bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of Aurora A kinase inhibitor MLN8237 combined with rituximab on antitumor activity in preclinical B-cell non-Hodgkin's lymphoma models
Authors: Zhang M. , Huck J. , Hyer M. , Ecsedy J. , Manfredi M. 
Published: August 2020

8553 Background: Aurora A kinase is a serine/threonine protein kinase that is essential for the successful transit of cells through mitosis. MLN8237 is a selective small molecule inhibitor of Aurora A kinase that has demonstrated anti-tumor activity in animal models of solid human tumors. In this study we explored the anti-tumor effect of MLN8237 in vivo in pre-clinical models of human Diffuse Large B-cell Lymphoma (DLBCL) both as a single agent and in combination with the anti-CD20 monoclonal antibody Rituximab. Methods: Three human DLBCL models were examined in SCID mice. In two of the models (Ly19 & WSU) the tumor cells expressed a constitutively active luciferase, enabling tumor burden analysis in either a subcutaneous or disseminated setting. The third model was a primary DLBCL recently obtained from a patient. Tumor bearing animals were treated for 21 days with MLN8237 (QD PO dosing at 3–20mg/kg), Rituximab (Q7D IV dosing at 10 mg/kg), or the two agents combined. Tumor burden was measured in the disseminated models as a function of luciferase-induced photon flux, and in the subcutaneous models using vernier calipers. Results: MLN8237 induced anti-tumor activity that was dose-dependent in all three models. In LY19 disseminated model, 3 mg/kg of MLN8237 combined with Rituximab induced synergistic anti-tumor activity (n=2); while 10 mg/kg MLN8237 (dosed QD) combined with Rituximab was additive. Importantly, combining MLN8237 with Rituximab led to complete cures in 100% of the animals. In the WSU model, combining MLN8237(3–10mg/kg) with Rituximab resulted in additive tumor growth inhibition. The mean survival endpoint was significantly longer (p=0.003 and <0.001 respectively) in the combination group when compared to the individual group. In the primary lymphoma model, MLN8237(10–20mg/kg) caused a significant anti-tumor effect during treatment period (TGI = 83–95%). Combining MLN8237 and Rituximab in primary model resulted in additive anti-tumor effect. Conclusions: MLN8237 combined with Rituximab was found to reduce tumor burden in an additive and/or synergistic mechanism in multiple DLBCL tumor models. MLN8237 is currently being tested as a single agent in a phase I clinical trail in patients with DLBCL. [Table: see text]
Observer variation in FDG PET-CT for staging of lymphoma
Authors: Hofman M. , Smeeton N. C. , Rankin S. C. , Rankin S. C. , Nunan T. , O'Doherty M. J. 
Published: August 2020

8557 Background: Evaluation of observer agreement is fundamental in the assessment of any new imaging modality. While many studies demonstrate high accuracy of positron emission tomography (PET) for lymphoma staging, few assess observer variation. This study aims to quantify intra- and inter- observer agreement amongst experienced readers for staging lymphoma with PET-CT. Methods: One hundred consecutive patients with biopsy proven lymphoma deemed appropriate for staging with PET-CT were reported independently by three experienced readers, with two readers reviewing each series a second time. Primary outcome variables were agreement of Ann Arbor stage, number of nodal regions and presence of extra-nodal involvement. Secondary outcome variables were agreement of specific nodal and extra-nodal sites. Weighted kappa (κw) was used to compare ratings from two readers, and interpreted according to the Landis-Koch benchmarks. Interclass-correlation coefficient (ICC) was used to assess total of nodal regions involved. Results: Both intra- and inter-reporter agreement for Ann-Arbor stage (κw=0.79–0.91), total number of nodal regions involved (ICC=0.83–0.93) and presence of extra-nodal disease (κ=0.74–0.86) was substantial or almost perfect. High agreement was also observed for specific nodal regions (κw>0.60) except hilar (κw=0.56–0.63) and infra-clavicular regions (κw=0.14–0.37). Conclusions: Amongst experienced readers there was a high level of agreement utilising PET-CT for lymphoma staging. This complements other studies demonstrating high accuracy and supports use of PET-CT as a robust non-invasive staging tool. Further research is needed to evaluate reporter variability for restaging during and after completion of chemotherapy. [Table: see text] No significant financial relationships to disclose.
Mature T-/NK-cell lymphomas: Prognostic factors and treatment outcome of patients treated on studies of the German High-Grade Lymphoma Study Group (DSHNHL)
Authors: Schmitz N. , Ziepert M. , Nickelsen M. , Wolf S. P. , Truemper L. , Loeffler M. , Ho A. , Metzner B. , Rosenwald A. , Pfreundschuh M. 
Published: August 2020

8564 Background: T-cell lymphomas represent a heterogeneous group of malignancies difficult to diagnose and to treat. We evaluated patients (pts) diagnosed according to WHO standards and treated on prospective studies of the DSHNHL. Chemotherapy regimens (CHOP-14 and CHOEP) had significantly improved outcomes of patients with aggressive B-NHL. Methods: Between 1993 and 2006 we treated 329 pts with ALK-positive ALCL (73 pts), ALK-negative ALCL (108 pts), PTCL, NOS (68 pts), AITL (28 pts), NK-/T-cell lymphoma (18 pts), and rare T-cell lymphomas on prospective studies. All pts received CHOP ± etoposide (E) every 2 or 3 weeks; in pts <=60 yrs C, H, and E were escalated to further improve outcomes. Results: The majority of pts with ALK-positive ALCL presented with IPI 0, 1 (62%) or IPI 2 (26%) and had an excellent overall survival (OS) of 89 % and event-free survival (EFS) of 75% at 3 yrs. E significantly improved TTTF for pts <=60 yrs (p=0.007). Pts with other histologies did significantly worse (OS 58%, EFS 44 % at 3 yrs). The IPI discriminated between pts with a favorable (IPI 0, 1: OS 73%), moderate (IPI 2: OS 55%), and poor prognosis (IPI 3: OS 35%; IPI 4, 5: OS 19%) at 3 yrs. OS, EFS were significantly better for ALK-positive ALCL but did not significantly differ for pts in other histological subgroups. Neither shortening of the treatment interval (CHOP-14) nor the addition of E (CHOEP-21 or -14) significantly improved outcome of elderly pts. In younger pts (ALK-positive ALCL were excluded) and good-risk disease (LDH <= N) there was a trend for better EFS after the addition of E to CHOP (EFS 63% vs. 48%, p = 0.065). The MegaCHOEP protocol (Schmitz et al., CANCER 2006) failed to improve treatment results for younger pts with poor-risk disease (EFS at 3 yrs: 25.9%, 95% CI: 10.4–41.4); the prospective study comparing MegaCHOEP with CHOEP-14 was stopped for pts with T-cell lymphoma. Conclusions: CHO(E)P results in excellent OS of pts with ALK-positive ALCL and selected pts with other histologies and low IPI. All other pts did poorly; CHOP-14 or the addition of E failed to significantly improve outcomes. Notably, also the MegaCHOEP protocol characterized by repetitive high-dose therapy and ASCT did not result in significant improvement. No significant financial relationships to disclose.
Complete response (CR) to ifosfamide, gemcitabine, and vinorelbine (IGEV) and outcome in relapsed/refractory Hodgkin's lymphoma (HL) patients
Authors: Anastasia A. , Mazza R. , Giordano L. , Balzarotti M. , Magagnoli M. , Castagna L. , Spina M. , Michieli M. , Tirelli U. , Santoro A. 
Published: August 2020

8568 Background: High dose chemotherapy with autologous stem cells transplant (ASCT) is the gold standard in patients with relapsed/refractory HL. Response to induction chemotherapy (chemosensitive patients) plays a major role in prognosis, however the role of CR status after induction therapy has not been established. Methods: One hundred twenty one patients with relapsed/refractory HL received 4 courses of IGEV followed by single (N=59) or tandem (N=19) ASCT (Santoro et al., Haematologica 92, 2007). Response to IGEV was evaluated by Cheson criteria (1999).The aim of this study was to evaluate the role of CR versus no-CR to IGEV induction therapy on the outcome in terms of progression free survival (PSF) and overall survival (OS). Statistical analysis was performed by using the Kaplan-Meier method and Cox proportional hazard model. Results: IGEV induced an overall response rate of 75% with 46% of CR. In the univariate analysis favourable factors for outcome were CR vs no-CR to IGEV (PFS: p <0.001, OS: p 0.002), A vs B symptoms (PFS: p 0.003; OS: p 0.05), limited vs advanced stage (PFS: p 0.03; OS: p 0.03), and 1 vs≥2 previous chemotherapy lines (PFS: p 0.03, OS: p 0.02); response to last therapy (relapsed vs refractory) influenced PFS (p 0.03) but not OS (p 0.70). The multivariate analysis confirmed the favourable prognostic role of CR to IGEV (PFS HR: 2.5, CI 95%:1.3; 4.6 - OS HR 2.3, CI 95%:1.1;4.8) and of the number of previous chemotherapy lines (PFS HR:1.8, CI 95%:1.0;3.2 - OS HR 2.1, CI 95%:1.1;3.9). Conclusions: According to our data, we conclude that: 1. CR to IGEV is the strongest indicator of outcome in relapsed/refractory HL. 2. Achievement of CR to IGEV overcomes the role of initial disease status. 3. Efforts are warranted to increase the CR rate by induction therapy. No significant financial relationships to disclose.
ABT-263 activity and safety in patients with relapsed or refractory lymphoid malignancies in particular chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL)
Authors: Wilson W. , O'Connor O. O. , Roberts A. W. , Czuczman M. , Brown J. , Xiong H. , Xiong H. , Chiu Y. , Krivoshik A. , Enschede S. , Humerickhouse R. 
Published: August 2020

8574 Background: ABT-263, a novel, orally bioavailable, BH3 mimetic, binds with high affinity (Ki ≤ 1nM) and inhibits multiple antiapoptotic Bcl-2 family proteins. ABT-263 displays activity (EC50 ≤ 1μM) against human lymphoid and small cell lung cancer cell lines. Mechanism based preclinical toxicities include reductions in circulating lymphocytes, apoptosis of circulating platelets, and decreased spermatogenesis, mediated by inhibition of Bcl-2, Bcl-XL, and Bcl-w, respectively. Methods: Safety and activity of ABT-263 in 2 enrolling phase I studies in relapsed/refractory lymphoid malignancies (M06–814) and CLL (M06–873) was evaluated. Patients (pts) were dosed on days 1–14 of a 21 d cycle, 10–440mg (M06–814) or 10–250mg (M06–873). Continuous 21/21 d dosing (CD) post lead-in dose is being explored in both studies. Results: 55 pts, 14/21 d dosing, enrolled in the 2 studies. ABT-263 PK were linear from 10 - 440mg (N=55) and the terminal half-life was 14 - 20 h (n=35). Among 27 CLL/SLL pts, 3 have confirmed radiographic partial responses (PR) (99%, 92% and 72%) and 2 have unconfirmed regressions, 51% and 72%. 6 pts maintained a ≥50% decrease in circulating lymphocytes for ≥ 2 months and 11 pts have stable disease; of these 5 experienced minor radiographic responses (range of 36% to 49%). In addition, among 40 (M06–814) lymphoma pts, 3 with follicular lymphoma achieved PR and one had a minor response (49% regression). With CD dosing (16 pts), activity includes 1 unconfirmed PR in SLL & and 3 CLL pts with ≥50% lymphocyte reduction for ≥2 months duration. Pharmacodynamic toxicities included dose-dependent thrombocytopenia (TCP) resulting from on-target activity against Bcl-XL. Dose limiting toxicities, 14/21 d dosing, in M06–814 occurred at 160mg (bronchitis), 315mg (elevated ALT and grade 4 TCP) and 440mg (worsening pleural effusion in a pt with underlying afib), and in M06–873 at 110mg (tumor lysis and grade 4 TCP) and 250mg (grade 4 TCP). Conclusions: ABT-263 showed favorable PK and safety profiles with anti-tumor activity in relapsed/refractory CLL/SLL and follicular lymphoma. Identification of optimal dose and schedule for phase II trials continues. [Table: see text]
Final results of a phase I study of oral belinostat (PXD101) in patients with lymphoma
Authors: Zain J. M. , Foss F. , Kelly W. K. , DeBono J. , Petrylak D. , Narwal A. , Neylon E. , Blumenschein G. , Lassen U. , O'Connor O. A. 
Published: August 2020

8580 Background: Belinostat (Bel) is a histone deacetylase inhibitor with broad preclinical activity. A phase I of oral Bel in patients (pts) with solid tumors found a recommended dose for day (d) 1–14, q3w, of 750 mg QD, with option for intra-patient dose escalation if limited toxicity. The current study was initiated to assess if the same dose could be utilized in pts with lymphoma. Methods: Objectives included safety and efficacy of oral Bel in cohorts of 3–6 pts (A 750; B 1000; C 1250; mg QD) treated d 1–14, q3w. Pts with relapsed/refractory non-Hodgkin lymphoma (NHL) or Hodgkin's disease (HD) with evaluable disease and acceptable organ functions were eligible. Dose limiting toxicity (DLT) assessed in cycle 1 included: related non-hem grade (gr) 3/4 tox; gr 4 neutropenia > 5 d or with fever > 100.5 °F; gr 4 thrombocytopenia > 7 d. Results: 9 pts (3 per cohort), median age 51 (range 21–92), median 5 (range 2–7) prior regimens (83% had BM transplants, including 1 pt with allogeneic) have been enrolled. Diagnoses include mantle cell lymphoma (MCL; 4 pts), HD (3 pts), other NHL (2 pts). Most frequent adverse events (regardless of attribution or gr) in 7 pts fully evaluable for tox: anorexia (7 pts), fatigue, (6 pts), diarrhea (6 pts), and constipation, fever, and cough (each in 3 pts). Non-hem gr 3 events (no gr 4 noted): diarrhea (1 pt each in cohorts A and B, both in cycle 2), fatigue, anorexia, and leg DVT (each in 1 pt; all after cycle 1). One gr 3, and 1 gr 4 (from baseline gr 2; duration gr 4 <7 d) thrombocytopenia were seen in cohort C. In 6 pts evaluable for efficacy, stable disease have been noted in 5 pts for 3 to +7 cycles, including 3 of 3 pts (one refractory) with MCL and 2 of 2 pts (both refractory) with HD. Tumor shrinkage of 43 to 49% have been found in 1 HD and 2 MCL pts after cycle 2. Conclusions: Oral Bel can be delivered safely with a d 1–14, q3w schedule in pts with lymphoma at a daily dose higher than what has been established for pts with solid tumors. No protocol defined DLTs have yet been encountered in the dose range 750 to 1250 mg QD in pts with lymphoma. Final evaluation will include additional pts and possible dose escalation. The safety profile and early tumor shrinkage noted in MCL and HD warrants continued evaluation of Bel, especially in combination with other active compounds. [Table: see text]
An open-label, multicenter, phase II study of AT-101 in combination with rituximab (R) in patients with untreated, grade 1-2, follicular non-Hodgkin's lymphoma (FL)
Authors: Kingsley E. , Richards D. , Garbo L. , Gersh R. , Robbins G. , Leopold L. , Brill J. , Di Bella N. 
