bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lymphoma recurrence 5 years or more following diffuse large B-cell lymphoma: Clinical characteristics and outcome
Authors: Larouche J. , Berger F. , Chassagne-Clement C. , Sebban C. , Ghesquieres H. , Salles G. , Coiffier B. 
Published: August 2020

8562 Background: Diffuse large B-cell lymphoma (DLBCL) usually relapses early following treatment but some relapses happen 5 years or later. Few data exist regarding clinical characteristics and outcome of these patients (pts). Methods: We performed a retrospective analysis of all pts from two centers in Lyon/France between 1980–2003 who presented a biopsy proven relapse 5 years or later following diagnosis of DLBCL. All available biopsies were revised and immunohistochemistry (IHC) completed. Results: Among 1492 pts with DLBCL, 54 were eligible. Clinical characteristics at diagnosis were: median age 57 y; stage I-II 63% (34/54); IPI low/low intermediate 84% (41/49) and extranodal involvement (EN) 66% (35/53). IHC at diagnosis: CD20 100% (46/46), CD10 28% (10/36), bcl-6 53% (9/17), MUM1 48% (11/23), bcl-2 68% (19/28), germinal-center phenotype (GC) 57% (12/21) and non-GC 43% (9/21). 47/53 received CHOP/ACVBP-like regimens, 1 autologous transplantation (ASCT) and 1 rituximab. Median time from diagnosis to relapse was 7.4 years (5–20.5 years). 44 pts (81%) had DLBCL histology at time of relapse and 10 pts (19%) indolent histology. MUM1 expression at diagnosis was associated with DLBCL histology at relapse (p=0.037). Clinical characteristics at relapse were: median age 66 y; stage I-II 48% (26/54); 73% (31/43) with DLBCL at relapse had EN. 54% (15/28) with DLBCL at relapse had a GC phenotype and 46% (13/28) a non-GC phenotype. Treatment at relapse included rituximab in 21/54 and ASCT in 15/54 with 7 pts receiving both. Estimated 5-year event-free survival (EFS) and overall survival (OS) after relapse were 25% and 35% for all pts. Pts with DLBCL histology at relapse had an estimated 5-year EFS and OS of 18% and 28%. Pts with indolent histology had an estimated 5-year EFS and OS of 55% and 67%. Conclusions: Patients with DLBCL who present a late relapse usually had localized stage, favorable IPI and extranodal involvement at diagnosis. However, even if initial characteristics at time of first treatment were favorable, outcome of pts with DLBCL at time of relapse remains poor and aggressive treatment, such as ASCT, should be pursue whenever possible. Some patients relapsed with indolent histology and have a better outcome. No significant financial relationships to disclose.
Evaluation of the effect of TRU-016, an anti-CD37 directed SMIP in combination with other therapeutic drugs in models of non-Hodgkin's lymphoma
Authors: Baum P. R. , Cerveny C. , Gordon B. , Nilsson C. , Wiens J. , Rafiq S. , Lapalombella R. , Muthusamy N. , Byrd J. C. , Wahl A. 
