bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of premature venetoclax (Ven) discontinuation/interruption on outcomes in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): Phase III MURANO study results.
Authors: Mato Anthony R. , Sharman Jeff P. , Biondo Juliana , Wu Mei , Mun Yong , Kim Su Young , Humphrey Kathryn , Boyer Michelle , Zhu Qian , Seymour John F. 
Published: May 2020

8028 Background: Ven + rituximab (VenR) has a manageable safety profile and improves survival in patients (pts) with R/R CLL, but discontinuation/interruption is frequent. We present new data from the Phase III MURANO study on the impact of Ven early discontinuation/interruption on outcomes in pts with R/R CLL. Methods: Time-dependent Cox proportional hazards regression models, stratified by 17p deletion and risk status, evaluated the impact of Ven discontinuation/interruption on investigator-assessed PFS and OS. Analyses were performed retrospectively (without type-1 error control) in intent-to-treat pts with R/R CLL from the fixed-duration VenR arm of MURANO (NCT02005471; data cut-off: May 8, 2019). Results: 140/194 pts (72%) in the VenR arm completed 2 years of therapy. Early discontinuation occurred in 54/194 (28%) pts (adverse events [AEs]: 29, disease progression [PD]: 12, withdrawal: 5, physician decision: 3, death: 2, other: 2, non-compliance: 1). Median Ven durations for pts discontinuing due to AEs and PD: 11.3 (0.5–24.6) and 17.1 (4.6–25.1) months, respectively (p = 0.08). Inferior PFS was observed in pts who discontinued Ven early for any reason except PD or due to AEs, versus those who completed therapy (Table). Greater cumulative Ven exposure significantly reduced risk of a PFS/OS event (PFS: HR 0.93, 95% CI 0.88–0.99, p = 0.0168; OS: HR 0.85, 95% CI 0.79–0.92, p < 0.0001). Treatment interruption for AEs occurred in 134/194 (69%) pts, most commonly due to neutropenia (84/194; 43%), per protocol requirements. Median duration of interruption: 9 (1–93) days. Treatment interruption, regardless of duration, had no impact on PFS or OS (Table). 36 (19%) pts with interruptions later discontinued Ven. Conclusions: In MURANO, early Ven discontinuation was associated with suboptimal outcomes; Ven interruption was not. These data highlight the importance of effective control of toxicity to realize the full benefit of VenR treatment. Clinical trial information: NCT02005471 . [Table: see text]
Machine learning prediction of survival in diffuse large B-cell lymphoma based on gene-expression profiling.
Authors: Merdan Selin , Subramanian Kritika , Ayer Turgay , Koff Jean Louise , Chang Andres , Weyenbergh Johan Van , Flowers Christopher 
Published: May 2020

8047 Background: The current clinical risk stratification of Diffuse Large B-cell Lymphoma (DLBCL) relies on the International Prognostic Index (IPI) comprising a limited number of clinical variables but is imperfect in the identification of high-risk disease. Our study aimed to: (1) develop a risk prediction model based on the genetic and clinical features; and (2) evaluate the model’s biological implications in association with the estimated profiles of immune infiltration. Methods: Gene-expression profiling was performed on 718 patients with DLBCL for which RNA sequencing data and clinical covariates were available by Reddy et al (2017). Unsupervised and supervised machine learning methods were used to discover and identify the best set of survival-associated gene signatures for prediction. A multivariate model of survival from these signatures was constructed in the training set and validated in an independent test set. The compositions of the tumor-infiltrating immune cells were enumerated using CIBERSORT for deconvolution analysis. Results: A four gene-signature-based score was developed that separated patients into high- and low-risk groups with a significant difference in survival in the training, validation and complete cohorts (p < 0.001), independently of the IPI. The combination of the gene-expression-based score with the IPI improved the discrimination on the validation and complete sets. The area-under-the-curve at 2 and 5 years increased from 0.71 and 0.69 to 0.75 and 0.74 in the validation set, respectively. Conclusions: By analyzing the gene-expression data with a systematic approach, we developed and validated a risk prediction model that outperforms existing risk assessment methods. Our study, which integrated the profiles of immune infiltration with prognostic prediction, unraveled important associations that have the potential to identify patients who could benefit from the various therapeutic interventions, as well as highlighting possible targets for new drugs.
