Abstract: 8045 Background: The PTLD-1 trials have established risk-stratified sequential treatment of B-cell PTLD. After rituximab induction, patients (pts) in complete remission (25 %) received rituximab consolidation, while all others received R-CHOP. The PTLD-2 trial tests modified risk-stratification including clinical risk factors. These are the results of the 2 nd scheduled interim analysis (40/60 planned pts). Methods: The prospective, multicenter phase II PTLD-2 trial (NCT02042391) enrols treatment-naïve adult SOT recipients with CD20-positive PTLD. Key exclusion criteria are CNS involvement, ECOG 〉 2, pregnancy, and severe organ dysfunction or severe, active infection. Treatment consists of rituximab (1400 mg SC; first application 375 mg/m 2 IV) on days 1, 8, 15 and 22. After restaging, pts in CR as well as those in PR with ≤ 2 IPI risk factors at diagnosis (low-risk group) continue with four three-weekly courses of rituximab. Most other pts (high-risk group) receive 4 cycles of R-CHOP-21, while thoracic SOT recipients who progress under rituximab (very-high-risk group) receive six cycles of alternating R-CHOP-21 and R-DHAOx. The primary endpoint (event-free survival in the low-risk group) is not analyzed here. Secondary endpoints presented here are response and overall response (ORR) by computed tomography, overall survival (OS), time to progression (TTP) and treatment-related mortality (TRM) overall and by risk group. Results: 40 pts were recruited at 12 centers (2015 – 2019). 21/40 were kidney, 11 lung, 4 liver, 3 heart, and 1 liver/kidney transplant recipients. Median age was 54 years. 38/40 PTLD were monomorphic and 15/40 EBV-associated. 38 pts were evaluated for response at interim staging: 13 were allocated to the low-risk, 17 to the high-risk and 8 to the very-high-risk group. ORR was 28/30 (93 %, CR: 16/30 [53 %]). With a median follow-up of 1.9 years, the 1-year/3-year Kaplan-Meier (KM) estimates of TTP and OS in the intention-to-treat population (40 pts) were 85 %/80 % and 70 %/70 %, respectively. In the low-risk group, the 2-year KM estimate of OS was 100 %. The frequency of infections (all grades) was 50 %, and TRM occurred in 3/40 pts (8 %). Conclusions: One third of enrolled pts were treated in the low-risk group and the recruitment goal for evaluation of the primary endpoint will likely be reached. Interim efficacy and toxicity data with rituximab SC and modified risk-stratification are encouraging despite the inclusion of 35 % thoracic SOT recipients. Clinical trial informa tion: NCT02042391 .

Abstract: Acquired hemophilia A (AHA) is a rare autoimmune disorder caused by neutralizing autoantibodies against coagulation factor VIII (FVIII:C). Immunosuppressive treatment may result in remission of disease over a period of days to months. Until remission, patients are at high risk of bleeding and complications from immunosuppression. Prognostic parameters to predict remission and the time needed to achieve remission could be helpful to guide treatment intensity, but have not been established so far. GTH-AH01/2010 was a prospective multicenter cohort study using a standardized immunosuppressive treatment protocol. The primary study endpoint was time to achieve partial remission (PR, defined as FVIII:C activity 〉 50 IU/dl after cessation of any hemotherapy for 〉 24h, and no active bleeding). Secondary endpoints were time to achieve complete remission (CR, defined as PR plus negative FVIII:C inhibitor, steroid tapered to 〈 15 mg/d prednisolone, and cessation of any other immunosuppressive treatment), and overall survival (OS). Enrolment was strictly prospective and only allowed within 7 days of starting immunosuppression. Outcome data were recorded in all patients enrolled. The treatment protocol consisted of prednisolone (100 mg/d from day 1 to the day of PR, then tapered down to 〈 15 mg/d over 5 weeks), oral cyclophosphamide (150 mg/d, from day 21-42, unless PR was achieved), and rituximab (375 mg/m2 weekly for 4 weeks starting on day 43, unless PR was achieved). If AHA was first diagnosed in patients previously on prednisolone 〉 15 mg/d, or equivalent, they received