bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lumiliximab with fludarabine, cyclophosphamide, and rituximab (FCR) for patients with relapsed chronic lymphocytic leukemia (CLL)
Authors: O’Brien S. , Byrd J. C. , Kipps T. J. , Forero-Torres A. , Flinn I. W. , Wynne D. I. , Molina A. 
Published: March 2020

6597 Background: Lumiliximab, an anti-CD23 monoclonal antibody, had pharmacologic activity and an outstanding safety profile in a recently completed phase 1, single-agent study. Based on evidence of clinical activity, favorable safety profile, and preclinical data suggesting synergy with both fludarabine and rituximab, we initiated a combination study of lumiliximab with FCR in previously treated patients. Methods: Patients ≥18 years of age with relapsed CD23+ B-cell CLL were eligible for this open-label, dose-escalation, phase 1/2 study. Sample size was planned for ≤37 patients. Patients received either 375 mg/m2 or 500 mg/m2 of lumiliximab in combination with each 28-day cycle of FCR for 6 cycles. Primary objectives were to determine the safety profile, recommended phase 2 dose, and clinical activity of lumiliximab with FCR. Results: Accrual began in June 2004; 30 of the 31 patients were enrolled by December 2005; data are available for 28 patients. No dose-limiting toxicity was noted in the phase 1 component (375 mg/m2 dose, n=3, and 500 mg/m2 dose, n=6) and 500 mg/m2 was chosen for the phase 2 dose. All enrolled patients had progressive, symptomatic CLL as defined by NCI criteria, median 2 prior treatments (range, 1 to 9), median age 58, 64% males, 96% WHO performance status of ≤1. Seventeen patients experienced CTC Grade 3 or 4 adverse events (hematologic toxicity typically associated with FCR). Sixteen patients completed ≥3 cycles of treatment and were evaluated for response using NCI-WG criteria: 7 (44%) patients with confirmed complete responses (CRs); 1 with unconfirmed CR (pending marrow confirmation), 3 with partial responses (PRs), 4 with PRs awaiting confirmation, and 1 with disease progression. Twelve patients are not yet evaluable for response. Conclusions: Lumiliximab in combination with FCR is well tolerated and may enhance the activity of FCR for treatment of patients with progressive CLL after prior therapy. [Table: see text]
Phase II study of talabostat and rituximab in fludarabine/rituximab-resistant or refractory patients with CLL
Authors: Khan K. D. , O’Brien S. , Rai K. R. , Brown J. R. , Abboud C. , Hurd D. D. , Conkling P. , Yang Z. , Haltom E. J. , Uprichard M. J. 
Published: March 2020

6598 Background: Talabostat (TAL) is an orally administered small molecule inhibitor of dipeptidyl peptidases such as CD26 and fibroblast activation protein (FAP) in bone marrow, lymph nodes, and stroma of solid tumors, and TAL induces cytokine and chemokines in lymph nodes and spleen. TAL enhances the activity of rituximab (RTX) in a mouse model of lymphoma. This study evaluates the efficacy of TAL + RTX in patients with advanced CLL who failed fludarabine (FLU) and/or RTX. Methods: Single-arm, open-label study of RTX 375mg/m2 weekly × 4 weeks, and TAL-300mcg BID for 6 days following each RTX infusion for a tx course of 28 days. Additional courses permitted depending on tolerability. Eligibility criteria include ECOG PS 0–2, CD20+ B-CLL, Rai Stage III/IV or Rai I/II with marked lymphadenopathy, no CNS metastases, and primary resistance or PD following FLU and/or RTX. Primary endpoint is response rate per NCI-WG criteria. Secondary endpoints include response duration, PFS, and survival. Results: 40 patients (32 men, 8 women), median age 64.0 (range 42–83) have entered the study. Most (85%) are caucasian, and 78% of patients are Rai Stage IV. Mean serum B2 microglobulin is 6.5mg/L. The median number of prior regimens is 4 (range 1 to 10); 78% of patients received prior RTX and 33% prior alemtuzumab. Partial response (PR) has been reported in 8/36 evaluable patients (22%), 6 of whom had failed RTX; 3 of these patients had also failed alemtuzumab. Response duration currently ranges from 2 to 10 months (median 5.0 months). Most toxicities are Grade 1 or 2, and include nausea, fever (28% each), and edema (25%). Fever with associated Grade 3 or 4 neutropenia is reported in 2 and 1 patient, respectively. Other Grade 3 AEs include dyspnea (n=3), fatigue (n=2), and aspergillus pneumonia and a dermal fungal infection in 1 patient each. Grade 4 AEs are thrombocytopenia, hypoglycemia, and pulmonary embolism in 1 patient each. 4 patients died due to CLL (2 due to PD) or related complications (PE or MRSA pneumonia, 1 each). Conclusions: TAL + RTX shows promising activity in CLL patients with advanced disease who failed FLU and/or RTX. AEs are similar to those seen with RTX, with the exception of edema in 25% of patients. Updated results, including median PFS and survival will be presented at the annual meeting. [Table: see text]
Immune anemias in patients with chronic lymphocytic leukemia treated with chemoimmunotherapy regimen of fludarabine, cyclophosphamide and rituximab as initial therapy
Authors: Borthakur G. , O’Brien S. , Wierda W. G. , Thomas D. A. , Cortes J. E. , Kantarjian H. , Lerner S. , Keating M. J. 
Published: March 2020

6604 Background: Auto-immune hemolytic anemia (AIHA) has been reported with the use of fludarabine in the treatment of chronic lymphocytic leukemia (CLL). Since rituximab has been used to treat AIHA, it was anicipated that rituximab might reduce the incidence of AIHA when combined with fludarabine to treat CLL. We analyzed the incidence of immune anemias in 300 patients (pts) with CLL treated with fludarabine, cyclophosphamide and rituximab (FCR) as initial therapy. Methods: Diagnosis of AIHA was based on clinical evidence of hemolysis (elevated indirect bilirubin, reticulocyte count, lactate dehydrogenase) combined with positive Coomb’s test and/or low haptoglobin level. Pure red cell aplasia (PRCA) was diagnosed based on absence of erythroid precursors in bone marrow aspirate and/or biopsy. Results: 29 of 300 (9.5%) pts with CLL treated on a single-arm study of FCR showed evidence of immune anemias (age range18 to 86 years,median 62 years; 24 male and 5 female). 24 pts had AIHA, 3 had PRCA and 2 pts had positive Coomb’s test only (hemoglobin>10 gm/dL). Higher beta2-microglobin and bone marrow lymphocyte percentage were associated with higher risk of developing AIHA in multivariate analysis. Immune anemia was present in 9 pts prior to FCR treatment, developed in 15 on FCR and in 5 after completion of FCR (1 month to 4 years later). AIHA was detected after a median of 4 cycles (range 1 to 6) in pts who developed it while on therapy. Coomb’s test was positive in 14 pts and negative in 15. Haptoglobin levels were low in 16, normal in 10 and not measured in 3 pts. Coomb’s test was negative in 14 of 16 pts with AIHA and low haptoglobin levels. 9 pts were treated with oral prednisone. Others treatments included cyclosporine, intravenous immunoglobulin, rituximab and splenectomy. 3 of 9 pts who had AIHA prior to starting FCR had sustained correction of anemia with FCR treatment alone. 2 pts had inadequate response to treatment of immune anemia; 1 of them developed myelodysplastic syndrome. Conclusions: The incidence of immune anemias in pts treated with FCR is comparable to other series. Low haptoglobin levels in appropriate clinical context can help to establish the diagnosis of AIHA in the face of negative Coomb’s test. [Table: see text]
SPC2996—A Bcl-2 RNA antagonist being studied in chronic lymphocytic leukemia
Authors: Hansen B. J. , Westergaard M. , Frieden M. , Hansen H. F. , Kjaerulff L. S. , Thrue C. A. , Wissenbach M. H. , Dalby L. W. , Kearney P. , Oerum H. 
