bluuebunny/crossref_metadata_2025_split huggingface dataset:
Response rates with pembrolizumab in combination with rituximab in patients with relapsed follicular lymphoma: Interim results of an on open-label, phase II study.
Authors: Nastoupil Loretta J. , Westin Jason R. , Fowler Nathan Hale , Fanale Michelle A. , Samaniego Felipe , Oki Yasuhiro , Obi Chizobam , Cao JingJing , Cheng Xiaoyun , Ma Man Chun John , Wang Zhiqiang , Chu Fuliang , Feng Lei , Zhou Shouhao , Davis Richard Eric , Neelapu Sattva Swarup 
Published: September 2018

7519 Background: Follicular lymphoma (FL) tumors are infiltrated with antitumor T cells, however, their function is impaired by immune checkpoints such as PD-1/PD-ligand pathway. Blocking PD-1 enhances the function of antitumor T cells in FL. In addition, blocking PD-1 on NK cells has been shown to enhance the ADCC effect of NK cells. We reasoned that the combination of pembrolizumab (P), an anti-PD-1 antibody (ab), and rituximab (R), an anti-CD20 ab that induces ADCC, is likely to be synergistic through activation of both the innate and adaptive immune systems and result in enhanced clinical activity in FL. Methods: We evaluated P and R in an open-label, non-randomized, single institution, phase II trial (N=30). Key inclusion criteria included adult (age ≥ 18 years), FL grade 1-3a, ECOG 0-1, in relapse after ≥1 prior therapy (tx) and R sensitive disease, defined as a complete (CR) or partial response lasting at least 6 months (mos) after most recent R-containing therapy. Pts received R (375 mg/m2 IV) on days 1, 8, 15, and 22 of cycle 1 and P (200mg IV) q 3 weeks for up to 16 cycles starting on day 2 of cycle 1. Primary endpoint was overall response rate (ORR). Results: 27 pts have initiated therapy, median age 65 (range 42-79), 52% male, 76% had intermediate or high risk FLIPI, 56% met GELF criteria. Median prior tx =1 (range 1-4). Adverse events (AE) regardless of causality were mild, most grade 1-2. Grade 3 AE’s included nausea (N=2), infusion reaction (N=2), aseptic meningitis (N=1), pneumonia (N=1). Immune-related AEs included grade 2 diarrhea (N=2), grade 2 pneumonitis (N=1), grade 2 skin rash (N=1). At the pre-planned interim analysis (N=15), ORR was 80%, CR rate was 60%. With a median follow up of 7 mos (range 0.5-17), median DOR, PFS, and OS has not been reached. PD-L1 expression was tested in 8 baseline tumor samples using PD-L1 22C3 IHC pharmDx and was detected in histiocytes in all 8 tumors, present in only 1-8% of tumor cells in 5 tumors. Additional biomarker analyses are ongoing. Conclusions: The combination of P and R is well tolerated in relapsed FL and is associated with high overall and CR rate. These interim results warrant further investigation of this combination in FL. Clinical trial information: NCT02446457.
Ongoing phase 1/2 study of INCB050465 for relapsed/refractory (R/R) B-cell malignancies (CITADEL-101).
