bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sintilimab for relapsed/refractory (r/r) extranodal NK/T cell lymphoma (ENKTL): Extended follow-up on the multicenter, single-arm phase II trail (ORIENT-4).
Authors: Li Jianyong , Tao Rong , Fan Lei , Song Yongping , Hu Yu , Zhang Wei , Wang Yafei , Xu Linxinyu , Sun Xing , Zhou Hui 
Published: May 2020

8050 Background: Patients with r/r ENKTL have a poor prognosis after failing an asparaginase-based regimen. The overexpression of PD-L1 induced by EBV infection is a potential mechanism for ENKTL to avert immune surveillance. Sintilimab, a fully human anti-PD-1 monoclonal antibody, has demonstrated efficacy in r/r ENKTL after the primary analysis of the ORIENT-4 study. Here, we report the updated efficacy and safety results with extended follow-up. Methods: Patients with pathologically confirmed r/r ENKTL were enrolled. Sintilimab was given 200 mg IV Q3W, until PD, death, unacceptable toxicity, or withdrawal from the study. Treatment beyond PD is allowed. Tumor response evaluation was performed by both PET-CT and CT/MRI with contrast. The primary endpoint was objective response rate per Lugano 2014. Data cut-off date for this analysis was Jan 17, 2020. Results: A total of 28 patient were enrolled and treated. With a median follow-up of 26.9 months (range, 23.3 to 28.6), the median treatment duration was 24.15 months (range, 1.4 to 28.7). Of 20 patients with progressive disease (PD) by investigator per Lugano 2014 criteria, 19/20 (95%) patients received treatment beyond PD. The median OS has not been reached and 24-month OS rate was 78.6% (95% CI, 58.4% to 89.8%). ORR was 67.9% (95% CI, 47.6% to 84.1%), including 4 pts who experienced PD prior to having a response. DCR was 85.7%, including 5 pts who experienced PD before SD or response. Median duration of response was 4.1 months (range, 1.9 to 15.2+). After treatment, the mean EQ-5D-5L VAS Score (from 79.3 to 90.8), EQ-5D-5L Index Value (from 0.8 to 0.9) and EORTC QLQ-C30 (from 70.5 to 87.3) were all increased. The Treatment-related adverse events (TRAEs) of any grade occurred in 28 (100%) pts; grade 3 occurred in 11 (39.4%) pts, most commonly, decreased lymphocyte count (2 [7.1%]) and diabetes (2 [7.1%]); no grade 4-5 TRAE. Conclusions: In addition to an encourage response, sintilimab also demonstrated long-term clinical benefit, with 78.6% of 24-month OS rate, and favorable long-term safety profile after extended follow-up. Considering the high rate (95%) of treatment beyond PD, Lugano 2014 may not be a suitable criteria for evaluating the efficacy of anti-PD-1 antibody in r/r ENKTL. Clinical trial information: NCT03228836 .
Prognostic relevance of CD4+ T-cells in the microenvironment of newly diagnosed follicular lymphoma (FL) patients is independent of the tumor gene expression profile.
Authors: Mondello Patrizia , Fama Angelo , Larson Melissa C. , Feldman Andew L. , Yang Zhi-Zhang J , Villasboas Jose Caetano , Huet Sarah , Tesson Bruno , Slager Susan L. , Link Brian K. , Syrbu Sergei , Novak Anne , Habermann Thomas Matthew , Witzig Thomas E. , Nowakowski Grzegorz S. , Salles Gilles A. , Cerhan James Robert , Ansell Stephen M. 
