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Key Points Consistent with previous results, pola + BR has a tolerable safety profile.The survival benefit of pola + BR vs BR persists with longer follow-up; efficacy in the pola + BR extension and randomized arms was similar., Visual Abstract, Polatuzumab vedotin plus bendamustine and rituximab (pola + BR) received regulatory approvals for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) based on primary results from the randomized arms of the GO29365 study. After the randomized phase, 106 additional patients received pola + BR in a single-arm extension cohort. We report updated results from the randomized arms and results of the extension cohort. In this phase 1b/2 study, patients with R/R DLBCL who were transplant ineligible received up to six 21-day cycles of pola + BR or BR. The primary end point of the randomized arms was the complete response (CR) rate at end of treatment. Primary objectives of the extension cohort were safety, pharmacokinetic profile, and efficacy of pola + BR. As of 7 July 2020, a total of 192 patients with R/R DLBCL were enrolled in the pola + BR cohort (n = 152 [safety run-in, n = 6; randomized, n = 40; extension cohort, n = 106]) or the BR cohort (n = 40). Significant survival benefit with pola + BR vs BR persisted in the randomized arms (median progression-free survival, 9.2 vs 3.7 months [hazard ratio, 0.39; 95% confidence interval, 0.23-0.66]; median overall survival, 12.4 vs 4.7 months [hazard ratio, 0.42; 95% confidence interval, 0.24-0.72]). In the extension cohort, the independent review committee–assessed objective response rate was 41.5%, and the CR rate was 38.7%; median independent review committee–assessed progression-free survival and overall survival were 6.6 months and 12.5 months, respectively. No new safety signals with pola + BR were identified. Pola + BR is an effective treatment option for patients with R/R DLBCL, with a well-characterized and manageable safety profile. This trial was registered at www.clinicaltrials.gov as #NCT02257567.

In the phase 3 POLARIX study (NCT03274492), polatuzumab vedotin combined with rituximab plus cyclophosphamide, doxorubicin and prednisone (Pola-R-CHP) significantly improved progression-free survival (PFS) compared with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with similar safety in previously untreated diffuse large B-cell lymphoma. Patients were randomized 1:1 to 6 cycles of Pola-R-CHP or R-CHOP plus 2 cycles of rituximab alone. For registration of POLARIX in China, consistency of PFS in an Asia subpopulation (defined as ≥50% of the risk reduction in PFS expected in the global population) was evaluated. Overall, 281 patients were analyzed: 160 patients from Asia in the intent-to-treat (ITT) population of the global study and 121 from an ITT China extension cohort. Of these, 141 were randomized to Pola-R-CHP and 140 to R-CHOP. At data cut-off (June 28, 2021; median follow-up 24.2 months), PFS met the consistency definition with the global population and was superior with Pola-R-CHP versus R-CHOP (hazard ratio 0.64; 95% confidence interval [CI], 0.40-1.03). Two-year PFS was 74.2% (95% CI, 65.7-82.7) and 66.5% (95% CI, 57.3-75.6) with Pola-R-CHP and R-CHOP, respectively. Safety was comparable between Pola-R-CHP and R-CHOP, including rates of grade 3-4 adverse events (AEs; 72.9% vs 66.2%, respectively), serious AEs (32.9% vs 32.4%), grade 5 AEs (1.4% vs 0.7%), AEs leading to study treatment discontinuation (5.0% vs 7.2%), and any-grade peripheral neuropathy (44.3% vs 50.4%). These findings demonstrate consistent efficacy and safety of Pola-R-CHP versus R‑CHOP in the Asian and global populations in POLARIX.

Background: Despite therapeutic advances in classical Hodgkin lymphoma (cHL), only half of patients with relapsed/refractory (R/R) cHL are cured with salvage chemotherapy followed by stem cell transplantation (SCT). Most studies to date have been undertaken in Europe or North America and data on treatment patterns and clinical outcomes from other regions are limited. We present the results from the B-CD30+ HOdgkin Lymphoma International Multi-center Retrospective Study of Treatment PractIces and OutComes (B-HOLISTIC), which assessed cHL treatment pathways, clinical outcomes and healthcare resource utilization across East Asia, Latin America, Middle East, South Africa, Australia and Russia (data as of 04 March 2020). Methods: Data were collected retrospectively for patients (≥18 years) diagnosed with stage IIB-IV cHL or R/R cHL between 01 January 2010 and 31 December 2013, until death or last follow-up (whichever occurred first) across 13 countries. Patients with initial diagnosis of cHL and subsequent progression to R/R cHL were included in both groups, provided R/R cHL was diagnosed within the study period. The primary endpoint was progression-free survival (PFS) in patients with R/R cHL. Secondary endpoints included overall survival (OS), best clinical response, and adverse events (AEs). Results: In total, 1703 patients were enrolled from East Asia (n=426), Latin America (n=366), Middle East and South Africa (n=694), Australia (n=56) and Russia (n=161): 1598 and 426 patients were eligible for the cHL and R/R cHL groups (321 patients in the cHL group progressed to R/R cHL and were included in both groups). Median study follow-up was 65.2 and 53.2 months for the cHL and R/R cHL groups. Baseline patient characteristics are shown in Table 1. All patients in the cHL group received first-line chemotherapy: the most common regimens were ABVD (1363/1598; 85.3%) and BEACOPP (104/1598; 6.5%). First-line radiotherapy was given to 357/1598 (22.3%) patients in the cHL group. For R/R cHL, intensive chemotherapy was used as first-line salvage in 372/426 (87.3%) patients: the most common regimens were ESHAP (98/372; 26.3%) and DHAP (65/372; 17.5%), with an overall response rate of 62.0% (complete remission in 30.8% and partial remission in 31.2%). Of the 426 patients with R/R cHL, 292 (68.5%) were eligible for SCT at relapse/refractory diagnosis; 10 patients who were initially ineligible for SCT subsequently became eligible. In total, 222/302 (73.5%) eligible patients underwent SCT; 63/222 (28.4%) patients relapsed after SCT. Median PFS (95% CI) for the R/R cHL group was 13.2 (9.9-20.2) months following initial therapy (Figure 1), with estimated 1-, 3- and 5-year PFS rates of 51.2%, 38.7%, and 33.9%, respectively (Table 2). Median PFS was not reached for the first-line cHL group. Factors for PFS in the R/R cHL group are shown in Table 3. Median OS was not reached for both groups. All-cause, any grade AEs were reported by 783/1598 (49.0%) patients with cHL and by 233/426 (54.7%) patients with R/R cHL. Serious AEs were reported by 303/1598 (19.0%) patients with cHL and by 103/426 (24.2%) patients with R/R cHL: the most common (≥2.0%) were febrile neutropenia, pneumonia and pyrexia for cHL, and febrile neutropenia and pyrexia for R/R cHL. Conclusion: Results from B-HOLISTIC show that PFS rates remain low in patients with R/R cHL receiving salvage therapy; the greatest risk was among patients with inadequate response to salvage chemotherapy. The low PFS rates highlight the importance of considering novel targeted therapies to address unmet medical needs. PFS rates in patients with cHL were comparable with previous studies from Italy, Spain, and Israel (Avigdor A et al. EHA 2020) and the ECHELON-1 study (Bartlett NL et al. ASH 2019). The higher OS rates compared to PFS rates may be related to the effect of modern salvage regimens. Approximately half of patients with R/R cHL underwent SCT which may support the use of targeted therapies. Overall, these results from 2010-2013 show that despite the differences in healthcare systems, ethnicities and treatment patterns in B-HOLISTIC, clinical outcomes remain consistent. The authors note that given that the management of high-risk cHL has changed dramatically since 2013, further investigation in diagnostic criteria, response assessment and treatment patterns is needed. Study support: Data analysis (IQVIA) and medical writing (Synergy Vision) funded by Takeda Pharmaceuticals. Disclosures Ferhanoglu: Takeda: Other: Advisory Board; Abbvie: Other: Advisory Board; Roche: Other: Advisory Board; Janssen: Other: Advisory Board. Kim:Novartis: Consultancy; AstraZeneca and Korea Health Industry Development Institute: Research Funding; Sanofi: Consultancy; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Consultancy; Voronoi: Consultancy; Boryung: Consultancy; AstraZeneca: Consultancy; Takeda: Consultancy. Karduss:Takeda: Honoraria. Rivas-Vera:Takeda: Current Employment, Other: Steering Committee in Clinical Research; Roche: Consultancy. Lim:National Cancer Centre Singapore: Current Employment. Yeh:AbbVie: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees. Abdillah:Takeda: Current Employment. Huang:Takeda: Current Employment. Dalal:Takeda: Current Employment, Current equity holder in publicly-traded company. Wan:Takeda: Current Employment. Hertzberg:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support of parent study and funding of editorial support; Gilead: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; BMS: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Introduction: Polatuzumab vedotin (Pola) is a novel antibody-drug conjugate targeting CD79b on B-cell non-Hodgkin lymphoma. In the randomized cohort of GO29365, a Phase [Ph] Ib/II study (NCT02257567; data cut-off: April 30, 2018), Pola plus bendamustine and rituximab (Pola+BR) improved progression-free survival (PFS) and overall survival (OS) compared with BR alone in patients (pts) with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). The study met its primary endpoint, with an independent review committee (IRC)-assessed complete response (CR) rate of 40.0% with Pola+BR vs 17.5% with BR. These results led to regulatory approvals of Pola+BR for the treatment of pts with R/R DLBCL. The study was later amended to include a single-arm Ph II extension (Ext) cohort of additional pts who received Pola+BR. Here, we report updated results from the GO29365 study, including the Ph Ib safety run-in cohort, Ph II randomized arms, and previously unpublished results from the Ext cohort. Methods: This open-label study enrolled pts with R/R DLBCL (aged ≥18 years, stem cell transplant [SCT]-ineligible, ECOG performance status of 0-2). Pts with Grade [Gr] >1 peripheral neuropathy [PN] were excluded. In the initial study, Pola+BR was investigated in DLBCL in a Ph Ib safety run-in cohort (Pola+BR; N=6) and Ph II randomized arms (Pola+BR vs BR; N=80); full methods were previously described (Sehn et al. J Clin Oncol 2020). Pts in the Ext cohort received Pola+BR with the same dosing regimen (Pola 1.8mg/kg IV with each cycle of BR). The primary endpoint was IRC-assessed CR at primary response assessment [PRA] by PET-CT (modified Lugano criteria). Secondary endpoints included objective response rate (ORR), best objective response (BOR), OS, PFS, duration of response (DOR), and safety. Results: As of January 2, 2020, median follow-up for pts treated with Pola+BR was 56.1 mo in the safety run-in cohort (N=6), 42.9 mo in the randomized arm (N=40), and 9.7 mo for the Ext cohort (N=106). Baseline characteristics (Table 1) were largely similar between the randomized Pola+BR arm and the Ext cohort. Updated survival data from the randomized cohort (Pola+BR vs BR) showed the median IRC-assessed PFS (95% confidence interval [CI]) was 9.2 (6.0-13.0) vs 3.7 (2.1-4.5) mo (hazard ratio [HR] 0.4; 95% CI: 0.2-0.7); median OS (95% CI) was 12.4 (9.0-32.0) vs 4.7 (3.7-8.3) mo (HR 0.4; 95% CI: 0.2-0.7), respectively (Figure). In the Pola+BR arm, 6 pts (15%) had an IRC-assessed DOR of >24 mo (range: 26.6-38.6 mo) at last follow-up; 5 pts received no new treatment, 1 pt underwent an allogeneic SCT. In the Ext cohort (N=106), the primary endpoint of IRC-assessed PET-CR at PRA was 39.6% (n=42; 95% CI: 30.3-49.6) (Table 2), consistent with that observed in the randomized Pola+BR arm (16/40; 40.0%). The BOR rate was 56.6% and best CR rate was 52.8%. The median (95% CI) IRC-assessed PFS and OS were 6.1 (5.1-8.0) and 11.0 (8.3-14.2) mo, respectively; however, OS was not fully mature. An exploratory subgroup analysis of all Pola+BR-treated pts (N=152) showed differences in median (m) PFS and OS between: pts who were primary refractory (n=97) vs non-primary refractory (n=55) (mPFS: 4.8 vs 12.6 mo; mOS: 7.8 vs 32 mo); pts who were refractory to last treatment (n=116) vs pts who were not (n=36) (mPFS: 5.3 vs 14.2 mo; mOS: 9.1 mo vs not reached); and pts who had received 1 (n=50) vs ≥2 (n=102) prior lines of therapy (mPFS: 10.4 vs 6 mo; mOS: 14 vs 9.5 mo). There were no new safety signals with Pola+BR. A safety analysis of all pts who received Pola+BR in the safety run-in, randomized and Ext cohorts (N=151) showed that 121 (80.1%) pts had Gr 3-4 adverse events (AEs), 84 (55.6%) had serious AEs, most commonly infections, febrile neutropenia, and pyrexia, and 18 (11.9%) had Gr 5 AEs, which were primarily infections. PN events of any grade were reported in 46 (30.5%) pts; 3 pts experienced Gr 3 PN, 2 of which were reported as muscular weakness. Secondary malignancies were reported in 4 (2.6%) pts. Conclusions: With additional follow-up for the randomized arms, the significant improvement in PFS and OS seen with Pola+BR vs BR persisted. The Ext cohort of additional pts who received Pola+BR (N=106) shows overall consistent efficacy with the randomized Pola+BR arm. No new safety signals were identified with Pola+BR. These data further strengthen the evidence that Pola+BR is an effective treatment for R/R DLBCL. An updated clinical cut-off date providing more mature data will be presented. Disclosures Sehn: Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Apobiologix: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Acerta: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Merck: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Teva: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Chugai: Consultancy, Honoraria; TG therapeutics: Consultancy, Honoraria; Verastem Oncology: Consultancy, Honoraria. Hertzberg:Bristol Myers Squibb: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Opat:CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Epizyme: Research Funding; AstraZenca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Herrera:Immune Design: Research Funding; AstraZeneca: Research Funding; Karyopharm: Consultancy; Pharmacyclics: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Other: Travel, Accomodations, Expenses, Research Funding. Assouline:AbbVie: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Research Funding; Pfizer: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; BeiGene: Consultancy, Honoraria, Research Funding. Flowers:Cancer Prevention and Research Institute of Texas: Research Funding; Eastern Cooperative Oncology Group: Research Funding; TG Therapeutics: Research Funding; Millennium/Takeda: Consultancy, Research Funding; Bayer: Consultancy; V Foundation: Research Funding; Kite: Research Funding; National Cancer Institute: Research Funding; BeiGene: Consultancy; Spectrum: Consultancy; Acerta: Research Funding; Pharmacyclics/Janssen: Consultancy; Karyopharm: Consultancy; OptumRx: Consultancy; Celgene: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Denovo Biopharma: Consultancy; AbbVie: Consultancy, Research Funding; Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; Burroughs Wellcome Fund: Research Funding. Kim:Takeda: Consultancy; Sanofi: Consultancy; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Consultancy; Voronoi: Consultancy; Boryung: Consultancy; AstraZeneca and Korea Health Industry Development Institute: Research Funding; Novartis: Consultancy; AstraZeneca: Consultancy. McMillan:Celgene: Honoraria, Other: Travel expenses, Speakers Bureau; Pfizer: Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Other: Travel expenses, Speakers Bureau. Ozcan:Janssen: Other: Travel support, Research Funding; Abdi Ibrahim: Other; Sanofi: Other; Jazz Pharmaceuticals: Other; Amgen: Honoraria, Other: Travel support; Bristol Myers Squibb: Other: Travel support; F. Hoffmann-La Roche Ltd: Other: Travel support, Research Funding; Takeda: Honoraria, Other: Travel support, Research Funding; Celgene: Research Funding; Bayer: Research Funding; AbbVie: Other: Travel support, Research Funding; MSD: Research Funding; Archigen Biotech: Research Funding. Salles:Karyopharm: Consultancy; Janssen: Consultancy, Honoraria, Other: Participation in educational events; Celgene: Consultancy, Honoraria, Other: Participation in educational events; Gilead: Consultancy, Honoraria, Other: Participation in educational events; Abbvie: Consultancy, Honoraria, Other: Participation in educational events; Genmab: Consultancy; Autolus: Consultancy; Debiopharm: Consultancy; Amgen: Honoraria, Other: Participation in educational events; Kite: Consultancy, Honoraria, Other; MorphoSys: Consultancy, Honoraria, Other; F. Hoffman-La Roche Ltd: Consultancy, Honoraria, Other; Takeda: Consultancy, Honoraria, Other; Novartis: Consultancy, Honoraria, Other; Epizyme: Consultancy; Bristol Myers Squibb: Consultancy, Other. Musick:Roche/Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Hirata:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Chang:F. Hoffmann-La Roche: Current Employment, Current equity holder in private company. Ku:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Matasar:Rocket Medical: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Merck: Consultancy; Juno Therapeutics: Consultancy; Immunovaccine Technologies: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; IGM Biosciences: Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Teva: Consultancy.