prednisolone (100 mg/d) and rituximab from day 1. If cyclophosphamide was contraindicated, patients received prednisolone (100 mg/d) and rituximab from day 21. One hundred twenty-four patients from 21 treatment centers in Germany and Austria were enrolled between April 2010 and April 2013 (36 months). The patients from two centers not compliant with the treatment protocol were excluded (N=18), as were patients in whom AHA was not confirmed (N=2) or follow-up was too short at the time of this analysis (N=7). The remaining 97 patients from 17 centers were followed for a median of 256 days (interquartile range [IQR] 84-561). Median age was 74 years (IQR 64-82). AHA was associated with other autoimmune disorders (19%), malignancy (12%), pregnancy or puerperium (5%), but was most often idiopathic (66%). The median FVIII:C activity at baseline was 1 IU/dl (IQR 〈 1-3), and the median inhibitor titer was 20 BU/ml (IQR 7.7-78). PR and CR were achieved after a median time of 35 and 102 days, respectively. Patients achieving PR prior to day 21 (N=22) compared with patients not achieving PR within 21 days (N=75) had a higher baseline FVIII:C activity (median 3 vs. 〈 1 IU/dl, p 〈 0.01) and a lower FVIII:C inhibitor (median 12 vs. 29 BU/ml, p 〈 0.05). Multivariate analysis with adjustment for age, sex, underlying disorder, and WHO performance status on admission demonstrated that baseline FVIII:C activity ( 〈 1 IU/dl vs. 〉 =1 IU/dl) had a strong impact on the time to achieve PR (HR 2.76 [95% confidence interval 1.73-4.42] , p 〈 0.001) and CR (HR 2.36 [1.34-4.14], p 〈 0.01). Baseline FVIII:C activity was also a predictor of PR and CR when other cutoffs were used (2 or 3 IU/dl instead of 1 IU/dl), or when it was analyzed as a continuous variable in Cox regression analysis. In contrast, FVIII:C inhibitor titer assessed by the local laboratory did not affect time to PR or CR significantly. OS after 300 days, estimated by the Kaplan Meier method, was 69%. Age, WHO performance status, and FVIII:C activity at baseline were independent predictors of OS. In summary, GTH-AH 01/2010 is the largest prospective study of patients with AHA treated according to a standardized protocol. The study demonstrated a robust effect of baseline FVIII:C activity on the time needed to achieve PR and CR. Baseline FVIII:C activity, together with age and performance status, also affected OS. Therefore, baseline FVIII:C activity may be considered to guide individually tailored immunosuppression in future studies. Disclosures: Tiede: Baxter: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Biotest: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novo Nordisk: Consultancy, Honoraria, Research Funding; Biogen Idec: Consultancy; CSL Behring: Consultancy, Honoraria, Research Funding. Off Label Use: Prednisolone, cyclophosphamid, and rituximab for immunosuppression in acquired hemophilia. Klamroth:Bayer: Honoraria, Research Funding; Baxter: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Novo Nordisk: Honoraria, Research Funding. Gottstein:Novo Nordisk: Honoraria; Baxter: Honoraria. Holstein:Baxter: Honoraria, Speakers Bureau. Scharf:CSL Behring: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Biotest: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria; Baxter: Consultancy, Honoraria, Research Funding. Huth-Kühne:SRH Kurpfalz Hospital and Hemophilia Center: Consultancy, Employment, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Greil:Roche: Consultancy, Honoraria, Research Funding. Miesbach:Novo Nordisk: Consultancy, Honoraria, Research Funding; Baxter: Consultancy, Honoraria, Research Funding. Trappe:Roche: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau, Travel Other; AMGEN: Research Funding, Travel, Travel Other; CSL Behring: Honoraria, Research Funding, Speakers Bureau, Travel, Travel Other; Mundipharma: Research Funding, Travel, Travel Other; Takeda: Consultancy, Research Funding, Travel Other; Novartis: Consultancy, Research Funding, Travel, Travel Other; Novartis: Research Funding, Travel Other; Cellgen: Travel, Travel Other. Knoebl:Novo Nordisk: Consultancy, Honoraria; Baxter: Consultancy, Honoraria.

