bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II study of cpi-0610, a bromodomain and extraterminal protein inhibitor (BETi) alone or with ruxolitinib (RUX), in patients with myelofibrosis (MF).
Authors: Kremyanskaya Marina , Hoffman Ronald , Mascarenhas John , Bose Prithviraj , Gupta Vikas , Schiller Gary J. , Liew Elena , Lebedinsky Claudia , Senderowicz Adrian Mario , Mertz Jennifer , Trojer Patrick , Verstovsek Srdan 
Published: March 2020

7056 Background: BETi have been shown to regulate NF-κB, MYC, BCL2, and TGF-β signaling, important drivers of marrow fibrosis. Preclinical studies have suggested that combined BETi and JAK2 inhibition synergistically reduce MF-related splenomegaly, bone marrow fibrosis and the malignant allele burden (Kleppe, 2018). CPI-0610 is a selective and potent oral BETi, being evaluated in the first study of a BETi in MF. Methods: Phase 2 trial with 3 arms: CPI-0610 monotherapy (Arm 1) or RUX + CPI-0610 “add-on” (Arm 2) in pts who have progressed/ had an inadequate response to RUX, or CPI-0610 + RUX in JAK inhibitor-naïve pts with anemia (Arm 3). Arms 1 and 2 are stratified: transfusion dependence (TD) yes: A/no: B. The primary objectives are to evaluate the effect of CPI-0610 on transfusion dependence (TD, 1A and 2A) and spleen volume (1B, 2B and 3). A Simon two-stage design: if 2 responses are seen will advance to the 2nd stage. Results: 4 pts enrolled in Arm 1, 14 pts in Arm 2, no pts accrued to Arm 3 yet. Median age: 69 years (46-83), gender: 9 male pts; 11 pts received ≥1 prior therapy besides RUX. JAK2/MPL/CALR mutations: 17/18 pts, ≥3 mutations: 10 pts, ASXL1 mutations: 11 (61%) pts. Hemoglobin <10 g/dL at baseline: 11 (61%) pts. 6 pts received ≥ 24 weeks of CPI-0610 treatment at this analysis. 2 TD pts in Arm 2 became transfusion independent, both remain on treatment free of transfusions. Hgb increase of ≥1.5 g/dL from baseline was observed with successive cycles of therapy in anemic pts: 2/2 pts in Arm 1 (100%) and 3/9 pts in Arm 2, (33%). Spleen volume reduction, by MRI (6-44%) was observed in all 10 evaluable pts irrespective of their driver mutation. Symptom improvement and reductions of cytokine levels were observed. In Arm 1: 2/2 evaluable pts had marrow fibrosis improvement with Hgb increase; additionally, thrombocytosis resolved in 2/2 pts (baseline ≥791 103/uL). Most common adverse events were mild diarrhea, nausea/vomiting; and reversible and non-cumulative thrombocytopenia. Conclusions: CPI-0610 is a well-tolerated, and an effective therapeutic agent for the treatment of MF. Collectively, these data indicate that CPI-0610 +/- RUX might have disease modifying effects. Updated data will be provided. Clinical trial information: NCT02158858.
TRANSCEND CLL 004: Minimal residual disease (MRD) negative responses after lisocabtagene maraleucel (Liso-Cel; JCAR017), a CD19-directed CAR T cell product, in patients (pts) with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL).
Authors: Siddiqi Tanya , Dorritie Kathleen Anne , Soumerai Jacob Drobnyk , Stephens Deborah Marie , Dubovsky Jason A , Gillenwater Heidi H. , Gong Lucy , Thorpe Jerill , Yang Lin , Wierda William G. 
