a prospective, multicenter, phase-ii trial of ibrutinib plus venetoclax in patients with creatinine clearance >= 30 ml/min who have relapsed or refractory chronic lymphocytic leukemia (rr-cll) with or without tp53 aberrations

Conditions: Chronic Lymphocytic Leukemia in Relapse; Chronic Lymphocytic Leukemia in Remission

Summary: the aim of the current trial is to evaluate if combination treatment with venetoclax + ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia (rr cll) can lead to mrd negativity, which may induce long lasting remissions for mrd-negative patients randomized to stopping treatment after 15 induction cycles.


Eligibility criteria:
inclusion criteria: * 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 /μl 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) ≥ 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) ≤ 3.0 x upper limit of normal (uln) * bilirubin ≤1.5 x uln (unless bilirubin rise is due to gilbert's syndrome or of nonhepatic 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. exclusion criteria: * 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.