Phase Ib trial combining rapid determination of drug-drug interaction (DDI) followed by a dose finding period to assess safety and preliminary efficacy of fimepinostat plus venetoclax in patients with aggressive B-cell lymphoma.
Authors: Phillips Tycel Jovelle , De Vos Sven , Westin Jason , Barta Stefan K. , Cohen Jonathon Brett , Patel Krish , Smith Sonali M. , Pagel John M. , Kansra Vikram , Grayson Dena , Younes Anas , Batlevi Connie Lee 
Published: May 2020

8056 Background: Fimepinostat (F), a dual inhibitor of PI3K (α, β, δ) and HDACs type 1/2, causes suppression of MYC levels (Shulman et al., 2017). A pooled analysis of diffuse large B-cell lymphoma (DLBCL) pts treated with F in two Ph 1/2 trials revealed an objective response rate in evaluable/ITT MYC-altered DLBCL pts of 29%/23%, respectively (Landsburg et al., 2018). Based on compelling preclinical activity of F in combination with venetoclax (V) (a Bcl2 inhibitor), we initiated a Ph 1b/2 study of F + V in pts with relapsed or refractory (R/R) DLBCL or high-grade B-cell lymphoma (HGBL), with or without MYC alteration. V is metabolized primarily by CYP3A, and preclinical studies showed that F may inhibit CYP3A4 (IC50 of 13.58 and 0.28 µM for midazolam and testosterone, respectively), suggesting F could cause DDI with V. Methods: Cohorts of patients received increasing dose levels of F administered on a 5-days-on/2-days-off (5/2) schedule in combination with daily V in 21-day cycles (Cohort 1: F 30 mg QD 5/2 + V 400 mg QD; Cohort 2: F 60 mg QD, 5/2 + V 400 mg QD; Cohort 3: F 60 mg QD 5/2 + V 800 mg QD). A potential DDI was assessed during Cycle 0 (Table), where PK for V (10 mg) monotherapy was compared to that for V (10 mg) in the presence of F. Patient PK samples were collected, analyzed and reviewed in < 10 days to determine the final ramp-up dose level of V. Results: As of 1-Feb-2020, 16 pts have been enrolled in 2 dose cohorts. Intensive PK analysis of 13 pts showed only mild (≤ 2-fold) to no increase in V exposure in the presence of F. In Cohort 1 (n = 6), the mean AUC increased 1.6-fold, and mean Cmax by 1.5-fold. In Cohort 2 (n = 7), no increase in mean AUC (0.9-fold) or Cmax (1.0-fold) was observed. Accordingly, all pts ramped up V to 100% of the target dose (400 mg) upon entering Cycle 1; rapid escalation of V was well tolerated. DLT was observed in 1 pt (Grade 3 diarrhea) in Cohort 2. Overall, 75% of TEAEs have been mild or moderate (Grade 1/2), and most were of limited duration. 11 pts (69%) experienced SAEs; 4 pts (25%) had SAEs considered related to either F or V. Conclusions: Real-time PK evaluation showed that F had only a mild to no DDI with V. F + V is well tolerated at clinically active dose levels, and evaluation of higher dose-level cohorts was ongoing. Enrollment in Cohort 2 remains on-going. Clinical trial information: NCT01742988 . [Table: see text]
Safety and efficacy of TQ-B3525, a novel and selective oral PI3K α/δ inhibitor, in Chinese patients with advanced malignancies: A phase I dose-escalation and expansion trial.
