Een wetenschappelijk onderzoek met nieuwe middelen, Ibrutinib en Venetoclax, bij patiënten met chronische lymfatische leukemie (CLL), waarbij de ziekte na eerdere behandeling is teruggekeerd of eerdere behandeling onvoldoende respons heeft opgeleverd.

♦ Documented CLL or SLL requiring treatment according to IWCLL criteria after either being refractory to first line therapy or relapse after initial therapy.

♦ Age at least 18 years.

♦ Adequate bone marrow function defined as:

- Absolute neutrophil count (ANC) >0.75 x 109/L

- Platelet count >30,000 /¦ÌL 30 x 109/L.

- Hemoglobin >8.0 g/dL (5 mmol/L)

Unless directly attributable to CLL infiltration of the bone marrow, proven by bone marrow biopsy

♦ Creatinine clearance (CrCL) ¡Ý 30ml/min calculated according to the modified formula of Cockcroft and Gault or directly measured with 24hr urine collection.

♦ Adequate liver function as indicated

- Serum aspartate transaminase (AST) or alanine transaminase (ALT) ¡Ü 3.0 x upper limit of normal (ULN)

- Bilirubin ¡Ü1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin)

- Prothrombin time (PT)/International normal ratio (INR) <1.5 x ULN and PTT (activated partial thromboplastin time [aPTT]) <1.5 x ULN (unless abnormalities are related to coagulopathy or bleeding disorder).

♦ Negative serological testing for hepatitis B (HBsAg negative and anti-HBc negative; patients positive for anti-HBc may be included if PCR for HBV DNA is negative and HBV-DNA PCR is performed every month until 12 months after last dose), negative testing for hepatitis C RNA within 42 days prior to registration.

♦ WHO/ECOG performance status 0-3 (appendix C), stage 3 only if attributable to CLL.

♦ Negative pregnancy test at study entry (for women of childbearing potential).

♦ Male and female subjects of reproductive potential must agree to use both a highly effective method of birth control (e.g. implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], complete abstinence , or sterilized partner) and a barrier method (e.g., condoms, cervical ring, sponge, etc.) during the period of therapy and for 90 days after the last dose of study drug.

♦ Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements.

♦ Written informed consent.

♦ Any prior therapy with ibrutinib and/or venetoclax.

♦ Transformation of CLL (Richter¡¯s transformation).

♦ Patients with a history of confirmed progressive multifocal leukoencephalopathy (PML).

♦ Malignancies other than CLL currently requiring systemic therapies or not being treated in curative intention before or showing signs of progression after curative treatment.

♦ Known allergy to xanthine oxidase inhibitors and/or rasburicase.

♦ Known bleeding disorders (e.g., von Willebrand¡¯s disease or hemophilia).

♦ Uncontrolled or active infection.

♦ Patients requiring treatment with a strong cytochrome P450 (CYP) 3A inhibitor (see appendix K). or anticoagulant therapy with warfarin or phenoprocoumon or other vitamin K antagonists. Please note: Patients being treated with NOACs can be included, but must be properly informed about the potential risk of bleeding under treatment with ibrutinib.

♦ History of stroke or intracranial hemorrhage within 6 months prior to registration.

♦ Major surgery within 28 days prior to registration.

♦ Use of investigational agents which might interfere with the study drug within 28 days prior to registration.

♦ Vaccination with live vaccines within 28 days prior to registration

♦ Steroid therapy within 7 days prior to registration, with the exception of inhaled steroids for asthma, topical steroids, steroids up to 25 mg of prednisolone daily to control autoimmune phenomenon¡¯s, or replacement/stress corticosteroids.

♦ Pregnant women and nursing mothers.

♦ Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule.