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Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive T-cell malignancy that arises in a proportion of individuals who are long-term carriers of human T-lymphotropic virus type 1. The median survival of aggressive subtypes is 8 to 10 months; with chemotherapy-based approaches, overall survival has remained largely unchanged in the ∼35 years since ATL was first described. Through the use of 4 representative case studies, we highlight advances in the biological understanding of ATL and the use of novel therapies such as mogamulizumab, as well as how they are best applied to different subtypes of ATL. We discuss the implementation of molecular methods that may guide diagnosis or treatment, although we accept that these are not universally available. In particular, we acknowledge discrepancies in treatment between different countries, reflecting current drug licensing and the difficulties in making treatment decisions in a rare disease, with limited high-quality clinical trial data.

TO THE EDITOR: Adult T-cell leukemia/lymphoma (ATL) is caused by human T-cell lymphotropic virus type 1.[1][1][⇓][2]-[3][3] Patients, especially those with an aggressive variant (acute, lymphoma, and unfavorable chronic subtypes),[4][4],[5][5] have an extremely poor prognosis.[1][1][⇓][2][⇓][

Background: CC chemokine receptor 4 (CCR4) is expressed on several T cell subsets and is implicated in the pathogenesis of a variety of leukemias and lymphomas. Mogamulizumab is a humanized monoclonal antibody targeting CCR4 receptors and is indicated for treatment of adult patients with cutaneous T-cell lymphoma (relapsed or refractory mycosis fungoides or Sézary syndrome). The objectives of these analyses were to (1) develop a population pharmacokinetics (PPK) model to characterize mogamulizumab PK following administration to subjects who have lymphomas or solid tumors, (2) evaluate patient covariates that influence the variability in PK, (3) simulate mogamulizumab PK at 2 mg/kg every four weeks (Q4W) dosing and compare with the PK at 1 mg/kg every two weeks (Q2W) dosing and (4) assess the exposure-response (ER) relationship between mogamulizumab exposures and adverse events (AEs). A Phase 2 clinical study is ongoing to obtain PK, efficacy, and safety data for 2 mg/kg Q4W dosing (NCT04745234). Methods: Plasma or serum pharmacokinetic data from 525 subjects with cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL), adult T-cell leukemia-lymphoma (ATL), or solid tumors were included in this analysis. Mogamulizumab was administered over 0.01 mg/kg to 3 mg/kg dose range as mono- or combination-therapy. Nonlinear mixed effects modeling was used to develop a base PPK model followed by covariate evaluation. Simulations were performed to estimate exposure metrics to support ER analyses and to compare 2 mg/kg Q4W and 1 mg/kg Q2W dosing scenarios following four 1 mg/kg weekly doses in the first cycle of treatment. Comparisons between mogamulizumab exposures and grade 3 and grade 4 AEs were conducted. Results: A two-compartment PPK model with linear elimination and log-normal variability on clearance and the volumes of distribution of the central and peripheral compartments, described the PK data. Body weight, albumin, and tumor type were identified as statistically significant covariates affecting mogamulizumab exposure. Other covariates that were tested but did not demonstrate statistically significant effect on mogamulizumab exposure included age, race, creatinine clearance, degree of CCR4 expression, combination- vs. mono-therapy, CTCL subtype (when applicable), and mild hepatic impairment. The PK simulations demonstrated that the overall exposures (AUC ss) achieved with mogamulizumab 2 mg/kg Q4W dosing were comparable to mogamulizumab 1 mg/kg Q2W dosing, with C max predicted to be 47% greater and C min to be 29% lower. Evaluations of dose and exposure (AUC ss, C max, C min) vs. incidence of grade 3 and grade 4 AEs showed no relationship. Conclusions: The PPK model adequately characterized the mogamulizumab PK over the doses ranging from 0.01 to 3 mg/kg. There was no relationship between the exposure of mogamulizumab and the emergence of grade 3 or grade 4 AEs across the dose range explored. Thus, the mogamulizumab 2 mg/kg Q4W dosing is not expected to lead to increased incidences of grade 3 and grade 4 AEs. From a PK and safety perspective, this analysis supports 2 mg/kg Q4W Mogamulizumab as an appropriate alternative dosing strategy to the approved, 1 mg/kg Q2W, dosing posology in T-cell lymphomas. Acknowledgements: We would like to express special appreciation to Dr. Roland Meier, MD, PhD, for sponsoring this abstract. Disclosures Mehta: Kyowa Kirin: Current Employment. Patel: Kyowa Kirin: Current Employment. Vuppugalla: Kyowa Kirin: Current Employment. Tudor: Kyowa Kirin: Current Employment. Dwyer: Kyowa Kirin: Current Employment; Bristol Myers Squibb: Current Employment. Hruska: Viatris: Current equity holder in publicly-traded company; Viking: Current equity holder in publicly-traded company; Durect: Current equity holder in publicly-traded company; CymaBay: Current equity holder in publicly-traded company; Takeda: Current equity holder in publicly-traded company; Pfizer: Current equity holder in publicly-traded company; Merck: Current equity holder in publicly-traded company; Johnson & Johnson: Current equity holder in publicly-traded company; GlaxoSmithKline: Current equity holder in publicly-traded company; Genmab: Current equity holder in publicly-traded company; Gilead: Current equity holder in publicly-traded company; Biohaven: Current equity holder in publicly-traded company; AbbVie: Current equity holder in publicly-traded company; Bristol Myers Squibb: Current equity holder in publicly-traded company; Kyowa Kirin: Current Employment. Marsteller: Kyowa Kirin: Current Employment. OffLabel Disclosure: Yes. Mogamulizumab is a CCR4-directed monoclonal antibody indicated for the treatment of adult patients with relapsed or refractory mycosis fungoides or Sézary syndrome after at least one prior systemic therapy - new dosing regimen under examination.

Background: Mogamulizumab is a humanized anti-CCR4 antibody approved for the treatment of mycosis fungoides and Sézary Syndrome. Despite almost universal expression of CCR4 in these diseases, many patients eventually develop resistance to mogamulizumab (moga). The mechanisms of resistance to moga have not been characterized. An understanding of the resistance mechanisms will shed light on the disease biology and inform selection of next line therapies and the development of future CCR4-directed treatments for patients with cutaneous T cell lymphoma (CTCL). Methods: We identified 19 patients with mycosis fungoides or Sezary syndrome in whom moga had been discontinued due to lack or loss of response to therapy. Archival blood and skin and/or lymph node biopsies after discontinuation of treatment were studied. Specimens collected prior to initiation of moga were also procured whenever available. CCR4 protein expression was determined by immunohistochemistry (IHC; clone L291H4; Biolegend). Targeted sequencing was performed using the Agilent XTHS2 platform (Agilent) with a custom Agilent SureSelect panel that included full coverage of the exonic regions of CCR4. Results: Fourteen patients had Sézary syndrome and five had mycosis fungoides. Twelve patients were classified as primary refractory to treatment and the remaining seven patients had secondary resistance. Median duration of treatment with moga was 3.5 months (range: 2-41). CCR4 expression was non-detectable in post-treatment specimens of 8 of 14 (57%) patients with evaluable specimens. Targeted DNA sequencing of post-treatment samples revealed novel coding mutations of CCR4 in three patients. Only one of the 3 mutations (L21V) overlapped with the known N-terminal mogamulizumab binding epitope. The other two mutations occurred in transmembrane domains (M116R, T161-W162 delinsSR). Two patients with mutations in CCR4 also had unequivocal copy number loss involving the CCR4 locus. Acquisition of CCR4 genomic alterations corresponded with lack of CCR4 expression by immunohistochemistry. In-vitro validation of the novel CCR4 mutations is ongoing and results from these experiments will be included in the final presentation. Conclusion: Overall our study indicates that potential loss of CCR4 expression, with or without underlying genomic aberrations, represents a major hurdle in the development of future CCR4 targeting strategies in CTCL. This finding has important implications for management and monitoring of cutaneous T cell lymphoma patients receiving CCR4 directed therapies. Disclosures Beygi: Kite/Gilead: Current Employment. Kim: Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; CRISPR: Research Funding; Eisai: Research Funding; Soligenix: Research Funding; Portola: Membership on an entity's Board of Directors or advisory committees, Research Funding; Elorac: Research Funding; Galderma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; Corvus: Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Kirin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Secura Bio: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion, AstraZeneca Rare Disease: Other: Study investigator; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon: Research Funding. Khodadoust: Alexion, AstraZeneca Rare Disease: Other: Study investigator; Myeloid Therapeutics: Membership on an entity's Board of Directors or advisory committees; CRISPR Therapeutics, Nutcracker Therapeutics: Research Funding.

Introduction: Adult T-cell leukemia/lymphoma (ATL) is an aggressive peripheral T-cell lymphoma caused by human T-cell lymphotropic virus type I. In younger patients, allogeneic hematopoietic stem cell transplantation (HSCT) has been shown to improve prognosis through a graft-versus-ATL (GvATL) effect. On the other hand, elderly patients with ATL are often not amenable to HSCT, and the prognosis is extremely poor with existing chemotherapy. The most widely used chemotherapy for ATL, CHOP (combination of cyclophosphamide-doxorubicin-vincristine-prednisone) and similar chemotherapy, have shown a complete response (CR) rate of about 20% and a long-term prognosis of less than 10%. In a phase II study of mogamulizumab, a humanized defucosylated anti-C-C chemokine receptor 4 monoclonal antibody, in concurrent combination with chemotherapy (mLSG15), the primary endpoint of CR was 52% in the mLSG15 + mogamulizumab group compared to 33% in the mLSG15 alone group. However, no improvement was observed in overall survival (OS) or progression-free survival (PFS). In addition, mLSG15 is a potent chemotherapy and not feasible in majority of elderly patients. Considering the possibility that mogamulizumab may unlock the tumor immune evasion mechanism by removing regulatory T cells and exert an immunological effect like GvATL, we investigated its usefulness as an immunological consolidation therapy following chemotherapy, with the aim of suppressing recurrence. Methods: New-onset treatment-naive ATL patients who were not eligible to HSCT received 3 courses of CHOP (combination of cyclophosphamide div 750 mg/m 2/day1, doxorubicin iv 50 mg/m 2/day1, vincristine iv 1.4 mg/m 2/day1 [max. 2.0 mg/body, and prednisone po/iv 100 mg/body/day1-5) at 21-day intervals, and then the first course of mogamulizumab (1 mg/kg for 8 doses at 2-week intervals) was initiated between the start of the third course of CHOP-21 and day 42. The primary endpoint was OS at months 12. Secondary endpoints were proportion of subjects with PFS, OS, overall response rate (ORR), organ-specific response rate, CR rate and adverse events (AEs) at month 12. Results: A total of 24 patients were enrolled and the median age was 75.5 years (range, 64-85). The median follow-up period was 11.0 (3.0-30.6) months. Five subjects discontinued study treatment before mogamulizumab administration attributable to insufficient effect (n=2), continuation deemed inappropriate (n=2), and start of the next course extended (n=1). ORR was 87.5%. Organ-specific response rates for peripheral blood, other than peripheral blood, target lesion, and skin lesion were 83.3%, 87.5%, 79.2%, and 66.7%, respectively. OS and PFS rates in the full analysis set (FAS) at months 12 were 52.6 (30.9-70.4)% and 26.6 (10.9-45.3)%, respectively. The median survival time (MST) and 80% confidence interval (CI) for OS was 12.1 (5.0 -21 .0) months (Figure 1). Since the lower limit of the 80% CI was below the threshold of 6 months, this treatment was not considered to be effective. However, the point estimate of MST was 12.1 months, which was equivalent to the expected value. One possible reason for the failure to reach statistical significance could be attributable to occurrence of events in the early stage of the protocol regimen. In other words, patients who did not respond to the preceding chemotherapy did not benefit from mogamulizumab, and only patients who managed to overcome chemotherapy benefited from the immune effects of mogamulizumab, resulting in long-term survival (Figure 1). In the long-term follow-up, the MST (95% CI) of the FAS was 12.4 (4.9-21.0) months, and the median OS (95% CI) at 24 months was 25.1 (9.6-44.1) %. AEs were observed in 16 subjects, of which serious AEs (grade 4/5) were observed in 5 subjects (acute respiratory distress syndrome, ventricular fibrillation, heart failure, hyponatremia, and pneumonia). Largely, AEs were resolved/recovered in 14 subjects including 3 subjects with serious AE; 2 subjects resulted in death, which were not considered treatment-related. Conclusions: Mogamulizumab as an immunological consolidation therapy after CHOP 21 might be one of the treatment options for transplant-ineligible elderly patients with previously-untreated ATL, despite not clearly showing improved OS. Further studies are warranted to examine the dosing timing of mogamulizumab to obtain its maximum benefit for prolonged survival. Figure 1 Figure 1. Disclosures Kato: Abbvie: Consultancy, Research Funding; AstraZeneca: Consultancy; Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Dainippon-Sumitomo: Honoraria; Eisai: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; MSD: Honoraria; Mundi: Honoraria; Novartis: Consultancy, Research Funding; Ono: Honoraria, Research Funding. Suzuki: Kyowa-kirin: Honoraria, Research Funding, Speakers Bureau; Chugai: Honoraria, Research Funding, Speakers Bureau; Taiho: Research Funding; Ohtsuka: Honoraria, Research Funding; Takeda: Research Funding, Speakers Bureau; Shionogi: Research Funding; Eisai: Honoraria, Research Funding; Bristol-Meyer Squib: Honoraria; MSD: Honoraria; Janssen: Honoraria; Abbvie: Speakers Bureau; Meiji Seika: Honoraria, Speakers Bureau; Ohtsuka: Honoraria. Akashi: Sumitomo Dainippon Pharma: Consultancy; Kyowa Kirin: Consultancy, Research Funding; Celgene: Research Funding; Astellas Pharma: Research Funding; Shionogi: Research Funding; Asahi Kasei Pharma: Research Funding; Chugai: Research Funding; Bristol-Myers Squibb: Research Funding.

