ALBERT

Description: Objective We report on the real world population-based study of patterns of care of DLBCL in Belgium (2013-2015) with a specific focus on the elderly population. Methods The Belgian Cancer Registry (BCR) collects, processes and analyses data on all new cancers diagnosed in Belgian residents by independent collection of double input: oncological care programs and pathology reports. Coded data were thus obtained of all adult (≥ 20 year) DLBCL diagnosed between 2013 and 2015 (n=1,890). From pathology reports we extracted immunohistochemistry (IHC) expression of CD10, BCL2, BCL6, IRF4 and MYC proteins, cell of origin (COO) classification estimated by Hans algorithm and BCL2, BCL6 or MYC gene translocation by FISH and/or PCR. Belgian health insurance data were used to infer DLBCL treatment modalities (chemotherapy schemes based on the combination of reimbursed drugs, HSCT and/or radiotherapy received) as well as to assess comorbidities. First-line treatments were grouped into 3 main categories: "standard" R-CHOP (≥6 or ≥4 cycles if Ann-Arbor = 1, including R-miniCHOP); other anthracycline containing schemes (other R-CHOP, CHOP, (R-)ACVBP, (R-)CHOP-like, intensified regimens); non-anthracycline treatments (COP and bendamustine schemes, palliative treatments). Results COO was available in 63% of cases; KI-67, BCL2, BCL2 & MYC expressions in 58%, 62% and 16% of cases respectively; MYC, BCL2 & MYC gene rearrangements in 11% and 9% of cases. Of the evaluable cases, 49% were double expressor (DE) and 10% were double-hit DLBCL (FISH only performed in ±10%). The negative prognostic markers identified from univariable models were: age, WHO PS, Ann-Arbor stage, non-GCB COO, MYC rearrangement, BCL2 expression, BCL2/MYC DE, comorbidities, other malignancies. First line systemic treatment was started in 84% of patients (Rituximab-containing in 96%) divided in standard R-CHOP (52%), other anthracycline schemes (39%) and non-anthracycline regimens (10%). The median [IQR] delay from diagnosis to treatment was 19 [9-31] days. In 18% of treated patients 2nd line therapy was initiated for refractory (10%) or relapsed disease (8%). This contained either a platinum-derivative (with or without cytarabine), HD cytarabine, anthracycline or bendamustine in 54%, 6%, 6 and 3% of cases respectively. Autologous HSCT was performed in 67 patients (BEAM-like conditioning in 88%), allogeneic HSCT in only 4 cases (〈 65 yr-old). Importantly 56% of patients were ≥ 70 yr-old (transplant-ineligible) and 44% ≥ 80 yr-old (unfit for intensive treatments). In patients older than 80 (and +85) years, no systemic treatment was administered in 38% (57%) of which 27% did receive radiotherapy. First line treatment was started in 62% (43%): "standard" R-(mini)CHOP in 22% (11%); other anthracycline schemes in 23% (13%) and non-anthracycline regimens in 17% (19%) (Table 1). In this elderly population treated with R-CHOP, the median number of cycles and interval still remained 6 and 21 days showing feasibility of dose-dense therapy. Second line therapy was started in 6% and no HSCT was performed. The 2-yr overall survival [95% IC] between the different age categories [20-59], [60-69], [70-79], [80-84] and ≥85 yr-old were 84 [80-87], 74 [69-78], 62 [58-66], 44 [38-49] and 31 [25-36], respectively (Figure 1). Survival curves of treatments by age categories showed that the older patients [70-84 yr-old] still benefit from the R-(mini)CHOP treatment (Figure 2). In the multivariable analyses the following variables were associated with a significant hazard ratio: sex, age, WHO PS, respiratory comorbidity, tumor history 〉 1,5 year after diagnosis, "standard" R-CHOP treatment. Conclusions This real world population-based study allows to assess patients usually excluded from clinical trials (elderly population, patients with comorbidities including malignancies (13%). Although limitations due to treatment inference and to the absence of some prognostic markers, this real world analysis of diagnostic-work up and inference of treatment modalities of DLBCL in Belgium showed that the disease characteristics of the elderly population did not seem to be different from the younger population. The majority (63%) of older patients [70-84 yr-old] are started on first line treatments with curative intent. Our study suggests that a substantial fraction of this elderly population qualifies for standard R-(mini)CHOP treatment and benefits from it. Disclosures No relevant conflicts of interest to declare.