Authors: Ramchandren Rod , Phillips Tycel Jovelle , Wertheim Michael , Gutierrez Martin , Edenfield William Jeffery , Akard Luke Paul , Caimi Paolo Fabrizio , Call Justin , Persky Daniel Oscar , DeMarini Douglas James , Zhou Li , Yeleswaram Swamy , Forero-Torres Andres 
Published: September 2018

7530 Background: INCB050465 is a selective PI3Kδ inhibitor with no preclinical hepatotoxicity at clinically relevant doses. We report emerging safety and efficacy data from a phase 1/2 study of INCB050465 in patients (pts) with r/r B-cell malignancies (NCT02018861). Methods: The protocol was initiated with a single patient cohort, treated with INCB050465 5 mg QD PO. Subsequent cohorts used a 3+3 design and evaluated doses of 10–45 mg QD. Based on PK/PD, the 20 and 30 mg QD cohorts were expanded. Responses were assessed Q9W by the Lugano Classification or International Working Group on Chronic Lymphocytic Lymphoma (CLL) criteria. Results: As of the data cutoff (Nov 1, 2016), 52 pts were treated (median age, 65 y [range, 30–88]; baseline tumors: diffuse large B-cell lymphoma [DLBCL], n=14; follicular lymphoma [FL], n=10; Hodgkin lymphoma [HL], n=9; marginal zone lymphoma [MZL], n=8; CLL, n=6; mantle cell lymphoma [MCL], n=5; 62% had >3 prior systemic regimens). Median duration of therapy was 3.3 mo (range, 0.6–13.4); no DLTs were identified. 67% of pts discontinued therapy (disease progression, 31%; AEs, 25%); 33% had dose interruption; 4% had reduction. Most common nonhematologic AEs (all grade [Gr]; Gr ≥3): nausea (38%; 0%), diarrhea (31%; 6%), vomiting (25%; 0%); Gr ≥3 hematologic AEs: neutropenia (21%), lymphopenia (17%), thrombocytopenia (10%), anemia (4%). 40% of pts had serious AEs, most frequently colitis, diarrhea, hypotension (all n=3). 1 pt had Gr 3 pneumonitis; none had Pneumocystis jirovecii pneumonia (PJP) or Gr ≥2 elevated transaminase. Objective responses (ORs) occurred at all doses (Table), except 5 mg QD; 90% were observed at first assessment. Conclusions: INCB050465 demonstrated manageable toxicities with no clinically meaningful transaminitis/PJP. OR rates were generally high, with 90% observed at first assessment. Different dosing regimens/schedules, long-term safety, and disease-specific cohorts are being evaluated. Clinical trial information: NCT02018861. [Table: see text]
Phase II study of single-agent copanlisib in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).
Authors: Lenz Georg , Hawkes Eliza , Verhoef Gregor , Haioun Corinne , Thye Lim Soon , Heo Dae Seog , Ardeshna Kirit , Chong Geoffrey , Christensen Jacob Haaber , Shi Vivian , Lippert Susanne , Hiemeyer Florian , Piraino Paolo , Pena Carol Elaine , Buvaylo Viktoriya , Childs Barrett H. , Gorbatchevsky Igor , Salles Gilles A. 
Published: September 2018

7536 Background: Relapsed/refractory (r/r) DLBCL patients (pts) are characterized by poor prognosis. Copanlisib is a pan-Class I phosphatidylinositol 3-kinase (PI3K) inhibitor, with modest single-agent activity in unselected DLBCL pts. Here we report the treatment effect of copanlisib in r/r DLBCL pts with regards to cell of origin (COO) and molecular biomarker profiles (NCT02391116). Methods: Patients with r/r DLBCL and ≥1 prior lines of therapy were eligible. Copanlisib (60 mg IV infusion) was administered on days 1, 8 and 15 of a 28-day cycle. Tumor samples were evaluated for COO, CD79B mutations and > 400 genes by next generation sequencing (NGS). The primary endpoint was objective tumor response rate (ORR; per Lugano Classification, 2014) by COO and CD79B status. Results: The full-analysis (FAS) and per-protocol sets (PPS; ≥3 doses, post-baseline scans and NGS/COO data) included 67 and 40 pts, respectively. Pts were 58% male, median age 69 (range 25-93), ECOG status 0/1/2 22%/57%/21%, and heavily pretreated (median prior lines = 3, range 1-13). In the PPS, COO (and mutant CD79B status) analysis identified 22 GCB DLBCL (2 mutant), 16 ABC DLBCL (6 mutant), and 2 unclassifiable. The ORR in the PPS was 25% (10 of 40), with 5 complete responses (CR) and 5 partial responses (PR); stable disease in 12 pts. The ORR was 13.6% with 1 CR in GCB pts and 37.5% with 4 CRs (25%) in ABC pts. Response to copanlisib was 25% in pts with (2/8) and without (8/32) CD79B mutations. Five of 10 ABC DLBCL-wtCD79B pts and one GCB DLBCL-mCD79B responded (ongoing > 17 cycles). NGS analysis in 54 pts detected 348 mutations; BCL2 (54% of pts), TP53 (41%), BCL6 (30%), MYC (22%), CD79B (19%)/A (6%), MYD88 (19%), TNFAIP3 (17%), CARD11 (13%), and NFKBIA (9%). Response to copanlisib was not significantly different based on BCL2, BCL6, MYC, and MYD88 mutations. With a median of 6 cycles (range 1-29), the most common AEs (% all grade/gr3+4) were diarrhea (36/2), nausea (31/2), fatigue (31/3), fever (21/2) and transient hypertension (40/33) and hyperglycemia (34/31). There were 14 gr5 AEs (none drug-related). Conclusions: Copanlisib treatment of r/r DLBCL pts resulted in encouraging responses, especially in the ABC subtype, with a manageable toxicity. Clinical trial information: NCT02391116.
