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Nodal peripheral T-cell lymphomas (PTCL), the most common PTCLs, are generally treated with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)-based curative-intent chemotherapy. Recent molecular data have assisted in prognosticating these PTCLs, but most reports lack detailed baseline clinical characteristics and treatment courses. We retrospectively evaluated cases of PTCL treated with CHOP-based chemotherapy that had tumors sequenced by the Memorial Sloan Kettering Integrated Mutational Profiling of Actionable Cancer Targets (MSK-IMPACT) next-generation sequencing (NGS) panel to identify variables correlating with inferior survival. We identified 132 patients who met these criteria. Clinical factors correlating with increased risk of progression (by multivariate analysis) were advanced-stage disease (HR, 5.1; 95% CI, 1.1-22.5, P=.03) and bone marrow involvement (HR, 3.0; 95% CI, 1.1-8.4; P=.04). The only somatic genetic aberrancies correlating with inferior progression-free survival (PFS) were TP53 mutations (HR, 3.1; 95% CI, 1.4-6.8; P=.005) and TP53/17p deletions (HR, 4.1; 95% CI, 1.1-15.0, P=.03). PFS remained inferior when stratifying by TP53 mutation status, with a median PFS of 4.5 months (95% CI, 3.8-13.9) for PTCL with a TP53 mutation (n=21) vs 10.5 months (95% CI, 7.8-18.1; P

A modification of the SMILE regimen with dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide (mSMILE) followed by Intensity-Modulated Radiotherapy (IMRT) at lower than usual dose, has been adopted as standard of care for extranodal NK/T cell lymphoma (ENKL) at our institution. mSMILE is a short course, intensive regimen incorporating pegylated asparaginase. Here we describe clinical details, outcome and safety of patients receiving mSMILE. Among 28 patients with ENKL treated, response post mSMILE was 93% (CR 68%), response post IMRT was 95% (CR 87.5%). Among early-stage patients/low PINK-E (n=13), overall survival (OS) was 100% at the median follow up of 31 months; progression-free survival (PFS) was 92%. Advanced-stage and intermediate/high PINK-E patients fared similarly (OS 43%, PFS 33.3% at the median follow-up). 32% of the patients experienced G3–4 non-hematologic toxicity, all experienced hematologic toxicity. Most localized-stage patients achieved long-term disease control. Despite high response rates, most of the advanced stage patients relapsed quickly.

Summary Background The risk of BIA-ALCL for patients with textured breast implants has been estimated between 1/2832 and 1/30,000 women. Existing studies estimating the numbers exposed and at risk, may have under reported cases, and/or lacked comprehensive follow-up. Our objective is to determine the risk of BIA-ALCL in a defined cohort of patients reconstructed with macro-textured breast implants and consistently followed long-term. Methods A prospective cohort study was conducted in patients who underwent breast reconstruction by a single surgeon at Memorial Sloan Kettering Cancer Center (MSKCC) from December 1992 to December 2017. Major events related to implants were prospectively recorded. We identified cases of BIA-ALCL by cross-checking clinical, pathology and external records data. Patients were followed until lymphoma occurrence or last follow-up. The primary outcomes were incidence rate per person-years and cumulative incidence. Results From 1992 to 2017, 3546 patients underwent 6023 breast reconstructions, mainly after breast cancer removal, or contralateral prophylactic mastectomy, using macro-textured surface expanders and implants. All reconstructions were performed by a single surgeon (PGC). Median follow-up was 8.1 years (range, 3 months – 30.9 years). Ten women, 1/354, developed ALCL after a median exposure of 11.5 years (range, 7.4–15.8 years). Overall risk of BIA-ALCL in our cohort is 1/355 women or 0.311 cases per 1000 person-years (95% CI 0.118 to 0.503). Discussion This study, the first to evaluate the risk of macro-textured breast implants from a prospective database with long term follow-up, demonstrates that the incidence rate of BIA-ALCL may be higher than previously reported. These results can help inform implant choice for women undergoing breast reconstruction.

Recurrent chromosomal rearrangements are a hallmark of hematologic malignancies and play critical roles in pathogenesis. The TP53 analog TP63 is rearranged in 5-10% of diverse subtypes of both aggressive T- and B-cell lymphomas. Patients with TP63-rearranged lymphomas have dismal outcomes, with 5-year overall survival rates between 0-17%, depending on cohorts. The function and mechanisms of TP63 rearrangements and TP63 fusion proteins in tumorigenesis are poorly understood. As a result, attempts to treat these patients to date have been largely empiric. Thus, there is an urgent need to understand how TP63 fusions contribute to tumorigenesis and to translate the findings into novel therapeutic options for these patients. Here, we demonstrated that TP63 fusions are essential for the propagation of T-cell lymphomas (TCLs). Knockdown of TP63 fusions with specific shRNAs in TCL cell lines harboring TP63 fusions suppressed both cell growth in vitro and tumor growth in vivo. Retroviral expression of TBL1XR1-TP63, the most common TP63 fusion, conferred cytokine independence in Ba/F3 cells, consistent with its role as an oncogene. To investigate the role of TP63 fusions in T- and B-cell lymphomagenesis, we engineered a CAG-Loxp-Stop-Loxp-TBL1XR1-TP63 conditional knock-in mouse model and crossed with hCD2-Cre mice. This results in expression beginning during early lymphoid development. As observed in patients, transgenic mice developed multiple subtypes of both T- and B-cell lymphoma. To define the effects and mechanisms of TP63 fusions within T cells, we performed CRISPR scanning, transcriptomic, epigenomic, and proteomic analyses. Our data showed that domains within both the N-terminal TBL1XR1 and C-terminal TP63 portions contribute to the function of this fusion. We found that the N-terminal component of TP63 fusions interacts with components of the NCOR/SMRT complex. At the same time, the C-terminal portion of TP63 (which recapitulates the deltaN-p63 isoform expressed in some carcinomas) interacts with the enhancer modifier KMT2D and its complex members. TBL1XR1-TP63 binds to a novel distal enhancer to drive MYC expression, and thus upregulates the expression of the histone H3K27 methylase EZH2. Finally, we assessed whether EZH2 is a vulnerability of TP63-rearranged lymphomas. We found that knockdown of EZH2 in TP63-rearranged lines significantly impaired cell growth, as did treatment with the EZH2 and 1 dual inhibitor valemetostat. Valemetostat, which is now being tested in patients with lymphoma, counteracted the oncogenic effects of TP63 fusions in multiple preclinical models in vivo. Together, our results identify the TP63 fusion as a highly unique oncogenic driver in lymphomagenesis capable of recruiting multiple epigenetic modifier complexes and inducing a targetable dependence on EZH2. Citation Format: Gongwei Wu, Noriaki Yoshida, Jihe Liu, Xiaoyang Zhang, Yuan Xiong, Tayla Heavican-Foral, Huiyun Liu, Geoffrey Nelson, Lu Yang, Renee Chen, Katherine Donovan, Marcus Jones, Mikhail Roshal, Yanming Zhang, Ran Xu, Ajit Nirmal, Salvia Jain, Catharine Leahy, Kristen Jones, Kristen Stevenson, Natasha Galasso, Nivetha Ganesan, Tiffany Chang, Wen-Chao Wu, Abner Louissaint, Lydie Debaize, Hojong Yoon, Paola Dal Cin, Wing Chan Chan, Shannan Ho Sui Ho Sui, Samuel Ng, Andrew Feldman, Steven M. Horwitz, Mathew Meyerson, Karen Adelman, Eric Fischer, Chun-Wei Chen, David Weinstock, Myles Brown. TP63 fusions drive enhancer rewiring, lymphomagenesis, and dependence on EZH2. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5755.

Signaling through JAK1 and/or JAK2 is common among tumor and nontumor cells within peripheral T-cell lymphoma (PTCL). No oral therapies are approved for PTCL, and better treatments for relapsed/refractory disease are urgently needed. We conducted a phase 2 study of the JAK1/2 inhibitor ruxolitinib for patients with relapsed/refractory PTCL (n = 45) or mycosis fungoides (MF) (n = 7). Patients enrolled onto 1 of 3 biomarker-defined cohorts: (1) activating JAK and/or STAT mutations, (2) ≥30% pSTAT3 expression among tumor cells by immunohistochemistry, or (3) neither or insufficient tissue to assess. Patients received ruxolitinib 20 mg PO twice daily until progression and were assessed for response after cycles 2 and 5 and every 3 cycles thereafter. The primary endpoint was clinical benefit rate (CBR), defined as the combination of complete response, partial response (PR), and stable disease lasting at least 6 months. Only 1 of 7 patients with MF had CBR (ongoing PR > 18 months). CBR among the PTCL cases (n = 45) in cohorts 1, 2, and 3 were 53%, 45%, and 13% (cohorts 1 & 2 vs 3, P = .02), respectively. Eight patients had CBR > 12 months (5 ongoing), including 4 of 5 patients with T-cell large granular lymphocytic leukemia. In an exploratory analysis using multiplex immunofluorescence, expression of phosphorylated S6, a marker of PI3 kinase or mitogen-activated protein kinase activation, in

PURPOSE We conducted a phase II study evaluating pembrolizumab plus gemcitabine, vinorelbine, and liposomal doxorubicin (pembro-GVD) as second-line therapy for relapsed or refractory (rel/ref) classical Hodgkin lymphoma (cHL) (ClinicalTrials.gov identifier: NCT03618550 ). METHODS Transplant eligible patients with rel/ref cHL following first-line therapy were treated with two to four cycles of pembrolizumab (200 mg intravenous [IV], day 1), gemcitabine (1,000 mg/m2 IV, days 1 and 8), vinorelbine (20 mg/m2 IV, days 1 and 8), and liposomal doxorubicin (15 mg/m2, days 1 and 8), given on 21-day cycles. The primary end point was complete response (CR) following up to four cycles of pembro-GVD. Patients who achieved CR by labeled fluorodeoxyglucose-positron emission tomography (Deauville ≤ 3) after two or four cycles proceeded to high-dose therapy and autologous hematopoietic cell transplantation (HDT/AHCT). HDT/AHCT was carried out according to institutional standards, and brentuximab vedotin maintenance was allowed following HDT/AHCT. RESULTS Of 39 patients enrolled, 41% had primary ref disease and 38% relapsed within 1 year of frontline treatment. 31 patients received two cycles of pembro-GVD, and eight received four cycles. Most adverse events were grade 1 or two, whereas few were grade 3 and included transaminitis (n = 4), neutropenia (n = 4), mucositis (n = 2), thyroiditis (n = 1), and rash (n = 1). Of 38 evaluable patients, overall and CR rates after pembro-GVD were 100% and 95%, respectively. Thirty-six (95%) patients proceeded to HDT/AHCT, two received pre-HDT/AHCT involved site radiation, and 13 (33%) received post-HDT/AHCT brentuximab vedotin maintenance. All 36 transplanted patients are in remission at a median post-transplant follow-up of 13.5 months (range: 2.66-27.06 months). CONCLUSION Second-line therapy with pembro-GVD is a highly effective and well-tolerated regimen that can efficiently bridge patients with rel/ref cHL to HDT/AHCT.

