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Follicular lymphoma (FL) is considered an indolent disorder with a relatively favourable course. With modern day treatments, long remissions are often achieved both in front-line and relapsed settings. However, a subset of patients has a more aggressive course and a poorer outcome. Both, PET-CT and minimal residual disease (MRD) evaluation by PCR defines groups of patients with different prognoses. MRD measurement by NGS is being studied to predict relapse prior to diagnostic imaging in large B cell lymphoma; however, it has never been used in FL. The aim of the present study is to validate a sensitive and standardizable approach to measure liquid Biopsy MRD (LiqBio-MRD) by NGS with >90% applicability and 2E-4 resolution, and to analyse its prognostic impact in FL patients. Firstly, the best source to identify genetic MRD markers was determined. Genomic DNA from paraffin embedded (FFPE) lymph node biopsies and/or cell free DNA (cfDNA) from peripheral blood (PB) was obtained from 29 FL cases at diagnosis and sequenced with a short length Ampliseq Custom Panel (Thermo-Fisher). This panel was designed to cover all coding regions of 56 lymphoma specific genes in FFPE and cfDNA samples. By applying this panel with an average depth of 700X, a total of 122 somatic mutations were detected in 37 baseline samples. 15 of these lymph node samples presented 65 mutations (average of 4 mutations per patient, rank 1-9), with a mean Variant Read Frequency (VRF) of 0.33 (0.06-0.77). On the other hand, the 21 cfDNA samples presented 71 mutations (average of 3 mutations per patient, rank 0-8), with a mean VRF of 0.21 (0.02-1.0). Notably, in 3 cases the mutations were only detected in the lymph node. Paired samples were available for 13 cases. Of the 72 somatic mutations identified in these cases, only 14 were present in both samples (Figure 1A, left). Besides the higher number of mutations in the lymph nodes, a mean decrease of 0.14 VRF was observed in cfDNA (0.21; 0.03-0.53) compared to lymph nodes (0.35; 0.09-0.76) (Figure 1A, Right). From the initial 29 FL cases, 16 had PB sequential samples available. Three patients were put under observation and the rest received an anthracycline based regimen plus R-maintenance. In treated patients, PET-CT was carried out at diagnosis and after 4 and 6 cycles of treatment. During follow-up, cfDNA was available after 4 (n=10) and 6 cycles of treatment (n=10). Median follow up was 18 months. To quantify LiqBio-MRD in the 31 follow-up samples, we defined an approach involving the sequencing of 12 NGS data points per mutation identified at diagnosis. Three of these data points were tumour sample replicates. The other 9 points were obtained from healthy control donor DNA. All LiqBio-MRD samples were sequenced with at least 100.000x and analysed applying the NGS-MRD algorithm described elsewhere (Onecha, E et al. Hematologica 2019). The mean mutation rate (noise) in controls for the studied mutations was 1.4E-5 (0 - 8E-5) below the targeted sensibility of 2E-4. The LOD was defined for every follow-up sample based on the initial amount of cfDNA used in the test. On average 39.6ng (13-66 ng) were used for cfDNA MRD monitoring. All somatic mutations were considered potential MRD markers (Figure 1B), however the degree of MRD in each follow-up sample was defined by the somatic mutation with higher VRF. MRD values were significantly lower in complete response (CR) cases compared to those with active disease (p=0.001, Figure 1C, left). Notably, MRD positivity in the interim or at the end of treatment resulted in significantly inferior PFS (median 12 months vs not reached, P = 0.09, Figure 1C, right). An extension of the cohort and clinical impact of LiqBio-MRD test will be presented at the meeting. Our results demonstrate for the first time that NGS based MRD quantification is feasible in Liquid Biopsies from FL. Despite the marked spatial genetic heterogeneity of FL, which is better identified in cfDNA, the dilution of the signal in these samples suggests the use of both; lymph node biopsies and cfDNA at diagnosis to identify all potential MRD markers. The lower degree of MRD in CR evaluations (according to the 2014 Lugano response assessment) and the existence of patients in CR with positive and negative MRD suggest the potential of our LiqBio-MRD test to prospectively identify patients with different outcome. Nevertheless, more patients and a longer follow-up are necessary to draw meaningful conclusions. Figure 1 Disclosures Heredia: Altum sequencing: Current Employment. Rufian:Altum sequencing: Current Employment. Carrillo:Altum sequencing: Current Employment. Wang:Hosea Precision Medical Technology Co., Ltd: Current Employment. Canales:Janssen: Honoraria; Karyopharm: Honoraria; Celgene: Honoraria; Takeda: Speakers Bureau; Sandoz: Honoraria; Janssen: Speakers Bureau; Novartis: Honoraria; Sandoz: Speakers Bureau; Janssen: Speakers Bureau; Takeda: Speakers Bureau; Roche: Honoraria; iQone: Honoraria; Janssen: Honoraria; Sandoz: Honoraria; Novartis: Honoraria; Roche: Honoraria; Roche: Speakers Bureau; Karyopharm: Honoraria; Gilead: Honoraria; Sandoz: Speakers Bureau; Roche: Speakers Bureau. Martinez-López:Janssen, BMS, Sanofi, Novartis, Incyte, F. Hoffmann-La Roche and Amgen: Honoraria, Other: Advisory boards; Janssen, Novartis, BMS, Incyte: Consultancy; Hosea and Altum: Membership on an entity's Board of Directors or advisory committees.