Early disease progression in patients (pts) with newly diagnosed localized nasal extranodal NK/T-cell lymphoma, nasal type (ENKL) treated with radiotherapy with dexamethasone, etoposide, ifosfamide, and carboplatin (RT-DeVIC).
Authors: Yamaguchi Motoko , Suzuki Ritsuro , Oguchi Masahiko , Asano Naoko , Miyazaki Kana , Terui Yasuhito , Kubota Nobuko , Maeda Takeshi , Kobayashi Yukio , Amaki Jun , Soejima Toshinori , Saito Bungo , Shimoda Emiko , Fukuhara Noriko , Tsukamoto Norifumi , Shimada Kazuyuki , Choi Ilseung , Utsumi Takahiko , Ejima Yasuo , Katayama Naoyuki ,   NKEA Project
Published: September 2018

7546 Background: Approximately 25% of all pts with localized nasal ENKL experience disease progression during the first two years (yrs) after diagnosis under new treatments including concurrent chemoradiotherapy. The clinical features of those pts are largely unknown. Methods: The database of our study (NKEA project; UMIN000015491) was used for the present analysis. Data from pts with newly diagnosed localized (stage IE and contiguous IIE) nasal ENKL diagnosed between 2000 and 2013 at 31 institutes in Japan and treated with RT-DeVIC were retrospectively analyzed. Progression of disease within 2 yrs (POD24) (Casulo, JCO 2015) was applied as the definition of early progression. Results: Of 162 pts, 38 were in the POD24 group (23%) and 124 were in the reference group. Treatment yrs and doses of RT and DeVIC were not associated with the incidence of POD24. With a median follow-up of 5.8 yrs, the overall survival (OS) of the POD24 group was inferior to that of the reference group ( P < 0.00001; 2-yr OS, 26% vs. 100%; 5-yr OS, 23% vs. 89%). The POD24 group showed the following features more frequently than the reference group: serum soluble interleukin-2 receptor (sIL-2R) level > upper limit of normal (ULN) (25/33, 76%; P = 0.000012), C-reactive protein (CRP) > ULN (28/37, 76%; P = 0.013), and detectable Epstein-Barr virus (EBV)-DNA in peripheral blood (15/17, 88%; P = 0.033). The positive predictive value and negative predictive value of elevated sIL-2R for POD24 were 42% and 90%, respectively; those of elevated CRP were 31% and 87%, respectively; and those of detectable EBV-DNA were 39% and 90%, respectively. Of the 9 pts who were negative for all three factors, none experienced POD24. A multivariate analysis in the POD24 group identified elevated sIL-2R as an independent predictive factor for worse OS (HR 3.16; 95% CI, 1.07 - 9.32). Conclusions: Pretreatment sIL-2R, CRP, and EBV-DNA were associated with POD24 among pts with localized nasal ENKL treated with RT-DeVIC. The strong association of elevated sIL-2R with early progression and short OS in the POD24 group provides a rationale for targeting strategies.
Circulating tumor DNA assessment in patients with diffuse large B-cell lymphoma following CAR-T therapy.