Background: IL-21 expanded NK cells have high expression of CD16 and have demonstrated antibody-dependent cell-mediated cytotoxicity (ADCC) activity in combination with monoclonal antitumor antibodies (mAb). Mogamulizumab (moga) is a mAb targeting CCR4 that is defucosylated to enhance its binding to CD16, thereby enhancing ADCC of NK cells against targets expressing CCR4. We designed a pilot phase I clinical trial studying this combination in patients with relapsed/refractory (r/r) CTCL and ATLL. The study is soon opening to accrual at the OSU James Cancer Center (NCT04848064). Study is conduced under IND 26888. Preclinical data: Allogeneic NK cells obtained from buffy coat (Red Cross Blood Bank), were expanded for 14 days on CSTX002 feeder cells, cryopreserved, and then thawed and recovered for 48 hours prior to testing. Malignant T-cells were incubated with moga (at 10ng/µl) for 30 minutes prior to co-culture with NK cells and cytotoxicity was determined by the calcein release assay (Somanchi et al, J Vis Exp 2011). Malignant T-cells were obtained from peripheral blood from 3 patients with multiply relapsed CTCL and all have circulating Sezary cells and from CCRF-CEM cell line (T-ALL cell line that expresses CCR4). No significant cytotoxicity was observed with moga alone and significant synergy in cytotoxicity was observed between and moga and NK cells in all 3 patient samples and also CCRF-CEM cell line (figure 1: A and B). Two-fold increase in ADCC was observed with addition of moga to NK cells (p=0.0272; figure 1C) Design: Patients will receive lymphodepleting chemotherapy (Fludarabine/Cyclophosphamide) on days -5 to -3 prior to cell infusion, moga weekly for 4 doses starting on day -7 (prior to the first NK cell infusion) and then every 2 weeks until toxicity or progression. Patients will receive third-party ideal-donor mbIL-21 expanded NK cells once every 2 weeks for 6 total doses (Figure 1D). Donors meeting ideal-donor characteristics from National Marrow Donor Program were identified in collaboration with Be The Match Biotherapies. PBMNC were collected by apheresis, CD3-depleted, expanded for 14 days as previously described, and cryopreserved in ready-to-infuse aliquots. NK cells will be thawed and infused in 2 dosing cohorts; 3x10 7 and 1x10 8 cells/kg in a standard dose-escalation design. Primary endpoint is the maximum tolerated dose of NK cells given in combination with standard-dose moga. Dose-limiting toxicity (DLT) is defined as any steroid refractory graft vs host disease (GVHD), severe NK cell-related toxicities, or other unusual events occurring from D-7 until D+84 post last dose of NK cells. Dose-escalation will proceed in the standard 3+3 fashion. Secondary endpoints include overall response rate (ORR) per ISCL/USCLC/EORTC consensus panel, for CTCL, and international consensus panel, for ATLL and progression-free and overall survival. Correlative endpoints include quality of life impact as captured by Skindex-16 score, serum cytokine levels in blood, persistence of NK cells by chimerism studies, correlation between CCR4 staining of tumor cells in skin and trafficking of NK cells to skin by immunohistochemistry or immunofluorescence in serial skin biopsies and ORR (Figure 1D). Abbreviated eligibility: Eligible patients will be 18 years, or older, with biopsy-proven, measurable, stage IB-IVB relapsed or refractory CTCL or ATLL, progressing on at least one standard chemotherapy. Other eligibility criteria include: ECOG performance status of ≤ 1, no systemic anti-neoplastic therapy within a week or 3 half-lives, adequate laboratory parameters including: absolute neutrophil count ≥1000/mm³, platelet count ≥50,000/mm³, total bilirubin ≤ 2 x upper limit of normal (ULN), AST/ALT ≤ 3 x ULN or ≤ 5 x ULN in patients with documented hepatic involvement by lymphoma, and calculated creatinine clearance ≥ 50 ml/min., disease free of prior malignancies for ≥ 2 years with exception of treated basal cell, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix or breast and life expectancy ≥ 90 days. Patients who were pre-treated with moga, pregnant, HIV positive, with active hepatitis B and C, active CNS involvement, active grade II-IV acute or extensive chronic GVHD or other serious medical comorbid conditions are excluded. Figure 1 Figure 1. Disclosures William: Kyowa Kirin: Consultancy; Incyte: Research Funding; Merck: Research Funding; Dova Pharmaceuticals: Research Funding; Guidepoint Global: Consultancy. de Lima: Miltenyi Biotec: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Devine: Be the Match: Current Employment; Johnsonand Johnson: Consultancy, Research Funding; Orca Bio: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Magenta Therapeutics: Current Employment, Research Funding; Tmunity: Current Employment, Research Funding; Vor Bio: Research Funding; Kiadis: Consultancy, Research Funding. Vasu: Boehringer Ingelheim: Other: Travel support; Seattle Genetics: Other: travel support; Kiadis, Inc.: Research Funding; Omeros, Inc.: Membership on an entity's Board of Directors or advisory committees. Lee: Courier Therapeutics: Current holder of individual stocks in a privately-held company; Kiadis Pharma: Divested equity in a private or publicly-traded company in the past 24 months, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. OffLabel Disclosure: Will discuss combination of mogamulizumab and NK cells in a context of a clinical trial

Background MAVORIC was a phase 3, open-label, multi-center, randomized controlled trial that evaluated the safety and efficacy of mogamulizumab compared with vorinostat in patients with relapsed/refractory mycosis fungoides (MF) or Sézary syndrome (SS) (NCT01728805). Mogamulizumab-associated rash was the second most common TEAE of any cause or grade in the mogamulizumab treatment arm and the most common TEAE leading to treatment discontinuation, resulting in a discontinuation rate of 7% (13/184). Grade 1-2 and 3 drug rashes occurred in 20% (36/184) and 4% (8/184) of mogamulizumab-treated patients, respectively. The objectives of this analysis were to describe histopathological and other characteristics of drug rash in patients who received mogamulizumab in MAVORIC. Methods In MAVORIC, 372 patients were randomized 1:1 to receive either intravenous mogamulizumab at 1.0 mg/kg once weekly for Cycle 1 (28 days) and then on days 1 and 15 of subsequent cycles or oral vorinostat at 400 mg daily. Confirmed overall response rate (ORR; complete response + partial response) was based on a global composite response involving all four disease compartments and verified at two consecutive visits. Guidance to investigators was provided in the protocol for evaluation and management of new drug rash on mogamulizumab treatment. Patients with an initial Grade 1 drug rash were allowed to continue treatment with use of topical steroids as needed. For patients with Grade ≥2 drug rash, mogamulizumab was temporarily stopped, and treatment of the drug rash with topical steroids was advised. Use of systemic steroids was prohibited during the study. Treatment could resume if the drug rash resolved to Grade ≤1 within 2 weeks. Biopsies were evaluated by an on-site pathologist, and a central blinded review was also conducted. Results This analysis included 44 patients who were treated with mogamulizumab and experienced drug rash during MAVORIC. Pathologically, central review assessed rashes as granulomatous, histiocytic spongiotic, lichenoid, eosinophilic, psoriasiform, or a combination of these patterns with no clear predominant histological pattern. Among the 44 patients with drug rash, 59.1% (26/44) were ≥65 years of age, and more patients with SS [56.8 (25/44)] than MF [43.2% (19/44]) experienced drug rash. Median (Q1, Q3) exposure among patients with drug rash was 344 days (162, 652) in patients with SS and 185 days (85, 463) in patients with MF. Mogamulizumab did not result in any cases of anaphylaxis or SJS/toxic epidermal necrolysis (TEN). Concomitant or immediate prior CTCL therapies that may make patients prone to drug rash were examined, and no trend toward increased incidence of drug rash was observed with any particular agent or class. The proportion of SS responders with drug rash was significantly higher than responders without rash (P=0.02; Figure 1); the proportion of MF responders with drug rash did not differ from responders without rash (P=0.21). Overall, the median (Q1, Q3) time to onset of drug rash was 106 days (36, 254). Initial drug rash occurred after response to mogamulizumab in 70% (14/20) of patients who experienced both. Thirty-five patients (80%) in the drug rash cohort resumed treatment with mogamulizumab upon resolution of initial drug rash per-protocol. After these patients resumed treatment, the median (Q1, Q3) duration of exposure to mogamulizumab was 183 days (58, 332). Conclusions Mogamulizumab-associated rashes displayed heterogeneous histopathology without one predominant feature; therefore, close correlation of suspected drug rash with clinical features is advised to differentiate it from disease progression. A trend toward higher rate of drug rash was observed in patients with SS, the group more likely to respond to mogamulizumab. Therefore, drug rash may be attributable to increased exposure, but rash may also involve underlying disease characteristics or treatment-induced immune alterations; further investigations are warranted. Nevertheless, the observation that 80% of patients on trial were able to continue mogamulizumab for >6 months following resolution of their initial rash suggests that appropriate evaluation, identification, and management of these reactions may prevent premature discontinuation. Disclosures Musiek: Kyowa Kirin: Honoraria; Helsinn: Honoraria; miRagen: Other: Investigator; Elorac: Other: Investigator; Soligenix: Other: Investigator. Horwitz:ASTEX: Consultancy; Affirmed: Consultancy; Vividion Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Corvus: Consultancy; Innate Pharma: Consultancy; Mundipharma: Consultancy; Portola: Consultancy, Research Funding; Beigene: Consultancy; C4 Therapeutics: Consultancy; Daiichi Sankyo: Research Funding; GlaxoSmithKline: Consultancy; Janssen: Consultancy; ADCT Therapeutics: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Kura Oncology: Consultancy; Miragen: Consultancy; Myeloid Therapeutics: Consultancy; Aileron: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Bagot:Helsinn/Recordati: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin: 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. Huen:Kyowa Kirin: 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, Research Funding; GlaxoSmithKline: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Galderma: Other: Travel expense reimbursement, Research Funding; miRagen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Helsinn: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Research Funding; Rhizen: Consultancy, Research Funding. Fisher:Dana-Farber Cancer Institute: Current Employment; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees. Haun:Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees; Karger, Inc.: Patents & Royalties: Textbook royalties. Vermeer:Kyowa Kirin: Consultancy, Research Funding; Takeda: Research Funding; PIQUR: Research Funding; Innate Pharma: Consultancy. Ito:Kyowa Kirin Pharmaceutical Development, Inc.: Current Employment. Dwyer:Kyowa Kirin Pharmaceutical Development, Inc.: Current Employment. Herr:Kyowa Kirin, Inc.: Current Employment. Kim:Elorac: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Corvus: Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees; Kyowa-Kirin Pharma: Research Funding; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Research Funding; Galderma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon Pharma: Consultancy, Research Funding; miRagen: Research Funding; Merck: Research Funding; Solingenix: Research Funding; Trillium: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Neumedicine: Consultancy, Research Funding; Portola: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Introduction: Mogamulizumab is a humanized monoclonal antibody against CCR4 (CC chemokine receptor 4), which is frequently expressed on certain T-cell malignancies such as adult T-cell leukemia-lymphoma (ATL), peripheral T-cell lymphoma (PTCL), and cutaneous T-cell lymphoma (CTCL), and in addition, on normal immune T-cells such as regulatory T-cells (Tregs). Mogamulizumab is approved as monotherapy in Japan for relapsed or refractory CCR4-positive ATL, PTCL, and CTCL, and in the United States for adult patients (pts) with relapsed or refractory mycosis fungoides (MF) and Sézary syndrome (SS) - two subtypes of CTCL - after ≥1 prior systemic therapy. Based on retrospective analysis of ATL pts in Japan, evidence suggests that a shorter interval ( Methods: A review of clinical trial pts in the West identified two pts from the open-label, phase 3, randomized controlled MAVORIC trial (ClinicalTrials.gov number: NCT01728805), which compared treatment with mogamulizumab to vorinostat in patients with relapsed or refractory MF/SS; crossover was allowed from the vorinostat to the mogamulizumab treatment arm upon progressive disease or intolerable toxicity. A third pt was identified from an open-label, single-arm phase 2 trial for previously treated PTCL (NCT01611142) in patients with relapsed or refractory CCR4-positive PTCL. In both studies, pts received mogamulizumab 1.0 mg/kg intravenously (IV) on a weekly basis for the first 28-day cycle, then on days 1 and 15 of subsequent cycles. Results: Pts were 49, 61, and 22 years of age with MF, MF/SS, and PTCL, respectively (Table). All pts had received at least 1 prior systemic treatment regimen for their disease. The last dose of mogamulizumab was administered 54, 17, and 45 days prior to allo-HSCT, respectively. Post-transplant, all three pts experienced at least one occurrence of GVHD, both steroid refractory and responsive, with grades ranging from 1 to 4 in the skin, abdomen, colon, and eye. The pts with MF and SS were alive at 1399 days and 1187 days post-transplant, respectively. The pt with PTCL died on day 330 post-transplant. Conclusions: This is the first published case study report to describe three pts with non-ATL T-cell malignancies who received mogamulizumab approximately 50 days or less prior to allo-HSCT and who experienced varying types and severity of GVHD. Two pts with MF/SS-type CTCL, who received mogamulizumab within 55 days of transplant, survived ≥1187 days. Further research is needed to understand the efficacy, safety, and appropriate timing of mogamulizumab prior to allo-HSCT in pts with T-cell malignancies. Disclosures Lechowicz: Kyowa Kirin Inc: Consultancy; Spectrum: Consultancy. Leoni:Kyowa Kirin Pharmaceutical Development, Inc.: Employment. Tabachri:Kyowa Kirin Pharmaceutical Development, Inc.: Employment. Herr:Kyowa Kirin, Inc.: Employment. Lamar:Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy.

Introduction: Mogamulizumab (Mog) is an anti-CCR4 (C-C motif chemokine receptor 4) antibody, which induce antibody dependent cellular cytotoxicity against cells expressing CCR4. Administration of Mog before allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with adult T-cell leukemia/lymphoma (ATL) is considered to raise the risk of graft versus host disease (GVHD). Since not only ATL cells but regulatory T cells (Tregs) express CCR4, both are targeted by Mog. Tregs play a crucial role in maintaining and suppressing excessive immune responses especially in GVHD, and the depletion of Tregs by Mog is considered to result in the progression of GVHD. The aim of this study is to elucidate the characteristics of GVHD observed in patients treated by Mog, and further tried to predict the risk of GVHD by incorporating the information of serum concentration of Mog, the number of Tregs, and the alteration in Treg fractions (naïve/resting Treg; nTreg, effector Treg; eTreg). Patients and Methods: In this study, we analyzed 25 ATL patients who received allo-HSCT. The serum concentration of Mog was measured by SRL Medisearch (Tokyo, Japan). The fraction of Tregs in peripheral blood mononuclear cells (PBMNCs) were analyzed by flow cytometry (BD FACSCalibur, BD biosciences). Statistical analysis (the cumulative incidence of Grade II-IV GVHD and the number of Tregs) were performed with EZR (Easy R) software (Jichi Medical University, Saitama, Japan). Results: In comparison to allo-HSCT without Mog (Mog-, n=14), the risk of Grade II-IV GVHD was increased in the allo-HSCT with Mog (Mog+, n=11). Stage 3 or more skin GVHD was observed in 4 patients of Mog+ (36 %) and 1 patient of Mog- (7 %), respectively. Notably, stage 3 or more gut GVHD was observed in 6 patients of Mog+ (54 %), and 4 patients died with GVHD or infectious complications, whereas 3 Mog- (21 %) experienced non-fatal gut GVHD. Moreover, cytomegalovirus enteritis was observed only in the Mog+ cases. Mog was detectable in serum for approximately 6 months after the last administration (cut off level; 5.0 ng/ml), and the number of Tregs, especially eTreg (Foxp3 high, CD45RA low) was continuously suppressed during this period. In the Mog+ case, the number of eTregs recovered 180 days after allo-HSCT in most cases. Among 7 patients who received Mog before allo-HSCT, 5 patients who developed gut GVHD were performed allo-HSCT on average 52 (19-87) days after the last administration of Mog. The serum level of Mog was 100-1000 ng/ml in the period, and this concentration of Mog was considered to be critical for the onset of severe GVHD. Conclusion: Use of mogamulizumab before allo-HSCT for ATL patient is a significant risk for severe GVHD, especially gut GVHD. Although the number of patients in this study is limited, our results suggest that the serum concentration of mogamulizumab (≥10 ng/ml) and the number of eTregs in PB at the time of allo-HSCT may enable to predict the risk of developing GVHD. Disclosures Yoshimitsu: Sanofi: Speakers Bureau; Chugai: Speakers Bureau; Takeda: Speakers Bureau; Bristol-Myer-Squibb,: Speakers Bureau; Shire: Speakers Bureau; Novartis: Speakers Bureau. Ishitsuka:Daiichi Sankyo: Consultancy, Honoraria; Alexion: Honoraria; Kyowa Hakko Kirin: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Otsuka Pharmaceutical: Honoraria; Eisai: Honoraria, Research Funding; MSD: Research Funding; Asahi kasei: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria, Research Funding; mundiharma: Honoraria; MSD: Research Funding; Celgene: Honoraria; Shire: Honoraria; Mochida: Honoraria, Research Funding; Sumitomo Dainippon Pharma: Honoraria, Research Funding; Eli Lilly: Research Funding; Genzyme: Honoraria; sanofi: Honoraria; Bristol-Myers Squibb: Honoraria; sanofi: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Genzyme: Honoraria; Alexion: Honoraria; Takeda Pharmaceutical: Honoraria, Research Funding; Sumitomo Dainippon Pharma: Honoraria, Research Funding; mundiharma: Honoraria; Eisai: Honoraria, Research Funding; Taiho Pharmaceutical: Honoraria, Research Funding; Mochida: Honoraria, Research Funding; Janssen Pharmaceutical: Honoraria; Shire: Honoraria; Otsuka Pharmaceutical: Honoraria; Novartis: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Teijin Pharma: Research Funding; Pfizer: Honoraria; Yakult: Research Funding; Astellas Pharma: Honoraria, Research Funding; Asahi kasei: Research Funding; Eli Lilly: Research Funding; Janssen Pharmaceutical: Honoraria; Celgene: Honoraria; Teijin Pharma: Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Taiho Pharmaceutical: Honoraria, Research Funding; Yakult: Research Funding.