BackgroundGenetics have provided hints on potential molecular pathways involved in neurodegenerative diseases (NDD). However, the number of cases caused exclusively by genetic alterations is low, suggesting an important contribution of environmental factors to NDDs. Among these factors, viruses like herpes simplex viruses (HSV-2), capable of establishing lifelong infections within the nervous system (NS), are being proposed to have a role in NDDs. Despite promising data, there is a significant lack of knowledge on this and an urgent need for more research.MethodsWe have set up a mouse model to study HSV latency and its associated neuroinflammation in the spinal cord. The goal of this model was to observe neuroinflammatory changes caused by HSV latent infections, and if those changes were similar to alterations observed in the spinal cord of amyotrophic lateral sclerosis (ALS) patients.ResultsIn infected spinal cords, we have observed a strong leukocyte infiltration and a severe alteration of microglia close to motor neurons. We have also analyzed ALS-related proteins: we have not found changes in TDP-43 and Fus in neurons, but interestingly, we have found decreased protein levels of C9orf72, of which coding gene is severely altered in some familial forms of ALS and is critical for microglia homeostasis.ConclusionsLatent infection of HSV in the spinal cord showed altered microglia and leukocyte infiltration. These inflammatory features resembled to those observed in the spinal cord of ALS patients. No changes mimicking ALS neuropathology, such as TDP-43 cytoplasmic inclusions, were found in infected spinal cords, but a decrease in protein levels of C9orf72 was observed. Then, further studies should be required to determine whether HSV-2 has a role in ALS.

INTRODUCTION AND OBJECTIVE:Identifying biomarkers to predict BCG response before beginning the treatment is an unsolved need in the clinical practice for patients with high risk non-muscle invasive...

INTRODUCTION AND OBJECTIVE:There is an increasing interest in finding a valid alternative for patients with non-muscle invasive bladder cancer (NMIBC). HIVEC-HR is a pilot trial that aims to compar...

Background: Primary mediastinal B-cell lymphoma (PMBCL) is a rare subtype of aggressive B-cell lymphoma. Most relapses occur within the first few months resulting in a dismal prognosis; therefore, it's important to identify primary chemorefractory patients at an early stage, to improve their prognosis. Our group have demonstrated that Circulating Tumor DNA (ctDNA) detected by deep sequencing (DeepSeq) constitute a new non-invasive marker for monitoring response in follicular lymphoma (Jimenez-Ubieto A. et al. ASH 2020). CtDNA monitoring in PMBCL might help to better assess therapeutic response, correct false positive PET/CT results due to residual uptake of the mediastinum and define patients who will benefit from radiation therapy (RT). Here we analyzed the potential value of ctDNA monitoring in 11 PMBCL treated with R-DA-EPOCH between 2018-2020 in the Hospital 12 de Octubre. Methods: Genomic DNA from paraffin embedded (FFPE) lymph node biopsies were obtained from 11 PMBCL cases at diagnosis. Samples were sequenced with a short length Ampliseq Custom Panel (Thermo-Fisher) designed to cover all coding regions of 56 lymphoma specific genes with an average depth of 700x. After annotation and filtering, 5-8 somatic mutations previously described in lymphoma were selected to be screened in plasma samples. The plasma derived cfDNA was obtained from 8-16mL of peripheral blood collected in EDTA tubes and processed in less than 4h by column purification (QIAamp Circulating Nucleic Acid Kit, Qiagen). A total of 31 different plasma time-points were sequenced in triplicates. On average 78ng (9-224 ng) of cfDNA was used for the DeepSeq of the specific mutations selected in each patient. An average coverage of 236.000x per triplicate was obtained for each mutation. The detection cut-off of 1E-4 was defined based on the LOD obtained in healthy controls donors. 