Ofatumumab Added to Fludarabine-Cyclophosphamide vs Fludarabine-Cyclophosphamide Combination in Relapsed Subjects With Chronic Lymphocytic Leukemia

Overall survival is defined as the time from randomization to death due to any cause. Each participant was followed at the time when the last IRC-assessed PFS events occurred. Participants who had not died were censored at the date of last contact.

Time to response is defined as the time from randomization to the first response. Complete Response/remission(CR) all the criteria at least 2 months after last treatment: no lymphadenopathy(Ly) > 1.5 cm/ hepatomegaly/spleenomegaly/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. Incomplete bone marrow recovery(CRi): CR criteria, persistent anemia/thrombocytopenia/neutropenia unrelated to CLL but related to drug toxicity. Partial Remission/response(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. Nodular PR(nPR): persistent nodules BM.

DOR is defined as the time from the initial response (CR, CRi, nPR, or PR) to the first documented sign of PD or death due to any cause. PD requires at least one of the following: lymphadenopathy, appearance of any new lesion such as enlargerd lymph nodes (>1.5 cm) spleen or liver or other infiltrates or an increase by 50% or more in the greatest diameter of any previous site; an increase by 50% or more in the previously noted enlargement of the liver or spleen, an increase by 50% or more in the numbers of blood lymphocytes with at least 5000 lymphocytes per microliter, transformation to a more aggressive histology, or occurrence of cytopenia attributable to chronic lymphocytic leukaemia.

Time to progression is defined as the time from the date of randomization to PD. PD requires at least one of the following: lymphadenopathy, appearance of any new lesion such as enlargerd lymph nodes (>1.5 cm) spleen or liver or other infiltrates or an increase by 50% or more in the greatest diameter of any previous site; an increase by 50% or more in the previously noted enlargement of the liver or spleen, an increase by 50% or more in the numbers of blood lymphocytes with at least 5000 lymphocytes per microliter, transformation to a more aggressive histology, or occurrence of cytopenia attributable to chronic lymphocytic leukaemia.

Time to next therapy is defined as the time from randomization until the start of the next-line of treatment. Data are presented for participants who took anti-cancer therapies and participants in the ITT population.

The ECOG performance status scales and criteria are used by doctors and researchers to assess how a participant's disease is progressing, how the disease affects the daily living, and determines appropriate treatment and prognosis. ECOG performance status are measured at Cycle 2 Day1, Cycle 3 Day1, Cycle 4 Day1, Cycle 5 Day1 and Cycle 6 Day1. During follow period, 1 M after study drug therapy, then every 3 month up to 5 year (up to 60 months). Improvement is defined as a decrease from baseline by at least one step on the ECOG performance status scale (yes/no).

Participants with no B-symptoms (B-Sy) (no night sweat, no weight loss, no fever and no extreme fatigue) and at least one indicated B-sy(night sweats, weight loss, fever or extreme fatigue) were presented at Screening, Cycle 1 Day 1, Cycle 2 Day1, Cycle 3 Day1, Cycle 4 Day1, Cycle 5 Day1, Cycle 6 Day 1 and during follow up period at 1 M after study drug therapy, then every 3 M up to 5 year (up to 60 months).

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]). CR (all the criteria at least 2 months after last treatment): no lymphadenopathy (Ly) > 1.5 cm/ 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. nPR: persistent nodules BM.

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]). CR (all the criteria at least 2 months after last treatment): no lymphadenopathy (Ly) > 1.5 cm/ 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. nPR: persistent nodules BM.

Responder = CR + CRi + NPR + PR

MRD refers to small number of leukemic cells that remain in the participant during treatment or after treatment at the time the participant achieved a confirmed CR. MRD analysis was performed for the participants who were suspected of achieving a primary endpoint CR. MDR was performed by flow cytometry on a bone marrow or peripheral blood sample taken at least 2 months after final treatment. MRD negative was defined as less than one CLL cell per 10000 leukocytes.

MRD refers to small number of leukemic cells that remain in the participant during treatment or after treatment at the time the participant achieved a confirmed CR. MRD analysis was performed for the participants who were suspected of achieving a primary endpoint CR. MDR was performed by flow cytometry on a bone marrow or peripheral blood sample taken at least 2 months after final treatment. MRD negative was defined as less than one CLL cell per 10000 leukocytes.

An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury.

Serum samples for analysis of HAHA were collected at Baseline (Screening), after 3 cycles were compelted, after 1 M and 6 M post last dose. All samples were first tested in a screening step; positive samples from the screening were further evaluated in a confirmation test. The confirmed positive samples were reported as HAHA-positive.

AIHA is a condition where the body's immune system fails to recognize red blood cells as "self" and begins destroying these red blood cells. The number of participants experienced AIHA are presented.

An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury. Maximum severity grades were evaluated according to the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) version 3.0 (1, mild; 2, moderate; 3, severe; 4, life-threatening/disabling; 5, death).

Participants with at least one Grade 3 or Grade 4 myelosuppression (anemia, neutropenia, and thrombocytopenia) are presented. Myelosuppression is defined as the decrease in the ability of the bone marrow to produce blood cells. AEs were graded according to NCI common terminology criteria for adverse events (CTCAE) grade, version 3.0 (1, mild; 2, moderate; 3, severe; 4, life-threatening/disabling; 5, death).

Participants who received no transfusion and at least one transfusion during the study are presented. Participants who took any blood products or blood supportive care product are included.