Background: Anti-tumor immunity plays a key role in tumor development and progression and the landscape of tumor immune microenvironment could affect the clinical outcome of patients. The concept of immunoscore based on immune cell infiltration has been actively applied to solid tumors including colon cancer and malignant melanoma and successfully predicted prognosis of patients. However, a potential utility of immunoscore in predicting prognosis of patients with diffuse large B-cell lymphoma (DLBCL) remains unclear. For easy application of immunoscore to daily practice, we investigated the prognostic value of tumor-infiltrating CD3+ T-cell density which is routinely stained for diagnosing malignant lymphomas, and then explored the feasibility of immunoscore application in DLBCL. Method: One-hundred-four patients with DLBCL treated with R-CHOP therapy, whose tumors were prospectively immunoprofiled for routine clinical diagnosis, were enrolled in this study. Immunohistochemistry was performed on representative whole formalin-fixed paraffin-embedded tissue sections using CD3, CD20, MYC, BCL2, BCL6, CD10 and MUM1. Cell-of-origin was determined using the Hans' algorithm and MYC/BCL2 double expressor (DE) was defined as the co-expression of MYC (in ≥ 40% of tumor cells) and BCL2 (in ≥ 70% of tumor cells). Whole-slide scanning was performed, whole tumor regions were annotated, and images were analyzed with Aperio ImageScope v.12.4.3 software (Leica Biosystems, Nussloch, Germany). The CD3+ density was quantified in three different methods: the total numbers of CD3+ cells/area (mm 2), CD3+ cells/total cells and CD3+ cells/CD20+ cells. Correlation between the CD3 density and clinicopathologic parameters and prognostic impact of the CD3 density were analyzed. To validate the findings, publicly available mRNA and clinical datasets of two DLBCL cohorts were downloaded and analyzed (Schmitz et al. 2018 and Sha et al. 2019). To dichotomizing low versus high CD3 density cases, the optimal cut-off values for overall survival were determined by ROC curve analysis using MedCalc Software v 19.4 (MedCalc Software, Ostend, Belgium). Remaining all statistical analyses were performed using SPSS version 25.0 (SPSS). Result: All three methods assessing CD3+ cell density showed high concordance (CD3+ cells/area vs CD3+ cells/total cells, k=0.540 p=0.000; CD3+ cells/total cells vs CD3+ cells/CD20+ cells, k=0.394 p=0.000; CD3+ cells/CD20+ cells vs CD3+ cells/area, k=0.739 p=0.000). Patients with low CD3 density had elevated serum LDH (all, p Conclusion: Low CD3 density was a poor prognostic factor in DLBCL independent of other poor prognostic parameters such as IPI score and DE status. Therefore, evaluating CD3 density might be suitable for immunoscoring DLBCL cases to predict prognosis. Disclosures Kim: Boryung: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeyondBIO: Consultancy, Membership on an entity's Board of Directors or advisory committees; Hanmi: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca/MedImmune: 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; AstraZeneca-KHIDI: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: 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; GI CELL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Background: BR101801 not only blocks the signaling responsible for cell growth caused by PI3K, but also efficiently induces cell cycle arrest and apoptosis through inhibition of DNA-PK activation and stimulates decreasing stability of the oncogenic protein, c-Myc(AACR2020 abstract #655). This phase I study evaluated safety, tolerability, pharmacokinetics and preliminary activity of the BR101801 (PI3Kγ/δ and DNA PK inhibitor) in patients with advanced hematologic malignancies. Method: This is a Phase I, multi-center, open-label, first-in-human study. The Phase Ia (dose escalation) part of the study was designed to determine the maximum tolerated dose (MTD)/recommended dose for expansion (RDE) of BR101801. BR101801 was administered orally once daily in 28-day cycles. The dose escalation part was initiated with a dose titration in the initial cohort, followed by a 3 + 3 design. Results: 11 patients were enrolled and have been treated at 4 dose levels: 50mg, 100mg, 200mg, 325mg and expanded 200mg through fifth cohort escalation. Pathological subtypes include 7 PTCL, 2 DLBCL, 1 MZBL and 1 composite CTCL/MF. 3 females and 8 males have been treated to date. Median age is 58 (range 30-71) and ECOG PS is in the range of 0-1. All patients had taken at least one prior chemotherapy. 10 of total patients have completed at least one cycle except 1 premature drop-out case due to disease progression. First interim analysis after completion of cycle 3 of the last patient of 200mg QD cohort had been conducted, which was to include 5 patients (1 DLBCL and 4 PTCLs). No DLT had been identified in Cohorts 1-3, and 2 patients discontinued the study treatment due to adverse event (G4 thrombocytopenia, not related to IP) and disease progression, respectively. The PK values from multiple dosing range of 50mg to 200mg cohort resulted in an approximate 2.92-fold and 4.97 fold increase in exposure based on Cmax and AUCtau, respectively. BR101801 PK profile showed that the exposure of concentration increased in a dose dependent manner and there was no accumulation observed in the dose range of 50mg to 200mg. 2 DLTs was observed at 325mg QD cohort. The dose was de-escalated to the previous lower dose level (200mg QD) and was expanded to 3 additional patients. The expansion cohort is ongoing at present. 2 of 11 patients had G3 skin reaction and 3 had G3 hepatotoxicites. All adverse effects were manageable and recovered to grade 0-1 upon BR1010801 discontinuation. Total 5 patients have been currently ongoing. For overall tumor response assessment, 4 SDs and 2 PRs have been obsereved. Summary/Conclusion: 200 mg QD of BR101801 was shown to provide target exposure for clinical efficacy with the tolerable and safe profiles. BR101801 was well tolerated and showed preliminary signs of activity in patients with relapsed or refractory hematologic malignancies. The phase Ib/II study of BR101801 is warranted in relapsed/refractory NHL. This study is registered at clinicaltrials.gov identifier NCT04018248. Disclosures Kim: AstraZeneca-KHIDI: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: 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; GI CELL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Hanmi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boryung: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeyondBIO: 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; AstraZeneca/MedImmune: Consultancy, Membership on an entity's Board of Directors or advisory committees. Curran: Servier pharmaceuticals and Amgen: Consultancy. Kim: Boryung pharmaceuticals: Current Employment.