18F-fluorodeoxyglucose (FDG) PET/CT scans were performed on a General Electric Discovery MI Scanner at basal, interim (after 4 cycles), end of induction (EOI) and after radiotherapy (RT). Results: The median age was 33 years and 63.6% were female. Most cases (81.8%) were diagnosed with stage I or II disease and 27.3% cases present with extranodal involvement. On interim PET, 4 patients reached Complete response (CR) and 7 Partial Response (PR, DS4). At EOI, the number of CR turned to 6/11 (55%). All patients in PR at EOI (n=5) and two patients in CR (DS3) with residual mass received RT consolidation (median dose 32Gy). After RT the rate of CR was 91% (10/11). One patient progressed to a classical Hodgkin lymphoma (cHL). None of the patients in CR have relapsed after a median follow-up of 22 months. One patient died due to a mediastinal synovial sarcoma. A total of 125 somatic mutations were detected in the 11 baseline samples with a median of 8 per patient (rank 5-35). The three most frequently mutated genes were SOCS1 (73%), B2M (55%) and TNFAIP3 (46%). Despite the reduced size of our cohort, the mutational frequencies were comparable to the described by Mottok A. et al (Blood 2018, Figure 1A). The DeepSeq of six diagnosis plasma samples showed a lower Variant Read Frequency (VRF) in cfDNA. On those paired samples, 25/28 mutations were detected in plasma, with a median VRF of 2% (0-53%) vs 24% (5.5%-87%) in Lymph nodes (Figure 1B). The rest of the plasma samples corresponded to 1st cycle (n=5), 4th cycle (n=6), EOI (n=7) and after RT (n=5). After 1 cycle of chemotherapy 3/4 patients who reached CR at EOI had already undetectable ctDNA (Figure 1C). One patient with positive ctDNA after 1 cycle needed RT to convert to CR. All the CR evaluations by PET-TC who had available ctDNA data, presented undetectable ctDNA (n=9). In the EOI analysis all+ patients except the one who progressed to cHL had undetectable ctDNA. In the PR interim evaluations 2/5 had undetectable ctDNA and converted to CR at EOI. Of the three patients with detectable ctDNA, one progressed to cHL (Figure 1D) and 2 needed RT to convert to CR. Conclusions: Our results demonstrate that disease monitoring using DeepSeq of plasma ctDNA is feasible in PMBCL. Regarding prediction of relapse, the positive predictive value of ctDNA was 100%. An early ctDNA analysis (even after only one R-DA-EPOCH cycle) was able to predict patients in need of RT. Despite the DeepSeq of ctDNA could be useful to disease monitoring to prevent relapse and toxicity reduction by selecting cases in need of RT, more patients are necessary to draw meaningful conclusions. Figure 1 Figure 1. Disclosures Martín-Muñoz: Altum sequencing: Current Employment. Dorado: Altum sequencing: Current Employment. Heredia: Altum sequencing: Current Employment, Current equity holder in publicly-traded company. Rufian: Altum sequencing: Current Employment. Canales: Incyte: Consultancy; iQone: Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Sanofi: Consultancy; Eusa Pharma: Consultancy, Honoraria; Sandoz: Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Speakers Bureau; Gilead/Kite: Consultancy, Honoraria. Juarez: Altum sequencing: Current Employment. Sanchez: Altum sequencing: Current Employment. López-Muñoz: Amgen: Consultancy. Ayala: Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Celgene: Honoraria. Martínez-López: Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfizer: Consultancy; Roche, Novartis, Incyte, Astellas, BMS: Research Funding. Barrio: Altum sequencing: Current Employment, Current equity holder in publicly-traded company.