Abstract: 8030 Background: The prospective, multicenter international phase II PTLD-1 trial of sequential treatment (ST, 4 cycles of weekly rituximab followed by 4 cycles of CHOP-21 + G-CSF) in adult CD20-positive PTLD demonstrated excellent efficacy (90% overall response rate, ORR) and safety (11% treatment-related mortality, TRM). As the response to rituximab predicted overall survival (OS), the trial was amended in 2007 introducing risk-stratified sequential treatment (RSST) according to the response to rituximab (NCT00590447). Methods: Following rituximab on days 1, 8, 15 and 22, RSST consisted of 4 3-weekly courses of rituximab monotherapy for patients (pts) in complete remission (CR, low risk) while all others (high risk) received 4 cycles of R-CHOP-21 + G-CSF. Key exclusion criteria were CNS involvement, HIV infection, severe organ dysfunction not related to PTLD, and ECOG 〉 2. Primary endpoint was ORR. This is an analysis of the first 91 patients treated with RSST. Results: 79/91 pts had monomorphic, 12 polymorphic PTLD. 41/91 pts were kidney, 27 liver, 12 heart, 7 lung or heart+lung, 3 heart+kidney and 1 kidney+pancreas transplant recipients. Median age at diagnosis was 60 years (range 20-82). 73/91 pts had late PTLD and 39/85 PTLDs were EBV-associated. 1 pt died before initiation of treatment; 5 pts discontinued treatment after 4 cycles rituximab. TRM of RSST was 7/90 (8%) including 5 deaths with unknown remission status. ORR was thus 74/80 (93%, 95%CI: 84-97%; CR: 62/80 [78%]). 24/90 pts (27%) achieved CR with 4 cycles of rituximab. After a median follow up of 〉 3 years, relapse rate in low risk pts was not increased by rituximab consolidation in RSST compared to CHOP consolidation in ST (3/23 vs. 5/14, p=0.104]). In patients in PD after rituximab, R-CHOP was more effective than CHOP in achieving CR (15/23 vs. 3/11, p=0.038). OS at 3 years was higher with RSST (70%, 95% CI: 60-82%) compared to ST (61%, 95%CI 49-72%) but this difference was not significant. Conclusions: With RSST 27% of pts were classified as low risk and achieved durable tumor control without chemotherapy while R-CHOP seems more efficient than CHOP in in high risk patients.

Abstract: Introduction: Post-transplant lymphoproliferative disorder (PTLD) is a rare and often aggressive disease in the setting of immunosuppression following solid organ transplant (SOT). Epstein-Barr virus (EBV) infection of B cells is responsible for about 50% of cases, either due to reactivation of the virus after transplantation or primary EBV infection. Although there is no approved therapy for patients (pts) with PTLD, guidelines include reduction of immunosuppression (RIS) as a part of initial treatment and may be sufficient for pts with early lesions. Rituximab, either as monotherapy or in combination with chemotherapy (CT), is used in addition to RIS as initial treatment. Pts with EBV + PTLD following SOT who fail rituximab plus CT have poor outcomes with limited treatment options. There are ongoing clinical studies investigating innovative therapies to address unmet needs in these pts. Published data on clinical outcomes of these pts remain limited and not well documented. We aimed to characterize the outcomes for pts diagnosed with EBV + PTLD following SOT who fail initial rituximab plus CT in a multi-national real-world setting. Methods: We conducted a large multinational, multicenter, retrospective chart review study of pts with EBV + PTLD following allogeneic hematopoietic cell transplantation (HCT) or SOT who received rituximab or rituximab plus CT between January 2000‒December 2018 and were refractory (failed to achieve complete response [CR] or partial response [PR] ) or relapsed at any point after such therapy. Treatment response was assessed either by clinical diagnosis, radiographic/imaging, biopsy/cytology, or a combination of such assessments. Data were collected from 29 centers across North America (United States and Canada) and the European Union. Study population was aligned to the ongoing investigational trial (Clinicaltrials.gov Identifier: NCT03394365). This analysis includes pts with EBV + PTLD following SOT who were refractory/relapsed to rituximab plus CT. The Kaplan-Meier method was utilized to estimate the overall survival (OS). Results: A total of 86 pts with EBV + PTLD following SOT who failed rituximab plus CT were included in the analysis; 65 (75.6%) pts were refractory while 21 (24.4%) relapsed after initial response of CR or PR. Median age at PTLD diagnosis was 43 years (range 1‒78) and median time to PTLD onset from transplant was 1.7 years (range 0.1‒27.9). Median follow up time was 12.9 months from the date of PTLD