Description: Introduction Cutaneous T-cell lymphoma (CTCL), a heterogeneous group of rare non-Hodgkin's lymphomas, is characterized by infiltration of malignant clonally expanded T lymphocytes in the skin and is very challenging to treat at advanced stages. Around 65% of the CTCL cases are mycosis fungoides (MF), which usually starts as indolent disease with accumulation of neoplastic resident memory T lymphocytes in the skin, evolving from patch to plaque and later to tumor stage with poor prognosis. Sézary syndrome (SS) involves erythroderma in the skin, malignant circulating clone, and lymphadenopathy. The CTCL pathogenesis is incompletely understood but suggests a complex interplay between neoplastic T cells and the tumor microenvironment. Glycoengineered ARGX-110 potently blocks CD70/CD27 signaling, which is thought to inhibit evasion of tumor immune surveillance as well as tumor cell proliferation and survival. The ARGX-110 effector functions, i.e., complement-dependent cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP), and enhanced antibody-dependent cellular cytotoxicity (ADCC), efficiently kill CD70-expressing tumor cells. With only limited expression in normal tissues and strong expression on tumor cells, CD70 is a very attractive target for antibody-based therapy in cancer. The role of CD70 and treatment with ARGX-110 was further investigated as part of a Phase 1/2 study in advanced CTCL patients. Methods As part of a non-randomized, open-label, multicenter Phase 1/2 study (NCT01813539), a total of 27 patients with CD70-expressing advanced CTCL of different subtypes and stages were included for determination of the optimal dose, to evaluate exploratory efficacy and safety, and to characterize pharmacokinetics and biomarkers of drug activity (immunohistochemistry [IHC] staining for drug- and disease-related markers, profiling of malignant and non-malignant immune cells by flow cytometry, quantitative polymerase chain reaction [qPCR] and Nanostring). ARGX-110 was administered intravenously at 1 (N=11) or 5 mg/kg (N=16) every three weeks (Q3W). Adverse events were graded according to NCI-CTCAE v. 4.03. Results ARGX-110 was safe and well tolerated at both 1 and 5 mg/kg in heavily treated CTCL patients with a median age of 67 years (range: 25-84 years). At cut-off (26th June 2018), a total of 110 treatment-emergent adverse events (TEAE) were reported in 27 patients of which 12 were grade 3-5; 40 events in 18 patients were considered drug-related by the investigator. The most common TEAE was pyrexia (7 events in 5 patients), and infusion-related reactions (IRRs) was the most common drug-related TEAE. The best response was 1 complete response (CR), 5 partial response (PR), and 7 stable disease (SD) in 26/27 patients evaluable for response, meaning overall response (ORR) in 23% of the patients and disease stabilization in 27% of the patients. The mean duration on the study was around 4.8 months. Two patients were still on the study at cut-off: 1 patient (subcutaneous panniculitis-like T-cell lymphoma, 24 months) with CR and 1 SS patient with PR (6.5 months). Pharmacokinetics (PK) revealed a mean half-life of 8-12 days, in line with previously published data. The 5 mg/kg dose was chosen as the recommended phase 2 dose (RP2D) based on PK and immunogenicity data. IHC staining for drug- and disease-specific markers showed results in line with clinical reduction of modified Severity Weighted Assessment Tool (mSWAT) and regression from plaque to patch stages. Molecular and cellular profiling indicated a complex interplay between the tumor and the microenvironment, in which CD70/CD27 plays a role. Conclusions ARGX-110 was safe and well tolerated at both dose levels (1 and 5 mg/kg) in advanced CD70-expressing CTCL patients. Clinical anti-tumor activity in patients with various types of CTCL was observed after treatment with ARGX-110, indicating ARGX-110 as a safe and promising treatment option for advanced CTCL. Disclosures Bagot: Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees; Actelion: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Maerevoet:Karyopharm: Membership on an entity's Board of Directors or advisory committees; takeda: Membership on an entity's Board of Directors or advisory committees, Other: travel grant; roche: Other: travel grant; abbvie: Membership on an entity's Board of Directors or advisory committees, Other: travel grant. Zinzani:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra Zeneca: Speakers Bureau; TG Pharmaceuticals: 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, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Morschhauser:Janssen: Other: Scientific Lectures; Epizyme: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ribrag:Incyte Corporation: Consultancy; Amgen: Research Funding; Infinity: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; epizyme: Consultancy, Honoraria; NanoString Technologies: Consultancy, Honoraria; Roche: Honoraria, Other: travel; Servier: Consultancy, Honoraria; pharmamar: Other: travel; argenX: Research Funding; BMS: Consultancy, Honoraria, Other: travel; MSD: Honoraria. Dalle:Kyowa Hakko Kirin Pharmaceutical: Research Funding. Cayuela:Cepheid: Other: financial sponsor to attend John Goldman Conference 2017. Hultberg:argenx: Employment. Gandini:argenx: Employment. Moshir:argenx: Employment. Delahaye:argenx: Employment. Zabrocki:argenx: Employment. Silence:argenx: Consultancy. Van Rompaey:argenx: Employment. De Haard:argenx: Employment. Leupin:argenx: Employment.

