A Study of Ibrutinib in Combination With Bendamustine and Rituximab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

PFS was defined as the interval between the date of randomization and the date of disease progression or death, whichever was first reported. IWCLL 2008 criteria for PD: New enlarged nodes \>1.5 cm, new hepatomegaly or splenomegaly, or other new organ infiltrates, bone lesion, ascites, or pleural effusion confirmed due to chronic lymphocytic leukemia (CLL); \>=50% increase in existing lymph nodes; \>=50% increase in enlargement of liver or spleen; \>=50% increase from baseline in lymphocyte count (and to \>=5\*10\^9/L) or \>=50% increase from nadir count confirmed on \>=2 serial assessments if absolute lymphocyte count (ALC) \>=30,000 per microliter and lymphocyte doubling time is rapid, unless considered treatment-related lymphocytosis; new cytopenia (Hemoglobin b \[Hgb\] or platelets) attributable to CLL; and transformation to a more aggressive histology.

Time frame: Up to 5 years

Population: Intent to treat (ITT) population included all participants randomized into the study regardless of treatment actually received.

Change from baseline in beta2 microglobulin at end of treatment at time of primary analysis was reported.

Time frame: Baseline to EOT (Up to 2 years)

Population: ITT population included all participants randomized into the study regardless of treatment actually received. Here, 'N' (number of participants analyzed) signifies number of participants evaluable for this endpoint.

EORTC QLQ-C30 Physical Functioning Score is a questionnaire to assess quality of life of cancer patients. It is composed of 30 items, multi-item measure (28 items) and 2 single-item measures. For the multiple item measure, 4-point scale is used and the score for each item range from 1 = not at all to 4 = very much. Higher scores indicate worsening. The 2 single-item measure involves question about the overall health and overall quality of life which was rated on a 7-point scale ranging from 1 = very poor to 7 = excellent. Lower scores indicate worsening. All scale and item scores were linearly transformed to be in range from 0-100. A higher score represents a higher (better) level of functioning, or a higher (worse) level of symptoms.

Time frame: Baseline to EOT (up to 2 years)

Population: ITT population included all participants randomized into the study regardless of treatment actually received. Here, 'N' (number of participants analyzed) signifies number of participants evaluable for this endpoint.

The EORTC QLQ-CLL 16 is a 16-item disease specific module that comprises 5 domains of patient-reported health status important in CLL. There are three multi-item scales that include fatigue (2 items), treatment side effects and disease symptoms (8 items), and infection (4 items), and 2 single-item scales on social activities and future health worries. Responses are measured on a 4 point scale ranging from 1 (not at all) to 4 (very much).

Time frame: Baseline to EOT (up to 2 years)

Population: ITT population included all participants randomized into the study regardless of treatment actually received. Here, 'N' (number of participants analyzed) signifies number of participants evaluable for this endpoint. Here, 'n' signifies the number of participants analyzed for the specified symptoms.

The EuroQol-5 is a five dimensional health state classification. Each dimension is assessed on a 3-point ordinal scale (1=no problems, 2=some problems, 3=extreme problems). The responses to the five EQ-5D dimensions were scored using a utility-weighted algorithm to derive an EQ-5D health status index score between 0 to 1. High score indicating a high level of utility.

Time frame: Baseline to EOT (up to 2 years)

Population: ITT population included all participants randomized into the study regardless of treatment actually received. Here, 'N' (number of participants analyzed) signifies number of participants evaluable for this endpoint.

The EQ-5D questionnaire is a brief, generic health-related quality of life assessment (HRQOL) that can also be used to incorporate participant preferences into health economic evaluations. The EQ-5D questionnaire assesses HRQOL in terms of degree of limitation on 5 health dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) and as overall health using a visual analog scale with response options ranging from 0 (worst imaginable health) to 100 (best imaginable health).

Time frame: Baseline to EOT (up to 2 years)

Population: ITT population included all participants randomized into the study regardless of treatment actually received. Here, 'N' (number of participants analyzed) signifies number of participants evaluable for this endpoint.

