bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nomograms to predict serious adverse events (SAEs) in patients (pts) enrolled in phase II clinical trials of molecularly targeted agents (MTAs)
Authors: Pond G. R. , Siu L. L. , Moore M. J. , Oza A. M. , Hirte H. , Winquist E. , Goss G. , Hudes G. , Degendorfer P. , Townsley C. A. 
Published: March 2020

6601 Background: The likelihood of experiencing a SAE in clinical trials with a MTA is of interest for clinicians discussing treatment options. Adverse event data from clinical trials in the Princess Margaret Hospital Phase II Consortium [PMH2C] database were analyzed to address this question. Methods: All pts in the PMH2C database treated at the phase II dose level with either a MTA alone or in combination regimens since 2001 were included. Generalised estimating equations were used to construct optimal regression models predicting the increased/decreased odds of a SAE of all causalities (defined as a grade 3+ non-hematologic adverse event, or a grade 4+ hematologic adverse event) during the first cycle of treatment relative to a ‘reference’ pt. Nomograms were constructed to ease interpretation and internal validation explored using bootstrapping on trials larger than 35 pts. Results: 576 pts (median age=60, 55% male, ECOG PS 0:1:2=259:284:35) were accrued to 42 studies. In order of statistical significance, higher ECOG PS, increased LDH, decreased albumin, increased Charlson score, increased number of target lesions, not having prior radiotherapy and decreased age were predictive of increased odds of cycle 1 SAE. As an example, a 56-year old patient with ECOG 2, Charlson score=0, 5 target lesions, LDH=1.70x upper limit of normal [ULN], albumin=0.84xULN and no prior radiation would have ∼3 times increased odds of a SAE in cycle 1, compared to a 63-year old with ECOG 1, Charlson score=0, 1 target lesion, LDH=0.76xULN, albumin=0.68xULN and no prior radiation. Internal validation of the 4 largest studies indicated moderate-good accuracy (estimated area under the receiver operating characteristic curve = 0.57–0.86). Conclusions: A nomogram was produced allowing estimation of the increased odds of a SAE during cycle 1 of therapy in a phase II trial setting. Actual risk can then be further estimated by incorporating clinical judgment of risks for an average pt when given a particular MTA. This nomogram can potentially improve patient knowledge, risk estimates and the decision-making process. External validation of the model is still necessary to adequately assess model reliability. No significant financial relationships to disclose.
Colony stimulating factor use and outcomes for breast, lung, and colorectal cancer patients in Washington State
Authors: Ramsey S. D. , Sullivan S. D. , Malin J. , Blough D. K. , Clarke L. , McCune J. S. 
Published: March 2020

6616 Background: Guidelines recommend colony stimulating factor (CSF) primary prophylaxis (PP) with chemotherapy if febrile neutropenia risk (FN) is =20%. Use of and outcomes for persons receiving CSF in clinical practice are relatively unknown. Methods: Using claims for Medicare and Medicaid enrollees linked to the Puget Sound SEER registry, breast (BCa), lung (LCa) and colorectal cancer (CRCa) patients diagnosed 2002–04 who received chemotherapy were categorized as: CSF at the start of chemotherapy (PP); other CSF; no CSF. Logistic regression was used to determine predictors of CSF PP and hospitalization for FN, controlling for cancer stage, age, sex, race, chemotherapy FN risk (from the National Comprehensive Cancer Network), radiation therapy, CSF use, health insurance, surgery =30 days of chemotherapy. Results: 364 BCa, 908 LCa, and 452 CRCa patients received chemotherapy. 43% of BCa, 30% of LCa, and 15% of CRCa patients received CSF. Only 9%, 6%, and 0.6% of patients initiated CSF as PP in the first cycle of chemotherapy. CSF use increased for all cancers, but most for BCa, (36% in 2002 to 70% in 2004); PP increased from 5% to 26%. Significant predictors (p<0.05) of PP were: BCa–local vs distant stage (OR 0.2), regional vs distant (OR 0.6), chemotherapy FN risk high vs low (OR 6.7); LCa–chemotherapy FN risk high vs low (OR 8.9), intermediate vs low (OR 6.3). FN incidence was 11%, 18% and 32% for BCa, CRCa, LCa, respectively. Significant predictors of FN were: BCa–nonwhite race (OR 2.7); LCa–surgery within 30 days (OR 1.7); CRCa–regional vs. distant (OR 0.4) and chemotherapy FN risk intermediate vs. low (OR 4.2). Conclusions: CSF use has increased significantly, but often in settings where efficacy is uncertain. Cancer type, stage and chemotherapy risk of FN influenced use of primary prophylaxis. Non-chemotherapy factors also appear to influence risk for FN. No significant financial relationships to disclose.
Patterns of initial treatment and survival among older patients with glioblastoma multiforme: Evidence from SEER-Medicare data
Authors: McGarry L. J. , Morissette N. , Earle C. C. , Thompson D. , Liepa A. M. 
Published: March 2020