Published: August 2020

8571 Background: TRU-016, a single chain anti-CD37 Fc fusion molecule has been shown to display pro-apoptotic and Fc-dependent cellular cytotoxicity activities against primary CLL cells and NHL cell lines. The pro-apoptotic signal generated by TRU-016 binding to CD37 on CLL cells has been shown to be caspase-independent and distinct from the signal generated by many other therapeutics including rituximab. We have tested drug combinations using the mantle cell lymphoma line Rec-1 and diffuse large B-cell lymphoma line SU-DHL-6 in vitro and extended these results to in vivo settings using the follicular lymphoma cell line DOHH2 treated with the combination of TRU-016 and bendamustine. Methods: To determine TRU-016 interactions with the established therapeutics rituximab, doxorubicin, rapamycin, and bendamustine, drugs were tested alone or in combination with TRU-016 and the anti-proliferative effects on cell lines measured after 96 hours. Combination index analysis was performed for drug combinations over the 20–90% effect levels using the Calcusyn software package. To determine if in vitro synergy could be recapitulated in vivo, SCID mice were implanted with DOHH2 cells and therapeutic treatment was initiated when tumor volumes reached 200 mm3. Treatments consisted of TRU-016, bendamustine, or the combination of TRU-016 and bendamustine. Results: Combination index analyses determined that TRU-016 is synergistic with rituximab, bendamustine, or rapamycin and additive with doxorubicin in NHL models. In vivo results show that treatment with the combination of TRU-016 and bendamustine resulted in increased efficacy compared to the efficacy attained with the individual drugs. This demonstrates that the in vitro synergy results were extendable to a more complex in vivo disease model. Conclusions: TRU-016 in combination with rituximab, rapamycin, or bendamustine increases cell killing of NHL cells. Furthermore, the combination of TRU-016 and bendamustine displayed greater in vivo anti-tumor activity than either agent alone against a follicular lymphoma tumor model. [Table: see text]
Dynamic CD8 T-cell responses to tumor-associated Epstein-Barr virus (EBV) antigens in patients with EBV-negative Hodgkin's disease
Authors: Kohrt H. E. , Advani R. , Hoppe R. , Rosenberg S. , Horning S. , Lee P. P. 
Published: August 2020

8573 Background: Multiple translational efforts in HD are actively investigating augmentation of the anti-tumor immune response by stimulating cytotoxic T lymphocytes (CTL) against tumor-associated EBV antigens. It has previously been believed that this therapeutic strategy and presence of EBV-specific CTLs are limited to EBV-positive HD. Here, we challenge this belief by characterizing EBV-specific CTL responses in EBV-negative HD. Methods: Among 52 consecutive patients with EBV-negative HD, CTL responses to latent antigens (LMP2, LMP2a) and lytic antigens (BMLF, BRLF) were serially assessed at diagnosis, during chemotherapy, and throughout followup for 2 years by IFN-γ Elispot and flow cytometric tetramer analysis. Results: We detected weak EBV-specific responses to both lytic and latent antigens by IFN-γ Elispot among patients with EBV-negative HD. Response to lytic antigen, BMLF1, was more robust in function and size among healthy donors compared to patients as determined by IFN-γ Elispot and flow cytometry of BMLF1-tetramer positive, CD8 T cells. Chemoradiotherapy was associated temporally with an initial decrease in LMP2A- and BMLF1-specific responses during the first 5–15 weeks of treatment, which subsequently became more robust 20–50 weeks after diagnosis, 2 to 4-fold greater compared to response at diagnosis. At final follow-up (24 months), increases in both lytic (2.6-fold) and latent (2.5-fold) CTL responses were observed with robustness of lytic-specific response equivalent to healthy controls. No significant change in control peptide response was observed. Conclusions: We confirm evidence of EBV-specific CTLs in patients with EBV-negative HD and provide the first report of dynamic variance in this population during treatment, challenging prior belief that patients with HD remain immunodeficient following therapy and arguing that the clinical significance of EBV-specific immune responses in EBV-negative HD should be further investigated. [Table: see text] No significant financial relationships to disclose.
Correlation of surface expression of CD11b or CD32 in polymorphonuclear cells (PMNs) and CD69 in natural killer cells (NK) with progression-free survival (PFS) following chemoimmunotherapy with rituximab and liposomal doxorubicin (LD) in patients (pts) with relapsed or refractory B-cell lymphoma
Authors: Ritesh P. , Pahuja S. , Chavez J. , Braddy W. , Skipper M. , Bernstein Z. P. , Chanan-Khan A. , Ramanarayanan J. , Czuczman M. S. , Hernandez-Ilizaliturri F. J. 
Published: August 2020

8583 Antibody dependent cellular citotoxicity (ADCC) play a significant role in rituximab's anti-tumor activity. FcγRIIIa polymorphisms have been associated with clinical responses to rituximab. The predictive value of FcγRIIIa polymorphisms is lost when rituximab is combined with chemotherapy. Alternative assays to assess the immune system had not been studied in patients treated with rituximab plus chemotherapy. To this end, we prospectively studied the pre-treatment quality and function of PMNs and NK cells from pts with refractory/relapsed B-cell lymphomas in a Phase I/II trial. Forty-two B-cell lymphoma patients pts completed treatment. Demographics: 22M:20F; Median age = 61.8 (range 35–83); Patients received R (375 mg/m2/dose) on day 1 and LD (30 mg/m2/dose) on day 3 q21 day × 6 cycles. Pre-treatment flow cytometry was performed to assess surface expression of CD11b, CD62, CD69, CD16, CD32 and CD64 in PMNs or NKcells was performed. Serum or PBMC's were isolated from each patient and used 51Cr release assays to study rituximab-associated complement mediated cytotoxicity (CMC) or ADCC. To correlate laboratory parameters with response rate, and PFS patients were divided in tertiles. Overall, R+LD was very well-tolerated. Overall response rate (ORR) = 68% (39% CR, 19% PR); median time-to-progression (TTP) = 12 m. Surface expression of CD32 in PMNs, and CD69 in NKcells correlated with better response rates. Surface expression of CD11b and CD32 in the PMN's correlated with a longer PFS (P = 0.040 and P = 0.015, respectively).There was a non-statistically significant trend towards an improved in PFS in those patients whom their PBMC's exhibited a higher degree of ex-vivo rituximab ADCC. Our data suggest that R+LD is a safe and effective regimen and that the quality of the immune system prior to a chemo-immunotherapy regimen may play a role in clinical outcomes, specifically the expression of CD11b and CD32 in PMNs or CD69 in NKcells. Our data supports further research in seeking ways to enhance the quality of the immune system to improve responses to rituximab ± chemotherapy. [Table: see text]
Evaluation of the potential of histone deacetylase inhibitors to synergize the antineoplastic effects of the proteasome inhibitor bortezomib in mantle cell lymphoma (MCL)
Authors: Paoluzzi L. , Scotto L. , Seshan V. E. , O'Connor O. A. 
Published: August 2020

8584 Background: Romidepsin (R) and belinostat (B) are inhibitors of histone deacetylases (HDACI). HDACIs are known to induce cell death in malignant cells through multiple mechanisms, including up-regulation of death receptors, disruption of Hsp90 function and generation of reactive oxygen species. Mantle cell lymphoma is an aggressive subtype of non-Hodgkin lymphoma characterized by the reciprocal translocation t(11;14)(q13;q32) leading to the overexpression of cyclin D1. Methods: We investigated the cytotoxicity of romidepsin and belinostat alone and in combination with the proteasome inhibitor bortezomib in cell lines of mantle cell lymphoma (HBL2, Granta519, Jeko1). Cell Titer-Glo assay followed by luminometric acquisition was used for all cytotoxicity assays. Drug:drug interactions in terms of synergism, additivity or antagonism were computed using the Relative Risk Ratio Analysis (RRR, GraphPad software) with a RRR < 1 defining synergism, RRR=1 additivity and RRR>1 antagonism. Results: The IC50 values for R and B alone at 24 hours were: HBL-2: R=4.7nM, B=490nM; Jeko-1: R=3nM, B=750nM; Granta519: R=45nM, B=30,700nM. As single agent, romidepsin was about 100 fold more potent than belinostat. The combination of belinostat (100–1000nM) or romidepsin (1–40nM) with bortezomib (3–4nM) showed synergism in all cell lines at different concentrations. For romidepsin plus bortezomib, RRR in Granta519=0.05–0.14, RRR in Jeko1=0.1–0.75, RRR in HBL2=0.03–0.81. For belinostat plus bortezomib, RRR in Granta519= 0.07–0.38, RRR in Jeko1=0.16–0.49, RRR in HBL2=0.04–0.69. Flowcytometry for apoptosis, cell cycle analysis and mitochondrial membrane potential as well as immunoblottings for hystone H3 acetylation, cyclin D1, Bcl-XL, Mcl-1, BIM and IKB-α suggest this strategy may modulate cyclin D1 and p27 in MCL which is known to be grossly deregulated for these proteins. Conclusions: In this analysis, while romidepsin had improved single agent activity, when combined with bortezomib both HDACI showed potent synergism. [Table: see text]
Benefit of thalidomide (THAL) in total therapy 2 (TT2) of multiple myeloma (MM) exhibiting both cytogenetic abnormalities (CA) and low-risk (LR) by gene expression profiling (GEP)
Authors: Waheed S. , Shaughnessy J. , Szymonifka J. , Pineda-Roman M. , Hollmig K. , Sawyer J. , Crowley J. , Barlogie B. 
