HO182 CLL: Treatment of patients with chronic lymphocytic leukemia (CLL) with 6 cycles of rituximab in combination with 6 or 26 cycles of venetoclax upon recurrence of the disease after previous treatment

Prior treatment

• Active treatment with anti-neoplastic drugs in another clinical trial.
• Patient received prior venetoclax treatment within 24 months of registration OR patient had progressed during previous venetoclax treatment.
• Malignancies other than CLL/SLL currently requiring systemic therapy, not treated with curative intent, or showing signs of progression after curative treatment.
• Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, etc.).
• Previous participation in the HO139 CLL or HO140 CLL trial, and eligible for and willingness to participate in the HO159 CLL trial.

Other illness

• Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
• Patient with a history of confirmed progressive multifocal leukoencephalopathy (PML).
• Known allergy to xanthine oxidase inhibitors and/or rasburicase.
• History of drug-specific hypersensitivity or anaphylaxis to any study drug.
• Severe cardiovascular disease (arrhythmias requiring chronic treatment, congestive heart failure or symptomatic ischemic heart disease) (CTCAE grade III-IV).
• Severe neurological or psychiatric disease (CTCAE grade III-IV).
• Active fungal, bacterial, and/or viral infection that requires systemic therapy.
• Patient known to be HIV-positive.
• Patient who has difficulty with or are unable to swallow oral medication, or have significant gastrointestinal disease that would limit absorption of oral medication.

Age

• Fertile men or women of childbearing potential unless: (1) surgically sterile or ≥ 2 years after the onset of menopause; (2) willing to use a highly effective contraceptive method such as oral contraceptives, intrauterine device or sexual abstinence during study treatment and for 30 days after last dose of venetoclax and/or 12 months after the last dose of rituximab.

Other

• Transformation of CLL (Richter’s transformation).
• Patient with central nervous system involvement.
• Severe pulmonary dysfunction (CTCAE grade III-IV).
• Patient with Child Pugh C.
• Pregnant women and nursing mothers.

• Documented relapsed or refractory CLL or SLL following at least one systemic 1st-line treatment.
• TP53 mutation status tested after last treatment.
• Del17p mutation status tested after last treatment.
• Patient is able and willing to adhere to the study visit schedule and other protocol requirements.
• Written informed consent.
• Patient is capable of giving informed consent.
• Requiring treatment according to IWCLL 2018 criteria.
• Age at least 18 years.
• WHO performance status 0-3; stage 3 only if attributable to CLL/SLL.
• Adequate BM function defined as:  Hemoglobin (Hb) > 5.0 mmol/l, unless low Hb is directly attributable to CLL/SLL infiltration of the BM;  Absolute neutrophil count (ANC) > 0.75 x 109/L (1,000/μL), unless low ANC is directly attributable to CLL/SLL infiltration of the BM;  Platelet count > 30 x 109/L (30,000/μL), unless low platelets is directly attributable to CLL/SLL infiltration in the BM.
• Estimated Glomerular Filtration Rate (eGFR) (MDRD) or estimated creatinine clearance (CrCl) ≥ 30ml/min (Cockcroft-Gault).
• Adequate liver function as indicated:  serum aspartate transaminase (ASAT) and alanine transaminase (ALAT) ≤ 3.0 x upper limit of normal (ULN); bilirubin ≤ 1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or controlled autoimmune hemolytic anemia).
• Negative serological testing for hepatitis B virus (Hepatitis B surface antigen (HBsAg) negative and hepatitis B core antibody (anti-HBc) negative) and hepatitis C virus (hepatitis C antibody). Patients who are positive for anti-HBc, HBsAg, or hepatitis C antibody must have a negative PCR result before enrollment. Those who are PCR positive will be excluded.
• IGHV mutation status assessed at least once.