6625 Background: There is a lack of published data describing routine treatment patterns for glioblastoma multiforme (GBM), particularly in older patients (pts). We report on initial therapies used for treatment of newly diagnosed GBM and related survival among US pts aged 65 years and older. Methods: GBM pts (ICD-O histology codes 9440–9442) were identified in the SEER-Medicare database from 1992 to 2002 and followed through 2004 or until death. Included in the analysis were pts aged 65+ years at diagnosis with no prior cancer diagnosis, enrolled in Medicare Parts A and B, and not enrolled in a Medicare health maintenance organization (HMO). Initial treatment was defined as treatment received within 1 month prior to or 3 months after diagnosis. Use of first-line treatment for GBM was analyzed over all pts, as well as by year of GBM diagnosis; Kaplan-Meier methods were used to assess survival by initial treatment. Results: 3,407 pts met all eligibility criteria. Median age at GBM diagnosis was 75 years; 51.3% of pts were male and 91.9% were white. 88.4% of pts aged 65–74 received active treatment (craniotomy, chemotherapy and/or radiotherapy [RT]), compared to 76.7% of pts aged 75–84, and 50.4% of pts aged 85+. Craniotomy plus RT was the most common initial treatment (40.4% of all pts), followed by craniotomy only (14.9%), RT only (14.7%) and craniotomy plus RT plus chemotherapy (7.8%). Complexity of treatment tended to decrease with age: multiple treatment modalities were used in 62.1% of pts aged 65–74, 42.7% of pts aged 75–84 and 21.3% of pts aged 85+. No notable trend in distribution of initial treatments was observed over the 10-year study period. Pts undergoing craniotomy plus RT plus chemotherapy survived longest (median: 7.6 months; 95% confidence interval: 7.2–8.3 months), followed by those undergoing craniotomy plus RT (6.5; 6.2–7.1). Pts undergoing craniotomy only (2.1 months; 2.0–2.2) and receiving no treatment (2.0; 1.5–2.1) had the shortest survival. Conclusions: The majority of pts aged 65 years or older receive active treatment for newly diagnosed GBM. Among these pts, receipt and complexity of treatment is highest for younger pts and tends to decrease with age. More aggressive initial therapy is associated with longer survival. No significant financial relationships to disclose.
Clinical trial eligibility determination using an oncology electronic medical record system interfaced to a caBIG-certified trial database
Authors: Goldwein J. W. , Van Der Pas M. , Tis L. , Nickens R. , Comis R. 
Published: March 2020

6626 Background: One reason for the low numbers of patients entered on cancer clinical trials is the difficulty and inconvenience encountered in determining whether patients are eligible. The introduction of electronic medical record (EMR) systems in cancer facilities provides a means by which clinical parameters may be electronically collected and compared against clinical trial eligibility criteria, with the potential to facilitate eligibility determination. We hereby describe a widely utilized EMR system interfaced to a caBIG-certified searchable clinical trials database which facilitates eligibility determination. Materials and Methods: MOSAIQ is a widely utilized oncology- specific EMR system that is operational in radiation and medical oncology facilities world-wide. During the routine course of patient care, clinical trial eligibility parameters such as diagnosis, stage, age, and performance status are entered into defined data fields within the EMR. Trialcheck is an independently maintained caBIG bronze level certified database that lists thousands of clinical trials from Cooperative Groups, NCI/PDQ, the pharmaceutical industry and trials being conducted exclusively at particular oncology facilities. TrialCheck registrants can screen trials for patient eligibility as well as filter and track the status of trials that have been activated at their facility. In addition, a real-time, secure Internet interface between MOSAIQ and TrialCheck extracts eligibility parameters from a patient record, sends that information to TrialCheck, and returns a listing of matched clinical trials. Results: In a test screen of 4 MOSAIQ EMR patients against 257 TrialCheck clinical trials, the system matched a patient with Stage IV breast cancer to 7 available trials in less 2 seconds, a patient with Stage IIIB colon cancer to 3 trials in 5 seconds, a Stage IV prostate cancer to 5 trials in 4.4 seconds, and a patient with stage II esophageal cancer to 2 trials in 3.7 seconds. Conclusion: This product demonstrates a novel and innovative solution to one of the problems inherent in the clinical trial registration process in an efficient, reliable and secure manner. No significant financial relationships to disclose.
Extent and nature of advertising in leading hematology-oncology journals
Authors: Sieber D. , Lee J. A. , Keller J. K. , Mathiason M. A. , Go R. S. 
Published: March 2020