Romidepsin (histone deacetylase inhibitor), lenalidomide (immunomodulatory agent), and carfilzomib (proteasome inhibitor), have efficacy and lack cumulative toxicity in relapsed/refractory lymphoma. We performed two investigator initiated sequential phase I studies to evaluate the maximum tolerated dose (MTD) of romidepsin and lenalidomide (regimen A) and romidepsin, lenalidomide, and carfilzomib (regimen B) in relapsed/refractory lymphoma. Cohorts in T-cell lymphoma (TCL), B-cell lymphoma (BCL) were enrolled at the MTD. 49 patients were treated in study A (27 TCL, 17 BCL, 5 HL) and 27 (16 TCL, 11 BCL) in study B. The MTD of regimen A was romidepsin 14 mg/m2 IV on days 1, 8, and 15 and lenalidomide 25 mg oral on days 1-21 of a 28-day cycle. The MTD of regimen B was romidepsin 8mg/m2 on days 1 and 8, lenalidomide 10mg oral on days 1-14 and carfilzomib 36mg/m2 IV on days 1 and 8 of a 21-day cycle. In study A, 94% had AEs ≥Grade 3, most commonly neutropenia (49%), thrombocytopenia (53%), and electrolyte abnormalities (49%). In study B 59% had AEs ≥Grade 3, including thrombocytopenia (30%) and neutropenia (26%). In study A the ORR was 49% (50% TCL, 47% BCL, 50% HL). In study B the ORR was 48% (50% TCL, 50% BCL). For study A and B the median progression free survival (PFS) was 5.7 months and 3.4 months respectively with 11 patients proceeding to allogeneic transplant. The combinations of romidepsin and lenalidomide and of romidepsin, lenalidomide and carfilzomib showed activity in relapsed/refractory lymphoma with an acceptable safety profile. This article is protected by copyright. All rights reserved.

Histone deacetylase inhibitors (HDACi) are active agents for peripheral T-cell lymphoma (PTCL). Anecdotally angioimmunoblastic T-cell lymphoma (AITL) appears to respond better than PTCL–not otherwise specified (NOS) to HDACi. The new World Health Organization classification shows that a subgroup of PTCL carries similarities in phenotype and gene expression profiling to AITL, comparable to T follicular helper (TFH) cells. The disease might behave similarly to AITL when treated with HDACi. We analyzed 127 patients with AITL or PTCL-NOS treated with HDACi at relapse as a single agent or in combination. We re-reviewed the pathology of all PTCL-NOS to identify the TFH phenotype. Patients received HDACi at relapse as a single agent in 97 cases (76%, 59 TFH, 38 non-TFH) or in combination in 30 cases (24%, 18 TFH, 12 non-TFH) including duvelisib, lenalidomide, lenalidomide plus carfilzomib, and pralatrexate. Seven PTCL-NOS had TFH phenotype; 2 PTCL-NOS were reclassified as AITL. Overall response rate (ORR) was 56.5% (28.9% complete response [CR]) in TFH and 29.4% (19.6% CR) in non-TFH phenotype patients (P = .0035), with TFH phenotype being an independent predictor of ORR (P = .009). Sixteen patients sufficiently responded to HDACi or HDACi in combination with another agent to proceed directly to allogeneic transplantation; 1 of 16 responded to donor lymphocyte infusion (12 TFH, 4 non-TFH). Our results, although retrospective, support that HDACi, as a single agent or in combination, may have superior activity in TFH-PTCL compared with non-TFH PTCL. This differential efficacy could help inform subtype-specific therapy and guide interpretation of HDACi trials.

Introduction Mutational profiling in peripheral T-cell lymphoma (PTCL) is increasingly used to aid in diagnosis (Wang. Blood 2015), predicting response (Ghione. Blood Adv 2020), and prognosis (Watatani. Leukemia 2019). However, many analyses lack details of upfront treatment and survival outcomes. The Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) is a custom hybridization capture-based assay encompassing the protein-coding exons of >400 targeted genes (Cheng. J Molec Diag 2015). Using the MSK-IMPACT data generated from a large TCL patient (pt) population (N=396), we sought alterations which may predict resistance to or high rates of relapse after CHOP-based chemotherapy. Methods PTCL pts with MSK-IMPACT were detected in the CBioPortal online platform. We included histologies treated with curative intent CHOP-based induction +/- autologous stem cell transplant (ASCT). This included PTCL-not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), PTCL with a T-follicular helper phenotype (FH-TCL), ALK+ and ALK- anaplastic large cell lymphoma (ALCL), and monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL). Univariate analysis (UVA) for PFS and OS based on the presence of recurring genetic alterations was done using Cox proportional hazard regression analysis. Mutations (mut) assessed included TET2, DNMT3A, RHOA, IDH2, TP53, FAT1, STAT3, STAT5B, JAK1, SETD2, and copy number alterations (CNA) in TP53 and CDKN2A. Comparisons of survival curves were performed by log-rank test. As many pts were sequenced at relapse, to minimize bias, relevant findings were confirmed in the smaller set of pts sequenced at diagnosis and/or before relapse (prospective cohort). Results In total, 131 pts met inclusion criteria and had >1 MSK-IMPACT. One pt with a 49-gene panel was also included (N=132). The prospective cohort had 73 (55%) pts. Histologies were PTCL-NOS (N=36, 27%), AITL (N=62, 47%), FH-TCL (N=9, 7%), ALK-ALCL (N=15, 11%), ALK+ALCL (N=6, 5%), and MEITL (N=4, 3%). Regimens were CHOP + etoposide (N=59, 45%), CHOP (N=40, 30%), brentuximab + CHP (N=15, 11%), other CHOP-based (N=18, 14%). The most frequent mut were TET2 (N=69, 52%), RHOA (N=40, 30%), DNMT3A (N=25, 19%), TP53 (N=21, 16%), and IDH2 (N=15, 11%), and for CNA were losses of TP53 (N=9, 7%) and CDKN2A (N=9, 7%). TET2 mut were most frequent in AITL (N=51, 82%), FH-TCL (N=6, 67%), and PTCL-NOS (N=10, 28%). RHOA mut were found in 2 cases of PTCL-NOS (6%) with the rest in AITL (N=33, 53%) and FH-TCL (N=5, 56%). DNMT3A mut were most frequent in AITL (N=19, 31%) and FH-TCL (N=4, 44%). IDH2 mut were exclusive to AITL (N=14, 23%) and FH-TCL (N=1, 11%). TP53 mut were found in all histologies: ALK-ALCL (N=5, 33%), PTCL-NOS (N=10, 28%), FH-TCL (N=2, 22%), AITL (N=2, 3%), and in one case each of ALK+ALCL (17%) and MEITL (25%). The 24-month PFS was 28% for the entire cohort, and 42% for the prospective cohort. On UVA for genetic alterations, only TP53 mut (P=0.0011) and TP53 deletions (P=0.009) associated with inferior PFS. On MVA, only TP53 mut remained significant (HR 2.0 [95% CI 1.1-3.5] P=0.02). No alteration associated with inferior OS. For the entire cohort, median PFS was 4.5 mos for TP53 mut (N=21) vs. 10.5 mos for TP53 wild-type (WT) (N=111) (log-rank P=0.0008). This was similar in the prospective cohort with a median PFS of 4.1 vs. 19.7 mos (log-rank P=0.02) (Figure 1). Compared to TP53 WT, TP53 mut were more likely to have PTCL-NOS (P=0.03), concurrent deletions of TP53 (P=0.0005), and a higher median number of alterations (P=0.01). There were no differences in age, stage, marrow disease, or IPI/PIT scores between TP53 mut and TP53 WT pts. There was a trend towards fewer CR (P=0.054) in TP53 mut. There were no differences in ITT with ASCT between the groups (P=0.5). This was similar in the prospective cohort (P=0.4). Six total (29%) TP53 mut received ASCT, and PFS was similar to ASCT in TP53 WT (median 18.2 vs. 19.7 mos, P=0.5), but 5/6 (83%) ultimately relapsed. Conclusions TP53 mut correlated with lower rates of CR, higher rates of relapse, and shorter PFS in this dataset of PTCL treated with CHOP-based chemotherapy. OS was not different compared to TP53 WT tumors. The confounding impact of histology and other prognostic factors as well as the lack of uniform prospective mutational profiling in this retrospective series precludes definitive conclusions and requires prospective confirmation. Figure 1 Figure 1. Disclosures Sauter: Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Genmab: Consultancy; Precision Biosciences: Consultancy; Kite/Gilead: Consultancy; Celgene: Consultancy, Research Funding; Gamida Cell: Consultancy; GSK: Consultancy; Bristol-Myers Squibb: Research Funding. Khan: Seattle Genetics: Research Funding. Moskowitz: ADC Therapeutics: Research Funding; Beigene: Research Funding; Seattle Genetics: Consultancy, Research Funding; Miragen: Research Funding; Bristol-Myers Squibb: Research Funding; Merck: Consultancy, Research Funding; Janpix Ltd.: Consultancy; Imbrium Therapeutics L.P./Purdue: Consultancy; Takeda: Consultancy; Incyte: Research Funding. Dogan: Seattle Genetics: Consultancy; Roche: Consultancy, Research Funding; Peer View: Honoraria; EUSA Pharma: Consultancy; Takeda: Consultancy, Research Funding; Physicians' Education Resource: Honoraria. Horwitz: ADC Therapeutics: Consultancy, Research Funding; Acrotech Biopharma: Consultancy; Affimed: Research Funding; Aileron: Research Funding; Celgene: Research Funding; C4 Therapeutics: Consultancy; Daiichi Sankyo: Research Funding; Forty Seven, Inc.: Research Funding; Kyowa Hakko Kirin: Consultancy, Research Funding; Janssen: Consultancy; Kura Oncology: Consultancy; Millennium /Takeda: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Trillium Therapeutics: Consultancy, Research Funding; SecuraBio: Consultancy, Research Funding; Myeloid Therapeutics: Consultancy; ONO Pharmaceuticals: Consultancy; Shoreline Biosciences, Inc.: Consultancy; Tubulis: Consultancy; Vividion Therapeutics: Consultancy; Verastem: Research Funding.