Published: March 2020

7501 Background: Eradication of MRD in CLL patients may be necessary for deep and durable responses. We assessed safety, pharmacokinetics, and efficacy of liso-cel, an investigational, anti-CD19 CAR T cell product administered as a defined composition of CD4+/CD8+ CAR T cells, in the ongoing phase 1/2 TRANSCEND CLL 004 study. Methods: Eligible pts had CLL/SLL, received ≥2 prior lines of therapy (including Bruton’s tyrosine kinase inhibitors [BTKi] unless medically contraindicated), and had ECOG PS ≤1. Post lymphodepleting chemotherapy, pts received liso-cel infusion at either dose level (DL)1 = 50 × 106 or DL2 = 100 × 106 total CAR+ T cells. Patients were monitored for dose-limiting toxicities (DLTs). Response was assessed by iwCLL 2008 criteria. MRD was assessed by flow cytometry in blood (10−4) and by NGS in bone marrow (BM; 10−6). Results: At data cutoff, 16 pts received liso-cel: DL1, n = 6; DL2, n = 10. 75% of pts had high-risk features ( TP53 mutation, complex karyotype, or del17p); 100% had prior ibrutinib and 50% had prior venetoclax. Median (range) number of prior lines of therapy was 4.5 (2‒11). There was 1 DLT of grade (G) 4 hypertension (DL2). The most common G3/4 treatment-emergent adverse events were cytopenias (thrombocytopenia, 75%; anemia, 69%; neutropenia, 63%; leukopenia, 56%). 1 pt had G3 cytokine release syndrome (CRS); 3 pts had G3 neurological events (NE). Best overall response rate (ORR) in 15 evaluable pts was 87% (13/15). 7 pts (47%) achieved complete remission with/without complete blood count recovery (CR/CRi). ORR at 6 mo was 83% (5/6). 10/15 pts (67%) achieved undetectable MRD (uMRD) in blood by day 30 and in 7/8 pts (88%) in BM. MRD-negative CRs were seen in patients who had failed both BTKi and venetoclax. Median time to peak blood CAR+ T cell level was 16 days (4‒30). Conclusions: In this study of heavily pretreated pts with standard- and high-risk CLL/SLL and previous ibrutinib treatment, liso-cel-related toxicities (ie, CRS and NEs), were manageable. Pts rapidly achieved CR/CRi and uMRD. Additional follow-up will be presented. Clinical trial information: NCT03331198.
First-line therapy of T-cell lymphoma: Allogeneic or autologous transplantation for consolidation—Final results of the AATT study.
Authors: Shmitz Norbert , Truemper Lorenz , Ziepert Marita , Bouabdallah Kamal , Cartron Guillaume , Nickelsen Maike , Milpied Noel Jean , Gisselbrecht Christian , Wulf Gerald , Maury Sébastien , Gyan Emmanuel , Jaccard Arnaud , De Leval Laurence , Gaulard Philippe , Rosenwald Andreas , Friedrichs Birte , Reimer Peter , Wilhelm Martin , Altmann Bettina , Tournilhac Olivier 
Published: March 2020

7503 Background: In patients (pts) with peripheral T-cell lymphoma (PTCL) results of first-line therapy remain poor; guidelines recommend consolidation with autologous transplantation (autoSCT) in transplant-eligible pts. AATT (Autologous or Allogeneic Transplantation in T-cell lymphoma) sought to improve first-line therapy and compared alloSCT with autoSCT. Methods: This was a prospective randomized trial comparing autoSCT with alloSCT in younger pts (18-60 yrs) with newly diagnosed PTCL who had achieved CR, PR, or SD after 4 courses of CHOEP and 1 course of DHAP. Pts were to receive BEAM followed by autoSCT or myeloablative conditioning (fludarabine, busulfan, cyclophosphamide) followed by alloSCT from a matched related or unrelated donor. Primary endpoint was 3-year event-free survival (EFS). The study was stopped prematurely after a pre-planned interim analysis (JCO 33, 2015, suppl 8507a). Results: 103 pts randomized upfront to autoSCT (n=54) or alloSCT (n=49) formed the full analysis set. Median age was 50 years, 63% were male. 36 pts (35%) could not proceed to transplantation mostly due to early progression. Median observation time for EFS was 42 months. 3-year EFS and overall survival (OS) did not significantly differ between alloSCT and autoSCT (EFS: 43% (95% CI29-57%) vs. 38% (25-52%), p=0.58, OS: 57% (43-71%) vs. 70% (57-82%) (p=0.41). Comparing pts who actually received autoSCT (n=41) or alloSCT (n=26) EFS, PFS, and OS also showed no significant difference. No patient relapsed but eight pts (31%) died of treatment-related mortality (TRM) after alloSCT compared to 13 relapses (36%) but no TRM observed after autoSCT. Comparison of pts with aaIPI 2/3 vs. 0/1 showed significant differences for all endpoints. Conclusions: AlloSCT or autoSCT given to consolidate response in pts with PTCL showed no significant survival differences. While exerting a strong GvL-effect alloSCT resulted in substantial TRM. For younger pts with PTCL autoSCT remains the preferred consolidation, in particular, because pts. relapsing after autoSCT can be successfully salvaged with alloSCT. Clinical trial information: 2007-001052-39.