Description: Key Points We have established a novel culture system for long-term proliferating murine lymphoid progenitors without any genetic manipulation. The cultured lymphoid progenitors can differentiate to lymphoid and myeloid lineages in vitro and in vivo.

Description: Background: Duvelisib (DUV) is a first-in class, oral dual inhibitor of PI3K-δ,-γ being developed for the treatment of advanced B- and T-cell malignancies. To date 304 patients (pts) with relapsed/refractory (RR) CLL/SLL have been treated with DUV monotherapy 25 mg BID in 4 studies: Study IPI-145-02 [NCT01476657], a Phase 1 study in advanced hematologic malignancies; DYNAMOTM [NCT01882803], a Phase 2 study in iNHL; DUOTM [NCT02004522], a Phase 3 study in CLL/SLL; and Study IPI-145-12 [NCT02049515], a Phase 3 crossover study from DUO. Here we present pooled efficacy and safety analyses from these 4 studies in RR CLL/SLL, examining the baseline characteristics, incidence and timing of AEs, and response in the subset of pts who received DUV monotherapy for 〉2 years in order to characterize the factors that contribute to long-term treatment with DUV. Methods: In this analysis we examined pts treated with DUV for 〉2 years (n=45) referred to as long-term (LT) pts. Efficacy and safety data from 4 studies of DUV monotherapy in pts with RR CLL/SLL treated at 25 mg BID were pooled. Response was based on investigator assessment per IWCLL/IWG criteria. Treatment-emergence (TE) was defined as those adverse events (AEs) that occurred from first dose to 30 days post last dose of DUV. All AEs were coded using MedDRA version 16.1; severity was assessed by investigators according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 4.03. Results: Baseline characteristics of LT pts were similar to pts who discontinued 3 years and 3 pts on DUV 〉4 years. The majority of LT pts (60%) remain on treatment as of June 2018. The median PFS in LT pts was 37 months, with an investigator-assessed ORR of 89%; best responses included 16% CR/CRi, 73% PR, and 11% SD. Among LT pts, 98% had an AE, 80% had a ≥ Gr 3 AE, 46% an SAE, and 9% an AE leading to discontinuation (after 2 years on DUV); 69% of pts had at least 1 dose modification due to an AE (69% hold, 40% reduction). Table 1 shows the incidence of AEs in LT pts by 6-month treatment intervals. Overall, ≥ Gr 3 AEs occurred less frequently over time but still occurred in 27% pts after 2 years. The rate of colitis was consistent over the 2 years of treatment (≤ 2.2% per 6-month interval). No ≥ Gr 3 AEs of diarrhea were observed within the first 6 months of treatment, while the overall rate of all grade diarrhea was consistent over time (16-27% per 6-month interval); dose modification for the management of diarrhea increased over time allowing pts to remain on therapy. Neutropenia, ALT increase, and lipase increase were more common in the first 6 months; most ≥ Gr 3 AEs of neutropenia did not require any dose modification. Compared to all pts with RR CLL/SLL treated with DUV (n=442), the incidences and types of AEs in LT pts were generally similar. Four (9%) LT pts discontinued DUV due to an AE, and included: colitis (n=2), diarrhea (n=1), Clostridium difficile colitis (n=1), and rectal adenocarcinoma (n=1). Pneumocystis jirovecii pneumonia occurred in 1 LT pt (not on prophylaxis at the time) and was the only opportunistic infection reported for this population. There have been no fatal events in the LT pts. Conclusions: 45 pts with RR CLL/SLL have been on DUV 25 mg BID for 〉2 years, with a median of 31 months on treatment. The investigator-assessed ORR for these long-term pts was 89% (16% CR/CRi, 78% PR) and the median PFS was 37 months. A majority (60%) of the long-term pts remain on treatment. Baseline characteristics were similar in these long-term pts compared to pts who discontinued 〈 2 years. Most of the commonly occurring ≥ Gr 3 AEs decreased over time, with the exception of diarrhea. The majority of ≥ Gr 3 AEs were managed through dose modification (dose interruption and or reduction). These data support DUV monotherapy as a long-term treatment option for pts with RR CLL/SLL with the potential for durable response and good tolerability over time. Disclosures