ALBERT

Description: Extracorporeal photopheresis (ECP) is an effective frontline therapy for patients with leukemic cutaneous T-cell lymphoma (L-CTCL), but the mechanisms of action are not fully understood. To elucidate molecular mechanisms underlying the efficacy of ECP, we used Agilent Whole Human Genome Microarrays to examine blood transcriptional profiles in L-CTCL patients after ECP therapy. Ten L-CTCL patients including 5 clinical responders and 5 non-responders were studied. Their peripheral blood was collected before ECP (baseline), at Day 2, and one month post-ECP. Total RNA extracted from peripheral blood mononuclear cells was assayed with Whole Human Genome Oligo Microarrays (4 × 44 K) (Agilent, Santa Clara, CA). The differentially expressed gene analysis (DGA) was done using the paired t-test with Benjamini- Hochberg correction (P value 〈 0.05) between post-ECP and baseline. The fold change of gene expression between post-ECP and baseline were calculated from the normalized values. Hierarchical clustering of differentially expressed genes was performed with the Pearson correlation. The DGA between responders and non-responders were cross-compared. Canonical biological pathways were identified using Ingenuity Pathway Analysis (IPA, Ingenuity Systems, Redwood City, CA). Differentially expressed gene profiles were different in responders from non-responders. As indicated in Figure 1, there were more genes differentially regulated in responders than in non-responders post-ECP at both Day 2 (549 genes in responders versus 66 genes in non-responders) and at one month (472 genes in responders versus 95 genes in non-responders). Among 472 differentially expressed genes in responders at one month post-ECP, almost twice as many genes (313) were down-regulated compared to up-regulated genes (159). The top down-regulated genes were IL-1β, EGR1, CCL3, CCL3L3, and CXCL2. The down-regulated genes were mainly related to functions of platelets, immune and/or stress responses, and chromatin remodeling. The upregulated genes were mainly related to functions of the nucleolus and included USP34, POLR3F, ZNF529, C22orf35, and BAT2D1. The ingenuity pathway analysis revealed that the top 5 pathways affected by ECP at one-month in responders were 1) integrin signaling; 2) granulocyte adhesion and diapedesis; 3) signaling by Rho Family GPTases; 4) agranulocytes (lymphocyte, monocyte and macrophage) adhesion and diapedesis; and 5) triggering receptor expressed on myeloid cells 1 (TREM1) signaling (Table 1). In contrast, these pathways and genes were less affected in non-responders. Of note, a comparison of all DGA results indicated that the responder group overlapped in the differentially expressed genes between Day 2 group (RD2) and one month group (RM1), but had few genes in common to the non-responder group (NM1). There were 94 genes consistently downregulated among RD2 and RM1 while only 6 genes were found in common between the RM1 and NM1 group. Similarly, 61 genes were consistently upregulated in group RD2 and RM1 while only 3 genes were found in common between the RM1 and NM1 group. In summary, the blood transcriptional profiling by this study identifies a signature of genes and pathways relevant to clinical response to ECP in L-CTCL patients. These findings expand our understanding of molecular mechanisms of ECP. Further validation of these genes and pathways is warranted in the future studies. Table 1. Top canonical pathways affected by ECP in L-CTCL patients responded to ECP at one-month Canonical Pathways Downregulated genes Upregulated genes Integrin Signaling 15/201 (7%) ITGA2B, MAP3K11, ITGA5, MYLK, ITGB3, MYL9, PARVB, AKT1, RHOB, CAPN1, ACTN4, CTTN, ARPC4, ACTN1, ITGB5 2/201 (1%) ITGB1, PPP1R12A Granulocyte Adhesion and Diapedesis 14/179 (8%) CSF3R, ICAM1, PPBP,ITGA5, CXCL5, SDC4, CCL3, ITGB3, GNAI2, CLDN5, CCL3L3, IL1B, CXCL1, CXCL2 1/179 (1%) ITGB1 Signaling by Rho Family GTPases 13/236 (6%) SEPT5, MAP3K11, ITGA5, MYLK, GNAZ, CDC42EP2, GNAI2, MYL9, GNG11, GNA15, RHOB, GNB2, ARPC4 3/236 (1%) ITGB1, DIAPH3, PPP1R12A Agranulocyte Adhesion and Diapedesis 13/190 (7%) ICAM1, PPBP, ITGA5, CXCL5, SDC4, CCL3, GNAI2, MYL9, CLDN5, CCL3L3, IL1B, CXCL1, CXCL2 1/190 (1%) ITGB1 TREM1 Signaling 7/76 (9%) ICAM1, AKT1, NLRP12, ITGA5, IL1B, CD83, CCL3 2/76 (3%) ITGB1, NLRC3 Figure 1. Differentially expressed genes post-ECP between responders and non-responders Figure 1. Differentially expressed genes post-ECP between responders and non-responders Disclosures Duvic: Therakos: Research Funding. Ni:Therakos: Research Funding.

