bluuebunny/crossref_metadata_2025 huggingface dataset:
Personalized end-of-life care: Associations between patient preferences and treatment intensity near death
Authors: Wright A. A. , Mack J. W. , Trice E. D. , Balboni T. A. , Block S. D. , Prigerson H. G.
Published: August 2020

6516

Background: Medical treatment at the end-of-life (EOL) should be responsive to patient values, but research shows it may instead reflect the regional supply of health services and/or physician practice patterns. We sought to determine whether patients' preferences are associated with EOL medical care and place of death. Methods: Coping with Cancer is an NCI/NIMH-funded, multi-site prospective, longitudinal cohort study of patients with advanced cancer, conducted from September 2002-February 2008. Analyses were based upon 317 deceased patients interviewed at baseline and followed until death, a median of 4.4 months later. EOL care was obtained from chart review, and regressed on patients' baseline preferences for life-extending therapy. Analyses were adjusted for significant confounds; i.e., socio-demographics, cancer type, patient denial, EOL discussion, do-not resuscitate (DNR) order, and treatment center. A sub-analysis examined EOL care within three different medical centers to determine whether patients' preferences and treatment intensity varied by region/practice type. Results: 90 of 317 patients (28.4%) reported a desire to receive life-extending therapy at baseline. Patients' preferences did not differ by proximity to death or performance status, but patients who preferred life-extending therapy had higher rates of denial (75.0% vs. 55.6%, p = 0.002) and were less likely to report having an EOL conversation (24.4% vs. 48.9%, p = 0.0002) or a DNR order (24.4% vs. 48.9%, p < 0.0001). These patients were more likely to undergo ICU admission (AOR 4.6, 95% CI 1.9–11.1) and ventilation (AOR 3.0, 95% CI 1.2–7.3), and die in an ICU (AOR 6.7, 95% CI 2.4–18.7) instead of at home (AOR 0.6, 95% CI 0.3–0.9). A sub-analysis of patients treated at Yale, Parkland, and New Hampshire Oncology-Hematology confirmed that patients' preference for life-extending treatment was associated with higher rates of ICU admission in all three centers. Conclusions: Advanced cancer patients' treatment preferences may play a more important role in determining the intensity of medical care at the EOL than previously recognized. Future research should determine whether these preferences are informed and thus reflect patients' true values for EOL care.

No significant financial relationships to disclose.
Association between lung cancer survival and pessimistic explanatory style
Authors: Novotny P. J. , Colligan R. , Szydlo D. , Clark M. , Rausch S. , Wampfler J. , Sloan J. A. , Yang P.
Published: August 2020

6518

Background: Several studies have demonstrated the importance of pessimism in cardiovascular disease. However, this construct has not been well explored in oncology. Methods: This study examined the survival time of 534 adult who were diagnosed with lung cancer. These patients had completed the Minnesota Multiphasic Personality Inventory (MMPI) approximately 18.2 years prior to their lung cancer diagnosis. MMPI Optimism-Pessimism (PSM) scores were divided into high (60 or more) and low scores (less than 60), and log-rank tests and Kaplan-Meier curves were used to determine survival differences. Multivariate Cox models were used for assessing prognostic values of pessimism along with other known predictors for survival outcome. Results: At the time of diagnosis, patients were on average 67 years old, 48% were female, 85% had non-small cell lung cancer (NSCLC), 15% had small cell lung cancer (SCLC), 30% were stage I, 4% were stage II, 31% were stage III/Limited, and 35% were stage IV/Extensive. Patients who exhibited a non-pessimistic explanatory style survived approximately six months longer than patients classified as pessimists. Pessimists have significantly worse survival rates even after adjusting for other known prognostic variables. Conclusions: Among lung cancer patients, having a pessimistic explanatory style was related to surviving on average six months less compared to patients with a non-pessimistic explanatory style.

[Table: see text]

No significant financial relationships to disclose.
Quality of life (QOL) with sunitinib versus interferon-alfa (IFN-α) as first-line therapy in patients with metastatic renal cell carcinoma (mRCC): Final results
Authors: Cella D. , Michaelson M. D. , Cappelleri J. C. , Bushmakin A. G. , Charbonneau C. , Kim S. T. , Li J. Z. , Motzer R. J.
Published: August 2020

6529

Background: In an international, randomized phase 3 trial (Figlin et al, ASCO. 2008), sunitinib showed superior progression-free survival (the primary endpoint) and objective response rate over IFN-α (11 vs. 5 mo and 47% vs. 12%, respectively; p < 0.000001) as first-line mRCC therapy, with a median overall survival of more than 2 years. Here, we report the final health-related QOL results from this trial. Methods: 750 treatment-naïve mRCC patients were randomized 1:1 to receive sunitinib 50 mg orally once-daily in recurring cycles of 4 weeks on drug and 2 weeks off or IFN-α 9 MU subcutaneously thrice-weekly. QOL was measured by the Functional Assessment of Cancer Therapy-General (FACT-G), which has 4 subscales, the FACT-Kidney Symptom Index-15 item (FKSI-15), which includes a Disease-Related Symptoms (FKSI-DRS) subscale, and the EQ-5D questionnaire's utility index (EQ-5D Index) and visual analog scale (EQ-VAS). The primary QOL endpoint was FKSI-DRS. Higher scores indicated better outcomes. Patients completed questionnaires on days 1 and 28 of each cycle. Data were analyzed for the intent-to-treat population using mixed-effects models (MM), supplemented with pattern-mixture models (PMM). We also compared QOL of patients in the United States (US) with patients in the European Union (EU; France, Germany, Italy, Poland, Spain and United Kingdom). Results: Patients on sunitinib reported better FKSI-15 and FKSI-DRS scores than those on IFN-α, with a significant difference in the overall means across cycles (4.06 and 2.36, respectively; p < 0.0001; MM). Similarly, differences in means for FACT-G (and all subscales), EQ-5D Index, and EQ-VAS all significantly favored sunitinib (p < 0.05). Based on pre-set, required minimum score differences, between-treatment differences in the mean scores were clinically meaningful for FKSI-15, FKSI-DRS, FACT-G, and the FACT-G functional well-being subscale. Between-treatment differences were similar for both the US and EU populations. Across all analyses, results from PMM were similar to those from MM. Conclusions: Sunitinib provides superior QOL over IFN-α, in addition to superior efficacy, as first-line mRCC therapy.

[Table: see text]
Comorbidities in Medicare patients with and without breast cancer
Authors: Danese M. , O'Malley C. , Kim D. , Lindquist K. , Gleeson M. , Griffiths R. , Wyszynski D.
Published: August 2020

6533

Background: Patients with comorbidities may be at increased risk for adverse effects from treatment. We used the SEER-Medicare linked dataset to see if patients with breast cancer had a higher prevalence and subsequent incidence (after diagnosis) of comorbid conditions compared to patients without breast cancer. Methods: We selected all women with breast cancer across all stages, diagnosed from 1998–2002 with follow up through 2005. Patients were at least 66 years old with at least 12 months of non-HMO Medicare coverage prior to diagnosis. One non-cancer patient was matched to each breast cancer patient on sex and county of residence, and was assigned the cancer diagnosis date of her matched subject. Comorbidities were identified through groups of comorbidity-specific International Classification of Diseases, 9th revision (ICD-9) codes used in Medicare claims. Claims only for diagnostic testing were excluded, and outpatient-based diagnosis codes were required to be present at least twice with at least 30 days in between to be included. Prevalence at baseline (%) and incidence rates (per 1,000 person-years) and their 95% confidence intervals were calculated for each comorbidity. Rates in the non-cancer group were standardized to the age and race distribution of the breast cancer group to control for potential confounding. Results: 52,977 cancer patients met the inclusion criteria. See table for prevalence and incidence estimates. Conclusions: Physicians should be aware that patients with breast cancer have higher prevalence and subsequent incidence of these comorbidities compared to non-cancer subjects. These differences may be related to the diagnostic process, as well as to therapies used in cancer treatment.

[Table: see text]

[Table: see text]
Preliminary evaluation of quality of psychosocial care indicators: Results from the Quality Oncology Practice Initiative (QOPI)
Authors: Jacobsen P. B. , Kadlubek P. , Neuss M. N.
Published: August 2020

6534

Background: To gauge the opportunity for improvements in psychosocial care, ASCO's QOPI program tested two new quality indicators in 2008. Similar to other QOPI indicators, these were presented as questions to be answered (yes/no) based on review of patient records: 1) was current emotional well-being assessed within one month of a first visit with a medical oncologist; and 2) was action taken for a patient identified as having a problem with emotional well-being. In addition to examining variability on these indicators, performance of assessments of pain (another QOPI indicator) and emotional well-being were directly compared. Methods: Practices participating in the Spring 2008 QOPI data collection round were included if they reported results for psychosocial care indicators with at least 40 patients. This criterion was met by 96 practices, which provided information on 9,045 patient records. Results: Across practices, rates of assessment of emotional well-being ranged from 0–100% (Mdn = 78%), with 27% of practices achieving rates < 50%. In contrast, rates of assessment of pain ranged from 12–100% (Mdn = 88%), with 9% of practices achieving rates < 50%. Mean rates of assessment of pain (83%) and emotional well-being (70%) differed significantly across practices (t = 4.61, p < 0.001). Problems in emotional well-being were documented in 10% of records. Among these records, rates of documentation of action taken ranged from 0–100% (Mdn = 73%, M = 72%), with 26% of practices achieving rates < 50%. Conclusions: Wide variability in the documentation of psychosocial care was evident among the practices surveyed, with at least 26% showing substantial opportunity for improvement (i.e., performance < 50%). Additional findings suggest that, to date, efforts to promote routine symptom assessment have been more successful for pain than for emotional well being.

No significant financial relationships to disclose.
Hospital characteristics associated with surgery for non-small cell lung cancer
Authors: Virgo K. S. , Fedewa S. A. , Chen A. Y. , Stewart A. K. , Flanders W. D. , Ward E. M.
Published: August 2020

6543

Background: Previous research suggests that black patients are less likely to undergo curative-intent surgery for early stage non-small cell lung cancer (NSCLC) compared to whites, holding all else constant. Among Medicare beneficiaries 65 and older, the likelihood of patients undergoing surgery is significantly reduced in hospitals with racial compositions of > 30% black patients after controlling for hospital and patient characteristics. This study analyzes whether hospital racial composition is associated with curative-intent surgery among early stage NSCLC patients of all ages. Methods: All adult patients ages 19–104 diagnosed with an invasive initial primary early stage (TNM I-II) NSCLC during 2003–2005 were selected from the National Cancer Data Base (NCDB). Facility characteristics were extracted from the NCDB and American College of Surgeons (ACoS) Commission on Cancer (CoC) Facility Information Profile System (FIPS). Hospital racial composition of lung cancer patients, operationalized as percent black, was initially divided into tertiles; sensitivity analyses used dichotomous definitions. Generalized estimating equations with a logistic model were used to control for clustering by facility. Results: Of 52,853 evaluable patients seen at CoC-approved hospitals, blacks were primarily (74%) seen at hospitals with a racial composition of > 11% black patients. Hispanics (72%), non-Hispanic whites (69%), and Asians or other (72%) were primarily seen at hospitals with < 11% black patients. In sensitivity analyses, irrespective of the cutpoint used to classify hospitals by racial composition of black patients (10, 20, or 30%), black patients seen at hospitals with a high black racial composition were significantly less likely to undergo curative-intent surgery than black patients seen at hospitals with a lower black racial composition. After controlling for patient characteristics in multivariate models, however, high black racial composition at the facility level was no longer significant. Conclusions: Hospital racial composition (% black) was not predictive of reduced likelihood of curative-intent surgery among patients > 18 years of age with NSCLC. Patient-level predictors accounted for the majority of the variation in likelihood of curative-intent surgery.