Introduction: Adult T-cell leukemia/lymphoma (ATLL) is a rare and quite refractory peripheral T-cell lymphoma. The human T-lymphotropic virus type 1 (HTLV-1) retrovirus causes ATLL. Tax protein produced by HTLV-1 has oncogenic activities, and its peptides can be recognized as tumor antigens by the host immune system. Therefore, some immunological approaches to treat ATLL are effective. Mogamulizumab (Moga), an anti-CCR4 monoclonal antibody, and lenalidomide, an immunomodulator, have been recently approved for newly diagnosed and/or relapsed/refractory aggressive ATLL in Japan. However, to date, satisfactory treatment results have not been obtained with these drugs. Before approval of Moga and lenalidomide, VCAP-AMP-VECP (mLSG15) therapy was one of the standard combination chemotherapies for aggressive ATLL. A randomized phase II study comparing Moga plus mLSG15 and mLSG15 alone showed a higher %CR in Moga plus mLSG15 arm but no significant difference in overall survival (OS) between the two arms. In this study, we compared the outcomes of Moga plus EPOCH with those of Moga plus mLSG15. Methods: Aggressive ATLL patients, who were ineligible for hematopoietic stem cell transplantation (HSCT) and were newly diagnosed after June 2000 in our hospital, were retrospectively analyzed. Results: Table 1 summarizes the patient characteristics. Twenty-two patients were treated with Moga plus EPOCH, and 16 were treated with Moga plus mLSG15. There was no significant difference in gender and disease subtype between the groups. Moga-induced skin disorders, such as rash and erythema, were observed in 14 (64%) patients treated with Moga plus EPOCH group and 9 (56%) patients treated within Moga plus mLSG15; the difference was not significant. Figure 1 shows OS of both groups. There was no significant difference (P=0.3092), but a 30% risk reduction was observed in the Moga plus EPOCH group (hazard ratio [HR]: 0.6859, 95% confidence interval [CI]: 0.3165−1.430), though patients treated with Moga plus EPOCH were significantly older than those treated with Moga plus mLSG15 (Table 1). Figure 2 shows OS of patients with and without Moga-induced skin disorders in both groups. The OS of patients with skin disorders was significantly greater than that of those without skin disorders (P Conclusion: Improved OS was observed more frequently in the Moga plus EPOCH group than in the Moga plus mLSG15 group. However, to date, Moga plus chemotherapy has not shown a significant impact on OS for newly diagnosed aggressive ATLL patients in non-HSCT settings, except for patients with Moga-induced skin disorders. Elevation of the Tax-specific CTL percentage was observed in some patients with Moga-induced skin disorders. We previously reported in the 2014 ASH annual meeting that several aggressive ATLL patients, who obtained long-time survival using chemotherapy alone, had maintained Tax-specific CTLs for long periods. Therefore, it might be necessary to induce, up-regulate, and maintain ATLL-specific CTLs to obtain long-time survival. Moga is useful, but insufficient, for inducing such CTLs by suppressing regulatory T-cells. No effective method is available to activate an ATLL-specific cellular immune response. Further studies are urgently needed to establish effective methods for attaining ATLL-specific CTLs. Disclosures No relevant conflicts of interest to declare.

Introduction There have been few recent therapeutic advances in T-acute lymphoblastic leukemia/lymphoma (T-ALL/LBL), a rare and aggressive malignancy. Intensive chemotherapy +/- allogeneic transplantation (AlloHCT) can effect cure, realized by only a minority of adults. In distinction to B-ALL, there have been no safe/effective targeted therapies developed in T-ALL/LBL. We therefore performed a focused tissue array to identify novel tumor proteins, including CCR4; evaluated together with established immunophenotypic (IP) T-ALL/LBL subtypes [early-T-precursor (ETP), early non-ETP (Pre/Pro-T), common & late thymocyte]. We evaluated the clinical phenotype and outcome together with clinical and epidemiologic data in patients diagnosed at the 3-site Mayo Clinic Cancer Center (MCCC: Rochester, MN; Phoenix, AZ; and Jacksonville, FL). Methods Following IRB approval, we identified 50 consecutive T-ALL/LBL patients from 1997 -2019 diagnosed at the 3-site MCCC. Available remnant leukemia/lymphoma paraffin blocks were identified (n=28). Using immunohistochemistry (IHC) we evaluated expression of leukemic antigens of interest (CCR4, CD47, BCL2, BCL6, PD-L1, CD38 and CD123); these were selected based on clinical availability of novel targeted agents, approved or in development for other indications. Tissue array studies were performed and interpreted by a single hematopathologist (L.J) blinded to clinical data, using positive and negative controls, according to standard techniques. We also evaluated the clinical and epidemiological parameters, including different IP subtypes [ETP: CD1a-, sCD3- & CD8-, Pre/Pro-T: CD1a-, sCD3- & CD8+ or CD8- (11 marker T-ALL IP score was used to distinguish CD8- ETP vs. Pre/Pro-T), thymic: CD1a+ and mature: CD1a- & sCD3+] (Khogeer et al., Br J Haematol., 2019) & the presence of the unique MLLT10-PICALM fusion (n=6), as well as therapy and outcome. Comparisons of characteristics and outcomes of interest were made using a Wilcoxon rank sum test (continuous characteristics) or Fisher's exact test (categorical characteristics), unadjusted Cox proportional hazards regression models (overall survival), or unadjusted logistic regression models (complete remission after first line treatment). Results We identified the expression of novel targetable tissue proteins in all adult T-ALL/LBL cases [Table 1]. BCL2, CD38 & CD47 were expressed in majority of the cases, and CCR4 [Fig. 1] was expressed in 11/28 (39.3%) cases. CCR4 expression was significantly more common in the Pre/Pro-T (75%) vs. other IP subtypes (19%) (p=0.011); there was no other association of CCR4 expression with clinical characteristics/outcomes. We also observed differences in T-ALL vs. T-LBL, specifically T-ALL patients were more likely to be male (71% vs. LBL 38.9%, p=0.038). Surprisingly, T-LBL patients were more likely to have a family history of leukemia/lymphoma (41.2% vs. T-ALL 0%, p In contrast, we observed an important association of IP subtype with outcome after therapy, including complete remission (p=0.035), & a trend suggesting differences in survival (p=0.069) [Table 3]. However, MLLT10-PICALM was not associated with any unique clinical features or with outcome (death, p=0.85; CR, p=0.98), although 4/6 patients underwent AlloHCT, suggesting an important role of AlloHCT in this subgroup. No other significant association of epidemiologic risk factors with phenotype or outcome was noted. Conclusion Using focused tissue array we have identified expression of tumor associated proteins in T-ALL/LBL including CCR4 (Pre/Pro-T IP) & others, which may be targets of therapeutic agents like mogamulizumab. Furthermore, our analysis demonstrates an important clinical impact of IP subtype in T-ALL/LBL, as well as important clinical & therapeutic differences in T-ALL vs. LBL. This study will help guide development of targeted clinical trials in T-ALL/LBL (CCR4 trial already in development). Further analyses are planned to determine the clinical & epidemiologic association of genetic lesions in this cohort. Disclosures Foran: Agios: Honoraria, Research Funding.

Introduction: Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common types of cutaneous T-cell lymphoma (CTCL). Incidence rates for CTCL are higher in blacks than Caucasians (9.0 vs 6.4 cases per million persons). Retrospective studies suggest that black patients with CTCL present with younger age at diagnosis, lower male to female ratio, higher cutaneous disease burden, and inferior survival (Nath S, et al. Clin Lym Myel Leuk 2014). Prospective data on treatment outcomes in this patient subset are rare. Mogamulizumab, an anti-CCR4 monoclonal antibody, was recently FDA approved for relapsed/refractory (R/R) MF and SS with improved response rates and progression-free survival (PFS) vs comparator vorinostat. Here we report the clinical characteristics and outcomes of black patients treated in the MAVORIC trial with a specific focus on responses to mogamulizumab. Methods: The MAVORIC trial was an international, open-label, randomized phase 3 trial comparing mogamulizumab vs vorinostat in R/R MF/SS. Complete study design and results were recently published (Kim YH, et al. Lancet Oncol 2018). Patients were randomized 1:1 and stratified by both clinical stage (IB-II vs III-IV) and disease type (MF vs SS). The primary endpoint was PFS, based on investigator assessment. Key secondary endpoints included overall response rate (ORR), duration of response, response by compartment (blood, skin, nodal, and visceral). We conducted a subset analysis on black vs non-black patients who were enrolled in the intention-to-treat population (ITT). Results: 372 patients were enrolled of which 37 (10%) self-identified as black. Compared to non-black patients (N=335), the median age was younger (53 vs 66 years). Twenty-one (56.8%) were male, similar to 58.2% in non-black patients. Skin stage distribution in the black patients was: T1, N=0; T2, N=18 (48.6%); T3, N=4 (10.8%); and T4, N=15 (40.5%). Twenty-seven (73%) had blood involvement and 32 (86.5%) had lymphadenopathy. A greater fraction of the randomized black patients had MF compared to non-black (73% vs 52.8%); the opposite was true for SS (27% vs 47.2%). More black patients were randomized to mogamulizumab (N=24) than vorinostat (N=13). Median exposure to mogamulizumab was 170 days for all populations analyzed (black, non-black, and ITT). Instead median exposure to vorinostat was longer in black vs non-black patients (105 vs 83 days), and in blacks vs ITT (105 vs 84 days). Nearly two thirds (61.5%) of black patients randomized to vorinostat crossed over to mogamulizumab, slightly less than in the ITT population (73%). Median follow-up for black patients and for the entire MAVORIC cohort were 20.8 months and 17 months, respectively. In the ITT cohort, PFS was superior in patients randomized to mogamulizumab vs vorinostat (7.7 vs 3.1 months; HR 0.53; P Conclusion: These results support mogamulizumab as an effective treatment for MF/SS in black patients with similar PFS and ORR, including by disease compartments (blood and skin) and responses by disease type (MF or SS), as non-black patients. Safety signals for black vs non-black patients were similar with mogamulizumab, including drug eruptions. Figure Disclosures Porcu: Viracta: Honoraria, Other: Scientific Board, Research Funding; Kyowa: Honoraria, Other: Scientific Board, Research Funding; Innate Pharma: Honoraria, Other: Scientific Board, Research Funding; Daiichi: Research Funding; BeiGene: Other: Scientific Board, Research Funding; Incyte: Research Funding; Spectrum: Consultancy; ADCT: Research Funding.

Background: The acute and lymphoma subtypes Human T-lymphotropic virus 1-associated adult T-cell leukemia/lymphoma (HTLV-1 ATLL) are frequently characterized by chemo-refractoriness, a generally aggressive clinical course, and poor outcomes. Despite progress in characterizing the disease biology and the development and implementation of newer agents such as mogamulizumab, survival remains poor, especially for patients with relapsed or refractory disease. Furthermore, besides these many challenges, there is a paucity of comprehensive published data in Western (i.e. non-Japanese) patients. Methods: In a retrospective analysis, we identified 109 patients with pathologically-confirmed ATLL evaluated at our institution since 2001. 11 were excluded due to lack of clinical follow-up. Patient, disease, and treatment information was extracted for analysis. The International Prognostic Index (IPI) and Prognostic Index for PTCL-U (PIT) were calculated at time of diagnosis. Response rate was calculated based on the best response (CR/PR) during induction, with response retrospectively assessed based on available data using Lugano criteria. Median survival was calculated using Kaplan-Meier analysis and follow-up using a reverse Kaplan-Meier method, with survival and follow-up as of July 2019 Results: Ninety eight patients were included in our cohort (Table 1); 46 patients (47%) received initial treatment at another institution. The most common ATLL subtypes were lymphoma (n=43, 44%) acute (n=39, 40%), and smoldering/chronic (n=16, 16%). The median age at diagnosis was 53 years (range 30-92) and the median duration of follow-up from diagnosis was 65 months (95% CI: 41 to 178). With a median follow-up in survivors of 41.2 months, 21 patients are alive. The most common cause of death was disease (69/77 patients, 90%). The median overall survival (OS) among all patients was 13.2 months (Figure 1; range 1.3-240). For acute/lymphoma subtype disease, most patients initially received EPOCH/CHOEP (54 patients), CHOP (18 patients), or BV-CHP (3 patients); practice patterns evolved since the late 2000's to include more etoposide and BV-CHP rather than CHOP. Among 76 patients with lymphoma/acute with reviewable restaging information, 30 (40%) achieved CR. For patients with active disease following induction, a variety of subsequent therapies were used, most commonly romidepsin and pralatrexate, each utilized in 15 patients. Of 68 patients considered for transplant (55 saw a transplant physician, 13 had HLA typing sent), 23 patients ultimately underwent transplant, including 5 autologous and 18 alloSCT. Among patients referred who did not undergo transplant (N = 30), the most common reason was disease-related (24 patients, 80%) followed by patient preference (4 patients, 13%). Since 2010, only two patients underwent autoSCT at our center: one experienced primary graft failure necessitating autologous reconstitution and another lacked suitable allograft donor. Most patients, 13/18 (72%), were in CR at time of alloSCT; 11 patients underwent transplant in first remission, 7 at subsequent timepoints. Donor and graft sources included matched related (n=6), one identical twin, matched unrelated (n=2), mismatched related (n=1), mismatched unrelated (n=2), cord blood (n=4) and haploidentical (n=2). Four patients relapsed after autoSCT, 6 patients following alloSCT, and 2 treatment-related deaths occurred post alloSCT. Progression-free and OS at median follow-up of 39.2 months among alloSCT recipients was 60.6% and 64.1%, respectively (Figure 2). Conclusions: We describe the treatment patterns and outcomes for a large series of non-Japanese patients at our center with ATLL. We confirm the poor outcomes with conventional therapy seen in other studies, with only 40% of lymphoma/leukemia subtype patients achieving CR with first-line therapy, and a median OS of 13.2 months among all patients. AlloSCT offers promise as an effective option that achieved durable long-term responses in many patients, yet its applicability is limited by chemorefractory disease. Larger studies are needed to confirm our findings and to identify effective salvage therapies to attain remission and bridge patients to alloSCT. For patients ineligible for alloSCT due to age/comorbidity, lack of suitable donor, or disease refractoriness, novel therapeutic approaches are urgently needed to improve outcomes. Disclosures Moskowitz: Bristol-Myers Squibb: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Incyte: Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Merck: Research Funding; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Incyte: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; ADC Therapeutics: Consultancy; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Cell Medica: Consultancy; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Incyte: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: 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; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Merck: Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Merck: Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Dogan:Roche: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Novartis: Consultancy. Kumar:Seattle Genetics: Research Funding. Matasar:Genentech, Inc.: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Bayer: Consultancy, Honoraria, Other; Roche: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Merck: Consultancy, Equity Ownership; Juno Therapeutics: Consultancy; Teva: Consultancy; Rocket Medical: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Other: Travel, accomodation, expenses, Research Funding; Daiichi Sankyo: Consultancy; GlaxoSmithKline: Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Bayer: Other: Travel, accommodation, expenses. Noy:Medscape: Honoraria; Janssen: Consultancy; Prime Oncology: Honoraria; NIH: Research Funding; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Perales:Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; NexImmune: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Medigene: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Kyte/Gilead: Research Funding; Miltenyi: 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. Zelenetz:Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees. 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; GSK: Consultancy. Horwitz:Millennium/Takeda: Consultancy, Research Funding; Affimed: Consultancy; Celgene: Consultancy, Research Funding; Kura: Consultancy; Trillium: Research Funding; Mundipharma: Consultancy; Celgene: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy; Portola: Consultancy; Kura: Consultancy; Infinity/Verastem: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Portola: Consultancy; Celgene: Consultancy, Research Funding; Portola: Consultancy; Astex: Consultancy; Seattle Genetics: Consultancy, Research Funding; Miragen: Consultancy; Miragen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Aileron: Research Funding; ADCT Therapeutics: Research Funding; Forty-Seven: Research Funding; Aileron: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Forty-Seven: Research Funding; Trillium: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Consultancy; Astex: Consultancy; Celgene: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Kura: Consultancy; Kyowa Hakko Kirin: Consultancy; Forty-Seven: Research Funding; Astex: Consultancy; Mundipharma: Consultancy; Innate Pharma: Consultancy; Trillium: Research Funding; Astex: Consultancy; Kyowa Hakko Kirin: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Affimed: Consultancy; Seattle Genetics: Consultancy, Research Funding; Aileron: Research Funding; Kyowa Hakko Kirin: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kura: Consultancy; Innate Pharma: Consultancy; Aileron: Research Funding; Innate Pharma: Consultancy; Mundipharma: Consultancy; Trillium: Research Funding; Affimed: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADCT Therapeutics: Research Funding; ADCT Therapeutics: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Miragen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Mundipharma: Consultancy; Portola: Consultancy; Forty-Seven: Research Funding; Miragen: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Affimed: Consultancy.