Description: Background: A histologic finding of large cell transformation (LCT) in Mycosis fungoides (MF) is often associated with an aggressive clinical course and inferior prognosis (Arulogun et al. Blood 2008). In patients (pts) with advanced MF (stage IIB-IV), LCT has been established as an independent prognostic factor (Scarisbrick et al. JCO 2015). Although CD30 expression is observed more frequently in MF with LCT vs without LCT, a wide range of CD30 expression levels is observed in LCT lesions and the level of expression lacks prognostic value for MF (Vergier et al. Blood. 2000). The ALCANZA study (NCT01578499) demonstrated significantly better rates of objective response lasting ≥4 months (ORR4) (∆43.8%; p

Description: Introduction: MAVORIC was an open-label, multicenter, randomized phase 3 study evaluating the safety and efficacy of mogamulizumab (moga) compared to vorinostat (vori) in patients with mycosis fungoides (MF) or Sézary syndrome (SS) who had failed at least one prior course of systemic therapy (NCT01728805). Primary results have been reported (Kim et al. Lancet Oncol 2018) and were based on a data cutoff date of December 31, 2016. The primary endpoint was progression-free survival (PFS); patients in the moga treatment arm experienced significantly longer PFS compared to patients in the vori treatment arm (median 7.7 months vs 3.1 months; p

Description: Background: CTCL represents a rare group of non-Hodgkin lymphomas with substantial negative impact on patient (pt) quality of life and mortality in advanced-stage disease. Mycosis fungoides (MF), the most common subtype of CTCL, and the rarer leukemic variant Sézary syndrome (SS) are distinct subtypes of CTCL. Mogamulizumab is a first-in-class, defucosylated monoclonal antibody directed against C-C chemokine receptor 4 (CCR4), which is highly expressed on malignant T-cells in CTCL. Primary results from the MAVORIC study (data cut-off December 2016), a phase 3 trial comparing mogamulizumab to FDA-approved vorinostat in adults with relapsed/refractory MF/SS, showed mogamulizumab significantly prolonged median progression-free survival compared with vorinostat (7.7 vs 3.1 months, P351 d was defined as cut-off for long-term exposure. Baseline characteristics across exposure groups are shown in the Table. Significant trends were observed for baseline Eastern Cooperative Oncology Group performance status (ECOG PS; P=0.04), disease type (P=0.03), and blood involvement (defined as ≥B1 per Olsen et al J Clin Oncol 2011; P351 d of exposure to mogamulizumab were drug eruption (9/45 [20%]), thrombocytopenia (5/45 [11%]), stomatitis (4/45 [9%]), and anemia (4/45 [9%]). Conclusions: This follow-up analysis of the phase 3 MAVORIC study demonstrated mogamulizumab treatment of pts with MF/SS for approximately 1 year was not associated with an increased safety risk. Significant long-term clinical benefit was observed in pts with blood involvement at baseline, regardless of CCR4 expression status. A higher proportion of pts who had long-term (〉351 days) exposure attained confirmed global response versus those who had less exposure. Disclosures Bagot: Takeda: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees; Actelion: Membership on an entity's Board of Directors or advisory committees. Dalle:Kyowa Hakko Kirin Pharmaceutical: Research Funding. Sokol:Mallinckrodt Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Spectrum Pharmaceuticals: Consultancy. Tsianakas:Kyowa Kirin: Research Funding. Musiek:Seattle Genetics: Honoraria; Kyowa Kirin: Honoraria; Actelion: Other: Scientific Advisory Committee . Ortiz-Romero:Innate Pharma: Consultancy; Takeda: Consultancy; MEDA: Research Funding; Actelion: Consultancy; 4SC: Consultancy. Poligone:Johnson and Johnson: Research Funding; Kyowa Hakko Kirin: Research Funding; Soligenix: Research Funding; Mallinckrodt: Speakers Bureau; Stemline Therapeutics: Honoraria; Seattle Genetics: Honoraria. Duvic:Clinical Care Options: Consultancy; Soligenix, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Mallinckrddt Pharmaceuticals (formerly Therakos): Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Huron