Background: Positron emission tomography-computed tomography (PET-CT) is used for staging and response assessment in classical Hodgkin lymphoma (cHL) and for evaluation and management of refractory/relapsed Hodgkin lymphoma (RRHL). According to the World Health Organization's Global Atlas of Medical Devices 2017 report, 92-95% of lower-middle and low-income countries have no PET/CT unit, and only 3% of upper-middle income countries have 1 PET scanner/million people, versus 29% of high-income countries. Real-world data on PET scan use in cHL and RRHL outside Europe and North America are limited. The B-CD30+ HOdgkin Lymphoma International Multi-center Retrospective Study of Treatment Pract Ices and Out Comes (B-HOLISTIC) study assessed real-world treatment practices and clinical outcomes in patients with stage IIB-IV cHL and RRHL in countries outside Europe and North America and imaging results are presented here. Methods: The B-HOLISTIC study retrospectively reviewed patients (≥18 years) with stage IIB-IV cHL or RRHL between 2010 and 2013. Patients initially diagnosed with cHL who progressed to RRHL during the study were included in both groups. Details of PET and CT scans at baseline and during/end of frontline/salvage treatment, were reported in both groups. Results: Overall, 1703 patients (cHL: 1598, RRHL: 426, both: 321) were enrolled (East Asia: 426, Latin America: 366, Middle East and South Africa: 694, Australia: 56, Russia: 161). Median follow-up was 5.4 and 4.4 years in the cHL and RRHL groups, respectively. PET and CT results for cHL and RRHL groups are shown in Tables 1 and 2, respectively. The proportion of patients with PET scan was 73.2% in the cHL group with a median (interquartile range [IQR]) frequency of 2.0 (2.0-4.0) and 72.3% in the RRHL group with a median (IQR) frequency of 3.0 (2.0-5.0). In both groups, the proportion of PET scans at baseline was lower (cHL: 54.4%; RRHL: 32.8%) than during/ end of frontline treatment (cHL: 85.8%; RRHL: 58.8%) and at relapse/refractory diagnosis (54.5%). In contrast, the proportion of CT scans was higher (cHL: 76.4%; RRHL: 79.1%), particularly at baseline (cHL: 66%; RRHL: 51.6%). The highest proportion of PET scans was reported in Australia and lowest in Russia. The highest proportion of CT scans was in Russia in the cHL group and in Australia and East Asia in the RRHL group, while the lowest was in Middle East and South Africa in both groups. The frequency of interim PET scans was low in both cHL and RRHL groups, and were rarely used in cHL surveillance. In the RRHL group, interim PET scans during the frontline therapy were higher after cycles 3-4 and 5-6 than after cycles 1-2. Deauville 5-point scale (5-PS) was used for PET assessment at interim treatment cycles, end of frontline/salvage treatment, relapse, and surveillance in both groups with increased scans reporting a 5-PS rating towards the end of treatment and surveillance. However, its overall use was suboptimal with a minority ( Discussion and Conclusion: This study provides real-world evidence on PET use in cHL and RRHL outside Europe and North America, which is suboptimal. Although PET is part of standard care for cHL now, during 2010-2013 it was more commonly used only in RRHL, as reflected in the higher PET use in RRHL than cHL in this study. Lower overall PET use than CT and the regional differences may reflect the comparatively limited access and availability of PET, especially in low-income countries. Lower PET use at baseline may have been due to low accessibility of PET at the beginning of the study, which improved over time. Higher PET use at the end of frontline treatment in cHL is in line with the literature, and suggestive of its recognized benefits in guiding further treatment if used early in treatment. Lack of data on Deauville ratings could be because its use was uncommon during the time of the study. However, the increased Deauville score reporting towards the end of the study suggests a trend for its use. Overall, the low interim PET use, regional differences, and lack of data on use of Deauville rating in this study, suggest an existing gap in real-world practice and highlight the global inequities in access to PET. These findings suggest the need for upscaling numbers and access to PET scanners outside Europe and North America through careful planning and in-depth assessment of socioeconomic, demographic, and epidemiological circumstances of each country. Figure 1 Figure 1. Disclosures Ferhanoglu: Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Zerga: Takeda: Honoraria; Sandoz: Honoraria; Bristol Myers Squib: Honoraria; Jansen: Honoraria; Roche: Honoraria. Kim: Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeyondBIO: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boryung: Consultancy, Membership on an entity's Board of Directors or advisory committees; Hanmi: Consultancy, Membership on an entity's Board of Directors or advisory committees; GI CELL: 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; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca-KHIDI: Research Funding; AstraZeneca/MedImmune: Consultancy, Membership on an entity's Board of Directors or advisory committees. Karduss: Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees. Kwong: Amgen: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding. Wu: Takeda: Current Employment, Current equity holder in publicly-traded company. Huang: Takeda: Current Employment, Current equity holder in publicly-traded company. Hertzberg: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Introduction: Despite the curative intent of the R-CHOP regimen in the first-line treatment of diffuse large B-cell lymphoma (DLBCL), 35-40% of patients who received R-CHOP will eventually succumb to their disease (Coiffier, et al. Blood 2010; Sarkozy and Sehn. Ann Lymphoma 2019). As such, improved treatments are needed. Mosunetuzumab (Mosun) is a T-cell-engaging bispecific antibody that redirects T cells to eliminate malignant B cells by binding to CD3 on T cells and CD20 on B cells. Mosun monotherapy has a manageable safety profile and promising efficacy, including durable complete responses (CR), in patients (pts) with relapsed and/or refractory (R/R) non-Hodgkin lymphoma (NHL) (Schuster, et al. ASH 2019). This is the first report describing the safety and efficacy of Mosun plus CHOP (M-CHOP) in pts with R/R NHL and newly diagnosed DLBCL in the ongoing GO40515 (NCT03677141) study. Methods: Pts with R/R NHL and with newly diagnosed DLBCL received six 21-day cycles of M-CHOP. In Cycle (C) 1, Mosun was administered in step-up doses on Day (D) 1 (1mg), D8 (2mg), and D15 (13.5mg and 30mg in R/R NHL; 30mg in newly diagnosed DLBCL) to mitigate cytokine release syndrome (CRS). Full dose Mosun (C1D15 dose) was given on D1 of subsequent cycles in addition to CHOP. Interim and primary response assessments were obtained after C4 and C6, respectively. Primary prophylaxis with granulocyte colony-stimulating factor was mandatory for all pts. Pts with a partial response or stable disease at the end of C6 could continue Mosun monotherapy for up to 11 additional cycles. Response rates were based on the Lugano criteria (Cheson, et al. J Clin Oncol 2014). Results: As of June 3, 2020, 43 pts had received M-CHOP: seven patients with R/R NHL, and 36 pts with newly diagnosed DLBCL. Pts with disease stage II-IV were enrolled, with a median IPI score of 3 (range: 2-4) and ECOG performance status between 0 and 2. Median age was 66 (range: 39-87) and 17 pts (42%) were female. In pts with R/R NHL treated with M-CHOP (n=7), the overall response rate (ORR) was 86%, with 71% of pts achieving a CR. Twenty-seven out of 36 pts with previously untreated DLBCL started treatment at least three months prior to data cut-off date; in these pts the ORR was 96%, with a CR rate of 85% (Table). Grade (Gr) ≥3 adverse events (AEs) occurred in 37 pts (86%) and serious AEs in 19 pts (44%). Two pts (29%) with R/R NHL experienced CRS (one with Gr 1 and one with Gr 2; ASTCT grading, Lee et al. Biol Blood Marrow Transplant 2019); one pt received tocilizumab. Nineteen pts (53%) with previously untreated DLBCL had CRS events (14 with Gr 1, five with Gr2); one pt received tocilizumab. No pts required vasopressors or high-flow oxygen. All CRS events occurred in C1, resolved without sequelae, and did not result in discontinuation or delay in treatment. No immune effector cell-associated neurotoxicity syndrome (ICANS) events were observed. Neutropenia occurred in two pts with R/R NHL (29%; Gr 4 n=2) and 23 pts with newly diagnosed DLBCL (64%; Gr 3 n=3, Gr 4 n=20). Febrile neutropenia occurred in two pts (29%) with R/R NHL, and six pts (17%) with newly diagnosed DLBCL. Gr 5 AEs, excluding disease progression, were reported in two pts: one due to Pneumocystis jirovecii pneumonia in a pt with R/R NHL, and one due to pneumonia in a pt with newly diagnosed DLBCL. All pts with R/R NHL have completed treatment. Among pts with newly diagnosed DLBCL, four have completed treatment and 29 remain on treatment; one pt died on-study (Gr 5 pneumonia), and two withdrew from the study treatment due to AEs (one due to treatment-unrelated esophageal perforation; one due to treatment-related pneumonitis). Linear pharmacokinetics (PK) were observed for Mosun. No differences were seen in Mosun exposure for pts with R/R NHL and previously untreated DLBCL. Similar PK characteristics were seen with M-CHOP as with Mosun monotherapy, indicating no impact when co-administered with CHOP. Conclusions: Preliminary data show that Mosun, a novel CD20/CD3 bispecific antibody, when combined with CHOP confers high response rates and a manageable safety profile in pts with R/R NHL and previously untreated DLBCL. End of treatment response rate data for pts with previously untreated DLBCL, and correlative studies of T-cell response, will be presented. Disclosures Phillips: Incyte: Consultancy, Other: travel expenses; AstraZeneca: Consultancy; Seattle Genetics: Consultancy; Bayer: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Pharmacyclics: Consultancy; Cardinal Health: Consultancy; BMS: Consultancy; Beigene: Consultancy; Karyopharm: Consultancy. Olszewski:TG Therapeutics: Research Funding; Adaptive Biotechnologies: Research Funding; Spectrum Pharmaceuticals: Research Funding; Genentech, Inc.: Research Funding. Munoz:Alexion: Consultancy; Portola: Research Funding; Janssen: Consultancy, Research Funding, Speakers Bureau; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy; Bayer: Consultancy, Research Funding, Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Verastem: Speakers Bureau; Juno/Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; Beigene: Consultancy, Speakers Bureau; Fosunkite: Consultancy; Innovent: Consultancy; Acrotech/Aurobindo: Speakers Bureau; AstraZeneca: Speakers Bureau; Genentech/Roche: Research Funding, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Merck: Research Funding; Incyte: Research Funding; Millenium: Research Funding. Kim:AstraZeneca: Consultancy; Novartis: Consultancy; Takeda: Consultancy; Sanofi: Consultancy; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Consultancy; Voronoi: Consultancy; Boryung: Consultancy; AstraZeneca and Korea Health Industry Development Institute: Research Funding. Yoon:Celltrion: Honoraria; Samyang: Research Funding; Amgen, Chongkundang, Celgene, Astrazeneca: Consultancy. Greil:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; MSD Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; BMS/celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Daiichi Sankyo, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Astra zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding. Westin:Novartis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Curis: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; 47: Research Funding; Janssen: Consultancy, Research Funding; Amgen: Consultancy; Kite: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Jaeger:Novartis: Consultancy, Honoraria, Research Funding; Amgen: Honoraria; Infinity: Honoraria; BMS/Celgene: Consultancy, Honoraria, Research Funding; True North: Honoraria, Research Funding; Miltenyi: Consultancy, Honoraria; CDR Life AG: Consultancy, Research Funding; Karyopharm: Honoraria; Gilead: Honoraria, Research Funding; Takeda: Honoraria; AbbVie: Honoraria; F. Hoffmann-La Roche: Honoraria, Research Funding. Canales:Celgene, Gilead, iQone, Janssen, Karyopharm, Novartis, F. Hoffmann-La Roche, Sandoz: Honoraria; Janssen, F. Hoffmann-La Roche, Sandoz, Takeda: Speakers Bureau. Chen:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company; Bristol-Myer Squibb: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Janssen Pharmaceuticals: Current equity holder in publicly-traded company. Althaus:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. O'Hear:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Negricea:F. Hoffmann-La Roche: Current Employment. Xie:F. Hoffmann-La Roche: Current Employment. McCord:Genentech, Inc.: Current Employment; F. Hoffman-La Roche: Current equity holder in publicly-traded company. Purev:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Vallurupalli:Received Research funding to University of Kansas to conduct the ongoing GO40515 clinical trial for which the abstract is being submitted.: Research Funding; On Kite speaker Bureau but do not receive any honorarium.: Speakers Bureau. OffLabel Disclosure: Mosunetuzumab (RG7828; CD20-TDB) is a full-length, fully humanized immunoglobulin G1 (IgG1) bispecific antibody targeting both CD3 (on the surface of T cells) and CD20 (on the surface of B cells). Mosunetuzumab redirects T cells to engage and eliminate malignant B cells. Mosunetuzumab is an investigational agent.

