Citations

Abstract Abstract 94 Background: Lymphoma diagnosed during pregnancy is a rare occurrence. Further, there is heterogeneity in clinical presentation and a range of lymphoma histologies resulting in a continued deficiency of lymphoma-specific data in the literature regarding prognosis, optimal therapy, maternal complications, and fetal outcome. Methods: A comprehensive retrospective analysis was completed for patients (pts) diagnosed (dx) with Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL) during pregnancy at 9 large U.S. academic centers over a 13-year period (1998–2011). The vast majority of cases were co-managed with high-risk maternal fetal medicine. Data on maternal disease characteristics, treatment details, obstetric complications, and fetal outcomes were analyzed. Results: 88 cases were identified with complete data available in 82. The median age of pts was 31 yrs (18–40). Lymphoma dx occurred at a median of 24 weeks (wks) gestation (5–40). 15% of pts were dx during the 1st trimester, 46% during the 2nd trimester, 35% during the 3rd trimester, while 4% (n=3) of pts had a pre-existing NHL dx (follicular lymphoma (FL)). 52% (n=43) of pts had NHL and 48% (n=39) HL. Of NHL cases, 83% (n=33) were B-cell and 17% (n=10) T-cell. B-cell histologies were DLBCL n=23 (including 2 primary CNS and 1 'double hit' NHL), FL n=5 (including 1 leukemic phase FL), Burkitt's lymphoma n=3, and mixed histology n=1; T-cell histologies were anaplastic large cell n=6, PTCL not otherwise specified n=2, and T-cell/NK NHL n=2. Pts with B-cell NHL and HL were dx at a median age of 29 yrs (range, 18–40), while T-cell NHL pts were dx at a median of 34 years (19–37). MRI without gadolinium was the most common imaging modality utilized for staging. 63% of NHL and 19% of HL pts had stage III/IV disease (25% of HL with stage IIB). Pregnancy was terminated in 6 pts (n=4 aggressive NHL and n=2 HD) to enable immediate chemotherapy (five in the 1st trimester [at 5, 8, 10, 10, and 12 wks] and 1 pt in the early 2nd trimester who required high-dose methotrexate). 48 pts (63%) initiated anti-lymphoma therapy at a median of 25 wks gestation (range, 13–37) with 79% of pts initiating therapy in the 2nd trimester (see Table 1). The median gestation at time of lymphoma dx for pts who received intra-partum treatment was 20 wks vs 34 wks for pts who had therapy deferred to post-delivery (p<0.0001). The overall response rate among pts who received therapy was 87% (74% complete remission). Notably, gestation went to full-term in 54% with delivery occurring at a median of 37 wks (31–40). Therapy was deferred until post-delivery in 28 pts (37%) and the majority of these pregnancies were also carried to term (median delivery at 38 wks). At a median follow-up of 41 months (6–157), the 3-year PFS and OS for all pts were 79% and 89% respectively. Histology-specific 3-year PFS and OS were: B-cell NHL: 73% and 82%, respectively; T-cell NHL: 50% and 90%, respectively; and HL: 90% and 95%, respectively (Figure 1). Detailed obstetrical information was available in 59 pts. There were minimal pre-term complications, the most common being induction of labor in 45%. Perinatal events included spontaneous rupture of membranes in 5% and pre-eclampsia in 8%. Further, there were no differences in these events detected among pts who received intra-partum treatment vs deferred therapy. No episodes of chorioamnionitis or endometritis were noted. There was 1 stillbirth that occurred at 19 wks gestation in a 34-year-old pt with double-hit NHL following 1 cycle of R-CHOP. The median birth weight of infants was 2427 grams (1005–5262) with no difference among pts who received intra-partum chemotherapy vs not (2637 grams vs 2212 grams, respectively; p=NS). Microcephaly was reported in 1 case following 4 intra-partum cycles of CHOP for DLBCL; there were otherwise no malformations detected. Conclusions: To our knowledge, this represents one of the largest experiences reported of lymphoma in pregnancy. Our data show that standard NHL and HL chemotherapeutic regimens (without anti-metabolites) administered during the 2nd and 3rd trimester, including as early as 13 wks gestation in select cases, is associated with minimal maternal complications or fetal detriment. In addition, pts with low risk clinical scenarios (e.g., indolent NHL and/or late gestational dx) had therapy safely deferred to post-partum. In our experience, this approach was associated with overall expected lymphoma-related survival. Disclosures: No relevant conflicts of interest to declare.

Abstract CD80 is an immune costimulatory molecule expressed on the cell surface of follicular and other lymphomas. Galiximab, a macaque-human chimeric anti-CD80 monoclonal antibody, has been shown to have antitumor activity in patients with relapsed or refractory, follicular lymphoma. Preclinical work suggested antibody-dependent cellular cytotoxicity (ADCC) as a mechanism for galiximab-induced cell lysis. Single-nucleotide polymorphisms (SNPs) for high-affinity Fc gamma receptor IIIa and high interferon-gamma production have been associated with increased ADCC activity. For this report, genomic DNA from peripheral blood of clinical study patients was analyzed for Fc gamma receptor IIIa and interferon-gamma gene SNPs after PCR amplification. In addition, the frequency of interferon-gamma secreting cells in peripheral blood samples was evaluated by ELISPOT. SNP and ELISPOT results were then evaluated for correlation with clinical response (CR or PR) to galiximab and reduction in tumor burden (SPD of indicator lesions). Of 35 follicular lymphoma patients evaluable for response to galiximab, 2 CRs and 1 PR were observed; time to best response was delayed (Months 3, 9, and 12). Of 34 patients with Fc gamma receptor IIIa SNP results, 6 were homozygous for the high-affinity receptor. Of 33 pts with interferon-gamma SNP results, 4 were homozygous for the high-producing allele. None of the 3 responders were homozygous for high-affinity Fc gamma receptor IIIa or high interferon-gamma production, and the degree of tumor burden reduction was smaller in these homozygotes than in the others. In addition, pretreatment interferon-gamma ELISPOT data did not predict clinical response to galiximab or tumor burden reduction. In summary, high-affinity Fc gamma receptor IIIa and high interferon-gamma production do not predict clinical responsiveness of follicular NHL to galiximab, suggesting that ADCC may not be a primary mechanism of action for this antibody. Ongoing studies are evaluating other potential mechanisms including the immunomodulatory effects of blocking CD80.

Abstract Abstract 2799 Background: Aurora A kinase (AAK) is important in a diverse set of mitotic processes and is amplified or overexpressed in a number of heme-lymphatic malignancies. MLN8237 is an investigational, orally administered, selective AAK inhibitor in clinical development for the treatment of hematologic and solid tumors. This multicenter study (NCT00697346) is the first phase 1 program to assess safety and pharmacology of MLN8237 in patients with advanced hematologic malignancies. Methods: Eligible patients were aged ≥18 yr, had response-evaluable, relapsed or refractory hematologic malignancies, and had ECOG performance status 0–2; there was no restriction on the number of prior therapies, but prior allogeneic transplant was excluded. Patients received escalating doses of MLN8237 as powder-in-capsule formulation in a 3+3 design. Endpoints included safety, dose-limiting toxicity (DLT), maximum tolerated dose (MTD), pharmacokinetics, and response. Results: Twenty-eight patients were included; median age was 62 yr (range 41–74), 50% were male, 86% were white, and 43% had prior transplant. Diagnoses were non-Hodgkin's lymphoma (68%), including diffuse large B-cell (DLBCL), mantle cell, follicular, and small lymphocytic lymphoma; multiple myeloma (29%); and chronic lymphocytic leukemia (4%). Seventy-nine percent of patients had received ≥3 prior therapies. Patients initially received a 21-day treatment schedule of MLN8237 25 or 35 mg (BID loading dose on Day 1, then QD on Days 2–21) followed by a 7-day rest period (28-day cycles). Based on results with the first two cohorts, subsequent cohorts received a 14-day treatment schedule of MLN8237 35, 45, 65, or 90 mg (BID loading dose on Day 1, then QD on Days 2–14) followed by a 14-day rest period (28-day cycles). Median number of cycles administered was 2 (range 1–14+). After escalation to 90 mg (maximum administered dose), two DLTs per cohort led to de-escalation to 65 mg and then 45 mg, which was the MTD on the 14-day schedule. The most common treatment-related adverse events (AEs) were neutropenia (46%), thrombocytopenia (36%), and asthenic conditions (32%); grade ≥3 treatment-related AEs were reported in 14 (50%) patients, and 13 (46%) had a serious AE. DLTs included grade 3–4 myelosuppression associated with infection or delay in treatment, which were generally manageable by reduction in dose or schedule. AEs were generally reversible and manageable, although 5 (18%) patients discontinued due to AEs. Three patients died, from causes (renal failure; airway obstruction; progressive large cell lymphoma) not considered related to MLN8237. Following multiple doses, an overall median Tmax of 2 hr, a mean t1/2 of 23 hr, and a peak/trough ratio of 5 were observed. The geometric mean of steady-state AUC increased from 19,534 to 30,811 nM*hr when the daily dose was increased from 25 to 65 mg. With the 14-day schedule, antitumor activity was observed in a patient with relapsed DLBCL treated with 65 mg and reduced to 45 mg, who enrolled after disease progression following ifosfamide-carboplatin-etoposide (ICE) salvage therapy. A durable PR coupled with resolution of B symptoms sustained for >1 yr was observed in a patient with post-transplant grade 3B follicular lymphoma treated with 35 mg, escalated per protocol to 45 mg and then 65 mg. Stable disease (SD; 5 months) was observed in a patient with myeloma treated at 90 mg. Conclusions: MLN8237 toxicities were consistent with AAK inhibition in proliferating tissue (chiefly bone marrow), and were generally manageable. The MTD was 45 mg on the 14-day schedule in these patients with advanced hematologic malignancies. Antitumor activity was observed, and repeat cycles were tolerable over 6–12 months in some patients who achieved PR or SD. The results support further investigation of MLN8237 in heme-lymphatic malignancies, and ongoing clinical development includes alternative schedules and formulations. Disclosures: Padmanabhan: Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding. Off Label Use: Investigational agent in clinical development for the treatment of advanced hematologic malignancies. Shea:Millennium Pharmaceuticals, Inc: Consultancy, Research Funding. Vose:Millennium Pharmaceuticals, Inc.: Research Funding. Goy:Millennium Pharmaceuticals, Inc., Celgene, GSK, Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zhou:Millennium Pharmaceuticals, Inc.: Employment. Liu:Millennium Pharmaceuticals, Inc.: Employment. Fingert:Millennium Pharmaceuticals, Inc.: Employment, Equity Ownership. Fowler:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Research Funding; Cephalon: Research Funding; Genentech: Honoraria, Research Funding; Celgene: Honoraria.

