Ofatumumab vs Physician's Choice in Subjects With Bulky Fludarabine-Refractory Chronic Lymphocytic Leukemia

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.

Time frame: From the randomization date up to 60 months post the randomization date.

Population: Intent-to-treat (ITT) population: all participants who were randomised to receive OFA or PC at the first randomisation.

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 (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; Week (W) 12 (W4 of Cycle\[C\] 3), W24 (W4C6), W36 (W4C9), W48 (W4C13); during Follow-up which was every month for Months (M) 1-6, every 8 weeks for M7-12 and every 3 months up to M60; and then at PD.

Time frame: From the randomization date up to 60 months post the randomization date.

Population: Intent-to-treat (ITT) population: all participants who were randomised to receive OFA or PC at the first randomisation.

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 enlarged 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. Par. who were alive and had not progressed at the time of analysis or if a progression event occurred after extensive lost-to-follow-up time (\>= 12 weeks) were censored at the date of the last visit with adequate assessment. Par. with unknown or missing responses were considered as non-responders.

Time frame: From the randomization date up to 60 months post the randomization date.

Population: ITT population. Only those participants with data available at the indicated time points were analyzed. Only responders (CR, CRi, PR, nPR) were included in the analysis.

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. A score of 3 or less indicates improvement from Baseline. HCQ was assessed at Screening; Week (W) 12 (W4 of Cycle\[C\] 3), W24 (W4C6), W36 (W4C9), W48 (W4C13); during follow-up which was every month for Months 1-6, every 8 weeks for M7-12 and every 3 months up to M60; and then at PD..

Time frame: From the randomization date up to 60 months post the randomization date.

Population: Population Description:~Intent-to-treat (ITT) population: all participants who were randomised to receive OFA or PC at the first randomisation.

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. IgA, IgG, and IgM were measured in the blood samples of the participants. Immunoglobulin testing was performed at Screening (SCR), Cycle 3 Week 4 (C3W4), Cycle 7 Week 4 (C3W4) ,Cycle 9 Week 4 (C3W4), 6 Month Follow-up Visit (6M FU), 9 Month Follow-up (9M FU), 12 Month Follow-up (12M FU), 18 Month Follow-up (18M FU), 24 Month Follow-up (24M FU), 30 Month Follow-up (30M FU), 36 Month Follow-up (36M FU), 42 Month Follow-up (42M FU). A cycle is defined as the time between one round of treatment until the start of the next round.

Time frame: Screening and every 3 months during treatment, every 6 months after last treatment until PD or until 42 Month Follow-up Visit

Population: Safety Population: all participants who received at least one dose of any study treatment (OFA or PC) at the first randomization.

The presence of HAHA in human serum was determined using a validated electrochemiluminescent assay in a multi-tier assay format. All samples were first assessed in a screening (SCR) assay, and the potential positive (Pos) samples were further tested in the confirmation (CNF) assays. Confirmed positives were reported as HAHA positive and titer was determined for each positive sample. The drug tolerance of the HAHA assay is 200 microgram/milliliter (µg/mL); thus, samples that tested negative in the assay and had ofatumumab concentrations no more than 200 µg/mL were considered as conclusive negative (Neg) results.

Time frame: From the randomization date up to 60 months post the randomization date.

Population: Safety Population. Only those participants with post-OFA treatment HAHA results were analyzed.

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. A 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 or incapacity, is a congenital anomaly or birth defect.

Time frame: From the first dose of study medication to 60 days after the last dose of study medication and until follow-up for SAEs unless initiation of subsequent anti-CLL therapy

Population: Safety Population: all participants who received at least one dose of any study treatment (OFA or PC) at the first randomization.

AEs of special interest included cytopenias (neutropenia \[decreased neutrophil count\], anaemia \[decreased hemoglobin\], and thrombocytopenia \[decreased platelet count\]), autoimmune haematologic complications (autoimmune haemolytic anaemia and haemolytic anaemia), infusion reactions, infections, mucocutaneous reactions, Tumour Lysis Syndrome (TLS), cardiovascular events, and small bowel obstruction.

Time frame: From the first dose of study medication to 60 days after the last dose of study medication and until follow-up for SAEs unless initiation of subsequent anti-CLL therapy

Population: Safety Population: all participants who received at least one dose of any study treatment (OFA or PC) at the first randomization.

ORR is defined as the number of participants achieving either complete response (CR) or partial response (PR). Overall response was measured using the IWCLL updated NCI-WG guidelines 2008. CR requires all of the following criteria: 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 and no lymphoid nodules. PR requires the following criteria for at least 2 months: \>=50% decrease in LC, reduction in Ly (i.e., \>=50% decrease in lymph node size or no increase or new lymph nodes), \>=50% decrease in the 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, neutrophils\>1500/μL. Nodular PR (nPR) indicates persistent nodules in the BM.

Time frame: From the randomization date up to 60 months post the randomization date.

Population: ITT Population. Not evaluable is defined as insufficient data present to classify into one of the other categories.

ORR is defined as the number of participants achieving either complete response (CR) or partial response (PR). ORR was measured using the IWCLL updated NCI-WG guidelines 2008. CR requires all of the following criteria: 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 and no lymphoid nodules. PR requires the following criteria for at least 2 months: \>=50% decrease in LC, reduction in Ly (i.e., \>=50% decrease in lymph node size or no increase or new lymph nodes), \>=50% decrease in the 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, neutrophils\>1500/μL. Nodular PR (nPR) indicates persistent nodules in the BM.

Time frame: From the randomization date up to 60 months post the randomization date.

Population: ITT Population. Not evaluable is defined as insufficient data present to classify into one of the other categories.

Overall survival (OS) is defined as the time from randomization to death due to any cause. Kaplan-Meier plots were used to estimate the reported median OS time.

Time frame: From the randomization date up to 60 months post the randomization date.

Population: ITT population. Only those participants with data available were analyzed, participants who had not died were censored at the date of last contact.

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.

Time frame: From the randomization date up to 60 months post the randomization date.

Population: Intent-to-treat (ITT) population: all participants who were randomised to receive OFA or PC at the first randomisation.

Time to next therapy is defined as the time from randomization until the start of the next line of treatment.

Time frame: From the randomization date up to 60 months post the randomization date.

Population: ITT population. Only those participants with data available were analyzed.

Time to progression is defined as the time from the date of randomization to disease progression (PD). PD requires at least one of the following: lymphadenopathy, appearance of any new lesion such as enlarged 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. Participants who were alive and had not progressed at the time of analysis or if a progression event occurred after extensive lost-to-follow-up time were censored at the date of the last visit with adequate assessment.

Time frame: From the randomization date up to 60 months post the randomization date.

Population: ITT population. Only those participants with data available were analyzed.

Time to response is defined as the time from randomization to the first response (Complete Remission\[CR\], Complete Remission with incomplete bone marrow recovery\[CRi\], partial response\[PR\], or 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. Participants with unknown or missing responses were considered as non-responders.

Time frame: From the randomization date up to 60 months post the randomization date.

Population: ITT population. Only responders (CR, CRi, PR, nPR) were included in the analysis. Response was measured using the International Workshop for CLL (IWCLL) updated National Cancer Institute-sponsored Working Group (NCI-WG) guidelines 2008.