BACKGROUND: Relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL) remains an area of high unmet patient need and no curative options are currently available. Odronextamab (REGN1979) is a first-in-class, hinge-stabilized, fully human IgG4-based bispecific antibody that binds to CD20-expressing cells and CD3 on T cells, targeting CD20+ cells via T-cell-mediated cytotoxicity independent of T-cell receptor recognition. The safety, tolerability, and anti-tumor activity of odronextamab monotherapy was evaluated in a global, multicenter, Phase 1 study in heavily pretreated patients with R/R B-NHL (NCT02990951; Bannerji et al, ASH 2019). Intravenous infusion of odronextamab has demonstrated an acceptable safety profile at doses up to 320 mg weekly (QW), and the maximum tolerated dose was not reached. Broad and durable anti-tumor responses were observed in both indolent and aggressive lymphomas, including in patients who progressed after prior CAR T-cell therapy. An assessment of pharmacokinetics, efficacy and safety data from the Phase 1 study informed the recommended Phase 2 dosing regimens. METHODS: This global, Phase 2, open-label, multi-cohort study (R1979-ONC-1625; NCT03888105) is designed to assess the anti-tumor activity and safety of odronextamab in patients with B-NHL. There are five disease-specific cohorts, each with independent parallel enrollment. The study includes patients with: (1) R/R follicular lymphoma (FL) Grade 1-3a after ≥2 prior lines of systemic therapy, including an anti-CD20 antibody and an alkylating agent; (2) R/R diffuse large B-cell lymphoma (DLBCL) after ≥2 lines of systemic therapy, including an anti-CD20 antibody and an alkylating agent; (3) R/R mantle cell lymphoma (MCL) following or with failure to tolerate Bruton's tyrosine kinase inhibitor therapy; (4) R/R marginal zone lymphoma (MZL) after ≥2 lines of systemic therapy; (5) other R/R B-NHL subtypes, excluding Waldenström macroglobulinemia, after ≥2 lines of systemic therapy (Fig. 1). Estimated total enrollment is 481 patients. Key eligibility criteria are: age ≥18 years; not appropriate for other approved therapy with established benefit; ≥1 bi-dimensionally measurable nodal lesion of ≥1.5 cm; Eastern Cooperative Oncology Group performance status ≤1; and adequate bone marrow, renal, and hepatic function. Key exclusion criteria are: prior anti-CD20 x CD3 bispecific antibody therapy; prior CAR T-cell therapy; primary central nervous system (CNS) lymphoma or known involvement by non-primary CNS NHL; and history of allogeneic hematopoietic stem cell transplantation. Odronextamab is administered using a step-up dose schedule consisting of an initial dose at Week (W)1, an intermediate dose at W2, and thereafter, a fixed weekly dose until W12 followed by maintenance Q2W dosing until progression or discontinuation (Fig. 2). The dose for indolent B-NHL is 80 mg QW followed by 160 mg Q2W, and for aggressive B-NHL is 160 mg QW followed by 320 mg Q2W. All patients with durable complete responses of 9 months will transition from Q2W to Q4W dosing. The primary endpoint for each cohort is objective response rate (ORR) by independent central review, as assessed from first dose until completion of 28 weeks of study treatment, or study withdrawal. Secondary endpoints include complete response (CR) rate, progression-free survival, duration of response, disease control rate (DCR), overall survival, incidence and severity of treatment-emergent adverse events, pharmacokinetics, immunogenicity, and patient-reported outcomes. ORR, CR rate and DCR with a two-sided 95% confidence interval (CI) will be summarized. Time-to-event endpoints will be summarized by median and corresponding 95% CI using the Kaplan-Meier method. The study is actively accruing patients at sites across North America, Europe, and Asia-Pacific. Disclosures Kim: AstraZeneca: Consultancy; Novartis: Consultancy; Takeda: Consultancy; Sanofi: Consultancy; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Consultancy; Voronoi: Consultancy; Boryung: Consultancy; AstraZeneca and Korea Health Industry Development Institute: Research Funding. Stevens:Amgen, MorphoSys: Consultancy. Poon:Astrazeneca, Pfizer, Takeda, Janssen, Roche, Novartis: Honoraria. Le Gouill:Loxo Oncology at Lilly: Consultancy; Roche Genentech, Janssen-Cilag and Abbvie, Celgene, Jazz pharmaceutical, Gilead-kite, Loxo, Daiichi-Sankyo and Servier: Honoraria. Carpio:Takeda, Regeneron: Consultancy. Keating:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Taiho: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Hoffman La Roche: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Adriaens:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: Dosing regime that mitigates cytokine release syndrome for therapeutic antibodies (status: pending). Ufkin:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Sabir:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Li:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Jankovic:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Zhu:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Brouwer-Visser:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Leng:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Sirulnik:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Chaudhry:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Ambati:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Won Seog:Roche, Takeda, J&J, Kyowa-Kirin, Celltrion ,Pfizer, Donga: Research Funding. OffLabel Disclosure: The Trial in Progress abstract will report on use of odronextamab in a Phase 2 clinical trial of patients with B-NHL

Background: CD47 is a myeloid checkpoint upregulated by tumor cells to evade the host's immune response. ALX148 is a fusion protein comprised of a high affinity CD47 blocker linked to an inactive human immunoglobulin Fc region. In combination with anti-tumor antibodies, ALX148 enhances the innate and adaptive immune response against cancer. ALX148 has previously been shown to be well tolerated both as a single agent and in combination with pembrolizumab or trastuzumab in a range of solid tumors with no maximum tolerated dose (MTD) identified (SITC 2018 #P335, ASCO 2019 #2514). Characterization of ALX148's safety profile and antitumor activity in combination with rituximab are reported in patients (pts) with both aggressive and indolent histologies of non-Hodgkin Lymphoma (NHL). Methods: Patients with relapsed or refractory CD20-positive B-cell NHL for which no curative therapy was available received ALX148 (10 mg/kg QW) in combination with rituximab (375 mg/m2 weekly for 4 doses followed by once monthly for 8 doses). The primary endpoint for the safety confirmation population was first cycle dose limiting toxicity (DLT). Tumor response, pharmacokinetic (PK), and pharmacodynamic (PD) markers were assessed in all pts. Preliminary clinical data from the fully enrolled cohort is reported as of July 15, 2019. Results: Twenty pts (15 males, 5 females) with NHL were administered ALX148 in combination with rituximab (DLBCL, n=11; mantle cell lymphoma, n=4; follicular lymphoma, n=3; and marginal zone lymphoma, n=2). The pts median age was 66 years (range 32-80) and ECOG PS 0/1 was 7/13. Patients had a median of 3 prior lines of therapy (range 1-7) with 50% having rituximab-refractory tumors. There were no dose limiting toxicities reported and the MTD of ALX148 in combination with rituximab was not reached. The maximum administered dose was 10 mg/kg QW. Sixteen pts experienced any AE, while 11 pts reported mostly low grade treatment-related adverse events (TRAE). The most common TRAEs were rash (20%, n=4); anemia, fatigue, nausea, neutropenia and decreased platelets (10%, n=2 each). One TRAE ≥ G3 of neutropenia occurred in more than 1 patient (1G3, 1G4). As of the data cut off with a median follow-up time of 3 (0.3-14) months, preliminary tumor response was assessed in 17 evaluable pts using the Lugano Classification, 2014. The ORR was 35% across all tumor histologies, with a 50% ORR reported in indolent (FL+MZL), and 31% ORR reported in aggressive (DLBCL+MCL) histologies. The overall DCR was 41%. Six pts achieved partial response [(2) follicular, (2) DLBCL, (2) mantle cell]. Four pts achieved SD [(1) each of follicular, marginal zone, DLBCL(>1yr), and mantle cell]. Preliminary results indicate favorable ALX148 PK and near complete CD47 receptor occupancy across the dosing interval. Results will be updated at time of presentation. Conclusions: ALX148 demonstrates excellent tolerability with favorable PK/PD characteristics in combination with rituximab in patients with relapsed/refractory NHL. The MTD of ALX148 in combination with rituximab was not reached. Encouraging preliminary activity in combination with rituximab was observed with objective responses reported in heavily pretreated and rituximab-refractory patients. Clinical trial information: NCT03013218 Disclosures Kim: AstraZeneca: Consultancy, Research Funding; Novartis: Consultancy; Sanofi: Consultancy; Bayer: Consultancy; Takeda: Consultancy. Lakhani:ALX Oncology Inc.: Research Funding; Ascentage Pharma: Research Funding; Asana Biosciences: Research Funding; BeiGene: Research Funding; Constellation Pharmaceuticals: Research Funding; Alexion Pharma: Research Funding; Cerulean Pharma: Research Funding; Forty Seven: Research Funding; Loxo: Research Funding; Macrogenics: Research Funding; Merck: Research Funding; Pfizer: Research Funding; Regeneron: Research Funding; TaiRx: Research Funding; Apexian: Research Funding; Formation Biologics: Research Funding; Coordination Therapeutics: Research Funding; Symphogen: Research Funding; CytomX: Research Funding; InhbRx: Research Funding; Incyte: Research Funding; Jounce Therapeutics: Research Funding; Livzon: Research Funding; Northern Biologics: Research Funding; Tesaro: Research Funding; Innovent Biologics: Research Funding. Gainor:BMS: Research Funding; Genentech/Roche: Other: grant; Takeda: Other: grant, personal fees; Blueprint: Research Funding; Loxo: Research Funding; Oncorus: Other: grant , personal fees; Regeneron: Other: grant,personal fees; Pfizer: Other: grant personal fees; Incyte: Other: grant personal fees; Novartis: Other: grant, personal fees; Merck: Other: grant personal fees; Agios: Other: personal fees; Amgen: Other: personal fees; Array: Research Funding; Tesaro: Research Funding; Moderna: Other: grant; Adaptimmune: Other: grant; ALX Oncology: Other: grant; Ironwood Pharma: Equity Ownership. Kamdar:AstraZeneca: Consultancy; Pharmacyclics: Consultancy; Genentech: Consultancy; Seattle Genetics: Speakers Bureau. Fanning:ALX Oncology Inc: Employment, Equity Ownership. Squifflet:IDDI: Employment; ALX Oncology Inc: Consultancy. Jin:ALX Oncology Inc.: Consultancy. Wan:ALX Oncology Inc.: Employment, Equity Ownership. Pons:ALX Oncology Inc.: Employment, Equity Ownership; venBio: Employment, Membership on an entity's Board of Directors or advisory committees. Randolph:ALX Oncology Inc: Employment, Equity Ownership; venVio: Consultancy; Carrick: Equity Ownership. Kim:Novartis: Research Funding; Donga: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; J + J: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Celltrion: Research Funding.