Introduction: Enhancer of zeste homolog 2 (EZH2) and EZH1 are alternative subunits of polycomb repressive complex 2 that catalyze the tri-methylation of lysine 27 residue of histone H3. This histone modification epigenetically regulates gene expression and may play an important role in tumor progression. Valemetostat (DS-3201) is a potent and highly specific orally bioavailable dual inhibitor of EZH2 and EZH1 demonstrating anti-tumor activity against various hematological malignancies in preclinical studies (Honma D, et al. Cancer Sci 2017; Fujita S, et al. Leukemia 2018). Valemetostat demonstrated clinical activity as a novel oral therapeutic option for both B-cell and T-cell NHLs in the interim analysis of a phase I study (Maruyama D, et al. ASH 2017). Here we report the updated results of this phase I study focusing on ATL patients. ATL is a peripheral T-cell malignancy caused by human T-cell leukemia virus type I (HTLV-1), and is divided into aggressive and indolent subtypes. Aggressive ATL has an extremely poor prognosis, with a median survival time of only 8 to 10 months (Katsuya H, et al. Blood 2015). Although conventional chemotherapeutic agents, anti-CCR4 antibody mogamulizmab, and oral immunomodulator lenalidomide have been used for treatment of aggressive ATL patients, most patients eventually become resistant to treatment. In addition, allogenic hematopoietic stem cell transplantation is not available for elderly patients. Therefore, new therapeutic options are urgently needed. Methods: This ongoing open-label, single-arm phase I study consists of the dose escalation part (NHLs including ATL and peripheral T-cell lymphoma [PTCL]) and the expansion part (ATL and PTCL). The drug was administered orally once daily (QD) continuously over 28-days (1 cycle) until disease progression or intolerance. Results: Thirty-eight patients (15 females) with a median age of 69 (44-88) were enrolled in this study as of the data cut-off of 24 January 2019. Of 38 patients, 25 patients were enrolled in the dose-escalation part, and additional 13 patients (7 ATLs and 6 PTCLs) were treated in the expansion part with 200 mg of valemetostat. In all patients, adverse events (≥30%) on treatment with all grades included; platelet count decreased (73.7%), dysgeusia (52.6%), anemia (42.1%), lymphocyte count decreased (39.5%), neutrophil count decreased (39.5%), and white blood cell count decreased (39.5%). Preliminary efficacy was based on investigator's assessment with an objective response rate (ORR) of 47.2%. Fifteen patients were able to stay on valemetostat for more than 24 weeks with tumor shrinkage. Of the 9 ATL patients in the study (2 in dose escalation and 7 in dose expansion), baseline characteristics are as follows: age, median age 74 (range 61-78 yrs); sex, 7 males and 2 females; ATL subtype, 6 acute- and 3 lymphoma-subtypes; median number of prior therapies, 2 (range 1-8). Adverse events (≥30%) on treatment with all grades in the 9 ATL patients included; platelet count decreased (77.8%), dysgeusia (66.7%), neutrophil count decreased (44.4%), white blood cell count decreased (44.4%), anemia (33.3%), alopecia (33.3%), and dry skin (33.3%). No grade 4 and 5 adverse events were detected. Grade 3 adverse events included; white blood cell count decreased (33.3%), platelet count decreased (22.2%), neutrophil count decreased (22.2%), lymphocyte count decreased (11.1%), and anemia (11.1%), which are consistent with those in all population. Responses for the 9 ATL patients included; 1 unconfirmed complete remission (CRu), 3 partial remission (PR), and 3 stable disease (SD) (ORR = 44.4%; 4/9). Of the 6 prior mogamulizumab treated patients, 3 patients demonstrated a response (ORR = 50%; 3/6). Five of 9 ATL patients continued on valemetostat treatment for more than 12 weeks with tumor shrinkage (Figure). Four ATL patients continue on treatment. The latest study results will be presented. Conclusion: The updated results of this ongoing phase I study showed that the oral EZH1/2 dual inhibitor valemetostat has demonstrated acceptable safety and promising preliminary efficacy in NHL. In addition, the results of ATL patients, including mogamulizumab pretreated patients, showed promising clinical activity. A subsequent pivotal phase II study for ATL will soon be initiated. Clinical trial information: NCT02732275 Disclosures Ishitsuka: Novartis: Honoraria, Research Funding; sanofi: Honoraria; Celgene: Honoraria; Astellas Pharma: Honoraria, Research Funding; Pfizer: Honoraria; Takeda Pharmaceutical: Honoraria, Research Funding; Janssen Pharmaceutical: Honoraria; Janssen Pharmaceutical: Honoraria; Shire: Honoraria; Eisai: Honoraria, Research Funding; Otsuka Pharmaceutical: Honoraria; Mochida: Honoraria, Research Funding; Shire: Honoraria; Teijin Pharma: Research Funding; Sumitomo Dainippon Pharma: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding; Sumitomo Dainippon Pharma: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Genzyme: Honoraria; Genzyme: Honoraria; Eisai: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Teijin Pharma: Research Funding; MSD: Research Funding; Yakult: Research Funding; Asahi kasei: Research Funding; MSD: Research Funding; Asahi kasei: Research Funding; Eli Lilly: Research Funding; Eli Lilly: Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Kyowa Hakko Kirin: Honoraria, Research Funding; mundiharma: Honoraria; Taiho Pharmaceutical: Honoraria, Research Funding; Alexion: Honoraria; Mochida: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria, Research Funding; mundiharma: Honoraria; Taiho Pharmaceutical: Honoraria, Research Funding; Otsuka Pharmaceutical: Honoraria; Ono Pharmaceutical: Honoraria, Research Funding; Yakult: Research Funding; Bristol-Myers Squibb: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Pfizer: Honoraria; Alexion: Honoraria; sanofi: Honoraria. Izutsu:Eisai, Chugai, Zenyaku: Honoraria; Chugai, Celgene, Daiichi Sankyo, Astra Zeneca, Eisai, Symbio, Ono, Bayer, Solasia, Zenyaku, Incyte, Novartis, Sanofi, HUYA Bioscience, MSD, Astellas Amgen, Abbvie, ARIAD, Takeda, Pfizer: Research Funding; Celgene: Consultancy; Eisai, Symbio, Chugai, Zenyaku: Research Funding; Kyowa Kirin, Eisai, Takeda, MSD, Chugai, Nihon Medi-physics, Janssen, Ono, Abbvie, Dainihon Sumitomo, Bayer, Astra Zeneca, HUYA Japan, Novartis, Bristol-Byers Squibb, Mundi, Otsuka, Daiichi Sankyo, Astellas, Asahi Kasei: Honoraria. Kusumoto:Chugai Pharmaceutical Co., Ltd.: Consultancy, Honoraria, Research Funding; Kyowa Kirin Co., Ltd.: Honoraria, Research Funding. Araki:Daiichi Sankyo: Employment. Adachi:Daiichi Sankyo: Employment. Yamashita:Daiichi Sankyo: Employment. Atsumi:Daiichi Sankyo: Employment. Tsukasaki:Eisai: Research Funding; Mundi Pharma: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Huya: Consultancy, Honoraria, Research Funding; Byer: Research Funding; Kyowa Kirin: Honoraria; Ono Pharmaceutical: Consultancy; Celgene: Honoraria, Research Funding; Daiichi Sankyo: Consultancy. Tobinai:Eisai: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Takeda Pharmaceutical: Consultancy, Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Zenyaku Kogyo: Consultancy, Honoraria; Meiji Seika: Honoraria; Verastem: Honoraria; Solasia: Honoraria; Janssen Pharmaceutical: Honoraria, Research Funding; Yakult: Honoraria; AbbVie: Research Funding; Ono Pharmaceutical: Consultancy, Honoraria, Research Funding; Mundi Pharma: Consultancy, Honoraria, Research Funding; HUYA Bioscience: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria.

In this issue of Blood , Narita et al demonstrate that inhibition of cyclin-dependent kinase 9 (CDK9) signaling with the novel agent BAY 1143572 abrogates proliferation and induces apoptosis of adult T-cell leukemia/lymphoma (ATL) cells in cell lines, patient samples, and in xenografts in NOG mice. 1 This makes CDK9 a potentially promising therapeutic target in ATL, a deadly disease.

Aims: Patients with the cutaneous T-cell lymphoma subtypes mycosis fungoides (MF) and Sézary syndrome (SS) often require multiple lines and types of systemic therapy. The phase 3 MAVORIC study (NCT01728805) showed that mogamulizumab (MOGA), a monoclonal antibody directed against C-C chemokine receptor 4 (CCR4), is superior to vorinostat (VORI) in median progression-free survival (PFS; 7.7 vs 3.1 months, P Methods: Patients with MF/SS who had failed ≥1 systemic therapy were randomized to MOGA 1.0 mg/kg intravenously or VORI 400 mg orally daily until disease progression or unacceptable toxicity. Confirmed ORR was based on a global composite response score in each of four disease compartments (skin, blood, lymph nodes, and viscera), achieved at two consecutive visits. PFS, ORR, and the interaction with time from treatment were assessed based on immune activity of last prior regimens, and analyzed using Cox proportional hazards and logistic regression models, respectively. Results: In total, 372 patients (median age: 64 years) were randomized (MOGA, n=186; VORI, n=186). Baseline characteristics, including number and type of prior systemic therapies, were similar between cohorts. The most common last prior systemic therapies in patients randomized to MOGA were oral bexarotene (n=46; 25%), chemotherapy (n=44; 24%), methotrexate (n=20; 11%), interferon alpha (n=17; 9%), extracorporeal photophoresis (ECP; n=16; 9%), and romidepsin (n=16; 9%). Confirmed ORRs in MOGA-treated patients after 1, 3, or ≥6 prior therapies were 25%, 35%, and 30%, respectively. Patients who crossed over to MOGA from VORI, due to progression or intolerance, had an ORR of 30%. ORR and duration of response to MOGA did not vary by last prior systemic therapy (Table). Logistic regression analyses demonstrated that neither the impact of immune activity of the last prior therapy (immune stimulatory or immunosuppressive regimens) nor the time from prior treatment had an effect on PFS or ORR observed in response to MOGA (P>0.05) Conclusions: This post hoc analysis of the MAVORIC study shows no difference in MOGA response by the number of prior systemic therapies, type, or immune activity of last prior therapy. Disclosures Zinzani: MSD: Honoraria, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau. Horwitz:Spectrum: Research Funding; Innate Pharma: Consultancy; Forty Seven: Consultancy, Research Funding; Trillium: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Kyowa-Hakka-Kirin: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Portola: Consultancy; Celgene: Consultancy, Research Funding; Mundipharma: Consultancy; Aileron Therapeutics: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Corvus: Consultancy. Kim:Medivir: Membership on an entity's Board of Directors or advisory committees; Portola: Research Funding; miRagen: Research Funding; Neumedicine: Consultancy, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Kyowa-Kirin-Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetralogic: Research Funding; Galderma: Research Funding; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon Pharma: Consultancy, Research Funding; Soligenix: Research Funding; Merck: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Research Funding. Moskowitz:ADC Therapeutics: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol Myers-Squibb: Consultancy, Research Funding; Merck: Research Funding; Incyte: Research Funding; Takeda: Honoraria. Porcu:Innate Pharma: Consultancy. Scarisbrick:National Health System, UK: Employment; Kyowa: Consultancy; Takeda: Consultancy; Helsinn: Consultancy; Actellion: Consultancy; Mallinkcrodt: Consultancy; 4SC: Consultancy; Innate Pharma: Consultancy. Leoni:Kyowa Kirin: Employment. Dwyer:Kyowa Kirin: Employment. Sun:Kyowa Kirin: Employment. Nikonova:Kyowa Kirin: Employment. Bagot:Takeda: Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin: 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; Actelion: Membership on an entity's Board of Directors or advisory committees.

Adult T-cell leukemia/lymphoma (ATLL) is highly aggressive CD4+ T cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1). Normal cellular counterpart of ATLL is considered to be CD4+Foxp3+ regulatory T cells (Tregs) and therefore ATLL cell and Treg cell show similar phenotypic characteristics including the expression of CD25, Foxp3 and CCR4. Treg is immunosuppressive cells which has a critical role to suppress GVHD after allogeneic HSCT. Humanized anti-CCR4 monoclonal body, Mogamulizumab (Mog), is used for treatment of ATLL. We recently reported that pretransplant use of Mog was significantly associated with an increased risk of GVHD-related mortality (Fuji et al, JCO 2016). Since Tregs also express CCR4, the negative impact of Mog on transplantation tolerance was assumed to be a result from poor Treg recovery under the presence of Mog. However, it has not been well studied the interactional association of the sequential Mog concentration, the recovery of Tregs and the transition of residual ATLL cells after allogeneic HSCT in patients with peri-transplant administration of Mog. To tackle this issue, we here studied the clinical and laboratory sequences of patients who received Mog administration to control chemo-refractory ATLL in the peri-transplant period, as comparing patients without Mog treatment. Peripheral blood samples were obtained before and at 2, 4, 6, 8, and 12 weeks after HSCT and thereafter every 3 months. Total 7 patients were studied; 3 patients who received Mog before SCT, 1 patient who received Mog after SCT to treat early relapse of ATLL and 2 patients who did not received Mog. Tregs were defined as CD4+CD7+CADM1-CD25+CD127- and ATLL cells were defined as CD4+CD7-CADM1+, and these were compared with CD4+ conventional T cells (Tcons) in the same individual samples. Gated Tregs and ATLL cells were examined the expression of Foxp3, Helios, CCR4, CD45RA, CD31, Ki-67, BCL2, PD-1 and PD-L1. Mog concentrations in plasma were measured by ELISA. Plasma levels of TARC/CCL17 and MDC/CCL22, endogenous ligands of CCR4, were also measured. Our data indicated that peak levels of Mog were basically dependent of total administrated dose and residual ATLL cells were promptly reduced in blood. After the final dose of Mog, Mog levels were gradually declined (average of estimated half-life was 11.2 days). Shorter clearance rate was observed in a patient with high tumor burden (half-life 5.2 days) and in a patient received plasma exchange (half-life 8.4 days). All patients with Mog treatment failed the early expansion of Treg as compared with patients without Mog. Especially, CCR4-expressing effector-phenotype Treg was completely depleted from blood just after Mog treatment and 3 of 4 Mog-treated patients developed grade 2-4 GVHD. Of note, the delayed Treg recovery was prolonged over 12 months even after Mog was under detectable levels. After Mog decreased, concentrations of endogenous TARC and MDC were subsequently elevated in return. Expression of CCR4 on Treg was thereafter increased slowly but CD45RA+CD31+ recent-thymic emigrant population of Treg remained in the quite low levels over a year and the total Treg number was critically suppressed, suggesting that Mog treatment disturbed Treg homeostasis for a long period after HSCT. Taken together, our data demonstrated that both ATLL cells and Tregs are very susceptible to Mog treatment. Mog treatment not only exerts direct cytotoxicity on Treg but also appears to alter Treg homeostasis including the differentiation balance and distribution, at least in part, by the sequential enhancement of exogenous and endogenous ligand of CCR4. Our data might provide important information to develop safe and efficient HSCT for CCR4-positive ATLL and PTCL. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