Rituximab maintenance for patients with diffuse large B-cell lymphoma in first complete remission: Results from a randomized HOVON-Nordic Lymphoma Group phase III study.
Authors: Lugtenburg Elly J. , Brown Peter , van der Holt Bronno , D'Amore Francesco , Koene Harry R , de Jongh Eva , Fijnheer Rob , Loosveld Olaf , Böhmer Lara H , Pruijt Hans , Verhoef Gregor , Hoogendoorn Mels , Bilgin Yavuz , Nijland Marcel , Lam King H , de Keizer Bart , de Jong Daphne , Zijlstra Josee M 
Published: March 2020

7507 Background: This randomized phase III trial assessed whether intensification of rituximab (R) during the first 4 cycles of R-CHOP can improve outcome of diffuse large B-cell lymphoma (DLBCL) patients compared with standard R-CHOP. Patients in complete remission (CR) after induction treatment were randomized between rituximab maintenance and observation. Intensification of rituximab was not more effective than standard R-CHOP, showing same CR-rates and progression free survival after induction (ASCO 2016 # 7504). Here, we report the results of the second randomization for rituximab maintenance therapy. Methods: Patients in CR after R-CHOP were randomized between 24 months of rituximab maintenance 375 mg/m2 intravenous every 8 weeks (n = 199 ) or observation (n = 199). CT scans were performed at 6, 12, 18 and 24 months in both arms. The primary endpoint was disease free survival (DFS) from maintenance randomization. Secondary endpoints were overall survival (OS) and adverse events (AEs). ( www.trialregister.nl NTR1014). Results: Median age was 65 years (range 31-80), 48% were 66 years or older and 49% were male. The majority of patients (54%) had a high-intermediate or high aa-IPI score. After a median follow-up of 79.9 months (maximum 125.7 months), the 5-year DFS rate was 79% for rituximab maintenance versus 74% for observation. This difference was not statistically significant, with a hazard ratio of 0.83 (95% confidence interval 0.57-1.19, p= 0.31, adjusted for age and aa-IPI). The secondary endpoint OS was also not significantly different (85% versus 83% at 5 years). No clinical subgroup benefited from rituximab maintenance. Toxicity was mild. Among patients who received rituximab maintenance CTCAE grade 3 and 4 AEs were reported in 17% and 6% of patients, respectively. Infection was the most frequent AE, a grade 3 infection occurred in 6% of patients. Neutropenia was seen in 1% (grade 3) and 3% (grade 4) of patients. Conclusions: Rituximab maintenance therapy provides no additional benefit for DLBCL patients in first CR after R-CHOP. Clinical trial information: www.trialregister.nl NTR1014.
Outcomes in chronic lymphocytic leukemia (CLL) patients with NOTCH1 signaling pathway mutations.
Authors: Helbig Daniel R. , Abu Zeinah Ghaith F , Bhavsar Erica B. , Allan John N. 