Introduction Every year, approximately 110,000 cancer patients treated with cytotoxic chemotherapy in the US endure at least one episode of febrile neutropenia (FN). Each FN episode will require an approximate 8-9-day admission costing $25,000 and may have associated mortality rates as high as 7% . Timely detection and awareness of severe neutropenia (i.e., Absolute Neutrophil Count (ANC) Methods We conducted a multicenter study to evaluate the usability and diagnostic performance of PointCheck™ in a cohort of 26 participants. The primary study objectives were to assess device usability when operated by first-time users and to meet a priori specified diagnostic performance goals in achieving 92% sensitivity (true positive rate) and 80% specificity (true negative rate). Study coordinators read a short script providing the participants with information about how to use the device. In addition, participants watched a 1-minute tutorial video, were provided with a one-page user guide before attempting to take a measurement on their own following the on-screen Graphical User Interface instructions (Fig. 1-B). They did so autonomously to simulate home usage. Usability data was collected using a combination of methods, including the think-aloud technique, a short-answer qualitative questionnaire, and a standardized quantitative System Usability Survey (SUS)- a usability evaluation method widely used in UI/UX design comprising 10 questions. Participants were also given the opportunity to document their thoughts, feelings, and experience using the device in the form of an e-questionnaire containing 4 questions about their perceptions. Design and functionality issues were primarily identified by the research staff through observation of participants and documentation of missed or incorrectly completed steps. Participants also had their blood drawn for a comparison with their complete blood count (CBC) to assess diagnostic performance. PointCheck™ measurement results were compared with clinical standard CBC tests and assessed for accuracy in classifying subjects as severely neutropenic ( Results Usability and diagnostic performance data was gathered from untrained cancer patients and healthy volunteers. We included patients with lymphoma and myeloma, among other tumor types, who visited either Boston Medical Center (BMC) and Hospital Universitario 12 de Octubre (H12O) for routine chemotherapy administration. The healthy volunteers were recruited at the Massachusetts Institute of Technology Clinical Research Center (MITCRC). The PointCheck™ device detected severe neutropenia with 92% sensitivity and 83% specificity in 24 subjects (Fig. 1-C). Two out of 26 subjects were flagged and excluded by the device Quality Control system. With respect to usability, we found that 80.8% of participants scored above 80.8 on the SUS scale across all sites, with a mean SUS score of 89.1 across all sites (Fig. 1-D). The most common user errors seen were incorrect placement of the finger, hand, and arm. Discussion We have shown that PointCheck™, a novel technology for non-invasive, home-based neutropenia detection, is accurate and easy to use by first-time users in a simulated home environment with a mean SUS score of 89.1, indicating above average perception of user experience and falling within the top 10% of systems as evaluated by the SUS scale. The technology accurately detects severe neutropenia in the cohort of patients presented here, which included liquid tumors, other cancer conditions, and healthy volunteers. These preliminary results show that PointCheck™ is a promising technology to aid in the detection of severe neutropenia in the home setting. These results need to be confirmed in a larger patient cohort with a final device design. Figure 1 Figure 1. Disclosures Lamaj: Leuko Labs, Inc.: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Pablo-Trinidad: Leuko Labs, Inc.: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Butterworth: Leuko Labs, Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Bell: Leuko Labs, Inc.: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Benasutti: Leuko Labs, Inc.: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Verdone: Leuko Labs, Inc.: Current Employment, Current holder of stock options in a privately-held company. Bourquard: Leuko Labs, Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Patents & Royalties. Sanchez-Ferro: Leuko Labs, Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Patents & Royalties. Castro-Gonzalez: Leuko Labs, Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Martínez-López: Roche, Novartis, Incyte, Astellas, BMS: Research Funding; Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfizer: Consultancy. Sloan: Pharmacosmos: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; Stemline: Honoraria.

