ALBERT

Description: Abstract 719 Background: Fludarabine (FLU), cyclophosphamide and rituximab or other FLU based regimens have shown improvement in response rates, progression-free survival, and in some studies overall survival in patients (pts) with previously untreated CLL or SLL. However, the value of FLU based therapies in older pts is less clear with both clinical trial and retrospective analyses showing no improvement in progression-free and overall survival with FLU based therapy. In contrast, regimens that contain rituximab appear to provide benefit across all age groups. OFA is a fully human Immunoglobulin G1 kappa, monoclonal antibody that targets a unique epitope on the CD20 molecule. Pre-clinical data indicate that OFA has greater NK cell and monocyte mediated killing, complement dependent cytotoxicity, and direct killing against CLL cells. Based on pre-clinical and clinical studies indicating possible increased efficacy of OFA in pts with CLL, our aim was to develop an antibody-only regimen for older pts and pts who refuse FLU-based regimens. Methods: Eligible pts had previously untreated CD20+ B-cell CLL(B-CLL) or SLL according to NCI criteria, ECOG PS of ≤2, and were either ≥ 65 years of age, or pts 18–64 years of age who had declined FLU-based regimens. All pts in this study received OFA as an IV infusion once weekly for a total of 8 weeks. To reduce the possibility of infusion reactions, the first dose of OFA was administered at a dose of 300mg. If the initial 300mg dose of OFA was well tolerated, without occurrence of any infusion associated AEs of ≥ grade 3, subsequent doses of OFA (i.e., Week 2 through Week 8) were given at a dose of 2000mg for cohort 1 and 1000mg for cohort 2. Eight weeks after the 8-week induction treatment (tx) ended; pts were assessed for response to the tx. Pts who progressed received no further tx. Pts who responded to the tx or who did not have disease progression received maintenance therapy - OFA at a dose of 2000mg IV for cohort 1 and 1000mg for cohort 2 every 2 months for 2 years (for a total of 12 doses, in the absence of PD or intolerable toxicity) beginning 3 months after the last dose of OFA. Results: Between 8/2010 and 12/2011, 77 pts were accrued (44 pts on cohort 1, 33 pts on cohort 2), median FU for Cohort 1 was 16.1 months (11.6–20.9) and Cohort 2 7.2 months (3.6–10.7). Median age of cohort 1 was 69 (range 47–88) and cohort 2 was 75 (range 50–93). Rai stage at study entry was I/II/III/IV (cohort 1 15/5/11/14 and cohort 2 9/10/7/7). All pts have completed induction therapy. The most common reason for early discontinuation was due to progressive disease (7 pts). Neutropenia was the most common grade 3/4 hematologic adverse event (10 pts). There were no G3 related non-hematologic AEs in either cohort. Two pts have died (1 due to MI, 1 due to CVA). Response by NCI 1996 criteria and IWCLL 2008 criteria and FISH category are shown below; at the time of this analysis 44 pts on C1 and 22pts on C2 were evaluable for response. Kaplan-Meier estimate of PFS is 74% at 15 months for cohort 1. Time to event data for cohort 2 are immature at this analysis but PFS but will be presented at the meeting. Conclusions: OFA, when given as a single agent, is well tolerated as front-line therapy in pts with CLL/SLL. Response rates and PFS compare favorably to our previous studies with rituximab using the same response criteria, particularly when differences in the age of pts entered onto the study are considered. The optimal single-agent dose of OFA in the front-line setting remains to be determined. Further follow-up of these data my provide insight in the dose/response relationship. Disclosures: Off Label Use: Ofatumumab as front-line treatment for CLL/SLL.