Published: May 2020

8052 Background: A significant proportion of patients with FL experience an early relapse and a subsequent poor outcome. While several prognostic indices have been developed, none were designed to predict early failure. Recently, we established that lack of intrafollicular CD4+ T-cell expression predicted risk of early failure, and integrating this microenvironment biomarker with the Follicular Lymphoma International Prognostic Index, termed BioFLIPI, further improved identification of FL patients at risk of early failure ( Blood 2019;134(suppl1):121). However, the microenvironment may be influenced by the genetic composition of tumor. We investigated whether the CD4 biomarker and BioFLIPI were impacted by genetic features of the tumor as assessed by a 23-gene expression prognostic score ( Lancet Oncol 2018;19:549-61). Methods: Of the 186 cases with FL grade 1-3A treated with immunochemotherapy (IC) in our prior study, 152 had digital expression quantification of 23 selected genes (23-GEP score), which used RNA from formalin-fixed, paraffin-embedded samples. Event-free survival (EFS) was defined as time from diagnosis to progression, relapse, retreatment, or death. Early failure was defined as failing to achieve EFS at 24 months. Risk of early failure was estimated using odds ratios (ORs) and 95% confidence intervals from logistic regression models. We also used Cox regression to assess associations with continuous EFS and overall survival (OS). Results: 28% of patients failed to achieve EFS24. Lack of CD4+ intrafollicular expression (38% of patients, OR = 2.33, p = 0.024) and high risk 23-GEP score (26% of patients, OR = 3.52, p = 0.001) each predicted early failure, and in a multivariable model that included FLIPI, both CD4+ (OR = 2.26, p = 0.046) and 23-GEP score (OR = 2.26, p = 0.0.057) remained predictors. Similarly, BioFLIPI modeled as a continuous score (1-4, OR per one point increase = 2.31, p < 0.001) predicted early failure, and the association remained (OR = 2.14, p < 0.001) when the high risk 23-GEP score (OR = 2.79, p = 0.013) was included in the model. When stratified on 23-GEP score, BioFLIPI was a stronger predictor of early failure in low risk (74%, OR = 2.51, p = 0.002) relative to high risk (26%, OR = 1.55, p = 0.27) patients. Similar patterns were observed for EFS and OS. Conclusions: CD4+ T-cell infiltrate and tumor gene expression appear to be independently predictive of early failure in newly diagnosed FL patients treated with IC. Future studies should integrate and validate these measures.
Identification of predicted neoantigen vaccine candidates in follicular lymphoma patients.
Authors: Ramirez Cody , Frenkel Felix , Plotnikova Olga , Belousov Vladislav , Bagaev Alexander , Ocheredko Elena , Kiwala Susanna , Hundal Jasreet , Skidmore Zach L , Watkins Marcus , Becker-Hapak Michelle , Fronick Catrina , Fulton Robert , Schreiber Robert , Bartlett Nancy L. , Kahl Brad S. , Ataullakhanov Ravshan , Griffith Malachi , Griffith Obi , Fehniger Todd A. 
Published: May 2020

8054 Background: Follicular lymphoma (FL) is incurable with conventional therapies and poorly responsive to immune checkpoint blockade. There is a need for new therapies without long-term complications of chemotherapy and with curative potential. We hypothesize that FL contains tumor-specific mutant antigens (TSMAs) that can be targeted by the immune system by vaccination. Recent reports have highlighted the potential for unique immunoglobulin peptides to elicit immune response in lymphomas. We utilized whole exome sequencing (WES) and RNA sequencing (RNA-Seq) of FL patient samples to infer HLA genotype, and predict TSMAs with the goal of designing a personalized cancer vaccine, supported by recent reports of this approach in solid cancers. Methods: DNA and RNA from 58 patients’ FL biopsies underwent WES and RNA-Seq. pVACtools and MiXCR predicted potential somatic and B-cell clonotype neoantigens, which were filtered to identify high quality TSMAs. B-cell oligoclonality was determined by comparison to B-cell receptor (BCR) repertoire profiling of healthy individual lymph nodes. RNA-seq data allowed us to identify expressed TSMAs. Complementary in silico analysis based on mRNA-based peptide reconstruction and custom HLA affinity binding predictions were performed. Results: An average of 52 somatic mutations per patient (range: 2-172) were identified. At least one high quality TSMA was predicted for 57 of 58 patients. Five or more TSMA candidates were identified for 52 (90%) patients with a mean of 17 predicted peptides per patient (range: 0-45). 81% (813/1,004) of the total predicted TSMA peptides arose from missense mutations, 9% (94/1,004) from indels, and 10% (97/1,004) from BCR. 78% (45/58) of patients have both somatic and BCR vaccine candidates, while 21% (12/58) of patients had only somatic vaccine candidates. Predicted TSMAs were identified in multiple genes recurrently mutated in lymphoma (e.g., BCL2). There was a high prediction concordance with the orthogonal BostonGene Vaccine Module V1 pipeline. These pre-clinical results led to a first-in-human pilot trial of personalized TSMA vaccine combined with anti-PD-1 mAb for rel/ref FL patients (NCT03121677), with one response observed within 4 patients evaluable for response to date. Conclusions: TSMA peptides suitable for cancer vaccines were identified for most FL patients via next-generation sequencing, MiXCR and pVACtools. This pre-clinical study suggests that FL patients will be candidates for TSMA vaccine clinical trials and pilot clinical results provide proof of concept for this approach.
REFLECT real-world evidence (RWE) prospective study update: Efficacy and safety results of Sandoz biosimilar rituximab (SDZ-RTX) for the treatment of diffuse large B-cell lymphoma (DLBCL).
