bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prevention of active multiple myeloma (MM) using IL-1 receptor antagonist (IL-1ra) and low-dose dexamethasone (Dex) and monitoring the high sensitivity C-reactive protein (hsCRP)
Authors: Lust J. A. , Lacy M. Q. , Zeldenrust S. R. , Dispenzieri A. , Gertz M. A. , Greipp P. R. , Witzig T. E. , Kumar S. , Geyer S. M. , Donovan K. A. 
Published: March 2020

8105 Background: IL-6 is the central myeloma growth factor and we have shown that abnormal production of IL-1beta in the myeloma microenvironment stimulates the generation of paracrine IL-6. A Phase II trial was completed using IL-1ra, which inhibits paracrine IL-6 production, and low dose Dexamethasone (Dex), which decreases IL-1 levels through myeloma cell apoptosis, in patients with smoldering/indolent MM (SMM/IMM). These patients are at the greatest risk for progression to active MM and most likely to benefit from anti- cytokine therapy. Methods: Patients that had ≥ 10% bone marrow plasma cells and/or an IgG or IgA M-spike ≥ 3 g/dL and did not require immediate chemotherapy were eligible. A total of 47 patients received 100 mg of IL-1ra SQ qd for 6 months unless clinical progression occurred. Responding patients were allowed to continue on therapy with IL-1ra alone. Low dose Dex (20 mg qweek) was added after 6 months of IL-1ra in non-responding patients. The primary endpoint was progression-free survival (PFS). Results: The 47 patients were at high risk for progression to active MM with 98% having ≥ 10% plasma cells, 89% generating IL-1 levels consistent with myeloma (≥ 1.0), and 32% having bone lesions. All 47 patients received IL-1ra initially and 25/47 subsequently received IL-1Ra/Dex. For the group of 47 patients, the median overall progression-free survival was 37.5 months. Three patients achieved a minor response (MR) to Anakinra alone; 5 pts achieved a PR and 4 patients an MR after addition of Dex. Seven patients had a decrease in the plasma cell labeling index (PCLI; a marker of myeloma cell growth) on Anakinra alone which paralleled a decrease in the high sensitivity CRP (a marker of serum IL-6 levels). The median PFS for patients without (n=12) and with (n=35) a ≥ 15% decrease in their baseline hsCRP was 6 months and > 3 yrs, respectively (p=0.002). Conclusions: In SMM/IMM patients at high risk for progression to active myeloma, treatment with IL-1 inhibitors (IL-1ra ± Dex) results in an increased PFS in patients that demonstrate a ≥15% reduction in the baseline CRP compared to those that do not respond. No significant financial relationships to disclose.
Fully human antibody MOR202 against CD38 for the treatment of multiple myeloma and other blood-borne malignancies
Authors: Tesar M. 
Published: March 2020

8106 MOR202 is one of MorphoSys’ internal development programs targeting the cell surface antigen CD38 that is found to be expressed on various cell lines derived from B cell, T cell, and myeloid/monocytic tumors. Especially in the indication of multiple myeloma (MM), which remains an incurable malignancy with a median survival of 3–4 years, a strong expression has been reported in the majority of patients’ tumor samples. CD38-specific human antibodies were selected from MorphoSys’ proprietary HuCAL GOLD phage display library by cell panning strategies. A lead candidate (MOR202) was selected from several antibodies recognizing different epitopes on CD38 and subjected to further in vitro and in vivo characterization as follows: MOR202 exhibits an affinity in the low nanomolar range, recognizes CD38 on many cell lines of different cancer origin and most importantly on all primary MM-patient samples in FACS and IHC. The fully human IgG1 MOR202 is able to kill CD38-expressing cell lines and primary MM cells from patients efficiently by ADCC in a concentration-dependent manner, whereas early progenitor cells are not affected as demonstrated by a clonogenic assay. Finally, excellent efficacy could be shown in a SCID-mouse xenograft model, resulting in significantly reduced tumour growth (RPMI8226) and overall survival, which was even superior to bortezomib tested in the same model. No significant financial relationships to disclose.
Outcome following multiple lines of salvage chemotherapy prior to autologous stem cell transplant for relapsed or refractory diffuse large B-cell lymphoma (DLBCL)
Authors: Stakiw J. , Kuruvilla J. , Al-Farsi K. , Zadeh S. , Nagy T. , Keating A. , Crump M. 
Published: March 2020

8120 Background: The standard of care for chemosensitive relapsed or refractory DLBCL is autologous stem cell transplant (ASCT). There is no standard approach for patients (pts) whose disease fails to respond to platinum-based salvage chemotherapy (pSC) although pts who undergo further salvage chemotherapy to demonstrate chemosensitivity may benefit from ASCT (Chen, et al, BMT 2002). We analyzed the overall response rate (ORR) to each line of salvage therapy for pts with relapsed or refractory DLBCL and the impact of the number of salvage regimens necessary to demonstrate chemosensitivity on overall and progression-free survival (OS and PFS) post-ASCT. Methods: We retrospectively reviewed our computerized database and charts between Jan 1/99 - Dec 31/05 and identified 203 pts relapsed after or refractory to anthracycline-based chemo treated with pSC. Pts typically received 2–3 cycles of pSC to assess chemotherapy sensitivity. Responding patients received etoposide 60 mg/kg and melphalan 160 mg/m2 supported by autologous PBSCs. Pts with stable or progressive disease following first line salvage chemotherapy (SC1) were offered alternate non-cross resistant second-line salvage chemotherapy (SC2) and proceeded to ASCT if chemosensitive. Results: Pt characteristics: Median age at time of salvage chemotherapy: 52 years (range 21–65); primary refractory: 48%; advanced stage disease at salvage: 50%; prior rituximab: 17%; prior radiation 26%. 119/203 pts did not respond to SC1, 81 pts received SC2 and 10 pts received 3 salvage regimens (SC3). ORRs to salvage were: SC1: 40%, SC2: 14%, SC3: 10%. Pts able to proceed to ASCT were: SC1: 37%, SC2: 14%, SC3: 0. With a median follow-up of 1.8 years, the 2-year OS post ASCT for the SC1 and SC2 groups was 69% and 56% respectively. The 2-year PFS post ASCT for the SC1 and SC2 groups were 58% and 40%. Conclusions: The ORR to platinum-based SC is low in this cohort of primary refractory/relapsed patients (40%), and only 14% of pts who received SC2 after pSC responded. Although some have prolonged PFS following SC2 and ASCT, additional strategies should be investigated in these patients. No significant financial relationships to disclose.
Effect of rituximab (R) on clinical outcomes after autologous stem cell transplantation (ASCT) in pts with relapsed or refractory diffuse large B-cell lymphoma (DLBCL)
Authors: Adegbola O. , Andreadis C. , Schuster S. J. , Chong E. A. , Nasta S. D. , Porter D. L. , Luger S. M. , Tsai D. E. , Cunningham K. , Stadtmauer E. A. 
Published: March 2020

8122 Background: First-line chemotherapy cures ∼50% of pts with DLBCL, while salvage therapy followed by ASCT can cure another ∼30%. R significantly improves response rates to 1st line therapy. This retrospective study was designed to test the hypotheses that: 1) ASCT is effective in pts relapsed after R-chemotherapy and 2) addition of R to salvage improves outcomes after ASCT. Methods: We identified 84 pts with relapsed/refractory DLBCL who underwent ASCT at our institution between 1990 and 2006. In all, 32% received a R-chemo 1st line regimen and 27% received R with salvage. The median age at ASCT was 49 yrs and the median time from diagnosis to ASCT was 16 mos. High-dose regimens included BCV (48%), BEAM (8%) and alkylator/TBI (20%). Results: Overall response rate (ORR) after ASCT was 52%, with 37% of pts in CR by day 100. Among those in CR, 16% had a CR pre-ASCT, 72% had a lesser response, and 9% were chemo-resistant. The addition of R to salvage (23/84 pts) was favorably associated with ORR after ASCT (OR: 5.2, 95% CI: 1.1 - 25, p=0.029), even in pts who had failed a prior R regimen (p=0.013). Other factors favorably associated with ORR were response to salvage (p=0.046) and time to ASCT >12 mos (p=0.017). At last f/u (med: 22 mos, iqr: 7 - 55 mos), event-free (EFS) and overall survival (OS) were both 35%. The only factor associated with EFS and OS in univariate and multivariate analyses was ORR after ASCT (HR: 0.16, 95% CI: 0.07 - 0.37, p<0.001 and HR: 0.12, 95% CI: 0.05 - 0.28, p<0.001 respectively). Age at ASCT, time to ASCT, year of ASCT, mobilization/conditioning regimen, and failure of a R-chemo regimen were not associated with EFS or OS. Conclusions: Pts with DLBCL who have failed a R-chemo first-line regimen derive an equal benefit from ASCT as pts who are R-naïve, with significant long-term EFS and OS. Additionally, inclusion of R in salvage therapy prior to ASCT provides superior response rates, even after a failed prior R-chemo regimen. These results confirm the benefit of ASCT for pts with DLBCL in the rituximab era and argue for the incorporation of R and related agents in studies of high-dose therapy and ASCT. No significant financial relationships to disclose.
Predicting clinical outcome through gene expression profiling in stage III melanoma
Authors: John T. , Black M. A. , Toro T. , Gedye C. A. , Davis I. D. , Leader D. , Guilford P. , Cebon J. S. 
Published: March 2020

8502 Background: Melanoma patients with clinically involved regional lymph nodes (Stage IIIB&C) represent a prognostically heterogeneous population. Current prognostic factors cannot distinguish the 30% of patients who will achieve long term survival from those who will relapse early. We hypothesized that gene expression profiling could identify these different prognostic groups and provide a greater understanding of the genetic mechanisms involved. Methods: Lymph node sections from 29 patients with Stage IIIB & IIIC melanoma and divergent clinical outcome as defined by time to tumor progression (TTP), including 16 poor (TTP<6 months) and 13 good (TTP>28 months) prognosis patients, were subjected to molecular profiling using spotted oligonucleotide arrays containing 30,888 probes as an initial test set. The differentially expressed genes were determined using a Wilcoxon-Mann-Whitney t-test with the false discovery rate controlling method of Benjamini-Hochberg and validated using quantitative real-time RT-PCR. Using logistic regression, a predictive score algorithm was developed based on the 15 genes for which the correlation between the two platforms was the strongest. The score was then applied to two independent validation sets of 10 and 14 patient samples. Results: Supervised analysis using differentially expressed genes was able to distinguish the two prognostic groups in the test set. The score correlated directly with clinical outcome, with higher scores associated with improved TTP. When the score was then applied to two independent sets of Stage III melanoma patient samples, it predicted clinical outcome accurately in 90% of samples. Conclusions: Stage IIIB and IIIC melanoma can be prognostically sub-classified according to the expression of 15 genes. To our knowledge this is the first study focused on Stage III disease using ex vivo patient samples. These results are encouraging and this genetic signature is currently being validated on a larger cohort. This method will allow appropriate stratification of stage III melanoma patients in adjuvant clinical trials, ameliorating the inherent biological heterogeneity that can confound these studies. [Table: see text]
Long-term protective effect of mature DC-LAMP+ dendritic cell accumulation in sentinel lymph nodes containing micrometastatic melanoma. An EORTC Melanoma group study
Authors: Scolyer R. A. , Elliott B. , Suciu S. , Eggermont A. M. , Mackie R. , Robert C. , Thompson J. F. , Angevin E. , Cook M. G. , Spatz A. 
Published: March 2020

8509 Background: In a previous immunohistochemical study of dendritic cells (DCs) in sentinel lymph nodes (SLNs) draining regressing melanomas we found that the accumulation of mature DC-LAMP+ DCs in SLNs was associated with local expansion of antigen- specific memory effector cytotoxic T lymphocytes and the absence of metastasis in downstream lymph nodes. The aim of this study was to investigate the prognostic importance of the maximal density of mature DCs in SLNs using the anti-DC LAMP antibody. Methods: 458 consecutive patients with micrometastatic melanoma within SLNs and 3 yrs follow-up after SLN procedure or death within 3 yrs were eligible for analysis. Semi-quantitative evaluation of mature DCDC-LAMP+ maximum density was made as follows: the slide was examined at intermediate magnification (x100) to select the area containing the maximum number of DC-LAMP+ DCs, the number of DC-LAMP+ cells per mm2 was then determined at high magnification (x400) in 3 mm2 in high density areas. Results were reported as number of cells /mm2. The maximal density of mature DC-LAMP+ DCs was evaluated by three independent observers and categorized into three classes (<100/mm2, 100- <200/mm2, ≥200/mm2) according to previously reported cutpoints. Results: There was excellent inter-observer reproducibility for maximum density of mature DC-LAMP+ DCs scores (kappa score = 0.82). There were differences in the maximal density scores and staining intensity according to the center (P<0.001). The higher the mature DC density in the SLN the longer the duration of survival [p=0.047; hazard ratio (95% CI) = 0.70 (0.50–1.00)]. Conclusions: This study is the first to report the prognostic value of DC-LAMP+ DC counts in SLNs containing metastatic melanoma. Patients with a high density of mature DCs (≥200/mm2) have the lowest risk of death. It also provides evidence that a lack of DC maturation in the SLNs is important in biological facilitation of melanoma progression. No significant financial relationships to disclose.
Outcome analysis for melanoma patients undergoing deep pelvic lymph node dissection
Authors: Badgwell B. , Xing Y. , Gershenwald J. , Lee J. , Mansfield P. , Ross M. , Cormier J. 
Published: March 2020

8514 Background: The benefits of deep pelvic lymph node dissection (DLND) for node-positive melanoma patients continue to be debated. The objective of our analysis was to assess factors associated with metastatic disease to deep pelvic nodes and examine survival outcomes following DLND. Methods: We retrospectively reviewed the records of 804 patients undergoing lymph node dissection (1990-2001). 97 patients underwent a superficial inguinofemoral lymph node dissection along with a DLND for indications which included: suspicious radiologic imaging (n= 31), documented superficial disease and concern for deep involvement (n = 57), and in-transit disease undergoing limb perfusion (n=9). Logistic regression was performed to identify factors associated with the metastatic tumor spread to deep nodes. Associations between clinicopathologic factors and disease-specific survival (DSS) were estimated using the Cox proportional hazards model. Results: Fifty-four patients (56%) had metastatic disease (median 2 positive lymph nodes, range 1–12) within their deep pelvis. With a median follow-up of 7.5 years, the 5-year DSS was 42% for patients with positive deep pelvic nodes and 52% for those with negative deep pelvic nodes (p = 0.07). When the number of metastatic deep nodes was stratified, the 5-year DSS for patients with 1 positive node, 2–3 positive nodes, and >3 positive nodes was 49%, 48%, and 27%, respectively (p = 0.04). Age ≥ 50 years (odds ratio [OR] = 3.5, p = 0.03), increasing number of positive superficial nodes (OR = 2.1, p < 0.001), and suspicious findings on pelvic CT images (OR = 11.9, p < 0.001) were associated with metastatic deep nodes. In the multivariate analysis, the number of positive deep nodes (hazard ratio [HR] = 1.1, p = 0.03), male gender (HR = 1.9, p = 0.03), and extra-capsular nodal extension of tumor (HR = 2.7, p < 0.001) were identified as adverse prognostic factors for DSS. Conclusions: Survival outcomes in patients with melanoma metastatic to ≤ 3 deep pelvic lymph nodes are comparable to those in patients without deep nodal involvement. These favorable outcomes support an aggressive surgical approach (i.e., DLND) in patients ≥ 50 years, with multiple positive superficial nodes, and suspicious CT findings. No significant financial relationships to disclose.
Assessment of PI3 kinase as a druggable target in melanoma
Authors: Aziz S. A. , Pick-Golan E. , McCarthy M. M. , Flaherty K. T. , Camp R. L. , Rimm D. L. , Kluger H. M. 
Published: March 2020

8521 Background: PI3 (phosphatidylinositol-3) kinase is central to a major intracellular signal transduction pathway that influences numerous cellular functions, including growth, differentiation and survival. Drugs that target PI3 kinase have demonstrated preclinical activity, and are undergoing further development. The PI3 kinase inhibitor, SF1126 is expected to enter clinical trials in 2007. The hallmarks for a valuable drug target include differential expression between normal and malignant cells and an association with disease progression. PI3 kinase expression has not been thoroughly evaluated in melanoma. We sought to determine the expression and prognostic value of PI3 kinase in a large cohort of primary and metastatic melanomas and to compare the expression with that of benign nevi. Methods: Tissue microarrays containing 548 melanomas and 540 benign nevi were employed to assess PI3 kinase expression. We used a novel method of in situ automated quantitative analysis (AQUA) of protein levels. We applied S100 conjugated to Cy3 to identify a melanoma tumor mask within a histospot, and measured PI3 kinase expression levels using Cy5 conjugated antibodies within the mask. Continuous AQUA scores were correlated with clinical and pathological variables. Results: PI3 kinase expression was higher in melanomas than in nevi by unpaired t-tests (p < 0.0001), and was significantly higher in metastatic than in primary specimens (p < 0.0001). High PI3 kinase scores were associated with Clark levels of IV-V (p = 0.0126), Breslow thickness > 2mm (p = 0.044) and absence of tumor infiltrating lymphocytes (p = 0.014). High PI3 kinase expression strongly correlated with decreased survival by Cox univariate analysis (p = 0.0024), but was not independent of disease stage. Conclusions: PI3 kinase expression is remarkably higher in malignant melanocytes than in benign nevi. Moreover, high PI3 kinase expression is associated with disease aggression, making PI3 kinase an attractive drug target for melanoma. This is the first large study assessing PI3 kinase levels in melanoma in a quantitative fashion. Assessment of the association between PI3 kinase levels and response to therapy is warranted. No significant financial relationships to disclose.
Survival of patients (pts) with metastatic melanoma treated with the anti-CTLA4 monoclonal antibody (mAb) CP-675,206 in a phase I/II study
Authors: Gomez-Navarro J. , Antonia S. , Sosman J. , Kirkwood J. M. , Redman B. , Gajewski T. F. , Pavlov D. , Bulanhagui C. , Ribas A. , Camacho L. H. 
Published: March 2020