Introduction: The standard approach for relapsed or refractory (RR) classical Hodgkin lymphoma (cHL) following front-line treatment failure is second line therapy (SLT) aimed to achieve complete response (CR), followed by consolidation with high dose therapy and autologous hematopoietic cell transplantation (HDT/AHCT). No one standard SLT exists and options include regimens containing platinum, gemcitabine, and more recently brentuximab vedotin (BV). Complete response rates associated with these regimens range from 50-70%. Due to the increasing use of BV in the front-line setting, development of SLT regimens that are both highly effective and BV-sparing are needed. Programmed death-1 (PD-1) inhibitors are highly active in RR cHL and have the potential to enhance the efficacy of standard chemotherapy. Here we report the results of our phase II study evaluating a novel anti-PD-1-based regimen, pembrolizumab plus gemcitabine, vinorelbine, and liposomal doxorubicin (pembrolizumab-GVD), as SLT for RR cHL. Methods: Transplant eligible patients (pts) with RR cHL following failure of 1-line of therapy were eligible. Treatment consisted of 2 to 4 cycles of pembrolizumab (200mg IV, day 1), gemcitabine (1000mg/m2 IV, days 1 and 8), vinorelbine (20mg/m2 IV, days 1 and 8) and liposomal doxorubicin (15mg/m2, days 1 and 8), given on 21-day cycles. Pts who achieved CR by PET (Deauville ≤3) after 2 or 4 cycles proceeded to HDT/AHCT. HDT/AHCT was carried out according to institutional standards and BV maintenance was allowed following HDT/AHCT. The primary endpoint was CR rate after 2 or 4 cycles of pembrolizumab-GVD. Enrollment occurred according to a Simon 2-stage design with sample size based upon a projected CR rate of 70%. In stage 1, 23 pts enrolled and 12 or more CRs were required to proceed to stage II; in stage II, an additional 16 pts enrolled. Out of a total of 39 pts, 24 CRs were required to declare this regimen promising. Results: Among 39 patients enrolled, 37 are evaluable for toxicity (2 pts have not yet started treatment) and 34 are evaluable for response (4 pts too early, 1 pt found to have composite lymphoma after enrollment). Of 37 treated pts, median age is 36 (range 21-71), 43% are male, 23 (62%) had advanced stage disease, and 15 (41%) had primary refractory disease. With regard to RR cHL risk factors (B-symptoms, extranodal disease, and relapse/refractory disease within 1 year of initial treatment), 4(11%) had no risk factors (RFs), 21 (57%) had 1 RF, 9 (24%) had 2 RFs, and 3 (8%) had all 3 RFs. Treatment was well tolerated with most adverse events being grade 1 or 2 (see figure 1). Grade 3 AEs included rash (n=1), elevated AST/ALT (n=3), oral mucositis (n=2), and neutropenia (n=3). Figure 2 shows the outcome for all 37 treated pts. Among 34 evaluable pts, 31 (91%) achieved CR after 2 cycles and 3 achieved partial response. An additional 1 pt achieved CR after 4 cycles of pembrolizumab-GVD, therefore in total, 32 of 34 (94%) achieved CR following pembrolizumab-GVD. 4 pts with CR after 2 cycles received an additional 2 cycles of pembrolizumab-GVD in order to delay HDT/AHCT during the height of the COVID-19 pandemic (n=3) or due to refusing HDT/ASCT (n=1). To date, 32 have undergone HDT/AHCT following 2 (n=27) or 4 (n=5) cycles of treatment. 1 pt is awaiting HDT/AHCT; 1 pt refused HDT/ASCT and received pembrolizumab maintenance instead. 2 pts received involved site radiation therapy to initial area of relapsed disease prior to planned HDT/AHCT and 10 pts received post-HDT/ASCT maintenance with BV. Median follow-up post-HDT/AHCT is 9 mos (range 0.03-20.9 mos) and all pts remain in remission to date. Conclusion: Second-line therapy with pembrolizumab-GVD is a highly effective and well-tolerated regimen that can efficiently bridge pts with RR cHL to HDT/AHCT. Updated results including all 39 enrolled pts will be presented at the meeting. Given the high CR rate observed with pembrolizumab-GVD, an expansion cohort evaluating 8 cycles of pembrolizumab maintenance (instead of HDT/AHCT) for patients who achieve CR after 4 cycles of pembrolizumab-GVD is planned. Disclosures Moskowitz: Merck: Consultancy; Incyte: Research Funding; Miragen Therapeutics: Consultancy; Seattle Genetics: Consultancy; Imbrium Therapeutics, L.P.: Consultancy; Merck: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding. Shah:Amgen Inc.: Research Funding; Janssen: Research Funding. Kumar:AbbVie: Research Funding; Celgene: Honoraria, Other: Honoraria for Advisory Board; Seattle Genetics: Research Funding; Astra Zeneca: Honoraria, Other: Honoraria for Advisory Board; Celgene: Research Funding; Kite Pharmaceuticals: Honoraria, Other: Honoraria for Advisory Board; Adaptive Biotechnologies,: Research Funding; Pharmacyclics: Research Funding. Lahoud:MorphoSys: Other: Advisory Board. Batlevi:Life Sci, GLG, Juno/Celgene, Seattle Genetics, Kite: Consultancy; Janssen, Novartis, Epizyme, Xynomics, Bayer, Autolus, Roche/Genentech: Research Funding. Hamlin:J&J Pharmaceuticals: Research Funding; Portola: Research Funding; Incyte: Research Funding; Portola Pharmaceutics: Consultancy; Juno Therapeutics: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy; Molecular Templates: Research Funding. Straus:Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees; Imedex, Inc.: Speakers Bureau; Targeted Oncology: Consultancy, Speakers Bureau; NY Lymphoma Rounds: Consultancy; Takeda Pharmaceuticals: Research Funding, Speakers Bureau; OncLive: Speakers Bureau; Elsevier: Membership on an entity's Board of Directors or advisory committees, Other: CME writer; ASH: Other: Conference in December 2019 on HL to other physicians during ASH; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Horwitz:ASTEX: Consultancy; Verastem: Consultancy, Research Funding; Myeloid Therapeutics: Consultancy; Miragen: Consultancy; Kura Oncology: Consultancy; Janssen: Consultancy; GlaxoSmithKline: Consultancy; Daiichi Sankyo: Research Funding; C4 Therapeutics: Consultancy; Affirmed: Consultancy; Vividion Therapeutics: Consultancy; Beigene: Consultancy; Portola: Consultancy, Research Funding; Mundipharma: Consultancy; Innate Pharma: Consultancy; Corvus: Consultancy; Trillium: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Forty Seven: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Aileron: Consultancy, Research Funding; ADCT Therapeutics: Consultancy, Research Funding. Falchi:Genmab: Research Funding; Roche: Research Funding. Joffe:Epizyme: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees. Noy:Pharmacyclics: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Rafael Pharma: Research Funding; NIH: Research Funding; Morphosys: Consultancy; Medscape: Consultancy; Targeted Oncology: Consultancy. Matasar:Teva: Consultancy; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Merck: Consultancy; Bayer: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; IGM Biosciences: Research Funding; Janssen: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Immunovaccine Technologies: Honoraria, Research Funding; Rocket Medical: Consultancy, Research Funding; Takeda: Consultancy, Honoraria; Daiichi Sankyo: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding. Vardhana:Other: Other: SAV has received honoraria from Agios Pharmaceuticals and Rheos Pharmaceuticals, is an advisor for Immunai and has consulted for ADC Therapeutics. von Keudell:Genentech: Research Funding; Bayer: Research Funding; Pharmacyclics: Research Funding. Zelenetz:Novartis: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Adaptive Biotechnology: Consultancy; BeiGene: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Gilead: Research Funding; Genentech/Roche: Consultancy; Gilead: Consultancy; Sandoz: Research Funding; Celgene: Research Funding; MEI Pharma: Research Funding; MorphoSys: Research Funding. OffLabel Disclosure: Pembrolizumab as second-line therapy for Hodgkin lymphoma

