated with factor Xa inhibitors (e.g. rivaroxaban, apixaban, edoxaban), direct thrombin inhibitors (e.g. dabigatran) LMWH, or anti-platelets agents (e.g. aspirin, clopidogrel) can be included, but must be properly informed about the potential risk of bleeding under treatment with ibrutinib * Malabsorption syndrome or other condition that precludes enteral route of administration * Any uncontrolled active systemic infection requiring intravenous antimicrobial treatment * Known history of human immunodeficiency virus (HIV) infection. Active hepatitis B infection (defined as the presence of detectable HBV DNA, HBe antigen or HBs antigen). Patients with serologic evidence of prior vaccination (HBsAg negative, anti-HBs antibody positive, anti-HBc antibody negative) are eligible. Patients who are HBsAg negative/HBsAb positive but HBcAb positive are eligible, provided HBV DNA is negative. Active hepatitis C, defined by the detectable hepatitis C ribonucleic acid (RNA) in plasma by polymerase chain reaction (PCR) * Active, uncontrolled autoimmune phenomenon (autoimmune hemolytic anemia or immune thrombocytopenia) requiring steroid therapy with \> 20mg daily of prednisone dose or equivalent * Known hypersensitivity to trial drugs or to any component of the trial drugs * Known allergy to both xanthine oxidase inhibitors and rasburicase * Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risk associated with trial participation or investigational product administration or may interfere with the interpretation of trial results and/or would make the patient inappropriate for enrollment into this trial