Background: Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive peripheral T-cell neoplasm caused by human T-cell leukemia virus type 1 (HTLV-1). Although most patients respond to initial therapy, relapse is inevitable and the overall prognosis is dismal. Therefore, we developed a novel immune therapy consisting of autologous dendritic cells (DC) pulsed with Tax peptides (ATL-DC-101) to prevent relapse. The used peptides are corresponding to the major epitopes of HTLV-1 Tax-specific cytotoxic T lymphocytes (CTLs) that potentially act as anti-ATL effectors. Mogamulizumab is an anti-CCR4 antibody, which binds to ATL cells and regulatory T cells. A preceding pilot study suggested the safety of ATL-DC-101 monotherapy, and then we conducted a phase Ia/Ib study to investigate safety and efficacy of ATL-DC-101 combined with mogamulizumab. Methods: ATL patients pretreated and stable for at least 4 weeks were enrolled. Peripheral blood mononuclear cells were obtained by apheresis and differentiated into DC, which was pulsed with Tax-peptides. The study consisted of 2 cohorts, i.e., Ia and Ib phase, in which patients were assigned ATL-DC-101 monotherapy and ATL-DC-101 combined with mogamulizumab, respectively. The protocol consisted of three subcutaneous injections of ATL-DC-101 at 2-week intervals. Mogamulizumab was administered once before ATL-DC-101 in Ib phase. The primary endpoint of the study was to evaluate safety and feasibility of ATL-DC-101. The secondary endpoints were anti-tumor effects, progression-free survival (PFS), overall survival (OS), and time to next treatment, estimated by Kaplan-Meier method. The safety and disease status were accessed at day 56 and followed until 2 years. Results: Six aggressive ATL patients who were in stable condition by previous therapies were enrolled in this study from 2015 to 2016. Frequent DC- related toxicities were mild injection site reaction (n=5, 83.3%), decreased WBC count (n=3, 50%), and liver damage (n=2, 33.3%), all of which were grade 1 or 2. Notably, 2 patients (1 in each cohort) with partial response (PR) after chemotherapy were converted into complete response (CR) after ATL-DC-101. The 2-year PFS and OS were both 83.3%. All three patients who received ATL-DC-101 monotherapy (Ia) maintained CR for more than two years. Although one patient in phase Ib developed progressive disease after one year, the other two patients remained in CR. Interestingly ATL cells in a relapsed case harbored deletion of Tax gene, which resulted in the loss of the target peptide presentation. After a median follow-up of 29 months, 5/6 patients are alive without any additional chemotherapy after ATL-DC-101. Conclusions: ATL-DC-101 was well tolerated and successfully maintained CR more than 2 years in 5/6 patients irrespective of additional mogamulizumab, indicating that this therapy could be a safe and effective long-lasting maintenance therapy even for elderly ATL patients. Currently, we are preparing Phase II trial to confirm anti-tumor effects of ATL-DC-101 monotherapy. Disclosures Shiratsuchi: Kyowa Hakko Kirin Co.Ltd: Research Funding; Chugai Pharmaceutical Co.Ltd: Research Funding; Daiichi Sankyo Co.Ltd: Research Funding. Fukuda:Chugai Pharmaceutical: Speakers Bureau. Ishida:Kyowa Hakko Kirin Co.Ltd: Honoraria, Research Funding; Celgene K.K: Honoraria, Research Funding; Bayer AG: Research Funding; Mundiparma K: Honoraria. Akashi:Ono Pharmaceutical: Research Funding; MSD: Research Funding; Taiho Pharmaceutical: Research Funding; sanofi: Research Funding; Celgene: Research Funding, Speakers Bureau; Eli Lilly Japan: Research Funding; Novartis pharma: Research Funding; Kyowa Hakko Kirin: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Otsuka Pharmaceutical: Research Funding; Eisai: Research Funding; Pfizer: Research Funding; Astellas Pharma: Research Funding; Asahi-kasei: Research Funding; Chugai Pharma: Research Funding. Matsuoka:Bristol Myers Squibb: Research Funding. Suehiro:Kyowa Hakko Kirin: Research Funding; Ono Pharmaceutical: Research Funding; Chugai Pharmaceutical: Research Funding; Takeda Pharmaceutical: Research Funding.

Aims: Sezary Syndrome (SS) is the most aggressive form of cutaneous T cell lymphoma (CTCL), characterized with high blood involvement and expression of Killer cell immunoglobulin like receptor 3DL2 (KIR3DL2). IPH4102 is a first-in-class monoclonal antibody that targets KIR3DL2. Very limited effective treatment options are available for SS patients with refractory disease. We conducted a phase 1 study testing IPH4102 in patients with refractory CTCL. Here we report results from the SS subset. Methods: IPH4102-101 study is a multicenter phase I trial composed of a dose escalation and cohort expansion portions that evaluated IPH4102 in patients with refractory CTCL. Key eligibility criteria included failure of ≥ 2 prior systemic therapies. KIR3DL2 testing was performed for all patients at baseline and at different time points throughout the study. IPH4102 was given Q1w x 4 weeks, followed by Q2w x 10 weeks then Q4w until disease progression or unacceptable toxicity. Primary endpoint is safety. Main 2ry endpoints include best global response (BGR) using the Olsen criteria, progression-free survival (PFS), duration of response (DOR), quality of life (QOL) and biomarker analyses. Results: The study included 35 SS patients, 20 in the dose escalation and 15 in the cohort expansion, with a median age of 70 years (37-90). Median time from initial SS diagnosis to starting IPH4012 was 22.8 months. Nineteen patients (54%) received IPH4102 as ≥ 4th line of systemic therapy and 7 (20%) were previously treated with mogamulizumab. Thirteen patients (37%) had lymph node involvement as per investigator assessment and based on radiological examination while 7 patients (20%) had evidence of large cell transformation. KIR3DL2 expression was observed in either skin or blood in 33 patients (94%) and in both in 28 patients (80%). Most common adverse events (AEs) were asthenia (26%), peripheral edema (26%), and fatigue (23%), which were all grade 1-2. Possibly related grade ≥ 3 AEs were observed in 7 patients (20%), and only 2 patients (6%) stopped treatment for an AE. Table 1 shows BGR and response by compartment. Overall response rate was 42.9% [95% CI: 28.0% - 59.1%], with median time to response of 4.8 months. Median DOR and PFS were 5.6 months [95% CI: 3.2-not reached] and 12.8 months [95% CI: 8.1-not reached], respectively. Mogamulizumab pretreated patients showed BGR, median DOR and PFS of 42.9%, 13.8 and 20.9 months, respectively. Quality of life assessment was performed using the Pruritus VAS score andSkinDex29. Patients with CR, PR or SD showed marked improvement overtime of all evaluated parameters including SkinDex29 global, symptoms, emotional, and functional scores. Biomarker analysis showed progressive decrease in CD4/CD8 ratio in responding patients. The decrease of KIR3DL2+ expressing cells in skin evaluated by immunohistochemistry at week 5 and 14 was able to predict BGR (AUC=0.749, 0.714, respectively). Figure 1 shows reduction in KIR3DL2 expressing cells at week 5 and week 14 in a patient who had PR as BGR. To date, 9 patients are still ongoing treatment. Updated clinical and correlative research analyses will be presented at the meeting. Conclusions: IPH4102 is highly effective in patients with refractory SS. It induces meaningful clinical activity and improves quality of life placing it as an encouraging treatment option for these patients. Further development in SS and other T-cell malignancies is underway. Disclosures Bagot: Actelion: 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; Takeda: Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees. Porcu:Innate Pharma: Consultancy. Khodadoust:Innate Pharma: Research Funding. Sicard:Innate Pharma: Employment, Equity Ownership. Azim:Innate Pharma: Employment, Equity Ownership. Kim:miRagen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon Pharma: Consultancy, Research Funding; Galderma: Research Funding; Tetralogic: Research Funding; Neumedicine: Consultancy, Research Funding; Soligenix: Research Funding; Portola: Research Funding; Forty Seven Inc: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees; 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; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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, P Methods: This was an open-label, randomized, international, phase 3 study (NCT01728805). Pts with MF/SS who were treated with ≥1 prior systemic therapy were randomized 1:1 to receive mogamulizumab (1.0 mg/kg, administered once weekly for the first 28-day cycle, then on Days 1 and 15 of subsequent cycles) or oral vorinostat (400 mg daily). In this follow-up analysis (data cut-off September 2017), exposure quartiles were determined, and baseline demographics, confirmed global response rate, and safety were analyzed by exposure group. To detect linear trends across exposure quartiles, frequencies were analyzed using Chi-square test and continuous data were assessed by analysis of variance. Results: A total of 184 pts randomized to mogamulizumab were included in this analysis. Mean time of mogamulizumab exposure was 275 days (d; standard deviation [SD]: 292 d; range: 1-1617). Based on quartile assessment, >351 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, 76% had a confirmed global response (ie, either complete or partial response). The percentage of pts reporting a treatment-emergent adverse event (AE) or serious AE did not vary with increasing exposure to mogamulizumab (351 d: 21% and 4%, respectively). The most common treatment-related AEs reported by pts after >351 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.

Mycosis fungoides (MF) is the most common primary cutaneous T-cell lymphoma variant and is closely related to a rare leukemic variant, Sézary syndrome (SS). MF patients at risk of disease progression can now be identified and an international consortium has been established to address the prognostic relevance of specific biologic factors and define a prognostic index. There are a lack of randomized clinical trial data in MF/SS and evidence is based on a traditional “stage-based” approach; treatment of early-stage disease (IA-IIA) involves skin directed therapies which include topical corticosteroids, phototherapy (psoralen with UVA or UVB), topical chemotherapy, topical bexarotene, and radiotherapy including total skin electron beam therapy. Systemic approaches are used for refractory early-stage and advanced-stage disease (IIB-IV) and include bexarotene, interferon α, extracorporeal photopheresis, histone deacetylase inhibitors, and antibody therapies such as alemtuzumab, systemic chemotherapy, and allogeneic transplantation. However, despite the number of biologic agents available, the treatment of advanced-stage disease still represents an unmet medical need with short duration of responses. Encouragingly, randomized phase 3 trials are assessing novel agents, including brentuximab vedotin and the anti-CCR4 antibody, mogamulizumab. A broader understanding of the biology of MF/SS will hopefully identify more effective targeted therapies.

In this issue of Blood, Duvic et al demonstrate that mogamulizumab, a humanized monoclonal antibody targeting the chemokine receptor CCR4, is well tolerated and has significant clinical activity (overall response rate 36.8%, median duration of response 10.4 months) in heavily pretreated patients with mycosis fungoides (MF) and Sezary syndrome (SS).

This phase 1/2 study evaluated the efficacy of mogamulizumab, a defucosylated, humanized, anti-CC chemokine receptor 4 monoclonal antibody, in 41 pretreated patients with cutaneous T-cell lymphoma. No dose-limiting toxicity was observed and the maximum tolerated dose was not reached in phase 1 after IV infusion of mogamulizumab (0.1, 0.3, and 1.0 mg/kg) once weekly for 4 weeks followed by a 2-week observation. In phase 2, patients were dosed with 1.0 mg/kg mogamulizumab according to the same schedule for the first course followed by infusion every 2 weeks during subsequent courses until disease progression. The most frequent treatment-emergent adverse events were nausea (31.0%), chills (23.8%), headache (21.4%), and infusion-related reaction (21.4%); the majority of events were grade 1/2. There were no significant hematologic effects. Among 38 evaluable patients, the overall response rate was 36.8%: 47.1% in Sezary syndrome (n = 17) and 28.6% in mycosis fungoides (n = 21). Eighteen of 19 (94.7%) patients with ≥B1 blood involvement had a response in blood, including 11 complete responses. Given the safety and efficacy of mogamulizumab, phase 3 investigation of mogamulizumab is warranted in cutaneous T-cell lymphoma patients. This trial was registered at www.clinicaltrials.gov as #NCT00888927.

Introduction Adult T-cell leukemia-lymphoma (ATL), a rare peripheral T-cell lymphoma, is caused by human T-cell lymphotropic virus type 1 (HTLV-1). Mogamulizumab-a humanized anti-CCR4 monoclonal antibody-shows antitumor activities in patients with ATL, and was approved in Japan for the treatment of CCR4+ relapsed/refractory ATL, followed by treatment of CCR4+ untreated ATL under the combination with chemotherapies. However, relapse may still be a problem in some patients with ATL, even in those who achieve complete hematological remission after mogamulizumab treatment. Therefore, highly accurate monitoring of ATL cells could be useful for elucidating the mechanisms of hematological relapse. Detecting ATL cells among peripheral blood mononuclear cells (PBMCs) has been performed clinically by measuring abnormal lymphocytes, HTLV-1 provirus DNA using PCR, and analyzing surface markers using flow cytometry. These, however, cannot reveal the entire picture of heterogeneous ATL cell populations. Because ATL is a malignant form of differentiated T cell and expresses a specific T-cell receptor (TCR), we conducted a TCR repertoire analysis of peripheral blood to elucidate the complete ATL clonotype using next generation sequencing (NGS). Methods PBMCs were obtained sequentially at pre-, during-, and post-treatment from patients with ATL who received mogamulizumab (n = 11). Total RNA was extracted from these PBMCs, and TCR alpha- and beta-chain variable regions were amplified by the SMARTer 5'RACE method using a 3' primer positioned in the constant region. The amplified variable regions were sequenced using Ion PGM sequencer (Thermo Fisher Scientific). Germline usage [Variable (V), Diversity (D), and Joining (J) gene segments] of each sequence was identified using IgBlast (NCBI) and frequency of each germline was calculated. The major germline gene segments in the pre-treatment samples, which are presumed to be ATL clones, were monitored during treatment and their frequency changes were analyzed. Results Tens of thousands sequence reads of the TCR variable region were obtained from each sample. In most cases, the majority of PBMCs at pre-treatment were considered to be ATL cells as evidenced by the HTLV-1 virus load. Therefore, the highly frequent TCR germline gene segments detected in the pre-treatment samples were thought to be derived from ATL cells. Such gene segments were significantly decreased in the post-mogamulizumab treatment samples (Table 1). In a patient who received mogamulizumab, the frequencies of the most abundant TCRa and TCRb clones were 66.8% and 32.8%, respectively, before treatment and decreased to 0.00617% and an undetectable level, 109 days after initial treatment-66 days after discontinuation of treatment, along with HTLV-1 virus load decrease. In this patient, the same clones increased again to 66.5% and 7.54%, respectively, along with HTLV-1 virus load increase, 342 days after initial treatment-299 days after discontinuation. Increase of the clones was detected as early as 167 days after initial treatment-124 days after discontinuation. In 4 of 11 patients with ATL who received mogamulizumab, a resurgence of clones that were dominant at pre-treatment was detected. These recurrent clones were thought to express CCR4-measured by quantitative PCR in PBMCs-because the change in CCR4 gene expression levels during treatment were correlated with the changes in HTLV-1 virus load, frequency of dominant clones, and expression of the HBZ gene, which is transcribed from the HTLV-1 genome. Discussion and Conclusions The TCR repertoire analysis using NGS made it possible to track specific ATL clones during mogamulizumab treatment. We observed that most ATL clones were drastically depleted after mogamulizumab treatment. However, in some patients, regrowth of ATL cells in blood was observed. By the TCR repertoire analysis, it was indicated that these regrown ATL clones were derived from the same ones that were dominant at pre-treatment. Moreover, these clones were thought to express CCR4. Thus, TCR repertoire analysis using NGS may be useful for elucidating the mechanisms of hematological relapse after mogamulizumab treatment, as well as early detection of hematological relapse. Disclosures Saito: Kyowa Hakko Kirin Co., Ltd.: Employment. Ishida:Celgene KK: Research Funding; Kyowa Hakko Kirin, Co., Ltd.: Honoraria, Research Funding; Bayer Pharma AG: Research Funding. Urakawa:Kyowa Hakko Kirin Co., Ltd.: Employment. Ishii:Kyowa Hakko Kirin Co., Ltd.: Employment. Suzuki:Kyowa Hakko Kirin: Research Funding. Inagaki:Kyowa Hakko Kirin: Research Funding. Takahashi:Kyowa Hakko Kirin Co., Ltd.: Employment. Ueda:Kyowa Hakko Kirin: Research Funding; Mundipharma KK: Consultancy. Iida:Celgene: Honoraria, Research Funding; Janssen Pharmaceuticals: Honoraria, Research Funding.

