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: 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: 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: The antibody-drug conjugate polatuzumab vedotin (pola) has recently been approved in combination with bendamustine and rituximab (pola-BR) for patients with refractory or relapsed (r/r) large B-cell lymphoma (LBCL). To investigate the efficacy of pola-BR in a real-world setting, we retrospectively analyzed 105 patients with LBCL who were treated in 26 German centers under the national compassionate use program. Fifty-four patients received pola as a salvage treatment and 51 patients were treated with pola with the intention to bridge to chimeric antigen receptor (CAR) T-cell therapy (n = 41) or allogeneic hematopoietic cell transplantation (n = 10). Notably, patients in the salvage and bridging cohort had received a median of 3 prior treatment lines. In the salvage cohort, the best overall response rate was 48.1%. The 6-month progression-free survival and overall survival (OS) was 27.7% and 49.6%, respectively. In the bridging cohort, 51.2% of patients could be successfully bridged with pola to the intended CAR T-cell therapy. The combination of pola bridging and successful CAR T-cell therapy resulted in a 6-month OS of 77.9% calculated from pola initiation. Pola vedotin-rituximab without a chemotherapy backbone demonstrated encouraging overall response rates up to 40%, highlighting both an appropriate alternative for patients unsuitable for chemotherapy and a new treatment option for bridging before leukapheresis in patients intended for CAR T-cell therapy. Furthermore, 7 of 12 patients with previous failure of CAR T-cell therapy responded to a pola-containing regimen. These findings suggest that pola may serve as effective salvage and bridging treatment of r/r LBCL patients.

Abstract: The prospective multicentre Phase II PTLD-2 trial (NCT02042391) tested modified risk-stratification in adult SOT recipients with CD20-positive PTLD based on principles established in the PTLD-1 trials: sequential treatment and risk-stratification. After rituximab monotherapy induction, patients in complete remission as well as those in partial remission with IPI  〈  3 at diagnosis (low-risk) continued with rituximab monotherapy and thus chemotherapy free. Most others (high-risk) received R-CHOP-21. Thoracic SOT recipients who progressed (very-high-risk) received alternating R-CHOP-21 and modified R-DHAOx. The primary endpoint was event-free survival (EFS) in the low-risk group. The PTLD-1 trials provided historical controls. Rituximab was applied subcutaneously. Of 60 patients enrolled, 21 were low-risk, 28 high-risk and 9 very-high-risk. Overall response was 45/48 (94%, 95% CI 83–98). 2-year Kaplan–Meier estimates of time to progression and overall survival were 78% (95% CI 65–90) and 68% (95% CI 55–80) – similar to the PTLD-1 trials. Treatment-related mortality was 4/59 (7%, 95% CI 2–17). In the low-risk group, 2-year EFS was 66% (95% CI 45–86) versus 52% in the historical comparator that received CHOP ( p  = 0.432). 2-year OS in the low-risk group was 100%. Results with R-CHOP-21 in high-risk patients confirmed previous results. Immunochemotherapy intensification in very-high-risk patients was disappointing.