Published: August 2020

8590 Background: We recently reported an update of TT2 and observed an unexpected preferential benefit from THAL for OS in the subgroup of patients with CA (Blood, 2008). We now re-examined these results with further follow-up of 81 months in the context of GEP-defined risk. Methods: OS and EFS were examined in the 668 patients enrolled in TT2 according to treatment arm, CA status and by GEP risk status. Results: Median overall and event-free survival (OS, EFS) are 9yr and 5yr, with a significant benefit from THAL v the control arm (p=0.04, p=0.0004). We confirmed the ongoing unique survival benefit of THAL in the CA group with 6-yr OS estimates of 53% v 35% (p<0.001), while patients not exhibiting CA had similar OS of 70% and 68%. EFS was superior with THAL regardless of CA status, 56% v 45% without CA (p=0.02) and 38% v 20% with CA (p=0.008). With respect to GEP, THAL benefited the LR group with 6-yr OS/EFS rates of 73%/56% v 63%/36% without THAL (p=0.10/p=0.002); the corresponding data for high-risk (HR) patients showed OS/EFS with THAL of 35%/19% v 15%/10% without THAL (p=0.36/p=0.43). When examined in the context of both GEP and CA, THAL only benefited the 33 patients with both CA and LR with 6-yr OS of 72% v 37% among the 47 without THAL (p=0.003). For the remaining subgroups (CA/HR; no CA/LR, no CA/HR), the addition of THAL did not impact OS. Conclusions: The unique benefit of THAL to the CA/LR subgroup may be linked to its greater efficacy in proliferative MM (enabling CA detection) that can only be sustained in the LR (lacking amplification of 1q21?) but not in the HR subset. The concomitant examinations of MM genetics by both GEP and cytogenetics enabled the discovery of this subgroup-specific treatment benefit. Data on TT3 with the addition of bortezomib will be presented in the context of the CA/GEP-risk scenario. [Table: see text]
Use of alternate splicing to identify subgroups in uniformly treated newly-diagnosed myeloma
Authors: Munshi N. C. , Li C. , Minvielle S. , Moreau P. , Amin S. B. , Magrangeas M. , Anderson K. C. , Avetloiseau H. 