Flinn: ArQule: Research Funding; Infinity: Research Funding; Verastem: Research Funding; BeiGene: Research Funding; Curis: Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding; Agios: Research Funding; Forma: Research Funding; Portola: Research Funding; Kite: Research Funding; Forty Seven: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Celgene: Research Funding; Verastem: Consultancy, Research Funding; Incyte: Research Funding; Janssen: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding; Pharmacyclics: Research Funding; Pfizer: Research Funding; Trillium: Research Funding; Novartis: Research Funding; Calithera: Research Funding; Constellation: Research Funding. Montillo:Roche: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau. Davids:BMS: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy; Merck: Consultancy; Surface Oncology: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; MEI Pharma: Consultancy, Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees. Le:Verastem Oncology: Employment. Lustgarten:Verastem Oncology: Employment.

Description: Key Points Humanized cytokine KI mice support engraftment of human favorable-risk AML. Engraftment and gene-enrichment analysis suggest M-CSF dependency of inv(16) AML.

Description: Key Points Low ADAMTS13 activity is associated with ischemic stroke. ADAMTS13 activity improved the accuracy of ischemic stroke risk predictions beyond the traditional risk factors.

Description: Key Points The spleen but not bone marrow microenvironment induces CD44v6 variants in CLL, which promote early engraftment. CD44v6 expression is linked to NF-κB and MAPK signaling in murine and human B-cell leukemia and contributes to proliferation.

Description: Introduction: Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) primarily affects older patients (pts) who often have medical comorbidities along with disease-related immunosuppression and myelosuppression. Although alkylating agents such as chlorambucil (clb) have been commonly used in these pts, novel therapies are needed. Ibrutinib (ibr) is a first-in-class, oral, covalent inhibitor of Bruton's tyrosine kinase FDA-approved for pts with CLL who received ≥1 prior therapy and for del17p CLL (including first-line). Ibr showed high activity in treatment-naïve pts age ≥65 years, with an overall response rate (ORR) of 84% (complete response [CR] in 23%) and 30-month progression-free survival (PFS) of 96% (Byrd et al. Blood 2015). We conducted a randomized, open-label phase 3 trial to evaluate efficacy and safety of single-agent ibr vs clb in treatment-naïve older pts with CLL/SLL. Methods: Pts aged ≥65 years with treatment-naïve CLL/SLL were randomized 1:1 to receive 420 mg ibr daily until progression or clb 0.5 mg/kg (up to maximum of 0.8 mg/kg) on days 1 and 15 of a 28-day cycle for up to 12 cycles. Pts with del17p were excluded. Primary endpoint was independent review committee (IRC)-assessed PFS per iwCLL 2008 criteria, with 2012 clarification for treatment-related lymphocytosis. Secondary endpoints included overall survival (OS), ORR, event-free survival (EFS), rate of hematologic improvement, and safety. Pts with IRC-confirmed progression could transfer to an extension study where next-line therapy (including ibr) could be initiated if they had an iwCLL indication for treatment. Results: Among 269 pts enrolled, median age was 73 years (70% ≥70 years). Baseline characteristics were balanced between arms; 45% had advanced Rai stage, 20% had del11q, and 69% had comorbidities at baseline including CIRS score 〉6, reduced creatinine clearance, or ECOG status of 2. For pts treated with clb, 40% completed 12 cycles of therapy (mean dose 0.6 mg/kg). At a median follow-up of 18.4 months (mos), ibr significantly prolonged IRC-assessed PFS vs clb (median not reached [NR] vs 18.9 mos; HR 0.16, 95% CI 0.09-0.28, P