No significant financial relationships to disclose.
Clinical benefit in oncology trials: Is this a patient-centered or tumor-centered endpoint?
Authors: Ohorodnyk P. , Eisenhauer E. A. , Booth C. M.
Published: August 2020

6564

Background: Clinical benefit (CB) was first successfully used as an endpoint in 1997 in the pivotal study of gemcitabine in advanced pancreas cancer. In the trial by Burris et al (J Clin Oncol. 1997) CB was a composite measure of pain, performance status, and weight. Here we describe how CB has been used in oncology trials since that time. Methods: We performed an electronic search ( www.jco.org ) for reports of all clinical trials (phase I, II, III) published in the Journal of Clinical Oncology 1997–2008 citing ‘clinical benefit.‘ Eligible trials were those reporting clinical benefit as an endpoint. Details related to study methodology, sponsorship, and endpoints were abstracted. Use of CB was classified as patient-centered if it referred to improvement in the clinical parameters used by Burris et al or in other disease-related symptoms. CB was classified as tumor-centered if it related to objective tumor criteria for partial/complete response and/or stable disease. Descriptive statistics were used to summarize findings and the chi-square test used to compare proportions. Results: 71 trials reporting CB as an endpoint were identified: 37 in breast, 8 in pancreas, and 26 in other cancers. The definition of CB was patient-centered in 21 trials (30%) and tumor-centered in 50 trials (70%). Only 20% (14/71) of trials (including all 8 pancreas studies) used the original Burris definition. In the second half of the study period there was an increase in the number of trials using CB as an endpoint (17 to 54 trials) and in the proportion of trials with a tumor-centered definition (10/17, 59% to 41/54, 76%, p = 0.09). Study variables associated with the use of a tumor-centered definition include: disease site (breast 35/37, 95%; all others 16/34, 47%, p < 0.001) and intervention (hormone or targeted agent 38/40, 95%; chemotherapy 13/31, 42%, p < 0.001). There was no association with sponsorship (industry 41/56, 73%; non-industry 10/15, 67%, p = 0.86) or phase of trial (phase I/II 36/48, 75%; phase III 15/23, 65%, p = 0.56). Conclusions: Despite its initial definition, clinical benefit is often used to describe objective tumor findings. Clinical trials should use endpoints in a consistent manner to enable clear communication between investigators, clinicians, and patients about the benefit of novel therapies.

No significant financial relationships to disclose.
Adjuvant hormone strategies in postmenopausal women with breast cancer: An economic evaluation based on the EBCTCG meta-analyses
Authors: Younis T. , Rayson D. , Skedgel C.
Published: August 2020

6574

Background: Meta-analyses conducted by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) demonstrated significant improvements in breast cancer (BC) outcomes associated with tamoxifen (TAM) and/or aromatase inhibitor (AI) therapy. We conducted an economic evaluation, based on these meta-analyses, to examine the cost-effectiveness (CE) of adjuvant TAM, sequential TAM-AI and upfront AI in post menopausal (PM) women with BC. Methods: A generic model was developed to calculate cumulative costs and quality adjusted life year gains (QALYG) over 25-year horizon in hypothetical cohorts of PM women with BC undergoing 5-year treatment with TAM alone, upfront AI, or sequential TAM-AI. We examined different cohorts with varying 10-year baseline recurrence risk (RR) without adjuvant hormonal treatments to reflect the natural spectrum of breast cancer disease encountered (low = 25%; average = 38%; high = 50%; very high = 75%). The efficacy outcomes were derived from the EBCTCG meta-analyses, with 10-year duration of benefit assumed for all strategies. Costs and utilities were derived from the literature, and local resources. The analysis took a direct payer perspective and reports costs in 2008 Cdn$. Costs and benefits were discounted at 3%. CE was based on the $50,000/QALY gained threshold. Adverse events were not included in the primary analysis. Sensitivity analyses were conducted. Results: Adjuvant hormonal treatments with TAM and/or AI are CE strategies in PM women with BC. The costs and QALYG associated with hormonal treatments were dependent on the baseline RR: CE estimates were more favorable in cohorts with higher as opposed to lower RR. The baseline RR also influenced the choice of the optimal economic strategy. Upfront AI was associated with higher costs and more QALY gains compared to TAM-AI. CE however was favorable in patients with average to very high RR and unfavorable in patients with low RR. Conclusions: Adjuvant treatments with TAM and/or AI are associated with favorable CE in PM women with BC. The optimal CE strategies, however, are dependent on the baseline RR without hormonal treatment. A risk-tailored hormonal treatment choice could optimize the overall health system efficiency.

