Abstract: We report 28 patients (pts) who experienced late onset severe neutropenia (NCI/CTC grade III/IV) after rituximab. Rituximab had been given for the treatment of DLCL(N=15), follicular lymphoma (N=9), mantle cell lymphoma (N=2), CLL (N=2). Rituximab was administered as a front line treatment (N=11), for recurrent disease (N=17), before ASCT (N=1) or after ASCT (N=5). Rituximab was given as a single agent (N=14), with CHOP (N=9) or with other regimen (N=5). Rituximab was given at a dose of 375mg/m2 at weekly intervals over a period of 4 weeks when used as a single agent, or as a single dose of 375mg/m2 with chemotherapy. Characteriscs of neutropenia are summarized in Table. At the time of the neutropenia, all the pts were in CR or VGPR. In 3 pts, the neutropenia had relapsed. All 3 pts were still in CR, and had not been retreated with rituximab. 3 patients were retreated with rituximab for a recurrence of their NHL after the outbreak of neutropenia and 1 pt experienced a further episode of neutropenia after the reintroduction of rituximab. Tests for anti PMN antibodies were performed in 6 pts. In 4 pts, antibodies bound to the surface of neutrophils were detected by the direct neutrophil immunofluorescence test. No antibody could be detected in the serum. A direct toxic effect of rituximab can be ruled out as granulocytes and uncommitted hematopoietic precursor stem cells do not express CD 20. We propose the following hypothesis. The rituximab-induced depletion of the normal B-lymphocyte population was followed by the acquisition of a new immune repertoire under non physiological condition which could promote the transient production of autoantibodies. Some of these antibodies might target either neutrophils or hematopoietic precursors. Some of these antibodies might also be directed against other cells since other delayed-onset cytopenia have been reported after the administration of rituximab, pure red aplasia in particular. An other possible mechanism can be proposed. Rituximab administration could lead to the production of antibodies directed against the complex formed when rituximab is bound to the FcγRIIIb receptor on the PMN. This hypothesis does not account for the delay between the administration of rituximab and the onset of the neutropenia. Characteristics of neutropenic episodes. Characteristics N *: interval between the last infusion of rituximab and the nadir of neutropenia. **: 1 pt was lost to follow-up for 4.5 months but had a normal blood count subsequently. Median time to neutropenia (range) (weeks)* 15 (4–33) Nadir PMN 10x9/L median (range) 0.135 (0–0.760) Bone marrow aspiration 14 Hypocellular marrow 7 Normocellular marrow with severe reduction in mature neutrophils 6 Normal 1 Fever/sepsis 6/1 Patients treated with G-CSF/duration (range) (days) 12/6 (3–21) Duration of neutropenia (range) (days) Patients treated with G-CSF N=12 4 (2-53) Patients not treated with G-CSF N=16 12 (4–105)** Follow-up from the nadir of neutropenia (range) (month) 6 (0.5–36) NHL/CLL status at follow-up CR or CRu 22 VGPR 1 Progression 5 Status of PMN count at follow-up Normal 26 Neutropenia 2

Abstract: Background: Systemic anaplastic large cell lymphoma (sALCL) is a CD30-positive aggressive subtype of mature T-cell lymphoma. Approximately 50% of patients (pts) with sALCL develop recurrent disease after frontline treatment (Savage, 2008). Outcomes have historically been poor for pts with relapsed T-cell lymphomas, including sALCL, with a median overall survival (OS) and progression-free survival (PFS) of 5.5 months (mos) and 3.1 mos, respectively (Mak, 2013). A phase 2 study evaluated the efficacy and safety of brentuximab vedotin, a CD30-directed antibody-drug conjugate, in pts with relapsed or refractory sALCL (ClinicalTrials.gov #NCT00866047). Four-year follow-up data from this ongoing trial are presented. Methods: Pts received 1.8 mg/kg brentuximab vedotin every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles. Response was assessed according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Assessments of response and durability of response per an independent review facility (IRF) have been previously reported. Following a protocol amendment that removed the requirement for routine CT scanning during the follow-up period, response is now being assessed per the investigator. Survival and disease status are being assessed every 3 mos for 2 years, every 6 mos during years 3 to 5, and annually thereafter. CT scans are required if progression is suspected clinically. Results: The enrolled population of 58 pts was heavily pretreated with poor prognosis. As previously reported, 72% of patients had ALK-negative disease, 62% had primary refractory disease (defined as no complete remission [CR] or relapse within 3 months of frontline therapy), and 26% had failed a prior autologous stem cell transplant (SCT). Pts had received a median of 2 prior systemic chemotherapy regimens (range, 1 to 6). Per investigator, the objective response rate (ORR) with brentuximab vedotin was 83% (48 pts) and the CR rate was 62% (36 pts), which were similar to the previously reported ORR (86%) and CR (59%) rates per IRF. At the time of this analysis (data cut June 2014), all pts had discontinued treatment and the median observation time from first dose was 46.3 mos (range, 0.8 to 57.7). Sixty-two percent (36 of 58) of pts were alive at last follow-up and the estimated 4-year survival rate by Kaplan-Meier analysis was 64% (95% CI: 51%, 76%). Median OS by best clinical response was CR (n=36): median not reached; partial remission (n=12): 11.6 mos; stable disease (n=4): 6.9 mos; and progressive disease (n=2): 4.2 mos. Median PFS was 20.0 mos (95% CI: 9.4, – [range, 0.8 to 54.9+]) for all pts and was not reached in pts with CR. Median PFS for pts with ALK-positive (25.5 mos) and ALK-negative (20.0 mos) disease were similar. Median PFS for pts with PET-negative disease at Cycle 4 (n=28) was not reached, whereas median PFS for pts with PET-positive disease at Cycle 4 (n=20) was 6.7 mos. After discontinuing treatment, 18 pts received a hematopoietic SCT (9 allogeneic, 9 autologous). The median PFS for the pts who achieved a CR and did not receive a post-treatment SCT (n=21) was 37.7 mos (95% CI: 14.1, - [range, 2.8 to 51.1+] ) and the median PFS was not reached for the pts who achieved a CR and received a subsequent SCT (n=15) (95% CI: 9.5, - [range, 8.0 to 54.4+]). Of the 36 pts who achieved CR per the investigator, 17 (47%) remain in follow-up free of progression: 10 pts received a consolidative SCT following treatment with brentuximab vedotin and 7 pts received no further therapy after completing brentuximab vedotin treatment. As previously reported, adverse events (AEs) in ≥20% of pts were peripheral sensory neuropathy, nausea, fatigue, pyrexia, diarrhea, rash, constipation, and neutropenia. AEs ≥ Grade 3 that occurred in ≥5% of pts were neutropenia, thrombocytopenia, peripheral sensory neuropathy, anemia, recurrent ALCL, and fatigue. Conclusions: After a median observation time of approximately 4 years from first dose of brentuximab vedotin, the 4-year survival rate was 64%. Forty-seven percent of patients with CR remain in follow-up with no evidence of progression, suggesting that brentuximab vedotin treatment may be curative for some patients. A randomized phase 3 study is being conducted to evaluate brentuximab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone for frontline treatment of CD30-positive mature T-cell lymphomas, including sALCL (ClinicalTrials.gov #NCT01777152). Figure 1 Figure 1. Disclosures Pro: Seattle Genetics, Inc.: Consultancy, Research Funding, Travel expenses Other. Advani:Takeda Pharmaceuticals International Co.: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Janssen Pharmaceuticals: Research Funding; Genentech: Research Funding; Seattle Genetics, Inc.: Other, Research Funding. Brice:Seattle Genetics, Inc.: Research Funding; Takeda Pharmaceuticals International Co.: Honoraria, Research Funding; Roche: Honoraria. Bartlett:Genentech: Research Funding; ImaginAb: Research Funding; Celgene: Research Funding; MedImmune: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Pfizer: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Seattle Genetics, Inc.: Other, Research Funding; Janssen: Research Funding; AstraZeneca: Research Funding. Rosenblatt:Seattle Genetics, Inc.: Research Funding; University of Miami: Employment. Illidge:Seattle Genetics, Inc.: Consultancy, Research Funding; Takeda Pharmaceuticals International Co.: Consultancy, Honoraria. Matous:Seattle Genetics, Inc.: Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Onyx: Speakers Bureau; Takeda Pharmaceuticals International Co.: Speakers Bureau. Ramchandern:Seattle Genetics, Inc.: Research Funding, Speakers Bureau. Fanale:Seattle Genetics, Inc.: Consultancy, Honoraria, Other, Research Funding. Connors:Seattle Genetics, Inc.: Research Funding; Roche: Research Funding. Wang:Seattle Genetics, Inc.: Employment, Equity Ownership. Huebner:Takeda Pharmaceuticals International Co.: Employment, Equity Ownership. Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership. Shustov:Seattle Genetics, Inc.: Research Funding.

Abstract: Abstract 1232 Poster Board I-254 B-Chronic Lymphocytic Leukemia (CLL) shows a strong familial risk and also co-aggregates with other indolent lymphomas. Monoclonal B-cell lymphocytosis (MBL) is an asymptomatic hematologic condition characterized by small B-cell clones, most with a surface phenotype similar to that of chronic lymphocytic leukemia (CLL). These clones are detectable at low absolute lymphocyte cell (ALC) numbers in otherwise healthy individuals using sensitive 6 or 8 color flow cytometry analysis and can be a precursor to CLL. In the general population, MBL increases with age with a prevalence of 5% in individuals over age 65. In contrast, the rate of MBL is 13-18% in first degree relatives of CLL patients in high risk families. In the largest study to date, we report the characteristics of MBL among 430 first-degree relatives of CLL patients (with no associated lymphoproliferative diseases [LPD]) in 132 high risk families. Patients and Methods Individuals studied came from “high risk” families (defined as those with two or more confirmed cases of CLL) that are participating in the Genetic Epidemiology of CLL Consortium. Multi-parameter flow cytometry analysis with a detection sensitivity of 0.02% was performed on either fresh or cryopreserved PBMC and MBL was classified according to previously published criteria (Marti et al, Br. J Haematol 130:325, 2005). Both the ALC and the absolute B cell count (B-ALC) were calculated for each individual. Survival analysis was used to compute the probability of developing MBL with age using the life table method. Results The overall rate of MBL was 17% (73/430) among first–degree relatives but the probability for developing MBL by age 90 was 51%. Males had a slightly higher (but non-significant) risk for MBL than females. MBL patients had significantly higher ALC and B-ALC than did those with normal immunophenotype. The mean ALC was 2.5×109/L among MBL patients, and 20% had an ALC greater than 3 ×109/L. The B-ALC count averaged 0.51 ×109/L. Ninety percent of the MBL cases had a CLL-like phenotype (CD20dim, CD5+, CD23+). Conclusions MBL is found at a very high rate in families selected for having 2 or more patients with CLL suggesting that MBL reflects inherited predisposition to CLL. Although most of the MBL cases in these families had low cell counts and thus have a presumed low likelihood of progressing to CLL or other LPD, a higher proportion of them had lymphocytosis compared to those with normal immunophenotype. We hypothesize that if MBL is an early step in the process of development of CLL, then germ line genes are likely to be acting early in carcinogenesis with more “hits” required before CLL develops. By looking for genes associated with MBL or CLL in families or in the population, we could substantially increase our power to identify germ line genes predisposing to CLL. Disclosures Kay: Biogenc-Idec, Celgene, Genentech, genmab: Membership on an entity's Board of Directors or advisory committees; Genentech, Celgene, Hospira, Polyphenon Pharma, Sanofi-Aventis: Research Funding.

Abstract: Background MBL is a precursor to chronic lymphocytic leukemia (CLL) and is subclassified into low-count (LC) MBL (absolute B-cell count & lt;0.5x109/L) and high-count (HC) MBL (absolute B-cell count between 0.5 and 5x109/L). We previously reported that a polygenic risk score (PRS) based on a weighted average of 41 CLL-susceptibility variants was associated with risk of both MBL and CLL among a cohort of individuals from CLL families. Here we evaluate this PRS in an independent cohort of MBL and CLL individuals of European ancestry (EA), all of whom were ascertained agnostic to CLL family-history status. We also evaluate the PRS by MBL subtype (LC/HC), and in African American (AA) CLL cases and controls. Methods We genotyped 535 EA MBLs (139 HC-MBL, 396 LC-MBLs), 735 CLLs (640 EA, 95 AA), and 2,866 controls (2,631 EA, 235 AA) from the Mayo Clinic CLL Resource, Duke University, and Weill Cornell Medical College. We computed the CLL-PRS for each individual and used logistic regression to estimate odds ratios (OR) and 95% confidence intervals, adjusting for age and sex. To assess discriminatory accuracy, we computed the c-statistic. Among EA individuals, we calculated a trend test among LC-MBL, HC-MBL, and CLL risk using the P-value for heterogeneity from a polytomous logistic regression analysis. Moreover, we plotted a boxplot for the PRS among controls, LC-MBL, HC-MBL, and EA CLL, as well as for AA CLL cases and controls, and tested the statistical difference using the Kruskal Wallis test and Mann-Whitney test, respectively. Results We found a significant association of PRS with overall MBL risk (OR=1.87, P=1.1x10-28) with good discrimination (c-statistic=0.72). Significant associations were also found for LC-MBL (OR=1.75, P=7.5x10-19, c-statistic=0.72), HC-MBL (OR=2.22, P=1.4x10-17, c-statistic=0.74), and CLL of EA (OR=2.60, P=1.2x10-62, c-statistic=0.78), with a significant difference among these cohorts (Figure 1.A) and a significant positive trend across these cohorts (Pheterogeneity=8.4x10-6). Although we observed a 33% increased risk of CLL in AA (c-statistic=0.57), the PRS was borderline significant (P=0.07, Figure 1.B). Conclusion The CLL-PRS is a strong prediction-tool for risk of CLL and MBL among individuals of EA. Future studies are needed to improve the PRS for AAs including performing GWAS of AA in order to identify CLL-susceptibility SNPs that are more representative within known CLL loci and to discover novel CLL loci that are unique for AAs. Disclosures Parikh: GlaxoSmithKline: Honoraria; Janssen: Honoraria, Research Funding; Ascentage Pharma: Research Funding; AbbVie: Honoraria, Research Funding; Merck: Research Funding; TG Therapeutics: Research Funding; Genentech: Honoraria; Pharmacyclics: Honoraria, Research Funding; MorphoSys: Research Funding; AstraZeneca: Honoraria, Research Funding; Verastem Oncology: Honoraria. Braggio:DASA: Consultancy; Bayer: Other: Stock Owner; Acerta Pharma: Research Funding. Brander:Genentech: Consultancy, Honoraria, Other, Research Funding; Juno/Celgene/BMS: Other, Research Funding; MEI Pharma: Other, Research Funding; Ascentage: Other, Research Funding; ArQule: Consultancy, Other, Research Funding; NCCN: Other; Teva: Consultancy, Honoraria; Tolero: Research Funding; AstraZeneca: Consultancy, Honoraria, Other, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other, Research Funding; Pfizer: Consultancy, Other; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Novartis: Consultancy, Other; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Tolero: Research Funding; Teva: Consultancy, Honoraria; DTRM: Other, Research Funding; BeiGene: Other, Research Funding; Novartis: Consultancy, Other; NCCN: Other; Verastem: Consultancy, Honoraria, Other, Research Funding. Cerhan:NanoString: Research Funding; BMS/Celgene: Research Funding. Kay:Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Agios Pharma: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Research Funding; Juno Theraputics: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Cytomx: Membership on an entity's Board of Directors or advisory committees; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; MEI Pharma: Research Funding; Abbvie: Research Funding; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees. Furman:Acerta: Consultancy; AstraZeneca: Consultancy, Research Funding; Beigene: Consultancy; Abbvie: Consultancy; Pharmacyclics: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy; Incyte: Consultancy; Genentech: Consultancy; Janssen: Consultancy, Speakers Bureau; Loxo Oncology: Consultancy; Oncotarget: Consultancy. Shanafelt:Mayo Clinic: Patents & Royalties: and other intellectual property; Genentech, Pharmacyclics LLC, an AbbVie Company, AbbVie, GlaxoSmithKline, and Merck: Research Funding.

Abstract: Limited data exist to describe the clinical features and outcomes for elderly patients with follicular lymphoma (FL). The Follicular Lymphoma Analysis of Surrogacy Hypothesis (FLASH) group performed a prospectively planned pooled analysis of individual patient data from first-line randomized controlled trials (RCTs) and examined associations between age (≤70 vs & gt;70 years), clinical characteristics, and FL outcomes. We identified 18 multicenter clinical RCTs in the FLASH database that enrolled elderly patients ( & gt;70 years). Primary end points were early disease outcomes, CR24 and CR30, and progression-free survival (PFS) at 24 months (PFS24). Secondary end points were PFS and overall survival (OS). We identified 5922 previously untreated FL patients from 18 RCTs. Patients age & gt;70 years (vs ≤70 years) more commonly had elevated lactate dehydrogenase, hemoglobin & lt;12 g/dL, ECOG PS ≥2, and elevated β2-microglobulin. Median follow-up was 5.6 years. Patients & gt;70 years did not differ from patients ≤70 years in rates of CR24, CR30, or PFS24. With a median OS of 14.6 years for all patients, median OS was 7.4 and 15.7 years for patients & gt;70 and ≤70 years of age, respectively (hazard ratio = 2.35; 95% confidence interval = 2.03-2.73; P & lt; .001). Age & gt;70 years was a significant predictor of OS and PFS due to higher rates of death without progression, but not PFS24, CR24, or CR30. FL patients & gt;70 years treated on trials have similar early disease outcomes to younger patients. There is no disease-specific outcome difference between age groups. Age alone should not disqualify patients from standard treatments or RCTs.

Abstract: Chronic lymphocytic lymphoma (CLL) has one of the highest familial risks among cancers. Monoclonal B-cell lymphocytosis (MBL), the precursor to CLL, has a higher prevalence (13%-18%) in families with 2 or more members with CLL compared with the general population (5%-12%). Although, the rate of progression to CLL for high-count MBLs (clonal B-cell count ≥500/µL) is ∼1% to 5%/y, no low-count MBLs have been reported to progress to date. We report the incidence and natural history of MBL in relatives from CLL families. In 310 CLL families, we screened 1045 relatives for MBL using highly sensitive flow cytometry and prospectively followed 449 of them. MBL incidence was directly age- and sex-adjusted to the 2010 US population. CLL cumulative incidence was estimated using Kaplan-Meier survival curves. At baseline, the prevalence of MBL was 22% (235/1045 relatives). After a median follow-up of 8.1 years among 449 relatives, 12 individuals progressed to CLL with a 5-year cumulative incidence of 1.8%. When considering just the 139 relatives with low-count MBL, the 5-year cumulative incidence increased to 5.7%. Finally, 264 had no MBL at baseline, of whom 60 individuals subsequently developed MBL (2 high-count and 58 low-count MBLs) with an age- and sex-adjusted incidence of 3.5% after a median of 6 years of follow-up. In a screening cohort of relatives from CLL families, we reported progression from normal-count to low-count MBL to high-count MBL to CLL, demonstrating that low-count MBL precedes progression to CLL. We estimated a 1.1% annual rate of progression from low-count MBL, which is in excess of that in the general population.

Abstract: Abstract 2443 Background: There is strong and consistent evidence that a genetic component contributes to the etiology of chronic lymphocytic leukemia (CLL). A recent genome-wide association (GWA) study of CLL identified genetic variants located on chromosomes 2q13, 2q37.1, 6p25, 11q24, 15q23, and 19q13 that increased the risk of CLL within a European population. We replicated 5 of these 6 loci in an independent sample of CLL cases and controls from the United States. We now investigate whether these loci also influences MBL, a reported precursor condition of CLL. In addition, a follow-up analysis of the initial GWA study identified four more CLL-susceptibility loci on 2q37.3, 8q24.21, 15q21.3, and 16q24.1. Herein, we also evaluate the association of these four loci with risk of CLL. Methods: Peripheral blood samples were obtained from three ongoing studies: the Genetic Epidemiology CLL (GEC) Consortium, the Mayo Clinic non-Hodgkin lymphoma (NHL)/ CLL study, and the Mayo Clinic Biobank. We implemented rigorous genotyping quality-control measures, and successfully genotyped a total of 407 CLL patients, 965 controls, and 60 MBLs from these studies. Within each locus, the previously reported single nucleotide variants (SNPs) or variants in high linkage disequilibrium (LD) with the previously reported SNPs were evaluated with risk of MBL or CLL. Tests for association was done using the Cochran-Armitage trend test, and unconditional logistic regression was used to estimate odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for CLL or MBL risk Results: In our evaluation of the six initially reported CLL-susceptibility loci (2q13, 2q37.1, 6p25, 11q24, 15q23, and 19q13) with MBL risk, we found three of the six had suggestive associations (p-value 〈 0.20) with ORs comparable to and in the same direction as those observed from CLL risk. Our strongest finding was with rs13397985 at locus 2q37.1 (OR= 1.56; 95% CI: 1.05, 2.31; p-trend = 0.041), followed by rs17483466 at locus 2q13 (OR= 1.49; 95% CI: 0.99, 2.24; p-trend = 0.074). As expected given our previously reported findings with CLL risk, the association between rs11083846 on chromosome 19q13 and MBL risk was not significant (p-trend = 0.70). Of the four recently reported CLL-susceptibility loci SNPs located on 2q37.3, 8q24.21, 15q21.3, and 16q24.1, we found all to be associated with CLL risk but one. Specifically, the strongest association was seen for locus 8q24.21 (best tagged SNP rs1021955; OR = 1.37; 95% CI: 1.10, 1.70; p-trend = 0.005), followed by locus 16q24.1 (best tagged SNP rs305065; OR= 0.77; 95% CI: 0.61, 0.97; p-trend = 0.024). However, we found no associations for locus 15q21.3 for the previously reported SNP nor for any SNPs in LD with the previously reported SNP. Conclusions: Our MBL results provide additional robust genetic evidence that MBL is a precursor to CLL and that it shares similar underlying genetic predisposition. Also our results confirm three of the four recently reported CLL-susceptibility loci and further support the role of a genetic basis in the etiology of CLL. More research is needed to elucidate the potential manner in which these genetic loci function in CLL or MBL. Disclosures: No relevant conflicts of interest to declare.

Abstract: Abstract 2745 Background: Systemic anaplastic large cell lymphoma (sALCL) is a CD30-positive malignancy that accounts for 2–5% of all non-Hodgkin lymphoma (NHL) cases. Approximately 40–65% of patients with sALCL develop recurrent disease after frontline treatment and few effective treatment options exist for this population. Brentuximab vedotin (ADCETRIS®) comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to monomethyl auristatin E (MMAE), a microtubule-disrupting agent. Brentuximab vedotin selectively induces apoptotic death of CD30-positive cells by binding, internalizing, and releasing MMAE. A phase 2 study was conducted to determine the efficacy and safety of brentuximab vedotin in patients with relapsed or refractory sALCL (ClinicalTrials.gov #NCT00866047); long-term follow-up data from this ongoing trial are presented. Methods: Patients received 1.8 mg/kg brentuximab vedotin every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles. The primary endpoint was the objective response rate (ORR) per independent review according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results: 58 patients were enrolled at 22 clinical sites in the US, Canada, and Europe. The median age was 52 years (range 14–76) and 57% were male. 72% of patients had ALK-negative disease, 62% had primary refractory disease (defined as no complete remission [CR] or relapse within 3 months of frontline therapy), and 26% had failed a prior autologous stem cell transplant (SCT). As previously reported, the ORR was 86% (50 of 58 patients) and the CR rate was 59% (34 of 58 patients). At the time of this analysis (datacut April 2012), all patients had discontinued treatment and the median observation time from first dose was 22.8 months (range, 0.8–32.2). The median duration of objective response for all patients was 13.2 months (range, 0.1–27.7+) and the median duration of response for patients who obtained a CR has not yet been met (range, 0.7–27.7+). Of the patients who achieved a CR, over half (18 of 34; 53%) were in continued remission at the time of this analysis. The median progression-free survival (PFS) for all patients was 14.6 months and the median overall survival has not yet been reached. After discontinuing treatment in the study, 16 patients (28%) received a hematopoietic SCT (8 allogeneic, 8 autologous). The median PFS has not yet been met for the group of patients who achieved a CR and received a subsequent SCT (range, 8.1–29+), while the median PFS for the group who achieved a CR and did not receive post-treatment SCT was 18.4 months (range, 2.6–26+). All subgroups of patients analyzed in the study achieved a similar level of antitumor activity regardless of baseline disease characteristics, tumor burden, or prior treatment history. Median PFS did not appear to be influenced by ALK status; in the subgroup of ALK-positive patients (n=16) PFS was 14.6 months versus 14.3 months for ALK-negative patients (n=42). The median overall survival has not yet been met for either ALK-positive or ALK-negative patients. The most common (reported in ≥20% of patients) adverse events (AEs) observed in the study were peripheral sensory neuropathy (41%), nausea (40%), fatigue (38%), pyrexia (34%), diarrhea (29%), rash (24%), constipation (22%), and neutropenia (21%). The majority of AEs were Grade 1 or 2 in severity. Ten patients (17%) experienced Grade 3 events of peripheral neuropathy as defined by a Standardised MedDRA Query; no Grade 4 events were observed. Resolution or at least 1 grade of improvement in peripheral neuropathy has occurred in 79% of patients with neuropathy events (26 of 33 patients) and the median time to resolution or improvement was 13.4 weeks (range, 0.3–48.7). Conclusions: 34 of 58 patients (59%) with relapsed or refractory sALCL obtained a durable CR with brentuximab vedotin and treatment was associated with manageable toxicity. PFS did not appear to be influenced by ALK status. These long-term follow-up results underscore the durability of clinical benefit obtained with brentuximab vedotin. A randomized phase 3 study is planned to evaluate brentuximab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone for frontline treatment of CD30-positive mature T-cell lymphomas. Disclosures: Pro: Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Advani:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Pharmacyclics: Research Funding; Abbott: Research Funding. Brice:Seattle Genetics, Inc.: Honoraria, Research Funding; Roche: Honoraria. Bartlett:Seattle Genetics, Inc.: Consultancy, Research Funding, Travel expenses Other. Rosenblatt:Seattle Genetics, Inc.: Research Funding. Illidge:Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Honoraria. Matous:Seattle Genetics, Inc.: Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Speakers Bureau. Ramchandren:Seattle Genetics, Inc.: Research Funding, Speakers Bureau. Fanale:Seattle Genetics, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel expenses Other. Connors:Seattle Genetics, Inc.: Research Funding. Yang:Seattle Genetics, Inc.: Employment, Equity Ownership. Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership. Shustov:Seattle Genetics, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Abstract: Introduction: The near-universal genetic amplification events at 9p24.1 in classic Hodgkin lymphoma (cHL) results in overexpression of the programmed death 1 (PD-1) ligands and betrays an unusual dependence on the PD-1 pathway. Inhibition of this pathway by use of pembrolizumab has shown effective antitumor activity and acceptable safety in patients with relapsed or refractory cHL (R/RcHL) in the multicohort KEYNOTE-087 study. This led to FDA approval of pembrolizumab for the treatment of adult and pediatric patients who have refractory cHL or who have relapsed after ≥3 prior lines of therapy. A critical remaining question is the durability of responses, specifically whether a subgroup of patients can have durable remission with PD-1 blockade. Therefore, we present the results for the total population and by cohort, with an additional ~12 months of follow-up from last presentation. Methods: The multicenter, single-arm, phase 2 KEYNOTE-087 (NCT02453594) study was conducted to evaluate pembrolizumab in patients with R/R cHL that progressed after autologous stem cell transplantation (ASCT) and subsequent brentuximab vedotin (BV) therapy (cohort 1); salvage chemotherapy and BV (cohort 2); or ASCT but not treated with BV after ASCT (cohort 3). Patients received pembrolizumab 200 mg intravenously every 3 weeks. Response was assessed every 12 weeks per 2007 Revised Response Criteria for Malignant Lymphomas. Primary end points were safety and overall response rate (ORR) per blinded independent central review in all patients and in each cohort; secondary end points were complete remission rate (CRR), progression-free survival (PFS), duration of response (DOR), and overall survival (OS). All patients who received at least 1 dose of pembrolizumab were included in the analyses. Results : At data cutoff (Mar 21, 2018), median follow-up was 27.6 mo (range, 1.0-32.9), and 5 of 210 enrolled patients were still in treatment. Baseline characteristics were previously presented (Chen et al. J Clin Oncol. 2017; 35(19):2125-2132). In the total population, ORR was 71.9% (95% CI, 65.3-77.9); CRR, 27.6% (95% CI, 21.7-34.2); partial response (PR), 44.3% (95% CI, 37.5-51.3). Response rates by cohort were as follows: cohort 1 (n=69): ORR: 76.8%; CRR: 26.1%; cohort 2 (n=81): ORR: 66.7%; CRR: 25.9%; cohort 3 (n=60): ORR: 73.3%; CRR: 31.7%. Median DOR was 16.5 mo overall (range 0.0+ to 27.0+; [+, no progressive disease at last assessment]). Of 151 responders, 87 (75.6%) had response ≥6 mo; 61 (58.5%) had response ≥12 mo; 16 (42.5%) had response ≥24 mo; 37 (24.5%) pts had ongoing response. Median DOR by cohort was 22.1 mo in cohort 1, 11.1 mo in cohort 2, and 24.4 mo in cohort 3 (Table). In patients with CR (n=58), median DOR was not reached (NR) in the total population and was 25.0 mo in cohort 1, 19.2 mo in cohort 2, and NR in cohort 3. In patients with PR (n=93), median DOR was 10.9 mo overall, 19.5 mo in cohort 1, 7.9 mo in cohort 2, and 13.9 mo in cohort 3. Median PFS for all patients was 13.7 mo (95% CI, 11.1-17.0) (Table); 24-mo PFS rate was 31.3%. In patients with CR, median PFS was NR in the total population, 27.6 mo in cohort 1, 21.9 mo in cohort 2, and NR in cohort 3 (Table). In patients with PR, median PFS was 13.8 mo in the total population, 22.2 mo in cohort 1, 13.4 mo in cohort 2, and 19.4 mo in cohort 3. Median OS was not reached in the total population or in any cohort; 24-mo OS rate was 90.9% in the overall population, 92.5% in cohort 1; 90.6% in cohort 2, and 89.4% in cohort 3 (Table). Any-grade treatment-related adverse events (AEs) occurred in 153 (72.9%) patients; those occurring in ≥10% patients were hypothyroidism (14.3%), pyrexia (11.4%), fatigue (11.0%), and rash (11.0%). Grade 3/4 treatment-related AEs occurred in 25 (11.9%) pts, most commonly, neutropenia (5 [2.4%] ) and diarrhea (3 [1.4%]); none resulted in death. Treatment-related AEs led to discontinuation in 14 (6.7%) patients. Conclusions: With more than 2 years of median follow-up, pembrolizumab continued to demonstrate effective antitumor activity with high ORR, durable response, and manageable safety in patients with R/R cHL in 3 cohorts of patients in whom treatment history was different. ORR, DOR, and PFS seemed higher in patients in cohorts 1 and 3 than in cohort 2, in which patients likely had more chemoresistant disease; nonetheless, pembrolizumab is still an effective treatment in this hard-to-treat patient population. Table. Table. Disclosures Zinzani: Astra Zeneca: Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; MSD: Honoraria, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Chen:Affimed: Research Funding; Genentech Inc.: Consultancy; Millennium Pharmaceuticals: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck & Co., Inc.: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding. Johnson:Bristol-Myers Squibb: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria, Other: travel, Research Funding; Roche: Consultancy, Honoraria, Other: travel, Research Funding; Seattle Genetics: Honoraria; AbbVie Inc.: Consultancy, Honoraria, Research Funding. Radford:Pfizer: Research Funding; AstraZeneca: Equity Ownership; Takeda: Consultancy, Research Funding, Speakers Bureau; Celgene: Research Funding; ADC Therapeutics: Consultancy, Research Funding; GlaxoSmithKline: Equity Ownership; Novartis: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Ribrag:Gilead: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Other: travel; epizyme: Consultancy, Honoraria; argenX: Research Funding; NanoString Technologies: Consultancy, Honoraria; Incyte Corporation: Consultancy; Amgen: Research Funding; MSD: Honoraria; Infinity: Consultancy, Honoraria; pharmamar: Other: travel; Servier: Consultancy, Honoraria; Roche: Honoraria, Other: travel. Molin:Merck & Co., Inc: Honoraria; Takeda Pharmaceuticals: Research Funding; Bristol-Myers Squibb: Honoraria; Roche Holding AG: Honoraria. Vassilakopoulos:Genesis Pharmaceuticals: Consultancy, Other: travel; Takeda Pharmaceuticals: Consultancy, Honoraria, Other: travel; Roche: Consultancy, Honoraria, Other: travel; Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Von Tresckow:Amgen: Honoraria; Novartis: Consultancy, Honoraria, Other: travel, Research Funding; Merck Sharp & Dohme: Research Funding; Celgene: Honoraria; Takeda Pharmaceuticals: Consultancy, Honoraria, Other: travel, Research Funding. Shipp:AstraZeneca: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Merck: Research Funding. Nahar:Merck & Co., Inc.: Employment, Equity Ownership. Balakumaran:Amgen: Equity Ownership; Merck & Co., Inc.: Employment, Equity Ownership. Moskowitz:Celgene: Consultancy; Genentech: Consultancy, Research Funding; Merck & Co: Consultancy, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding.