BACKGROUND: Based on the encouraging activity and manageable safety profile observed in a phase 1 study, the ECHELON-2 trial was initiated to compare the efficacy and safety of brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone (A+CHP) versus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for the treatment of CD30-positive peripheral T-cell lymphomas.METHODS: ECHELON-2 is a double-blind, double-dummy, randomised, placebo-controlled, active-comparator phase 3 study. Eligible adults from 132 sites in 17 countries with previously untreated CD30-positive peripheral T-cell lymphomas (targeting 75% with systemic anaplastic large cell lymphoma) were randomly assigned 1:1 to receive either A+CHP or CHOP for six or eight 21-day cycles. Randomisation was stratified by histological subtype according to local pathology assessment and by international prognostic index score. All patients received cyclophosphamide 750 mg/m2 and doxorubicin 50 mg/m2 on day 1 of each cycle intravenously and prednisone 100 mg once daily on days 1 to 5 of each cycle orally, followed by either brentuximab vedotin 1·8 mg/kg and a placebo form of vincristine intravenously (A+CHP group) or vincristine 1·4 mg/m2 and a placebo form of brentuximab vedotin intravenously (CHOP group) on day 1 of each cycle. The primary endpoint, progression-free survival according to blinded independent central review, was analysed by intent-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01777152.FINDINGS: Between Jan 24, 2013, and Nov 7, 2016, 601 patients assessed for eligibility, of whom 452 patients were enrolled and 226 were randomly assigned to both the A+CHP group and the CHOP group. Median progression-free survival was 48·2 months (95% CI 35·2-not evaluable) in the A+CHP group and 20·8 months (12·7-47·6) in the CHOP group (hazard ratio 0·71 [95% CI 0·54-0·93], p=0·0110). Adverse events, including incidence and severity of febrile neutropenia (41 [18%] patients in the A+CHP group and 33 [15%] in the CHOP group) and peripheral neuropathy (117 [52%] in the A+CHP group and 124 [55%] in the CHOP group), were similar between groups. Fatal adverse events occurred in seven (3%) patients in the A+CHP group and nine (4%) in the CHOP group.INTERPRETATION: Front-line treatment with A+CHP is superior to CHOP for patients with CD30-positive peripheral T-cell lymphomas as shown by a significant improvement in progression-free survival and overall survival with a manageable safety profile.FUNDING: Seattle Genetics Inc, Millennium Pharmaceuticals Inc, a wholly owned subsidiary of Takeda Pharmacuetical Company Limited, and National Institutes of Health National Cancer Institute Cancer Center.

Infections caused by HSV-1 and their typical outbreaks invading the nervous system have been related to neurodegenerative diseases. HSV-1 infection may deregulate the balance between the amyloidogenic and non-amyloidogenic pathways, raising the accumulation of amyloid-&beta, peptides, one of the hallmarks in the neurodegenerative diseases. An effective treatment against both, HSV-1 infections and neurodegeneration, is a major therapeutic target. Therefore, gold nanoparticles (NPAus) have been previously studied in immunotherapy, cancer and cellular disruptions with very promising results. Our study demonstrates that a new NPAus family inhibits the HSV-1 infection in a neural-derived SK-N-MC cell line model and that this new NPAus reduces the HSV-1-induced -secretase activity, as well as amyloid- accumulation in SK-APP-D1 modifies cell line. We demonstrated that NPAuG3-S8 crosses the blood-brain barrier (BBB) and does not generate cerebral damage to in vivo CD1 mice model. The NPAuG3-S8 could be a promising treatment against neuronal HSV-1 infections and neuronal disorders related to the A&beta, peptides.

Background Tipifarnib is a potent and selective inhibitor of the enzyme farnesyltransferase (FT). FT catalyzes post-translational attachment of farnesyl groups required for localization of signaling molecules to the inner cell membrane. CXCL12 is a ligand for CXCR4 that is essential for T cell homing to lymphoid organs and the bone marrow, and for the maintenance of immune cell progenitors. We have previously shown that FT inhibition by tipifarnib downregulates CXCL12 secretion. Herein we report preliminary efficacy, safety and biomarker data from a Phase 2 study of tipifarnib in angioimmunoblastic T-cell lymphoma (AITL) and CXCL12+ peripheral T-cell lymphoma (PTCL) patients (pts). Methods This Phase 2 study (NCT02464228) is a multi-institutional, single-arm, open-label trial initially designed as a two-stage (11+7 pts) design to determine the efficacy, safety and biomarkers of tipifarnib in pts with relapsed/refractory (R/R) PTCL age >/=18 years and a performance status of 0-2. Based on initial findings, the study was amended