Authors: Wang Huaqing , Jiang Wenqi , Li Su , Wang Yu , Sun Peng , Zhou Pei , Zheng Yang , Zhan Jing , Li Zhiming 
Published: May 2020

8058 Background: TQ-B3525 is a novel and selective oral PI3K α/δ inhibitor with activity 41 and 138 folds higher than Buparlisib against PI3K α and PI3K δ in pre-clinical research. This Phase I study (NCT03510767) assessed the safety, tolerability, pharmacokinetics and antitumor activity of TQ-B3525 in Chinese patients with advanced malignancies. Methods: Patients with relapsed or refractory (R/R) lymphoma who have experienced at least two prior systemic anti-cancer treatments, and advanced solid tumor who have failed standard anti-cancer treatment, were enrolled. TQ-B3525 was administered orally from 2mg, 5mg, 10mg, 20mg once daily (qd) to 10mg, 20mg twice daily (bid). DLT was observed in the first cycle (28 days) of dose-escalation phase. Dose-expansion phase started at the dose level which objective response occurs. Results: Between June 2018 and December 2019, a total of 40 patients were enrolled, Including 27 patients with R/R lymphoma and 13 patients with advanced solid tumor. Three DLTs (both grade 3 hyperglycemia) were observed: two in the 20mg bid dose cohort and one in the 10mg bid. The common AEs of all grades were hyperglycemia (65.0%), glycosylated hemoglobin increased (35.0%) and diarrhea (32.5%). Grade 3 or 4 treatment-related AEs occurred in 11 patients (27.5%), with the most common one also being hyperglycemia (10.0%). TQ-B3525 was rapidly absorbed (Tmax: 1-2 h) and moderately eliminated (T1/2: 10-12 h). At steady state, the geometric mean AUC0-24 and Ctrough of TQ-B3525 at 20mg qd were 1060.7 ± 198.6 h*ng/mL and 23.4 ± 9.5 ng/mL, which was above IC50 (4.2 ng/ml). 23 lymphoma patients were evaluable for clinical response per 2014 Lugano Classification. The overall response rate (ORR) was 60.9% (95% CI, 38.5-80.2). The ORR at ≥10mg qd was 70.0% (14/20, [95% CI, 49.9-90.1]). For R/R FL, the ORR was 72.7% (8/11, [95% CI, 46.4-99.1]). At data cut-off (2nd February, 2020), the median PFS for lymphoma was not reached (events rate: 33.3%). The longest duration of response at data cutoff was 11.8 months in a patient with FL. Conclusions: TQ-B3525 is well-tolerated in Chinese patients with advanced malignancies, and demonstrated high promising antitumor activity in R/R lymphoma patients. Recommended phase II dose was established at 20mg qd. A single-arm phase 2 trial of TQ-B3525 in patients with R/R FL is currently underway. Clinical trial information: NCT03510767 .
The BCR repertoire comparison, lymphoma typing model and OS predicted model in 5 different pathological lymphomas: T-LBL/ALL, PTCL-NOS, B-MCL, B-FL, and DLBCL.
Authors: Jiang Wenhua , Zhou Shiyong , Li Jian , Gao Mingyou , Zhao Kuo , Zhang Limeng , Xie Xiaojing , Zhao Ning , Tian Caijuan , Xu Zanmei , Zhang Zhenzhen , Yan Fang , Pan Yi , Liu Pengfei 
Published: May 2020

8059 Background: Lymphatic system cancer is characterized by high heterogeneity in histology and clinical manifestations, B-cell antigen receptor (BCR) plays a vital role in anti-tumor immune responses. This study aimed to compare the BCR repertoire and identify some specific immune markers for different pathological lymphomas. Methods: 5 pathological types of non-Hodgkin's lymphoma (T-LBL/ALL, PTCL-NOS, B-MCL, B-FL, DLBCL) were collected, with reactive lymph node (RLN) hyperplasia as control. All patients were tested by high-throughput immunohistochemical sequencing (HTS-IR) to analyze the correlation between B-cell immunohistochemistry and clinical indicators, and constructed new strategy typing and overall survival (OS) predicted models for lymphomas. Results: The BCR repertoire had the highest diversity in RLN, followed by T-LBL/ALL, PTCL-NOS, DLBCL, B-MCL and B-FL. The diversity of BCR repertoire and similarity of B cell antigens were higher in B-MCL and B-FL patients. Similar to RLN, T-LBL/ALL and PTCL-NOS had broad and diverse V-J pairs, and rare in B-MCL, B-FL and DLBCL. RLN patients were with the highest average number of amino acids, followed by T-LBL/ALL, DLBCL, PTCL-NOS, B-MCL and B-FL. The expressed amino acid sequencing of ARDLIALDY, ARRPGSFDY, ARDIAGWGAVAGLLGRAYYGMDV, and ARDGPYGGNSVEYFQH were markedly different among 5 groups. Patients tended to recurrence expressed ASLDSSPSGFC, ARGMTTVTTAPNY, ARVPLYDDQNINDV and AGGVGGYDWGSYYFDY (P = 0.01605, 0.02869, and 0.01569), and prone to metastasis with expressions of ARVKEFYGILTGYDY, AHSIIGSSWYNWFDP and VRDGGWQSNNWLGFDV (P = 0.04259, 0.0450 and 0.0481). For all patients, 18 (7 negative, 11 positive) and 12 (10 negative, 2 positive) IGH V-J pairs were respectively associated with lymphoma recurrence and metastasis. The top 3 most significant pairs were IGHV7-4-1_IGHJ4, IGHV3-53_IGHJ5 and IGHV3-7_IGHJ5 bound up with recurrence (P = 0.0019, 0.0020 and 0.0021), and IGHV3-74_IGHJ1, IGHV1-69_IGHJ3 and IGHV1-2_IGHJ1 related to metastasis (P = 0.0022, 0.010 and 0.019). The accuracy of typing model in training and test sets was 78.125% (25/32) and 60% (6/10), respectively. The OS model can predict long (≥ 24 months) or short ( < 24 months) OS. Conclusions: Our study identified new biomarkers, constructed novel lymphoma typing model and OS predicted model based on B cell repertoire. It provides a comprehensive understanding of immune response, and contributes to the diagnosis and prognosis of non-Hodgkin's lymphoma.
Update of CARTITUDE-1: A phase Ib/II study of JNJ-4528, a B-cell maturation antigen (BCMA)-directed CAR-T-cell therapy, in relapsed/refractory multiple myeloma.
Authors: Berdeja Jesus G. , Madduri Deepu , Usmani Saad Zafar , Singh Indrajeet , Zudaire Enrique , Yeh Tzu-Min , Allred Alicia J. , Olyslager Yunsi , Banerjee Arnob , Goldberg Jenna D. , Schecter Jordan , Geng Dong , Wu Xiaoling , Carrasco-Alfonso Marlene , Rizvi Syed , Fan Frank (Xiaohu) , Jakubowiak Andrzej J. , Jagannath Sundar 
Published: May 2020

8505 Background: JNJ-68284528 (JNJ-4528) is a chimeric antigen receptor T (CAR-T) cell therapy containing 2 BCMA-targeting single-domain antibodies. Here we present updated CARTITUDE-1 (NCT03548207) phase 1b results with longer follow-up. Methods: Pts had MM per IMWG criteria, measurable disease, received ≥3 prior regimens or were double refractory to a PI and IMiD, and received anti-CD38 antibody. Cyclophosphamide 300 mg/m2+ fludarabine 30 mg/m2 over 3 days were used for lymphodepletion. JNJ-4528 (median, 0.73x106 CAR+ viable T cells/kg) was given as a single infusion. Cytokine release syndrome (CRS) was graded by Lee et al2014 and neurotoxicity by CTCAE, v5.0 and ASTCT grading. Response was assessed per IMWG criteria. Results: As of 17 Jan 2020, median follow-up is 9 mo (3–17). Phase 1b enrollment is complete (N = 29 treated; median 5 (3–18) prior lines, 76% penta-exposed, 86% triple-refractory, 31% penta-refractory, 97% refractory to last line of therapy). Most frequent adverse events (AEs) were neutropenia (100%), CRS (93%), and thrombocytopenia (93%). Grade (Gr) ≥3 hematologic AEs were neutropenia (100%), thrombocytopenia (69%), and leukopenia (59%). 27 (93%) pts had CRS; 25 Gr 1–2, 1 Gr 3, and 1 Gr 5 (day 99 subsequent to dose-limiting toxicity of prolonged Gr 4 CRS). Median time to onset of CRS was 7 days (2–12). 4 pts had treatment-related neurotoxicity: 3 Gr 1–2 and 1 Gr 3. ORR was 100%, with 22 (76%) stringent complete responses (sCRs), 6 (21%) very good partial responses (VGPRs), and 1 (3%) PR. Median time to ≥CR was 2 mo (1–9). 26/29 pts are progression-free, with 6-mo progression-free survival rate of 93% and longest response ongoing at 15 mo. 1 death due to CRS and 1 to acute myeloid leukemia (not treatment-related) occurred during the study. All 16 pts (14 sCR, 2 VGPR) evaluable at 6 mo were minimal residual disease negative at 10−5 or 10−6. JNJ-4528 CAR+ T cell expansion peaked between day 10–14. At 6-mo individual follow-up, 22/28 pts had JNJ-4528 CAR+ T cells below the level of quantification (2 cells/µL) in peripheral blood, suggesting CAR-T persistence in peripheral blood did not seem to correlate with deepening of response. At peak expansion, preferential expansion of CD8+ CAR-T cells with a central memory phenotype was observed in peripheral blood. Conclusions: JNJ-4528 treatment led to responses in all pts. These responses were early, deep, and durable at a low dose of CAR-T cells with 26/29 (90%) pts progression free at median 9-mo follow-up. CRS was manageable in most pts, supporting outpatient dosing. Clinical trial information: NCT03548207 .
Long-term follow-up of BMT CTN 0702 (STaMINA) of postautologous hematopoietic cell transplantation (autoHCT) strategies in the upfront treatment of multiple myeloma (MM).
Authors: Hari Parameswaran , Pasquini Marcelo C. , Stadtmauer Edward Allen , Fraser Raphael , Fei Mingwei , Devine Steven Michael , Efebera Yvonne Adeduni , Geller Nancy , Horowitz Mary M. , Koreth John , Landau Heather Jolie , McCarthy Philip L. , Qazilbash Muzaffar H. , Shah Nina , Vesole David H. , Vogl Dan T. , Somlo George , Krishnan Amrita Y. , Giralt Sergio 
Published: May 2020

8506 Background: STaMINA was a phase III trial comparing progression-free survival (PFS) among 758 pts randomized to: 1. second autoHCT then lenalidomide (Len) maintenance (Auto/Auto, n = 247); 2. consolidation with Len/bortezomib/ dexamethasone (RVD) followed by Len maintenance (Auto/RVD, 254); 3. Len maintenance (Auto/Len, 257). All three arms were similar (Stadtmauer JCO 2018). Len maintenance was designed to continue for 3 years and amended to allow continuation until disease progression through a follow up protocol (07LT, NCT#02322320). We report 6 yr follow up for STaMINA and the results of Len discontinuation beyond 3 years. Methods: 07LT was offered to pts who were progression-free at 38 mo; completed planned Len maintenance and were within 4 years of BMT CTN 0702 follow up. Among 431 07LT eligible patients, 273 enrolled and 179 opted to continue maintenance until disease progression. All patients enrolled in STaMINA were reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) and long-term outcomes for patients not enrolled on 07LT (N = 166) were available through this mechanism. Before combining 07LT data and CIBMTR data for LTFU analysis, outcomes in both databases were analyzed separately and confirmed to be comparable. Results: Using intent-to-treat (ITT), 6yr PFS and overall survival (OS) was the same among Auto/Auto (43.9%; 73.1%), Auto/RVD (39.7%, 74.9%) and Auto/Len (40.9%, 76.4%)(p = 0.6; p = 0.8). Protocol defined high risk disease, (HR = 1.53, p < 0.0001) and age (p = 0.03) were adverse risks for PFS. In as treated analysis, 6yr PFS were 49.4%, 39.7% and 38.6% for Auto/auto (170), Auto/RVD (222) and Auto/Len (361), respectively (p = 0.01). 6yr PFS in high risk pts as treated analysis were 43.6% and 26% for Auto/auto and Auto/Len, respectively (p = 0.03). Landmark analysis at 38 mo included 215 pts who continued Len maintenance (either on 07LT study or commercial Len) vs. 207 who stopped. Baseline demographics; study arm on 0702, induction pre-autoHCT were similar. Len discontinuation after 38 mo was associated with inferior PFS (79.5% vs. 61% at 5yr; HR = 1.91, p = 0.0004) but similar OS. Incidence of all second primary malignancies (SPM)(81 cases with 43 heme-malignancies) was associated with age. Conclusions: Long term outcomes are similar using ITT, but as treated analysis suggested a PFS benefit for tandem autoHCT, driven mainly by pts with high risk MM. Len discontinuation even at 38 mo was associated with inferior PFS. Clinical trial information: NCT02322320 .