Authors: Dahiya Saurabh , Le Ryan , Hossain Nasheed Mohammad , Abramian Matthew , Muffly Lori S. , Miklos David Bernard 
Published: September 2018

7552 Background: Circulating tumor DNA(CTD) have been used for disease monitoring in Diffuse Large B Cell Lymphoma(DLBCL) (Kurtz ASCO 2016). Role of CTD assessment in DLBCL patients treated with CAR-T therapy has not been studied. We prospectively analyzed CTD of dynamics measured by next generation sequencing(NGS) of BCR using ClonoSeq MRD(Adaptive Biotechnologies), before and after CAR-T therapy to determine feasibility and clinical utility. Methods: At Stanford, 7 patients were enrolled on ZUMA-1 clinical trial NCT02348216, treating chemo-refractory DLBCL patients with anti-CD19, CAR-T. Complete radiologic data and CTD analysis was collected for six subjects. Tumor-DNA was extracted from archival paraffin-embeded tissue & analyzed using the NGS-based assay. PCR amplification of IGH-VDJ, IGH-DJ & IGK regions using universal consensus primers was performed followed by NGS to determine the tumor clonotype(s). Blood collected at day 0,7,14,28,60 & 90 days in relation to CAR-T infusion was used to detect CTD by ClonoSeq quantification of clonotypes. Results: Clonotypes were successfully determined for all 6 subjects, and 30 blood samples for 6 patients were prospectively analyzed. All patients had measurable disease burden pre-CAR-T infusion. CTD dynamics correlated with PET-CT outcomes in 100% of the patients. Increasing CTD temporally preceded progressive disease(PD) before PETCT recognition in 4 of 5 patients and was always increasing when PETCT showed PD. Preceding CTD quantification correlated with disease volume increase. One patient achieved durable KTE-19 complete response(CR) and detectable CTD became undetectable on day 14(and on subsequent samples) following CAR-T infusion, corresponding to 1 & 3 month PETCT CR. Additionally, the burden of disease measured by lymphoma molecules per ml allowed volumetric response assessment in all the patients who experienced massive reduction in tumor volume, but by traditional response definition had partial response. Conclusions: ClonoSeq CTD provides precise total tumor quantification of DLBCL in the CAR-T cell setting. This technology may overcome fundamental limitations of DLBCL imaging(cost, radiation exposure & limited repetition).
Interim metabolic tumor volume to predict response in diffuse large B-cell lymphoma.
Authors: Islam Prioty , Goldstein Jordan , Sethi Ila , Lee Daniel , Flowers Christopher 
Published: September 2018

7557 Background: DLBCL is a heterogeneous disease with varied clinical outcomes following treatment with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). [18F] fluorodeoxyglucose (FDG) – positron emission tomography (PET)/computed tomography (CT) imaging is ubiquitously used in monitoring of DLBCL. PET-derived metrics for analysis of tumor FDG uptake include: tumor maximum standardized uptake value (SUV); metabolically active tumor volume (MTV); and total lesion glycolysis (TLG), calculated from the intensity of FDG uptake in tumor volume. We evaluated the predictive value of interim SUV, MTV and TLG for patients (pts) with DLBCL treated with R-CHOP. Methods: Pts with DLBCL treated at Emory University 2005-2016 were eligible. Cases were included if there was a diagnosis of DLBCL confirmed by record review, available information on date of diagnosis, date of last contact or date of death. Analyses were restricted to patients who received R-CHOP and had PET/CT scans available at baseline, Cycle 2 or 4 and end of treatment. Maximum SUV, MTV, and TLG were calculated using MIM software for tumor with an SUV threshold of > 4. Logistic regression analysis was used to calculate the predictive value of interim PET/CT metrics on end of treatment response. Results: Pre-treatment PET/CT scans for 42 patients were identified, along with 28 interim and 31 post-treatment scans. The mean pre-treatment MTV was 303ml (range 4 – 1,327) and mean TLG was 3188 (range 28 – 16,176). MTV and TLG were undetectable in 79% of interim scans and 74% of the post-treatment scans. A Deauville score of 3 or less was observed in 71% of the interim PET/CT scans and 56% of the post-treatment scans. A positive interim MTV was correlated with a positive post-treatment MTV and post-treatment Deauville score at 0.58 and 0.66, respectively, and a positive interim MTV result was a significant predictor of a positive post-treatment MTV result (p = 0.02). Conclusions: PET-derived metrics of assessing interim tumor response to therapy offer significant predictive value for end of treatment response, and can guide a response-adapted treatment approach for DLBCL pts that builds on the R-CHOP backbone.