Introduction Breast Implant Associated Anaplastic Large Cell Lymphoma (BIA-ALCL) is a rare subtype of ALCL that arises as a seroma or a mass in the space surrounding textured breast implants. In July 2019 the FDA had reported 573 cases worldwide and 33 deaths connected to the lymphoma. However, collections of cases usually come from large groups of institutions or countries, with different approaches regarding surgery and treatment. Here we describe a cohort of 18 cases undergoing implant removal and capsulectomy and followed at Memorial Sloan Kettering Cancer Center (MSKCC) Methods We retrospectively analyzed all the cases of women with breast implants undergoing implant removal and capsulectomy for BIA-ALCL at MSKCC from January 2011 to June 2020. Results are expressed in absolute numbers and percentages, survival is calculated with the Kaplan Maier method. Results Of 27 total BIA-ALCL cases seen at MSKCC, 18 women had their primary surgery for implant removal and capsulectomy by our surgery division, analyzed in our central pathology and treated and/or expectantly monitored in our T cell lymphoma clinic. Sixteen patients (89%) had implants as reconstruction after breast cancer (of which 12/16, 75% had received adjuvant/neoadjuvant chemotherapy (CT), 3, 19% radiotherapy (RT). Two subjects (11%) had implants for cosmetic reasons). Four patients (25%) had undergone implants exchange after initial reconstruction. BRCA mutational status was known in 9 patients (56%), with 3/9 women (33%) having BRCA mutations (2 BRCA2, 1 BRCA1) and one additional woman initially thought to have a mutation of BRCA2, subsequently re-classified as polymorphism. After a median exposure of 11 years (STDEV 6 y), 10 years from last implant change, median age at BIA-ALCL diagnosis was 57 years (STDEV 10 y). Implant characteristics were as follows: 18/18 (100%) silicone surface, 17/18 (94%) had a biocell textured surface, 1/18 (6%) unknown surface, 9/18 (50%) silicone filled, and 9/18 (50%) saline filled. BIA-ALCL presented as effusion in 14/18 (78%) of cases, mass in 3/18 (17%) of cases, and PET+ intramammary lymphadenopathy in 1/18 (6%). Pre-surgery, cases were assessed with PET/CT in 15/18 (83%), US in 15/18 (83%) and MR in 7/18 (39%). Initial treatment was implant removal and capsulectomy for all women, with removal of all the implants in place. One early case received implant removal and replacement with a smooth textured implant with partial capsulectomy prior to confirmed diagnosis. Three of 18 (16%) who presented with higher stage disease received additional treatment: one received chemotherapy (Brentuximab Vedotin - cyclophosphamide - doxorubicin - prednisone, BV-CHP) followed by RT consolidation, and 2 received RT consolidation only. Patients were followed for a median of 26 months (STDEV 2.22 months) after diagnosis, with clinical exam every 3-6 months (100%), PET/CT in 16/18 (89%), and MR in 4/18 (22%). No patient died of lymphoma progression or recurrence. One patient died from progression of breast cancer. One woman (described above) recurred 2 years after receiving incomplete capsulectomy and smooth surface implant re-placement. She underwent repeat implant removal and bilateral capsulectomy and remains disease free at 6.5 years from the second surgery. Another patient was likely diagnosed at recurrence: she underwent unilateral implant removal and partial unilateral capsulectomy for recurrent delayed seroma (at the time of this implant removal BIA-ALCL could not be confirmed). 1.5 years later she developed a recurrent seroma on the contralateral side where a textured device remained. BIA-ALCL diagnosis was confirmed at this time. Overall survival (Figure 1), was 94% at 2 years and progression-free survival was 89% at 2 years. Conclusions Our data on this cohort of patietns with BIA-ALCL surgically treated and followed at a single institution, confirm the importance of adequate surgery (bilateral implant removal and complete capsulectomy) in patients presenting with seroma-confined disease. This dataset reinforces the high rates of progression free and overall survivalwhen diagnosis is identified and treatment performed in those with limited stage disease. Studies are ongoing to determine the role of somatic mutations like BRCA1-2. Figure: overall and progression-free survival of BIA-ALCL women operated and followed at MSKCC Figure 1 Disclosures Cordeiro: Inamed: Consultancy, Research Funding; Acelity: Consultancy; Allergan: Consultancy, Research Funding. Moskowitz:Bristol-Myers Squibb: Research Funding; Merck: Research Funding; Merck: Consultancy; Miragen Therapeutics: Consultancy; Seattle Genetics: Consultancy; Seattle Genetics: Research Funding; Incyte: Research Funding; Imbrium Therapeutics, L.P.: Consultancy. Dogan:Takeda: Consultancy; AbbVie: Consultancy; National Cancer Institute: Research Funding; Seattle Genetics: Consultancy; EUSA Pharma: Consultancy; Corvus Pharmaceuticals: Consultancy; Roche: Consultancy, Research Funding; Physicians Education Resource: Consultancy. Horwitz:Vividion Therapeutics: Consultancy; Affirmed: Consultancy; Daiichi Sankyo: Research Funding; GlaxoSmithKline: Consultancy; Janssen: Consultancy; Kura Oncology: Consultancy; ASTEX: Consultancy; C4 Therapeutics: Consultancy; Beigene: Consultancy; Portola: Consultancy, Research Funding; Mundipharma: Consultancy; Innate Pharma: Consultancy; Corvus: Consultancy; Trillium: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Forty Seven: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Aileron: Consultancy, Research Funding; ADCT Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Myeloid Therapeutics: Consultancy; Miragen: Consultancy.

Summary Rituximab-containing salvage chemotherapy followed by high-dose therapy and autologous stem cell transplant (ASCT) in chemosensitive patients remains the standard of care for patients with relapsed and refractory diffuse large B-cell lymphoma (DLBCL). However, its role in those patients achieving less than a complete response to first-line therapy (primary refractory disease) in the rituximab era is not well defined. We reviewed the outcomes of 82 transplant-eligible patients with primary refractory DLBCL who underwent salvage therapy with the intent of administering high-dose therapy and ASCT to patients achieving chemosensitive remission. The estimated 3-year overall and progression-free survival for all patients was 38% and 29%, respectively, and 65% and 60% respectively for patients proceeding to stem cell transplant. Long-term remission was achieved in 45% of patients achieving a partial response (PR) to initial induction therapy and

Introduction: Peripheral and cutaneous T cell lymphomas (TCL) are highly heterogeneous diseases that in the relapsed/refractory (R/R) stage have poor outcome. JAK/STAT, Pi3K/AKT and MAP kinase signaling are commonly involved in the pathogenesis of these lymphomas, and the efficacy of small molecule inhibitors targeting these pathways is being assessed in phase II trials. However, biomarkers to define patients most likely to benefit from specific inhibitors are lacking and mechanisms of acquired resistance in TCLs have not been reported. Methods: We are conducting two early phase trials in R/R TCL: 1) NCT02974647 targets JAK1/JAK2 with ruxolitinib (RUX, a JAK 1-2 inhibitor) and has enrolled 53 patients and 2) NCT02783625 targets Pi3K/AKT with duvelisib (DUV, a Pi3K gamma-delta inhibitor) in combination with either romidepsin or bortezomib and has enrolled 92 patients. We analyzed pre-, on and post- treatment biopsies with multiplex immunofluorescence (mIF) using the Vectra platform, and analyzed images for marker expression and cellular location using HALO software. We designed multiple mIF panels with 6 markers per slide, 3 identifying TCL cells based on disease-specific phenotypes (e.g. CD4+PD1+CD8- for angioimmunoblastic TCL), pSTAT3,5, pS6, and a macrophage marker (CD68). Areas of TCL involvement within biopsy slides were manually defined during image analysis based on mIF and comparison to clinical immunohistochemistry. Differences in marker expressions were analyzed with the Wilcoxon test using the program R. Results: We analyzed 53 biopsies from 39 patients with high-quality mIF images, of which 17 were from lymph nodes and 36 were from extranodal sites. Of 39 patients, 13 were treated with RUX (9 biopsies pre-, 7 on, 4 post- treatment) and 26 with DUV (20 biopsies pre-, 6 on, 10 post- treatment). Median number of total TCL cells in pre-treatment biopsies was 1041 (range, 97-6463) and median TCL cell fraction within involved areas was 27.86% (range, 5.12-88.02%). Median macrophage fraction within involved areas was 5.92% (range, 2.89-11.88%). For either agent, response to treatment was not associated with: 1) quantity of macrophages (p=0.1 for responders vs non-responders to DUV, p=0.53 for RUX), 2) average distance between TCL cells and closest macrophage, 3) TCL cell fraction within involved areas, or 4) fraction of TCL cells expressing pSTAT3/5 (Figure). In contrast, pS6 expression in Conclusions: mIF is a feasible platform for biomarker discovery and translation in TCL, a set of lymphomas with heterogeneous immunophenotypes. pS6 expression in Citation Format: Paola Ghione, Alison Moskowitz, Priadarshini Kumar, Andrea Knezevic, Venkatraman Seshan, Eric Jacobsen, Jia Ruan, Johnathan Schatz, Sarah Noor, Patricia Myskowski, Helen Hancock, Theresa Davey, Obadi Obadi, Carlissa Onwasigwe, Nivetha Ganesan, Lauren Pomerantz, Christine Jarjies, Allison Sigler, Mark Geyer, Ariela Noy, David Straus, Natasha Galasso, Giorgio Inghirami, Steven Horwitz, David Weinstock, Travis Hollmann, Ahmet Dogan. Multispectral immunofluorescence identifies pS6 as a biomarker of intrinsic resistance to ruxolitinib in patients with relapsed/refractory T-cell lymphomas [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4248.

e20028 Background: Breast Implant Associated Anaplastic Large Cell Lymphoma (BIA-ALCL), a subtype of ALCL, arises as a seroma in the space between the implant and the capsule, or as an adjacent mass. BIA-ALCL appears to be related to textured-surface implants, after 7-10 years of exposure. We conducted two large cohort studies. The 1st, a retrospective series (Sutton, 2019) assessed the incidental findings of masses or seromas in 1070 women with breast implants undergoing MR for FDA recommended screening for silent ruptures of silicone implants. Incidental finding of seromas or breast masses on MRI were found in 18/1070 (1.7%) women, of which 1/15 had BIA-ALCL, and was symptomatic at the time of MRI. The 2nd, a prospective study (Cordeiro, 2020) defined the incidence of BIA-ALCL (1/355) in a cohort of 3546 women with textured implants followed long term. Within this cohort, there were 28 clinically relevant delayed seromas (0.79%), 8 of which were BIA-ALCL (28.5%). We hypothesize that combining these databases will inform whether asymptomatic women with textured implants may benefit from MR to r/o BIA-ALCL. Methods: The two IRB approved databases were merged. Patients with incidental findings of seroma on MRI were identified. A majority of the MRIs in this merged cohort were performed to follow the FDA recommended screening for silent ruptures. We identified all clinically relevant late seromas sent to hematopathology to r/o BIA-ALCL by cross checking pathology reports containing the words “lymphoma” or “anaplastic” or “ALCL”. Results: 572 women were included in both studies: followed long term and received an MRI after a median time of 7.4 years after breast reconstruction. 8 of 572 women had an incidental finding of seroma on random MRI, and 2 had capsular masses. None of these 10 asymptomatic women have developed BIA-ALCL to date (median follow-up 9 years). 11 of 572 women had a symptomatic seroma or mass, 4 of which later developed BIA-ALCL, a fifth patient was found to have BIA-ALCL on a PET/CT + lymph node, despite being asymptomatic. Median time from last MR to lymphoma was 5 years (3-8 years). Conclusions: In this merged cohort of patients with textured breast implants, incidence of BIA-ALCL in patients with symptomatic late seromas is around 30%, while seromas found incidentally on MR of asymptomatic patients were negative for BIA-ALCL.