Primary analysis of the randomized phase II trial of bortezomib, lenalidomide, dexamthasone with/without elotuzumab for newly diagnosed, high-risk multiple myeloma (SWOG-1211).
Authors: Usmani Saad Zafar , Ailawadhi Sikander , Sexton Rachael , Hoering Antje , Lipe Brea , Hita Sandi , Durie Brian G. , Zonder Jeffrey A. , Dhodapkar Madhav V. , Callander Natalie Scott , Rajkumar S. Vincent , Voorhees Peter Michael , Richardson Paul G. , Orlowski Robert Z. 
Published: May 2020

8507 Background: The introduction of immunomodulatory agents, proteasome inhibitors, and autologous stem cell transplantation (ASCT) has improved outcomes for patients with multiple myeloma (MM), but those with high risk MM (HRMM) have a poor long-term prognosis. To date, no trials have addressed optimal treatment for these patients. Methods: S1211 is a randomized phase II trial (NCT01668719) comparing 8 cycles of lenalidomide, bortezomib and dexamethasone (RVd) induction followed by dose-attenuated RVd maintenance until disease progression with or without elotuzumab. Stem cell collection was allowed, but ASCT was deferred until progression. HRMM was defined by one of the following: gene expression profiling high-risk (GEPhi), t(14; 16), t(14; 20), del(17p) or amplification 1q21, primary plasma cell leukemia (pPCL) and elevated serum LDH (> 2X ULN). Median progression-free survival (PFS) was the primary end-point, using a one-sided stratified log-rank test at a one-sided significance level of 0.1. Secondary endpoints included overall response rate (ORR), adverse events (AE), serious adverse events (SAE) and OS. Response was assessed using the IMWG 2009 criteria. Results: S1211 enrolled 103 evaluable patients, RVd n = 54, RVd-Elo n = 49. 75% had ISS II/III, 47% amp1q21, 38% del17p, 12% t(14; 16), 9% GEPhi, 7% pPCL, 5% t(14; 20) and 4% elevated serum LDH (18.5% > 1 feature). With median follow-up of 53 months (mos.), no difference in median PFS was observed [RVd-Elo = 31 mos., RVd = 34 mos.,HR = 0.968 (80% CI = 0.697-1.344), p = 0.449]. No difference in OS was observed [RVd-Elo = 68 mos, RVd = not reached, HR = 1.279 (80% CI: 0.819, 2.000), p-value = 0.478]. 72% pts had > Grade 3 AEs, no differences in the safety profile were observed except >Grade 3 infections (RVd 8%, RVd-Elo 16%), >Grade 3 sensory neuropathy (RVd 8%, RVd-Elo 13%). Conclusions: In the first randomized HRMM study reported to date, the addition of elotuzumab to RVd induction and maintenance did not improve patient outcomes. However, the PFS and OS seen in both arms of the study exceeded the original statistical assumptions and support the role for PI/IMiD combination maintenance therapy for this patient population. The S1211 data will serve as an important benchmark for future HRMM clinical trials. Clinical trial information: NCT01668719 .