Published: August 2020

8602 Gene function is modulated at multiple levels. Besides expression level changes, post-transcriptional changes such as alternate splicing alter specificity of gene function. Misregulation of alternate splicing is associated with various disease processes including cancer. We have analyzed alternate splicing in myeloma (MM) using high throughput exon array analysis. Affymetrix Human Exon 1.0 ST Arrays used in this investigation, besides expression levels, also provides information on presence of each exon and identifies recurrent alternately spliced genes. We evaluated 170 newly-diagnosed patients with MM treated homogeneously in tandem transplantation IFM trials using CD138 purified MM cells. Xray array tool (Biotique systems) and dChip software was modified to analyze exon array data. We first normalized gene-level expression values across samples, and then identified differentially expressed exons to identify alternate splicing events. We observed over 100 genes with alternate splicing in myeloma with frequency in more than 20% patients. Unsupervised hierarchical clustering showed two groups within myeloma patients which differ in overall survival (OS). Dividing the group based on response, 52 alternately spliced exons were identified as influencing response to therapy including CD79A exon 4, XRCC exon 3 and 17, PRKDC exon 4, NIT 2 exon 4, Calmin exon2, MADH1 exon 7, TBX5 exon 2, Amyloid beta exon 14 with the highest frequency of alternate splicing. Amongst these, 32 genes had the most influence on response with over 50% differential frequency in patients achieving CR. Similarly 85 alternately spliced genes are influencing OS between groups at 48 month survival cut-off. 49 genes within this group had the most influence on OS. Shared spliced variants between both response and survival groups suggesting their biological and functional significance. Further validation of these alternate splicing is under investigations. This study highlights that alternate splicing is observed with significant frequency and demand need for evaluation of not only the expression level of genes but also post translational modifications. The spliced genes identified here are important target for therapy as well as possible immune modulation. No significant financial relationships to disclose.
A single center experience with high-dose (HD) IL-2 treatment for patients with advanced melanoma and pilot investigation of a novel gene expression signature as a predictor of response
Authors: Sullivan R. J. , Hoshida Y. , Brunet J. , Tahan S. , Aldridge J. , Kwabi C. , Gardiner E. , McDermott D. , Golub T. , Atkins M. B. 
Published: August 2020

9003 Background: HD IL-2 remains one of two FDA-approved therapies for the treatment of patients (pts) with advanced melanoma. Initial studies conducted 15–20 years ago reported 16% response rate with 8% of pts achieving durable responses. The toxicity of HD IL-2 limits its application to pts treated in specialized centers. We present the clinical outcome of pts treated over a recent 2 year period with HD IL-2 at a single institution and an associated retrospective pilot study evaluating the predictive value of a novel tumor gene expression signature. Methods: Clinical and radiological data were collected and analyzed on 49 consecutive pts treated with HD IL-2 at Beth Israel Deaconess Medical Center from 10/05 - 10/07. Response was evaluated via RECIST. Formalin-fixed paraffin embedded tumor was obtained on consenting pts and classified as either Class 1, defined by melanocyte-specific genes including MITF, or Class 2, represented by immune genes, using the DNA-mediated Annealing, Selection, and Ligation (DASL) technique. Two-sided Fisher's Exact test was used to compare the proportion of responses for pts in the two classes. Results: Clinical response occurred in 16 of the 49 pts (32.6%), with 5 pts (10.2%) having a CR. Two other pts had stable disease > 12 mos; 3 pts who progressed after response had resection to NED. 10 pts remain disease/progression free at a minimum of 16 mos following treatment. 28 pts (including 13 of 16 responders) had sufficient tumor for DASL analysis. Among the 21 categorized as Class 1, 7 (33%) were responders. Of the 7 classified as Class 2, 6 (86%) were responders. This difference in response was statistically significant (p = 0.0286). Conclusions: The overall and CR rates in a contemporary series of pts with metastatic melanoma treated with HD IL-2 are twice that reported in initial studies suggesting some treatment selection on clinical grounds since the 1990s. Pts with tumors expressing an immune signature by DASL appeared more likely to respond. This finding requires prospective validation, but suggests immune-related gene expression might contribute to IL-2 responsiveness. [Table: see text]
Phase I/II study of the combination of sorafenib and temsirolimus in patients with metastatic melanoma
Authors: Kim K. B. , Davies M. A. , Papadopoulos N. E. , Bedikian A. Y. , Hwu W. , Woodard K. , Washington E. W. , Dancey J. E. , Wright J. , Hwu P. 