Introduction:Breast Implant Associated Anaplastic Large Cell Lymphoma (BIA-ALCL) is an indolent subtype of ALCL, arising in the space between the implant and the capsule. BIA-ALCL seems to be directly related to the exposure to breast implants, and usually happens more than 7 years from implant placement. In 2011 the Food and Drug administration released the first safety communication on the risk of BIA-ALCL for women with breast implants, raising awareness of the disease. In 60-70% of the cases BIA-ALCL presents as a delayed seroma, a non-resolving fluid collection around breast implants arising after at least 1 year from implant placement. In previous studies, the risk of developing a late seroma ranged between 0.05% to 0.1% for people with textured surface breast implants. Among those with delayed seromas, the risk of BIA-ALCL has been estimated from retrospective cohorts to be 10%. (McGuire 2017, Clemens 2017, Maxwell 2015, Di Napoli 2017). Methods:A prospective cohort study was conducted in the population that underwent breast reconstruction with textured breast implants after mastectomy for breast cancer by a single surgeon at Memorial Sloan Kettering Cancer Center (MSKCC). Patients were enrolled from December 1992 to December 2017 at the time of tissue expander insertion, underwent long-term follow up and major events related to implants were prospectively recorded. We actively started looking for BIA-ALCL in late seromas in early 2011. All cases of BIA-ALCL were analyzed by our hematopathology service at MSKCC. We identified all late seromas sent to hematopathology to exclude BIA-ALCL by cross checking all the pathology reports containing the words "lymphoma" or "anaplastic" or "ALCL" in this population. We calculated the cumulative incidence of clinically relevant late seromas, considering death as a competing risk with the statistical program R version 3.5.1. Results:Between 1992 and 2017, 3521 women underwent breast reconstruction with textured surface expanders followed by permanent textured breast implants. Median age at surgery was 48 years (range 18-88), 1056 (30.0%) underwent unilateral reconstruction and 2464 (70.0%) bilateral reconstruction. Reason for mastectomy was lobular carcinoma in 675 (19.1%), 116 in situ, ductal carcinoma in 2529 (71.8%), 591 in situ, other histology in 59 (1.7%), unknown in 257 (7.3%). Besides surgery, additional treatments for breast cancer were: chemotherapy in 1015 (28.8%), radiotherapy in 285 (8.1%), chemo and radiotherapy in 706 (20.0%), none in 1514 (43.0%). Median follow up of the cohort was 8.2 years (range 3.4 months - 26.4 years). After a median exposure of 9 years (range 1.8 - 15.8 years), 28 women developed a clinically relevant delayed seroma, and 8 were diagnosed with BIA-ALCL (28.5% of the late seromas). The first late seroma was analyzed with flow cytometry in February 2011. All seromas sent to pathology were clinically relevant (main symptom was swelling of the breast - in 15 patients, tenderness/fullness of the breast - in 5 patients, asymmetry - in 3 patients, capsule contracture - in 5 patients). Three patients had previous drainage of peri-implant fluid that was not analyzed in pathology. 2 additional cases of BIA-ALCL were diagnosed in this population, one on an internal mammary chain lymph node biopsy, without fluid collection, and another with a capsular mass and lymph node involvement. Rate of late seroma accounting for the varying follow-up and death as a competing event was 1.6% at 15 years. Rough percentage getting a seroma was 0.79%, 1/126 women exposed. All the 28 samples were analyzed with cytology, and 22/28 with flow cytometry including CD30. 14/28 (50%) of these women removed the implants for several reasons, 3/28 (10.7%) immediately exchanged the implants with another textured surface device. Conclusions:in this population of breast cancer patients receiving textured breast implant reconstructions, the incidence of clinically relevant seromas and BIA-ALCL seems higher than previously reported. Similarly, the ratio of patients testing positive for BIA-ALCL on the total number of seromas analyzed higher than previously estimated. We believe these results will be informative for people with breast reconstructions after breast cancer and their surgeons, to better estimate the risk of seroma and BIA-ALCL with textured implants. Disclosures Cordeiro: Inamed: Research Funding; Acelity: Research Funding; Allergan: Research Funding. Dogan:Takeda: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Seattle Genetics: Consultancy; Corvus Pharmaceuticals: Consultancy; Roche: Consultancy, Research Funding. Horwitz:Seattle Genetics: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Trillium: Research Funding; Kyowa Hakko Kirin: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy; Astex: Consultancy; Portola: Consultancy; Affimed: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy; Kura: Consultancy; Celgene: Consultancy, Research Funding; Affimed: Consultancy; Trillium: Research Funding; Forty-Seven: Research Funding; Miragen: Consultancy; Mundipharma: Consultancy; Aileron: Research Funding; Affimed: Consultancy; ADCT Therapeutics: Research Funding; Trillium: Research Funding; ADCT Therapeutics: Research Funding; Innate Pharma: Consultancy; Affimed: Consultancy; Forty-Seven: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy; Portola: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy; Mundipharma: Consultancy; Mundipharma: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Innate Pharma: Consultancy; Aileron: Research Funding; Innate Pharma: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Miragen: Consultancy; Miragen: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy; Kura: Consultancy; Kura: Consultancy; Aileron: Research Funding; ADCT Therapeutics: Research Funding; Innate Pharma: Consultancy; Astex: Consultancy; ADCT Therapeutics: Research Funding; Astex: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Miragen: Consultancy; Astex: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Forty-Seven: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Aileron: Research Funding; Kura: Consultancy; Trillium: Research Funding; Portola: Consultancy; Forty-Seven: Research Funding.

Introduction: Signaling through JAK1 and/or JAK2 is common among tumor and non-tumor cells within peripheral and cutaneous T cell lymphomas (PTCL and CTCL). We conducted a phase II study of the JAK1/2 inhibitor, ruxolitinib, in patients (pts) with PTCL and CTCL and assessed the predictive value of genetic, immunohistochemical (IHC) and multiparametric immunofluorescence (mIF) biomarkers of JAK/STAT pathway activation for ruxolitinib response. Methods: This is an investigator-initiated multi-center phase II study for pts with relapsed or refractory (RR) PTCL or CTCL following at least 1 systemic therapy. Biopsies from each patient were subjected to next-generation sequencing for JAK1, JAK2, STAT3, STAT5 and other relevant genes along with IHC assessment for phosphorylated STAT3 (pSTAT3). Pts enrolled into biomarker-defined cohorts: 1) activating JAK and/or STAT mutations (allele frequency of 0.1 or greater); 2) no JAK/STAT mutation but ≥ 30% pSTAT3 expression among tumor cells by IHC; or 3) neither. Pts received treatment with ruxolitinib 20 mg BID until progression and were assessed for response after cycles 2, 5 and every three cycles thereafter. Tissue samples collected at baseline, on-treatment, and at progression were collected and assessed by mIF (Vectra platform, HALO analysis) using markers specific for lymphoma subtype, macrophage activation, JAK/STAT and PI3 kinase signaling. Results: The study completed enrollment with 53 pts, including 18 in cohort 1, 14 in cohort 2, and 21 in cohort 3. Cohort 3 includes 10 pts for whom JAK/STAT characterization is pending. Disease histologies per cohort are detailed in table 1. Treatment-related serious adverse events included HSV-1 stomatitis (n=1), spontaneous bacterial peritonitis (n=1), febrile neutropenia (n=3), and herpes zoster (n=1). Additional grade 3 or 4 drug-related adverse events affecting >1 pt included neutropenia (n=13), anemia (n=8), thrombocytopenia (n=5), and lymphopenia (n=3). Among the 53 pts, 4 have not yet reached first response assessment and 1 withdrew consent following only 1 week of treatment; therefore 48 are evaluable for response. Among 48 pts, there were 3 (6%) complete responses, 8 (17%) partial responses, and 6 (12.5%) with cytopenia improvement and disease stabilization lasting more than 6 months (SD>6 mo). Overall response rate (ORR) was 23% and overall clinical benefit rate (CBR) (ORR plus SD>6 mo) was 35%. Median duration of response was 7.3 months (range 1.3-26.1 months). ORRs in cohorts 1, 2 and 3 were 28%, 31%, and 12% (cohorts 1&2 vs 3, p=0.28). CBRs in cohorts 1, 2 and 3 were 44%, 46%, and 18% (cohorts 1&2 vs. 3, p=0.07) (table 2). More frequent responses were observed in the following histologies: angioimmunoblastic T cell lymphoma, peripheral T cell lymphoma with T-follicular helper phenotype, T-cell prolymphocytic leukemia, and large granular lymphocyte leukemia (table 3). Nine pre-treatment biopsies were analyzed by mIF from 4 ruxolitinib responders and 5 non-responders. The most notable finding was that responders to ruxolitinib had markedly lower pS6 expression within tumor cells of pre-treatment biopsies (mean pS6 expression 9.03 +/- 4.8 vs 48.19 +/- 6.6 for nonresponders; p=0.0027). In a patient with prolonged CR on ruxolitinib, progression biopsy was characterized by a marked increase in tumor cell pS6 staining. Additional samples are being analyzed and updated results will be reported at the meeting. Conclusion: The JAK1/JAK2 inhibitor ruxolitinib is a well-tolerated and readily available therapy for pts with relapsed/refractory PTCL and CTCL. Among patients with IHC and/or genetic evidence of JAK/STAT activation, ruxolitinib has similar efficacy to approved agents for relapsed/refractory T-cell lymphoma. The association between pS6 expression and response to ruxolitinib suggests that active PI3K/mTOR signaling confers intrinsic and acquired resistance to ruxolitinib. Disclosures Moskowitz: ADC Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; ADC Therapeutics: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; Cell Medica: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Merck: Research Funding; ADC Therapeutics: Consultancy; Cell Medica: Consultancy; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Erytech Pharma: Consultancy; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; ADC Therapeutics: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Merck: Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Incyte: Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Incyte: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Jacobsen:Acerta: Consultancy; Novartis: Research Funding; Astra-Zeneca: Consultancy; F. Hoffmann-LaRoche: Research Funding; Merck: Consultancy, Research Funding; Takeda: Honoraria; Pharmacyclics: Research Funding. Ruan:Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie company: Research Funding; Kite: Consultancy; Juno: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding. Geyer:Amgen: Research Funding; Dava Oncology: Honoraria. Noy:Medscape: Honoraria; Janssen: Consultancy; Prime Oncology: Honoraria; NIH: Research Funding; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Straus:Elsevier (PracticeUpdate): Consultancy, Honoraria; Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria. Dogan:Roche: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Takeda: Consultancy. Weinstock:Celgene: Research Funding. Horwitz:Aileron: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Kura: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Aileron: Research Funding; Trillium: Research Funding; Kyowa Hakko Kirin: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Consultancy; Miragen: Consultancy; Affimed: Consultancy; ADCT Therapeutics: Research Funding; Forty-Seven: Research Funding; Portola: Consultancy; Miragen: Consultancy; Mundipharma: Consultancy; Miragen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Innate Pharma: Consultancy; Affimed: Consultancy; ADCT Therapeutics: Research Funding; Millennium/Takeda: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy; Trillium: Research Funding; Astex: Consultancy; Astex: Consultancy; Celgene: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Kura: Consultancy; Kura: Consultancy; Kyowa Hakko Kirin: Consultancy; Trillium: Research Funding; Celgene: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Consultancy; Aileron: Research Funding; Forty-Seven: Research Funding; Innate Pharma: Consultancy; Forty-Seven: Research Funding; Mundipharma: Consultancy; Celgene: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Portola: Consultancy; Kyowa Hakko Kirin: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Trillium: Research Funding; Aileron: Research Funding; Kura: Consultancy; Miragen: Consultancy; Innate Pharma: Consultancy; Mundipharma: Consultancy; Mundipharma: Consultancy; ADCT Therapeutics: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy; Portola: Consultancy; Forty-Seven: Research Funding; Innate Pharma: Consultancy; Affimed: Consultancy; Affimed: Consultancy. OffLabel Disclosure: Off-label use of ruxolitinib for T-cell lymphoma will be discussed