Lenalidomide, doxorubicin hydrochloride and dexamethasone versus bortezomib, lenalidomide, and dexamethasone prior to scheduled stem cell transplant in newly diagnosed myeloma.
Authors: Knop Stefan , Langer Christian , Engelhardt Monika Martha , Wangemann Johanne , Muegge Lars Olof , Bassermann Florian , Schaefer-Eckart Kerstin , Blau Igor W. , Wolleschak Denise , Reichle Albrecht , Metzler Ivana von , Metzner Bernd , Röllig Christoph , Hertenstein Bernd , Pfreundschuh Michael , Brümmendorf Tim H. , Gramatzki Martin , Ritgen Matthias , Held Swantje , Einsele Hermann ,   Deutsche Studiengruppe Multiples Myelom
Published: September 2018

8001 Background: In younger, medically fit patients (pts) with newly diagnosed (ND) multiple myeloma (MM), autologous stem cell transplant (SCT) remains a standard of care. Prior to SCT, induction triplets with at least one of the newer compounds are recommended. Bortezomib (V), lenalidomide (R) and dexamethasone (D; VRD) ranks amongst the most effective treatments. VRD + SCT proved superior over VRD alone in a randomized, controlled trial (RCT). We found encouraging efficacy and low toxicity with RAD (RD and adriamycin) + SCT and decided to compare RAD versus VRD induction in an RCT. Methods: The DSMM XIV study was set up according to a double 2x2-factorial design to enroll NDMM pts up to 65 years (yrs). Post-induction (PI) CR rate was the efficacy endpoint for the initial study phase. We hypothesized CR rate with RAD would be non-inferior to an estimated 20% CR with VRD. The study was powered to confirm non-inferiority of RAD at a 10% margin with a one-sided α level of .05. Minimal residual disease (MRD) was analyzed by eight-color flow cytometry (EuroFlow standards) on marrow samples. Results: 476 pts were randomized between 05/2012 and 06/2016, 469 of whom (median age 55 (range, 32–65) yrs) received at least one dose of study drug. 18.3% of pts had ISS stage III MM and 17.2%, elevated LDH. 11.3% of pts had del17p; 11.1% had t(4;14); and 4% had t(14;16). 232 pts were randomized to 3 four-week RAD cycles and 237 to 3 three-week VRD cycles, respectively. 89.7% of RAD versus 93.2% of VRD pts completed all induction cycles. PI CR rate was 11.8% (90% CI, 7.9%-16.3%) with RAD versus 13.0% (90% CI, 8.9-18.0) with VRD, (P = .697). 72/317 pts (22.7%) with paired baseline/PI samples achieved negative MRD at a median sensitivity level of 6.73x10-6. 47 (20.3%) RAD versus 35 (14.8%) VRD pts experienced treatment-emergent SAEs (P = .144). Treatment-related induction mortality was 0% in either arm. Conclusions: To the best of our knowledge, this is the first RCT to compare two lenalidomide-based triplets prior to SCT. The endpoint was met with comparable PI CR rates for RAD and VRD, respectively. Tolerability was encouraging in both arms. Follow-up data is needed to analyze time-dependent endpoints. Clinical trial information: NCT01685814.
Impact of denosumab (DMB) compared with zoledronic acid (ZA) on renal function in the treatment of myeloma bone disease.