6634 Background: Advertising in most medical journals is dominated by pharmaceuticals in part due to journal policy. This is primarily a fiscal consideration. Because advertising clearly influence physicians’ prescribing pattern, an indirect conflict of interest exists and may potentially affect patient care. The objectives of this study were to evaluate the extent of advertising in leading hematology-oncology (HO) journals published in the U.S. and to compare the findings to those of multi-specialty journals. Methods: We evaluated the following high impact journals that publish original research and included all issues issued in 2006: Journal of National Cancer Institute (JNCI), Journal of Clinical Oncology (JCO), Blood, New England Journal of Medicine (NEJM), Journal of the American Medical Association (JAMA), and Annals of Internal Medicine (AIM). Of these, only JNCI (currently not affiliated with U.S. NCI) is not owned by a medical society. The number and nature of advertising for each journal were collected. Results: There was an average of 84, 283, and 459 pages for each issue of JNCI, JCO, and Blood, respectively. Overall, HO journals allocated 20% (range, 8–32) of their pages for advertising. JCO had the most, while JNCI the least, advertising, both classified (6% vs 1% vs 1%; P = 0.001) and non-classified (26% vs 10% vs 7%; P = 0.001). Among non- classified advertising, the major categories were drugs (48.5%), journal information (14.1%), conference announcements (10.1%), research/clinical trial (7%), disease information (6.4%), continuing medical education (3.6%), and others (10.3%). Among journals, JCO had the most drug advertising (72.5%), followed by Blood (65.6%), while JNCI did not have any (0%). Compared to multi-specialty journals, HO journals had less amount of classified (3% [range, 1–6] vs 15% [range, 10–19]; P = 0.001) and non-classified (17% [range, 7–26] vs 21% [range, 18–25]; P = 0.001) advertising. Conclusions: While less than their multi-specialty counterparts, HO journals allocated a substantial proportion of their pages to advertising, the overwhelming majority of which were sponsored by pharmaceutical companies. The extent of advertising varied by journal, but was most prominent with JCO. Notably, JNCI did not have any drug advertising. No significant financial relationships to disclose.
Hematopoietic cell transplantation (HCT) after low-dose, total body irradiation-based regimen increased leukemia-free survival (LFS) in elderly patients with cytogenetic high-risk AML compared to chemotherapy (OSHO 97 study)
Authors: Niederwieser D. , Becker C. , Krahl R. , Al-Ali H. , Lange T. , Gerhardt A. , Schulze A. , Hähling D. , Schulze M. , Freund M. 
Published: March 2020