Abstract Abstract 2699 Poster Board II-675 Introduction: High-dose chemotherapy with autologous stem cell transplant (SCT) is a standard treatment option for younger patients with aggressive non-Hodgkin's lymphomas (a-NHL) who fail to respond, or relapse after initial therapy. For patients who relapse after SCT there are few effective treatment options and prognosis remains poor (Vose et al Blood. 80(8):2142–8, 1992). A second SCT was shown to achieve only marginal responses and at an increased risk of toxic death (Lenain et al Hematol J. 5(5):403–9, 2004). Therefore, new approaches are needed for treatment of patients in this poor prognostic group. Lenalidomide (Revlimid®) is an immunomodulatory agent that has shown clinical activity in treatment of several B-cell malignancies. Two phase 2 studies of lenalidomide monotherapy in patients with relapsed or refractory (R/R) a-NHL were conducted in the US (NHL-002; Wiernik et al JCO 26:4952–7, 2008) and internationally (CC-5013 NHL-003). In an extended follow-up of the NHL-002 study, the overall response rate (ORR) was 35%, which included 12% of patients with a complete response (CR), and a median duration of response (DR) lasting 10.4 months (Wiernik et al 2008 EHA. Abst: 764). Comparable efficacy was observed in the larger confirmatory, phase 2, NHL-003 study of lenalidomide in a similar patient population. The goal of this analysis was to learn the ORR and DR to lenalidomide in patients with a prior SCT. Methods: Patient data from both phase II studies were pooled for this report. Eligibility for both studies was similar – patients with R/R a-NHL, which included diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), and follicular lymphoma grade III (FL-III), with measurable disease (≥ 2 cm), and ≥ 1 prior treatment regimen. Patients received oral lenalidomide 25 mg once daily on days 1–21 of a 28-day cycle. Protocol defined treatment continued for up to 52 wks in NHL-002, or until disease progression in NHL-003. Primary endpoint was ORR; secondary endpoints included DR, progression-free survival (PFS), and safety. Results: 87 patients with a prior SCT (14 patients from NHL-002; 73 patients from NHL-003) were included in this analysis. Median age of patients was 61 yrs (range, 23–76), with a median of 4 prior therapies (range, 2–12). The ORR to lenalidomide was 39% (34/87), with 13% (11/87) CR/CRu and 26% (23/87) partial response (PR). Median PFS for all 87 patients was 3.8 months (95% CI, 2.6, 5.6) and the DR for 34 responders was 9.7 months (95% CI, 4.2, 16.3). Responses occurred in 15 of 52 patients (29% ORR; 10% CR/CRu) with DLBCL, 12 of 19 patients with MCL (63% ORR; 26% CR/CRu), and in 6 of 10 patients with TL (60% ORR; 10% CR/CRu). The table summarizes responses for patients who did not have a transplant, for those who had a SCT anytime prior to lenalidomide; as the last therapy prior to lenalidomide; and not as last therapy prior to lenalidomide. Most common grade 3 or 4 adverse events were neutropenia (44%), thrombocytopenia (33%), and anemia (9%). Eighteen (20.6%) patients discontinued treatment due to adverse events. Patients with a prior history of SCT appeared to have a significantly higher rate of thrombocytopenia, all grades (51% v 30%; P = 0.001), and grades 3 or 4 (33% v 16%; P = 0.002). Patients with a prior SCT were also more likely to experience a dose reduction/interruption due to thrombocytopenia compared with those without a prior SCT (25% v 14%; P = 0.027). Conclusions: Based on a pooled dataset from two phase II studies, oral lenalidomide monotherapy appears to be a well tolerated and active therapy resulting in durable responses in patients with R/R a-NHL who had a prior SCT. Furthermore, the potential of achieving a response to lenalidomide appears to be independent of prior history of SCT. Disclosures: Vose: Celgene: Research Funding. Off Label Use: Lenalidomide for the treatment of relapsed/refractory aggressive non-Hodgkin's lymphoma. . Czuczman:Celgene: Research Funding. Zinzani:Celgene: Research Funding. Tuscano:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Pietronigro:Celgene: Employment, Equity Ownership. Ervin-Haynes:Celgene: Employment. Witzig:Celgene: Research Funding.

Abstract Background: Lenalidomide (Revlimid®), an immunomodulatory drug (IMiD®), was recently approved in the US for treatment of relapsed/refractory multiple myeloma and myelodysplastic syndromes associated with a deletion 5q[31] cytogenetic abnormality. Lenalidomide also has demonstrated activity in chronic lymphocytic leukemia and cutaneous T-cell lymphoma while thalidomide, a less potent IMiD®, has activity in non-Hodgkin’s lymphoma as both monotherapy and in combination with rituximab. Aim: To assess the safety and activity of lenalidomide monotherapy in subjects with relapsed/refractory aggressive non-Hodgkin’s lymphoma (NHL). Methods: Subjects with relapsed/refractory aggressive NHL following at least 1 prior treatment regimen with measurable disease are eligible. Subjects receive 25 mg lenalidomide orally once daily on Days 1–21 every 28 days and continue therapy for 52 weeks as tolerated or until disease progression. Response and progression are evaluated using the IWLRC methodology. Results: As of July 25, 2006, 32 subjects of a planned 40 have enrolled and 31 have received drug. Twenty-two subjects are currently evaluable for tumor response. The median age of the 22 response-evaluable subjects is 65 (46–83) and 13 are female. Histology is diffuse large B-cell lymphoma [DLBCL] (n=12), follicular center lymphoma grade 3 [FL] (n=3), mantle cell lymphoma [MCL] (n=5) and transformed [TSF] (n=2). Median time from diagnosis to lenalidomide monotherapy is 2.3 (0.7–7) years and median number of prior treatment regimens per subject is 2 (1–6). Seven subjects (32%) exhibited an objective response (2 complete responses unconfirmed (CRu) and 5 partial responses (PR)), 6 had stable disease (SD) for a tumor control rate (TCR) of 59% and 9 progressive disease (PD). Responses were produced in each of the aggressive histologic subtypes studied: DLBCL (3/12), FL (1/3), MCL (2/5) and TSF (1/2). Five of 11 subjects (45%) with 1–2 prior treatment regimens had an objective response, as did 2 of 3 subjects (67%) who had received a prior stem cell transplant. Median time-to-response was 2 months. Grade 3 or 4 adverse events occurred in 18 of 31 (58%) subjects receiving drug. These were predominantly Grade 3 hematological events (neutropenia, thrombocytopenia) with only 4 subjects (13%) experiencing a Grade 4 adverse reaction. Conclusion: Preliminary results indicate that lenalidomide monotherapy is active with manageable side effects in relapsed/refractory aggressive NHL.

Abstract Background: Lenalidomide (Revlimid®), an immunomodulatory drug (IMiD®), was recently approved in the US for treatment of relapsed/refractory multiple myeloma and myelodysplastic syndromes associated with a deletion 5q[31] cytogenetic abnormality. Lenalidomide also has demonstrated activity in chronic lymphocytic leukemia and cutaneous T-cell lymphoma while thalidomide, a less potent IMiD®, has activity in non-Hodgkin’s lymphoma (NHL) as both monotherapy and in combination with rituximab. Aim: To assess the safety and efficacy of lenalidomide monotherapy in subjects with relapsed/refractory indolent NHL. Methods: Subjects with relapsed/refractory indolent NHL following at least 1 prior treatment regimen with measurable disease are eligible. Subjects receive 25 mg lenalidomide orally once daily on Days 1–21 every 28 days and continue therapy for 52 weeks as tolerated or until disease progression. Response and progression are evaluated using the IWLRC methodology. Results: As of July 25, 2006, 23 subjects of a planned 40 have enrolled and received drug. Fifteen subjects are currently evaluable for tumor response. The median age of the 15 response-evaluable subjects is 64 (54–82) and 5 are female. Histology is small lymphocytic lymphoma [SLL] (n=8), follicular center lymphoma grades 1,2 [FL] (n=5) and nodal marginal B-cell lymphoma [NML] (n=2). Median time from diagnosis to lenalidomide monotherapy is 7.6 (3–14) years and median number of prior treatment regimens per subject is 3 (1–17). Two subjects (13%) exhibited an objective partial response (PR) at four months. Both responses, one FL and one NML, occurred in subjects with substantial tumor burden of 61.8 cm2 and 80.3 cm2, respectively. The 4-month time-to-response for these indolent NHL subjects is longer than the 2-month median time-to-response in aggressive NHL subjects (n=7) following lenalidomide monotherapy. Seven patients had stable disease (SD) for a tumor control rate (TCR) of 60% and 6 had progressive disease (PD). Grade 3 or 4 adverse events occurred in 9 (39%) subjects. These were predominantly Grade 3 hematological events (neutropenia, thrombocytopenia) with only 3 subjects (13%) experiencing a Grade 4 adverse reaction (all neutropenia). Conclusion: Early results of lenalidomide monotherapy in indolent NHL show evidence of activity with a safety profile similar to that established previously in other hematological malignancies.

Abstract Abstract 2738 Background: Mantle cell lymphoma (MCL) is an uncommon type of non-Hodgkin's lymphoma (NHL) with poor prognosis that necessitates the development of new treatments. Lenalidomide is a unique immunomodulatory agent with antiproliferative and tumoricidal effects on MCL cells. NHL-003 was a phase II, open-label, multicenter trial for subjects with relapsed aggressive NHL that tested single-agent lenalidomide 25 mg PO days 1–21 every 28 days. The primary endpoint was overall response rate (ORR); secondary endpoints included complete response (CR) rate, duration of response (DOR), survival, and safety. At the time of the initial publication (Witzig et al. Ann Oncol.2011;22:1622–1627), MCL subgroup analysis showed an ORR of 42%; the median DOR had not been reached. The purpose of this report is to provide long-term efficacy and safety results for the MCL subgroup from NHL-003. Results: Subjects with MCL (N=57) had a median age of 68 y (range, 33–82), were predominantly male (77%) with good ECOG performance status (89% PS 0–1) and advanced-stage disease (88% stage III/IV). Subjects had received a median of 3 (range, 1–13) prior systemic therapies. According to the current central review at a median follow-up of 12.4 mo, subjects achieved an ORR of 35% (CR/CRu 12%) following lenalidomide, including a median DOR of 16.3 mo (Table 1). The ORR to single-agent lenalidomide was 44% (CR/CRu 21%) by independent assessment, with a median DOR not yet reached. Median PFS was 8.8 mo by central review and 5.7 mo according to investigators. Subjects responded quickly, with a median time to first response of 1.9 mo (central and investigator). Median DOR for subjects in CR and overall survival for all subjects have not yet been reached. The most common grade 3/4 adverse events (AEs) were neutropenia (46%), thrombocytopenia (30%), fatigue (9%), and diarrhea (5%). Other AEs included one subject with grade 1 to 2 tumor flare reaction, one subject with grade 3 deep vein thrombosis, and two subjects with second primary malignancies suspected of being related to treatment (one grade 3 squamous cell carcinoma of the skin that resolved and one grade 4 AML in a heavily pretreated individual with 5 prior cancer therapies). Conclusions: This subset analysis from a phase II study further confirms the efficacy of lenalidomide in subjects with relapsed MCL. Responders have a long DOR with manageable side effects. These results support continued investigation of lenalidomide alone or in combination for the treatment of MCL. Disclosures: Zinzani: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees. Off Label Use: This is a phase 2 clinical study of safety and efficacy for lenalidomide in patients with MCL. Czuczman:Celgene: Consultancy, Consultant Celgene Advisory Board Other. Reeder:Celgene: Mayo Clinic receives funding from Celgene to support clinical trials Other, Research Funding. Haioun:Celgene: Celgene Advisory Board Consultant Other, Consultancy. Tilly:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Pietronigro:Celgene: Employment. Ervin-Haynes:Celgene: Employment. Li:Celgene: Employment. Witzig:Celgene: Research Funding.

Abstract Abstract 1618 Introduction: Primary breast lymphoma is a rare type of non-Hodgkin lymphoma (NHL), representing about 1% of breast tumors and 2% of extranodal NHL. Diffuse large B-cell lymphoma (DLBCL) is the most common primary subtype presenting in the breast. Due to the low incidence of primary breast DLBCL, outcome data is limited. The aim of this study was to retrospectively assess the natural history of primary breast DLBCL in the pre and post rituximab eras, with specific emphasis on the incidence of local, systemic and central nervous system (CNS) relapses. Methods: Data was retrospectively collected on patients with primary breast DLBCL from seven USA academic medical centers. Institutional review board approval was obtained at each participating site. Patients were identified through institutional databases and tumor registries at each site. Charts were reviewed to obtain demographic and clinical variables including treatment history and dates of relapse and death when applicable. Only patients with stage I/II disease (involvement of breast and localized lymph nodes) were included. All histologies apart from primary DLBCL were excluded. Overall survival (OS) was calculated from the diagnosis date to the date of death or last follow-up. Time to Progression (TTP) was calculated from diagnosis data until the date of pathological evidence of recurrence or death. Data were summarized using descriptive statistics, and survival was analyzed using the Kaplan-Meier method. Results: Between 1984 and 2012, 75 patients were identified who met the eligibility criteria. The median age was 62 years (range 17–87); 81% presented with a palpable mass; 12% had their disease detected incidentally by mammography; 4% presented with B-symptoms; 59% had right breast involvement; 67% had stage I and 33% had stage II disease. The stage-adjusted international prognostic index (IPI) score was 0 in 28% of patients, 1 in 41%, 2, in 25%, 3 in 4% and 4 in 1%. 91% of patients were treated with chemotherapy; 31% of these were treated in the pre-rituximab era and 69% received rituximab. Radiation therapy (RT) was utilized in 68% of patients and was the only treatment modality in 8% of those receiving RT. 8% of patients received CNS prophylaxis with intrathecal chemotherapy. After a median follow-up of 4.5 years (range 0.6 – 20.6 years), the Kaplan-Meier estimated median TTP was 10.4 years (95% CI 6.2 – 14.6 years) and the median OS was 14.6 years (95% CI 6.5 – 22.6 years). The 5-year TTP and 5-year OS were 65% (95% CI 53–77%) and 75% (95% CI 64–86%) respectively. Among the patients who relapsed, 67% occurred within the first 2 years. A total of 7 relapses in the breast were observed, none in patients treated with combination of chemotherapy and RT. In univariate analysis, rituximab exposure was not associated with any difference in TTP or OS. The stage-adjusted IPI was associated with OS; the 5-year OS was 88% (95% CI 79–98%) in patients with a score of 0–1 versus 48% (95% CI 25–71%) in those with a score of 2–4 (log rank p < 0.001). The very limited-disease group with a stage-adjusted IPI of 0 had a 5-year OS of 94% (95% CI 83–100%) compared to all others who had a 5-year OS of 67% (95% CI 52–81%; log rank p = 0.001). There was no difference in TTP and OS in patients with solitary versus multiple breast masses or between patients with tumors less than versus more than 7cm. Patients receiving RT in addition to chemotherapy had a longer TTP than those who did not (log rank p = 0.03), but RT was not associated with an improved OS. Patients who relapsed and underwent stem cell transplant (SCT) had similar OS to those who never relapsed. Ten patients (13%) had CNS relapse (3 with leptomeningeal disease, 5 with brain parenchymal disease and 2 with both). All CNS relapses occurred within the first 2.8 years from the time of diagnosis. There was no difference in the rate of CNS relapse in the patients who received IT prophylaxis versus those who did not. Conclusions: In this multicenter study, the largest published to date, primary breast DLBCL appears to have a worse prognosis than early-stage DLBCL in nodal or other extranodal sites. RT was associated with improved TTP. Patients who relapsed were successfully salvaged with SCT, and had similar survival times to those who never relapsed. A high CNS relapse rate (∼1 in 8 patients, including parenchymal disease in 70%) was observed. The small numbers preclude definitive conclusions on the value of intrathecal prophylaxis or the utility of rituximab. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 1676 Poster Board I-702 Introduction Aggressive NHL (a-NHL) comprises a heterogeneous group of B-cell malignancies, each characterized by a unique histology and molecular markers. The most common types are diffuse large B-cell lymphoma (DLBCL), transformed lymphoma (TL), follicular grade III (FL-III), and mantle cell lymphoma (MCL). Although initial therapy can be effective, up to 40% of patients with DLBCL either fail to respond or relapse after initial therapy (Habermann TM et al JCO 2006), and relapses are likely among patients with MCL. For such patients survival outcomes are particularly poor with few effective treatment options available. Lenalidomide (Revlimid®), an immunomodulatory agent with anti-proliferative as well as apoptotic activity was tested in a pilot study and demonstrated a 35% overall response rate (ORR) with a median duration of response (DR) of 10.4 months (Wiernik et al 2008 EHA. Abst: 764). Based on these encouraging data, we performed a large, international, confirmatory phase 2 study to assess the safety and efficacy of single-agent lenalidomide in patients with relapsed of refractory DLBCL or MCL (CC-5013-NHL-003). Methods Patients were required to have relapsed or refractory aggressive B-cell NHL after ≥1 prior therapies and have at least one measurable lesion '2 cm. Patients received oral lenalidomide 25 mg once daily on days 1–21 of a 28-day cycle, and continued therapy until disease progression or unacceptable toxicity. Results 217 patients were enrolled and received lenalidomide with 108 (50%) DLBCL, 57 (26%) MCL, 19 (9%) FL-III, and 33 (15%) TL (Table 1). The median age was 66 yrs (range, 21–87), 97 patients (45%) had intermediate (3) or high (4–5) IPI scores, and the median time from diagnosis was 2.7 yrs (range, 0.04–20.6). Patients had received a median of 3 prior therapies (range, 1–13), and rituximab was included as a part of the prior therapy in 94% (205/217) of patients. The ORR for all 217 patients was 35% (77/217), with 13% (29/217) complete response (CR)/unconfirmed CR (CRu), 22% (48/217) partial response (PR), and 21% (46/217) with stable disease (SD). Responses were observed in all histological types (Table 1). Patients with a prior stem cell transplantation had a 37% ORR (27/73). The ORR was 28% (27/95) in those patients who were refractory to their last therapy, and 33% (38/116) in patients who were rituximab refractory (defined as <6 months response or no response). Median progression-free survival (PFS) for all patients was 3.5 months (95% CI, 2.5, 4.4) and the median DR for the 77 responders was 11.6 months (95% CI, 6.2, not reached [NR]). The primary side effect of lenalidomide was reversible myelosuppression. Grades 3 or 4 neutropenia occurred in 41%, thrombocytopenia in 19%, anemia in 9%, and leucopenia in 7% of patients. Adverse events caused dose reductions or interruptions in 44% (96/217) of patients and led to treatment discontinuation in 22% (48/217). Conclusion This international study supports earlier pilot-study results showing that lenalidomide has promising anti-tumor activity in aggressive B-cell NHL, with a predictable and treatable toxicity profile. These data warrant further evaluation of lenalidomide in combination with other regimens in the treatment of each histological subtype, and further exploration of lenalidomide in the maintenance setting. Disclosures Witzig: Celgene: Research Funding. Off Label Use: Lenalidomide in relapsed/refractory aggressive NHL. Vose:Celgene: Research Funding. Zinzani:Celgene: Research Funding. Guo:Celgene: Employment, Equity Ownership. Pietronigro:Celgene: Employment, Equity Ownership. Ervin-Haynes:Celgene: Employment. Czuczman:Celgene: Research Funding.

One-third of peripheral T-cell lymphomas are “not otherwise specified” (PTCL-NOS), but they have been subdivided into 2 subgroups based on gene expression profiling. Amador and colleagues generated an immunohistochemical algorithm that parallels the molecular separation of PTCL-NOS and provides useful prognostic information.