Background: Adult T-cell leukemia-lymphoma (ATL) is a rare and refractory malignancy of regulatory T /TH2 cell associated with human T-lymphotropic virus type I (HTLV-1). In recent years, the introduction of intensive chemotherapy, allogeneic hematopoietic stem cell transplantation (Allo-HSCT), and mogamulizumab (anti-CCR4 antibody, which was approved in Japan in May 2012 for relapsed/refractory ATL, and in Dec. 2014 for newly diagnosed ATL) are expected to improve the prognosis of ATL. Meanwhile, the aging tendency of the ATL patient population has been recognized recently in Japan. Therefore, for the development of future treatment strategies for ATL, it is important to assess the therapeutic utilization and prognosis in patients with ATL not only in clinical trials but also in clinical practices. Aim: To report the current clinical features and outcomes of patients with ATL who were newly diagnosed during 2010-2011 from 114 hospitals in Japan. Methods: A questionnaire for each of 996 patients was sent to the hospitals, requesting information on treatment options and outcomes in detail. Statistical analysis was undertaken using Chi-squared tests to identify significant differences in the proportion, and using Kaplan-Meier curves to estimate the probability of overall survival (OS) with the log-rank test to identify significant differences in the probability, according to age, subtypes, and initial treatment. Results: We received 94.7% response rate from hospitals. Among 800 patients registered in this prognosis survey, 45 patients were not assessable for outcomes because of insufficient data, therefore, 755 (male 397, female 355, unknown 3) were included in the outcome analysis. The median age at diagnosis was 68 years old for all and the median follow-up time was 49 months for survivors. The distributions of ATL subtypes according to Shimoyama criteria were 382 (51%) for acute, 192 (25%) for lymphoma, 86 (11%) for chronic, and 95 (13%) for smoldering types, respectively. The median survival time and 2-year survival rate were: acute (n=377) (264 days, 24%), lymphoma (n=212) (293 days, 26%), chronic (n=71) (1,094 days, 56%), and smoldering (n=99) (1,900 days, 80%), respectively. Overall, the initial therapy-regimens used for aggressive ATL (acute and lymphoma subtypes) were VCAP-AMP-VECP-like regimen in 49%, CHOP-like regimen in 42%, and others in 9%. However, the utilization percentage of each option varied with age, VCAP-AMP-VECP-like regimen was used 68% of those aged 65 or younger but 32% of those over 65, respectively. CHOP-like regimen was used 29% for those aged 65 or younger but 52% for those over 65, respectively. Allo-HSCT for aggressive ATL was performed about 50% for those aged 55 or younger, 30% for those aged 56-65, but only 1% for those aged over 66, respectively. A total of 75 (10%) patients were treated with mogamulizumab. Fifty-six of them were treated with mogamulizumab after May 2012, when mogamulizumab was approved and generally adopted in Japan. When comparing the OS by pre- or post- general adoption of mogamulizumab, the 2-year OS was significantly worse in those treated after general adoption (18%) than those before (61%). When the response to initial chemotherapies was poor, the prognosis was worse regardless of treatment options, i.e., chemotherapy, allo-HSCT, and mogamulizumab. Response rate to initial chemotherapy differed by age, i.e., the older the age, the worse the response rate. Conclusion: This work highlights the difference in the treatment and the prognosis by age in patients with ATL in the current clinical practice in Japan. Intensive chemotherapy and allo-HSCT are not fully applicable for the elderly patients, who account for more than half of the ATL patients. Better strategies are required to improve clinical outcomes of the primary treatment, especially of the elderly ATL patients. Funding : This work was supported by Health and Labor Science Research Grant, Grant Number H26-ganseisaku-ippan-006. Disclosures Utsunomiya: Daiichi Sankyo Co., Ltd.: Speakers Bureau. Tobinai:Kyowa Hakko Kirin: Research Funding; Eisai: Honoraria, Research Funding; Abbvie: Research Funding; Chugai Pharma: Research Funding; Janssen Pharmaceuticals: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria; Celgene: Research Funding; GlaxoSmithKline: Research Funding; Ono Pharmaceutical: Research Funding; SERVIER: Research Funding; HUYA Bioscience: Honoraria; Mundipharma KK: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Daiichi Sankyo Co., Ltd.: Consultancy. Tsukasaki:Daiichi Sankyo Co., Ltd.: Consultancy; Takeda: Research Funding.

Introduction Adult T-cell leukemia/lymphoma (ATLL) is an aggressive peripheral T cell neoplasm that is resistant to conventional chemotherapy and carries a poor prognosis. The effect of mogamulizumab, an immunoglobulin (Ig) G1 monoclonal antibody targeting CCR4 for ATLL cells, was reported in a previous phase 2 study in which mogamulizumab monotherapy was evaluated in relapsed ATLL patients. The overall response rate (ORR), median progression-free survival (PFS) and median overall survival (OS) were 50%, 5.2 and 13.7 months, respectively. It was not stated whether these values were derived in the real world or in clinical practice. Here we evaluate the clinical impact of mogamulizumab treatment in CCR-4-positive aggressive ATLL patients in clinical practice. Patients and methods We retrospectively analyzed 101 CCR-4-positive ATLL patients who received at least one cycle of mogamulizumab infusion between March, 2012 and April, 2016 in 7 facilities in Miyazaki prefecture, an HTLV-1 endemic area in Southwestern Japan. The ORR, PFS, OS and adverse effects (AEs) were evaluated. We next compared OS in patients with at least one course of mogamulizumab therapy with that in historical control patients without mogamulizumab therapy. Results Of the 101 patients, 92 were evaluable for treatment response, survival and AEs. The median age was 70 years old (range; 45 to 90), and 52 patients (51%) were more than 70 years old. According to Shimoyama's criteria, 66 patients were classified as acute type, 32 as lymphoma type, and 3 as chronic type. All 3 chronic-type ATLL patients had at least one unfavorable risk factor. Of the 101 patients, 96 had refractory or relapsed ATLL when mogamulizumab treatment was started, and the prior treatments consisted of VCAP-AMP-VECP, CHOP, DeVIC or CHASE therapy, with an average of 2 courses. In the 5 remaining cases, mogamulizumab was administered as the initial therapy for ATLL. Mogamulizumab was administered as monotherapy in 87 cases (86%), and as combination therapy with other drugs in 14 cases (14%). The ORR was 37%, including a complete remission rate of 19%. The median PFS and OS were 1.8 and 4.2 months, respectively. Among the 101 patients treated with mogamulizumab, only 26 (26%) fulfilled the inclusion criteria of the phase 2 clinical study. Among patients who met those inclusion criteria, the median PFS and OS were 6.0 and 8.4 months, respectively. The use of mogamulizumab improved OS in clinical practice. The median OS of patients receiving mogamulizumab therapy was 12 months, whereas that of patients who did not receive mogamulizumab in the historical cohort was 8.4 months. Hematologic toxicity and skin rash were the most common AEs, and both were manageable Conclusion Mogamulizumab therapy showed clinically meaningful activity in ATLL patients, with an acceptable toxicity in clinical practice. Disclosures No relevant conflicts of interest to declare.

Adult T-cell leukemia-lymphoma (ATL) is an intractable mature T-cell neoplasm. We performed a nationwide retrospective study of allogeneic hematopoietic stem cell transplantation (HSCT) for ATL in Japan, with special emphasis on the effects of the preconditioning regimen. This is the largest study of ATL patients receiving HSCT. Median overall survival (OS) and 3-year OS of bone marrow or peripheral blood transplantation recipients (n = 586) was 9.9 months (95% confidence interval, 7.4-13.2 months) and 36% (32%-41%), respectively. These values for recipients of myeloablative conditioning (MAC; n = 280) and reduced intensity conditioning (RIC; n = 306) were 9.5 months (6.7-18.0 months) and 39% (33%-45%) and 10.0 months (7.2-14.0 months) and 34% (29%-40%), respectively. Multivariate analysis demonstrated 5 significant variables contributing to poorer OS, namely, older age, male sex, not in complete remission, poor performance status, and transplantation from unrelated donors. Although no significant difference in OS between MAC and RIC was observed, there was a trend indicating that RIC contributed to better OS in older patients. Regarding mortality, RIC was significantly associated with ATL-related mortality compared with MAC. In conclusion, allogeneic HSCT not only with MAC but also with RIC is an effective treatment resulting in long-term survival in selected patients with ATL.

Introduction: Adult T-cell leukemia-lymphoma (ATL) is a peripheral T-cell malignancy, which is caused by human T-cell leukemia virus type I (HTLV-1) and is considered to be derived from regulatory T cells (Treg). ATL is usually resistant to conventional chemotherapies and the patients with ATL have very poor prognosis. Mogamulizumab (Moga) is a humanized monoclonal antibody against CC chemokine receptor 4 (CCR4) which is expressed on T-helper type 2, Treg and tumor cells from most patients with ATL. It was reported that Moga used to treat ATL with 50% efficacy in a phase II study and frequently developed cutaneous adverse reactions (CAR). In that study, development of CAR was reported to be closely associated with the response to Moga therapy. To confirm efficacy and safety of Moga therapy for ATL, we retrospectively analyzed relapsed or refractory ATL patients who were treated by Moga at 4 institutes in Kagoshima, one of the endemic areas of HTLV-1 infection, Southwestern Japan. Patients and methods: There were 77 patients, who were received Moga therapy between March, 2007 (phase I study) and December, 2014. We studied about backgrounds (age, sex, subtypes of ATL, ECOG performance status (PS) at diagnosis and clinical stage) of the patients, contents of prior therapy and the response, prognostic index for acute and lymphoma type ATL (ATL-PI), PS and disease status at Moga therapy, response and adverse events (AE) of Moga therapy, and the survival. Results: Enrolled patients were 44 men and 33 women, and median age at Moga therapy was 65.6 years (range: 44-83 years). They consisted 54 acute, 18 lymphoma, and 5 chronic type ATL, and ATL-PI was low in 18, intermediate in 43 and high in 16 patients. Initial induction chemotherapies were mainly VCAP-AMP-VECP regimen in 41, CHOP like regimen in 19 patients. Median duration between diagnosis and Moga therapy was 8.1 months (range: 0.5-94.9 months). They were administered Moga median 5 cycles (range: 1-10 cycles). Disease status at Moga therapy were 23 relapsed and 54 refractory [partial response (PR): 8, stable disease (SD): 15, progressive disease (PD): 31] disease. Myelosuppression associated with Moga, development of cytomegalovirus antigenemia (19.5%) and other AE were tolerable. Best objective response rate was 42.9% including 18 complete remission (CR) and 15 PR. Fifty-four patients died after Moga therapy (50 from ATL, 4 from infection and so on). Median overall survival (OS) time from Moga therapy was 7.7 months (95%CI: 5.1-11.2 months) and 3-year OS rate was 18.2%. The cohort included 27 patients over 70 years, but their survival was no worse than younger. Twelve patients received allogeneic hematopoietic stem cell transplantation after Moga therapy, but had no survival advantage. Twenty-four patients suffered from CAR, which were developed median 7 cycles (range: 2-8 cycles). The severity of CAR according to CTCAE v3.0 was grade 1 in three, 2 in eight, 3 in eleven and 4 in two patients, respectively. In patients (n = 51) received Moga more than 4 cycles, 22 patients suffered from CAR and their OS (3-year OS: 43.6%) was significantly better than patients without CAR (median OS: 23.4 vs 7.9 months, p = 0.0003). Discussion: Moga therapy is effective and safe for ATL patients and the onset of moderate CAR is a favorable sign of the efficacy. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

[Introduction] Adult T-cell leukemia/lymphoma (ATL) is an aggressive peripheral T-cell lymphoma (PTCL) with a dismal prognosis. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment in ATL patients. Mogamulizumab, a humanized anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, is a novel immunotherapeutic agent, effective in treating patients with PTCL such as ATL, PTCL-not specified, and cutaneous T-cell lymphoma. However, in allo-HSCT setting, we should be careful to use mogamulizumab because CCR4 is expressed in regulatory T cells: The mogamulizumab treatment may accelerate GVHD by eradicating regulatory T cells in allo-HSCT patients. Here, we retrospectively analyzed the effect of mogamulizumab on GVHD development in ATL patients treated with mogamulizumab prior to allo-HSCT. [Patients and Methods] Data from the Fukuoka Bone Marrow Transplantation Group were retrospectively analyzed after the approval of mogamulizumab use in Japan. [Results] A total of 24 patients with ATL received mogamulizumab prior to allo-HSCT between April 2012 and April 2015 in our group. The median age at allo-HSCT was 58.5 years (range, 32-72). The median intervals from the last administration of mogamulizumab to allo-HSCT were 25 days (range, 9-126). The median total dose of mogamulizumab was 3 mg/kg (range, 1-8 mg/kg). After treatment with mogamulizumab, 18 patients (75%) had achieved in remission (CR in 4 patients and PR in 14) at allo-HSCT. Ten patients received unrelated bone marrow, 5 received related peripheral blood, and 9 received cord blood as stem cell sources. Eleven patients were treated with full-intensity conditioning and 13 received reduced-intensity conditioning. Graft-versus-host disease (GVHD) prophylaxis consisted of calcineurin inhibitors (cyclosporine or tacrolimus) with short-term methotrexate in 14 patients and mycophenolate mofetil in 9. The cumulative incidence (CI) of acute GVHD at 100 days was 66.6% in grade 2-4 and 33.3% in grade 3-4. The involved organs of acute GVHD were skin in 14 patients, gut in 10, and liver in 4. Among 14 patients who developed grade 2-4 acute GVHD, 5 had severe fluid retention such as pleural effusion or ascites associated with GVHD. Chronic GVHD was observed in 6 patients, and 5 of them were extensive disease. The CI of transplant-related mortality (TRM) and relapse at 1-year were 53.2% (95%CI, 29.3-72.3%) and 29.6% (95%CI, 12.6-48.9%), respectively. The leading cause of death was GVHD (n = 7). The 1-year overall survival and progression-free survival were 19.2% (95%CI, 5.7-38.8%) and 17.2% (95%CI, 4.9-35.7%), respectively. [Discussion] Use of mogamulizumab prior to transplantation in allo-HSCT patients has a merit to decrease the burden of ATL cells. However, it was associated with an increase of TRM due to severe GVHD. Although most of ATL patients achieved better disease status at allo-HSCT through mogamulizumab and the survival rate was expected to be 50% based on the previous data, the survival in the present study was ~20%. These data suggest that mogamulizumab administered before transplantation may have retained until an early phase of post-transplantation, and the donor or host-derived regulatory T cells might be eliminated, allowing the GVHD T-cell clone to expand. Since mogalizumab is a potent anti-ATL agent, we need to develop new treatment protocols integrating mogalizumab at a suitable dose or administration timing, to minimize the unwanted GVHD development in future studies. Disclosures Akashi: Asahi Kasei: Research Funding, Speakers Bureau; Shionogi: Research Funding, Speakers Bureau; Astellas: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Chugai: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Novartis Pharma K.K.: Consultancy, Research Funding, Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Consultancy, Research Funding, Speakers Bureau.