Abstract: Abstract 961 Background: Systemic anaplastic large cell lymphoma (sALCL) is a CD30-expressing malignancy comprising approximately 2–3% of all cases of non-Hodgkin lymphoma. The antibody-drug conjugate (ADC) brentuximab vedotin (SGN-35) delivers the highly potent antimicrotubule agent monomethyl auristatin E (MMAE) to CD30-positive malignant cells by binding specifically to CD30 on the cell surface and releasing MMAE inside the cell via lysosomal degradation. Binding of MMAE to tubulin disrupts the microtubule network within the cell, induces cell cycle arrest, and results in apoptotic death of the CD30-expressing tumor cell. In phase 1 studies, brentuximab vedotin demonstrated good tolerability and notable antitumor activity in patients with relapsed or refractory sALCL: 6 of 7 treated patients achieved complete remissions (CR). Methods: A phase 2, single-arm, multicenter study was conducted to evaluate the efficacy and safety of brentuximab vedotin in patients with relapsed or refractory sALCL. Brentuximab vedotin 1.8 mg/kg was administered every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles of treatment. Determination of antitumor efficacy was based on objective response assessments according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results: A total of 58 patients were treated in this study; interim data are presented for the first 30 treated patients. 53% of patients were female and median age was 55 years (range 14–71). The majority of patients had ALK-1 negative tumor (70%, or n=21) and 4 patients (13%) had bone marrow involvement at baseline. The median number of prior chemotherapy regimens was 2 (range 1–6) and 8 patients (27%) had failed previous autologous hematopoietic stem cell transplant (SCT). 19 patients (63%) had primary refractory disease, and 16 patients (53%) had not responded to the most recent prior therapy. The objective response rate (ORR) by investigator assessment was 87%; 57% of patients achieved a CR (n=17) and 30% of patients achieved a partial remission (PR; n=9). The remaining patients had stable disease (n=3) or were not evaluable for response (n=1). Similar proportions of ALK-1 negative and ALK-1 positive patients achieved CR and PR. Reduction in tumor burden was observed in 97% of patients. The median time to objective response was 6 weeks (range 5–12) and the duration of objective responses currently range from 4–36 weeks, with responses ongoing in 18 patients. B symptoms resolved in 9 of 10 patients (90%) who had these symptoms at baseline. After achieving a CR with brentuximab vedotin, 10 patients (33%) went on to receive an autologous or allogeneic SCT. The most common ( 〉 20%) adverse events (AEs) of any grade were nausea (47%), diarrhea (40%), peripheral sensory neuropathy (40%), pyrexia (33%), dyspnea (30%), fatigue (27%), insomnia (23%), and neutropenia (23%). Grade 3/4 AEs considered related to brentuximab vedotin observed in 〉 1 patient were neutropenia (17%), peripheral sensory neuropathy (13%), diarrhea (7%), and anemia (7%); no treatment-related Grade 5 events were observed. 7 patients (23%) discontinued treatment due to an AE. Conclusion: In this interim analysis of 30 patients with relapsed or refractory sALCL, the investigator-assessed ORR was 87% and the CR rate was 57%. Brentuximab vedotin treatment was associated with manageable AEs; the most common in the study were nausea, diarrhea, and peripheral sensory neuropathy. The rate of complete remissions observed thus far in this study with single-agent treatment suggests that brentuximab vedotin has potential for the treatment of sALCL. Results of the independent assessment of response for all patients, duration of response, progression-free survival, and updated safety data will be presented at the meeting. Disclosures: Shustov: Seattle Genetics, Inc.: Research Funding, Steering Committee member. Off Label Use: The clinical trial uses an investigational drug, brentuximab vedotin (SGN-35). Advani:Seattle Genetics, Inc.: Research Funding. Brice:Seattle Genetics, Inc.: Research Funding. Bartlett:Seattle Genetics, Inc.: Research Funding. Rosenblatt:Seattle Genetics, Inc.: Research Funding. Illidge:Seattle Genetics, Inc.: Research Funding; Roche: Consultancy; Biogen Idec: Consultancy; Amgen: Consultancy. Matous:Seattle Genetics, Inc.: Research Funding; Celgene: Honoraria, Speakers Bureau; Millennium: Speakers Bureau; Cephalon: Speakers Bureau. Ramchandren:Seattle Genetics, Inc.: Research Funding. Fanale:Seattle Genetics, Inc.: Research Funding. Connors:Seattle Genetics, Inc.: Research Funding. Yang:Seattle Genetics, Inc.: Employment. Sievers:Seattle Genetics, Inc.: Employment, Equity Ownership. Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership. Pro:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding.