bluuebunny/crossref_metadata_2025_split huggingface dataset:
Health related quality of life (HRQOL) evaluated with the EORTC C30 questionnaire in first line therapy of elderly patients with chronic lymphocytic leukemia (CLL): Results of a phase III trial of the German CLL Study Group (GCLLSG)
Authors: Eichhorst B. F. , Busch R. , Hallek M. 
Published: March 2020

7572 Background: The GCLLSG evaluated the efficacy of fludarabine (F) versus (vs.) chlorambucil (Clb) in first line therapy of older patients with advanced CLL. HRQOL was evluated by using the EORTC C30 questionnaire. Methods: Pts were randomized to receive 6 courses of F (25 mg/m²/day (d) IV for 5d; 92 pts) or 12 months (mo) of Clb (0.4–0.8 mg/kg/d PO, every 15d; 99 pts). All pts were previously untreated, aged between 65 and 79 years and in advanced stage Binet C or symptomatic Binet B or A. Primary endpoints were overall survival (OS) and progression free survival (PFS), secondary endpoint was HRQOL. The EORTC C30 questionnaire (version 2.0) was sent to all patients at baseline and after 6, 12 and 24 mo. Scores (0–100) for 15 different measures (1 global HRQOL, 5 functional, 3 symptom and 6 single item scales) were evaluated at each time point. Results: F induced significantly higher response rates and prolonged the PFS, while no significant difference in OS was observed. At baseline 130 of 191 pts (68%) completed the questionnaires followed by more than 80% at mo 6 to 24. Compliance rates were similar in both treatment arms. Between pts completing questionnaires or not no statistically significant differences in perfomance status, age, stage or response to treatment were observed. HRQOL differences in comparison to baseline values were significantly improved after F treatment in global HRQOL, role and social functioning after 12 months as shown by the table. Responders had a significantly better global HRQOL and social functioning as well. Except for an impaired physical functioning no differences in HRQOL were observed between different age groups (65–69, 70–74, 75–79). Conclusion: Elderly F treated patients with CLL showed improvement inglobal HRQOL. Elderly age groups had a similar HRQOL as younger age groups. [Table: see text] [Table: see text]
The mTOR inhibitor CCI-779 (temsirolimus) downregulates p21 and induces cell cycle arrest and autophagy in mantle cell lymphoma (MCL)
Authors: Yazbeck V. Y. , Georgakis G. V. , Li Y. , Younes A. 
Published: March 2020

7573 Background: Mantle cell lymphoma (MCL) is a distinct type of B-cell lymphoma associated with transient response to conventional chemotherapy, continuous relapses and median survival of only 3–4 years. The mammalian target of rapamycin (mTOR) pathway is activated in many human malignancies where it regulates cyclin D1 translation. In a phase II trial, temsirolimus (CCI-779), an inhibitor of mTOR kinase used as single agent achieved an overall response rate of 38% in relapsed MCL patients. Our goal was to determine the activity and the mechanism of action of CCI-779 in MCL cell lines and to examine whether CCI-779 may synergizes with proteasome inhibitors. Methods: The activity of CCI-779 was determined in 3 mantle cell lymphoma cell lines (Jeko 1, Mino, Sp 53). Cell viability was determined by MTS assay, and autophagy by Acridine orange. Analysis of cell cycle was performed by flow cytometry and apoptosis by Annexin-V binding. Molecular changes were determined by western blot . Results: CCI-779 induced cell growth arrest in all cell lines in a time and dose dependent manner. The antiproliferative activity was due to cell cycle arrest in the G0/G1 phase followed by autophagy. CCI-779 decreased S6 phosphorylation in Jeko 1,Sp 53 indicative of mTOR inhibition. Furthermore, CCI-779 downregulated p21 expression in all three cell lines, without altering p 27 expression. Moreover, CCI-779 decreased the expression of the antiapoptotic protein cFLIP and ERK in both Jeko1 and Sp 53, but had no effect on cyclin D1 expression. The proteasome inhibitor bortezomib was also effective in all MCL cell lines, but failed to demonstrate significant synergy with CCI-779. Conclusions: The antiproliferative activity of CCI-779 in MCL is mediated by p21 downregulation and autophagy, without significant effect on cyclin D1 expression. The lack of synergy between bortezomib and CCI-779 should be confirmed using fresh MCL tumor cells. No significant financial relationships to disclose.
Interleukin-10 promoter gene polymorphism (-819*C) associated with poor treatment outcome in DLBCL patients treated with 8 cycles of R-CHOP as a first line
Authors: Kim Y. K. , Kim H. N. , Lee J. J. , Yang D. H. , Ahn J. S. , Cho S. H. , Chung I. J. , Park M. R. , Kim H. J. 
Published: March 2020

