. 2017 Aug 22;18:387. doi: 10.1186/s13063-017-2138-6

Table 1.

Inclusion and exclusion criteria

Inclusion criteria	Exclusion criteria
• At least 18 years old • Maximum age of 75 years old • B-CLL with a characteristic immunophenotype, including small lymphocytic lymphoma • Binet’s stages B, C, or progressive stage A • Requiring therapy by the IWCLL criteria in that participants must have at least one of the following: ○ Evidence of progressive marrow failure as manifested by the development of, or worsening of, anaemia and/or thrombocytopenia ○ Massive (i.e. 6 cm below the left costal margin) or progressive or symptomatic splenomegaly ○ Massive nodes (i.e. 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy ○ Progressive lymphocytosis with an increase of more than 50% over a 2-month period or lymphocyte doubling time (LDT) of less than 6 months as long as the lymphocyte count is over 30 × 10⁹/L ○ A minimum of any one of the following disease-related symptoms must be present: ▪ Unintentional weight loss more than or equal to 10% within the previous 6 months ▪ Significant fatigue (i.e. Eastern Cooperative Oncology Group performance status (PS) 2 or worse; cannot work or unable to perform usual activities) ▪ Fevers of greater than 38.0 °C for 2 or more weeks without other evidence of infection ▪ Night sweats for more than 1 month without evidence of infection • Considered fit for treatment with FCR as determined by the treating clinician • World Health Organisation (WHO) PS of 0, 1 or 2 • Able to provide written informed consent • Biochemical values must be within the following limits within 14 days prior to randomisation and at baseline: ○ Alanine aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN). Aspartate aminotransferase (AST) ≤ 3 × ULN ○ Total bilirubin ≤ 1.5 × ULN, unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin	• Prior therapy for CLL • History or current evidence of Richter’s transformation • Major surgery within 4 weeks prior to randomisation • Active infection • >20% p53 deletion, determined by FISH • Past history of anaphylaxis following exposure to rat or mouse-derived CDR-grafted humanised monoclonal antibodies • Concomitant warfarin (or equivalent vitamin K inhibitor) or other orally administered anticoagulant treatment (anyone requiring anticoagulation treatment for more than 6 months is not eligible for trial entry. It is acceptable to be treated with LMW-heparin for < 6 months on the trial but other anticoagulation should be discussed with the CI) • Pregnancy, lactation or women of child-bearing potential unwilling to use medically approved contraception whilst receiving treatment and for 12 months after treatment with rituximab has finished, or 30 days after treatment with ibrutinib has finished, whichever is the latest. Women must agree to not donate eggs (ova, oocytes) for the purposes of assisted reproduction • Men whose partners are capable of having children but who are not willing to use appropriate medically approved contraception whilst receiving treatment and for 12 months after treatment with rituximab has finished, or 3 months after treatment with ibrutinib has finished, whichever is the latest, unless they are surgically sterile • CNS involvement with CLL • Symptomatic cardiac failure not controlled by therapy, or unstable angina not adequately controlled by current therapy (in patients with a significant cardiac history the left ventricular function should be assessed and patients with severe impairment should be excluded) • Respiratory impairment (bronchiectasis or moderate COPD) • Other severe, concurrent diseases or mental disorders that could interfere with participant’s ability to participate in the study • Inability to swallow orally administered medication • Disease significantly affecting gastrointestinal function and/or inhibiting small intestinal absorption (malabsorption syndrome, resection of the small bowel, poorly controlled inflammatory bowel disease, etc.) • Known HIV positive • Positive serology for hepatitis B (HB) defined as a positive test for HBsAg. In addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HB DNA test will be performed and if positive the subject will be excluded (anyone who is HBsAg − ve/HBcAb + ve/HB DNA–ve should be referred to a liver disease specialist before the start of treatment with rituximab. During treatment, participants should be monitored and managed to prevent HBV reactivation) • Positive serology for hepatitis C (HC) defined as a positive test for HCAb, in which case reflexively perform a HC RIBA immunoblot assay on the same sample to confirm the result • History of prior malignancy, with the exception of the following: ○ Malignancy treated with curative intent and with no evidence of active disease present for more than 3 years prior to screening and felt to be at low risk for recurrence by treating physician ○ Adequately treated non-melanomatous skin cancer or lentigo maligna melanoma without current evidence of disease ○ Adequately treated cervical carcinoma in situ without current evidence of disease • Persisting severe pancytopenia (neutrophils < 0.5 × 10⁹/L or platelets < 50 × 10⁹/L) unless due to direct marrow infiltration by CLL • Current treatment with prednisolone of > 10 mg/day • Active haemolysis (patients with haemolysis controlled with prednisolone at a dose of 10 mg or less per day can be entered into the trial) • Patients with a creatinine clearance of less than 30 mL/min (either measured or derived by the Cockcroft Gault formula or alternative locally approved formula) • History of stroke or intracranial haemorrhage within 6 months prior to enrolment • Requirement for treatment with a strong CYP3A4/5 inhibitoror inducer • Cardiac event (e.g. recent myocardial infarction, coronary artery stent) requiring dual antiplatelet treatment