Hui-qiang Huang and Won-Seog Kim contributed equally to this work. Introduction: NKTCLs are rare, Epstein-Barr virus-associated distinct subtypes of peripheral T-cell lymphoma. These are primarily extranodal and of the nasal type and are more common in Asia and Central/South America (Tse and Kwong. Blood 2013. 121:4997-5005). Outcomes for patients (pts) with R/R NKTCL are very poor, and with no standard therapy, there exists a highly unmet medical need for this pt population. Clinical data from NKTCL pts suggest CD38 as a new prognostic biomarker and novel target for therapy (Wang et al. Ann Hematol 2015. 94:1381-8). Daratumumab (DARA) is a human IgGk monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action that is approved for newly diagnosed and relapsed/refractory multiple myeloma (MM). Interim results from stage 1 of a phase 2 study (NCT02927925) of DARA monotherapy in pts with R/R NKTCL demonstrated high tolerability and pre-specified futility criteria were not met (Kim et al. Blood 2018. 132:1617). Here we present data from stage 2 of the study. Methods: This phase 2 study with Simon's 2-stage design evaluated DARA monotherapy in pts with histologically confirmed extranodal NKTCL nasal type per WHO classification that was refractory to or relapsed after ≥1 line of chemotherapy, and who were not candidates for other treatment modalities. Pts without available tumor samples for biomarker determination were not eligible. DARA 16 mg/kg was administered by IV infusion once weekly for 8 weeks, every other week for 16 weeks, and every 4 weeks thereafter until progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) based on blinded independent central review (BICR) per Revised Criteria for Response Assessment of Hodgkin and non-Hodgkin Lymphoma (Lugano classification). Additional endpoints included progression-free survival (PFS) and duration of response based on BICR, overall survival (OS), and safety. Protocol-specified futility criterion for ORR (defined as at most 1 of 15 pts with complete response [CR]/partial response [PR]) was not met at interim analysis of 16 pts; stage 2 enrolled an additional 16 pts. Results: A total of 32 pts were treated with DARA monotherapy. Median age was 56 years, 91% had an ECOG score of 0 or 1, median time from initial NKTCL diagnosis was 24.0 months, median (range) plasma EBV-DNA at baseline was 900 (0-94,800) kIU/L, and 50% of pts had CD38 expression values ≥50%. At the clinical cut-off (June 4, 2019), 91% of pts discontinued treatment (disease progression [66%], pt withdrawal [13%], physician decision [9%], and adverse event [AE; 3%]). At a median follow-up of 16.7 months, ORR based on BICR was 25.0% (Table 1). Response rates were similar for pts who received The most common (>20%) all-grade treatment-emergent adverse events (TEAEs) are listed in Table 2. Eighteen (56%) pts had grade 3/4 TEAEs; thrombocytopenia (22%), and anemia, leukopenia, and neutropenia (16% each) were most common (≥15%). Two pts discontinued treatment due to TEAEs. Infusion-related reactions (IRRs) occurred in 63% of pts and were generally mild: only 2 (6%) pts had grade 3 IRRs (urticaria, hypertension, hypotension), and no grade 4 IRRs were reported. Response to DARA was not associated with CD38 expression: mean (standard deviation) percentage of tumor cells that expressed CD38 was 41.6% (31.92) in non-responders and 56.7% (39.33) in responders. Reductions in NK cells, complement protein C1q, and CD38+ Treg cells were observed in the majority of pts after 1 cycle of DARA. The percentage of pts with an EBV-DNA load reduction from baseline of greater than 25% was 50% in responders and 16.7% in non-responders (Figure 1). Conclusions: DARA 16 mg/kg was well tolerated with no new safety concerns, and only 2 patients discontinuing due to TEAEs. DARA monotherapy demonstrated an encouraging response rate (ORR: 25%) in pts with R/R NKTCL and warrants further study in this poor prognosis pt population. Disclosures Kim: Donga: Research Funding; Kyowa-Kirin: Research Funding; Roche: Research Funding; Celltrion: Research Funding; Novartis: Research Funding; J&J: Research Funding; Mundipharma: Research Funding. Kim:Novartis: Consultancy; Sanofi: Consultancy; Bayer: Consultancy; Takeda: Consultancy; AstraZeneca: Consultancy, Research Funding. Yoon:J&J: Research Funding. Lim:National Cancer Centre Singapore: Employment. Qing:Janssen: Employment, Equity Ownership. Qi:Janssen: Employment. OffLabel Disclosure: Daratumumab is under investigation for NKTCL; daratumumab is approved for use as monotherapy in multiple myeloma.

Ischemia/reperfusion (I/R) injury in the kidney is a major cause of acute kidney injury (AKI) in humans and is associated with significantly high mortality. To identify genes that modulate kidney injury and repair, we conducted genome-wide expression analysis in the rat kidneys after I/R and found that the mRNA levels of fibrinogen (Fg)α, Fgβ, and Fgγ chains significantly increase in the kidney and remain elevated throughout the regeneration process. Cellular characterization of Fgα and Fgγ chain immunoreactive proteins shows a predominant expression in renal tubular cells and the localization of immunoreactive Fgβ chain protein is primarily in the renal interstitium in healthy and regenerating kidney. We also show that urinary excretion of Fg is massively increased after kidney damage and is capable of distinguishing human patients with acute or chronic kidney injury (n = 25) from healthy volunteers (n = 25) with high sensitivity and specificity (area under the receiver operating characteristic of 0.98). Furthermore, we demonstrate that Fgβ-derived Bβ15-42 peptide administration protects mice from I/R-induced kidney injury by aiding in epithelial cell proliferation and tissue repair. Given that kidney regeneration is a major determinant of outcome for patients with kidney damage, these results provide new opportunities for the use of Fg in diagnosis, prevention, and therapeutic interventions in kidney disease.