Introduction: The JAK/STAT pathway is frequently activated in peripheral T-cell lymphomas (PTCLs) and cutaneous T cell lymphomas (CTCLs) however the utility of JAK inhibition as a therapeutic strategy in these diseases is not known. We hypothesize that JAK/STAT pathway alteration (defined by elevated phospho-STAT3 (pSTAT3) expression or presence of JAK or STAT mutations) will predict for sensitivity to JAK inhibition in PTCL and CTCL. We are conducting a phase II study of ruxolitinib, a JAK1/2 inhibitor, in which we assess its efficacy in a cohort of patients (pts) with PTCL and CTCL enriched for JAK/STAT pathway alterations. Methods: This is an investigator-initiated multi-center phase II study evaluating the efficacy of ruxolitinib 20mg twice daily in PTCL and CTCL. Pts with relapsed or refractory (rel/ref) PTCL or CTCL following at least 1 systemic therapy are eligible to enroll onto one of three of the following cohorts: Cohort 1: Disease determined to have JAK or STAT mutations. Cohort 2: Disease with functional evidence of JAK/STAT activation (defined as ≥ 30% pSTAT3 expression by immunohistochemistry). Cohort 3: Disease does not meet criteria for cohort 1 or 2. Pts initially enrolled onto cohort 3 and determined to have JAK/STAT mutations or functional JAK/STAT activation after enrollment are moved to cohorts 1 or 2. Cohorts 1, 2, and 3 are enrolling up to 17, 17 and 18 pts respectively by Simon 2-stage design. Pts receive treatment until progression and are assessed for response to therapy after cycles 2, 5 and every three cycles thereafter. Results: The first stage has been completed for cohorts 1 and 3 and 33 out of planned 52 pts enrolled to date. Details regarding histology, mutations, and treatment course appear in the table and figure. For Cohort 1, 10 out of planned 17 pts enrolled. Mutations involved JAK1 (1), JAK3 (3), STAT3 (4), and STAT5B (4). Out of 8 evaluable pts, overall response rate (ORR) was 38% with 3 partial responses (PR). In addition, 3 pts have ongoing stable disease (SD) lasting 8-18 months. Altogether, 75% achieved clinical benefit (objective response or SD >6 months). For Cohort 2, 5 out of planned 17 pts enrolled. Among the 5 evaluable pts, ORR was 40% with 1 complete response (CR) and 1 PR. For Cohort 3, 18 pts out of planned 18 pts enrolled. Out of 14 evaluable pts, ORR was 21% with 3 PRs. Grade 3 or higher drug-related adverse events (AEs) observed among the 33 pts enrolled included anemia (4), neutropenia (7), thrombocytopenia (2), and lymphopenia (7). Treatment related serious adverse events (SAEs) included 1 episode each of HSV-1 stomatitis, spontaneous bacterial peritonitis, febrile neutropenia, and herpes zoster. Conclusion: Responses observed across all three cohorts of pts with PTCL and CTCL with a trend towards higher rates and more durable responses among pts with JAK/STAT alterations. Efficacy of ruxolitinib in PTCL and CTCL provides proof of concept that JAK/STAT activation is a viable target in T-cell lymphomas. Enrollment onto cohorts 1 and 2 and assessment for JAK/STAT alternations among pts in cohort 3 continues. Figure. Figure. Disclosures Moskowitz: Incyte: Research Funding; ADC Therapeutics: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol Myers-Squibb: Consultancy, Research Funding; Merck: Research Funding; Takeda: Honoraria. Jacobsen:Merck: Consultancy; AstraZeneca: Consultancy; Seattle Genetics: Consultancy. Weinstock:Travera: Equity Ownership; Astra Zeneca, JAX, Samumed, Regeneron, Sun Pharma, Prescient: Patents & Royalties; Novartis, Dragonfly, Travera, DxTerity, Travera: Consultancy; Novartis, Astra Zeneca, Abbvie, Aileron, Surface Oncology, Daiichi Sankyo: Research Funding; Novartis: Consultancy, Research Funding; Genentech/Roche, Monsanto: Consultancy. Horwitz:Aileron Therapeutics: Consultancy, Research Funding; Portola: Consultancy; Celgene: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Spectrum: Research Funding; Kyowa-Hakka-Kirin: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Innate Pharma: Consultancy; Trillium: Consultancy; Forty Seven: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Mundipharma: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Corvus: Consultancy.

Introduction: Most therapies for relapsed/refractory (rel/ref) T-cell lymphomas (TCLs) induce responses in about 25%-30% of pts. Phosphoinositide-3-kinase (PI3K) delta has a role in survival and proliferation of malignant T cells as well as T-cell receptor and cytokine signaling in nonmalignant T cells. Inhibition of PI3K gamma can reprogram macrophages and promote tumor phagocytosis. A phase I study of the PI3K-δ/γ inhibitor duvelisib (D) in pts with rel/ref TCLs showed promising activity, but high rates of grade (Gr) 3/4 ALT elevation at the MTD of 75 mg BID (Horwitz et al, Blood 2018). Based on in vitro evidence of synergy, we initiated a phase I/II study of D combined with either romidepsin (R) or bortezomib (B). Methods: Pts were enrolled into parallel phase I dose escalation arms utilizing a 3+3 design to define the maximum tolerated dose (MTD) of D combined with either R (Arm A) or B (Arm B) in cycle 1. D was dosed at 25 mg, 50mg, or 75 mg BID on days 1-28 with either R (10 mg/m2 on days 1, 8, & 15) or B (1 mg/m2 on days 1, 4, 8, & 11) each on 28-day cycles. Once the MTD was established with each combination, preplanned expansion cohorts were enrolled to further characterize safety and describe subtype-specific efficacy (PTCL and CTCL). Based upon promising safety and efficacy, a total of 39 pts were treated on Arm A (33 at the MTD, D 75 mg BID + R 10 mg/m2). All pts received prophylaxis against Varicella and Pneumocystis. Response assessments were performed q2 cycles for 6 months and then q3 cycles. To assess biomarkers of response and resistance to single-agent D, 10 pts in Arm A (75 mg BID) and 10 pts in Arm B (25 mg BID) were each treated with 1 cycle of D alone, with pretreatment and on-treatment biopsies. Pts who did not achieve CR on D alone at the end of cycle 1 proceeded to combination therapy. Results: The MTD was not reached in Arm A (R+D); thus, dose level 3(DL3); (D 75 mg BID + R 10 mg/m2 days 1, 8, & 15) was deemed the MTD and used for expansion. In Arm B there were no cycle 1 DLTs. However, Gr 3 elevations of ALT or AST following cycle 2 were observed in 3 pts at DL2 (D 50mg BID) and 2 pts at DL3 (D 75mg BID) leading to DL1 (D 25mg BID + B 1mg/m2 days 1, 4, 8, & 11) being accepted as MTD for expansion. Of Arm A pts at the MTD, 21/32 (65%) had adverse events (AEs) ≥Gr 3, possibly related to study drug. Events occurring in ≥10% of pts included: increased ALT/AST (n=5, 15%), neutropenia (n=6, 18%), and hyponatremia (n=4, 12%). Three pts had ≥Gr 3 diarrhea. There were no Gr 5 AEs related to protocol therapy. Strikingly, 4 of 5 pts with elevated transaminases (ALT [4], AST [1]) on combination began on the D-only Lead-In Arm at 75 mg BID. In contrast, only 1 of 22 (4%) pts receiving combination R+D in cycle 1 had Gr 3-4 transaminitis (p=.0242). Of the pts with Gr 3-4 diarrhea, 2 of 3 were on Lead-In (p=.0793). In Arm A, 35/39 pts were evaluable for response. Overall response rate (ORR) across all DLs was 51% (18/35) and CR rate (CR) was 17% (6/35). PTCL, ORR and CR rates were 55% (12/22) and 27% (6/22) respectively. Among CTCL, ORR was 46% (6/13), no CR. Reponses by histology are detailed in Table 1. Of these responders, 3 proceeded to allogeneic stem cell transplantation (allo SCT) with curative intent. Of note, 4 pts were not evaluable for response, described in Table 1. Median PFS for Arm A (all DL) was 8.8 m (PTCL) and 5.4 m (CTCL). Median follow up was 5.8 m, and median duration of response was 9.1 m. Of Arm B pts at the MTD, 10/22 (45%) had AEs ≥Gr 3, possibly related to study drug, of these, only neutropenia (n=4, 18%) occurred in ≥10% of pts at the MTD. There was 1 Gr 5 event, Stevens-Johnson syndrome, possibly related to protocol therapy. In Arm B, the ORR across all DLs was 32% (9/28), the CR rate was 11% (3/28). ORR in PTCL was 36% (5/14), 21% (3/14) achieved CR. ORR in CTCL was 28% (4/14), no CR. Responses by histology are detailed in Table 2. Of these responders, 1 proceeded to allo SCT with curative intent. Median PFS for Arm B (all DL) was 3.5 m (PTCL) and 4.6 m (CTCL). Median follow up was 7.2 m, and median duration of response was 9.3 m. Conclusion: Duvelisib in combination with romidepsin is highly active in pts with PTCL with tolerable side effects. Duvelisib can be safely combined with romidepsin at a 3-fold higher dose than with bortezomib (75 mg BID vs 25 mg BID) with much lower rate of Gr 3-4 transaminitis than single-agent duvelisib at the same dose. The high response rates and safety of Arm A (Duvelisib + Romidepsin) in PTCL appears to be a potential therapeutic advance and warrants further evaluation in a larger study. Disclosures Horwitz: Portola: Consultancy; Innate Pharma: Consultancy; Forty Seven: Consultancy, Research Funding; Kyowa-Hakka-Kirin: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Mundipharma: Consultancy; Corvus: Consultancy; Celgene: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Aileron Therapeutics: Consultancy, Research Funding; Spectrum: Research Funding; Trillium: Consultancy. Moskowitz:Takeda: Honoraria; Incyte: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol Myers-Squibb: Consultancy, Research Funding; Merck: Research Funding; ADC Therapeutics: Research Funding. Jacobsen:Seattle Genetics: Consultancy; Merck: Consultancy. Mehta-Shah:Spectrum: Consultancy; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Genetech: Research Funding; Verastem: Research Funding. Khodadoust:Innate Pharma: Research Funding. Fisher:Seattle Genetics Inc.: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Kim:Medivir: Membership on an entity's Board of Directors or advisory committees; Portola: Research Funding; miRagen: Research Funding; Kyowa-Kirin-Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Neumedicine: Consultancy, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetralogic: Research Funding; Merck: Research Funding; Galderma: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon Pharma: Consultancy, Research Funding; Forty Seven Inc: Research Funding; Soligenix: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding. Weinstock:Travera: Equity Ownership; Astra Zeneca, JAX, Samumed, Regeneron, Sun Pharma, Prescient: Patents & Royalties; Novartis, Dragonfly, Travera, DxTerity, Travera: Consultancy; Novartis, Astra Zeneca, Abbvie, Aileron, Surface Oncology, Daiichi Sankyo: Research Funding; Novartis: Consultancy, Research Funding; Genentech/Roche, Monsanto: Consultancy.