Published: March 2020

6610 Background: Bcl-2 protein is a critical regulator of programmed cell death and contributes to apoptosis resistance in many cancers, including chronic lymphocytic leukemia (CLL). The novel RNA antagonist, SPC2996, is a 16-mer oligonucleotide incorporating Locked Nucleic Acid (LNA) with unique high-affinity binding to Bcl-2 mRNA and enhanced resistance to nuclease digestion. We report the pharmacological properties of this new investigational drug and are currently evaluating clinical safety and initial efficacy in CLL patients. Methods: In vitro, the effects of SPC2996 on Bcl-2 mRNA and protein levels and phenotypic responses were evaluated in human cancer cell lines by quantitative polymerase chain reaction, Western blotting and biochemical assays. In vivo bio-distribution in rodents was assessed with tritium-labelled SPC2996 given intravenously. Anti-tumour efficacy was assessed in human prostate (PC3) and melanoma (518A2 and 607B) tumour cell line xenografts in immunodeficient mice. Preclinical toxicology and safety pharmacology were evaluated after intravenous treatment in rats and primates and tissue uptake measured by HPLC. Results: In vitro, low nanomolar concentrations of SPC2996 substantially reduced intracellular levels of Bcl-2 mRNA and protein and induced apoptosis in a dose-dependant manner. In vivo, systemically administered SPC2996 accumulated in liver, kidney, bone marrow, and lymph nodes. Repeated dosing at 10mg/kg inhibited growth of human xenografts in mice. Substantial down-regulation of Bcl-2 mRNA was observed in primate tissues after intravenous administration of SPC2996 at 3 and 6mg/kg. No acute toxicity was encountered on systemic bolus dosing of substantially higher doses in primates. An international phase I/II dose-escalating study in 42 patients with relapsed or refractory CLL is currently recruiting in the USA, UK, Denmark and France. Conclusions: SPC2996 is the first member of a new generation of specific RNA antagonising oligonucleotides with enhanced properties derived from LNA. SPC2996 has the potential to lower Bcl-2 levels in CLL cells without significant toxicity and with less frequent dosing than required with previous drugs. [Table: see text]
High efficiency transduction of chronic lymphocytic leukemia with adenovirus type 35
Authors: Hedjran F. , Whitacre D. , Kipps T. , Reid T. R. 
Published: March 2020

6612 Background: Adenovirus (Ad) vectors have been used extensively in genetic manipulation of cultured cells and gene therapy, with the group C Ad serotypes 2 and 5 being most widely used. The group C viruses have been shown to infect target cells in a two-step process. There is an initial high-affinity step in which Ad fiber protein binds to the the coxsackie/adenovirus receptor (CAR), increasing the local concentration of the virus at the cell surface. In the second step, the Ad penton base protein binds to integrins on the target cell surface and the virus is internalized. CLL cells to not express CAR and so require a very high concentration of Ad5 for transduction. Group B adenoviruses differ from other groups, having been shown to require CD46 (the measles virus receptor) to infect target cells. We are investigating Ad35 for use as a gene therapy vector and a laboratory tool for manipulating CLL cells ex vivo. Methods: We used a modified viral vector (Shayakhmetov et al., 2000 J Virol (74) pp 2567–83) with first 64 amino acids from the Ad5 fiber fused to the last 279 amino acids from the Ad35 fiber substituted into the Ad5 fiber ORF. This vector was used to assess the relative efficiency of the chimeric Ad5/35 vector compared to wild-type Ad5. Results: Primary CLL cells were transduced by the standard Ad5 and chimeric Ad5F35 vectors. Ad5F35 vector is about 100-fold more potent at transducing CLL cells compared to an Ad5 vector. Twelve CLL, PBMC and HeLa samples were tested for CD46 expression by flow cytometry. Each CLL population was 90–99% bright for CD46. Primary CLL cells and normal PBMCs were transduced by Ad5F35-GFP at an MOI of 10. The CLL cells are more transducible than normal PBMCs (p<0.05). This difference in transducibility is not a result of low CD46 expression. Conclusions: Adenovirus Type 35 is a promising vector for use in delivering gene therapy agents to CLL cells at significantly lower viral doses and more favorable therapeutic index compared with traditional Ad5 vectors. No significant financial relationships to disclose.