diagnosis. PTLD histological subtypes were 66 (76.7%) monomorphic, 18 (20.9%) polymorphic, and 2 (2.3%) early lesions. The most common PTLD subtype was diffuse large B-cell lymphoma (DLBCL) (58, 67.4%). Of the 86 pts, 49 (57%) received CT following rituximab monotherapy while 37 (43%) pts received CT concurrently with rituximab. Overall, 63 (73.3%) pts died. PTLD-specific mortality was observed in 41 (65.1%) pts, treatment-related mortality in 10 (15.9%) pts, mortality due to organ rejection/failure in 2 (3.2%) pts, mortality due to other causes in 7 (11.1%) pts, and mortality due to unknown causes in 3 (4.8%) pts. Median OS was 15.5 months (95% confidence interval [CI]: 8.3‒22.9) from PTLD diagnosis, and was 4.1 months (95%CI: 1.9‒8.5) from the earliest date when pts became refractory or relapsed following rituximab plus CT. Conclusions: The prognosis for pts with EBV + PTLD following SOT who fail rituximab plus CT remains poor, with an estimated median OS of about 4 months and a majority of pts dying from PTLD and related treatment. In this specific population, there remains a significant unmet medical need for effective and well-tolerated therapies. Figure 1 Figure 1. Disclosures Dharnidharka: Merck, Pfizer, Medronic, Cardinal Health: Current holder of stock options in a privately-held company; CareDx: Honoraria, Research Funding; Atara Bio, MedinCell: Consultancy. Thirumalai: Atara Biotherapeutics: Current Employment. Jaeger: 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; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Norvartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zhao: Atara Biotherapeutics: Current Employment. Dierickx: Roche: Consultancy, Research Funding; Novartis: Consultancy; Sanofi: Consultancy; Sandoz: Consultancy; Takeda, Incyte, Atara: Consultancy. Xun: Atara Biotherapeutics: Current Employment. Sawas: Flat Iron Health: Current Employment; Roche: Current holder of stock options in a privately-held company; Seattle Genetics, Acrotech: Consultancy; Daiichi-Sankyo, Seattle Genetics, Gilead: Other: Travel, accommodation, expenses, Speakers Bureau; Affimed, Trillium: Research Funding. Sadetsky: Atara Biotherapeutics: Current Employment. Barlev: Atara Biotherapeutics: Current Employment. Zimmermann: Roche, Atara: Research Funding; Celgene, Roche, Atara, Jansen: Other: Travel accomodations. Trappe: Celgene: Other: Travel support; Roche: Other: Travel support; Atara Biotherapeutics: Consultancy, Other: Travel support, Research Funding; Jansen: Other: Travel support; GSK: Other: Travel support; AbbVie: Other: Travel support.

Abstract: Introduction The antibody-drug conjugate polatuzumab vedotin (Pola) has recently been approved in combination with bendamustine and rituximab (Pola-BR) for patients with r/r diffuse LBCL (DLBCL). Methods To characterize the efficacy of Pola-BR in a real-world setting, we retrospectively analyzed data from 97 patients with r/r LBCL who were treated with Pola in 24 German centers within the national CUP. Clinical baseline and follow-up (FU) data were collected by chart review and summarized descriptively. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier and Cox regression methods. Fisher's exact test was used to compare categorical factors between groups of patients. Results 97 patients with LBCL (DLBCL n=90, High-grade B-cell lymphoma n=6, Primary mediastinal B-cell lymphoma n=1) were included as of July 22nd, 2020. 49 patients were treated with Pola as bridging concept to immunotherapies (bridging cohort: chimeric antigen receptor T-cells (CART) n=39, allogeneic stem cell transplantation (alloSCT) n=9, bispecific antibodies n=1), and 48 patients were treated with Pola in palliative intention (palliative cohort). Within the bridging cohort the median age was 61 years (range: 22-82). Patients were heavily pretreated with a median of 3 treatment lines (range: 2-6). 84% (41/49 patients) had been refractory to their last treatment line, and 31% had failed an autologous stem cell transplantation. Notably, 14% and 10% of patients had failed prior CART and alloSCT, respectively, and were planned for the alternate cellular immunotherapy. Based on an individual decision, patients were treated with Pola-Rituximab (Pola-R, n=20), Pola-chemotherapy (Pola-chemo, BR n=25; R-CHP n=1) or Pola-monotherapy (Pola-mono, n=3). With a median of 2 Pola cycles (range 1-6), overall response rate (ORR) of all evaluable patients was 33% (15/46 patients) including patients with complete response (CR n=1), partial response (PR n=9) and clinical response (n=5). Although not significant, ORR tended to be better in patients treated with Pola-chemo versus Pola-R/Pola-mono (ORR: 42% versus 20%, Fishers test p=0.1). 