[Table: see text]
Cost-effectiveness of predictive markers in breast cancer: An analysis from a Swiss perspective
Authors: Blank P. R. , Schwenkglenks M. , Pestalozzi B. C. , Moch H. , Szucs T. D.
Published: August 2020

6578

Background: Breast cancer has one of the highest cancer related death rates all over the world. New therapeutic agents like trastuzumab have yielded significant clinical benefits in human epidermal growth factor receptor 2 (HER-2) overexpressing tumors, but have also increased costs substantially. A cost-effectiveness analysis was performed to estimate the economic implications of testing HER-2-status in breast cancer patients. Methods: A Markov state transition model was used to assess the costs and effectiveness of a hypothetical cohort of 10,000 females at the age of 50 years. Probabilities for recurrence and cancer related death have been derived from published trials. The model was run life-long (i.e., for 50 years). Incremental costs were evaluated for diagnostic tests and treatments in both the HER-2 tested and the untested arm. Costs were estimated using data from a third party payer prospective in Switzerland. Results: Predictive testing with immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) accounted for €48 and €312, respectively. The costs for trastuzumab administration for a one year treatment summed up to €38,716 per patient. The life-long Markov model resulted in a total cost difference of €-17,774 in favor of the predictive test strategy. No difference in regard to the effectiveness was evident, yielding in 9 QALYs gained at the end of the modeling cycle for both strategies. The dominance of the testing regimen implied the analysis of the planned cost-effectiveness ratio being superfluous. The model showed robustness for variable variations in the deterministic sensitivity analysis. The probabilistic sensitivity analysis revealed no impact on parameter uncertainties of the model results. The position of the HER-2 testing group was never non dominant. Conclusions: Predictive tests for HER-2-status offer an economically favorable approach to identify patients deriving benefit from trastuzumab treatment. Over a life-long horizon, our model predicts confirms that the usage of HER-2 tests is the dominant strategy. The outcome was robust to changes in the model assumptions. Economically as well as clinically, using HER-2 testing is the preferred strategy in the direction to personalized cancer care.

No significant financial relationships to disclose.
An international comparison of barriers in opening oncology clinical trials
Authors: Wang-Gillam A. , Novello S. , Williams K. , Gao F. , Scagliotti G. V. , Govindan R.
Published: August 2020

6580

Background: Well designed clinical trials are critical to improve the outcomes of patients with cancer. There are significant barriers to accrue patients to clinical trials beginning with processes required to “open” a trial. This study aims to compare the procedures and time required to open thoracic oncology trials at a United States academic center to a similar center in Europe. Methods: A retrospective review was performed of all thoracic oncology therapeutic trials submitted for regulatory review between 2001–2008 at Washington University School of Medicine (WUSM) and the University of Torino, Italy (UT). A process map was drafted by both institutions to establish the order of required events. The timing data for each step was collected and analyzed for comparison. Results: A total of 137 therapeutic thoracic oncology trials were reviewed, 83 from WUSM and 54 from UT. Five major regulatory steps are required to open a trial in WUSM compared to three at UT. The median times to open a trial are 163 days (with inter-quartile range of 91 to 257 days) for WUSM and 122 days for UT (with inter-quartile range of 96 to 159 days) (p = 0.048). The median times for regulatory approval are 75 days (inter-quartile range, 26 to 131 days) for WUSC and 31 days (inter-quartile range, 10 to 67 days) for UT (p<0.0001), attributed to the additional requirement of Scientific Review Committee approval at WUSM prior to consideration by the Institutional Review Board (IRB), while regulatory approval is a single process at UT. However, the median time for contact approval process identified as the limiting step requiring a median of 115.1 (WUSM, inter-quartile range of 78 to 187) or 84 (UT, inter-quartile range of 44 to 124) days (p = 0.011). Conclusions: It takes additional steps and significantly longer time to open a therapeutic thoracic clinical trial at a representative U.S. site (WUSM) compared with a site in Europe (UT). As global trial collaboration increases, uniform strategies must be developed to shorten the administrative process, encouraging the creation of streamlined systems that enable centers to increase the number of agents under investigation.

No significant financial relationships to disclose.
Tracking clinical trial accrual strategies and barriers via a Web-based screening tool
Authors: Grubbs S. S. , Gonzalez M. , Krasna M. , Siegel R. , Bryant D. , Tschetter L. , Hayenga L. , Duggan B. , St. Germaine D. , Denicoff A.
Published: August 2020

6586

Background: The National Cancer Institute Community Cancer Centers Program (NCCCP) has developed a web based tracking tool to monitor screening of patients for clinical trial participation. The system is designed to collect data from multiple research sites throughout the geographically diverse group. The log blindly collects patient demographics, successful trial entry, and reasons for trial enrollment failure. Methods: Seven NCCCP sites utilized the log during the 60 day open accrual period for the Wake Forrest WFU 07–02–03 cancer control trial (chronic lymphocytic leukemia COLD- fX) in Novermber 2008 and December 2008. Results: 327 chronic lymphocytic leukemia patients were screened mostly by chart review. 162 (50%) were eligible for study entry. 45 (14%) entered the trial. 103 (31%) eligible patients declined entry. Of the 103, 72 (70%) did not wish to participate in research, 15 (15%) had travel constraints, 5 (5%) perceived excess toxicity, 9 (9%) gave no reason. 14 (3%) eligible had their physician decline entry. Overall, 28% of eligible patients entered the trial. 165 (50%) were trial ineligible. 82 (50%) for prior therapy, 30 (18%) for co morbid conditions, 10 (6%) missed an entry time requirement, 39 (24%) have incomplete data. Conclusions: The NCCCP trial screening log successfully captures real time clinical trial participation data from a diverse network of clinical trial sites. This data base will allow future analysis of individual clinical trial and site accrual barriers and empower strategies to increase trial participation.

No significant financial relationships to disclose.
International comparison of the quality of voluntary adverse event reports for cremophor-containing paclitaxel-associated anaphylaxis submitted to regulatory agencies in the United States, Europe, and Japan
Authors: Calhoun E. , Raisch D. , Luu H. , Carias E. , Irizarry L. , Fisher M. , Sartor O. , Bennett C.
Published: August 2020

6589

Background: Serious adverse drug events (sADEs) are a significant cause of morbidity and mortality. The FDA's MedWatch program is a voluntary adverse drug reporting program. In Europe and Japan, sADE reports are rarely reimbursed. We evaluated the quality of adverse events reporting in the US, Europe, and Japan for paclitaxel-associated anaphylaxis. Hypersensitivity reactions (presumably due to the diluent cremophor) occur in up to 42% of patients receiving paclitaxel (cremophor- containing paclitaxel was licensed in 1992, a cremophor-free paclitaxel was licensed in 2005). Methods: We reviewed reports of anaphylactic reactions to paclitaxel reported between 1997–2007 contained in the FDA Adverse Event Report System (AERS). Results: Of 171 unique case reports, 34% resulted in death. Cases that resulted in death were mostly incomplete in reporting descriptions of anaphylaxis symptoms and prophylaxis/therapy drug regimens in the US, Europe and Japan. (Table) The median duration between date of event and regulatory notification was 27, 55, and 18 days for the US, Europe, and Japan respectively. Conclusions: Overall, the quality of case reports of serious anaphylaxis reactions to cremophor-containing paclitaxel was poor in the US, Europe, and Japan, despite a substantial number of these reports being associated with death. Surprisingly, among the patients receiving prophylaxis with corticosteroids, anti-histamines, and/or H2-blockers, 36% of patients still died.

[Table: see text]

No significant financial relationships to disclose.
“Beating the bushes” to identify previously unreported cases of a rare and potentially fatal adverse drug reaction: Comparison of HIV-negative rituximab-associated progressive multifocal leucoencephalopathy (PML) cases obtained by the Research on Adverse Drug Events and Report (RADAR), the FDA, the manufacturer, and a literature review
Authors: Richey E. A. , Carson K. R. , Evens A. M. , Focosi D. , Bennett C. L.
Published: August 2020

6604

Background: PML is a rare and usually fatal viral reactivation syndrome. As of December 2008, notifications from the FDA and rituximab (R) manufacturers described 26 patients with R-associated PML. Potential risk factors for PML include chemotherapy, corticosteroids, and HIV-infection. The FDA and the manufacturer requested that clinicians report information on all potential cases of R-associated PML. In an independent pharmacovigilance effort, RADAR queried clinicians at academic lymphoma referral centers regarding possible unreported cases of R-associated PML. Methods: RADAR surveyed clinical lymphoma experts at 13 major academic centers and identified 21 previously unreported cases of R-associated PML. Quality of reports is compared to published case reports (n=15) and reports to the FDA and manufacturer of R (n= 20). Duplicate reports were identified based on age, sex, and underlying illness. The search period was from the first FDA approval granted for R in 1997 to December 31, 2008. Results: In this series, the case-fatality rate of R-associated PML was 90%. The estimated incidence is 1 PML case per 4,700 R-treated NHL patients (based on the number of cases in this report, manufacturer estimates of 1,560,000 total global R exposures, and an estimate of six R doses per patient). Conclusions: Clinicians at major academic referral centers assist independent pharmacovigilance efforts in part provided that the requests for information are brief (<20 minutes), patients and providers are assured confidentiality, and safety data is disseminated collaboratively as peer-reviewed abstracts and manuscripts.

[Table: see text]

No significant financial relationships to disclose.
Heparin use and venous thromboembolism (VTE) among cancer patients receiving chemotherapy with a prior history of VTE
Authors: Cherkowski G. , Dietrich J. , Chen F. , Fryzek J. , Bridges K.
Published: August 2020

6616

Background: Heparin is an effective treatment option for the prevention of venous thromboembolism (VTE) in cancer patients on chemotherapy. To date, information on the use of both low molecular weight heparin (LMWH) and non-LMWH in cancer patients receiving chemotherapy that have had a prior VTE is lacking. We evaluated heparin treatment patterns as well as the incidence of VTE in a cohort of cancer patients receiving chemotherapy, who have had a VTE prior to their cancer diagnosis. Methods: We conducted a retrospective cohort study using a large claims database representing the U.S. commercially-insured population. The cohort included all patients 18–64 years old from 2000 to 2007 who were diagnosed with cancer, were on chemotherapy, and who had a VTE occurring up to 12 months before cancer (n=331). We defined a diagnosis of cancer as two ICD-9 claims 30 days apart or more. A combination of ICD-9, HCPCS, and CPT codes were used to capture chemotherapy treatment after cancer. A VTE was identified by a single ICD-9 claim of 415.1, 451.2, 451.81, 451.9, 453.1, 453.2, 453.8, or 453.9. VTE claims occurring within 6 months of the index claim were considered part of the same VTE event. A patient was considered to have a VTE after cancer if they had a VTE claim that occurred both after the cancer diagnosis and at least 6 months beyond the most recent pre-cancer index VTE date. Results: Fifty-one percent of cancer patients with a history of VTE were prescribed an anticoagulant (n = 171). Fewer patients took LMWH compared to non-LMWH (6.7% versus 27.8%) while a portion took both (17.2%). A VTE after cancer was experienced by 49.1% of those on any kind of anticoagulant, 45.4% of those taking LMWH, 43.5% of those taking non-LMWH, and 59.6% of those who had taken both types. Fewer VTEs were reported among those taking no anticoagulants (29.4%). Conclusions: Approximately half of all cancer patients receiving chemotherapy were receiving heparin, with a smaller proportion using only LMWH. Even with prophylaxis, VTE recurs in half of cancer patients with a VTE history who receive chemotherapy. Recurrent VTE is a serious risk despite heparin or LMWH prophylaxis.

[Table: see text]
Association of serum 25-hydroxy vitamin D and body mass index in cancer
Authors: Gupta D. , Trukova K. , Vashi P. G. , Adams A. , Lambert G. M. , Lammersfeld C. A.
Published: August 2020

6625

Background: The association between vitamin D and obesity remains unsettled with studies reporting conflicting findings on the relationship between the two. This association assumes even greater importance in cancer because of the alleged role of vitamin D in cancer risk and survival. Currently, the dietary recommendations for Vitamin D do not take into account a person's body mass index (BMI). We investigated the relationship between serum 25-hydroxy-vitamin D [25(OH)D] and BMI in a large sample of cancer patients. Methods: A consecutive case series of 740 cancer patients seen at Cancer Treatment Centers of America from Jan 08 to June 08. Serum 25(OH)D was measured at presentation to the hospital. The cohort was divided in 4 BMI groups (<18.5, 18.5–24.9, 25–29.9, and >30.0 kg/m2). Correlation between 25(OH)D and BMI was evaluated using Spearman correlation coefficient. Mean 25(OH)D was compared across the 4 BMI groups using ANOVA. Linear regression was used to quantify the relationship between BMI and 25(OH)D. Results: Of 740 patients, 303 were males and 437 females. The mean age at presentation was 55.7 years (SD = 10.2). The mean BMI was 27.9 kg/m2 (SD = 6.7). Most common cancers were lung (134, 18.1%), breast (131, 17.7%), colorectal (97, 13.1%), pancreas (86, 11.6%), prostate (45, 6.1%) and ovarian (39, 5.3%). The mean serum 25(OH)D was 21.9 ng/ml (SD = 13.5). Analysis revealed that as BMI groups increased from normal to overweight or obese classifications, there was a significant decrease in 25(OH)D (Table). The Spearman correlation between 25(OH)D and BMI was -0.20 (p = 0.001). Every 1 kg/m2 increase in BMI was significantly associated with a 0.43 ng/ml decline in serum 25(OH)D (p = 0.001). Conclusions: We found that obese cancer patients (BMI >=30 kg/m2) had significantly lower levels of serum 25(OH)D as compared to nonobese patients (BMI <30 kg/m2). BMI should be taken into account when assessing a patient's vitamin D status and more aggressive vitamin D supplementation should be considered in obese cancer patients.

[Table: see text]

No significant financial relationships to disclose.
Single-agent activity of GCS-100, a first-in-class galectin-3 antagonist, in elderly patients with relapsed chronic lymphocytic leukemia
Authors: Cotter F. , Smith D. A. , Boyd T. E. , Richards D. A. , Alemany C. , Loesch D. , Salogub G. , Tidmarsh G. F. , Gammon G. M. , Gribben J.
Published: August 2020

7006

Background: GCS-100 is a polysaccharide antagonist of galectin-3, a protein whose overexpression on certain tumor cells is associated with poor prognosis in cancer patients. GCS-100 has been shown to induce apoptosis of patient CLL cells ex vivo. In addition, GCS-100 potentiates the in vitro activity of other agents commonly used to treat CLL, including rituximab. This phase II clinical trial evaluated the potential of GCS-100 as a novel single-agent therapeutic for relapsed CLL. Methods: Patients with Rai Stage II or higher CLL who had relapsed after one or two prior therapies were eligible. Prior therapies included a range of chemotherapy combinations including FCR, cyclophosphamide/vincristine/rituximab, and chlorambucil/prednisone. Patients received GCS-100 i.v. at 160 mg/m2 for 5 days every 21 days until disease progression. Peripheral blood was collected on study days 1, 4, and 8 of each cycle to assess peripheral leukocyte counts and apoptosis. CD38 and Zap70 expression were assessed where possible. Results: 24 pts were enrolled;16 men and 8 women (median age 67 years, range 40–86 years, 15/24 pts were over 65 years). GCS-100 was well-tolerated. There were no cases of drug-related grade 3 or 4 hematological toxicity or other serious AE. Two patients discontinued treatment due to rash, which resolved with cessation of treatment and which has been shown to be responsive to steroids. Six (25%) patients experienced PR, including 4 patients with >50% shrinkage of lymph node lesions. Currently 6 patients remain on study with a median duration of 5 months (range 4.5–9 months). In addition, apoptosis of peripheral leukocytes was confirmed by caspase activation and by DNA fragmentation. Conclusions: GCS-100 has significant single-agent activity in relapsed CLL. Its lack of myelosuppression and potential synergy with other agents makes GCS-100 a strong candidate for further development in CLL, particularly for elderly patients for whom there is a major need for less toxic agents.

[Table: see text]
Alternatively spliced truncated BCR-ABL1 protein in CML patients with resistance to kinase inhibitors
Authors: Bruey J. , Kantarjian H. , Ma W. , Yeh C. , Peralta R. , Lee T. , O'Brien S. , Estrov Z. , Cortes J. , Albitar M.
Published: August 2020

7026

Background: We have reported that some patients with imatinib-resistant chronic myeloid leukemia (CML) express an alternatively spliced BCR-ABL mRNA with a 35-bp insertion (BCR-ABL135INS), resulting in the addition of 10 residues and truncation of 653 residues. Molecular dynamic simulation suggested that this truncation and insertion of new 10 AA results in structural changes similar to those seen in BCR-ABL with T315I mutation. Here we evaluate the prevalence of BCR-ABL135INS in imatinib-resistant CML, examine the effect of this mutation on resistance to compared the efficiency of various kinase inhibitors in vitro, and suggest a model for persistent CML and a possible strategy to eradicate residual disease. Methods: Using a sensitive PCR method, we determined the prevalence of the alternatively spliced BCR-ABL135INS mRNA in 288 patients with chronic-phase CML resistant to imatinib. Expression of truncated protein was confirmed by Western blot. We then tested the effectiveness of various kinase inhibitors on human K562 CML cells expressing different levels of BCR-ABL135INS along with wild-type BCR-ABL1. Results: BCR-ABL135INS mRNA was detected in 210 (73%) of the 288 patients. Only 25% of BCR-ABL135INS positive cases showed coexistance of ABL1 kinase point mutation. Immunoprecipitation studies demonstrated that expression of the predicted 143-kD BCR-ABL135INS protein at levels proportional to those predicted by mRNA. Expression of BCR-ABL135INS in K562 cells was sufficient to conferred resistance to imatinib, dasatinib, and nilotinib in a dose-dependant fashion. However, no resistance was detected using aurora kinase inhibitor (MK 0457) or homoharringtonine (HHT). BCR-ABL135INS suppressed imatinib, nilotinib, and dasatinib-mediated dephosphorylation of CRKL, LYN, SRC, and STAT5, but had no effect on MK 0457-mediated dephosphorylation. The combination of imatinib with nilotinib or HHT showed strong synergy, overcoming BCR-ABL135INS-induced resistance in vitro. Conclusions: These findings emphasize the importance of the overlooked alternatively spliced BCR-ABL135INS protein and may provide a strategy to treat resistant disease and eradicate residual CML.

No significant financial relationships to disclose.
Subcutaneous omacetaxine mepesuccinate in chronic myeloid leukemia (CML) patients resistant or intolerant to two or more tyrosine kinase inhibitors (TKIs): Data from an ongoing phase II trial
Authors: Wetzler M. , Hellmann A. , Lipton J. , Roy L. , Jones D. , Schenk T. , Hochhaus A. , Benichou A. , Kantarjian H. , Cortes J.
Published: August 2020

7027

Background: Omacetaxine (OM), a first-in-class cetaxine, shows clinical activity against Ph+ CML with a mechanism of action independent to tyrosine kinase inhibition. Patients (Pts) who have failed multiple TKIs may benefit from an alternative therapy for CML. Methods: Pts include adult CML following resistance or intolerance to at least 2 TKIs. T315I+ Pts are enrolled in a separate trial. Pts receive OM induction at 1.25 mg/m2 subcutaneous (SC) BID for 14 days every 28 days followed by maintenance at 1.25 mg/m2 SC BID for 7 days every 28 days (maintenance after at least one induction cycle and achievement of hematologic response). Results: 60 pts (30 chronic phase [CP], 14 accelerated phase [AP], and 16 blast phase [BP] have been enrolled with 51% having failed at least 3 prior TKIs. Median age: 58 yrs; 50% male. Median disease duration: 74 months. At baseline, 38.5% of pts had Bcr-Abl mutations including 9.6% with compound mutations. The most frequently observed mutations were F317L (11.5%) and V299L (5.8%). OM is well tolerated with transient myelosuppression as the primary toxicity. Grade 3/4 non-hematologic events are rare with pyrexia occurring in 4.3% of patients. Efficacy data are available for 30 Pts: Conclusions: Omacetaxine in multi-TKI resistant or intolerant CML is well tolerated and has achieved hematologic and cytogenetic responses in these heavily pre-treated Pts.

[Table: see text]

[Table: see text]
Allogeneic hematopoietic cell transplant for multiple myeloma: Comparative results of planned therapy versus salvage therapy
Authors: Shune L. , Weisdorf D. J. , McClune B. , Ma L. , Burns L. J. , Miller J. , Slungaard A. , Arora M.
Published: August 2020

7035

Background: Despite advances in therapy for multiple myeloma, the disease remains incurable using chemotherapy or immune-modulating agents alone. Several newer hematopoietic cell transplant (HCT) strategies including tandem HCT, and non- myeloablative (NMA) regimens have reported encouraging results. However, the appropriate timing for utilizing these strategies is not clear. Methods: We report outcomes in 51 patients with multiple myeloma who received an allogeneic HCT; either as salvage therapy (after failing a prior autologous HCT), n= 15 or as planned therapy, n= 36, between the years 1996 and 2008 at University of Minnesota. Results: Patients in salvage therapy group were significantly older than in planned therapy group (median age 58 versus 49 years) and had a longer interval from diagnosis to transplant (median 47 versus 10 months). Forty four patients received a HCT from a HLA-identical sibling. Five received umbilical cord blood (four in salvage therapy, one in planned therapy group) and two received unrelated donor HCT (one in each group). Thirteen patients in planned therapy group underwent a tandem transplant (planned autologous followed by NMA sibling HCT). All patients in salvage therapy group, and 50% in planned therapy group received NMA HCT. Patients in salvage therapy group were more heavily pre-treated, all having failed a prior autologous HCT. Complete response was seen in 34% versus 47% of recipients in the two groups, respectively. After a median follow-up of 24 and 41 months, similar relapse was seen, but transplant related mortality (TRM) was significantly higher in salvage therapy group, leading to significantly lower two year survival and disease free survival (DFS) in salvage group. Conclusions: Good overall survival and low transplant related mortality was seen in patients undergoing a planned allogeneic transplant. In heavily pre-treated patients, receiving allogeneic HCT as salvage therapy, despite lower relapse, the high TRM led to lower survival.