Inclusion criteria

Exclusion criteria

• At least 18 years old
• Maximum age of 75 years old
• B-CLL with a characteristic immunophenotype, including small lymphocytic lymphoma
• Binet’s stages B, C, or progressive stage A
• Requiring therapy by the IWCLL criteria in that participants must have at least one of the following:
○ Evidence of progressive marrow failure as manifested by the development of, or worsening of, anaemia and/or thrombocytopenia
○ Massive (i.e. 6 cm below the left costal margin) or progressive or symptomatic splenomegaly
○ Massive nodes (i.e. 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy
○ Progressive lymphocytosis with an increase of more than 50% over a 2-month period or lymphocyte doubling time (LDT) of less than 6 months as long as the lymphocyte count is over 30 × 10⁹/L
○ A minimum of any one of the following disease-related symptoms must be present:
▪ Unintentional weight loss more than or equal to 10% within the previous 6 months
▪ Significant fatigue (i.e. Eastern Cooperative Oncology Group performance status (PS) 2 or worse; cannot work or unable to perform usual activities)
▪ Fevers of greater than 38.0 °C for 2 or more weeks without other evidence of infection
▪ Night sweats for more than 1 month without evidence of infection
• Considered fit for treatment with FCR as determined by the treating clinician
• World Health Organisation (WHO) PS of 0, 1 or 2
• Able to provide written informed consent
• Biochemical values must be within the following limits within 14 days prior to randomisation and at baseline:
○ Alanine aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN). Aspartate aminotransferase (AST) ≤ 3 × ULN
○ Total bilirubin ≤ 1.5 × ULN, unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin

• Prior therapy for CLL
• History or current evidence of Richter’s transformation
• Major surgery within 4 weeks prior to randomisation
• Active infection
• >20% p53 deletion, determined by FISH
• Past history of anaphylaxis following exposure to rat or mouse-derived CDR-grafted humanised monoclonal antibodies
• Concomitant warfarin (or equivalent vitamin K inhibitor) or other orally administered anticoagulant treatment (anyone requiring anticoagulation treatment for more than 6 months is not eligible for trial entry. It is acceptable to be treated with LMW-heparin for < 6 months on the trial but other anticoagulation should be discussed with the CI)
• Pregnancy, lactation or women of child-bearing potential unwilling to use medically approved contraception whilst receiving treatment and for 12 months after treatment with rituximab has finished, or 30 days after treatment with ibrutinib has finished, whichever is the latest. Women must agree to not donate eggs (ova, oocytes) for the purposes of assisted reproduction
• Men whose partners are capable of having children but who are not willing to use appropriate medically approved contraception whilst receiving treatment and for 12 months after treatment with rituximab has finished, or 3 months after treatment with ibrutinib has finished, whichever is the latest, unless they are surgically sterile
• CNS involvement with CLL
• Symptomatic cardiac failure not controlled by therapy, or unstable angina not adequately controlled by current therapy (in patients with a significant cardiac history the left ventricular function should be assessed and patients with severe impairment should be excluded)
• Respiratory impairment (bronchiectasis or moderate COPD)
• Other severe, concurrent diseases or mental disorders that could interfere with participant’s ability to participate in the study
• Inability to swallow orally administered medication
• Disease significantly affecting gastrointestinal function and/or inhibiting small intestinal absorption (malabsorption syndrome, resection of the small bowel, poorly controlled inflammatory bowel disease, etc.)
• Known HIV positive
• Positive serology for hepatitis B (HB) defined as a positive test for HBsAg. In addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HB DNA test will be performed and if positive the subject will be excluded (anyone who is HBsAg − ve/HBcAb + ve/HB DNA–ve should be referred to a liver disease specialist before the start of treatment with rituximab. During treatment, participants should be monitored and managed to prevent HBV reactivation)
• Positive serology for hepatitis C (HC) defined as a positive test for HCAb, in which case reflexively perform a HC RIBA immunoblot assay on the same sample to confirm the result
• History of prior malignancy, with the exception of the following:
○ Malignancy treated with curative intent and with no evidence of active disease present for more than 3 years prior to screening and felt to be at low risk for recurrence by treating physician
○ Adequately treated non-melanomatous skin cancer or lentigo maligna melanoma without current evidence of disease
○ Adequately treated cervical carcinoma in situ without current evidence of disease
• Persisting severe pancytopenia (neutrophils < 0.5 × 10⁹/L or platelets < 50 × 10⁹/L) unless due to direct marrow infiltration by CLL
• Current treatment with prednisolone of > 10 mg/day
• Active haemolysis (patients with haemolysis controlled with prednisolone at a dose of 10 mg or less per day can be entered into the trial)
• Patients with a creatinine clearance of less than 30 mL/min (either measured or derived by the Cockcroft Gault formula or alternative locally approved formula)
• History of stroke or intracranial haemorrhage within 6 months prior to enrolment
• Requirement for treatment with a strong CYP3A4/5 inhibitoror inducer
• Cardiac event (e.g. recent myocardial infarction, coronary artery stent) requiring dual antiplatelet treatment

CDR complementarity-determining regions, CI chief investigator, CLL chronic lymphocytic leukaemia, CNS central nervous system, COPD chronic obstructive pulmonary disease, DNA deoxyribonucleic acid, RIBA Recombinant Immunoblot Assay, FISH fluorescent in situ hybridisation, IWCLL International Workshop on CLL, LMW low molecular weight