Published: August 2020

8582 Background: Bcl-2 family proteins are overexpressed in the majority of patients with FL and contribute to resistance to therapy. AT-101 is a pan-Bcl-2 inhibitor (Bcl-2, Bcl-XL, Bcl-W, and Mcl-1) and potent inducer of proapoptotic proteins. It is active as a single agent and in combination with R in NHL tumor models. Methods: Patients with untreated FL who did not require immediate chemotherapy were eligible. Treatment consisted of an induction cycle of AT-101 (30mg po daily × 21) and R (375 mg/m2 weekly × 4) followed by up to 4 maintenance cycles of AT-101 (30mg po daily × 21) and R (375 mg/m2) every 8 weeks in nonprogressors. Endpoints evaluated the response rate (RR) at week 8 (primary), overall response rate (ORR), molecular response rate (BCL-2JH rearrangement in blood and bone marrow), and safety of the combination. A mini-Max, 2-stage design (52 pts planned) was used to detect >70% RR with power of 90% and alpha of 0.10. Results: 23 pts enrolled: median age 64 yrs; FLIPI 0–5: 0%/17%/65%/13%/4%; Grade 1/2: 61%/39%; bulky disease (>5cm3): 35%; stage: 1–4 4%/4%/30%/61%; bone marrow + 48%. All pts received induction and 18 pts received 1 or more maintenance cycles. RR following induction was 26% (95%CI=10.2–48.4), 4% CR and the best ORR was 70% (95%CI=47.1–86.8), 35% CR. Molecular response analysis is ongoing. Grade 3/4 AEs that occurred in ≥2 pts: nausea 4(17%), vomiting 2(9%), abdominal pain 2(9%), fatigue 2(9%), and small bowel obstruction 2(9%). AT-101 was reduced to 20mg daily x 21 which improved GI tolerability. Conclusions: The combination of AT-101 and R was well tolerated. The week 8 RR did not meet statistical criteria to enroll stage II. The best ORR is at the upper limit of reported ORR for R alone; therefore a randomized trial is required to definitively determine activity of the combination. [Table: see text]
Methylation reversal in high-grade B lymphoma cell lines and novel epigenetic changes conserved between immunocompetent and HIV-positive hosts
Authors: Bower M. , Syed N. , Papoudou-Bai A. , Stebbing J. , Naresh K. , Hatzimichael E. , Powles S. , Crook T. 
Published: August 2020

8585 Background: Methylation-dependent transcriptional silencing is an important mechanism of tumour suppressor gene inactivation in neoplasia, including lymphoma. Methods: Pharmacological “unmasking” of transcriptionally silenced genes in B lymphoma cell lines was achieved using 5' deazacytidine ± Trichostatin A and subsequent analysis of mRNA levels on micro-array. Candidate genes thus identified, were further analysed by qPCR, methylation-specific PCR (MSP) and bisulphite sequencing in B lymphoma cell lines and by MSP in clinical samples from sporadic (immunocompetent) (18 cases) and HIV-infected patients (14 cases). Samples in both patient groups were diffuse large B cell lymphoma (DLBCL) and Burkitt's lymphoma (BL). Additionally, we analysed 8 cases of marginal zone lymphoma (MZL) from the immunocompetent group. Results: We report the identification of 13 novel genes, not previously described in the literature, which are subject to methylation-dependent transcriptional silencing in high-grade lymphoma and whose expression can be reactivated by demethylating agents. The novel genes encode proteins involved in diverse functional classes and include pro-apoptotic members of the p53 pathway (Scotin), transcriptional regulators (Baz2B) and regulators of telomerase (Smrf2). The frequency of methylation in individual genes varied from approximately 10% to 75% in specific lymphoma subtypes, but was in general similar in high grade lymphomas in immunocompetent and HIV-infected hosts. Conclusions: Using pharmacological reversal of methylation, we have identified a number of genes, not previously implicated in human neoplasia, which are subject to transcriptional silencing in high-grade B lymphomas. The similar frequencies of methylation, observed in immunocompetent and HIV positive patients implies that the genes are fundamental in suppression of lymphomagenesis. Detection of methylated DNA of one or more of these genes may have utility as biomarkers of clinical outcome in each patient group. No significant financial relationships to disclose.
Evaluation of the melanocortin-1-receptor gene in melanoma predisposition, progression, and recurrence
Authors: Sidash S. , Ostrer H. , Goldberg J. D. , Belitskaya-Levy I. , Lobach I. V. , Polsky D. , Shapiro R. L. , Berman R. S. , Osman I. , Manga P. 