[Table: see text]

No significant financial relationships to disclose.
Outcomes of autologous bone marrow transplantation in non-Hodgkin's lymphoma patients who failed peripheral blood stem cell mobilization
Authors: Sola C. B. , Silva L. , Saliba R. , De Lima M. , Giralt S. , Qazilbash M. , Champlin R. , Khouri I. , Popat U. , Hosing C.
Published: August 2020

7040

Background: Patients (pts) with relapsed/refractory non-Hodgkin's lymphoma (NHL) who fail to mobilize adequate peripheral blood stem cells (PBSC) often undergo bone marrow (BM) harvest for autologous transplantation. The outcome of these pts is not known. Methods: In this retrospective study (May 1996-September 2006), we identified 36 out of a total of 750 pts with advanced NHL, who failed to collect adequate PBSC and subsequently underwent BM harvest followed by ABMT. Decision to harvest BM was left to the treating clinician. Median age at transplant was 53 years (range 15–73). Twenty of 36 pts (55%) were male. Histology was intermediate grade in 31 (86%) patients and low grade in 5 (14%). Twelve pts (35%) had history of BM involvement with lymphoma. Median number of chemotherapy cycles received prior to mobilization was 3 (range 1–6). At the time of stem cell mobilization 18 (50%) were in complete remission (CR), 13 (37%) were in partial remission (PR) and 5 (13%) had progressive disease (PD). Twenty four (67%) pts underwent chemo-mobilization and 12 (33%) were mobilized with cytokines alone. Results: The median total nucleated cell dose and CD34+ cell dose harvested/kg were 3.72 x 108 (range 0.25–58.0) and 1.6 x 106 (range 0.03–5.8), respectively. After ABMT, 33 of 35 evaluable (94%) pts engrafted neutrophils with median time to ANC 0.5 x 109/L of 23 days (range 8–47). Median time to platelet count 20 x 109/L was 63 days (range 11–375). Two of 35 (6 %) evaluable pts failed to engraft. After ABMT, 25/36 (70%) pts achieved a CR. The incidence of NRM at 100 days was 15%. Sixteen (45%) pts relapsed at a median of 11 months (range 2–59) from ABMT. After a median follow-up of 34 months (range 0.4–100), the 3-year OS and DFS were 47% and 35%, respectively. Causes of death were: disease progression/relapse in 15 (60%), secondary malignancy in 3 (12%), multiorgan failure in 5 (20%), and unknown in 2 (8%). Conclusions: ABMT is feasible in pts who fail to mobilize adequate PBSC, however, these pts have longer time to engraftment. Although the CR rate after transplant is high, the NRM is higher than expected. Non-myeloablative allogeneic transplantation may provide better outcomes with similar toxicity and needs to be further studied.

No significant financial relationships to disclose.
Multiple myeloma: Autologous stem cell transplantation versus conventional chemotherapy—A retrospective age and stage matched analysis
Authors: Gupta A. , Kumar L. , Dabkara D. , Gupta D. , Sharma O. , Sreeniwas V.
Published: August 2020

7041

Background: We retrospectively analyzed results of MM patients who underwent high-dose chemotherapy and stem cell transplantation (ASCT). In age and stage matched analysis, we compared with those patients who received conventional chemotherapy. Methods: Between January 1995 and June 2007, 95 patients underwent ASCT (Tx Group). 149 age and stage matched patients received conventional chemotherapy (CC Group). High-dose melphalan (200 mg/m2) was used for conditioning in Tx group. Baseline characteristics were comparable in both groups: median age was 50 years (range, 26 to 68 years) in Tx group versus 52 years (range 24 to 68 years) in CC group, p < 0.05; M:F = Tx Group -68:27 versus CC Group 98:51, p = 0.34; stage 3A/3B = 76.8%/23.2% in Tx Group versus 62.4%/37.6%, p = 0.02; mean Hb (Gm/dl) 9.1(range, 3.3–14.3) versus 8.6 (3.3–14.8), p = 0.21; median serum albumin (Gm/dl) 3.5 (range, 1.8–5.2) versus 3.4 (1.6–6.2), p = 0.7, respectively in two groups. Results: Following treatment, the response rates (CR + VGPR + PR = 81%) were significantly higher in Tx group compared to CC group (55%), p = 0.001. CR rate was higher in Tx group, 34.7% versus 12.8%, p < 0.001. The median overall survival was significantly higher in Tx group (75 months, 95%CI [72–106 months]) versus (24 months, 95%CI [19–36months]), p = 0.001. The median progression free survival was 30 months in Tx group (95%CI [21–48 months]) compared to 6 months in CC group (95% CI 3–9 months), p < 0.0001. Estimated overall survival at 5 years in Tx group is 66.6% (95% CI [54.8%-75.9%]) compared to 20.7% (95% CI [13.5%-29%]) in CC group. Conclusions: High-dose chemotherapy followed by autologous stem cell transplantation results in higher overall and complete response rates in multiple myeloma patients. This is associated with improved progression free and overall survival. Low-dose maintenance therapy to sustain the survival benefit of transplant would be possible areas of research in future studies.

No significant financial relationships to disclose.