Published: March 2020

7524 Background: NOTCH1 is one of the most frequently mutated genes in CLL and has emerged as a marker of poor prognosis. Additional mutations in the NOTCH1 signaling pathway, specifically MED12, FBXW7, and SPEN, have been identified in CLL but their clinical significance has yet to be fully determined. We evaluated the clinical outcome of time to first treatment (TTFT) to compare patients with mutations to those who are wild type for NOTCH1, MED12, FBXW7, and SPEN, hypothesizing that patients with these mutations will behave similarly to NOTCH1 mutated patients and have a shorter TTFT. Methods: We conducted a single center retrospective database review of 506 patients diagnosed with CLL from 1980 to 2018 who underwent whole exome profiling between 2015 to 2018 with a lymphoid specific 75-gene next generation sequencing (NGS) panel (Genoptix Inc). The TTFT was estimated using Kaplan-Meier methods, and the difference between groups was compared using the log-rank test. Multivariate analysis (MVA) was performed with Cox proportional hazards regression. Results: Of the 506 patients who underwent NGS testing, 121 (23.9%) had at least one mutation in the NOTCH1 signaling pathway. These patients were diagnosed at an older age (62.0 years vs. 60.0 years, p=0.04) and had higher rates of CD38 positivity (40.9% vs. 22.9%, p≤0.001), Trisomy 12 (36.0% vs. 15.8%, p≤0.001), and IGVH unmutated status (71.3% vs. 44.1%, p≤0.001). They also had a shorter TTFT with a median of 3.93 years compared to 5.02 years in patients without any mutation in the NOTCH1 signaling pathway (p=0.002). In MVA, IGVH unmutated status and CD38 positivity remained independently predictive for TTFT. Conclusions: We identified three mutations in genes associated with regulation of NOTCH1 signaling that appear to signify poor prognosis, predict for a shorter TTFT, and associate with similar baseline factors that NOTCH1 does such as Trisomy 12 and IGVH unmutated status. NOTCH1 mutated patients have poor response to chemoimmunotherapy and are associated with aggressive disease biology. Future research is needed to determine whether mutations in MED12, FBXW7, or SPEN may also predict for poor response to frontline chemoimmunotherapy or novel agents currently used in CLL.
Diversity of genetic alterations of primary central nervous system lymphoma in Hispanic versus non-Hispanic population.
Authors: Barakat Mohamad , Albitar Maher , Whitney Robin L. , Chen Calvin , Kuo Yu-Hung , Silveira William , Bukari Mohammed SANI , Arekapudi Subramanyeswara Rao , Dhaliwal-Binning Karamjit , Abdulhaq Haifaa 
Published: March 2020

7535 Background: Primary central nervous system lymphoma (PCNSL) is a rare type of non-Hodgkin lymphoma, distinguished by poor prognosis. Previous studies have identified MYD88, CD79b and PIM1 as the most common genetic mutations in PCNSL. However, the extent to which mutations vary by ethnicity is unknown. The purpose of this study was to describe differences in genetic mutations and survival by Hispanic ethnicity in PCNSL. Methods: We retrospectively reviewed records of 30 patients with PCNSL diagnosed between January 2007- December 2017. We examined mutations in 275 genes by DNA analysis and 1382 genes by RNA analysis utilizing next generation sequencing. Results: Among the thirty patients, median age was 60 years, 60% were male, and 60% were Hispanic. Twenty-four patients had activated B-cell (ABC) and 5 patients had germinal center (GC) type per Hans criteria. Among 29 patients with complete mutation data, 125 different mutated genes were detected. Missense mutations were the most common (75%) followed by frame shift mutations (25%). The most commonly affected genes were: MYD88 (44%), CARD11 (21%), CD79b (17%), PIM1 (17%), KMT2D (17%) and ETV6 (14%). CD79b mutation was more common in GC type vs. ABC type (60% vs. 8%, P=.01). MYD88 mutation was less frequent in Hispanic patients (27% vs 66%, P=.02), while there were no statistically significant differences in CARD11 (22% vs 18%, P=.79), KMT2D (22% vs 9%, P=.36), CD79B (16% vs 19%, P=.92) and PIM1 (16% vs 19%, P=.92). There were more Hispanic patients with >3 mutated genes (89% vs 55 %. P=.03). Two-year progression-free survival (PFS) and overall survival (OS) were 46% and 50%, respectively. Both outcomes were superior among Hispanic vs. non-Hispanic patients (2-yr PFS 60% vs 27%, P=.09), (2-yr OS 60% vs 36%, P=.23), but this was not statistically significant. MYD88, CARD11, PIM1, and KMT2D were not associated with significant differences in 2-year OS or PFS. However, patients with CD79b mutations had superior 2-yr PFS (P=.04). Conclusions: We identified highly recurrent genetic alterations in PCNSL. Our data suggest that some heterogeneity in the most frequent mutations in PCNSL may be related to ethnicity. However, the superiority in 2-yr PFS and OS did not reach statistical significance in our Hispanic patients. Further studies on a larger patient population may further help to describe the differences in incidence, tumor biology, and outcomes in Hispanic patients.