Published: August 2020

9018 Background: The melanocortin-1-receptor (MC1R) gene is highly polymorphic in humans. Multiple studies have shown the association between MC1R allelic variants and increased risk of melanoma. Over seventy MC1R single nucleotide polymorphisms (SNPs) have been identified making MC1R a likely target for the development of genetic markers for melanoma predisposition and progression. Alleles described as R and r result in a protein with reduced function compared to wild type, with r alleles having the greatest effect. We sought to investigate the impact of MC1R genotype on risk of developing melanoma and will test for association with disease progression and recurrence in a cohort of melanoma patients enrolled in a prospective study. Methods: Our cohort includes 291 newly diagnosed melanoma patients seen at the New York University Langone Medical Center. The control cohort included 449 subjects. DNA was isolated from leukocytes and analyzed for MC1R SNP status by PCR and direct sequencing. Associations were tested for R-variant R151C and r-variants V60L and V92M. Fisher's Exact test was used to detect significant differences in allele frequency. Odds ratios and confidence intervals were computed for each SNP. Results: Allele frequencies were significantly different in cases and controls for each of the variants (p<0.01). The greatest effect was seen with V60L (Odds Ratio=6.281 95% Confidence Interval 1.77- 22.20). Conclusions: Variants that result in reduced MC1R function increase an individual's risk of developing melanoma. We will continue to test associations with additional variants and determine if these alleles also contribute to risk of disease progression and recurrence. In addition, these variants will be tested for utility as biomarkers for risk assessment of melanoma in a clinical setting. No significant financial relationships to disclose.
Effect of TKI258 on plasma biomarkers and pharmcokinetics in patients with advanced melanoma
Authors: Shi M. , Kim K. B. , Chesney J. , Wang X. , Motwani M. , Wang J. , Steed M. , Anak O. , Jones G. , Saro J. , Kirkwood J. 
Published: August 2020

9020 Background: TKI258 (dovitinib lactate), is a multi-tyrosine kinase inhibitor of VEGF receptors-1,2,3, FGF receptors-1, 2, 3, PDGFR-β, and c-KIT. A phase I study was conducted to determine the maximum tolerated dose (MTD), the biological activity and the preliminary efficacy of TKI258 in patients with advanced melanoma. A panel of plasma biomarkers of angiogenesis and soluble receptors were evaluated to determine the pharmacodynamic effect of TKI258. Methods: Patients were treated orally with 200, 300, 400 or 500 mg/day on a once daily continuous dose schedule. The MTD was defined at 400 mg/day. Plasma samples from 43 patients were collected. Plasma concentration of TKI258 was measured by LC/MS/MS. Plasma VEGF, placental growth factor (PLGF), basic FGF (bFGF), and soluble VEGFR1 and VEGFR2 (sVEGFR1 and 2), and c-Kit were measured by multiplex assays using the Meso-Scale Discovery platform. Plasma FGF23 was evaluated by ELISA as a pharmcodynamic marker of FGFR1 inhibition. Results: Following 400 mg or 500 mg continuous daily dosing, the mean plasma exposure (AUC24hr) was approximately 3000 ng/mL*h and 4100 ng/mL*h, respectively. No accumulation in TKI258 plasma exposure was observed at doses of 400mg or below, while accumulation up to 2.5-fold was observed on day 15 following the 500 mg daily dose. At the end of the first treatment cycle, mean plasma VEGF, PLGF and FGF23 levels increased over baseline by 100%, 198% and 68%, respectively, while mean plasma sVEGFR2 levels decreased by 15% in patients treated with 400 and 500 mg/day TKI258. Further analysis of correlations with pharmacokinetic and clinical parameters is ongoing. Conclusions: TKI258 therapy is associated with increases of plasma VEGF and PLGF as well as decreases of sVEGFR2 suggesting VEGFR inhibition. Induction of plasma FGF23 suggest that FGFR may be inhibited at doses of 400 mg/day and above. This panel of circulating proteins may have utility as pharmacodynamic biomarkers of TKI258 activity in patients with advanced melanoma. [Table: see text]