REtreatment With VEnetoclax and Acalabrutinib After Venetoclax Limited Duration (REVEAL)
REtreatment With VEnetoclax and Acalabrutinib After Venetoclax Limited Duration (REVEAL)
Fixed-duration regimens containing combinations of venetoclax with CD20 targeting agents are
 expected to soon become standard practice in first-line patients with chronic lymfocytic
 leukemia (CLL). The advantage of a fixed duration venetoclax combination as part of
 first-line treatment is the potential to retreat with venetoclax in patients who develop
 relapsed disease after a treatment free period. However, efficacy of venetoclax retreatment
 following a fixed duration venetoclax combination is still hypothetical as clinical data are
 lacking. Thus, there is an urgent need for data proving efficacy of venetoclax combinations
 following venetoclax treatment cessation. Testing of a novel venetoclax-containing regimen
 for relapsed CLL without the repeat of anti-CD20 monoclonal antibody (mAb) is a rational
 approach.
First-line venetoclax and CD20 antibody containing regimens that are currently being tested
 are based on either a fixed duration schedule or on an MRD-based time-limited schedule. The
 assumption of these regimens is that, aside from the deep (often uMRD) and often longstanding
 remissions, relapsed disease can be retreated with a venetoclax-based regimen. This, however,
 has not been formally proven.

 In this study, patients who received a first line regimen with either venetoclax and
 rituximab (GAIA/CLL13/HOVON 140 trial, [NCT02950051] ) or venetoclax and the second
 generation anti-CD20 antibody obinutuzumab (GAIA/CLL13/HOVON 140 trial, and the HOVON139
 trial [Netherlands Trial Registry ID number #NTR6043]) and have relapsed with the need for a
 subsequent treatment are eligible to enter the study and to receive a combination of
 venetoclax with the highly selective BTK inhibitor acalabrutinib. Combination of venetoclax
 with acalabrutinib is expected to lead to uMRD, making discontinuation of therapy possible.
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 following
 initial study treatment: venetoclax-rituximab in HOVON 140/GAIA or
 venetoclax-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 directly
 attributable to CLL infiltration of the BM, proven by BM biopsy

 -  Platelet count >30 x 109/L (30,000/μL) without transfusion and irrespective
 whether 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 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 activated
 partial thromboplastin time (aPTT) <1.5 x ULN;

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

 -  Patient is able and willing to adhere to the study visit schedule and other protocol
 requirements;

 -  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 after
 venetoclax 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 in
 curative 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 Willebrand
 disease);

 -  Active fungal, bacterial, and/or viral infection that requires systemic therapy;
 Please note: active controlled as well as chronic/recurrent infections are at risk of
 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 other
 vitamin K antagonists; Please note: Patients being treated with DOACs apixaban,
 edoxaban or rivaroxaban can be included, but must be properly informed about the
 potential 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, congestive
 heart failure or symptomatic ischemic heart disease, myocardial infarction within 6
 months) (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 have
 significant 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 inhaled
 steroids for asthma, topical steroids, steroids up to 20 mg or dose equivalents of
 prednisolone daily to control autoimmune phenomenon's, or replacement/stress
 corticosteroids;

 -  Pregnant women and nursing mothers;

 -  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, sexual
 abstinence or combination of male condom with either cap, diaphragm, or sponge with
 spermicide (double barrier methods) during study treatment and for 30 days after end
 of treatment;

 -  Current participation in other clinical trial (other than follow up
 HOVON139/HOVON140);

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