REtreatment With VEnetoclax and Acalabrutinib After Venetoclax Limited Duration (REVEAL)

Inclusion Criteria:

• Documented CLL or SLL requiring treatment according to IWCLL criteria (appendix A)after at least (clinical) partial response as best response after the followinginitial study treatment: venetoclax-rituximab in HOVON 140/GAIA orvenetoclax-obinutuzumab in HOVON 139/GIVE or HOVON 140/GAIA;

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

• Age at least 18 years;

• Adequate BM function defined as:

• Hemoglobin >5 mmol/l or Hb > 8 g/dL

• Absolute neutrophil count (ANC) >0.75 x 109/L (750/μL), unless directlyattributable to CLL infiltration of the BM, proven by BM biopsy

• Platelet count >30 x 109/L (30,000/μL) without transfusion and irrespectivewhether it is attributable to CLL infiltration in the BM;

• Estimated Glomerular Filtration Rate (eGFR) (MDRD) or estimated creatinine clearance (CrCl ≥ 30ml/min (Cockcroft-Gault appendix E); Please note: in case eGFR or CrCl is <50ml/min the patient needs to be considered high risk for TLS

• Adequate liver function as indicated:

• Serum aspartate transaminase (ASAT) and alanine transaminase (ALAT) ≤ 3.0 xupper limit of normal (ULN);

• Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or ofnonhepatic origin);

• Prothrombin time (PT)/International normal ratio (INR) <1.5 x ULN and activatedpartial thromboplastin time (aPTT) <1.5 x ULN;

• Negative serological testing for hepatitis B virus (HBV) (Hepatitis B surfaceantigen (HBsAg) negative and hepatitis B core antibody (anti-HBc) negative) andhepatitis C virus (hepatitis C antibody). Subjects who are positive for anti-HBc orhepatitis C antibody may be included if they have a negative PCR within 6 weeksbefore enrollment. Those who are PCR positive will be excluded; Please note: Forpatients positive for anti-HBc HBV-DNA PCR has to be repeated every month until 12months after last dose of study treatment.

• Patient is able and willing to adhere to the study visit schedule and other protocolrequirements;

• Patient is capable of giving informed consent;

• Written informed consent.

Exclusion Criteria:

• Any prior therapy with BTK inhibitor;

• Prior treatment with venetoclax other than first line;

• Other therapy with exception of chemo-/immunotherapy which is allowed also aftervenetoclax first line relapse;

• Transformation of CLL (Richter's transformation);

• Patient with a history of confirmed progressive multifocal leukoencephalopathy (PML);

• Malignancies other than CLL currently requiring systemic therapy or not treated incurative intention or showing signs of progression after curative treatment;

• Known allergy to xanthine oxidase inhibitors and/or rasburicase;

• History of drug-specific hypersensitivity or anaphylaxis to any study drug (including active product or excipient components);

• Active bleeding or history of bleeding diathesis (e.g. hemophilia or von Willebranddisease);

• Active fungal, bacterial, and/or viral infection that requires systemic therapy;Please note: active controlled as well as chronic/recurrent infections are at riskof reactivation/infection during treatment;

• Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled:infection, auto-immune hemolysis, immune thrombocytopenia, diabetes, hypertension,hyperthyroidism or hypothyroidism etc.);

• Patient known to be HIV-positive;

• Patient requiring treatment with a strong cytochrome P450 (CYP) 3A inhibitor/inducer (see appendix J) or anticoagulant therapy with warfarin or phenoprocoumon or othervitamin K antagonists; Please note: Patients being treated with DOACs apixaban,edoxaban or rivaroxaban can be included, but must be properly informed about thepotential risk of bleeding under treatment with acalabrutinib. (see appendix J)

• History of stroke or intracranial hemorrhage within 6 months prior to registration;

• Severe cardiovascular disease (arrhythmias requiring chronic treatment, congestiveheart failure or symptomatic ischemic heart disease, myocardial infarction within 6months) (CTCAE grade III-IV, see appendix D);

• Severe pulmonary dysfunction (CTCAE grade III-IV, see appendix D);

• Severe neurological or psychiatric disease (CTCAE grade III-IV, see appendix D);

• Patient who has difficulty with or are unable to swallow oral medication, or havesignificant gastrointestinal disease that would limit absorption of oral medication;

• Vaccination with live vaccines within 28 days prior to registration;

• Use of any other experimental drug or therapy within 28 days of registration;

• Major surgery within 28 days prior to registration;

• Steroid therapy within 10 days prior to registration, with the exception of inhaledsteroids for asthma, topical steroids, steroids up to 20 mg or dose equivalents ofprednisolone daily to control autoimmune phenomenon's, or replacement/stresscorticosteroids;

• Pregnant women and nursing mothers;

• Fertile men or women of childbearing potential unless: (1) surgically sterile or ≥ 2years after the onset of menopause; (2) willing to use a highly effectivecontraceptive method such as oral contraceptives, intrauterine device, sexualabstinence or combination of male condom with either cap, diaphragm, or sponge withspermicide (double barrier methods) during study treatment and for 30 days after endof treatment;

• Current participation in other clinical trial (other than follow upHOVON139/HOVON140);

• Any psychological, familial, sociological and geographical condition potentiallyhampering compliance with the study protocol and follow-up schedule.