Authors: Raje Noopur S. , Roodman G. David , Willenbacher Wolfgang , Shimizu Kazuyuki , Garcia-Sanz Ramon , Durie Brian G. , Zhu Li , Cheng Paul C. , Bhatta Sumita , Terpos Evangelos 
Published: September 2018

8005 Background: Osteolytic bone disease and renal dysfunction are complications of multiple myeloma. ZA, used for the prevention and treatment of bone complications, can be nephrotoxic. DMB inhibits RANKL and thereby osteoclast function, and is not renally cleared. This international, phase III, randomized, double blind study evaluates the efficacy and safety of DMB compared with ZA in newly diagnosed myeloma patients (pts). Methods: Eligible pts were randomized 1:1 to DMB 120mg SC Q4W or ZA 4mg (renally adjusted) IV Q4W along with anti-myeloma therapy. Pts with baseline CrCl<30mL/min were excluded due to ZA dosing restrictions. The primary endpoint was non-inferiority of DMB to ZA with respect to time to first on-study SRE. Overall survival (OS) was a secondary endpoint; progression-free survival (PFS) was an exploratory endpoint. Renal toxicity and safety were assessed. Results: 1718 pts were randomized, 859 to each arm. Baseline renal insufficiency (CrCl ≤ 60mL/min) was reported in 26.7% of pts. DMB was non-inferior to ZA ( P = 0.01) in delaying time to first on-study SRE. Fewer AEs potentially related to renal toxicity were reported with DMB compared to ZA overall (10.0% vs 17.1%, P < 0.001) in those with baseline CrCl > 60mL/min (8.8% vs 14.2%) and particularly in those with baseline CrCl ≤ 60mL/min (12.9% vs 26.4%). 12.5% of pts on DMB experienced an increase in creatinine, compared to 20.8% of those on ZA. Median cumulative exposure (Q1, Q3) to DMB was 15.75 months (8.18, 25.79) compared to 14.78 months (7.46, 24.87) for ZA. PFS yielded a HR (95%CI) of 0.82 (0.68, 0.99); descriptive P = 0.036. OS HR (95%CI) between DMB and ZA was 0.9 ([0.70, 1.16]; P = 0.41), with fewer deaths in DMB (121 [14.1%]) than in ZA (129 [15.0%]). Conclusions: DMB achieved the primary endpoint of non-inferiority to ZA in delaying time to first on study SRE in pts with newly diagnosed MM. Pts on DMB had a significantly lower rate of renal AEs compared to ZA; more importantly this rate was 2-fold lower in pts with renal insufficiency (CrCl≤60mL/min). The bone specific benefits in combination with the renal function results and possible prolongation of PFS with DMB therapy is promising. Clinical trial information: NCT01345019.
Development of a fully human T cell engaging bispecific antibody for the treatment of multiple myeloma.
Authors: Buelow Ben , Pham Duy , Clarke Starlynn , Force Aldred Shelley , Dang Kevin , Pratap Payal , Ugamraj Harshad , Harris Katherine , Trinklein Nathan , Schellenberger Ute , Wiita Arun , Van Schooten Wim , Buelow Ben 
Published: September 2018

8017 Background: Although BCMA is a plasma cell specific surface molecule attractive as an antibody target in multiple myeloma, its scarcity on the cell surface may limit the efficacy of a conventional antibody. T-cell engaging bispecific antibody approaches are highly efficacious and are particularly well suited for a membrane target with limited expression, such as BCMA. Teneobio has developed a multivalent antibody platform based on modular human VH domains, which allowed us to build T cell engaging bispecific antibodies with low and high T cell agonistic activities. Methods: UniRats were immunized with either CD3 or BCMA antigens and antigen-specific UniAbs were identified by antibody repertoire sequencing and high-throughput gene assembly, expression, and screening. High affinity binding VH sequences were selected using recombinant proteins and cells. In vitro efficacy studies included T-cell activation by cytokine- and tumor cell kill by calcein-release assays. In vivo efficacy of the molecules was evaluated in NSG mice harboring myeloma cells and human PBMCs. Results: BCMA-specific UniAbs bound plasma cells with high affinities (100-700pM) and cross-reacted with cynomolgus plasma cells. Strong and weak T cell agonists were identified that bound human T cells with high and low affinities respectively and cross-reacted with cynomolgus T cells. T cell engaging bispecifics with a strong (H929 cytotoxicity:EC50=27pM) and a weak T cell activating arm (H929 cytotoxicity: EC50=1170pM) demonstrated T-cell activation and tumor-cell cytotoxicity in vitro; bispecifics with a weak CD3 engaging arm showed markedly reduced cytokine production even at doses saturating for cytotoxicity. In viv o, BCMAxCD3 bispecific antibodies reduced tumor load and increased survival when co-administered with human PBMCs as compared to controls. Conclusions: Our results suggest that T cell engaging bispecifics with low-affinity anti-CD3 arms could be preferred for the treatment of Multiple Myeloma.