Ofatumumab

NEDA-3 (yes/no) is defined as: 1. Absence of confirmed clinical relapse 2. Absence of new MRI activity (Gd+ T1 lesion or new/enlarged T2 lesion) with MRI re-baselined at Month 3 3. Absence of 3-month confirmed disability worsening

Magnetic Resonance Imaging (MRI) was used to measure presence of new or reduction in number of gadolinium enhancing T1 lesions. Each MRI scan was previewed by a local neuroradiologist. The quality of each scan performed was assessed by a central MRI reading center and evaluated for quality, completeness and adherence to the protocol. A nonresponder imputation (NRI) for missing data approach was applied. NRI assumes that a participant was a treatment failure, i.e. non-responder, if they did not have a valid Month 12 MRI assessment, or if they discontinued the study prematurely and did not have a valid Month 12 MRI assessment.

Magnetic Resonance Imaging (MRI) was used to measure presence of new or reduction in number of gadolinium enhancing T1 lesions. Each MRI scan was previewed by a local neuroradiologist. The quality of each scan performed was assessed by a central MRI reading center and evaluated for quality, completeness and adherence to the protocol. A sensitivity analysis of the primary endpoint was performed based on an observed data approach.

The primary endpoint of the study will be the regional glial activity on PET (GALP) measurements at 3 months and 9 months compared to baseline. Individualized z-score maps of brain parenchymal microglial activation were generated using a voxel-by-voxel comparison between each subject's 60-90 minute PET standardized uptake value ratio (SUVR) images (globally normalized) and a control dataset of 9 healthy individuals. GALP scores were calculated as the sum of voxel-by-voxel z-scores \>4 in a given region divided by the total number of voxels in that region. A z-score of 0 represents the reference population mean. Higher z-scores indicate worse outcomes. A z-score \>4 is considered positive and contributes to the average GALP score.

ARR is the number of confirmed relapses in a year calculated based on cumulative number of relapses by patient (adjusted for time-in-study by patient). Confirmed relapses are those accompanied by a clinically relevant change in the expanded disability status scale (EDSS). ARR was estimated from fitting a negative binomial regression model with log-link, and adjusted for prior MS therapies as a factor, number of relapses in previous year, baseline EDSS, baseline number of T1 Gd-enhancing lesions and the subject's age at baseline as covariates. The primary analysis describes the ARR with one-sided 95% confidence bound and test for null hypothesis (H0): ARR \>=0.18 versus alternative hypothesis (H1): ARR\<0.18.

PFS is the interval of time between the date of first randomization to the date of disease progression (PD) or death due to any reason, whichever occurred first. The date of PD was defined as the first occurrence of any criteria of progression. PD criteria requires at least one of the following: progression of lymphadenopathy, \>=50% increase in liver or spleen size, \>=50% increase in number of lymphocytes per microliter, more aggressive histology, occurence of cytopenia after treatment attributable to CLL. Disease progression was determined according to the 2008 International Workshop for Chronic Lymphocytic Leukaemia (IWCLL) update of the National Cancer Institute-sponsored Working Group CLL Guidelines for Response (NCI-WG). PFS was censored at the time of the last follow up for participants who have neither progressed or died.

Disease response assessments will be performed using the International Working Group (IMW)-revised response criteria for malignant lymphoma (Cheson 2007). Complete response requires a disappearance of all evidence of disease.

Bioequivalence of AUCtau ) will be measured over the time period of Week 8 to Week 12 dosing interval comparing the pre-filled syringe (PFS) and autoinjector (AI) devices both administered to the abdomen. Bioequivalence established if both measures meet the corresponding criterion specified by the reference-scaled average bioequivalence (RSABE) approach

Bioequivalence of Cmax will be measured over the time period of Week 8 to Week 12 dosing interval comparing the pre-filled syringe (PFS) and autoinjector (AI) devices both administered to the abdomen. Bioequivalence established if both measures meet the corresponding criterion specified by the reference-scaled average bioequivalence (RSABE) approach

Total number of Gd-enhancing T1 lesions across scans at Week 12, 16, 20, and 24 were adjusted for the different numbers of scans. This was calculated as a rate for population, rather than at patient level, using a negative binomial regression model with log link. The model included each patient's total number of Gd-enhancing T1 lesions as the response variable, and treatment, region, and subgroup of baseline number of Gd-enhancing T1 lesions (0 or \>=1) as explanatory variables, and logarithm of the patient's number of scans as the offset variable.

Proportion of patients responding according to international working Group on chronic lymphocytic leukemia criteria

OR is defined as the number of participants achieving an objective response (complete response \[CR\], CR with incomplete bone marrow recovery \[CRi\], partial response \[PR\], and nodular PR \[nPR\]), after 3 cycles, after 6 cycles, and after the last dose of ofatumumab and bendamustine treatment. CR (all the criteria at least 2 months after last treatment): no lymphadenopathy (Ly)/ hepatomegaly/ splenomegaly/ constitutional symptoms; neutrophils \>1500 per microliter (µL), platelets (PL) \>100,000/µL, hemoglobin (Hb) \>11 grams/deciliter (g/dL), lymphocytes (LC) \<4000/µL, bone marrow (BM) sample must be normocellular for age, \<30% LC, no lymphoid nodule. CRi: CR criteria, persistent anemia/thrombocytopenia/neutropenia unrelated to CLL but related to drug toxicity. PR: \>=50% decrease in LC, Ly, size of liver and spleen and at least one of the following results: PL \>100,000/µL or 50% improvement over Baseline (BL), Hb \>11 g/dL or 50% improvement over BL, LC \<4000/µL. nPR: persistent nodules BM.

Feasibility of mobilization with ofatumumab + chemotherapy is defined as successful collection of 2 x 10\^6CD34+ stem cell/kg and successful purging of the apheresis product of all the markers (i.e., monoclonal B-cells, bcl-2, bcl-1 and/or JH) that were found to be positive on pretreatment evaluation. Mobilization rate is number of participants with successful collection out of total study participants.

Complete response (CR) included all of the following: complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. All target nodes had to have regressed to ≤ 1.5cm in the longest diameter. Non-measureable nodes 1.1 to 1.5cm in the longest diameter and \>1cm in the short axis at baseline had to regress to ≤ 1cm in the short axis by visual estimation; enlarged spleen or liver (with nodules) must have returned to normal size and nodules disappeared and if bone marrow was involved, infiltrate had to have cleared on repeat biopsy sample. CR was not valid without imaging data. The corresponding 2-sided 95% exact confidence interval (CI) of the response rate was estimated by the Clopper-Pearson method.

The amount of ofatumumab and bendamustine in the blood will be measured when given individually or together to obtain Cmax and Area Under the Curve. Bendamustine levels will be collected at Cycles 1 and 2: Predose, 0.25, 0.5, 0.75, 1 (end of infusion), 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, and 24 hours. Ofatumumab will be collected at Cycle 4: Predose, end of infusion, then 1, 2, 24, and 72 hours after end of infusion, then once each on Days 8, 15, and 22.