Consulting Group: Consultancy; Taiwan Liposome Company LTD: Consultancy; Rhizen Pharma: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin, Co: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Oncology, LLC: Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; UT MD Anderson Cancer Center: Employment; Dr. Reddy's Laboratories (A.K.A. Promius Pharma): Consultancy; Defined Health: Consultancy; Medivir AB: Membership on an entity's Board of Directors or advisory committees; Medscape: Other: Speaker/Preceptor; Guidepoint Global: Consultancy; Jonathan Wood & Associates: Other: Speaker; Celgene Corp: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Evidera, Inc.: Consultancy; Kiniksa Pharmaceuticals: Consultancy; MEDACorp: Consultancy; The Lynx Group: Consultancy; Spatz Foundation: Research Funding; Forty Seven, Inc.: Membership on an entity's Board of Directors or advisory committees; Shape: Research Funding; Aclaris Therapeutics Int'l Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cell Medica Inc.: Consultancy, Honoraria; Allos: Research Funding; American Council on Extracorporeal Photopheresis (ACE): Membership on an entity's Board of Directors or advisory committees; Concert Pharmaceuticals, Inc.: Consultancy; Millennium Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MiRagen Therapeutics: Consultancy; Huya Bioscience Int'l: Consultancy; Array Biopharma: Consultancy, Honoraria; Oncoceuticals: Research Funding; Tetralogics: Research Funding. Elmets:NCI: Research Funding; Veterans Administration: Research Funding; California Wine Grape Association: Research Funding; Soligenix: Research Funding; Elorac: Research Funding; Leo Pharma: Other: Data and Safety Monitoring Board. Leoni:Kyowa Kirin: Employment. Dwyer:Kyowa Kirin: Employment. Sun:Kyowa Kirin: Employment. Nikonova:Kyowa Kirin: Employment. Kim:miRagen: Research Funding; Forty Seven Inc: Research Funding; Kyowa-Kirin-Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon Pharma: Consultancy, Research Funding; Merck: Research Funding; Soligenix: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees; Neumedicine: Consultancy, Research Funding; Portola: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Galderma: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetralogic: Research Funding.

Description: KIR3DL2 is expressed in all subtypes of cutaneous T-cell lymphomas (CTCL), irrespective of clinical stage, with the highest prevalence of expression in Sézary syndrome (SS) and transformed mycosis fungoides (MF), two subgroups of patients with a high unmet need for clinically impactful therapies. KIR3DL2 belongs to the killer immunoglobulin-like receptor (KIRs) family and is expressed on minor subpopulations of normal NK, CD8 and CD4 T cells. IPH4102 is a first-in-class anti-KIR3DL2 monoclonal antibody (mAb). It selectively depletes KIR3DL2-expressing cells by recruiting immune effectors. Its main modes of action include antibody-dependent cell-cytotoxicity (ADCC) and -phagocytosis (ADCP). IPH4102 has shown potent efficacy in preclinical models, in particular ex vivo autologous assays using primary CTCL cells. IPH4102 is currently being investigated in a first-in-human dose-finding phase 1 study (NCT02593045) evaluating repeated administrations of single-agent IPH4102 in relapsed/refractory CTCL patients. The primary objective is to assess the safety and tolerability of increasing doses of IPH4102. Secondary objectives include PK, immunogenicity and signals of anti-tumor clinical activity. Exploratory biomarkers aim to characterize KIR3DL2-expressing and non-expressing cells in involved tissue/disease compartments and to monitor changes during IPH4102 treatment. Minimal residual disease (MRD) is measured in the skin, blood and/or lymph nodes. Assessment of ex vivo NK cell-mediated ADCC against autologous tumor cells is also performed pre-dose on SS patient samples. The study has two sequential portions, a dose-escalation followed by a cohort expansion. The dose-escalation portion has a 3+3 design with accelerated titration and aims to determine the maximal tolerated dose (MTD) or recommended phase 2 dose (RP2D). In the cohort