Belimumab in Patients with Chronic Lymphocytic Leukemia

Inclusion Criteria:

• Male or female ≥18 years of age.

• Diagnosis of CLL/SLL established according to iwCLL criteria

• Refractory or relapsed CLL that warrants treatment (according to modified criteriafor initiation of therapy (Hallek et al., 2018)):

1. Massive (ie, lower edge of spleen ≥6 cm below the left costal margin),progressive, or symptomatic splenomegaly, or

2. Massive (ie, ≥10 cm in the longest diameter), progressive, or symptomaticlymphadenopathy, or

3. Progressive lymphocytosis in the absence of infection, with an increase inblood ALC≥50% over a 2-month period or lymphocyte doubling time of <6 months (as long as initial ALC was ≥30,000/L), or

4. Autoimmune anemia and/or thrombocytopenia that is poorly responsive tocorticosteroids or other standard therapy, or

5. Constitutional symptoms, defined as any one or more of the followingdisease-related symptoms or signs occurring in the absence of evidence ofinfection:

• Unintentional weight loss of ≥10% within the previous 6 months, or

• Significant fatigue (≥Grade 2), or

• Fevers >38.0°C for ≥2 weeks, or

• Night sweats for >1 month.

• CLL relapsing after any line of treatment that included radiotherapy, chemotherapy,immunotherapy, or small molecules. Patients who relapse after a previous therapywith venetoclax can be included in the study in case of a late relapse (i.e. >18months after venetoclax was discontinued.

• Discontinuation of all therapy (including radiotherapy, chemotherapy, immunotherapy,or small molecules) for the treatment of CLL ≥2 weeks before study treatmentexcluding systemic corticosteroids for symptomatic control.

• All acute toxic effects of any prior antitumor therapy resolved to Grade ≤1 beforetreatment (with the exception of alopecia [Grade 1 or 2 permitted], neurotoxicity [Grade 1 or 2 permitted], or bone marrow parameters [any of Grade 1, 2, 3, or 4permitted).

• Eastern Cooperative Oncology Group [ECOG] < 3.

• Required baseline laboratory data (within 4 weeks prior to treatment):

• Serum total bilirubin ≤1.5 x ULN (unless directly attributable to CLL disease or toGilbert's Syndrome)

• ALT/AST ≤2.5 x ULN

• Renal creatinine clearance >30 ml/min

• Neutrophile count >1.000/μl (unless directly attributable to CLL disease)

• Negative serological Hepatitis B and C test or negative PCR in case of positiveserological test without evidence of an active infection, negative HIV test within 6weeks prior to treatment.

• Written informed consent of the subject after clarification

Exclusion Criteria:

• (Suspicion of) transformation of CLL (i.e. Richter's transformation, pro-lymphocyticleukemia) or central nervous system (CNS) involvement

• IgG < 4 g/L under substitution of immunoglobulins

• Early relapse (i.e <18 months) after any line of treatment that included venetoclax.

• Malignancies other than CLL currently requiring systemic therapies

• Evidence of active systemic bacterial (e.g. tuberculosis), fungal, or viralinfection (e.g., CMV) at the time of initiation of therapy

• Confirmed progressive multifocal leukencephalopathy (PML)

• Known history of drug-induced liver injury (DILI), chronic/active hepatitis C (HCV),chronic/active hepatitis B (HBV)

• Requirement of therapy with strong CYP3A4 inhibitors/ inducers or anticoagulant withphenprocoumon or other vitamin K-antagonists

• Active inflammatory bowel disease

• History of prior allogeneic bone marrow or organ transplantation

• Ongoing immunosuppressive therapy. Subjects may use topical, enteric, or inhaledcorticosteroids as therapy for comorbidities and systemic steroids for autoimmuneanemia and/or thrombocytopenia. Ongoing use of low-dose systemic corticosteroids (≤5mg/day of methylprednisolone or equivalent) for rheumatologic conditions ispermitted

• History of primary immunodeficiency

• Concurrent participation in another therapeutic clinical trial

• History of serious suicide risk including any suicidal behaviour in the last 6months

• Live vaccination 30 days prior to treatment

• Hypersensitivity known from medical history to one of the drugs used or theiringredients or to drugs with a similar chemical structure

• Simultaneous participation in another interventional clinical trial (includingwithin the last 4 weeks before inclusion)

• Addictions or other illnesses that do not allow the person concerned to assess thenature and extent of the clinical trial and its possible consequences

• Pregnant or breastfeeding women

• Women of childbearing potential, except women who meet the following criteria:

• post-menopausal (12 months natural amenorrhoea or 6 months amenorrhoea withserum FSH > 40 U/ml)

• postoperative (6 weeks after bilateral ovarectomy with or without hysterectomy)

• regular and correct use of a contraceptive method with an Pearl Index < 1% peryear, which will have to be continued for up to four months after thediscontinuation of the study drug

• sexual abstinence

• Vasectomy of the partner

• Male subjects who are able to father a child, except men who meet the followingcriteria:

• willingness to abstain from heterosexual intercourse or use aprotocolrecommended method contraception from the screening visit throughoutthe study treatment period and for 90 days following the last dose of studydrug

• refrain from sperm donation from screening visit throughout the study treatmentperiod and for four months following the last dose of study drug

• Indications that the subject is unlikely to adhere to the protocol (e.g., lack ofcompliance)