Authors: Welslau Manfred , Marschner Norbert Walter , Otremba Burkhard Joerg , Topaly Julian , Bittencourt da Silva Larissa 
Published: May 2020

8060 Background: SDZ-RTX (Rixathon) is approved in more than 20 countries and regions, including highly regulated markets e.g. Europe, Japan and Switzerland for all labeled indications of reference rituximab. REFLECT is the first prospective post-approval study to evaluate a rituximab biosimilar as a curative therapy in untreated pts with CD20+ DLBCL. This interim analysis adds up efficacy and additional safety results on the previously presented data (Welslau et al, ASCO and EHA 2019). Methods: Adult patients (pts) were treated with SDZ-RTX and cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) according to the product label. The primary endpoint is to evaluate the effectiveness of Rixathon measured by complete response (CR) rate at the end of treatment. Secondary endpoints are overall response rate (ORR), progression-free survival at 24 months and adverse events (AEs). Data were collected at baseline and all scheduled treatment and follow-up visits, which is still ongoing. No imputation was made for missing values, and endpoints are summarized descriptively. Results: As of Sep 30, 2019, 170 pts were enrolled, and R-CHOP treatment was close to completion. The median age of pts was 70 years, and 52% were women. Overall, 38% of pts completed the first 12-month observation period, 41% were ongoing, while 21% of pts discontinued. Most of the pts (~80%) had an ECOG score of 0 (35%) or 1 (46%). Early staging (I–II2), low to intermediate disease risk (IPI 0-2), and known B symptoms were reported for 55%, 50%, and 30% of pts, respectively. CR rate at the end of treatment was 57% (defined as the revised response criteria for malignant lymphoma by Cheson et al, 2007 that excludes complete remission/unconfirmed [CRu]). Summary of efficacy is reported in the Table. Overall, 83% of pts experienced AEs, the most common being anemia (23%), fatigue (21%), and polyneuropathy (15%). Treatment-related AEs were reported for 28% of pts. Rates of any serious AEs (SAEs) and treatment-related SAEs were 37% and 6.5%, respectively. On-treatment deaths and all deaths were reported in 2.4% and 4.7% of pts, respectively. Conclusions: REFLECT is the first prospective post-approval study to evaluate a rituximab biosimilar as a curative therapy in untreated pts with DLBCL. This interim analysis results re-confirms the expected safety and efficacy profile for DLBCL patients treated with R-CHOP. [Table: see text]
Idecabtagene vicleucel (ide-cel; bb2121), a BCMA-targeted CAR T-cell therapy, in patients with relapsed and refractory multiple myeloma (RRMM): Initial KarMMa results.
Authors: Munshi Nikhil C. , Anderson, Jr Larry D. , Shah Nina , Jagannath Sundar , Berdeja Jesus G. , Lonial Sagar , Raje Noopur S. , Siegel David Samuel DiCapua , Lin Yi , Oriol Albert , Moreau Philippe , Yakoub-Agha Ibrahim , Delforge Michel , Petrocca Fabio , Connarn Jamie , Patel Payal , Huang Liping , Campbell Timothy Brandon , Hege Kristen , San Miguel Jesus ,   on behalf of the KarMMa Study Investigators
Published: May 2020

8503 Background: Outcomes are poor in triple-class exposed RRMM patients (pts) who progress on immunomodulatory agents (IMiDs), proteasome inhibitors (PIs), and CD38 antibodies (mAbs). Ide-cel, a BCMA targeted CAR T cell therapy, showed promising tolerability and efficacy in RRMM pts in the phase I CRB-401 study ( NEJM2019;380:1726). We present primary efficacy and safety data from the pivotal phase II KarMMa trial of ide-cel in RRMM (NCT03361748). Methods: Enrolled pts had ≥3 prior regimens (including IMiD, PI, and CD38 mAb) and were refractory to their last regimen per IMWG criteria. After lymphodepletion (cyclophosphamide 300 mg/m2+ fludarabine 30 mg/m2 x 3), pts received 150─450 × 106 CAR+ T cells (target dose range). Endpoints included overall response rate (ORR; primary), complete response (CR) rate, duration of response (DoR), and PFS. Results: Of 140 pts enrolled, 128 received ide-cel. Median age was 61 y; median no. of prior regimens was 6; 84% were triple- and 26% were penta-refractory. Most pts (88%) had bridging therapy. At data cutoff (16 Oct 2019), median follow up was 11.3 mo. ORR was 73% and median PFS was 8.6 mo; both increased with higher dose (Table). All subgroups had an ORR ≥50%, including older and high-risk pts. Most common any-grade (Gr) toxicities were cytopenias (97%) and cytokine release syndrome (CRS; 84%). CRS was mainly Gr 1/2; 5 pts (5%) had Gr 3, 1 had Gr 4, and 1 had Gr 5 (at 300 × 106). Neurotoxicity developed in 23 pts (18%); 4 (3%) Gr 3 and 0 Gr ≥4. Median peak CAR+ T cell expansion occurred at 11 d. Expansion was higher in responders and parameters (AUC0−28d, Cmax) increased with higher dose, with exposure overlap across doses. Persistence was durable, with CAR+ T cells detected in 29/49 (59%) and 4/11 pts (36%) at 6 and 12 mo. Conclusions: Ide-cel demonstrated deep, durable responses in heavily pretreated RRMM pts. Efficacy and safety reflected prior reports and support a favorable ide-cel clinical benefit-risk profile across the target dose range. Clinical trial information: NCT03361748 . [Table: see text]
Depth of response prior to autologous stem cell transplantation to predict survival in light chain amyloidosis.