Description: Introduction A number of studies have shown clinical benefits for multiple myeloma (MM) patients who continue to stay on therapy with lenalidomide (LEN), including progression-free survival (PFS) and overall survival (OS) (Palumbo A, et al. NEJM. 2013, McCarthy P, et al. NEJM. 2013, Boccadoro. JCO. 2013). Dose modification is one factor used by physicians to achieve sustained duration of treatment (DOT), particularly to manage toxicities and/or pursue a continuous therapy regimen; in a clinical trial of LEN in newly diagnosed MM (NDMM) patients (pts) followed-up for a median of 30 mos, 42% of pts experienced a dose reduction (Palumbo A, et al. NEJM. 2012). This analysis evaluated whether there is supporting evidence, in a real-world setting, for physicians using LEN dose modification to achieve a longer time on therapy. Objective Medical claims analysis was performed to evaluate the relationship between lenalidomide (LEN), dose modification and DOT among patients with NDMM. Methods A retrospective cohort analysis was conducted using a claims database from a large US payer, covering approximately 14 million commercially insured and Medicare advantage members. Patients with at least two outpatient or one inpatient medical claims associated with a diagnosis of MM (ICD-9-CM code: 203.0x) between Jan 1, 2008 and Oct 31, 2012 were extracted from the database. Index date was defined as the date of the first diagnosis of MM. A minimum of 12 months pre-index and 6 months post-index enrollment with no MM treatment was required to define the NDMM patient population. To avoid DOT limitations imposed by fixed-length induction therapy, only pts without claims for stem cell transplant (SCT) were evaluated. DOT was compared among the group treated with LEN who had dose modification (increase or decrease in number of mg per day) relative to the group with no dose modification. Results Among the 236 pts meeting the inclusion criteria, 69 (29%) pts had LEN dose reductions, 15 (6%) had dose increases, and 152 (64%) had no dose change. DOT in pts without a dose change was 7.33 months ± 7.62 (mean ± SD), while pts who had a dose reduction had significantly longer DOT of 14.63 months ± 10.47 (p

Description: Introduction: Multiple clinical studies in patients (pts) with newly diagnosed multiple myeloma (NDMM) have shown benefits from continuous lenalidomide (LEN) treatment (Tx), including extended progression-free survival (PFS), time to progression (TTP), and overall survival (OS) (Facon, Blood 2013; Palumbo, NEJM 2012). Dose modifications are commonly utilized by physicians as part of continuous Tx plans to sustain control of disease while managing toxicities. Previous analysis has shown that dose modification of LEN was associated with longer duration of therapy (DOT) relative to non-dose modification, in the real-world setting (Lang, Blood 2013). This study aimed to evaluate whether LEN dose modification is associated with a longer TTP in NDMM pts, utilizing time to next therapy (TTNT) as a proxy measure available from claims data. Methods: A retrospective study was conducted using a large US medical and pharmacy claims database, covering 〉 25 million lives annually. NDMM pts were identified with at least 2 outpatient claims or 1 inpatient medical claim associated with a diagnosis of MM (ICD-9-CM code 203.0X), with the first such claim used to define the index date. A minimum of 12 months' pre-index enrollment and 6 months' post-index continuous enrollment between Jan 1 2006 and December 31 2012 was required. The analysis focused on NDMM pts treated with LEN who did not have claims for stem cell transplantation (SCT), to avoid DOT limitations imposed by fixed-length induction Tx. Median DOT and TTNT were compared in NDMM pts with and without LEN dose modifications (dose increase or decrease). Charlson comorbidity scores were determined to compare baseline measures between the groups. Results: Of the 1,360 pts who met the inclusion criteria, 470 (35%) had LEN dose modifications, including 154 pts with at least one dose increase and 421 pts with at least one dose decrease. The majority of pts had an initial dose of 25mg. The median DOT was 447 days in pts with LEN dose modification and 182 days in those pts with no dose modification (p 〈 0.001). The median DOT in pts with dose modification was consistent regardless of whether they experienced a dose increase or decrease, with no significant difference. The median TTNT in pts with LEN dose modification was 3.5 yrs compared to 2.0 yrs in pts without dose modification (p 〈 0.001; Figure 1). Charlson comorbidity scores were similar in pts with and without LEN dose modification. Figure 1 Figure 1. Conclusions: For non-SCT NDMM patients treated with LEN, dose modifications during their treatment were associated with a doubling of the median therapy duration and a 71% longer median TNTT, compared to pts without LEN dose modification. The DOT and TTNT in pts with dose modification were similar to median values reported for the LEN continuous Tx arm of the FIRST clinical trial (Facon, Blood 2013). This analysis suggests that LEN dose modification in the Tx of NDMM may be an effective tool in the real-world setting for pts to achieve sustained disease Tx and the associated prolonged time to progression, based on the proxy measure of TTNT. Disclosures Usmani: Celgene Corporation: Consultancy, Honoraria, Research Funding; Millennium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy; Array BioPharma: Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding. Off Label Use: Lenalidomide in newly diagnosed multiple myeloma patients. Binder:Celgene Corporation: Employment, Equity Ownership. Milentijevic:Celgene Corporation: Consultancy. Hu:Celgene: Employment. Nagarwala:Celgene Corporation: Employment. Corvino:Genesis Research LLC: Consultancy. Arikian:Genesis Research: Consultancy. Surinach:Genesis Research LLC: Consultancy. Harwin:Celgene Corporation: Honoraria.