to include a cohort of AITL (n=12) and PTCL (n=12) pts with the CXCL12 rs2839695 A/A genotype (wt CXCL12 3'UTR cohort). Pts received tipifarnib 300 mg administered orally twice daily on days 1-21 of 28-day treatment cycles until progression of disease (PD) or unacceptable toxicity. The primary endpoint of the study is overall response rate (ORR). Tumor Whole Exon Sequencing (WES) was generated by NGS and gene expression data generated by RNA Seq. Ancillary studies also investigated the prognostic value of CXCL12 expression in pts who received standard of care treatment. Results As of 24 May 2019, 50 PTCL pts (23 AITL, 25 PTCL-NOS, 1 ALK- ALCL, 1 gamma-delta TCL) have been treated with tipifarnib, 19 pts in stages 1 and 2, and 31 pts in the ongoing AITL histology and wt CXCL12 3'UTR cohorts. Median number of prior treatment regimens was 3; 19 pts had a prior stem cell transplant. All pts (n=48 with available safety data) had at least one treatment-emergent adverse event (TEAE); 42 (88%) had at least 1 study drug-related TEAE and 13 (27%) at least 1 drug related SAE. The most frequently observed drug-related TEAEs of Grade >3 occurring in 10% or more of pts were blood and lymphatic system disorders, including neutropenia (40%), thrombocytopenia (33%), leukopenia (25%), anemia and febrile neutropenia (19% each). There have been 14 deaths on study; one related to study drug (lung infection). Of 18 evaluable pts enrolled in Stages 1 and 2 of the trial, 3 partial responses (PR), 2 of them in pts with AITL histology, and 5 best responses of stable disease (SD) were observed. In the AITL cohort (11 evaluable of 16 pts enrolled), a 45% ORR and 73% clinical benefit rate (CBR; 3 CR, 2 PR and 3 SD) was observed. In the wt CXCL12 3'UTR cohort (n=12 evaluable pts), a 42% ORR was observed (3 CR, 2 PR), with 2 of the 3 CRs observed in patients of AITL histology (n=4). A total of 23 AITL subjects were enrolled in the overall study of whom 16 had WES data. A strong association with the activity of tipifarnib was observed in 8 of the 16 (50%) carrying KIR3DL2 gene variants C336R/Q386E: 50% CR rate, 75% ORR, 100% clinical benefit rate. These tumors expressed also very low levels of CXCL5, a ligand for CXCR2, that may mediate resistance to tipifarnib. High Allele Frequency of KIR3DL2 variants predicted CR to tipifarnib treatment (ROC AUC=0.94, p Conclusion The AITL and wt CXCL12 3'UTR cohorts met pre-specified statistical hypotheses supporting proof-of-concept for tipifarnib in PTCL. AITL histology, KIR3DL2 and CXCL12 genotype provided robust tools for the selection/stratification of PTCL subjects treated with tipifarnib. Extended enrollment of AITL patients continues and an update on enrollment and outcomes will be provided at the time of the presentation. Disclosures Sokol: EUSA: Consultancy. Foss:Mallinckrodt: Consultancy; Eisai: Consultancy; Spectrum: Other: fees for non-CME/CE services ; Acrotech: Consultancy; Seattle Genetics: Consultancy, Other: fees for non-CME/CE services ; miRagen: Consultancy. Kim:Donga: Research Funding; Celltrion: Research Funding; J&J: Research Funding; Roche: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; Mundipharma: Research Funding. Jacobsen:Kura Oncology: Research Funding. Advani:Kyowa Kirin Pharmaceutical Developments, Inc.: Consultancy; Kura: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Research Funding; Agensys: Research Funding; Stanford University: Employment, Equity Ownership; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Celmed: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forty-Seven: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cell Medica, Ltd: Consultancy; Gilead Sciences, Inc./Kite Pharma, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity Pharma: Research Funding; Millennium: Research Funding. Roncero:Kura Oncology: Research Funding. Terol:Janssen: Consultancy, Research Funding; Roche: Consultancy; Gilead: Research Funding; Astra Zeneca: Consultancy; Abbvie: Consultancy. Domingo-Domenech:Bristol-Myers Squibb: Other: Travel expenses; Roche: Other: Travel expenses; Seattle Genetics: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses. Piris:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Lecture Fees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jansen: Membership on an entity's Board of Directors or advisory committees, Other: Lecture Fees; Nanostring: Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees; Kura: Research Funding. Rodriguez:Kura Oncology: Research Funding. Bolognese:Kura Oncology: Consultancy. Kessler:Kura Oncology: Employment. Mishra:Kura Oncology: Employment. Curry:Kura Oncology: Employment. Kurman:Kura Oncology: Employment. Scholz:Kura Oncology: Employment, Equity Ownership, Patents & Royalties. Gualberto:Kura Oncology: Employment, Equity Ownership, Patents & Royalties.