Cardiovascular risk profile of breast cancer patients treated with anthracycline-taxane containing adjuvant chemotherapy and/or trastuzumab
Authors: Jones L. W. , Haykowsky M. , Peddle C. J. , Joy A. A. , Pituskin E. N. , Tkachuk L. M. , Courneya K. S. , Slamon D. J. , Mackey J. R. 
Published: March 2020

666 Background: With improving longevity, post-treatment cardiovascular disorders will become an increasingly important indicator of competing mortality in early-stage breast cancer. As such, we conducted a pilot study to comprehensively evaluate the CVD profile of a subset of early-stage breast cancer patients treated with adjuvant taxane-anthracycline containing chemotherapy and/or trastuzumab. Methods: Twenty-six breast cancer patients (mean 20 months post chemotherapy) who participated in Breast Cancer International Research Group 006 clinical trial and 10 healthy age-matched women were studied. We measured 14 metabolic and vascular established CVD risk factors, BMI, VO2peak and left ventricular systolic function. All assessments were performed within a 14-day period. Results: Cardiac abnormalities were suggested by LVEF <50% in 10% of patients, LVEF remained >10% below pre-treatment values in 38% while 50% presented with resting sinus tachycardia. BNP was significantly elevated in 40% and was correlated with LVEF (r = -0.72, p=<.001). For the majority of CVD risk factors, similar proportions of patients and controls (35% to 60%) were classified as ‘undesirable.’ A significantly higher proportion of patients were classified with low VO2peak (46% vs. 0%, p<0.01), being overweight/obese (72% vs. 50%, p<0.05), and having resting sinus tachycardia (50% vs. 0%, p<0.01) compared with controls. VO2peak and BMI were correlated with CV risk factors (r = -0.64 to 0.63, p<0.05; r = -0.63 to 0.67, p<0.05, respectively). Exploratory analyses revealed several differences between CVD risk factors based on chemotherapy regimen. Conclusions: Breast cancer survivors treated with adjuvant chemotherapy are at a higher risk of developing late-occurring CVD than age matched controls due to direct and indirect treatment-related toxicity. No significant financial relationships to disclose.
10-year follow-up of the efficacy of clodronate on bone mineral density (BMD) in early stage breast cancer
Authors: Saarto T. , Vehmanen L. , Blomqvist C. , Elomaa I. 
Published: March 2020

676 Background: We have previously reported that clodronate prevents bone loss in breast cancer patients (JCO 1997;15:1341, BJC 1997;75(4):602 and EJC 2001;37:2373). Here we report the 10-year follow-up data. Methods: 268 pre- (PRE) and postmenopausal (POST) node positive breast cancer patients were randomized to clodronate (CL), orally 1.6 g daily, or control groups for 3 years. PRE were treated with adjuvant chemotherapy and POST with antiestrogens (AE), tamoxifen 20 mg or toremifene 60 mg, for 3 years. The BMD of the lumbar vertebrae L1–4 (BMDLS) and femoral neck (BMDFN) was measured before the treatment and at 1, 2, 3, 5 and 10 years. 93 patients were eligible for 10-year analyses: 53 PRE and 40 POST. 132 patients had metastatic disease or died and 39 were either lost to follow-up or had to be excluded because having diseases or medications that influences bone metabolism. Results: PRE: BMDLS decreased -12.4% in the control and −8.7% in the CL group in 10 years: from 0 to 3 years −6.9 % vs. −4.2% and from 3 to 10 years −5.5% and −4.5%, respectively. BMDFN decreased −8.8% and −7.2%: from 0 to 3 years −2.9% vs. −2.6% and from 3 to 10 years −5.9% vs. −4.6%, respectively. POST: BMDLS decreased −3.0% in the AE and −1.7% in the AE+CL group in 10 years: from 0 to 3 years −1.5% vs. + 1.2% and from 3 to 10 years −1.5% vs. −2.9%, respectively. BMDFN decreased −7.7% and −6.0%: from 0 to 3 years −0.1% vs. +1.9% and from 3 to 10 years −7.6% vs. −7.9%, respectively. These differences do not reach statistical significance. At 10-years 18 patients had osteoporosis in LS and 15 in FN. Only 4 patients who had osteoporosis at 10 years had normal BMD before the therapy. Conclusions: As reported previously, clodronate prevents the bone loss during treatment in pre- and postmenopausal women. This beneficial effect seems to be maintained at least for 7 years after treatment termination in premenopausal. In postmenopausal women the effect seems to diminish within time. Due to small numbers of patients these differences are no longer statistically significant. Patients at risk of developing osteoporosis are among those who has pretreatment osteopenia i.e. baseline BMD measurement has predictive value. No significant financial relationships to disclose.
Alternative measures predicting clinical benefit in advanced non-small cell lung cancer (NSCLC) from Southwest Oncology Group (SWOG) randomized trials: Implications for clinical trial design
Authors: Lara P. N. , Redman M. W. , Kelly K. , Edelman M. J. , Williamson S. K. , Crowley J. J. , Gandara D. R. 
Published: March 2020

7006 Background: Although objective response (CR/PR) & overall survival (OS) are typical efficacy measures for new treatments in advanced stage NSCLC, each has its limitations; e.g., some patients (pts) have no measurable disease or achieve only disease stabilization (SD) while OS is influenced by effective salvage therapies. Alternative methods of determining “clinical benefit” are needed. Methods: Pooled data from 984 pts entered onto 3 randomized SWOG trials of platinum-based chemotherapy (S9509: carbo/paclitaxel (CP) vs. cisplatin/vinorelbine; S9806: carbo/gemcitabine ->P or cisplatin/vinorelbine -> docetaxel; & S0003: CP ± tirapazamine) were analyzed for survival using the Landmark method. Results: Pt characteristics: median age = 62 years; male sex = 647 pts (66%); stage IV = 826 pts (84%); weight loss ≥ 5% = 404 pts (42%); performance status (PS) 0/≥1 = 340 (36%)/606 (64%). Tumor response was seen in 260 pts (26%). Median time to response (TTR), time to progression (TTP) & OS were 1.9, 4.3 and 8.9 months. PS > 0 & weight loss were associated with worse survival (hazard ratio [HR] 1.38 and 1.28; p 0 (HR 0.75, p=0.03) and weight loss (HR 0.74, p = 0.03). Shorter TTP was associated with PS>0, stage IV, & weight loss (HR 1.34, 1.08, 1.34 and p = 0.0001, 0.01, < 0.00001). Of 886 pts alive at month 2 (time of initial response assessment following 2 treatment cycles), 62% had SD while19% had CR/PR for a disease control rate (CR+PR+SD, aka DCR) of 81%; 18% had progressive disease (PD). Although CR/PR at month 2 was associated with longer survival (HR 0.62, p<0.001), DCR had a much stronger association (HR 0.38, p<0.0001). Inclusion of DCR in the regression model improved its fit (p<0.00001), reducing the significance of CR/PR as an independent variable. Median survival among pts with CR/PR, SD, & PD were 13.5, 8.4, & 3.1 months. Conclusions: 1)DCR at month 2 is a more powerful predictor of subsequent survival than the CR/PR rate. 2) If validated, this “early look” statistical measure could enhance efficacy assessment. 3) These findings may have broad implications for the design of future trials in advanced NSCLC & will be prospectively tested in SWOG. No significant financial relationships to disclose.
Adjuvant chemotherapy in elderly patients: An analysis of National Cancer Institute of Canada Clinical Trials Group and Intergroup BR.10
Authors: Pepe C. , Hasan B. , Winton T. , Seymour L. , Pater J. , Livingston R. , Johnson D. , Rigas J. , Ding K. , Shepherd F. 