Authors: Vaxman Iuliana , Sidiqi M Hasib , Al Saleh Abdullah S. , Kumar Shaji , Muchtar Eli , Dispenzieri Angela , Buadi Francis , Dingli David , Lacy Martha , Hayman Suzanne R. , Leung Nelson , Gonsalves Wilson I. , Kourelis Taxiarchis , Warsame Rahma M. , Hogan William J. , Gertz Morie A. 
Published: May 2020

8516 Background: The role of induction therapy prior to autologous stem cell transplant (ASCT) in immunoglobulin light chain (AL) amyloidosis remains controversial. Data on the prognostic impact of response to induction in a transplanted cohort are lacking. The aim of this study was to assess the impact of response to induction therapy on survival in patients undergoing ASCT for AL amyloidosis. Methods: We conducted a retrospective study of all newly diagnosed AL amyloidosis patients who received induction prior to ASCT between January 2007 and August 2017 at Mayo Clinic, Rochester, Minnesota. Patients receiving only corticosteroids prior to transplant were excluded as were those with an involved light chain of less than 5 mg/dL (not measurable for response). Results: 134 patients met inclusion criteria. The median age at diagnosis was 60 (range 36-74) and 85 (63%) were men. The most commonly used induction regimen was proteasome inhibitor-based (73.1%, n=98). The overall response rate to induction was 83% (complete response 17%, very good partial response 30% and partial response 36%). With a median follow up of 56.5 months, the median PFS and OS was 48.5 months and not reached, respectively. Response depth to induction therapy was associated with improved PFS and OS and was independent of the bone marrow plasma cell percentage. The median PFS was not reached for patients achieving ≥VGPR prior to ASCT and 33.8 months for patient achieving PR or less (P=0.001). The median OS was longer in patients with deeper responses (not reached for patients achieving ≥VGPR vs. 128 months for patients achieving PR or less (P=0.02). On multivariable analysis, independent predictors of OS were melphalan conditioning dose (RR= 0.38; P=0.018) and depth of response prior to transplant (RR 2.52; P=0.039). Conclusions: Hematologic response prior to transplant predicts post-transplant outcomes in patients with AL amyloidosis. [Table: see text]
Ixazomib vs placebo maintenance for newly diagnosed multiple myeloma (NDMM) patients not undergoing autologous stem cell transplant (ASCT): The phase III TOURMALINE-MM4 trial.