Comparison of clinical scoring systems in aggressive B-cell lymphomas (BCL): An individual patient-level analysis across international trials (SEAL).
Authors: Ruppert Amy S. , Dixon Jesse G. , Salles Gilles A. , Wall Anna K. M. , Cunningham David , Poeschel Viola , Haioun Corinne , Tilly Herve , Ghesquieres Herve , Ziepert Marita , Flament Jocelyne , Flowers Christopher , Shi Qian , Shmitz Norbert 
Published: March 2020

7544 Background: Great heterogeneity in survival exists for patients (pts) newly diagnosed with aggressive BCL. Three scoring systems based on simple clinical parameters (age, lactate dehydrogenase, number/sites of involvement, stage, performance status) are widely used: the international prognostic index (IPI), revised-IPI (R-IPI), and National Comprehensive Cancer Network IPI (NCCN-IPI). We studied BCL pts treated with R-CHOP to determine which scoring systems best identifies subgroups with poor outcomes that might benefit from new approaches. Methods: Individual pt data from 7 multicenter trials (1998-2009) of pts with BCL (86% DLBCL) treated front-line with R-CHOP (or variant) were analyzed to determine whether IPI, R-IPI, or NCCN-IPI best discriminated overall survival (OS). The concordance index (c-index) from a proportional hazards model, stratifying on trial and induction therapy, quantified predictive accuracy of each scoring system. Results: 2561 pts (median age 63 yrs, 56% male) were classified into IPI, R-IPI, and NCCN-IPI risk groups (Table). With a median follow-up of 5 yrs, NCCN-IPI had the greatest absolute difference in OS estimates between the highest and lowest risk groups at 1, 3, and 5 yrs, and best discriminated OS (c-index = 0.631, Table). Conclusions: In an independent and large cohort of pts, NCCN-IPI performs best in risk-stratifying pts with aggressive BCL, readily distinguishing pts at high and low risk for treatment failure using clinical parameters (5-yr OS between 48 and 92%). Improvement over the simpler IPI appears incremental, and IPI may remain a valuable alternative. Work integrating molecular features of the tumor into the (NCCN-) IPI is in progress to define high risk groups where targeted novel approaches are needed most. [Table: see text]
Molecular profiling of primary central nervous system lymphoma as compared to activated B-cell subtype of diffuse large B-cell lymphoma.