11 of these 15 responders (24% of the entire bridging cohort) proceeded to CART or alloSCT, while 4 responders (8% of entire bridging cohort) experienced fast progression after their initial response and were referred to best supportive care. 15 of 31 non-responders (33% of entire bridging cohort) underwent immunotherapy with either stable disease (n=6), mixed response (n=2), or progression on Pola (n=7). The remaining 16 patients (35% of entire bridging cohort) were all refractory to Pola and either received alternative salvage treatments which enabled 8 further patients to proceed to the intended immunotherapy, or best supportive care. Taking the effects of CART or alloSCT into account, median OS from initiation of Pola treatment was 8.2 months (median FU 7.2 months, Fig. 1A). The palliative cohort tended to be older than the bridging cohort with a median age of 73.5 years (range: 37-86, p & lt;0.001). Patients were pretreated with a median of 3 treatment lines (range: 2-8), and 85% (41/48 patients) had been refractory to their last treatment line. Patients in the palliative cohort were treated with a median of 4 Pola cycles (range: 1-9). 65% received Pola-chemo (BR, n=30; R-Gemcitabine, n=1) and 35% Pola-R. The CR rate and ORR was 19% (9/48) and 56% (27/48), respectively. The 6-month PFS and OS from initiation of Pola was 36% and 51%, respectively (median FU of 9.7 months, Fig. 1B). Again, ORR and OS tended to be better in patients treated with Pola-chemo versus Pola-R (ORR: 61% versus 47%, Fishers test p=0.4; median OS 7.2 versus 4 months, HR 0.8, 95%CI 0.4-1.9, p=0.7). In univariate analysis, failure to respond to the last treatment line predicted inferior PFS (HR 2.4, 95%CI 1.2-5.0 p=0.02) and OS (HR 2.5, 95%CI 1.2-5.4 p=0.02). Patients with more than two prior treatment lines in total tended to have a shorter PFS (HR 2.0, 95% CI 0.9-4.5, p=0.1) and OS (HR 1.8, 95% CI 0.8-4.0, p=0.2), although significance was not reached. Conclusion Pola permits effective bridging to CART and alloSCT in r/r LBCL. In the palliative setting, Pola represents an effective salvage option for patients with transplantation-ineligible r/r LBCL. Compared to the approval study, the inferior outcome of the patients of this real-world analysis might be explained by their more advanced disease course. Disclosures Duell: Morphosys: Research Funding. Kerkhoff:BMS: Honoraria. Leng:Roche: Other: lecture fee; Celgene: Other: traveling expenses and congress attendance fee. Holtick:Miltenyi Biotec B.V. & Co. KG: Honoraria. Mayer:Amgen: Honoraria, Other: travel grants; Abbvie: Other: travel grants; Novartis: Honoraria; Roche: Honoraria. Hüttmann:Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Roche: Other: Travel expenses; Seattle Genetics: Research Funding; University Hospital Essen, University of Duisburg-Essen, Essen, Germany: Current Employment; Lead Discovery Center GmbH: Consultancy. Brunnberg:Gilead: Membership on an entity's Board of Directors or advisory committees; Hexal: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel grants; MSD: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Amgen: Other: Travel grants. Bullinger:Menarini: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Hexal: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Hess:Roche: Research Funding; Celgene: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genmab: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; EUSA: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Morphosys: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mueller-Tidow:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Deutsche Krebshilfe: Research Funding; BMBF: Research Funding; Wilhelm-Sander-Stiftung: Research Funding; Jose-Carreras-Siftung: Research Funding; Bayer AG: Research Funding; Daiichi Sankyo: Research Funding; BiolineRx: Research Funding; Janssen-Cilag Gmbh: Membership on an entity's Board of Directors or advisory committees; Deutsche Forschungsgemeinschaft: Research Funding. Lenz:Verastem: Research Funding; AQUINOX: Research Funding; BMS: Consultancy; AstraZeneca: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Agios: Research Funding; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy; Morphosys: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Dreger:Roche: Consultancy, Speakers Bureau; Neovii: Research Funding; AbbVie: Consultancy, Speakers Bureau; AstraZeneca: Consultancy; Gilead: Consultancy, Speakers Bureau; Janssen: Consultancy; Novartis: Consultancy, Speakers Bureau; Riemser: Consultancy, Research Funding, Speakers Bureau. Dietrich:Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees.