expansion portion, two CTCL subtype-specific cohorts will be studied, each to include 10 additional patients to further explore MTD or RP2D. Eligible CTCL patients must have received at least 2 lines of anti-neoplastic systemic therapy. Centrally assessed KIR3DL2 expression on malignant cells in skin or blood is required for inclusion. Patients receive IPH4102 administrations until progression or unacceptable toxicity. Intra-patient dose-escalation is allowed, only past the first complete clinical assessment at week 5 and provided the upper next dose-level is declared safe by the safety committee. Enrollment into study IPH4102-101 started in November 2015 and is currently ongoing. At time of abstract submission, dose-levels #1 to #6 have been completed. A total of 13 patients have been treated at these 6 dose-levels and are evaluable for safety and clinical activity. These patients comprise 10 SS (including 1 with evidence of large-cell transformation), 2 MF and 1 "not-otherwise-specified" CD4+ CTCL. Median age is 71 years (range 50 - 90). For these 13 patients, only grade 1 or 2 related adverse events (AEs) have been reported with IPH4102 treatment. No patient experienced a DLT or a related AE of grade ≥3. No IPH4102-related skin rashes or infections have been observed so far. Results of immuno-phenotyping of patients' blood lymphocytes show consistency of local and central assessments. In addition, ex vivo functional assay results confirm that SS patients' NK cells are functional and able to kill autologous tumor cells through ADCC with IPH4102. Our preliminary data from the phase 1 study of a novel targeted immune therapy show excellent tolerability in advanced CTCL patients. Updated results including exploratory biomarker assessment results will be presented and discussed at the meeting. Disclosures Bagot: Millenium: Other: Investigator in a clinical trial; Kiowa Hakko Kirin: Other: Investigator in a clinical trial; Innate Pharma: Equity Ownership, Other: Investigator in a clinical trial, Patents & Royalties, Research Funding. Porcu:celgene: Other: Investigator in a clinical trial; miRagen: Other: Investigator in a clinical trial; Innate Pharma: Other: Investigator in a clinical trial; Millenium: Other: investigator in a clinical trial. Ram-Wolff:Innate Pharma: Other: Investigator in a clinical trial. Battistella:Innate Pharma: Consultancy, Research Funding. Marie-Cardine:Innate Pharma: Research Funding. Mathieu:Innate Pharma: Other: Investigator in a clinical trial. Vermeer:Innate Pharma: Other: Investigator in a clinical trial. Whittaker:Seattle Genetics: Other: Investigator in a clinical trial; Innate Pharma: Other: Investigator in a clinical trial; Takeda: Membership on an entity's Board of Directors or advisory committees; Galderma: Research Funding. Duvic:Kiowa Hakko Kirin: Other: investigator in a clinical trial, Research Funding; Rhizen Pharmaceuticals: Other: Investigator in a clinical trial; Innate Pharma: Consultancy, Other: Investigator in a clinical trial; Millenium: Other: Investigator in a clinical trial; Angimmune LLC: Other: Investigator in a clinical trial; miRagen: Other: Investigator in a clinical trial. Bensussan:Innate Pharma: Patents & Royalties, Research Funding. Paturel:Innate Pharma: Employment, Equity Ownership. Bonnafous:Innate Pharma: Employment, Equity Ownership. Widemann:Innate Pharma: Employment. Bonin:Innate Pharma: Employment. Sicard:Innate Pharma: Employment, Equity Ownership. Paiva:Innate Pharma: Employment. Pilz:Innate Pharma: Consultancy. Kim:Kyowa Hakko Kirin: Consultancy, Honoraria, Other, Research Funding; Innate Pharma: Other: Investigator in a clinical trial; Millenium: Consultancy, Other: Investigator in a clinical trial; Seattle Genetics: Consultancy, Other: Investigator in a clinical trial; Merck: Other: Investigator in a clinical trial; Genentech: Other: Investigator in a clinical trial; MiRagen: Consultancy; Neumedicine: Consultancy; Soligenix: Consultancy; Eisai: Consultancy, Other: Investigator in a clinical trial; Actelion: Consultancy, Other: Investigator in a clinical trial; Celgene: Consultancy; Galderma: Consultancy; Horizon: Consultancy.