Authors: Dimopoulos Meletios A. , Spicka Ivan , Quach Hang , Oriol Albert , Hajek Roman , Garg Mamta , Beksac Meral , Bringhen Sara , Katodritou Eirini , Chng Wee Joo , Leleu Xavier , Iida Shinsuke , Mateos Maria-Victoria , Morgan Gareth , Vorog Alexander , Labotka Richard , Wang Bingxia , Palumbo Antonio , Lonial Sagar 
Published: May 2020

8527 Background: Maintenance therapy delays disease progression in non-ASCT NDMM patients. However, in practice, currently used maintenance therapies may be limited to fixed duration due to toxicity and route of administration; additional options are needed. Methods: 706 non-ASCT NDMM patients who received 6–12 months of standard-of-care induction therapy and achieved at least a partial response (≥PR) were randomized 3:2, double-blind, to the oral proteasome inhibitor (PI) ixazomib (n = 425; 3 mg, cycles 1–4, then, if tolerated, 4 mg, cycle 5 onwards) vs placebo (n = 281) on days 1, 8, and 15 of 28-day cycles for ≤2 yrs. Patients were stratified by prior PI exposure (yes vs no), pre-induction International Staging System (ISS) disease stage (I/II vs III), age ( < 75 vs ≥75 yrs), and post-induction best response (complete or very good partial response [CR/VGPR] vs PR). Primary endpoint was progression-free survival (PFS). Results: Baseline characteristics were well balanced. Overall median age was 73 yrs, 38% of patients were aged ≥75 yrs, 35% were ISS stage III, and 22%/40%/38% had CR/VGPR/PR post induction. Overall, 82% of patients received a PI and 33% an immunomodulatory drug as part of their induction regimen. At a median follow-up of 21.1 months, median PFS was 17.4 months with ixazomib vs 9.4 months with placebo (hazard ratio [HR] 0.659, 95% confidence interval [CI] 0.542–0.801, p < 0.001). Significant (p < 0.001) PFS benefit was seen in patients who achieved CR/VGPR post induction (Table). Overall survival data are not yet mature (19% of events); follow-up is ongoing. Treatment-emergent adverse events (TEAEs) were mostly grade 1–2 (37% vs 23% of patients had grade ≥3 TEAEs with ixazomib vs placebo). Common TEAEs for ixazomib vs placebo included nausea (27% vs 8%), vomiting (24% vs 4%), and diarrhea (23% vs 12%); 5% vs 6% of patients had new primary malignancies. No cumulative toxicities were observed. Conclusions: Ixazomib maintenance therapy in non-ASCT NDMM patients showed a clinically meaningful 34% reduction in the risk of progression or death, with a well-tolerated safety profile. Ixazomib is the first oral PI maintenance option for non-ASCT NDMM patients. Clinical trial information: NCT02312258 . [Table: see text]
Multiple myeloma (MM) vaccination (influenza, FV and pneumococcal, PV) rates worldwide and impact on infection, hospitalization, and death.
Authors: Thompson Michael A. , Costello Caitlin , Berdeja Jesus G. , Davies Faith , Zonder Jeffrey A. , Lee Hans Chulhee , Omel Jim , Spencer Andrew , Terpos Evangelos , Hungria Vania , Puig Noemi , Fu Cheng-Cheng , Skacel Tomas , Ferrari Renda H. , Ren Kaili , Stull Dawn Marie , Chari Ajai 
Published: May 2020

8528 Background: MM is a cancer of the immune system. Infections are common reasons for hospitalization and death in MM. As MM patients (pts) are living longer, with prolonged exposure to systemic therapy, there is a need to vaccinate pts and to determine the effectiveness of these vaccines. Vaccination in MM pts is underutilized, based on a study of vaccination patterns in a large health system (Alemu JPCRR 2017) and data collected via a pt self-report online portal (Thompson ASCO 2020). We analyzed FV and PV patterns and associated outcomes in INSIGHT MM, the largest global, prospective, observational study in MM to date. Methods: INSIGHT MM aims to understand MM pt and disease characteristics at diagnosis and relapse, treatment patterns, clinical outcomes, and treatment-associated tolerability, effectiveness, quality of life, and healthcare resource utilization. INSIGHT MM has enrolled 4318 MM pts from 15 countries worldwide; pts are being followed up prospectively for ≥5 yrs. Vaccine status is collected at study entry and yearly. We analyzed FV and PV patterns and associated outcomes of pts enrolled in July 2016–2019. Results: At data cutoff (Sep 1, 2019), 2562/2523 pts had study entry data on FV/PV status. Overall vaccination rates were low (FV 40%, PV 30%) and varied by region: FV 56%/38%/27%/4% and PV 43%/28%/21%/5% in US/Europe/Latin America/Asia. In evaluable pts, lack of vaccination was associated with higher infection and hospitalization rates for FV, and with increased risk of death (univariate analysis) for both FV and PV (Table; multivariate analysis underway). Infections, including influenza and pneumonia, were the cause of death in 19% (43/226) / 8% (9/108) (P = 0.018) of pts who did not receive FV / received it in the past 2 yrs and 19% (46/236) / 9% (9/100) (P = 0.027) of pts who did not receive PV / received it in the past 5 yrs, and in 7%/15%/20%/40% of pts who died in US/ Europe/Latin America/Asia (P < 0.0001). Conclusions: Global vaccination rates in MM pts were low and varied by region. Lack of vaccination correlated with rates of infection (FV), hospitalization (FV), and death (FV and PV). Further MM datasets should be analyzed to confirm the findings. Vaccination data should be collected in prospective clinical trials as it may affect survival. Vaccination is important in MM and should be encouraged. Clinical trial information: NCT02761187 . [Table: see text]