Introduction: Outcomes for transplant-ineligible R/R DLBCL patients remain poor. Pola is an antibody-drug conjugate that delivers the microtubule inhibitor MMAE to CD79b+ cells in B-NHL. Previously, we reported results from the Ph Ib/II pola + BG arms and results of the Ph II randomized arms comparing pola + BR versus BR (Matasar et al. EHA 2017; Sehn et al. ASCO 2018). Here, we report the longer-term follow-up results for these DLBCL cohorts with additional biomarker data (ClinicalTrials.gov: NCT02257567). Methods: R/R DLBCL transplant ineligible patients received pola 1.8mg/kg + B (90mg/m2/day x 2 days) and R (375mg/m2) or G (1000mg). Patients were treated every 21 days for up to 6 cycles. The study design is shown in Figure 1. The randomized cohort was stratified by duration of response (DoR) to last therapy ≤12 months versus >12 months. Responses were assessed using the modified Lugano Classification (complete response [CR] required positron emission tomography (PET) negativity and negative bone marrow biopsy if positive or unknown at screening). The primary aim of Ph Ib was safety and identification of the recommended Ph II pola dose. The primary aim of the randomized Ph II component was to assess the efficacy of pola + BR vs BR at end of treatment (EOT) by an independent review committee (IRC). Other aims included evaluation of DoR, progression free survival (PFS) and overall survival (OS) with additional evaluation of efficacy by cell-of-origin (COO) and MYC/BCL2 double expression. COO was determined by Nanostring Lymph2x. MYC/BCL2 immunohistochemistry cutoffs were >40% over background and >50% with moderate to strong (2 or 3+) staining, respectively. Results: Baseline characteristics were previously described (Matasar et al. EHA 2017; Sehn et al. ASCO 2018). As of April 30, 2018, median follow-up for the Ph Ib pola + BR, Ph II randomized pola + BR versus BR, and Ph Ib/II pola + BG arms were 37.6, 22.3, and 27.0 months, respectively. Safety: Updated safety results are similar to those previously described with no new safety signals identified. Efficacy: PET-CR rates at EOT by IRC and updated DoR and PFS (by investigator) and OS are shown in the Table. In the randomized Ph II portion, pola + BR showed significantly higher PET-CR rates versus BR alone (40% vs 18%; p=0.026) as assessed by IRC at EOT. Significantly longer DoR (HR, 0.44; p=0.032), PFS (HR, 0.34; p20 months. Preliminary biomarker analyses of COO showed in the BR arm: 16 ABC and 13 GCB, and in pola + BR: 14 ABC and 14 GCB. For ABC patients, median PFS (pola + BR vs BR) was 10.5 versus 2.5 months and median OS was 13.9 versus 4.3 months, respectively. For GCB patients, median PFS (pola + BR vs BR) was 4.7 versus 1.5 months and median OS was 9.3 versus 3.2 months, respectively. Of patients tested for MYC/BCL2 overexpression, BR had 6 double expressors (DE) and 13 non-DE, and pola + BR had 9 DE and 13 non-DE. For DE, median PFS (pola + BR vs BR) was 7.0 versus 0.7 months, and median OS was 12.9 versus 3.8 months. For non-DE, median PFS (pola + BR vs BR) was 6.3 versus 2.5 months and median OS was 10.5 versus 3.8 months. Conclusions: In a randomized setting, pola + BR showed significantly longer survival compared to BR, with median OS surpassing 12 months. In addition, results from the updated follow-up suggests that durable responses could be possible in some patients as responses of >20 months have been observed in patients treated with pola + BR/BG. Although the biomarker sample sizes were small, Pola + BR appears to provide benefit compared with BR regardless of COO or DE status. Pola + BR provides a promising treatment option for R/R DLBCL patients who are transplant ineligible. Disclosures Sehn: Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria. Herrera:Bristol-Myers Squibb: Consultancy, Research Funding; KiTE Pharma: Consultancy, Research Funding; AstraZeneca: Research Funding; Pharmacyclics: Consultancy, Research Funding; Immune Design: Research Funding; Genentech: Consultancy, Research Funding; Gilead Sciences: Research Funding; Merck, Inc.: Consultancy, Research Funding; Seattle Genetics: Research Funding. Matasar:Seattle Genetics: Honoraria. Kamdar:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Assouline:BMS: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding; Roche: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Research Funding, Speakers Bureau. Hertzberg:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees. Kim:J&J: Research Funding; Celltrion: Honoraria, Research Funding; Mundipharma: Research Funding; Novartis: Research Funding; Merck: Research Funding; Celgene: Research Funding; Eisai: Honoraria, Research Funding; Takeda: Research Funding; Roche: Honoraria, Research Funding; Kyowa-Kirin: Research Funding. McMillan:Roche: Consultancy, Honoraria, Other: travel support; Takeda: Other: travel support; Amgen: Honoraria; BMS: Honoraria; Celgene: Honoraria, Other: travel support; Pfizer: Research Funding; MSD: Honoraria. Özcan:Jazz: Other: Travel support; MSD: Other: travel support, Research Funding; Jazz: Other; BMS: Honoraria; Archigen: Research Funding; Bayer: Research Funding; Celgene: Other: Travel support, Research Funding; Roche: Honoraria, Research Funding; Abbvie: Other: Travel payment; Janssen: Other: Travel Support, Research Funding; MSD: Research Funding; Takeda: Honoraria, Other: Travel payment, Research Funding; Novartis: Research Funding. Hirata:Genentech: Employment; Roche: Equity Ownership. Penuel:Genentech Inc: Employment. Cheng:Roche: Employment. Ku:Genentech: Employment. Flowers:Gilead: Consultancy; Millennium/Takeda: Research Funding; Abbvie: Research Funding; Genentech/Roche: Consultancy; Acerta: Research Funding; National Cancer Institute: Research Funding; TG Therapeutics: Research Funding; OptumRx: Consultancy; Bayer: Consultancy; Genentech/Roche: Research Funding; Karyopharm: Consultancy; Celgene: Research Funding; Spectrum: Consultancy; Pharmacyclics/ Janssen: Consultancy; Gilead: Research Funding; BeiGene: Research Funding; Abbvie: Consultancy, Research Funding; Janssen Pharmaceutical: Research Funding; Denovo Biopharma: Consultancy; Pharmacyclics: Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; V Foundation: Research Funding.

Background: The cure rate for advanced classical Hodgkin lymphoma (cHL) is approximately 70%, which is calculated based on data from clinical trials performed in North American and/or European countries (Canellos GP, et al. N Engl J Med. 1992;327:1478-84; Carde P, et al. J Clin Oncol. 2016;34:2028-36; Gordon LI, et al. J Clin Oncol. 2013;31:684-91). However, there are limited outcome data available in other countries, apart from some small hospital-based studies (Ramirez P, et al. Rev Bras Hematol E Hemoter. 2015;37:184-9; Law MF, et al. Arch Med Sci. 2014;10:498-504; Jaime-Pérez JC, et al. Oncologist. 2015;20:386-92; Omer Al-Sayes FM, Sawan A. J Taibah Univ Med Sci. 2006;1:48-56). The B-HOLISTIC retrospective chart review study seeks to address the paucity of data on cHL treatment patterns, clinical outcomes, and healthcare resource utilization in 13 countries across Latin America, Africa, Middle East, and the Asia-Pacific region. Methods: The study will collect data from approximately 2,600 patients aged ≥18 years and newly diagnosed with stage IIB-IV cHL or relapsed/refractory cHL (RRHL) between 01 January 2010 and 31 December 2013, and will follow them until death or chart review, whichever occurs first. The primary objective is to describe progression-free survival (PFS) in patients with RRHL. Secondary objectives include describing demographic and clinical characteristics, clinical outcomes (overall survival, best clinical response after completion of treatment, response duration), key adverse events associated with each line of therapy, and cHL-related healthcare resource use. Results: As of 14 May 2018, a total of 165 patients from 12 sites have been included in the interim analysis, predominantly from Turkey and South Korea. At this time, 150 patients had cHL and 24 patients had RRHL, including 9 patients who were enrolled in the cHL group and had a documented relapse/progression during the study period. Here, we report the results of the newly diagnosed cHL group; data from the RRHL group will be reported in subsequent publications. At diagnosis, 64.7% of the cHL group were male, with a median age of 36.5 years (range, 18-89 years); 22.7% had stage IV disease, 30% had extranodal disease, 59.3% had 'B' symptoms, and 34.9% had an International Prognostic Score (IPS) of ≥4. Patients were classified as 13.3% in stage I-IIA; 24% in stage IIB; 53.3% in stage IIIA-IVB; and 9.3% as unknown. Patients classified as stage I-IIA are a deviation from the clinical study protocol and will be removed from the final study analysis. The proportion of patients alive was 94%, with the cause of death reported as either HL-related (44.4%), due to an adverse event (11.1%), or other (44.4%). Positron emission tomography (PET) or PET-computed tomography (CT) imaging was performed in 58.5% of patients at baseline, 48% of patients at interim, and 36.6% at end-of-treatment; CT imaging was performed in 68.7% of patients at baseline, 83.6% of patients at interim, and 59.7% of patients at end-of-treatment. At frontline treatment, 95.3% of patients received chemotherapy (mostly doxorubicin, bleomycin, vinblastine, dacarbazine [ABVD], 92.3% [median number of cycles, 6; range, 2-8]), 22.7% of patients received radiotherapy, with 22% of patients receiving radiotherapy and chemotherapy (median total dose, 34.5 Gy; range, 24-45 Gy). The majority of patients received involved-field radiotherapy (53.1%), with other modalities including involved-node (21.9%), involved-site (18.8%), whole body (3.1%), or other (3.1%). The proportion of patients who achieved a complete or partial response to frontline treatment was 52.1% and 21.1%, respectively. The PFS for treatment in frontline cHL in the overall patient population at 48 months was 81% (95% CI, 73.1-86.7; Figure 1), with a median duration of follow-up of 58.9 months (range, 2.6-128.3 months). The PFS for treatment in frontline cHL excluding ineligible patients classified as stage I-IIA (13.3%) at 48 months was 78.9% (95% CI 69.7-85.6). Due to the retrospective nature of this study, adverse events were under-reported and will be presented once the data are mature. Conclusion: The B-HOLISTIC study is ongoing, with final patient enrolment anticipated in December 2018. These interim data provide real-world information on the incidence, treatment, and outcomes of cHL in countries where little is known about this patient population. Disclosures Ferhanoglu: Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Yeh:GNT Biotech & Medicals Crop.: Research Funding. Brittain:Takeda: Membership on an entity's Board of Directors or advisory committees. Karduss:Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Kwong:Bayer: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Song:Peking University Cancer Hospital (Beijing Cancer Hospital): Employment. Zerga:Bristol Myers Squibb: Other: Conference fees; Roche: Other: Conference fees; Janssen: Other: Conference fees; Takeda: Other: Conference fees. Blair:Takeda Pharmaceuticals International Co.: Employment. Dalal:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd, Cambridge, MA, USA: Employment, Equity Ownership. Wan:Takeda Pharmaceuticals International Co.: Employment. Hertzberg:Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees.

Evidence for the epigenetic regulation of hematopoietic stem cells (HSCs) is growing, but the genome-wide epigenetic signature of HSCs and its functional significance remain unclear. In this study, from a genome-wide comparison of CpG methylation in human CD34+ and CD34− cells, we identified a characteristic undermethylation dip around the transcription start site of promoters and an overmethylation of flanking regions in undifferentiated CD34+ cells. This “bivalent-like” CpG methylation pattern around the transcription start site was more prominent in genes not associated with CpG islands (CGI−) than CGI+ genes. Undifferentiated hematopoietic cells also exhibited dynamic chromatin associated with active transcription and a higher turnover of histone acetylation than terminally differentiated cells. Interestingly, inhibition of chromatin condensation by chemical treatment (5-azacytidine, trichostatin A) enhanced the self-renewal of “stimulated” HSCs in reconstituting bone marrows but not “steady-state” HSCs in stationary phase bone marrows. In contrast, similar treatments on more mature cells caused partial phenotypic dedifferentiation and apoptosis at levels correlated with their hematopoietic differentiation. Taken together, our study reveals that the undifferentiated state of hematopoietic cells is characterized by a unique epigenetic signature, which includes dynamic chromatin structures and an epigenetic plasticity that correlates to level of undifferentiation.

Self-renewal of hematopoietic stem cells (HSCs) is key to their reconstituting ability, but the signaling pathways that regulate this process remain poorly understood. Here we show that transduction of adult mouse bone marrow cells with a constitutively activated form of Stat3 (Stat3-C) increased their regenerative activity in lethally irradiated recipients. Conversely, transduction of these cells with a dominant-negative form of Stat3 suppressed their regenerative activity. Serial transplantation and clonal tracking of the HSC progeny regenerated in vivo from STAT3-C–transduced HSCs demonstrated that the major effect of forced expression of STAT3-C was to enhance HSC self-renewal during the initial phase of hematopoietic recovery. This acquired potential for enhanced self-renewal divisions then became latent, but was reactivated when the cells were transferred to new irradiated recipients. Increased levels of activated STAT3 were also found to be associated with greater preservation of primitive hematopoietic cells in short-term cultures. These results indicate a novel biphasic regulation of HSC self-renewal in vivo in which activated STAT3 promotes HSC self-renewal under stimulated, but not homeostatic, conditions. STAT3 may thus be an important regulator of hematopoietic regeneration and a novel target for HSC engineering.