FACIT-Fatigue is an instrument for use as a measure of the effect of fatigue in patients with cancer and other chronic diseases. Responses to the 13-item FACIT Fatigue Scale are reported on a 5-point categorical response scale ranging from 0 (not at all) to 4 (very much). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worst score) to 52 (best score).

Time frame: Baseline to EOT (up to 2 years)

Population: ITT population included all participants randomized into the study regardless of treatment actually received. Here, 'N' (number of participants analyzed) signifies number of participants evaluable for this endpoint.

Time to improvement is defined as the time interval (months) from randomization to the first observation of improvement. FACIT-Fatigue is an instrument for use as a measure of the effect of fatigue in patients with cancer and other chronic diseases. Responses to the 13-item FACIT Fatigue Scale are reported on a 5-point categorical response scale ranging from 0 (not at all) to 4 (very much). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worst score) to 52 (best score).

Time frame: Up to 2 years

Population: ITT population included all participants randomized into the study regardless of treatment actually received.

Number of participants who received subsequent antineoplastic therapy was reported.

Time frame: Up to 5 years

Population: Safety analysis set included all the randomized participants who received at least 1 dose of study drug or placebo.

The disease-related symptoms included fatigue, weight loss, fevers, night sweats, abdominal discomfort/splenomegaly and anorexia.

Time frame: From the date of randomization to disease progression (Up to 2 years)

Population: ITT population included all participants randomized into the study regardless of treatment actually received.

ORR defined as number of participants achieving a complete response (CR), complete response with incomplete marrow recovery (CRi), nodular partial response (nPR) or partial response (PR). IWCLL 2008 criteria: CR- No lymphadenopathy and hepatosplenomegaly, no constitutional symptoms, neutrophils \>1.5\*10\^9/liter (L), platelets \>100\*10\^9/L, Hgb \>11 gram per deciliter (g/dL) and absolute lymphocyte count \<4000/microliter (mcL); CRi- CR with incomplete recovery of bone marrow; nPR- participants meet criteria for CR, but the bone marrow biopsy shows B-lymphoid nodules, may represent a clonal infiltrate; PR-2 of the following when abnormal at baseline: \>=50% decrease in ALC, \>=50% decrease in sum products of up to 6 lymph nodes, \>=50% decrease in enlargement of spleen or liver; and 1 of the following: neutrophils \>1.5\*10\^9/L, Platelets \>100\*10\^9/L and Hgb\>11 g/dL or \>=50% improvement over baseline in any of these; no new enlarged nodes or new hepatosplenomegaly.

Time frame: Up to 5 years

Population: Intent to treat (ITT) population included all participants randomized into the study regardless of treatment actually received.

OS was defined as the interval between the date of randomization and the date of death from any cause.

Time frame: Up to 5 years

Population: Intent to treat (ITT) population included all participants randomized into the study regardless of treatment actually received.

MRD-negative response was defined as the percentage of participants who reach MRD negative disease status (less than 1 chronic lymphocytic leukemia \[CLL\] cell per 10,000 leukocytes) in either bone marrow or peripheral blood. All randomized participants were included in this analysis. Participants with missing MRD data were considered non-responders.

Time frame: Up to 5 years

Population: Intent to treat (ITT) population included all participants randomized into the study regardless of treatment actually received.

Sustained hematologic improvement was defined as hematological improvement that was sustained continuously for greater than or equal to (\>=) 56 days without blood transfusion or growth factors: 1) Platelet counts greater than (\>)100\* 109/liter (L) if baseline less than or equal to (\<=) 100\*109/L or increase \>= 50 percent (%) over baseline; 2) Hemoglobin \>11 gram per deciliters (g/dL) if baseline \<= 11 g/dL or increase \>= 2 g/dL over baseline.

Time frame: Up to 5 years

Population: ITT population included all participants randomized into the study regardless of treatment actually received.