8524 Background: The fully human anti-CTLA4 mAb CP-675,206 has demonstrated clinical activity in pts with metastatic melanoma. Prolonged survival was observed in a prior single-dose phase I study, even in pts who did not achieve objective tumor responses. Methods: A multidose phase I/II trial was conducted in pts (N = 119) with histologically confirmed stage IIIc (unresectable) or stage IV recurrent metastatic melanoma and ECOG PS = 1. The study consisted of a phase I, open-label, multidose study (3, 6, and 10 mg/kg) and a phase I expansion cohort for HLA-A2.1+ pts (10 mg/kg monthly [Q1M]), followed by a phase II open-label study of 2 dosing regimens: 10 mg/kg Q1M and 15 mg/kg every 3 months (Q3M). The primary endpoint was safety in phase I, immune monitoring in the expansion cohort, and response in phase II. Survival was analyzed as a secondary endpoint. Results: In the phase I study, Kaplan-Meier estimates of median overall survival were 17.6 months for all dose groups combined (n = 28). In the phase II study, median survival was 10.3 months in the 10 mg/kg arm and 11.0 months in the 15 mg/kg arm. Survival outcomes were favorable, compared with historical median survival of 7 months, independent of whether pts achieved an objective response. Updated survival data will be presented. Conclusions: Patients participating in a multiple dose study of CP-675,206 showed a survival time that was greater than expected on historic controls. These observations support the endpoints of an ongoing randomized phase III study in melanoma to further evaluate survival in the frontline setting. [Table: see text] [Table: see text]
Interferon-α as adjuvant therapy for melanoma: An individual patient data meta-analysis of randomised trials
Authors: Wheatley K. , Ives N. , Eggermont A. , Kirkwood J. , Cascinelli N. , Markovic S. N. , Hancock B. , Lee S. , Suciu S. 
Published: March 2020

8526 Background: Many randomised trials have evaluated the role of adjuvant interferon-a (IFN) in high-risk melanoma, some suggesting benefit and others not. To assess the totality of current evidence, an individual patient data (IPD) meta-analysis of all available trials was performed. Methods: Standard IPD meta-analysis methods were used to assess event-free (EFS) and overall survival (OS), with odds ratios (OR) and 95% confidence intervals (CI) calculated. Trials were divided by dose of IFN - high (20 MU/m2), intermediate (5–10 MU), low (3 MU) and very low (1 MU). Subgroup analyses by patient age, gender and disease characteristics were also performed. Results: IPD was provided for 10 of 13 reported trials of IFN vs. no IFN (for the other 3 trials published data were used). 6067 patients (IPD available for 85%) were included in the analysis, with over 3,700 and 3,000 events for EFS and OS. There was statistically significant benefit for IFN for both EFS (OR=0.87, CI=0.81–0.93, p=0.00006) and OS (0.9, 0.84–0.97, p=0.008). There was no evidence of differences according to dose (Table 1; trend p>0.1) or duration of IFN. This proportional survival advantage translates into an absolute benefit of about 3% (CI 1%-5%) at 5 years. The effect of IFN did not differ with age, gender, tumor site, Breslow thickness, clinical nodes or disease stage. Only for ulceration was there some evidence of an interaction (p=0.03); patients with ulcerated tumors had greater benefit from IFN (EFS: OR=0.76, OS: OR=0.77) than those with no ulceration (EFS: OR=0.94, OS: OR=0.98). Conclusions: This meta-analysis provides evidence that adjuvant IFN significantly reduces the risk of relapse and improves overall survival, although the absolute survival benefit is relatively small. This analysis does not however, clarify the optimal (high, intermediate or low) dose of IFN. Given the large number of subgroup analyses performed, the apparent increased benefit in patients with ulceration requires confirmation. No significant financial relationships to disclose.