Published: August 2020

9026 Background: Inhibition of Signal transduction pathways at multiple levels may be a more effective therapeutic cancer strategy for advanced cancer patients. Sorafenib, a multikinase inhibitor and temsirolimus, an inhibitor of critical survival pathways, are targeted compounds with single agent anti-tumor activity in several solid tumors. Inhibition of mutant B-Raf and the AKT signaling pathway has been effective in vitro with melanoma cell lines. Therefore, we designed a phase I/II study of the combination of sorafenib and temsirolimus to inhibit multiple pathways for greater clinical efficacy.Methods: Patients (pts) with stage IV or unresectable or recurrent stage III melanoma and ECOG performance status of 0 to 1 were eligible. Pts with treated brain metastases were eligible if they had not progressed for 3 months. Sorafenib was given orally twice daily and temsirolimus was given intravenously once a week, both starting on day 1, with a 4-week cycle. Responses were assessed every 2 cycles per RECIST. Results: To date, 22 pts have been enrolled and treated. Median age was 56.5, and 17 were male. Median ECOG PS was 1. The MTD doses were sorafenib 400 mg in AM / 200 mg in PM daily and temsirolimus 25 mg IV weekly. The dose-limiting toxicity (DLT) included thrombocytopenia, hand-foot syndrome (HFS), serum transaminase elevation and hypertriglyceridemia. Other common adverse events were dry skin, fatigue, taste alteration, anorexia, flatulence, diarrhea, skin rash, insomnia, neuropathy, myalgia, and headaches, anemia, hypercholesterolemia, hyperglycemia and hypophosphatemia. There were 9 pts with stable disease among 21 evaluable pts for response. Conclusions: Sorafenib and temsirolimus can be administered concomitantly although with significant toxicity at higher dose levels. Currently, pts are enrolled in a dose expansion cohort. Pharmacokinetic data will be presented. Supported in part by NCI grant UO1 CA062461 and N01 CM17003. [Table: see text] No significant financial relationships to disclose.
Effect of ipilimumab treatment on 18-month survival: Update of patients (pts) with advanced melanoma treated with 10 mg/kg ipilimumab in three phase II clinical trials
Authors: O'Day S. , Weber J. , Lebbe C. , Maio M. , Pehamberger H. , Harmankaya K. , Siegel J. , Hoos A. , Humphrey R. , Wolchok J. 
Published: August 2020

9033 Background: The monoclonal antibody ipilimumab targets cytotoxic T lymphocyte antigen-4. Updated survival data (≤32.5 months follow-up) from 3 Phase II trials of ipilimumab in pts with mostly pretreated advanced melanoma are reported. Methods: Study CA184008 was an open-label, single-arm study of ipilimumab 10 mg/kg. Study CA184022 was a randomized, dose-ranging study of ipilimumab 0.3, 3, or 10 mg/kg. Study CA184007 was a randomized, placebo-controlled study of the effect of budesonide on gastrointestinal immune-related adverse events in pts receiving ipilimumab 10 mg/kg. In all studies, ipilimumab was given every 3 weeks (Q3W) × 4 (induction); eligible pts could continue to receive maintenance ipilimumab Q12W from week 24. Pts continue to be followed-up to determine long-term survival. Results: With a median follow-up ranging from 10.1 to 16.3 months and reaching up to 32.5+ months, pts receiving 10 mg/kg ipilimumab showed durable survival; 12- and 18-month survival rates are presented [ Table ]. The tail of the Kaplan-Meier curve flattened at 18 months, indicating that a substantial proportion of patients continued to survive beyond the updated follow-up period in all three studies. Long-term survivors include pts with disease progression (PD) per modified World Health Organization (mWHO) criteria. Conclusions: Ipilimumab may result in a long-term survival benefit in pts with advanced melanoma, where 18-month survival rates across 3 Phase II studies range from 34.5% to 39.4% for previously treated pts. These results indicate that more than 1/3 of ipilimumab-treated pts with advanced melanoma experience a long-term survival benefit, including some pts characterized as PD by mWHO. The survival data continue to mature, and follow-up is ongoing. [Table: see text] [Table: see text]