Published: March 2020

7009 Background: Recent trials have shown significant survival benefit from adjuvant chemotherapy after resection of NSCLC. Whether elderly patients tolerate platinum-based adjuvant chemotherapy and derive the same survival advantage is unknown. This retrospective study evaluated the influence of age on survival, chemotherapy delivery and toxicity in NCIC CTG BR.10. Methods: Pretreatment characteristics and survival benefit from treatment were compared for patients ≤65 & >65. Chemotherapy delivery and toxicity were compared for 213 treated patients. Results: There were 327 young and 155 elderly patients. Baseline prognostic factors by age were similar with the exception of histology (adeno 58% young, 43% elderly; squamous 32% young, 49% elderly; p=0.001) and PS (PS 0 53% young, 41% elderly; p=0.01). Overall survival by age showed a trend favoring the young in univariate (HR 0.77, CI 0.58–1.04, p=0.084) and multivariate analyses (HR 0.75, CI 0.56–1.01, p=0.059). Patients >75 years had significantly shorter survival than those aged 66–74 (HR 1.95, CI 1.11–3.41, p=0.02). Overall survival for patients >65 was significantly better with chemotherapy v observation (HR 0.61, CI 0.38–0.98, p=0.04). Chemotherapy administration and toxicity were evaluated in 63 elderly and 150 young patients. Mean dose intensities of vinorelbine (V) and cisplatin (C) were 13.2 and 18.0 in the young and 9.9 and 14.1 in the elderly (V p=0.0004; C p=0.001). The elderly received significantly fewer doses of V (p=0.014) and C (p=0.006). Fewer elderly patients completed treatment and more refused treatment compared to the young (p=0.03). There were no significant differences in toxicities, G-CSF use or hospitalization by age group, except for myalgias and mood alteration (more frequent among the young). Six of 126 deaths (4.8%) in the young were from non-malignant causes v 12 of 71 (16.9%) in the elderly (p=0.008). Conclusions: In spite of receiving less chemotherapy than young patients, adjuvant chemotherapy improves overall survival in patients aged >65 with acceptable toxicity. Adjuvant chemotherapy should not be withheld from elderly patients, although patients >75 years of age require further study. No significant financial relationships to disclose.
Concurrent chemotherapy plus cetuximab or chemotherapy followed by cetuximab in advanced non-small cell lung cancer (NSCLC): A randomized phase II selectional trial SWOG 0342
Authors: Kelly K. , Herbst R. S. , Crowley J. J. , McCoy J. , Atkins J. N. , Lara P. N. , Dakhil S. R. , Albain K. S. , Kim E. S. , Gandara D. R. 
Published: March 2020

7015 Background: Randomized clinical trials have failed to show a survival benefit for small molecule EGFR tyrosine kinase inhibitors plus chemotherapy in patients with advanced NSCLC. In contrast, pilot trials of EGFR targeted antibodies plus chemotherapy have suggested enhanced anti-tumor activity. This large randomized phase II trial was designed to select a cetuximab -chemotherapy regimen for future evaluation in a phase III setting. Methods: Untreated patients (pts) with stage IIIB (by pleural effusion) or IV (without brain metastases) NSCLC, with a performance status of 0–1 and adequate organ function were randomized to received paclitaxel (P) 225 mg/m2 and carboplatin (Cb) AUC=6 every 3 weeks plus cetuximab (C) 400 mg/m2 loading dose followed by 250 mg/m2, weekly for 4 cycles followed by maintenance C or the same doses of PCb for 4 cycles followed by C. C was continued until disease progression or 1 year of therapy. The primary endpoint was overall survival; the statistical design required a median survival of ≥ 10 months for a regimen to be selected for subsequent phase III trial evaluation. The probability of correctly choosing the superior arm is 91% when the true hazard ratio is 1.3. Results: From July 2004 to June 2005, 225 eligible pts were enrolled into the study. Preliminary results are described below: Conclusions: At the time of this analysis, efficacy and toxicity were similar in the two treatment arms; both regimens were well tolerated. Assuming these results are sustained, the concurrent regimen of PCb + cetuximab has met the criteria for continued evaluation. A phase II trial of PCb + cetuximab + bevacizumab (B) is in development in anticipation of a phase III trial testing PCbB ± cetuximab. Molecular correlative studies of the EGFR signaling pathway are ongoing. [Table: see text] [Table: see text]