To the editor: The anaplastic lymphoma kinase (ALK) gene is expressed in >50% of anaplastic large-cell lymphomas (ALCLs).[1][1] Although most patients with ALK-positive ALCL respond well to anthracycline-based chemotherapy, relapses do occur (5-year failure-free survival 60%) and require salvage

Introduction: Patients with transplant ineligible R/R FL or DLBCL have poor outcomes. Polatuzumab vedotin (PoV) is an antibody drug conjugate (ADC) designed for the targeted delivery of the potent microtubule inhibitor MMAE to cells expressing CD79b. PoV combined with R has previously demonstrated promising response rates in patients (pts) with R/R FL and DLBCL. The addition of B to PoV-R and substitution of G for R could improve outcomes in these pts. We report preliminary results from the safety run-in portion of a Phase Ib/II study evaluating PoV combined with BR or BG in R/R FL or DLBCL and the expansion cohort evaluating PoV combined with BG in R/R DLBCL (ClinicalTrials.gov NCT02257567). Methods: This multicenter, open-label study evaluates the safety and tolerability of PoV combined with B (90 mg/m2) and R (375 mg/m2) or G (1000 mg). Adult pts were treated with PoV 1.8 mg/kg intravenously with BR or BG every 28 days for FL pts and every 21 days for DLBCL pts for a total of 6 cycles. Response assessment was performed following 3 cycles of study treatment (tx), end of study tx, and every 6 months for 2 years during the follow-up period. Results: As of May 2, 2016, 45 pts have been enrolled; 24 pts (12 FL, 12 DLBCL) in the safety run-in portion and 21 R/R DLBCL pts the expansion cohort. Baseline characteristics for safety-evaluable patients are shown in Table 1. At the time of this report, all 24 pts in the safety run-in portion and 19 pts in the expansion cohort have completed at least one response assessment. Among the 44 pts enrolled in the FL and DLBCL cohorts who received at least one dose of study tx, the most common adverse events (AEs) in > 20% of pts were nausea (50%), diarrhea (45%), fatigue (39%), pyrexia (29%) and constipation (27%). In the FL safety run-in cohorts, 67% (8/12) patients had Grade 3/4 AEs and 25% (3/12) had serious AEs (SAEs). The most common Grade 3/4 AEs in ≥ 10% of FL pts were neutropenia (33%) and thrombocytopenia (17%) and were attributed to study tx. No single SAE occurred in more than 1 pt. AEs led to study tx interruption in 2 pts and one pt discontinued bendamustine due to grade 3 thrombocytopenia. Treatment-emergent Grade 1 peripheral neuropathy was reported in 3 pts and did not lead to study tx discontinuation. PoV was dose reduced from 1.8 mg/kg to 1.4 mg/kg in 1 pt with Grade 1 neuropathy who was able to complete study tx. In the DLBCL safety run-in and expansion cohorts, 78% (26/32) of safety-evaluable pts had Grade 3/4 AEs and 53% (17/32) of pts had SAEs. The most common Grade 3/4 AEs in ≥ 10% of pts were neutropenia (25%), thrombocytopenia (13%), and pneumonia (13%) and the most common SAEs ≥ 10% of pts were pneumonia (19%) and pyrexia (16%). AEs led to study tx interruption in 15 pts and led to study tx discontinuation in 5 pts. Three pts died due to AEs (1 due to general physical health deterioration, 2 due to pneumonia) all of which were not related to study tx. One pt died due to progressive disease. Grade 1 peripheral neuropathy was reported in 5 pts and did not lead to study tx interruption or discontinuation. Grade 2 peripheral motor neuropathy was reported in 1 pt, which led to study tx discontinuation. Best objective response by PET/CT for evaluable pts as of May 2, 2016 is reported in Table 2. The objective response rate (CR+PR) was 100% in R/R FL and 65% in R/R DLBCL. The majority of pts who achieved a CR or PR remain in response. Of the 3 DLBCL pts who achieved a CR or PR on the PoV + BR safety run-in cohort, all 3 remain in remission with a median follow-up of 8.4 months with one pt remaining in response for 14 months. 83% (5/6) of FL pts continue to be in CR or PR with 3 pts remaining in response for over 9 months. The duration of responses for pts treated on the PoV + BG is not reported due to insufficient follow-up and will be updated at the time of presentation. Conclusions: Preliminary evaluation of efficacy showed promising durable responses in heavily pre-treated R/R FL and DLBCL patients. In addition, PoV combined with BR or BG has an acceptable safety profile in pts with R/R FL and DLBCL and confirmed the PoV dose of 1.8 mg/kg to be the recommended phase 2 dose. The safety and efficacy data will be updated at the time of presentation. Disclosures Herrera: Genentech: Research Funding; Immune Design: Research Funding; Merck: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Adaptive Biotechnologies: Research Funding. Assouline:BMS: Speakers Bureau; Lundbeck: Consultancy; Janssen: Consultancy, Speakers Bureau; Pfizer: Speakers Bureau. Kamdar:Seattle Genetics: Speakers Bureau. Mehta:Merck: Research Funding; Pharmacyclics: Research Funding; Roche Genentech: Research Funding; Medimmune: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Bristol Myers Squibb: Research Funding. Fleury:Lundbeck: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Kim:Celltrion, Inc.: Consultancy, Honoraria. Bosch:Hoffman La Roche: Consultancy, Honoraria, Research Funding; Millennium: Research Funding. Radford:Novartis: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; GSK: Equity Ownership; Astra-Zeneca: Equity Ownership; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau. Bu:Roche: Employment. Hong:Genentech: Employment. Sehn:roche/genentech: Consultancy, Honoraria; amgen: Consultancy, Honoraria; seattle genetics: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; TG therapeutics: Consultancy, Honoraria; celgene: Consultancy, Honoraria; lundbeck: Consultancy, Honoraria; janssen: Consultancy, Honoraria.

Traditionally believed to be a very rare condition, the reported incidence of neurolymphomatosis (NL) seems to be increasing. Nonetheless the diagnosis of NL remains challenging, especially in patients with refractory or relapsed hematologic malignancies, often leading to delayed or obscured diagnosis. Here, we describe our experience with secondary peripheral NL in non-Hodgkin lymphoma (NHL) patients, with the emphasis on the diagnosis process. A retrospective chart review was conducted in 3 tertiary academic centers in Korea from January 2005 to December 2015. A total of 12 patients were recognized, and we analyzed data including patient demographics, clinical history and presentations including the time lag between first symptom and treatment initiation, radiologic findings, serum tests, cerebrospinal fluid findings, results of electrodiagnostic studies, and biopsy analysis. The most common underlying lymphoma subtype was diffuse large B-cell lymphoma (75%, 9/12). NL occurred as a progressive disease during the first line of chemotherapy in 3 patients, and as a relapse of a previously treated disease in the remaining 9. Secondary NL was diagnosed within a median interval of 10 months (range 5-41 months) after initial diagnosis of NHL.Peripheral nerves were the most frequently involved site and NL affected more than one anatomic structure in 5 (41.7%) patients (Table). The diagnostic modalities included CSF analysis performed in 9 out 12 patients (75.0%), electrodiagnostic studies obtained in 7 out of 12 patients (58.3%), radiologic studies carried out for all patients, and nerve biopsy done in 2 patients (16.7%). The diagnostic yield of FDG-PET was high at 83.3% (10/12 patients). The diagnostic yield of MRI was 80.0% (8/10 patients). For those 2 patients in whom the imaging modality was not definitively diagnostic, nerve biopsy was carried out. Biopsy was performed from sural nerve and right sciatic nerve. In contrast to imaging modalities, CSF cytology and electrodiagnostic studies do not seem to be very useful in NL diagnosis. Painful neuropathy was present in 66.7% of our series, but the diagnosis of NL was delayed in 9 out of 12 patients (75.0%) by median of 2 months. In 2 patients, neuropathy was thought to be related to chemotherapeutic agents, while in 5 patients the cause was thought to be of inflammatory origins (2 with adhesive capsulitis, 1 with myofascial pain syndrome, 1 with postherpatic neuralgia, 1 with non-specific age related process, respectively).. Our experience emphasizes that the first step to timely recognition of NL in patients with previous history of NHL is a high index of clinical suspicion. Second step to diagnosis of NL would be choosing the diagnostic modality with the greatest clinical utility. Since PET scans are highly sensitive and at the same time can readily visualize both the peripheral and cranial nerve involvement as well as other tissue involvements, it seems to be the better imaging modality. In conclusion, with its increasing incidence, a high index of clinical suspicion is the first step to early diagnosis of secondary NL. Such clinical suspicion should be followed by timely use of subjective image modalities, preferably FDG-PET. Future studies are warranted to standardize the diagnosis process and optimize the therapeutic approaches to secondary NL. Disclosures No relevant conflicts of interest to declare.