Background Tipifarnib is a potent and selective inhibitor of the enzyme farnesyltransferase (FT). FT catalyzes post-translational attachment of farnesyl groups required for localization of signaling molecules to the inner cell membrane. CXCL12 is a chemokine that is essential for T cell homing to lymphoid organs and the bone marrow, and for the maintenance of immune cell progenitors. Herein we report preliminary efficacy, safety and biomarker data from a Phase 2 study of tipifarnib in angioimmunoblastic T-cell lymphoma (AITL) and CXCL12+ peripheral T-cell lymphoma (PTCL) patients (pts). Methods This Phase 2 study is a multi-institutional, single-arm, open-label trial initially designed as a two-stage (11+7 pts) cohort to determine the efficacy, safety and biomarkers of tipifarnib in pts with relapsed/refractory (R/R) PTCL, age >/=18 years and a performance status of 0-2. Based on initial findings, the study was amended to include a cohort of AITL (n=12) and PTCL (n=12) pts with the CXCL12 rs2839695 A/A genotype (CXCL12+ cohort). Pts received tipifarnib 300 mg administered orally twice daily on days 1-21 of 28-day treatment cycles until progression of disease (PD) or unacceptable toxicity. The primary endpoint of the study is overall response rate (ORR). Ancillary studies are also ongoing to investigate the prognostic value of CXCL12 expression in patients who received standard of care treatment. Results As of 25 July 2018, 34 PTCL pts (13 AITL, 1 ALK- ALCL, 20 PTCL-NOS) have been treated with tipifarnib, 19 pts in stages 1 and 2, and 15 pts in the ongoing AITL histology and CXCL12 cohorts. Median number of prior treatment regimens was 3. The most common treatment-related adverse events (AE) (grade ≥ 3) are hematological, including neutropenia (50%), thrombocytopenia (43%), leukopenia (33%), febrile neutropenia (27%), and anemia (20%). Skin and subcutaneous tissue disorders were reported in 9 pts, 6 of them with AITL histology. One pt with AITL experienced an episode of possible Stevens Johnson Syndrome that resolved with dose discontinuation and did not recur upon re-challenge at one dose level reduction. Of 18 evaluable patients enrolled in Stages 1 and 2 of the trial, 3 partial responses (PR), 2 of them in pts with AITL histology, and 4 best responses of stable disease (SD) were observed. Pre-treatment tumor tissue CXCL12 expression correlated with favorable pt outcomes. In the AITL cohort (10 evaluable pts), 1 PR and 1 SD have been observed so far, with 5 pts pending cycle 2 response evaluation. In the CXCL12+ cohort (n=3 evaluable pts), 1 SD has been observed, with 2 pts pending cycle 2 response evaluation. Plasma levels of CXCL12 decreased over time with tipifarnib treatment. Expression of CXCL12 mRNA and other biomarkers in pre-treatment biopsies of pts in the AITL and CXCL12+ cohorts are being evaluated using RT-PCR assays. In addition, the prognostic value of CXCL12 is being investigated in approximately 100 diagnostic specimens of PTCL pts who received standard therapy. Preliminary data suggest that CXCL12 overexpression is observed in approximately 25% of PTCL and negatively affects pt survival. Conclusion Preliminary activity of tipifarnib was observed in PTCL pts, particularly in those with tumors of AITL histology and high CXCL12 expression and enrollment continues. Disclosures Witzig: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sokol:Mallinckrodt Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Spectrum Pharmaceuticals: Consultancy. Jacobsen:Merck: Consultancy; Seattle Genetics: Consultancy. Kim:Takeda: Research Funding; J&J: Research Funding; Mundipharma: Research Funding; Roche: Research Funding; Novartis: Research Funding; Kyowa-Kirin: Research Funding; Celltrion: Research Funding. Foss:Miragen: Consultancy, Speakers Bureau; Spectrum: Consultancy; Seattle genetics: Consultancy; Mallinkrodt: Consultancy. Advani:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kura: Research Funding; Merck: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Regeneron: Research Funding; Janssen: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Cell Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Autolus: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Gilead/Kite: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millenium: Research Funding; Agensys: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Infinity: Research Funding. Marin Niebla:Amgen: Other: Medical education of Staff, Speakers Bureau; Roche: Consultancy, Other: Medical education of Staff, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Other: Medical education of Staff, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Medical education of Staff, Speakers Bureau. Piris:Kura: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Gilead: Honoraria. Curry:Kura Oncology: Employment, Equity Ownership. Gualberto:Kura Oncology: Employment, Equity Ownership.