[Graphic][1] Introduction: Adult T-cell leukemia-lymphoma (ATL), a distinct subtype of peripheral T-cell lymphoma (PTCL), is caused by human T-lymphotropic virus type-I (HTLV-1). Although rare in the rest of the world, ATL accounts for 25% of PTCL cases diagnosed in Japan, where ATL cases are clustered in areas endemic for HTLV-1 infection. Studies of lenalidomide, an oral immunomodulatory agent that has antiproliferative and direct antineoplastic activity in cutaneous T-cell lymphoma and PTCL, have reported encouraging clinical activity. On the basis of the results from the ATLL-001 dose-finding study of lenalidomide (Uike et al. ASH 2012. Abstract 2737), this multicenter phase II study (ATLL-002) was designed to investigate the efficacy and safety of single-agent lenalidomide in Japanese patients with relapsed ATL. Methods: Patients with relapsed acute, lymphoma, or the unfavorable chronic subtype of ATL who were at least 20 years of age, had ECOG performance status 0-2, no prior allogeneic stem cell transplant, and who had failed at least 1 chemotherapy were included in the study. Patients refractory to their last prior therapy were excluded. Treatment consisted of oral lenalidomide 25 mg/day administered continuously until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR). The secondary endpoints were progression-free survival (PFS), duration of response (DOR), overall survival (OS), and safety. Response was assessed by central review using the criteria proposed by Tsukasaki et al in their international consensus report (J Clin Oncol. 2009;27:453-459.); safety was assessed per NCI CTCAE v4.0 criteria. The estimated number of patients required was 25, for 90% power to detect a lower limit of the 95% confidence interval (CI) exceeding the 5% threshold of ORR, based on the assumptions that the minimum required ORR to a new drug for relapsed or recurrent ATL is 5% and the expected ORR to lenalidomide is 25%. Results: Twenty-six patients were enrolled and received lenalidomide. The median age was 68.5 years (range, 53-81), with 15 (58%) acute, 7 (27%) lymphoma, and 4 (15%) unfavorable chronic type ATL patients. Patients had received a median of 2 (range, 1-4) prior chemotherapeutic or antibody agents for ATL, 11 (42%) of whom received prior mogamulizumab (anti-CCR4 antibody). At a median 3.8-month follow-up, lenalidomide met the primary endpoint by exhibiting an ORR of 42% (11/26; 95% CI, 23-63) (acute 33% [5/15], lymphoma 57% [4/7], unfavorable chronic 50% [2/4]), including 5 (19%) complete responses (CR)/CR unconfirmed (95% CI, 7 to 39; Table 1). Stable disease was 31%, and progressive disease was 27%. The median time to response was 1.9 months (95% CI, 1.8 to 3.7). Although the data were immature at the time of analysis, median DOR for all responders was not reached (NR) (95% CI, 0.5 months to NR), median PFS was 3.8 months (95% CI, 1.9 months to NR), and median OS was 20.3 months (95% CI, 9.1 months to NR). At the time of the data cut-off, 5 (19%) patients remained on lenalidomide treatment. The most common grade 3/4 adverse events (AEs), accounting for at least 10% of all cases, were neutropenia (65%), leukopenia (39%), lymphopenia (39%), thrombocytopenia (23%), anemia (19%), and hypokalemia (12%). Serious AEs were reported in 9 (35%) patients; only thrombocytopenia (2 patients [8%]) was observed in >1 patient. AEs led to dose reduction/interruption in 17 (65%) patients and study discontinuation in 6 (23%). Seven deaths occurred during the study, 6 due to disease progression and 1 due to pneumonia unrelated to lenalidomide treatment. Conclusions: In this multicenter, open-label, phase II study, lenalidomide monotherapy demonstrated a 42% ORR and acceptable tolerability profile. These results support the potential for lenalidomide monotherapy becoming a treatment option for patients with relapsed ATL. | ATL type | All patients (N = 26) | Acute (n = 15) | Lymphoma (n = 7) | Unfavorable chronic (n = 4) | | ------------- | ------------------------------ | ----------------------- | ------------------------- | --------------------------- | | ORR, n (%) | 11 (42) | 5 (33) | 4 (57) | 2 (50) | | CR/CRu, n (%) | 5 (19) | 3 (20) | 2 (29) | | | PR, n (%) | 6 (23) | 2 (13) | 2 (29) | 2 (50) | | SD, n (%) | 8 (31) | 6 (40) | | 2 (50) | | PD, n (%) | 7 (27) | 4 (27) | 3 (43) | | * CR, complete response; CRu, CR unconfirmed; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease. Table. Best response to lenalidomide in relapsed ATL Disclosures Fujiwara: Celgene: Honoraria, Other: Research funding to my institution; travel, accommodations, expenses. Off Label Use: Lenalidomide to treat ATL. Ishida: Celgene K.K.: Other: Research Funding to my institution; Bayer Pharma AG: Other: Research Funding to my institution; Kyowa Hakko Kirin Co., LTD: Honoraria, Other: Research Funding to my institution. Moriuchi: Celgene: Other: Research Funding to my institution; travel, accommodations, expenses, Speakers Bureau. Jo: Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Kyowa Kirin: Honoraria; Nippon Shinyaku: Honoraria. Ishizawa: Kyowa Kirin: Research Funding; Celgin: Research Funding; Janssen: Research Funding; Takeda: Research Funding; GSK: Research Funding; Takeda: Speakers Bureau; Kyowa Kirin: Speakers Bureau; Pfizer: Speakers Bureau; Celgin: Speakers Bureau. Tobinai: Gilead Sciences: Research Funding. Tsukasaki: Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Chugai: Consultancy, Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Mundipharma: Research Funding; Kyowa Kirin Hakkou: Research Funding. Ogura: Mundipharma: Consultancy, Research Funding; MeijiSeika Pharma: Consultancy; Zenyaku: Research Funding; Eisai: Research Funding; Pfizer: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Solaisia: Research Funding. Midorikawa: Celgene K.K.: Employment; Celgene Corporation: Equity Ownership. Ruiz: Celgene K.K.: Employment. Ohtsu: Celgene: Employment, Equity Ownership, Other: travel, accommodations, expenses. [1]: /embed/inline-graphic-2.gif

Introduction: Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell malignancy caused by human T-lymphotropic virus type I (HTLV-I). Most ATLL cells are CD4 and CCR4 positive, and CD8 negative. ATLL is classified into 4 clinical subtypes: smoldering, chronic, acute, and lymphoma. Acute and lymphoma type ATLLs, which are aggressive types, have a very poor prognosis. In Japan, aggressive ATLLs are commonly treated by intensive chemotherapies, such as VCAP-AMP-VECP, modified LSG15 therapy, and biweekly CHOP therapy. Recently, an anti-CCR4 monoclonal antibody (mogamulizumab) was approved for relapse and refractory ATLL in Japan. Mogamulizumab induces a highly potent antibody dependent cellular cytotoxicity, suggesting the importance of immuno-cell therapy for treatment of ATLL. We report here the extremely interesting results of aggressive ATLL patients with long-term survival and complete remission (CR) after activation of cellular immunity against ATLL cells following intensive chemotherapies. Patients and Methods: We retrospectively evaluated 46 cases of aggressive ATLLs diagnosed at the Nagasaki Genbaku Hospital between January 2001 and August 2011. Of these, 7 patients had long-term survival greater than 3 years with CR after intensive chemotherapies. Four of these 7 patients had human leukocyte antigen (HLA)-A02:01 or HLA-A24:02, and were investigated using anti-HTLV-I specific cytotoxic T-lymphocyte (CTL) analysis. The HTLV-I provirus load in peripheral blood was also analyzed. Results: Table 1 summarizes the characteristics of 7 aggressive type ATLL patients with long-term survival. Four patients were male and 3 were female. Six patients were classified as lymphoma type and 1 as acute type ATLL. The median age was 68 (range, 60–78) years. The median survival period from the onset of the disease was 111 (range, 36–165) months. In all 7 patients, the CD4/CD8 ratio reversed during, or shortly after, chemotherapy and CD8 predominance continued for more than 1 year (range, 13–165 months, median 24 months). Three patients had herpes virus infection during chemotherapy and reversal of the CD4/CD8 ratio appeared just after herpes virus infection in 2 of these patients. These observations suggested that HTLV-I specific CTLs were induced and contributed to the treatment of ATLL in these patients. An HTLV-I specific CTL analysis currently is available in patients with HLA-A02:01 and HLA-A24:02. Three of 7 aggressive ATLL patients with long-term survival and CR had HLA-A02:01 and 1 had HLA-A24:02. Therefore, HTLV-I specific CTL analysis and HTLV-I provirus load in the peripheral blood were performed in all 4 patients. Each patient was examined twice, once in 2012 and once in 2014. HTLV-I specific CTLs were detected in all patients (Table 2 and Figure 1). Although all patients maintained CR for, HTLV-I proviruses were detected in the peripheral blood in all patients (Table 2). This phenomenon was observed both in 2012 and in 2014 (Table 2 and Figure 1). Conclusions: The findings from this study suggest that HTLV-I specific CTLs can be induced in patients with aggressive types of ATLL. In patients having long survival with CR, these CTLs can contribute to treatment and may play a roll inhibiting the relapse of ATLL. The development of efficacious methods to induce HTLV-I specific CTLs in individual ATLL patients may lead to improved outcomes for aggressive types of ATLL. Table 1. Summary of aggressive type ATLL patients with long-term survival and complete remission PatientNo. Gender Age(year) Survival fromthe onset of ATLL (months) Duration ofCD4/CD8 reversal(months) Herpes virus infection 1 Male 69 165 165 + 2 Male 68 140 96 + 3 Female 71 71 65 - 4 Male 60 124 13 + 5 Female 61 111 18 - 6 Male 78 36 13 - 7 Female 65 56 24 - Table 2. A Summary of HTLV-I specific CTL analysis and HTLV-I provirus load in the peripheral blood Patient No. HLA 2012 2014 CTL HTLV-I provirus CTL HTLV-I provirus (%) (copies/1000 cells) (%) (copies/1000 cells) 1 A02:01 0.11 35.4 0.13 61.9 2 A02:01 0.78 24.4 1.56 14.7 5 A02:01 1.06 7.1 1.31 13.3 7 A24:02 2.07 26.4 3.64 27.9 Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

[Background and purpose] Mogamulizumab, a newly developed monoclonal antibody (mAb) targeting the receptor for C-C chemokine 4 (CCR4) has initially demonstrated a promising clinical outcome for the treatment of therapy-resistant Adult T cell leukemia (ATL) of which tumor cells broadly express CCR4. However, in practice, we sometimes encounter unsuccessful cases of ATL treated with mogmulizumab, especially in the setting of combination therapy with multiple anticancer agents. In those cases, ATL tumor cells were still positive for CCR4, but the chemotherapy-induced lymphocytopenia was reproducibly noticeable. Considering the pharmacologic action of mogamulizumab, the defucosylation-enhanced antibody-dependent cellular cytotoxicity (ADCC) exerted by FcγRIIIa (CD16) expressing effector cells in vivo, as observed for Natural Killer (NK) cells, we hypothesized that adoptive transfer of ADCC effector cells might be able to regain the anti-ATL efficacy of mogamulizumab. Accordingly, we examined in vivo the feasibility of T cells gene-modified to express a newly generated chimeric CD16-CD3ζ receptor as a transferable alternative effector cell for mogamulizumab. [Methods] A novel affinity-matured chimeric CD16 with a 158V/V-CD3ζ (cCD16ζ ) gene construct was lentivirally introduced into CD3+ T cells from both healthy individuals (n=4) and patients with adult T cell leukemia (ATL) (n=3) (cCD16ζ-T cells). Using ATL or HTLV-1 infected cell lines variably expressing CCR4 on the cell surface (n=7), and primary ATL tumor cells (n=3), in the context of ADCC activity, functional properties of cCD16ζ-T cells were extensively examined both in vitro and in vivo, compared with those of NK cells from healthy donors (n=3). Next, we examined the in vivo therapeutic efficacy of concomitantly infused cCD16ζ-T cells with mogamulizumab via tail vein using a xenografted mouse model. Finally, we examined the feasibility of double gene-modified T cells to express human telomerase reverse transcriptase (hTERT)-specific TCR and cCD16ζ receptor, because we recently demonstrated that HLA-A*24:02-restricted and hTERT461-469 (VYGFVRACL)-specific TCR gene-modified CD8+ T cells displayed the cytocidal activity against ATL tumor cells (Blood, 2014). [Results] cCD16ζ-T cells were readily expandable in ex vivo culture using anti-CD2/CD3/CD28 beads and recombinant human (rh)IL-2, and they successfully displayed ADCC-mediated tumoricidal activity against CCR4+ MT-4 and ATN-1 (ATL cell lines) cells, but not CCR4- K562 cells with mogamulizumab, in a effector cell number and an antibody dose dependent manner. Pharmacological dose of 0.1μg/ml mogamulizumab could bind to ATL cell line cells expressing variable extent of CCR4 ranging from MFI 1.01 for HUT102 cell line to 12.3 for MT-2 (0.57 for K562 as a negative control), and could mediate the similar degree of ADCC activity exerted by cCD16ζ-T cells. The magnitude of ADCC activity mediated by cCD16ζ-T cells against opsonized ATN-1 with mogamulizumab was almost similar to that by activated NK cells using rhIL-2. This cytotoxicity was inhibited by anti-CD16 mAb. During ADCC, ligation of opsonized cancer cells with mogamulizumab to cCD16ζ receptor stimulated cCD16ζ-T cells to release toxic granules shown by CD107a expression. cCD16ζ-T cells generated from patients with ATL (n=3) successfully displayed ADCC activity against autologous tumor cells in vitro. Human cCD16ζ-T cells infused concomitantly with mogamulizumab synergistically inhibited the growth of disseminated luciferase gene-modified ATN-1 cells in immunodeficient mice, demonstrated using an in vivo bioluminescence assay. Additionally, this tumor suppressive effect contributed to the longer survival of treated mice. Finally, the double-gene modified CD3+ T cells could successfully recognize ATN-1 through both the mogamulizumab-opsonized CCR4 and hTERT epitope/HLA-A24*02 complex on the cell surface. Disclosures Okamoto: CDM Center, Takara Bio Inc.: Employment. Mineno:Takara Bio Inc.: Employment. Shiku:Takara Bio Inc.: Research Funding.

Background: Pharmaceuticals and Medical Devices Agency (PMDA) in Japan, the US Food and Drug Administration (FDA) in the US and the European Medicines Agency (EMA) in the EU review drug applications for market approval. It was shown that most new molecular entity (NME) agents were first approved in the US because the FDA has reviewed applications more quickly (N Engl J Med. 2012; 366: 2284-93). However, differences in regulatory actions among Japan, the US and the EU in terms of relationship between the approval date and primary endpoints of pivotal trials in marketing applications including supplemental applications for additional indications have never been analyzed comprehensively. Methods: 93 indications of 55 hematologic anticancer drugs approved in Japan, the US or the EU (only central marketing authorization by the European Commission) between August 2000 and June 2014 were examined in this research. Information concerning regulatory decisions made by PMDA, the FDA and the EMA was obtained from publicly accessible data only such as PMDA’s review reports, the PMDA website, the FDA’s review reports, the Drugs@FDA website, the European public assessment reports published by the EMA’s Committee for Medicinal Products for Human Use (CHMP) and the EMA website. Results: 24, 60, and 9 indications were first approved in Japan, the US, and the EU, respectively. 2 NME agents were first approved in Japan and the EU each; mogamulizumab for relapsed CCR4-positive adult T-cell leukemia/lymphoma as well as relapsed CCR4-positive peripheral T-cell lymphoma/cutaneous T-cell lymphoma and tamibarotene for relapsed acute promyelocytic leukemia in Japan and pixantrone dimaleate for relapsed aggressive non-Hodgkin B-cell lymphoma and histamine dihydrochloride for acute myeloid leukemia in the EU. 17 indications were approved only in the US and 13 of these were approved based on response rate in single-arm trials. The other 4 indications were approved based on results of comparative trials. Of the 13 indications approved based on single-arm trials, 8 indications were approved through the accelerated approval scheme in the US. 5 indications (pixantrone dimaleate, histamine dihydrochloride, temsirolimus for relapsed mantle cell lymphoma, rituximab as maintenance therapy for relapsed follicular lymphoma and decitabine for acute myeloid leukemia) were approved only in the EU and 4 other indications (ibritumomab tiuxetan as consolidation therapy for follicular lymphoma and rituximab for diffuse large B-cell lymphoma, newly diagnosed chronic lymphocytic leukemia, and relapsed chronic lymphocytic leukemia) were approved the earliest in the EU. All these 9 indications were approved based on results of comparative trials. Of these 9 indications, only pixantrone dimaleate was approved through the conditional approval scheme and only histamine dihydrochloride was approved through the approval under exceptional circumstances scheme. Although 23 indications were approved only in Japan, most of them were additional indications of old drugs and not based on results of comparative trials. Primary endpoints were different between the US and the EU in 3 of 41 indications approved in both the US and the EU. All these 3 indications were approved earlier in the US and response rate or time to progression (TTP) in the US instead of progression-free survival (PFS) or overall survival (OS) in the EU was adopted as the primary endpoints as follows; thalidomide for newly diagnosed multiple myeloma (TTP in the US and OS in the EU), pomalidomide for relapsed multiple myeloma (overall response rate in the US and PFS in the EU), and azacitidine for myelodysplastic syndrome (complete remission rate in the US and OS in the EU). Conclusions: The conditional approval scheme or the approval under exceptional circumstances scheme in the EU and the accelerated approval scheme in the US are available, while there are no similar schemes for oncologic drugs in Japan. However, this analysis suggests that the FDA has taken a more active attitude to acceptance of surrogate endpoints. Therefore, not only shorter review time but also this attitude may lead to earlier marketing authorization of drugs for hematologic malignancy in the US. Disclosures Off Label Use: I will discuss off-label drug use in the US which has been approved in the EU or Japan..