Background Rituximab in combination with chemotherapy is the standard of care for patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). To improve patient convenience and to reduce healthcare resource burden, a subcutaneous (SC) formulation of rituximab has been developed and has been shown to be clinically comparable to intravenous (IV) rituximab. The aim of this study was to evaluate patient preference for rituximab IV or SC administration. Methods Prefmab (NCT01724021) is a randomized, open-label, crossover phase IIIb study. Eligible patients were aged ≥18 to ≤80 years with previously untreated CD20+ DLBCL (IPI 1-4 or 0 with bulky disease) or FL (FLIPI grade 1-3a), at least 1 bidimensionally measureable lesion ≥1.5cm at its largest dimension by computed tomography, and an ECOG performance status ≤3; all provided written informed consent. Patients received 8 cycles of rituximab according to 2 schedules: Arm A received 1 cycle of rituximab IV (375mg/m2) and 3 cycles of rituximab SC (1400mg) then 4 cycles of rituximab IV; Arm B received 4 cycles of rituximab IV (375mg/m2) then 4 cycles of rituximab SC (1400mg). Alongside rituximab, both arms received 6-8 cycles of chemotherapy (CHOP [cyclophosphamide, doxorubicin, oncovin, prednisone], CVP [cyclophosphamide, vincristine, prednisone], or bendamustine as per standard local practice). A Patient Preference Questionnaire (PPQ) was conducted post-rituximab therapy at cycles 6 and 8. The primary endpoint was overall preference for rituximab IV or SC. The strength of patient preference was also assessed (very strong, fairly strong, or not very strong). Adverse events (AEs), including administration-related reactions, were evaluated according to NCI-CTCAE version 4.0. Results At the primary data cut-off (January 19, 2015), the intent-to-treat population comprised 743 patients (Arm A: n=372; Arm B: n=371). The majority of patients had DLBCL (63%). The median age was 60 years (range 18-80) and baseline characteristics were balanced between arms. One hundred and twenty patients discontinued immunochemotherapy treatment prematurely, primarily due to AEs (n=52), but entered follow-up. A further 108 patients (Arm A: n=48; Arm B: n=60) discontinued the study and did not complete follow-up, primarily due to death (53 patients [DLBCL: n=48; FL: n=5], 19 of whom died due to progressive disease [DLBCL: n=16; FL: n=3]), patient request/withdrawal of consent (n=23), or AEs (n=9). Rates of study discontinuation and treatment discontinuation were balanced between arms. The PPQ was completed by 620 patients at cycle 6 and 591 at cycle 8. At cycle 6, rituximab SC was preferred by 80% (n=495) of patients (Arm A: 79%; Arm B: 81%) and rituximab IV by 10% (n=62; Arm A: 11%; Arm B: 9%), while 10% (n=63) had no preference (Arm A: 10%; Arm B: 10%). At cycle 8, the respective values were 81% (n=477; Arm A: 77%; Arm B: 84%), 11% (n=66; Arm A: 13%; Arm B: 10%), and 8% (n=48; Arm A: 10%; Arm B: 6%). The strength of patient preference for rituximab SC or IV is shown in Figure 1. Of patients who preferred rituximab SC, the main reasons were 'less time in the clinic' (cycle 6: 68%; cycle 8: 69%) and 'feels more comfortable during administration' (cycle 6: 37%; cycle 8: 37%). The mean cumulative rituximab administration time (mean ± standard deviation) was 865 ± 401 min for rituximab IV compared with 37 ± 100 min for rituximab SC. AEs were generally balanced between rituximab IV and SC administration, with the exception of gastrointestinal disorders (IV: 55%; SC: 31%) in patients with FL, notably nausea (IV: 28%; SC: 11%), constipation (IV: 14%; SC: 6%), and vomiting (IV 12%; SC 2%). No new safety signals were detected. Conclusions Most previously untreated patients with CD20+ DLBCL or FL preferred SC compared with IV administration of rituximab, mainly due to reduction in the duration and discomfort of administration. Figure 1. Figure 1. Disclosures Rummel: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Plenteda:Roche: Other: Sub-investigator. Mendoza:Roche: Employment. Smith:Roche: Employment. Osborne:Roche: Employment. Grigg:Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Background The prognosis of NTCL patients presenting in stage III/IV is extremely poor and there is no standard chemotherapy. Although L-asparaginase (L-asp) is known to be effective for NTCL, its significance has not been well demonstrated in a relatively homogenous subset. In addition, there were few studies to evaluate treatment outcomes and prognostic factors in stage III/IV NTCL. This study was undertaken to evaluate the efficacy of L-asparaginase-based combination chemotherapy (IMEP plus L-asp) and prognostic factors in stage III/IV NTCL. Methods A total of 70 patients with newly diagnosed NTCL at stage III/IV were enrolled from 3 Korean centers between Jan 2000 and Feb 2013. All patients received IMEP plus L-asp (N=22) regimens or combination chemotherapy without L-asp (N=48) as a first-line treatment. Recurrent cases were excluded. Clinical prognostic factors, treatment outcomes, and prognostic scores were compared between the groups. Independent prognostic factors for survivals were identified using multivariate analyses. Results The median age was 48.5 years (range, 18-73 years) with a male-to-female ratio of 2.2:1. After a median follow-up period of 12.8 months (range, 1.1-186.6 months), median progression-free survival (PFS) and overall survival (OS) were 5.6 months and 12.3 months, respectively. Clinical factors and treatment outcomes were compared between IMEP plus L-asp and chemotherapy without L-asp groups (Table 1). Higher response rate (RR) and complete response (CR) rates were observed in patients treated with IMEP plus L-asp compared with those treated with chemotherapy without L-asp (RR 90.0% vs. 34.8%, P< 0.0001; and CR rates 65.0% vs. 21.7%, P = 0.001). In addition, PFS and OS were significantly higher for IMEP plus L-asp group compared with chemotherapy without L-asp group (Table 1). Use of chemotherapy without L-asp (hazards ratio [HR]=2.29, 95% confidence interval [CI] 1.22-4.29; P = 0.010) and poor performance status (HR=2.10, 95% CI 1.23-3.59; P = 0.007) were independent predictors for reduced PFS. Independent factors adversely affecting OS were poor performance status (HR=1.99, 95% CI 1.08-3.65; P = 0.027), 2 or more extranodal sites (HR=2.91, 95% CI 1.25-6.77; P = 0.013), and chemotherapy without L-asp (HR=3.51, 95% CI 1.53-8.06; P= 0.003). Conclusions L-asparaginase-based combination chemotherapy (IMEP plus L-asp) is active against stage III/IV NTCL and an independent predictor for improved survivals. L-asp containing regimen might be useful as a first-line treatment for stage III/IV NTCL. Disclosures: No relevant conflicts of interest to declare.

Introduction Crizotinib (Xalkori®) is an ALK inhibitor with proven efficacy in patients with ALK-rearranged advanced non-small cell lung cancer (NSCLC; Shaw AT et al, New Engl J Med 2013;368:2385–9). However, ALK rearrangement is implicated in other types of malignancy, including anaplastic large-cell lymphoma (ALCL) and diffuse large B-cell lymphoma (DLBCL). Here we assess the safety and anti-tumor activity of crizotinib in patients with advanced ALK-rearranged hematologic malignancies enrolled in an open-label phase 1b study (Pfizer; A8081013; NCT01121588). Methods ALK-positivity was confirmed by IHC for cases of ALCL; other malignancies required confirmation by FISH, PCR, or sequencing. Patients with brain metastases were eligible if neurologically stable for 2 weeks with no ongoing treatment requirement. Eligible patients received crizotinib 250 mg twice daily. Responses were assessed every 6 weeks using RECIST v1.1 or Revised Response Criteria for Malignant Lymphoma 2007 (Cheson criteria); best overall response was determined by RECIST or Cheson if only one assessment was available, and by Cheson criteria if both were available. Adverse events (AEs) were assessed using CTCAE v4.0. Results Fifteen patients with advanced ALK-positive hematologic malignancies were enrolled; 14 with ALK-positive ALCL and one with ALK-positive DLBCL. At the data cutoff date of July 15, 2013, treatment was ongoing in 10 patients, and there were five discontinuations (1 due to early death, 1 due to global deterioration of health and 3 due to disease progression). Nine patients (60%) were male, and the median age was 25 years (range 15–37 years). Most patients were white (60%), with the remainder Asian. Two patients (13%) received prior radiation therapy. All patients received prior systemic therapy (median 2 lines [range 1–6]). ECOG performance status (ECOG PS) at baseline was 0 for 3 patients (20%), 1 for 7 patients (47%), 2 for 4 patients (27%), and 3 for 1 patient (7%). Median duration of treatment was 33 weeks (range 0.1–117 weeks). There were 9 confirmed responses (5 complete response [CR] and 4 partial response [PR]), for an objective response rate (ORR) of 60%. Additionally, 1 patient experienced stable disease (SD) of >12 months. Overall, the clinical benefit rate (CBR; CR + PR + SD) was 67%. AEs (all causality) were reported for all 15 patients and were predominantly of grade 1 or 2. The most common AEs were diarrhea (47% of patients), vomiting (47%, including 1 grade 3 event), visual impairment (40%), asthenia (27%), cough (27%), and neutropenia (27%, including 2 grade 3 events). Four patients experienced grade 4 events (abdominal pain, increased creatinine phosphokinase, lymphopenia, and multi-organ failure), and one of these patients also experienced a grade 5 event (central nervous system hemorrhage). Conclusions Crizotinib showed anti-tumor activity in advanced ALK-rearranged hematologic tumors. The high ORR (60%) and CBR (67%) with crizotinib in this cohort is consistent with the high response rates seen with crizotinib in ALK-rearranged advanced NSCLC, and the safety profile of crizotinib was also similar to previous clinical experience with crizotinib. These data suggest that ALK inhibition can be effective in patients with ALK-positive hematologic malignancy and further investigation may be warranted in this setting. Disclosures: Gambacorti-Passerini: Pfizer: Research Funding. Off Label Use: Crizotinib is an ALK inhibitor which is indicated for use in ALK-positive advanced NSCLC. This study investigates the use of crizotinib in patients with ALK-positive malignancies other than NSCLC. Braiteh:Pfizer: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Honoraria; Pfizer: Research Funding. Taylor:1. Bayer HealthCare Pharmaceuticals, Inc.: Membership on an entity’s Board of Directors or advisory committees; 1. Bayer HealthCare Pharmaceuticals, Inc.: Honoraria. Brega:Pfizer: Equity Ownership; Pfizer: Employment. Paolini:Pfizer: Equity Ownership; Pfizer: Employment. Selaru:Pfizer: Equity Ownership; Pfizer: Employment.

Epigenetic modification is a key regulatory element in cell fate decision and development, but their role in hematopoietic regulation remains unclear. To characterize the epigenetic status of undifferentiated hematopoietic cell populations, we compared genome-wide DNA methylation pattern of human umbilical cord blood-derived CD34+ and CD34- cells. The methylated CpG-enriched DNA fractions were immunoprecipitated from CD34+ andCD34- cells using antibody against methylated CpG dinucleotide, and analyzed through microarray-based platform (244K Human CpG Island Microarray, Agilent). Compared to CD34- cells, CD34+ cells exhibited a characteristic hypomethylation pattern over the regions around 200 bp of the transcription start site (TSS). The hypomethylation around TSS was observed for both CpG island (CpGI) positive and negative loci. However, TSS of CpGI negative loci were flanked by hypermethylation in the regions up to 1 kb of the TSS, indicating a bivalent configuration of DNA methylation in the CD34+ cells. Interestingly, targets of pluropotent genes including those of NOS (Nanog, Oct-4 and Sox-2) exhibited similar bivalent DNA methylation in CD34+ hematopoietic cells. We next compared the histone modification of CD34+ and CD34- cells. CD34+ cells exhibited higher levels of histone acetylation (H4-Ac) and active form histone modifications (H3K4-methyl), whereas CD34- cells were enriched with repressive histone modification (H3K9-methyl).Importantly, pulse-chase labeling assay showed that CD34+ cells are under higher turn-overrate of histone acetylation than CD34- cells, indicating a dynamic maintenance of open chromatin structure in undifferentiated hematopoietic cells. Next, to investigate the regulatory roles of epigenetic modification in hematopoietic cells, we examined the effects of epigenetic blockers, 5-Azacytidine (AZA) and trichostatin (TSA) on hematopoietic cells at different stage of differentiation. For effects on in-vivo repopulating cells, murinebone marrow cells were transplanted into irradiated recipient mice and recipients were i.p. injected with TSA or AZA for 2 weeks. CRU assays performed 18 weeks after the transplantation showed that TSA, rather than AZA increased HSCs during reconstitution(22, 738, and 248 CRUs for control, TSA, and AZA group, respectively). When examined for in-vitro culture, primitive Lin-Sca-1+c-kit+ (LSK) cells treated with TSA and AZA for 5days retained significantly higher levels of undifferentiated cells than control (45% vs. 12%of LSK cells for treated and control group, respectively, p