Authors: Barakat Mohamad , Albitar Maher , Xu-Monette Zijun , Young Ken H , Abdulhaq Haifaa 
Published: March 2020

7549 Background: The cell of origin of primary central nervous system lymphoma (PCNSL) remains controversial. Data using immunohistochemistry (IHC) and Hans algorithm suggested that both germinal-center B-cell–like (GCB) and activated B-cell-like (ABC) subtypes can be seen in PCNSL. We explored the potential of DNA and RNA molecular profiling in characterizing the biology of PCNSL and compared this profile with ABC subtype of diffuse large B-cell lymphoma (DLBCL). Methods: RNA and DNA were extracted from 30 formalin-fixed paraffin-embedded (FFPE) tissue samples from PCNSL patients and 30 FFPE tissue samples from cases with lymph node DLBCL of ABC subtype. Subtyping of DLBCL cases was performed using IHC and gene expression profiling. We sequenced the DNA using a 275 gene panel (Qiagen) and the RNA using a 1382 gene panel (Illumina). Next Generation Sequencing on Illumina platform was used for detecting mutations and expression profiling. The levels of RNA expression were normalized to that of PAX5. Mutations detected by RNA sequencing were compared to those detected by DNA sequencing. Results: There was no significant difference between DLBCL-ABC and PCNSL in mutation rate of MYD88, CD79B, CARD11 or KMT2D: 33.3%, 10%, 10%, and 13.3%, respectively, in DLBCL-ABC vs 30%, 10%, 10%, and 10%, respectively, in PCNSL. However, NOTCH2 mutations were significantly different and detected in 16.7% of DLBCL-ABC as compared with 3% in PCNSL (P=.001). An algorithm that uses expression profiling of 46 different genes and distinguishes DLBCL-ABC from GCB showed that all PCNSL cases classified as ABC. The GCB classical marker LMO2 was expressed at very low level in both DLBCL-ABC and PCNSL, but was at relatively higher level in PCNSL (P=.002, Kruskal-Wallis ANOVA). There was significantly higher expression of the adhesion molecule CXCR4 (P=.008), activation molecules BTK (P=.0003) and PLCG2 (P=.002), and BCL6 (P=.002) in PCNSL as compared with DLBCL-ABC. There was no significant difference between the two groups in MYC, Ki67, BCL2, CD44, or CD274 (PD-L1) expression. Conclusions: DNA and RNA molecular profiling of PCNSL suggests similarity to DLBCL-ABC subtype. However, PCNSL is unique by expressing higher levels of the adhesion molecule CXCR4 and the activation molecules BTK and PLCG2. The lack of increased expression of MYC and Ki67 suggests that PCNSL is unlikely to be similar to Burkitt lymphoma.
Efficacy of frontline treatment regimens in follicular lymphoma: A network meta-analysis of phase III randomized controlled trials.
Authors: Wang Yucai , Zhou Shouhao , Yang Fang , Nowakowski Grzegorz S. , Habermann Thomas Matthew , Wang Michael , Witzig Thomas E. 
Published: March 2020

7556 Background: The frontline treatment for advanced follicular lymphoma has evolved with the introduction of maintenance therapy, bendamustine (Benda), obinutuzumab (G), and lenalidomide (Len). We conducted a network meta-analysis of phase 3 randomized controlled trials (RCTs) to identify the regimens with superior efficacy. Methods: Data were extracted from 7 RCTs (FOLL05, StiL NHL1, BRIGHT, PRIMA, GALLIUM, StiL NHL7, and RELEVANCE). Progression-free survival (PFS) was compared between 11 regimens with different immunochemotherapy and maintenance strategies. To incorporate direct and indirect comparisons, random-effects Bayesian network meta-analyses were conducted after adjusting for study-wise variation. The posterior inference was derived based on Markov chain Monte Carlo methods and implemented using JAGS v4.3.0. Pairwise comparison of hazard ratios (HRs) and 95% credible intervals (CIs) were calculated. Results: PFS HRs of other regimens compared to the reference regimen are summarized in the Table. Compared to Rituximab(R)-Benda, R-CHOP had inferior PFS, R-CHOP-R, G-CHOP-G, and R-Len-R had similar PFS, while R-Benda-R, R-Benda-R4 and G-Benda-G had better PFS. Compared to R-CHOP-R, G-CHOP-G and R-Len-R had similar PFS, while R-Benda-R, R-Benda-R4 and G-Benda-G had better PFS. In addition, the PFS for G-Benda-G was similar to R-Benda-R4 (HR 0.94, 95% CI 0.78-1.09) but better than R-Benda-R (HR 0.82, 95% CI 0.75-0.97). Conclusions: Compared with the commonly used R-Benda and R-CHOP-R regimens, G-CHOP-G, R-Benda-R and R-Benda-R4 had better PFS, while the chemotherapy-free regimen R-Len-R had similar PFS. [Table: see text]