Background AFM13 is a bispecific, tetravalent NK cell-engaging antibody construct binding to CD30 on CD30+ tumor cells and CD16A on NK cells. By engaging CD16A-positive NK cells, AFM13 leads to NK cell-mediated killing of CD30-positive lymphoma cells (Reusch et al., 2014) making it an attractive agent to target classical Hodgkin lymphoma (HL). Pembrolizumab is a PD-1 blocking antibody which has shown high single-agent response rates in patients (pts) with relapsed/refractory HL (RRHL; Armand et al., 2016, Chen et al., 2017). AFM13 has shown clinical activity in RRHL as a single agent in a preceding Phase 1 study (Rothe et al., 2015). Preclinical in vivo data of the combination of AFM13 with PD-1 blockade showed synergistic activity and the potential for induction of cross-talk between innate and adaptive immunity (Zhao et al., 2016). We hypothesize that the combination of the two agents could improve outcomes in pts with RRHL. Methods This Phase 1b study is evaluating the safety and tolerability of the combination of AFM13 with pembrolizumab (Keytruda) as salvage therapy after failure of standard therapies including brentuximab vedotin (BV) in HL (NCT02665650). Pts receive escalating doses of AFM13 in combination with pembrolizumab at a dose of 200 mg flat administered every 3 weeks following a classical 3+3 design, followed by enrollment into an extension cohort at the maximum tolerated dose (MTD)/maximum administered dose (MAD). Response assessment is performed every 12 weeks by PET/CT according to the Lugano Classification (Cheson et al., 2014). The main objectives of the study is to ascertain the MTD/MAD along with the preliminary efficacy of the combination. Results As of June 29, 2018, 30 pts have been enrolled into the study. The median age is 34 years (range, 18-73), with a median of 4 (range 3-7) prior lines of therapy. All pts had relapsed or refractory disease (43% relapsed, 57% refractory) and had failed standard treatments including BV and 43% of pts (13/30) had BV as their latest therapy. Thirty seven percent (11/30) had undergone prior autologous stem cell transplantation. All 30 pts have completed the 6-week dose-limiting toxicity (DLT) observation period. Twelve pts were enrolled into the dose escalation cohorts (Cohorts 1 (n=3), 2 (n=3), and 3 (n=6)) and 18 into the Extension Cohort, with a total of 24 patients treated at the MAD (dose level 3). One DLT was observed in Cohort 3 (missing ≥25% of AFM13 during the DLT period) and another observed in the Extension Cohort (G4 infusion-related reaction; IRR). The most common related adverse events (AEs) were IRRs (80%), rash (30%), pyrexia (23%), nausea (23%), diarrhea (20%), fatigue (17%), headache (17%), increased aspartate aminotransferase (13%), and increased alanine aminotransferase (10%). Treatment related G3/4 AEs included IRRs (13%), elevated AST (3%), gastritis (3%), hypotension (3%), nausea (3%), neutropenia (3%), and vomiting (3%). The majority of IRRs were manageable with standard of care measures and did not lead to treatment discontinuations. Included in the efficacy analysis were the best response from 29 evaluable pts who had at least one post-baseline disease assessment as of the data cutoff on June 29, 2018. The overall response rate (ORR) and complete response (CR) rate for evaluable pts treated at the dose and schedule chosen for expansion (n=23; Cohort 3 and Extension Cohort) were 87% and 35% by the investigator-confirmed assessment, respectively. Independent assessment resulted in an ORR of 87% and CR rate of 39% for these pts. Updated data for all 30 patients will be presented at the meeting. Conclusions The combination of AFM13 and pembrolizumab is a well-tolerated salvage therapy in pts with RRHL. IRRs were the most frequently observed adverse events; however, most of these events were of mild or moderate severity and manageable. Both the ORR and CR rate compare favorably to monotherapy pembrolizumab in a similar RRHL population (Chen et al., 2017). The combination of AFM13 and pembrolizumab could be a potential new therapeutic option for HL patients. Disclosures Bartlett: Immune Design: Research Funding; Affimed: Research Funding; Bristol-Meyers Squibb: Research Funding; Merck & Co: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Novartis: Research Funding; Novartis: Research Funding; Millennium: Research Funding; ImaginAB: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees. Chen:Affimed: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech Inc.: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck & Co., Inc.: Consultancy, Research Funding, Speakers Bureau; Millennium Pharmaceuticals: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Domingo-Domenech:Affimed: Research Funding. Forero-Torres:Affimed: Research Funding. Garcia-Sanz:Affimed: Research Funding. Devata:Affimed: Research Funding. Rodriguez Izquierdo:Affimed: Research Funding. Lossos:Affimed: Research Funding. Reeder:Affimed: Research Funding. Sher:Affimed: Research Funding. Choe-Juliak:Affimed: Employment. Prier:Affimed: Research Funding. Schwarz:Affimed: Employment. Strassz:Affimed: Employment. Alland:Affimed: Employment. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Pfizer: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Merck & Co: Research Funding; Affimed: Research Funding; Takeda: Research Funding.