Introduction The management of heavily pre-treated patients with relapsed ATLL is challenging. These patients display chemo-refractory disease with limited therapeutic options. The Kyowa Hakko Kirin protocol 0761-009 is a randomized controlled trial of anti-CCR4 monoclonal antibody therapy (mogamulizumab) compared with physician choice of salvage chemotherapy in relapsed ATLL. ATLL arises in HTLV-1 infected patients with high pre-morbid HTLV-1 proviral loads (>4–10 HTLV-1 DNA copies/ml)1. Methods Three patients, female, age 38 - 72 years and of Afro Caribbean origin, with relapsed chronic ATLL, have been recruited to 0761-009 in London. All patients had received two or more lines of therapy: #1 zidovudine (ZDV)/Interferon-a (IFN), anti-CD25/bortezomib; #2 ZDV/INF, anti-CD25/bortezomib, etoposide, Gemcitabine/Oxaloplatin; #3 sodium valproate, ZDV/IFN, etoposide. Lymphocyte counts at study entry were 7.8 - 33.5 x 109/L with high HTLV-1 proviral loads (range 25.4 - 122.4 HTLV-1 DNA copies/100 PBMC). Anti-CCR4 mAb was administered at a dose of 1mg/kg over 1 hour, weekly for 4 weeks and every 2 weeks thereafter. Data were censored 17/06/2014. Results All three patients achieved complete hematological remission (CR) after 1 – 2 infusions. Patient #1 remains on treatment and in CR day 397. Patient #2 received 3 treatment cycles with normalization of lymphocyte count and complete resolution of extensive cutaneous lesions (baseline SWAT= 93.6) but treatment was discontinued after 3 cycles due to, now resolved, drug toxicity. Patient #3 remains on treatment and in CR at day 139. In each case HTLV proviral load fell to 0.02% < 0.7% and have remained Conclusions Although a small case series these data illustrate the efficacy of anti-CCR4 mAb in ATLL, particularly in the chronic form, despite prior treatment failure and support the data observed in the Japanese cohort where CR was achieved in patients with blood compartmental disease, particularly chronic ATLL2. However, the extent of reduction in HTLV-1 proviral load with anti-CCR4 was not observed previously in these patients (or others who achieved CR with zidovudine/interferon the first line treatment of chronic ATLL). The reduction in HTLV-1 proviral burden to Reference List (1) Hodson A, Laydon D, Bain BJ, Fields P, Taylor GP. Pre-morbid HTLV-1 proviral load, rather than percentage of abnormal lymphocytes, is associated with an increased risk of aggressive ATLL. Haematologica2013; 98(3):385-388. (2) Ishida T, Joh T, Uike N, Yamamoto K, Utsunomiya A, Yoshida S et al. Defucosylated anti-CCR4 monoclonal antibody (KW-0761) for relapsed adult T-cell leukemia-lymphoma: a multicenter phase II study. J Clin Oncol 2012; 30(8):837-842. Disclosures No relevant conflicts of interest to declare.

Background CC chemokine receptor 4 (CCR4) is the receptor for macrophage-derived chemokine (MDC/CCL22) and thymus activation-regulated chemokine (TARC/CCL17). CCR4 is expressed on tumour cells in approximately 30-65% of patients with PTCL (Ogura, 2014). PTCL-NOS patients who are CCR4 positive have been reported to have a poorer prognosis compared to CCR4 negative patients (Ishida T CCR 2004). Mogamulizumab (KW-0761) is a defucosylated, humanized, IgG1 Mab with enhanced antibody dependent cellular cytotoxicity, that binds to CCR4. Mogamulizumab was evaluated in both phase 1 and 2 trials in Japanese patients. A phase II trial in PTCL and cutaneous T-cell lymphoma (CTCL) patients (Ogura, 2014) reported an overall response rate (ORR) of 35% in patients who relapsed after last systemic therapy (ORR was 34% in PTCL), leading to its approval in Japan in patients with previously treated CTCL and PTCL, in addition to its first indication, previously treated adult T-cell leukemia-lymphoma. Here we report the preliminary results of a European phase II trial of mogamulizumab in patients with relapsed/refractory PTCL. Methods A multi-center phase II study of mogamulizumab monotherapy was conducted to determine efficacy, safety and immunogenicity in patients with CCR4+ PTCL. The primary endpoint was ORR and secondary endpoints included duration of response, progression-free survival (PFS) and overall survival (OS). At least 34 evaluable patients were needed to detect a significant improvement over 15% assuming 80% power and a 0.0240 alpha significance level (assumes 35% ORR for alternative). Patients received mogamulizumab once weekly for 4 weeks and subsequently once every 2 weeks until progressive disease (PD) or unacceptable toxicity at a dose of 1.0 mg/kg. Responses were assessed every 8 weeks according to IWG criteria (Cheson et al 2007). Results Based on a preliminary analysis of the data, a total of 38 patients received at least one administration of mogamulizumab and were evaluable for safety analysis; (Male/female 23/15 ;Median age 58.5 years (range 19-87)). Three patients are still ongoing in the study (1 complete response (CR) and 2 stable disease (SD)). ECOG performance status at baseline was 0 (32%); 1 (29%); 2 (39%) and 92% of patients had stage III (32%) or IV (61%) disease. The median number of prior treatments was 2 (range 1-8). Only 17 patients (49%) responded to the last treatment administered prior to study entry. The median number of mogamulizumab administrations was 6 (range 1-32). The majority of adverse events (AEs) were CTCAE grade 1-2. Skin rash related to drug was observed in 32% of patients (12/38) and related AEs > grade 3 occurred in 32% (12) of patients. Infusion related reactions occurred in 3 patients (2 were CTCAE grade 2 and 1 was grade 3). Thirty-five patients were evaluable for efficacy. The ORR rate was 11% and the stable disease rate was 34% with a SD or better rate of 46%. The response by histological subtype is specified in the table below. The median duration of response (including SD) is 2.9 months. The median PFS is 2.1 months. Two patients (ALCL-ALK-neg and PTCL-NOS) proceeded to allogeneic SCT. Although the ORR in this study was less than seen in the Japanese study, the PFS was comparable. There were differences in patient population/study conduct between the Japanese study and this study, respectively, which included: inclusion of only relapsed patients (100% vs 49%), ECOG PS 2 (0% vs 39%) and response assessments (after 4 and 8 weeks versus 8 weekly from week 8). Conclusions Based on preliminary data, mogamulizumab demonstrates a SD or better rate of 46% and an ORR of 11% with an acceptable safety profile in this phase II study of heavily pre-treated relapsed/refractory PTCL patients. TableBest Overall Response by Histological subtypeNo of subjectsCR/PR n (%)SDn (%)>SD n (%)PTCL-NOS152* (13%)6 (40%)8 (53%)AITL122 (17%)3 (25%)5 (42%)TMF301 (33%)1 (33%)ALCL-ALK neg402 (50%)2 (50%)ALCL-ALK pos1000Efficacy Evaluable Subjects354 (11%)12 (34%)16 (46%) *One patient had CR by CT scan but did not have bone marrow done for confirmation of CR Disclosures Zinzani: Sandoz: Consultancy; Celgene International Sàrl: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; MundiPharma International Ltd: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Pfizer Inc: Advisory Board Other, Honoraria, Speakers Bureau; Takeda Pharmaceutical Company Limited: Advisory Board Other, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Advisory Board Other, Honoraria; GlaxoSmithKline: Advisory Board, Advisory Board Other, Honoraria; Gilead: Advisory Board, Advisory Board Other; Bayer AG: Advisory Board Other, Consultancy. d'Amore:CTI Life Sciences: Speakers Bureau; Mundipharma: Speakers Bureau; Takeda/Seattle Genetics : Speakers Bureau; Sanofi-Aventis: Research Funding; Amgen: Research Funding; Roche: Research Funding; Kyowa-Kirin: Advisory Board Other. Haioun:Roche: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Pfizer: Honoraria; Janssen: Honoraria. Morschhauser:Genentech: Honoraria; Bayer: Honoraria; Spectrum: Honoraria; Mundipharma: Honoraria; Gilead: Honoraria.

Background Adult T-cell leukemia/lymphoma (ATL) is an aggressive peripheral T cell neoplasm caused by human T-cell lymphotropic virus type I with very poor prognosis. The relationship between chemotherapy dose intensity and clinical outcome of ATL in clinical practice remains unclear. Patients and methods To elucidate the clinical characteristics and outcome of ATL patients, we retrospectively analyzed 118 patients diagnosed with ATL at 7 institutes in Miyazaki Prefecture, Japan from 2010 to 2012. There were 67 males and 51 females. The median age of the patients was 70 years (range 44–92). Subtypes included acute- (n=85) and lymphoma-type (n=33). One hundred one patients were treated with one of the below combination chemotherapy: (1) VCAP-AMP-VECP (LSG15); (2) CHOP (including pirarubicin (THP)-COP); and (3) non-LSG15, non-CHOP regimen. The prognostic value of the recently proposed prognostic index for ATL, namely ATL-PI (Katsuya et al. J Clin Oncol. 2012), was evaluated in this cohort. Relative dose intensity (RDI) during the first 12 weeks of therapy was calculated based on the standard regimen. Average RDI (ARDI) for LSG15 and CHOP was calculated. Results The median survival time (MST), 1- and 2-years overall survival (OS) rates of the entire cohort were 8.5 months, 35.3% and 23.0%, respectively. MSTs of patients less than 70 years and patients 70 years or older were 11.8 and 5.7 months, respectively (p=0.03). MSTs among all age groups for acute- and lymphoma- type were 8.3 and 10.0 months, respectively (p=0.445). Although ATL-PI could efficiently discriminate high-risk patients, it failed to separate the intermediate- and low-risk patients in this cohort. As almost all patients in this cohort were stage III or IV, ATL-PI was modified to exclude the Ann Arbor stage from variables. This modified ATL-PI could stratify our cohort into three distinct risk groups. MSTs were 3.9, 10.9, and 18.1 months for patients in high, intermediate, and low risk groups, respectively (P < 0.01). Among this cohort, 38 patients have received LSG15 and 47 patients received CHOP. Variables known to affect outcome were similar in both groups, except the age. MSTs were 11.5 and 8.1 months for patients treated with LSG15 and CHOP, respectively (p=0.206). As the median age of CHOP group is about 10 years greater than that of LSG15 group, we examined the MST in each therapy group according to the age. The MSTs for less than 70 years old were 11.7 and 21.9 months for patients treated with LSG15 and CHOP, respectively (p=0.311). Similarly, the MSTs for 70 years or older were 8.6 and 5.5 months for patients treated with LSG15 and CHOP, respectively (p=0.142). In practice, we conclude that CHOP is still a standard therapy for ATL. We next examined the RDI in each therapy groups and its relationship with OS. During the first 12 weeks, 73.7% of patients treated with LSG15 received ≥50% of planned DI, whereas 50.0% of patients treated with CHOP received ≥50% of planned DI. MSTs were significantly longer in patients treated with higher ARDI (≥50%) than that in patients with lower ARDI ( Conclusion Our modified ATL-PI excluding the Ann Arbor stage from variables in original ATL-PI may have prognostic value for patients with ATL. In the daily practice in Japan, no superiority of LSG15 compared to CHOP could be demonstrated both in young and elderly patient groups. Reduced ARDI in the first line chemotherapy for ATL is pervasive. Considering the significantly poor outcome of patients treated with ARDI less than 50%, changes in therapy with alternative strategy such as applying mogamulizumab, relatively early in the course of treatment, may improve outcome. Disclosures: No relevant conflicts of interest to declare.

Abstract 795 Background: Mogamulizumab (KW-0761) is a humanized anti-CCR4 antibody engineered to exert potent ADCC by defucosylation. In a phase I study for patients with CCR4-positive T-cell malignancies, once weekly administration for 4 weeks of mogamulizumab was well tolerated up to 1.0 mg/kg, and encouraging efficacy was observed (J Clin Oncol 2010;28:1591). In a subsequent phase II study in CCR4-positive relapsed adult T-cell leukemia-lymphoma (ATL) patients, mogamulizumab exhibited an overall response rate (ORR) of 50% (J Clin Oncol 2012;30:837), leading to its approval in Japan in 2012 for relapsed/refractory ATL. In addition, a phase I/IIa study for previously treated cutaneous T-cell lymphoma (CTCL) in the USA showed an ORR of 37% (14/38) (T-CELL LYMPHOMA FORUM 2012). Based on these findings, a phase II study of mogamulizumab for relapsed peripheral T-cell lymphoma (PTCL) and CTCL was conducted in Japan. Methods: A multicenter phase II study of mogamulizumab monotherapy for patients with relapsed CCR4-positive PTCL and CTCL was conducted to evaluate efficacy, pharmacokinetic profile, and safety. The primary endpoint was ORR and secondary endpoints included progression-free survival (PFS) and overall survival (OS). At least 35 patients were needed to detect a lower limit of the 95% confidence interval (CI) exceeding the 5% threshold, with an expected ORR for mogamulizumab of 25% with 90% statistical power. Patients received intravenous infusions of mogamulizumab once per week for 8 weeks at a dose of 1.0 mg/kg. Responses were assessed after the 4th and 8th infusions of mogamulizumab by an independent efficacy assessment committee. The histopathological subtypes of PTCL were confirmed by an independent pathology review committee according to the 2008 WHO classification. In addition, we examined blood T-cell subset distributions. Results: A total of 38 patients were enrolled, and 37 patients (male/female 23/14; median age 64 years, range 33–80) received mogamulizumab. One patient was withdrawn due to an infectious complication. Twenty-nine of the 37 assessable patients had PTCL [PTCL- not otherwise specified (NOS), n=16; angioimmunoblastic T-cell lymphoma (AITL), n=12; anaplastic large cell lymphoma (ALCL)-ALK negative, n=1] and 8 had CTCL [mycosis fungoides (MF), n=7; cutaneous ALCL, n=1]. Performance status at enrollment was 0 (n=24), 1 (n=12), and 2 (n=1). The median number of prior systemic chemotherapy regimens was 2 (range 1–6). Of the 37 patients, 25 completed the schedule of 8 planned infusions. Nine patients (24%) discontinued the treatment protocol due to progressive disease and 3 due to adverse events (AEs). The ORR in 37 patients was 35% (13/37, 95% CI, 20 to 53%) with 14% having a complete response (5/37) (Table 1). By PTCL subtype, the ORR was 34% (10/29) for PTCL (3/16 for PTCL-NOS, 6/12 for AITL, and 1/1 for ALCL-ALK negative) and 38% (3/8) for CTCL (2/7 for MF and 1/1 for cutaneous ALCL). AEs possibly, probably, or definitely related to mogamulizumab monotherapy were as follows. Lymphopenia of all grades and that of grades 3–4 were observed in 78% and 70% of the 37 patients, respectively. Leukopenia of all grades and that of grades 3–4 were observed in 43% and 14% of the 37 patients. For all grades and grades 3–4, neutropenia was observed in 35% and 16%, thrombocytopenia in 35% and 3%, ALT increases in 22% and 3%, and skin eruptions in 49% and 8% of patients, respectively. Infusion-related toxicities occurred in 22%, which were all within grade 2 or lower. Fourteen severe AEs were observed in 7 patients, including a grade 3 polymyositis in 1 and grade 2 cytomegalovirus retinitis in 2. All severe AEs were improved. No grade 5 AEs were observed. Pharmacokinetic analysis demonstrated that Cmax and trough (C168h) after the 8th infusion were 45.9 ± 9.3 and 29.0 ± 13.3 μg/mL, respectively. No anti-mogamulizumab antibody has been detected. Updated results of PFS, OS, and T-cell subset analysis are being analyzed for presentation. Conclusions: Mogamulizumab monotherapy showed promising antitumor activity with acceptable toxicity profiles in patients with relapsed PTCL and CTCL, warranting further investigation. Disclosures: Ishida: Kyowa Hakko Kirin Co., Ltd,: Honoraria, Research Funding, Speakers Bureau. Ogura:Kyowa Hakko Kirin Co., Ltd,: Consultancy. Suzumiya:Kyowa Hakko Kirin Co., Ltd,: Consultancy. Inagaki:Kyowa Hakko Kirin Co., Ltd,: Consultancy. Tamura:Kyowa Hakko Kirin Co., Ltd,: Consultancy. Akinaga:Kyowa Hakko Kirin Co., Ltd,: Employment. Tomonaga:Kyowa Hakko Kirin Co., Ltd,: Consultancy. Ueda:Kyowa Hakko Kirin Co., Ltd,: endowed chair Other.