Description: Abstract 3912 Background: Fludarabine (FLU), cyclophosphamide and rituximab (FCR) or other FLU-based regimens have shown improvement in response rates, progression-free survival, and in some studies overall survival in patients with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). However, a randomized trial of older patients demonstrated no improvement in progression-free and overall survival with FLU-based therapy (Eichhorst BF, et al: Blood 114; 3382, 2009). A recent retrospective analysis of serial CALGB trials (Woyach J, et al: ASH 2011) confirmed the lack of PFS and OS advantage of fludarabine in elderly patients but did find benefit of the anti-CD20 antibody rituximab across all age groups. Ofatumumab (OFA) is a fully human immunoglobulin G1 kappa, monoclonal antibody that targets a unique epitope on the CD20 molecule. Pre-clinical data indicate that OFA has greater NK cell and monocyte-mediated killing, complement-dependent cytotoxicity and direct killing against CLL cells. Based on pre-clinical and clinical studies indicating possible increased efficacy of OFA in patients with CLL, our aim was to develop an antibody-only regimen for older patients and patients who refuse FLU-based regimens. Methods: Eligible patients had previously untreated, symptomatic CD20+ B-cell chronic lymphocytic leukemia (B-CLL) or small lymphocytic lymphoma (SLL), ECOG PS of ≤ 2, and were either ≥ 65 years of age, or patients 18–64 years of age who had declined FLU-based regimens. All patients in this study received OFA as an IV infusion once weekly for a total of 8 weeks. To reduce the possibility of infusion reactions, the first dose of OFA was administered at a dose of 300 mg. If the initial 300-mg dose of OFA was well tolerated, without occurrence of any infusion associated AEs of ≥ grade 3, subsequent doses of OFA (i.e., Week 2 through Week 8) were given at a dose of 2000 mg. Eight weeks after the 8-week study treatment period ended, patients were assessed for response to the treatment. Patients who progressed received no further treatment. Patients who responded to the treatment or who did not have disease progression received maintenance therapy consisting of OFA at a dose of 2000 mg IV every 2 months for 2 years (for a total of 12 doses, in the absence of PD or intolerable toxicity) beginning 3 months after the last dose of OFA. Results: Between 8/2010 and 4/2011, 42 patients were enrolled and are included in this analysis. Patients were 57% male with median age 69 yrs (range: 47–88 yrs). Fourteen patients (33%) were 〈 age 65. All but 1 patient had CLL; 1 patient had SLL. The median WBC at study entry was 41.1 (range 1.7–236.5). Rai stage at entry to study was Stage 0 = 8, Stage I = 8, Stage II – 4, Stage III – 10, Stage IV – 11. Interphase cytogenetics demonstrated 2/42 (5%) 17p-, 4/42 (10%) 11q-, 11/42 (26%) trisomy 12, 9/42 (21%) normal, 14/42 (33%) 13q-, and 2 (5%) unknown. To-date, 41 (98%) patients remain on study and 35 have completed 8 weeks of initial therapy with 24 (57%) having already begun maintenance therapy. Lymphocyte count normalized in 85% of patients at the end of the initial 8 weeks of therapy. Thirty patients have been evaluated for response according to IWCLL criteria (Hallek 2008): 13 patients (44%) achieved an objective response (CR, 0; PR, 13); 16 (53%) patients had SD; 1 patient (3%) had PD. SAEs were infrequent with 2 patients hospitalized for unrelated events: g2 fracture, g3 chest pain, g3 hematoma and g4 pulmonary emboli; 2 patients hospitalized for events possibly OFA-related had g2 fever, g3 anemia and g3 pneumonia. Only 1 patient experienced significant infusion-related toxicity that required repeat administration of the initial 300-mg dose instead of dose escalation at dose 2. Baseline FcγR polymorphisms for patients enrolled are currently being analyzed and will be presented. Conclusion: Single-agent OFA is a highly active and well tolerated front-line therapy for older patients with CLL or patients refusing FLU as evidenced by both early response and also ability of virtually all patients to proceed to maintenance therapy. A low incidence of serious infusion toxicity, infectious morbidity and other heme / non-heme toxicities was observed. Continued long-term assessment will further characterize the toxicity and efficacy of this single-agent OFA regimen in patients with CLL, as well as overall and progression-free survival rates. Disclosures: Flinn: GSK: Research Funding. Off Label Use: Ofatumumab in front-line CLL. Jones:Abbott Labs: Research Funding; GSK: Consultancy.