Immunoglobulins, or antibodies, are large proteins used by the immune system to identify and neutralize foreign particles such as bacteria and viruses. Their normal blood levels indicate proper immune status. Low levels indicate immuno-suppression. Blood samples were collected from each participant and IgA, IgG, and IgM were measured at Baseline, and 1M and 6M after last dose during follow up period.

CD5+ and CD19+ cells were counted by flow cytometry at Screening (Baseline) on Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 2 Day 15, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 during the treatment period and after last dose of study drug at 1 M and then every three month follow up up to 45 M. Flow cytometry is a technique for counting and examining microscopic particles with an electronic detection apparatus. Baseline is defined as the assessment closest to but prior to first dose (e.g. day 1 if available, otherwise, screening). Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

CD5- CD19+ cells were counted by flow cytometry at Screening (baseline) at Cycle 1 Day1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 2 Day 15, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 during treatment period and after last dose of study drug at 1 M and then every three month up to 45 M during follow up period. Flow cytometry is a technique for counting and examining microscopic particles with an electronic detection apparatus. Baseline is defined as the assessment closest to but prior to first dose (e.g. Day 1 if available otherwise screening). Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Blood samples were collected for the assessment of the following prognostic markers at BL: immunoglobulin heavy chain variable region(IgVH) homology; Zeta-Chain-Associated Protein Kinase 70(ZAP70), VH3-21 usage; Cytogenetics (by fluorescent in situ hybridization [FISH]); beta 2 microglobulin. Cox-regression model was used to explore the relationship between progression-free survival and the following explanatory variables: treatment group, cytogenetics (analyzed by FISH included 6q-,11q-, +12q, 17p-, 13q-) , ZAP-70 (positive, negative or intermediate), VH3-21 usage (Yes and No), IgVH homology (>98%, 97%-98% and <97%), beta 2 microglobulin (>3500 microgram per liter [µg/L] and <=3500 µg/L). For each covariate, a hazard ratio <1 indicates a lower risk on the first effect tested compared with the other effects tested. Cytogenetics Group (based on >=20%)=cytogenetics (CY G).

The EORTC QLQ-CLL16 is comprised of 16 questions that address 5 domains of health-related quality of life (HRQoL) important in CLL. There are 4 multi-item scales - fatigue (2 items), treatment side effects ([TSE], 4 items), disease symptoms (disease effects scale [DES], 4 items), and infection scale [IS] (4 items) - and single item scales (social activities [Social Problems (SP) Scale] and future health worries[Future Health (FH) Scale].). These are measured on a four point scale where 1 = not at all and 4 = very much. These scores are transformed to give a rating from 0 - 100, where 0 =no symptoms or problems and 100 = a severe symptoms or problems. EORTC QLQ-CLL16 was assessed at Screening; Cycle 4 Day 1 and during follow-up 1 M and every 3 M up to 24 months. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. The Baseline value was obtained at randomization.

EQ-5D is comprised of a 5-item health status measure and a visual analogue scale (VAS) and is used to generate two scores: the utility score and the thermometer score. The utility score measures mobility, self-care, usual activities, pain, discomfort, and anxiety/depression. Responses to each of the 5 health states are measured on a 3-point scale (level 1 = no problem; level 2 = some or moderate problem(s) and level 3 = unable, or extreme problems). Responses are typically converted into health utilities or valuations on a scale ranging from 0 (death) to 1 (perfect health). The thermometer score ranges from 0 (worst imaginable health state) to 100 (best imaginable health state). Change from Baseline was calculated as the post-Baseline value minus the Baseline value. A Negative health status describes health state worse than death.Baseline is the most recent, non-missing value prior to or on the first study drug dose date.

EORTC QLQ-C30, a self-reported, cancer-specific instrument assessing 15 domains: physical, role, emotional, cognitive and social functioning, pain,fatigue, nausea and vomiting, insomnia, loss of appetite, constipation, diarrhea, and dyspnea, financial difficulties and a global health status/quality of life (QOF). Functional and symptoms scales were measured on four point Likert scale where 1 = not at all and 4 = very much. Pat. assessed at Screening; Cycle 4 Day 1 and during follow-up 1 M and every 3 M up to 24 months. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Baseline is the most recent, non-missing value prior to or on the first study treatment dose date. Clinically meaningful changes or minimally important differences (MIDs)have been previously established for the EORTC QLQ C30, and categorized as 'small' if the mean change in scores is 5-10 points, 'moderate' if 10-20 points, and 'large' if >20points.

The HCQ consists of a single question in which the participant is asked if he/she has experienced any change in his/her health overall since beginning the study. For HCQ, values from 1 to 9 were assigned to the 9 responses in the HCQ questionnaire, ranging from 1 for 'my health is a great deal better' to 9 for 'my health is a great deal worse' since the beginning of the study. Lower scores represent better conditions.

Area under the time-concentration curve (AUC) over the dosing interval (AUC[0-tau]) was evaluated. Blood samples were collected from participants who received ofatumumab plus fludarabine and cyclophosphamide predose and 0.5 h after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4 (Days 1, 8, and 85). In addition, predose samples were collected prior to ofatumumab administration at Cycles 2, 3, 5, and 6 (Days 29, 57, 113, and 141).

Blood samples were collected to assess the plasma concentration of ofatumumab.Cmax and Ctrough were determined. Blood samples were collected from participants who received ofatumumab plus fludarabine and cyclophosphamide predose and 0.5 h after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4 (Days 1, 8, and 85). In addition, predose samples were collected prior to ofatumumab administration at Cycles 2, 3, 5, and 6 (Days 29, 57, 113, and 141).

Blood samples were collected from participants who received ofatumumab plus fludarabine and cyclophosphamide predose and 0.5 h after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4.