Abstract: Background: The PTLD-1 trial has demonstrated the efficacy and safety of 4 cycles of weekly rituximab followed by 4 cycles of CHOP-21 + G-CSF in CD20-positive PTLD after solid organ transplantation. Median overall survival (OS) was 6.6 years, a clear improvement over the preceding rituximab monotherapy trials (2.4 years). However, response to rituximab induction predicted OS after completion of therapy. Based on the hypothesis that rituximab consolidation might be sufficient treatment for patients already in a complete response (CR) after rituximab induction, trial treatment was changed in 2007 through a protocol amendment introducing risk-stratified sequential treatment (RSST): rituximab consolidation for patients in CR after rituximab induction and R-CHOP-21 consolidation for all others. Methods: In this international, multicenter phase II trial (PTLD-1, 3rd amendment; NCT00590447), treatment-naïve adult solid organ transplant recipients diagnosed with CD20-positive PTLD were treated with rituximab (375 mg/m2 IV) on days 1, 8, 15 and 22. After restaging, patients in CR continued with four three-weekly courses of rituximab monotherapy while all others received 4 cycles of R-CHOP-21 + G-CSF. In case of disease progression during rituximab monotherapy R-CHOP was commenced immediately. The primary endpoint was treatment efficacy measured as response rates and response duration. Analysis was by intention to treat. This is the final analysis of 152 patients treated with RSST from 2007 to 2014 at centers in Germany (72), Belgium (36), France (24), Australia (7), Poland (7) and Italy (6) with a median follow-up of 4.5 years. The 70 patients treated with rituximab followed by CHOP-21 in the original PTLD-1 trial (median follow-up 5.1 years) served as a control population. Inclusion criteria and follow-up schedule were identical; there were no significant differences in the transplant- and lymphoma-related baseline factors listed below. Results: 115/152 patients were male. 69/152 were kidney, 40 liver, 18 lung, 15 heart, 5 heart/kidney, 3 kidney/pancreas and 2 heart/lung transplant recipients. Median age at diagnosis was 56 years. PTLD was late ( 〉 1 year after transplantation) in 120/152 (79%) of patients. 67/145 (46%) PTLD were EBV-associated. 130/152 patients had monomorphic, 20 polymorphic and 2 early lesion PTLD. The overall response rate (ORR) was 111/126 (88%, CR: 88/126 [70%]). Median duration of remission (DR) was not reached; the 3-year Kaplan-Meier estimate was 82% (compared to 71% in PTLD-1). In the intention-to-treat population (152 patients), the median time to progression (TTP) was not reached either. The 3-year Kaplan-Meier estimate was 78% (69% in PTLD-1). Median OS by intention-to-treat was 6.6 years (95% CI 5.5 - 7.6) with a 3-year estimate of 70% in comparison to 61% in PTLD-1. There was no significant difference in ORR, DR, TTP or OS between EBV-positive and EBV-negative PTLD. On the other hand, response to 4 applications of rituximab was a highly significant predictor of OS, TTP and progression-free survival (PFS) despite treatment stratification (all p 〈 0.001). 37/148 patients (25%) achieved CR with 4 cycles of rituximab and were allocated to rituximab consolidation. In this group, TTP in the intention-to-treat population was significantly longer than in the corresponding group in the PTLD-1 trial (37 patients versus 14 patients, p 〈 0.05). In the 111 patients allocated to R-CHOP consolidation, ORR was 78/92 (85%) with 55/92 (60%) complete remissions (89% and 60%, respectively, in PTLD-1). Median TTP was not reached, the 3-year estimate was 73% (69% in PTLD-1). In patients refractory to rituximab induction, the CR rate was 22/38 (58%) with R-CHOP compared to 3/11 (27%) in PTLD-1 with CHOP (p=0.07); median PFS was 1.4 years versus 0.3 years in PTLD-1, p 〈 0.05. The frequency of grade 3/4 leukopenia and infections was 63% and 34%, respectively. Treatment-related mortality occurred in 7%. Conclusions: This largest trial cohort in PTLD to date demonstrates for the first time that treatment stratification by response to rituximab induction is feasible, safe and effective. Rituximab consolidation in early rituximab responders results in significantly better disease control compared to CHOP consolidation. The addition of rituximab to CHOP chemotherapy improves outcome in patients refractory to rituximab monotherapy. Disclosures Trappe: Mundipharma: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding, Speakers Bureau; CSL Behring: Research Funding, Speakers Bureau. Zimmermann:Roche: Honoraria; Celgene: Other: Travel support. Morschhauser:Genentech Inc./Roche: Other: Advisory boards. Mollee:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zaucha:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau. Dührsen:Roche: Honoraria, Research Funding; Alexion Pharmaceuticals: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Hüttmann:Amgen: Research Funding; Roche: Research Funding. Salles:Calistoga Pharmaceuticals, Inc.; Celgene Corporation; Genentech, Inc.; Janssen Pharmaceutica Products, L.P.; Roche: Consultancy; Celgene Corporation; Roche and Gilead Sciences: Research Funding; Celgene Corporation; Roche: Speakers Bureau. Kliem:Astellas: Honoraria; Fresenius: Honoraria; Genzyme: Honoraria; Novartis: Honoraria; Roche: Honoraria; Raptor: Honoraria. Leblond:Janssen: Consultancy, Honoraria, Speakers Bureau; Mundipharma: Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau. Choquet:Janssen: Consultancy; Roche: Consultancy.

