CLL11: A Study of Rituximab With Chlorambucil or Chlorambucil Alone in Patients With Previously Untreated Chronic Lymphocytic Leukemia (Stage 1b)

Event Free Survival

Event-free survival (EFS) was defined as the time between date of randomization and the date of disease progression/relapse, death, or start of a new anti-leukemic therapy. Progressive disease required at least one of the following: ≥50% increase in the absolute number of lymphocytes, appearance of new palpable lymph nodes (\>15 mm in longest diameter) or any new extra nodal lesion, ≥50% increase in the longest diameter of any previous site of clinically significant lymphadenopathy, ≥50% increase in the enlargement of the liver and/or spleen, Transformation to a more aggressive histology or After treatment, the progression of any cytopenia (a decrease of hemoglobin levels \>20 g/L or \<10 g/dL or a decrease of platelet counts \>50% or \<100 x 10\^9/L or by a decrease of neutrophil counts \>50% or \<1.0 x 10\^9/L).

Time frame: Randomization to clinical cutoff (median observation 57.7 months)

Overall Survival

Overall Survival (OS) was defined as the time between the date of randomization and the date of death due to any cause.

Time frame: Randomization to clinical cutoff (median observation 57.7 months)

Percentage of Participants With End of Treatment Response (EOTR)

EOTR was the first response assessment 56 days from the last dose according to the International Workshop on Chronic Lymphocytic Leukaemia (IWCLL) guidelines. CR required: Peripheral blood lymphocytes below 4 x 10\^9/L, Absence of significant lymphadenopathy, No hepatomegaly, No splenomegaly, Absence of disease, Blood counts above the following values (Neutrophils \>1.5 x 10\^9/L, Platelets \>100 x 10\^9/L, Hemoglobin \>11g/dL) and Bone marrow at least normocellular for age. CRi was CR with incomplete bone marrow recovery. PR required the following for at least 2 months from end of treatment: ≥50% decrease in peripheral blood lymphocyte count from the pre-treatment value AND Either a ≥ 50% reduction in lymphadenopathy OR ≥50% reduction of liver enlargement OR ≥50% reduction of spleen enlargement PLUS at least one of the following: Neutrophils \>1.5 x 10\^9/ or ≥50% increase, Platelets \>100 x 10\^9/L or ≥50% increase, Hemoglobin 11 g/dL or ≥50% increase.

Time frame: Randomization to clinical cutoff (median observation 57.7 months)

Percentage of Participants With Molecular Remission at the End of Treatment

Molecular remission was defined as a minimal residual disease (MRD)-negative result at the end of treatment (assessment that occurred between 56 days and 6 months of last treatment). Molecular remission was assessed for all patients using a blood sample. Additionally, a bone marrow sample was obtained from patients whom the investigator assumed to have a complete response, consistent with the IWCLL guidelines. A combined analysis of blood and bone marrow results was conducted. A patient was considered MRD negative if result was less than 1 CLL cell in 10000 leukocytes (MRD value \< 0.0001) based on the method of allele specific polymerase chain reaction (ASO-PCR).

Time frame: Randomization to clinical cutoff (median observation 57.7 months)

Progression Free Survival Based on Independent Review Committee (IRC) Data

PFS was defined as the time from randomization to the first occurrence of progression, relapse, or death from any cause as assessed by Independent Review Committee. Progressive disease required at least one of the following: ≥50% increase in the absolute number of lymphocytes, appearance of new palpable lymph nodes (\>15 mm in longest diameter) or any new extra nodal lesion, ≥50% increase in the longest diameter of any previous site of clinically significant lymphadenopathy, ≥50% increase in the enlargement of the liver and/or spleen, Transformation to a more aggressive histology or After treatment, the progression of any cytopenia (a decrease of hemoglobin levels \>20 g/L or \<10 g/dL or a decrease of platelet counts \>50% or \<100 x 10\^9/L or by a decrease of neutrophil counts \>50% or \<1.0 x 10\^9/L).

Time frame: Randomization to clinical cutoff date of 9 May 2013 (median observation 22.7 months)

Percentage of Participants With Progression Free Survival Events Based on Independent Review Committee (IRC) Data

Percentage of Participants with Progression Free Survival Events: progression, relapse, or death from any cause as assessed by an Independent Review Committee.

Time frame: Randomization to clinical cutoff date of 9 May 2013 (median observation 22.7 months)

European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Score

The EORTC Quality of Life Questionnaire QLQ-C30 was used to assess patient-reported outcomes (PRO) and symptom burden. The QLQ-C30 contains 30 items including the functional scales of physical functioning (5 items), role functioning (2 items), emotional functioning (4 items), cognitive functioning (2 items), social functioning (2 items) and symptom scales including fatigue (3 items), nausea and vomiting (2 items), and pain (4 items) and six single item scales on dyspnea, sleep disturbance, appetite loss, constipation, diarrhea and financial impact. Final scores are transformed such that they range from 0 - 100, whereby higher scores indicate greater functioning, greater quality of life, or a greater degree of symptoms, with changes of 5 - 10 points considered to be of minimally important difference to participants. A positive change from Baseline indicated improvement.

Time frame: Baseline and Cycle 4 Day 1 (Cy4D1)

European Organization for Research and Treatment of Cancer (EORTC) QLQ-CLL16 Questionnaire Score

EORTC Quality of Life Questionnaire (QLQ-CLL16) module was used to assess patient-reported outcomes and symptom burden. The QLQ-CLL16 module includes three multi-item scales assessing fatigue (2 items), treatment side effects and disease symptoms (8 items), infection (4 items) and two single item scales on social activities and future health worries. Final scores are transformed such that they range from 0 - 100, whereby higher scores indicate greater functioning, greater quality of life, or a greater degree of symptoms, with changes of 5 - 10 points considered to be of minimally important difference to participants. A positive change from Baseline indicated improvement.

Time frame: Baseline and Cycle 4 Day 1 (Cy4D1)

Time to Re-Treatment/New-antileukemic Therapy

Time to re-treatment/new anti-leukemic therapy was defined as time between the date of randomization and the date of first intake of re-treatment or new anti-leukemic therapy.

Time frame: Randomization to clinical cutoff (median observation 57.7 months)

Duration of Response

Duration of Response was defined as the date the response \[either Complete Response (CR) or Partial Response (PR)\] was first recorded until the date of Disease Progression or death due to any cause. Response was assessed according IWCLL guidelines.

Time frame: Randomization to clinical cutoff (median observation 57.7 months)

Percentage of Participants With Best Overall Response

Best overall response according to IWCLL guidelines was defined as the percentage of patients with CR, CRi,PR or nPR. CR required all of the following: Peripheral blood lymphocytes below 4 x 10\^9/L, Absence of significant lymphadenopathy, No hepatomegaly, No splenomegaly, Absence of disease, Blood counts above the following values (Neutrophils \>1.5 x 10\^9/L, Platelets \>100 x 10\^9/L, Hemoglobin \>11g/dL) and Bone marrow at least normocellular for age. CRi was CR with incomplete bone marrow recovery. PR required the following for at least 2 months from end of treatment: ≥50% decrease in peripheral blood lymphocyte count from the pre-treatment value AND Either a ≥ 50% reduction in lymphadenopathy OR ≥50% reduction of liver enlargement OR ≥50% reduction of spleen enlargement PLUS at least one of the following: Neutrophils \>1.5 x 10\^9/ or ≥50% increase, Platelets \>100 x 10\^9/L or ≥50% increase, Hemoglobin 11 g/dL or ≥50% increase.

Time frame: Randomization to clinical cutoff (median observation 57.7 months)