Description: INTRODUCTION AND OBJECTIVES: Folliculotrophic mycosis fungoides (FMF) is an uncommon and distinct variant of mycosis fungoides (MF) that is often difficult to diagnose and treat. To identify prognostic factors, we analyzed the prognostic relevance of clinical, and histologic features in FMF patients. MATERIALS AND METHODS: We queried the MD Anderson Cancer Center cutaneous T-cell lymphoma database for patients with a diagnosis of folliculotrophic mycosis fungoides (FMF). The patients' charts were reviewed and patients were included if they displayed a biopsy showing histologic and immunohistochemical features consistent with FMF. Clinical and histopathologic features, prognostic features including overall survival (OS), progression free survival (PFS), and disease free survival (DFS), and treatment options were described in 114 patients with biopsy proven F-MF with and without large cell transformation (LCT). Survival outcomes were assessed using the Kaplan-Meier method and Cox proportional hazards regression. RESULTS We evaluated 114 patients (54% male, 46% female) 72% were Caucasian with median age at diagnosis of 56 yrs (range 22-86 yrs). Median overall survival (OS) and disease free survival (DFS) was not reached but median time to progression was 7.6 years (95% CI). Histologic LCT in skin or nodes occurred in 24 patients (21%), including 12 within a year of initial diagnosis of FMF. Median survival for patients diagnosed with large cell transformation (LCT) at time of diagnosis of FMF was only 2.4 yrs (0.4, 6.3; 95% CI). Median time to progression was 1.5 yrs (0.4, 6.3: years; 95% CI and median PFS for patients diagnosed with LCT diagnosed at 1-year was 5.6 (1.9, 6.3) years. Patients 〉 65 years were about 4.5 times more likely to die than 65 4.52 [2.06, 9.88 ] 0.0002 2.20 [1.20, 4.02] 0.01 2.96[0.89, 9.78] 0.07 LCT 618 1.002 [1.001, 1.003] 0.0056 1.00 [1.000,1.002] 0.0076 1.00 [1.00, 1.00] 0.0145 Symptoms Erythroderma 4.73 [1.58, 14.7 ] 0.0054 3.10 [1.21, 7.96] 0.018 1.87 [1.33, 31.87] 0.020 FMF on Chest 3.6 [1.35, 9.59 ] 0.014 3.83 [1.82 , 8.04 ] 0.0004 1.41 [0.882, 19.1] 0.07 Pruritus 7.85 [1.06, 58.0 ] .043 5.069 [1.55, 16.5] 0.007 16.49 [0.00, NE] 0.99 CONCLUSIONS Folliculotropic mycosis fungoides is an important entity requiring proper diagnosis and early treatment with radiation, ECP, topical steroids and retinoids. FMF is clinically more aggressive than classic MF and was associated with large cell transformation in 21% of FMF patients. Prospective studies on the clinical course and treatment responsiveness of FMF are planned. Disclosures Duvic: Innate Pharma: Research Funding; MiRagen Therapeutics: Consultancy; Eisai: Research Funding; Soligenics: Research Funding; Spatz Foundation: Research Funding; Array Biopharma: Consultancy; Huya Bioscience Int'l: Consultancy; Oncoceutics: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Allos (spectrum): Research Funding; Rhizen Pharma: Research Funding; Therakos: Research Funding, Speakers Bureau; Cell Medica Ltd: Consultancy; Tetralogics SHAPE: Research Funding; Millennium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin, Co: Membership on an entity's Board of Directors or advisory committees, Research Funding.