Belimumab in Patients with Chronic Lymphocytic Leukemia

Prior treatment

• Requirement of therapy with strong CYP3A4 inhibitors/ inducers or anticoagulant with phenprocoumon or other vitamin K-antagonists
• History of prior allogeneic bone marrow or organ transplantation
• Concurrent participation in another therapeutic clinical trial
• Live vaccination 30 days prior to treatment
• Simultaneous participation in another interventional clinical trial (including within the last 4 weeks before inclusion)
• Male subjects who are able to father a child, except men who meet the following criteria:
  • willingness to abstain from heterosexual intercourse or use a protocolrecommended method contraception from the screening visit throughout the study treatment period and for 90 days following the last dose of study drug
  • refrain from sperm donation from screening visit throughout the study treatment period and for four months following the last dose of study drug

Other illness

• Malignancies other than CLL currently requiring systemic therapies
• Evidence of active systemic bacterial (e.g. tuberculosis), fungal, or viral infection (e.g., CMV) at the time of initiation of therapy
• Known history of drug-induced liver injury (DILI), chronic/active hepatitis C (HCV), chronic/active hepatitis B (HBV)
• Active inflammatory bowel disease
• Ongoing immunosuppressive therapy. Subjects may use topical, enteric, or inhaled corticosteroids as therapy for comorbidities and systemic steroids for autoimmune anemia and/or thrombocytopenia. Ongoing use of low-dose systemic corticosteroids (≤5 mg/day of methylprednisolone or equivalent) for rheumatologic conditions is permitted
• History of primary immunodeficiency
• History of serious suicide risk including any suicidal behaviour in the last 6 months
• Hypersensitivity known from medical history to one of the drugs used or their ingredients or to drugs with a similar chemical structure
• Addictions or other illnesses that do not allow the person concerned to assess the nature and extent of the clinical trial and its possible consequences

Lab values

• IgG \< 4 g/L under substitution of immunoglobulins
• Women of childbearing potential, except women who meet the following criteria:
  • post-menopausal (12 months natural amenorrhoea or 6 months amenorrhoea with serum 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% per year, which will have to be continued for up to four months after the discontinuation of the study drug
  • sexual abstinence
  • Vasectomy of the partner

Other

• (Suspicion of) transformation of CLL (i.e. Richter's transformation, pro-lymphocytic leukemia) or central nervous system (CNS) involvement
• Early relapse (i.e \<18 months) after any line of treatment that included venetoclax.
• Confirmed progressive multifocal leukencephalopathy (PML)
• Pregnant or breastfeeding women
• Indications that the subject is unlikely to adhere to the protocol (e.g., lack of compliance)

• 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 criteria for initiation of therapy (Hallek et al., 2018)):
  • Massive (ie, lower edge of spleen ≥6 cm below the left costal margin), progressive, or symptomatic splenomegaly, or
  • Massive (ie, ≥10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy, or
  • Progressive lymphocytosis in the absence of infection, with an increase in blood ALC≥50% over a 2-month period or lymphocyte doubling time of \<6 months (as long as initial ALC was ≥30,000/L), or
  • Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids or other standard therapy, or
  • Constitutional symptoms, defined as any one or more of the following disease-related symptoms or signs occurring in the absence of evidence of infection:
  • 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 therapy with venetoclax can be included in the study in case of a late relapse (i.e. \>18 months after venetoclax was discontinued.
• Discontinuation of all therapy (including radiotherapy, chemotherapy, immunotherapy, or small molecules) for the treatment of CLL ≥2 weeks before study treatment excluding systemic corticosteroids for symptomatic control.
• All acute toxic effects of any prior antitumor therapy resolved to Grade ≤1 before treatment (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 4 permitted).
• 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 to Gilbert'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 positive serological test without evidence of an active infection, negative HIV test within 6 weeks prior to treatment.
• Written informed consent of the subject after clarification