Description: Background. Melphalan plus prednisone and bortezomib combination is the most frequent standard of care used upfront for newly diagnosed elderly myeloma (eNDMM). Despite significant improvements with bortezomib sub-cutaneous administration and weekly schedule, safety profile issues remain with MPV, that only can be resolved with lowering the doses, albeit of the potential loss of efficacy. Carfilzomib (K), a novel generation proteasome inhibitor, has different safety profile with absence of neuropathy. Carmysap, a phase I/II trial of twice weekly Carfilzomib plus MP in eNDMM, demonstrated carfilzomib MTD at 36mg/m2. The safety profile appeared otherwise good for this frail population. We hypothesized that Carfilzomib can be used on a weekly schedule allowing to increase the dose of Carfilzomib given its positive safety profile. Methods. IFM2012-03 (carmysap weekly) is a phase 1/2 multicenter symptomatic eNDMM (65 and older) study to determine MTD during the phase 1 part and VGPR+CR rate (IMWG criteria) during the phase 2 part of KMP (Carfilzomib Weekly Plus Melphalan and Prednisone) regimen. Inclusion criteria required absolute neutrophils ≥1G/L, untransfused platelet count ≥75G/L, hemoglobine ≥8.5g/dL and clairance creatinine ≥30ml/min. Induction comprised nine 5 weeks cycles. K is given 36, 45, 56 and 70 mg/m2 on days 1, 8, 15, 22 IV route in combination to oral Melphalan 0.25mg/kg/j and oral prednisone 60mg/m2, both on days 1 to 4. Maintenance. Carfilzomib. 36 mg/m2 weekly, every two weeks IV route for 1 year. Melphalan and Prednisone is not pursued at maintenance. Analysis is done on ITT. Recruitment was 6 patients per cohort, 3 DLTs defined MTD at the lower N-1 dose. We will report at ASH the results of the phase 1 and 2. Results. 32 NDMM recruited, 30 treated in the study, 6 per cohort at K 36 mg/m², 45, 56, and 70 twice per DSMB request. The median age was 76 with 2/3rd older than 75, sex ratio M/F 1.2, R-ISS 2 and 3 in 80%.There was one DLT at K 36 (grade 4 lymphopenia), one at 45 (lysis syndrome complicated with grade 4 renal insufficiency, two at 56 (cardiac insufficiency grade 3 and febrile neutropenia grade 3) and 2 at 70 (vomiting grade 3 and liver cholestase enzyme grade 3) across the 2 70 cohorts. As a whole for the study, the ORR is 87.5%, with 45.7% at least in CR. At data cut-off, with a median follow-up at 15 months, one patient had progressed and 2 had died of whom one of cardiac dysfunction considered K related at 56. The safery profile appeared well tolerated, however, 22 SAE were reported for a total of greater than 200 cycles administered of KMP. Of particular interest, 19 SAEs were reported across the K 56 and 70 cohorts, 6 of which were cardiovascular origin. Conclusion. IFM2012-03, KMP weekly, Carfilzomib plus Melphalan and Prednisone in elderly NDMM has reached RP2D at 70mg/m2 of K. The SAE signal at the highest dose of K 70 raise concerns on using K 70 in patients older than 75-80 years old, and the DSMB may recommend for these patients to limit the RP2D at 56mg/m2 of K. Updated data for phase 1 and 2 portions will be presented at ASH for the first time. Disclosures Leleu: TEVA: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; LeoPharma: Honoraria; Pierre Fabre: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Karlin:celgene: Consultancy, Honoraria; Bristol: Consultancy; takeda: Consultancy; janssen-cilag: Consultancy, Honoraria; amgen: Consultancy, Honoraria. Meuleman:Celgene: Consultancy; Bristol-Myers-Squibb: Consultancy; Takeda: Consultancy; Amgen: Consultancy. Roussel:AMGEN: Consultancy, Other: lecture fees, Research Funding; sanofi: Other: lecture fees; celgene: Consultancy, Other: lecture fees, Research Funding; janssen: Consultancy, Other: lecture fees; BMS: Other: lecture fees. Decaux:The Binding Site: Other: supply of free light chain assays , Research Funding; SIEMENS: Honoraria, Other: supply of free light chain assays , Research Funding. Hulin:celgene: Honoraria; Bristol: Honoraria; Janssen: Honoraria; Amgen: Honoraria; takeda: Honoraria. Attal:amgen: Consultancy, Research Funding; sanofi: Consultancy; celgene: Consultancy, Research Funding; janssen: Consultancy, Research Funding. Moreau:Celgene: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Speakers Bureau; Amgen: Honoraria; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria. Facon:Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Bristol: Consultancy; Janssen: Consultancy, Speakers Bureau; Karyopharm: Consultancy; Novartis: Consultancy; Millenium/Takeda: Consultancy.