Abstract: Background: The PTLD-1 trials established 1 st-line risk-stratified sequential treatment (RSST) of CD20-positive B-cell PTLD in adult solid organ transplant recipients. After rituximab induction, patients (pts) in complete remission (CR) continue with 4 three-weekly courses of rituximab, while all others receive 4 cycles of R-CHOP-21 (Trappe RU et al., JCO 2017;35:536-43). Analyses of the initial PTLD-1 sequential treatment cohort uniformly treated with rituximab followed by CHOP identified the prognostic value of response to rituximab induction, international prognostic index (IPI) risk factors (≥ 3 vs & lt; 3) and thoracic SOT (Trappe RU et al., Am J Transplant 2015;15:1091-100). The PTLD-2 trial therefore tested modified risk-stratification based on these three risk factors. The key hypothesis was that rituximab SC monotherapy consolidation in an expanded low-risk group would be superior to CHOP consolidation in comparable pts of the PTLD-1 trial by demonstrating an improved event-free survival (EFS) at 2 years, based on a lower rate of grade 3/4 infections and similar efficacy. Methods: The prospective, multicenter phase II PTLD-2 trial (NCT02042391) enrolled treatment-naïve adult SOT recipients with CD20-positive PTLD. Key exclusion criteria were CNS involvement, ECOG & gt; 2, pregnancy, severe organ dysfunction or severe, active infection. Treatment consisted of rituximab SC on days (d) 1, 8, 15 and 22. After restaging on d50, pts in CR as well as those in partial remission with & lt; 3 IPI risk factors at diagnosis (low-risk group) continued with rituximab SC monotherapy. Most other pts (high-risk group) received 4 cycles of R SC-CHOP-21 chemotherapy, while thoracic SOT recipients who progressed under rituximab (very-high-risk group) received six cycles of alternating R SC-CHOP-21 and modified R SC-DHAOx. In case of progression before d50, subsequent treatment started immediately. The primary endpoint was EFS (event: infections grade 3/4 from d50 to d143, treatment discontinuation, progression, death) in the low-risk group. Secondary endpoints were response and overall response rate (ORR) by computed tomography at interim and final staging, overall survival (OS), time to progression (TTP), progression-free survival (PFS), response duration and treatment-related mortality (TRM) overall and by risk group. Results: 60 pts were recruited at 15 centers (2015 - 2020). 29/60 were kidney, 14 lung, 9 liver, 4 heart transplant recipients (4 others). Median age was 54 years. 58/60 PTLD were monomorphic and 23/60 EBV-associated. 26/58 pts (45%, 95% CI 33-58) responded at interim staging. 21 were allocated to the low-risk, 28 to the high-risk and 9 to the very-high-risk group. ORR at final staging was 45/48 (94 %, 95% CI 83-98). Grade 3/4 infections were reported in 25/59 pts who started treatment (42%, 95% CI 31-55). TRM occurred in 4/59 pts (7 %, 95 % CI 2-17). With a median follow-up of 2.8 years, the 2-year Kaplan-Meier (KM) estimates of TTP and OS in the intention-to-treat population (60 pts) were 78 % (95% CI 65-90, median not reached) and 68 % (95% CI 55-80, median OS 5.1 years), and thus in the range reported in the PTLD-1 trials. The prognostic value of response to rituximab induction, IPI risk factors (≥ 3 vs & lt; 3) and thoracic SOT was confirmed. The primary endpoint, 2-year EFS in the low-risk group, was 66 % (95% CI 45-86). Events were 4 grade 3 infections (19 %) and 5 relapses (24 %). There was no significant difference to the prespecified comparator group from the PTLD-1 ST trial cohort (52 % [95% CI 32-72]). The 3-year KM estimate of OS in the low-risk group was 100 %. Intensified chemotherapy in the very-high-risk group did not improve outcomes (median OS 7.4 months [95% CI 2.2-12.7] ) compared to PTLD 1 RSST (10.1 months). Conclusions: Overall efficacy and safety outcomes of the trial were comparable to the PTLD-1 trial despite the enrollment of 23% lung transplant recipients, who historically have poor outcomes (Zimmermann H et al. Transplantation Journal 2013;96:e18-9). 