7575 Background: IL-10 is an anti-inflammatory cytokine inhibiting Th1 functions, which may facilitate tumor escape from the immune response. Among the various IL-10 promoter genes, the IL-10–1082G, -819C and -592C alleles were reported to be associated with high serum IL-10 level. Methods: In present study, we studied the frequency of these 3 alleles and their influence to the clinical outcome in 50 DLBCL patients treated with 8 cycles of R (Rituximab, 375 mg/m2 on day 1 of each cycle)-CHOP every 3 weeks. Results: 50 patients with newly diagnosed DLBCL were included and all of them represented CD20 positivity. At diagnosis, median age was 60 (19∼85) and 24 (48%), 14 (28%), 8 (16%) and 4 (8%) patients belonged to the low, low-intermediate, high-intermediate and high risk group according to IPI reports, retrospectively. Of 50 patients, 8 (16%), 19 (38%) and 22 (44%) were found to carry IL-10–1082G, -819C and -592C alleles, retrospectively. As compared with -1082AA genotype, -1082G allele (GA/GG) failed to show better outcome (eg. higher CR or longer progression-free survival, PFS) after 8 cycles of R-CHOP. Further, patients with -819C or -592C alleles were not able to affect the response rates (CR or PR) compared with -819TT or -592AA genotype. On the other hand, the PFS was significantly shorter in patients carrying -819C allele than TT genotype (13.9 vs 26.9 ms, p<0.01). PFS also decreased in -592C allele compared with AA genotype (15.2 vs 26.5 ms, p<0.05). Of 30 patients with bcl2 positivity, patients carrying -819C alleles also showed significant lower PFS than TT genotype (12.4 vs 16.1 ms, p<0.05). In multivariate analysis including IPI, stage, IL-10–1082G, -819C and -592C allele frequencies, -819C allele remained as an independent prognostic factor predicting shorter PFS (RR=3.6, p<0.05). In a haplotype analysis, patients carrying ATA/ATA showed significant longer PFS than in other haplotypes (p<0.05). Conclusions: It is still a matter of debate to manage the DLBCL patients with refractory or progressive disease. This study suggests that the detection of IL-10 gene promoter polymorphism such as -819C allele helps us to predict the patients with poor prognosis and to establish a stratified treatment plan in DLBCL patients. No significant financial relationships to disclose.
Helicobacter pylori eradication in gastric MALT lymphoma: Results of 316 patients treated inside and outside of a clinical trial
Authors: Wündisch T. , Günther A. , Mösch C. , Huynh M. , Stolte M. , Neubauer A. 
Published: March 2020

7584 Background: Cure of infection induces remissions in most patients with early stage Helicobacter pylori- (Hp-) positive gastric MALT (mucosa-associated lymphoid tissue) lymphoma (GML). We compared the long-term outcome of 120 patients treated within a multicenter trial to that of 196 routinely treated patients. Methods: 120 patients with stage I1E disease from a prospective trial (cohort 1) were compared to 196 patients with GML treated outside a trail by sole Hp-eradication (cohort 2). The latter were evaluated in retrospect and only a minority had a complete staging at diagnosis. Histology was the standard for remission evaluation in all patients and performed by the same pathologist (MS). B-cell-clonality and the t(11;18) were assessed in cohort 1-patients. Results: Median endoscopic follow-up was 79 months (range, 1–121) in cohort 1-patients and 27 months (range, 0–120) in cohort 2-patients. In 41% of the cohort 2-patients no or one control endoscopy was performed after a first CR. Most patients are in continuous complete histological remission in both cohorts. 3 cohort 1- and 5 cohort 2-patients relapsed. 16 cohort 1- and 13 cohort 2-patients exhibited histological residual disease (RD) during follow up after a first CR; a watch-and-wait strategy was applied, and most entered into a second CR. Conclusions: Hp-eradication results in long term CR in the majority of patients with GML in both cohorts. Duration of remission, rate of relapse, and RD were similar, regardless of incomplete staging and follow-up procedures and higher age in the cohort 2-patients. No significant financial relationships to disclose.
Addition of tumor bulk to the International Prognostic Index (IPI) does not improve prognostication in diffuse large B-cell Lymphoma (DLBCL)
Authors: Panwalkar A. W. , Loberiza F. R. , Vose J. M. , Bociek R. G. , Bierman P. J. , Armitage J. O. 
Published: March 2020

7585 Background: Bulky disease in DLBCL has been linked to adverse outcomes. Tumor bulk was not included in the IPI due to lack of uniform data availability. Radiation to sites of bulky disease may result in improved outcomes. We evaluated the impact of tumor bulk as a prognostic factor combined with the IPI in predicting overall survival in DLBCL. Methods: A retrospective review of adult patients with newly diagnosed DLBCL from October 1982 through February 2000 was done, and data pertaining to tumor size, age, Ann Arbor stage, performance status (PS), lactate dehydrogenase level (LDH), extranodal involvement, radiation therapy and overall survival was collected. Surviving patients were followed through December 2005. Bulky disease was defined as largest tumor mass of ≥10 cm. Statistical analysis was performed using Cox proportional hazards regression. Results: Complete data was available on 669 patients. All patients received anthracycline or mitoxantrone based chemotherapy. Bulky disease was found in 27% of patients, while radiation was employed in 22% of patients. There was no significant association between use of radiation and tumor bulk. IPI was calculated as low risk—37%, low-intermediate—28%, high-intermediate—20% and high—14%. Median follow-up of survivors was 100 months (range <1 - 263). In univariate analysis, bulky disease alone was a significant predictor of inferior survival (RR 1.27, p = 0.044), however when combined with the IPI it was not a significant predictor of poorer overall survival as compared with non-bulky disease (RR 1.10, p = 0.36). Radiation therapy was associated with a significant increase in overall survival (RR 0.70, p = 0.005). Conclusions: Bulky disease is an important independent prognostic factor for overall survival in patients with DLBCL, however when combined with IPI it does not result in improved prediction. It is unclear whether this is due to insufficient power or due to possible inter-relation between tumor size, LDH and PS, the latter of which are included in the IPI. Radiation therapy to some patients with bulky disease may also have mitigated the adverse effect. Larger prospective studies may shed light on the utility of tumor bulk combined with IPI and possible alterations in management. No significant financial relationships to disclose.
High dose 90Yttrium ibritumomab tiuxetan with PBSC support in refractory-resistant NHL patients: Preliminary results of a phase I/II study
Authors: Vanazzi A. , Ferrucci P. , Grana C. , Cremonesi M. , Chinol M. , Papi S. , Calabrese L. , Radice D. , Paganelli G. , Martinelli G. 
Published: March 2020

7587 Background: Therapeutic options are limited in the treatment of relapsing NHL pts not suitable to HDCT. 90Yttrium ibritumomab tiuxetan (Zevalin) is active in DLBCL at 0.4 mCi/kg, but duration of response is usually short. We present feasibility and toxicity results of a phase I/II study of HD-Zevalin with PBSC support in resistant-refractory NHL pts. From 04/04 to 11/05, 14 pts were enrolled. Median age was 68ys. 13/14 pts had advanced stage disease (III/IV) at diagnosis. 8 DLBCL, 4 MCL, 1 FL G3, 1 transformed MZL. Median number of prior therapies were 3, including rituximab, RT and HD-CT. Methods: 3 dose levels were fixed: 0.8, 1.2, 1.5 mCi/kg. 4 pts received 0.8, 4 pts 1.2 and 6 pts 1.5 mCi/kg. 1wk prior to Zevalin all pts underwent dosimetry: if no abnormal uptake was observed they received the planned dose. On d13 pts received PBSC previously harvested. On d28 from reinfusion (+41 from Zevalin) engraftment was considered to be delayed if ANC <1.0×109/L or PLT<20.0×109/L. Results: Dosimetry showed acceptable radiation-absorbed doses to uninvolved organs, reaching max 20Gy. Only 1pt received 30Gy to the liver without developing toxicity. The median radiation-activity delivered was 90 mCi (range 57–150): 8 pts received a dose within 80 and 100 and 6 pts >100 mCi. Mean dose to red marrow: 0.8±0.2 mGy/MBq. All pts but 1 engrafted promptly. PLT/ANC count nadirs were observed 21/17 days after Zevalin (median values: 11×109/L and 0.01×109/L). No statistically significant difference in terms of hematological toxicity exists in PLT-recovering for pts receiving 1.5 mCi/kg and it is probably influenced by PLT count at baseline and by the several treatment previously received. Non-haematologic toxicity: 1 febrile neutropenia and 1HZV at 2nd level; 1 febrile neutropenia, 1 G3 liver toxicity, 1 bacterial pneumonia, 1HZV, 1HCV reactivation (pt died 4 months after treatment) at the 3rd level. 13/14pts are evaluable for response: 6CR, 2PR, 5PD. Conclusions: Zevalin at myeloablative activity with PBSC is feasible. It could be safely delivered in elderly and heavily pretreated pts, including those who previously received HDCT. Efficacy and mild toxicities suggest further investigation. We are continuing enrollment, including pts who previously received no more than 2 lines of CT. No significant financial relationships to disclose.
Thalidomide increases thrombin generation in multiple myeloma patients
Authors: Candelaria D. , Armijo B. , Montgomery R. , Lee F. , Moll S. , Garcia D. , Liebmann J. , Libby E. 
Published: March 2020

7602 Background: Numerous reports have demonstrated that the clinical use of thalidomide (THAL) carries a risk for deep venous thrombosis. Only limited investigations into the causative mechanisms for this complication have been conducted. Thrombin generation is a global measurement of hyper or hypocoagulability that has not been used to examine the hypercoagulable state caused by THAL. The aim of this study was to determine if THAL affects thrombin generation in patients with multiple myeloma (MM). Methods: MM patients on and off THAL were recruited. Patients were considered to be “on THAL” if they had been taking the medication for at least three months and “off THAL” if they had not been taking the medication for at least three months. Coagulation tubes of blood containing 3.2% sodium citrate were drawn from each patient. Platelet poor plasma was prepared from these specimens using standard technique. The samples were snap frozen at -70 C and stored until analysis. Thrombin generation was measured using the Calibrated Automated Thrombogram as described by Hemker(Pathophysiol Haemo Thromb 2003;33:4–15) using a microplate fluorometer, the Fluoroskan Ascent from Thermo Electron and the Thrombinoscope software package. The endogenous thrombin potential or ETP (area under the thrombin generation curve) and peak thrombin generation (the maximum release of thrombin per unit of time) were the variables of interest for this study. Results: Twenty seven patients were recruited. Five were excluded from analysis because they were on warfarin or enoxaparin. The normal ETP in females is 1803 ± 241 nM*min and in males is 1745 ± 259 nM *min. Normal peak thrombin generation in females is 318.5 ± 52.9 nM and in males is 293.4 ± 48.5 nM. The t-test was used to compare subjects to normal values.Peak thrombin generation was significantly increased in the 9 subjects taking THAL, 374 ± 10.6 nM (p<0.001) and in the 13 subjects not taking THAL, 352 ± 14.7 nM (p=0.009) when compared to normal values. The ETP was not significantly increased 1818 ± 10.7 nM*min (p=0.69) in subjects not taking THAL. However, ETP was increased in subjects taking THAL, 1939± 90 nM*min and showed a trend toward statistical significance (p=0.10). Conclusions: Thalidomide therapy increases thrombin generation significantly in patients with MM. [Table: see text]
In vivo changes in gene expression profiles (GEP) after bortezomib (V) for multiple myeloma (MM): Differential effects on plasma cells (PC) and micro-environment (ME)
Authors: Shaughnessy J. D. , Zhan F. , Huang Y. , Barlogie B. 
Published: March 2020

7603 Introduction: V, a proteasome inhibitor with potent anti-myeloma activity, is thought to act through effects on malignant PC and the ME. However, the in vivo effects of this drug have never been examined at the molecular level. Methods: Serial GEP analyses were performed of paired purified PC and bone marrow biopsies from 46 patients, obtained prior to and 48hr following administration of a single V dose at 1mg/m2. RNA was isolated from whole biopsies and purified PCs from each sample, converted to cRNA, and hybridized to Affymetrix U133 Plus2 microarrays. SAM analysis with 5% false discovery rate was employed to identify drug-altered genes. Results: Following V, 36 ME-associated genes (MAGs) were up-regulated, among them the osteoinductive factor osteoglycin (OGN), consistent with a V effect on osteoblastogenesis; CYR61, an angiogenesis inducer, significantly over-expressed in myeloma relative to normal marrow, was one of only 3 significantly down-regulated genes. V is known to induce expression of proteasome genes and PSMA6, PSMA1, and PSMA14 were among 15 genes up-regulated in PC. In contrast, early growth response (EGR1, EGR2, and EGR3), Krupple-like factor (KLR4, KLR5, KLR6, and KLR7) and nuclear receptor (NR4A1, NR4A2, and NR4A3) family members were down-regulated in PC by V. These differential PC and ME expression changes were only noted in low-risk MM, lacking over-expression of CKS1B. Conclusion: We report here, for the first time, on the differential molecular consequences of a single in-vivo dose of V on both tumor cells and cells of the microenvironment. The clinical implications of these findings are being further investigated and will be presented. [Table: see text]
Phase 1 first-in-human dose escalation study of cp-751,871, a specific monoclonal antibody against the insulin like growth factor 1 receptor
Authors: Lacy M. , Alsina M. , Melvin C. L. , Roberts L. , Yin D. , Petersen J. F. , Birgin A. , Poutney S. , Sharma A. , Gualberto A. 
Published: March 2020

7609 Background: Multiple lines of evidence indicate that the Insulin Like Growth Factor 1 Receptor (IGF-1R) plays a key role in the progression of multiple myeloma (MM). IGF-1 is a growth factor for MM cells. It promotes survival to the cytotoxic effects of chemotherapy in animal models of MM and its blood levels has been shown to correlate with those of paraprotein in MM patients. CP-751,871, a fully human monoclonal antibody, is a highly specific and potent inhibitor of the autophosphorylation of IGF-1R. Methods: Based on its mechanism of action and the potential relevance of IGF-1R in MM, a Phase 1 First-in-Human dose escalation study was initiated with the objective to define the safety and tolerability, and to characterize the pharmacokinetic and pharmacodynamic properties of CP-751,871 in this patient population. Patient’s eligibility included previously treated multiple myeloma in relapse or refractory phase and/or less than complete remission following autologous stem cell transplant or tandem transplant. Results: Following informed consent and screening, 10 dose-escalation cohorts of patients received from 0.025 to 10 mg/kg of CP-751,871 by iv infusion on Day 1 of 4-week cycles. In patients with a suboptimal response to CP-751,871 alone, oral dexamethasone was added to the treatment regimen. Patients received up to 14 cycles of CP-751,871 therapy, alone or in combination with dexamethasone. No dose limiting toxicities have been identified to date. Plasma CP-751,871 exposure increases with dose, and the pharmacokinetic characteristics are consistent with target-mediated disposition. Pharmacodynamic measurements indicate complete target saturation by CP-751,871 for the complete length of the dosing period. One near CR and 2 PR in combination with dexamethasone have been reported. Conclusions: These data indicate that CP-751,871 is well tolerated and may constitute a therapeutic approach for patients with multiple myeloma. [Table: see text]
Percutaneous vertebroplasty and/or kyphoplasty is an effective and safe treatment for painful vertebral compression fractures in multiple myeloma (MM)
Authors: Thomas S. K. , Wang M. L. , Yao K. , Villareal H. , Fukshansky M. , Suki D. , Mendel E. , Weber D. M. , Alexanian R. , Burton A. 
Published: March 2020

7610 Background: Painful vertebral compression fractures are a major source of morbidity in MM. Vertebroplasty involves percutaneous injection of polymethylmethacrylate (PMMA) into a vertebral body, while kyphoplasty involves inflation of a balloon for painful kyphotic deformity prior to stabilization with PMMA. Methods: We assessed safety and efficacy of 100 vertebroplasties and/or kyphoplasties in 81 consecutive myeloma patients between 12/2000 and 2/2005. Results: Median age was 63 (range 32–84), with 29% having prior radiotherapy to the vertebra treated. Contraindications included epidural compression of neural elements and failure to localize a symptomatic level. Kyphoplasty was preferred if kyphosis of > 20 degrees contributed to pain, or if the posterior vertebral cortex was disrupted so that controlled delivery of bone cement was difficult. Vertebroplasty was performed when vertebral collapse was either slight or so severe that insertion of balloon device was not possible, or if patient could not tolerate the general anesthesia required for kyphoplasty. The median preoperative visual analog pain score (0–10) was 8(range 2–10); the median postoperative pain score was 3 (range 0–10) (p < 0.01). There were no significant complications . Conclusions: Percutaneous vertebroplasty and kyphoplasty provided rapid and marked pain relief. These procedures are safe and feasible and represent the treatment of choice in selected MM patients with severe refractory pain due to pathologic compression fractures. No significant financial relationships to disclose.