Description: Background and objectives BAX 855 (Antihemophilic Factor [Recombinant] pegylated, rurioctocog alfa pegol) is an extended half-life (EHL) recombinant human coagulation factor VIII (rFVIII) modified with polyethylene glycol (PEG) (Turecek et al., 2012). It was recently approved in the US and Japan for on-demand treatment of bleeding events and for prophylactic treatment for patients with congenital severe hemophilia A. The efficacy and safety of BAX 855 were extensively studied during clinical development of this compound (Konkle et al., 2015). The assessment of BAX855 immunogenicity was of particular interest because the development of neutralizing antibodies (FVIII inhibitors) is the most serious complication following replacement therapies with FVIII products. FVIII inhibitors develop in about 20-32% of previously untreated patients (Gouw SC et al., 2013) and with a rate of 1.55- 3.8 per 1000 patients per year in previously treated patients (Kempton CL, 2010) with severe hemophilia A. To fully understand the potential of BAX855 to induce antibody responses, both FVIII inhibitors and total FVIII-binding antibodies were assessed. Furthermore, potential antibody development against PEG-FVIII, PEG and CHO proteins was investigated. Methods The clinical protocols (ClinicalTrials.gov identifier: NCT02585960, NCT02210091, NCT01736475, NCT01913405, NCT01945593, NCT01599819, NCT02615691) and the methods used for antibody analytics (Whelan et al 2013; Lubich et al 2016) were previously described. ELISA technologies were used for the analysis of total binding antibodies, the Nijmegen modification of the Bethesda assay was used for the detection of FVIII inhibitors. Correlation analyses were done to assess any potential correlation between the development of antibodies and potential adverse events. Results None of the 243 subjects (6 PUPs and 237 PTPs) included in the analysis developed FVIII inhibitors (≥ 0.6 BU/mL) A total of 44 subjects tested positive for binding antibodies against FVIII, PEG-FVIII or PEG at single time points. 28 of these 44 subjects showed pre-existing antibodies against FVIII, PEG-FVIII, or PEG prior to first exposure to BAX 855, which disappeared during the study. 13 subjects who tested negative at screening developed transient antibodies against FVIII, PEG-FVIII, or PEG at one or two consecutive study visits after exposure to BAX 855. Antibodies were transient and not detectable at subsequent visits or at completion of the study. Five subjects showed positive results for binding antibodies at study completion or at the time of the data cutoff. No conclusion can be drawn whether these antibodies are of transient or persistent nature. There was no confirmed causal relationship between the appearance of binding antibodies against FVIII, PEG or PEG-FVIII and adverse events, nor was there an impact on hemostatic efficacy in any of the 44subjects. No subject had pre-existing antibodies or developed de novo antibodies to CHO proteins during the study at any time point. Conclusion Our data indicate that BAX855 did not show an increased risk for PTPs to develop FVIII inhibitors. We did not see any FVIII inhibitor development in PUPs, but the small number of overall exposures does not allow general conclusions for PUPs. Importantly, the data suggest that BAX855 did not induce immune responses associated with impaired treatment efficacy or with altered PK parameters. Disclosures Horling: Shire: Employment. Allacher:IMC Krems: Research Funding. Koppensteiner:Shire: Employment. Engl:Shire, formerly Baxalta and Baxter: Employment, Equity Ownership. Scheiflinger:Shire: Employment, Research Funding. Abbuehl:Baxalta (now part of Shire): Employment. Reipert:Shire: Employment.