32 % of patients were treated with rituximab monotherapy in the low-risk group. The primary endpoint (improved EFS in this group vs. historical control) was not met. However, the observed 100% 3-year OS estimate in this population is an excellent outcome. The trial confirmed the poor prognosis of thoracic SOT recipients with progressive disease after rituximab induction. Intensified chemotherapy did not improve this outcome. Disclosures Zimmermann: Roche Germany: Research Funding; Atara Biotherapeutics: Other: Travel support, Research Funding; Janssen: Other: Travel support. Koenecke: Novartis: Consultancy; Janssen: Consultancy; BMS/Celgene: Consultancy; Kite/Gilead: Consultancy; EUSA Pharm: Consultancy. Dreyling: Bayer HealthCare Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Astra Zeneca: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; BeiGene: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau; Amgen: Speakers Bureau; Abbvie: Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Genmab: Consultancy; Gilead/Kite: Consultancy, Research Funding, Speakers Bureau. Dührsen: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; CPT Cellex Patient Treatment: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hahn: BMS: Consultancy, Honoraria; Merck: Consultancy, Honoraria; MSD: Consultancy, Other: Travel support, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Other: Travel support. Hauser: Roche: Honoraria; Astellas: Honoraria, Other: Travel Support; Biotest: Honoraria, Other: Travel support; Hexal: Other: Travel support; Neovii: Other: Travel support; Novartis: Consultancy, Honoraria. Wolf: Novartis: Honoraria, Research Funding; BMS-Celgene: Honoraria, Research Funding; MSD: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Gilead: Honoraria; Incyte: Honoraria; GEMOAB: Honoraria. Heuser: Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Research Funding; BergenBio: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Pharma AG: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolremo: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding. Schmidt: Novartis: Consultancy, Honoraria, Other: Travel support; Kite/Gilead: Consultancy, Honoraria, Other: Travel support, Research Funding; Takeda: Consultancy, Other: Travel support; BMS: Consultancy, Other: Travel support; Janssen: Other: Travel support. Ritgen: MSD: Consultancy, Other: Travel support; Chugai: Consultancy; Abbvie: Consultancy, Other: Travel support, Research Funding; Roche: Consultancy, Other: Travel support, Research Funding; Celgene: Other: Travel support. Siebert: AstraZeneca: Speakers Bureau. Anagnostopoulos: BMS: Consultancy, Honoraria, Other: Travel support; MSD: Consultancy, Honoraria, Other: Travel support. Trappe: Atara Biotherapeutics: Consultancy, Other: Travel support, Research Funding; Celgene: Other: Travel support; Jansen: Other: Travel support; AbbVie: Other: Travel support; GSK: Other: Travel support; Roche: Other: Travel support. OffLabel Disclosure: Rituximab is FDA-approved for the treatment of adult patients with CD20-positive, B-cell NHL, but not explicitly for PTLD, particularly as single agent treatment in DLBCL-PTLD.

Abstract: 7530 Background: Patients undergoing allogeneic hematopoietic cell transplant (HCT) or solid organ transplant (SOT) are at risk of developing Epstein–Barr virus driven post-transplant lymphoproliferative disorder (EBV + PTLD), a rare hematologic malignancy, which is often aggressive and life-threatening. Patients with relapsed or refractory (r/r) EBV + PTLD have few treatment options with poor outcomes, demonstrating a clear unmet medical need. Tabelecleucel is an investigational, off-the-shelf, allogeneic EBV-specific T-cell immunotherapy being studied in patients with serious EBV + diseases (NCT04554914 & NCT03394365) that has demonstrated clinical benefit and favorable safety profile in the treatment of EBV + PTLD after failure of rituximab (R) ± chemotherapy (Prockop, EBMT 2021, ATC 2021, ASH 2021). Methods: Atara Biotherapeutics supports an ongoing expanded access program (EAP) in Europe for patients with EBV + diseases who have no other treatment options. Here we report demographics, efficacy and safety results of r/r EBV + PTLD patients following SOT or HCT who presented between Jul 2020 and Nov 2021 and consented to research. Results: A total of 48 EAP requests from 9 countries for patients with EBV + diseases were received. Twenty-two patients from 7 countries consented to this research: 16 EBV + PTLD and 6 EBV + non-PTLD. Of the 16 PTLD patients 15 received at least one dose of tabelecleucel. Overall, 9 out of 15 (60%) patients achieved a response as assessed by the treating physician, with 6 complete responses and 3 partial responses. Eight out of nine responses were seen after the first cycle. No adverse events were reported as related to tabelecleucel by the treating physician. Conclusions: The successful execution of this European EAP demonstrates the feasibility to deliver an off-the-shelf allogeneic EBV + T-cell therapy in time-sensitive clinical situations when no other treatment options exist. These data show clinically meaningful outcomes for patients with r/r EBV + PTLD post-SOT or post-HCT treated with tabelecleucel consistent with previously reported favorable safety and efficacy profile (Prockop, ASH 2021).[Table: see text]