7509Background: Histone-deacetylase inhibitors are active agents for peripheral T-cell lymphomas (PTCL). Anecdotally, angioimmunoblastic T-cell lymphoma (AITL) may respond better to romidepsin than...

Background: Epigenetic manipulation and immunomodulation are therapeutic strategies in hematologic malignancies. In our previous study, the combination of romidepsin and lenalidomide showed a 51% overall response rate (ORR), 23% complete response (CR) rate in patients with relapsed/ refractory B-cell (BCL) and T-cell (TCL) lymphoma. Given the potential synergy of proteasome inhibitors with histone deacetylase inhibitors and lenalidomide, we conducted a phase Ib/IIa study evaluating the safety and toxicity of romidepsin and lenalidomide with carfilzomib in patients with relapsed/refractory lymphoma. Here we report the completed phase II results. Methods: Romidepsin and carfilzomib were given IV on days 1, 8 and lenalidomide was given orally on days 1-14 of a 21-day cycle. A standard 3+3 dose escalation was followed: The starting dose was romidepsin 8 mg/m2,lenalidomide 15 mg, carfilzomib 36mg/m2. Tumor response was based on disease-specific criteria.Patients could be treated until progression, intolerance, or response adequate to allow allogeneic transplantation. Results: 24 of the 27 patients treated as part of the study were evaluable for determination of the maximum tolerated dose. Additionally, one was evaluable for efficacy and 2 were evaluable for toxicity only. 16 patients were treated for TCL: PTCL-NOS-7, AITL-5, MF-2, transformed MF-1, extra-nodal NK/T-cell lymphoma-1. 11 patients were treated for BCL: DLBCL (7) mantle cell lymphoma (MCL) (2), follicular lymphoma (FL) (2). Of note, one of the aforementioned AITL patients had concurrent DLBCL and was evaluated for efficacy in both B-cell and T-cell cohorts. Dose level 2 (romidepsin 8 mg/m2,lenalidomide 15 mg, carfilzomib 45mg/m2) exceeded the MTD with 2/6 DLTs: 1 grade 3 thrombocytopenia resulting in treatment delay and 1 grade 4 thrombocytopenia. There were no DLTs among 6 patients treated in dose level 1 (romidepsin 8 mg/m2,lenalidomide 15 mg, carfilzomib 36mg/m2) and dose level 1 was deemed the MTD. Overall, grade 3-4 toxicities in >10% patients included neutropenia and thrombocytopenia. 16 treatment related serious adverse events were seen in 9 patients and included: anemia-1, vomiting/diarrhea-1, dyspenea-1, edema-1, febrile neutropenia-1, fever-2, generalized weakness-1, heart failure-1, hypotension-1, infection-2, gastrointestinal bleed-1, and DVT-1. Of the 11 TCL evaluable for response at the MTD, ORR was 45.5% (5/11, 95% CI: 23.4 to 83.3%). The complete response (CR) rate was 36.4% (4/11, 95% CI: 10.9 to 69.2%) and the partial response (PR) rate was 9% (1/11, 95% CI: 2.3 to 51.8%). The median event free survival (EFS) for patients with TCL was 13.6 w (95% CI: 5.7-74.6). Among all patients with TCL (N=16), the ORR was 50% (8/16). CRs were seen in 4/5 AITL and 1/7 PTCL-NOS; PRs were seen in PTCL-NOS-1, AITL-1, and transformed MF-1. Of the 8 BCL evaluable for response at MTD, the ORR was 50% (4/8, 95% CI: 0-41%) with 3 PRs and 1 CR. The median EFS for patients with BCL was 19.8 w (95% CI: 5.4-NR). Among all patients with BCL evaluable for response (n=10), PRs were seen in 4 patients with DLBCL and 1 patient with MCL. One patient with concurrent DLBCL and AITL achieved a CR. The median EFS for all patients treated at the MTD was 14.5 w (95% CI: 5.7 to NR). The median time to best response was 5.7 w. The median duration of response was 38.7 w (95% CI: 9.7 to NR). 3 patients with TCL and 1 with MCL underwent allogeneic transplantation following response to this therapy and were censored at time of transplant. Sustained complete responses were seen in 2 additional patients with TCL: one remained in CR for 11.7 months and another remains on treatment at 17 months. The median duration of follow up was 56.0 w (range 2.4 to 102.1 w). Conclusions: The MTD dose for phase 2 study was identified as romidepsin 8mg/m2, lenalidomide 15mg and carfilzomib 36mg/m2. No unexpected toxicities have emerged. At this dose, the overall response rate for BCL and TCL was 50%. Responses were seen across various BCL and TCL histologies. In particular, in AITL, the regimen has shown responses in all 5 patients. Given the promising overall and complete response rates, the regimen warrants further study. Disclosures Mehta-Shah: Celgene: Research Funding; Verastem: Research Funding; Bristol Myers-Squibb: Research Funding. Moskowitz: Bristol Myers-Squibb: Consultancy, Research Funding; Seattle Genetics: Honoraria, Research Funding; Takeda: Honoraria; ADC Therapeutics: Research Funding; Incyte: Research Funding. Lunning: Onyx: Consultancy; Pharmacyclics: Consultancy; Spectrum: Consultancy; Celgene: Consultancy; TG Therapeutics: Consultancy; Juno: Consultancy; Genentech: Consultancy; Gilead: Consultancy; BMS: Consultancy; AbbVie: Consultancy; Epizyme: Consultancy. Kumar: Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding. Gerecitano: Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Aratana: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mass Medical International: Honoraria, Membership on an entity's Board of Directors or advisory committees; Orexo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Samus Therapeutics: 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; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Royal Bank of Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Arcus Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees. Zelenetz: Amgen: Consultancy; Celgene: Consultancy. Hamlin: Gilead: Consultancy, Honoraria; Portola: Consultancy, Honoraria, Other: research support; Incyte: Other: research support; Celgene: Consultancy, Honoraria; Seattle Geneitcs: Other: research support; Novartis: Other: research support. Noy: Pharmacyclics LLC, an AbbVie Company: Honoraria, Other: Travel, Accommodation, Expenses, Research Funding, Speakers Bureau. Younes: Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Bayer: Honoraria; Johnson & Johnson: Research Funding; Novartis: Research Funding; Incyte: Honoraria; Roche: Consultancy, Honoraria, Other: Third-party medical writing assistance, under the direction of Anas Younes, was provided by Scott Malkin of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd.; Curis: Research Funding; Takeda Millenium: Honoraria; Seattle Genetics: Honoraria; Sanofi: Honoraria; Merck: Honoraria; Janssen: Honoraria. Dogan: Roche Pharmaceuticals: Consultancy; Peer Review Institute: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Horwitz: Mundipharma: Consultancy; Aileron Therapeutics: Research Funding; BMS: Consultancy; HUYA: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Kyowa-Hakka-Kirin: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Forty-Seven: Consultancy, Research Funding.

Introduction: Current therapies for relapsed/refractory (rel/ref) T-cell lymphomas (TCLs) induce responses in only 25-30% of patients (pts). Phosphoinositide-3-kinases (PI3K) play a pivotal role in cell signaling and PI3K isoforms have distinct roles in the development, function and survival of T cells. A phase I study of the oral PI3K-δ/γ inhibitor duvelisib (DUV) in pts with TCLs showed promising activity in rel/ref TCL (Horwitz, Blood 2014). We assessed mechanisms of response and resistance to DUV in T-cell lymphomas in vitro and in vivo. Based on in vitro evidence of synergy, we initiated a phase I study to evaluate the safety and efficacy of DUV combined with romidepsin or bortezomib in pts with rel/ref TCL. Methods: Preclinical: We characterized the PI3K-signaling pathway across 11 cell lines of TCL by immunoblotting and assessed the in vitro activity of isotype specific PI3K inhibitors, including DUV. A targeted phosphoproteomic approach (P100) was utilized to identify mechanisms of resistance and response of DUV across 6 cell lines in vitro. We assessed the effects of DUV on immune response within the TCL microenvironment in vivo using a patient-derived xenograft (PDX). Clinical: We conducted multicenter, parallel phase I trials of DUV in combination with romidepsin (arm A) or bortezomib (arm B) in rel/ref TCL. For each arm, a standard 3+3 phase I design was used to determine maximum tolerated dose (MTD). DUV was dosed at 25mg, 50mg, or 75mg BID on days 1-28. Romidepsin 10mg/m2 was dosed on days 1, 8, and 15 (arm A) or bortezomib 1mg/m2 on days 1, 4, 8, and 11 (arm B), both on 28-day cycles. All pts received prophylaxis against Varicella and Pneumocystis. Results: Preclinical: DUV potently killed 3 of 4 TCL cell lines that showed constitutive phosphorylation of AKT (pAKT) versus 0 of 7 lines lacking pAKT (p=0.024). Killing by DUV exceeded killing by the PI3K-δ-specific inhibitor idelalisib and was similar to pan-PI3K inhibition. The phosphoproteomic analysis identified resistance through either PI3Kα activation, which was overcome by pan-PI3K inhibition, or by epigenetic reprogramming, which was overcome by co-treatment with romidepsin. Administration of DUV to mice engrafted with a TCL PDX resulted in reprogramming of tumor-infiltrating macrophages from the immunosuppressive M2-like phenotype to the pro-phagocytic M1-like phenotype. Clinical: 12 pts (4 in each dose level [DL]) were treated on arm A (romidepsin+DUV); 8 are evaluable for efficacy. There were no dose limiting toxicities (DLTs), therefore DL 3 was accepted as MTD. 2 serious adverse events (SAEs) possibly related to study drug included grade (Gr) 3 fatigue and Gr 2 aspartate aminotransferase (AST) elevation. 1 fatal event (diffuse alveolar hemorrhage following allogeneic transplant) occurred 31 days after last dose of study drug and was assessed as unrelated to study treatment. Gr 3 or 4 adverse events (AEs) occurring in ≥10% of pts included only neutropenia (Gr 3, n=4, Gr 4, n=2). Overall response rate (ORR) and median time to response (TTR) were 4/8 (50%) and 51 (range 49-54) days. Two of 4 responders proceeded to transplant after 90 and 108 days and 1 remains on treatment for 107+ days. 17 pts were treated on arm B (bortezomib+DUV), including 8 in DL 1, 3 in DL 2, and 6 in DL 3; 15 pts are evaluable for efficacy. 1 out of 6 pts evaluable for DLT on DL 1 experienced DLT (pneumonia). There were no other DLTs, however Gr 3 elevations of alanine aminotransferase (ALT) or AST following cycle 2 were observed for 3 pts treated at DL 2 and 2 treated at DL 3 leading to DL 1 being accepted as MTD. There were 5 SAEs possibly related to study drug including Gr 3 pneumonia (n=2), Gr 3 infectious colitis (n=1), Gr 3 colitis (n=1), and Gr 4 AST/ALT elevation (1). Gr 3 or 4 AEs occurring in ≥10% of pts included only neutropenia (Gr 3, n=3). ORR, complete response (CR), and median time to response (TTR), were 8/15 (53%), 3/15 (20%), and 52 (range 47-57) days. Among the 8 responders, 5 remain on treatment for 103-377+ days. Conclusion: DUV shows activity in T-cell lymphomas with pre-clinical evidence of both tumor cell-autonomous and non-autonomous effects. The combinations of DUV plus romidepsin and DUV plus bortezomib are safe and well tolerated, with limited incidence of AST/ALT elevation from romidepsin+DUV. Promising response rates of at least 50% were observed across TCL histologies with both regimens. Expansion cohorts of pts with peripheral and cutaneous TCL are currently enrolling. Disclosures Moskowitz: ADC Therapeutics: Research Funding; Seattle Genetics: Honoraria, Research Funding; Takeda: Honoraria; Incyte: Research Funding; Bristol Myers-Squibb: Consultancy, Research Funding. Mehta-Shah: Celgene: Research Funding; Verastem: Research Funding; Bristol Myers Squibb: Research Funding. Dogan: Roche Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Peer Review Institute: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kim: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding; Soligenix: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy, Research Funding; Horizon Pharma: Consultancy, Research Funding; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa-Kirin-Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Consultancy, Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; miRagen: Research Funding; Neumedicine: Research Funding; Tetralogic: Research Funding; Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Jacobsen: GSK: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees. Horwitz: Forty-Seven: Consultancy, Research Funding; Aileron Therapeutics: Research Funding; Kyowa-Hakka-Kirin: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; BMS: Consultancy; Mundipharma: Consultancy; ADCT Therapeutics: Research Funding; Infinity/Verastem: Consultancy, Research Funding; HUYA: Consultancy.

Cutaneous T-cell Lymphoma (CTCL) is a heterogeneous group of diseases, derived from skin resident or skin homing T-cells, with Mycosis Fungoides (MF) and Sezary Syndrome (SS) being the most common subtypes. Although CTCL is the best-studied group among T-cell malignancies, our understanding of its pathogenesis remains limited, due to the paucity of comprehensive, large-scale genomic studies. Recent whole exome and targeted sequencing approaches have primarily elucidated mutations in genes affecting immune synapse signaling (PLCG1, CD28, JAK3) and epigenetic modulation (ARID1A, DNMT3A) in both MF and SS. In search of novel genetic alterations, we applied deep targeted sequencing in 71 freshly cryopreserved skin or peripheral blood samples derived from 61 patients with CTCL, including patients with MF, SS, primary cutaneous anaplastic large cell lymphoma (pcALCL), pleomorphic small/medium sized CD4+ CTCL and CD8+ CTCL. Genomic DNA was sequenced for the entire coding region of 585 known cancer-related genes on a HiSeq2500 Illumina instrument with a mean depth of 1000X. Sequences were analyzed for base substitutions, in-frame or frameshift insertions and deletions and splicing variants. Known germline variants reported at dbSNP and the 1,000 Genomes Project data were excluded, while confirmed somatic variants previously reported at the COSMIC database were included. Only variants with an allele frequency above 2% were further analyzed, in order to eliminate false positive data. Recurrent mutations were identified in genes responsible for tumor suppression (TP53, FAT1, FAT3), DNA damage response (ATM, MDC1), DNA mismatch repair (MSH3), chromatin remodeling (ARID1B), histone methylation (MLL2, MLL3, KDM6A) and DNA methylation (DNMT1). Moreover recurrent mutations pointed to robust activation of the three following signaling pathways: Receptor Tyrosine Kinase (IRS2, FOXO3) JAK/STAT (JAK3, STAT5A/B, SOCS1) and NOTCH (NOTCH1, NOTCH2). Finally, at a subclonal level we paradoxically identified mutations of the Androgen Receptor (AR) gene. Interestingly, the presence of large cell features correlated with a higher accumulation of molecular events, since transformed MF and pcALCL had a significantly higher number of genetic alterations compared to untransformed MF (Figure 1). In sum, the genomic landscape occurring from our targeted sequencing approach highlights the pathologic complexity of these neoplasms, suggesting multiple non-redundant mechanisms leading to lymphomagenesis. The characterization of this cohort is expected to provide an opportunity to comprehend intra-CTCL molecular heterogeneity and offer a better classification of CTCL entities along with novel potential therapeutic targets. Figure 1. Figure 1. Disclosures Levine: Foundation Medicine: Consultancy; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees; Loxo Oncology: Membership on an entity's Board of Directors or advisory committees. van den Brink:Merck: Honoraria; Boehringer Ingelheim: Consultancy, Other: Advisory board attendee; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria; Tobira Therapeutics: Other: Advisory board attendee. Palomba:Janssen: Consultancy.

Introduction: Approximately 10-15% of patients with DLBCL treated with R-CHOP chemotherapy have primary refractory disease at the completion of initial treatment. The standard treatment for patients with DLBCL in first relapse is rituximab and salvage chemotherapy. For those achieving chemosensitive remission, high-dose therapy and autologous stem cell transplant (ASCT) is the accepted standard of care. Data from three randomized studies in the rituximab era suggest that 40-50% of these patients are ultimately cured; however, the majority of patients in these studies did not have primary refractory disease. The outcomes and curability of primary refractory DLBCL patients in the rituximab era remain unknown. Methods: We identified transplant-eligible patients from 2002 to 2014 with DLBCL that was refractory to initial rituximab and anthracycline containing regimens based on radiographic (16) and/or biopsy-proven (83) progression at the end of therapy. Patients with primary refractory disease were defined as either partial responders (partial response to initial therapy) or primary progressors (minimal or no response to initial therapy). The majority of patients were treated with three cycles of platinum containing regimens; 72% received R-ICE. High-dose therapy and ASCT were administered in 52% of cases. Response criteria were per IHP when pre- and post- salvage PET were available, otherwise by SPD per IWG (Cheson JCO 1999). The Kaplan-Meier method and Cox proportional hazards model were used to evaluate progression-free survival (PFS) and overall survival (OS). Patient Characteristics: Ninety-nine patients were identified. Median age was 56 (range 22-73); 31% were older than 60. With respect to histology, 61% of patients had DLBCL-NOS, 17% had PMBL, 11% had transformed low-grade B cell lymphoma, 6% had T-cell rich B-cell lymphoma, 3% had grey zone lymphoma, and 2% had B-cell lymphoma unclassifiable. With respect to initial treatment response, 41% of patients were partial responders whereas 59% were primary progressors. An elevated LDH, Karnofsky Performance Status (KPS) 10 cm) and multiple (≥2) extranodal sites of disease were present in 18% and 35% of patients. An elevated second-line IPI (≥3) and aaIPI (≥3) were seen in 40% and 49% of patients, respectively. Outcomes: Median follow-up for survivors was 37 months. The overall response rate to salvage therapy was 56%, with 21% achieving a complete response and 35% achieving a partial response. As assessed by intention to treat (ITT), the estimated 3-year OS and PFS are 43% and 34% respectively (Figure 1). Within the ITT cohort, univariate analysis revealed that age ≥60, primary progressive disease, advanced AA stage, elevated LDH, KPS With respect to the 51 patients proceeding to ASCT, median follow-up from the date of SCT was 48 months. The estimated 3-year OS and PFS are 67% and 63% respectively. Within the transplanted cohort, univariate analysis revealed disease bulk >10 cm and an elevated IPI to be associated with inferior outcomes. Conclusion: This is the largest reported series of patients with primary refractory DLBCL treated with curative intent in the rituximab era. Salvage therapy with consolidative ASCT achieves long-term remissions in about 40% of patients. ASCT achieves long-term remissions in over 60% of patients. Therefore, the primary barrier to curative therapy in this population is achieving a sufficient response to salvage therapy, and future studies should be aimed towards increasing the response rate in this population. Older patients and patients with an elevated LDH respond poorly to conventional salvage therapy and investigational approaches may be more appropriate in this setting. Figure 1. OS and PFS of patients with primary refractory DLBCL. Figure 1. OS and PFS of patients with primary refractory DLBCL. Figure 2. PFS of patients based on the presence of elevated age (60+) and/or elevated LDH. Figure 2. PFS of patients based on the presence of elevated age (60+) and/or elevated LDH. Disclosures Moskowitz: Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees. Matasar:Genentech: Consultancy; Spectrum: Consultancy.