7003 Background: Even after reaching initial CR, most AML patients > 60 years relapse within 2 years of diagnosis. Cytogenetic high risk AML (abn 3q26, abn 11q23, -5/5q-, -7/7q- and complex) has an even worse prognosis. Attempts to improve survival by intensifying consolidation chemotherapy have so far failed. We investigated the role of allogeneic HCT in comparison to chemotherapy among patients with high risk cytogenetics entered into the OSHO AML 97 protocol. Methods: Initial treatment consisted of a course of induction therapy (AraC 2 g/m2 iv on day 1,3,5,7 + mitoxantrone 10 mg/m2 iv day 1 –3, repeated once in case of PR) followed by one consolidation course (AraC 240 mg/m2 iv day 1 –5 + mitoxantrone 10 mg/m2 iv day 1 –2). Patients in CR1 after the consolidation I were either treated with an additional consolidation therapy or with an allogeneic HCT from related (n=2) or unrelated (n=10) donors. Transplant patients were conditioned with fludarabine and TBI 200 cGy and immunosuppressed with cyclosporine and mycofenolate mofetil. Results: A total of 347 patients are evaluable. Of 105 (33%) patients with high-risk cytogenetics, 53 (50%) went into remission after one or two cycles of induction chemotherapy. Of these 53 patients, 42 received consolidation I and 35 patients were available for either consolidation II (n=23) or HCT (n=12). Median age of the patients receiving chemotherapy was 64 (range 61–77) years and that of the transplant patients was 64 (range 61–68) years. LFS at 4 years was 42 ± 14% after HCT and 15 ± 8% after chemotherapy. Major differences in relapse incidences were seen between the two groups, with the lowest RI at 4 years after HCT (36 ± 15%) followed by chemotherapy (85±8%, p<0.04). Treatment related mortality at 4 years was 35±17% and 0±0% for patients receiving HCT and chemotherapy, respectively (p<0.05). Conclusions: From these results, we conclude that consolidation with allogeneic HCT after minimal conditioning is superior to chemotherapy even in older patients with high risk cytogenetics. While differences in TRM were seen between the treatment arms, a lower relapse incidence after related and unrelated HCT contributed to the improved LFS. No significant financial relationships to disclose.
A phase III randomized trial of intensive induction and consolidation chemotherapy ± oblimersen, a pro-apoptotic Bcl-2 antisense oligonucleotide in untreated acute myeloid leukemia patients >60 years old
Authors: Marcucci G. , Moser B. , Blum W. , Stock W. , Wetzler M. , Kolitz J. E. , Thakuri M. , Carter T. , Stuart R. K. , Larson R. A. 
Published: March 2020

7012 Background: Overexpression of Bcl-2, an inhibitor of apoptosis, may render AML cells resistant to chemotherapy and has been associated with unfavorable outcome. Genasense is a phosphorothioate 18-mer antisense oligonucleotide directed against the first 6 codons of Bcl-2. In a phase I study of older (≥60 yrs) AML patients (pts) treated with Genasense in combination with cytarabine (Ara-C) and daunorubicin (DNR) induction and with high-dose cytarabine (HiDAC) consolidation, no antisense-related toxicity was reported. Furthermore, overexpression of Bcl-2 at diagnosis and down-regulation of the Bcl-2 target after antisense treatment was shown in pts achieving complete remission (CR). Methods: A phase III trial (CALGB 10201) randomized untreated older AML pts to induction treatment with Ara-C (100 mg/m2/d by CIVI on days 4–10) and DNR (60 mg/m2/d on days 4–6) followed by consolidation therapy with HiDAC (2 g/m2/d on days 4–8) with (Arm A) or without (Arm B) Genasense (7 mg/m2/d CIVI on days 1–10 for induction and days 1–8 for consolidation). The study was powered to identify a survival advantage for pts receiving Genasense. Results: 503 pts enrolled between 12/03 and 10/06; 76 had prior MDS and 24 prior chemoradiotherapy for unrelated cancers. The arms were balanced for age, sex, race, and performance status. No differences in toxicities were observed between the 2 arms. An interim futility analysis performed at 34 months from initiation of the study showed no differences in CR rates (48% vs 52%; p=0.75) or overall survival (OS; p=0.83) between the 2 arms. Estimated OS at 1 yr was 36% for Arm A and 40% for Arm B. Similarly, there were no differences in disease-free survival from date of CR (DFS; p=0.78) or event-free survival (EFS; p=0.77). DFS and EFS rates at 1 yr were 40% and 25% for Arm A, and 43% and 7% for Arm B, respectively. Conclusions: Addition of Genasense to induction and consolidation chemotherapy failed to improve the outcome of older AML pts. Pretreatment levels and post-antisense treatment changes in Bcl-2 expression are now being measured and correlated with outcome. No significant financial relationships to disclose.
Trough plasma imatinib concentrations are associated with responses to standard-dose imatinib in chronic myeloid leukemia and could improve its clinical management
Authors: Mahon F. , Etienne G. , Picard S. , Titier K. , Marit G. , Begaud B. , Reiffers J. , Moore N. , Molimard M. 
Published: March 2020

7027 Background: Variable responses to imatinib in the treatment of myelogenous leukemia (CML) are incompletely understood. Previous studies focused on cellular mechanisms of resistance to imatinib. Another hypothesis for variable response lies in pharmacokinetic variability that may reduce drug exposure in patients receiving imatinib. Methods: Using high- performance liquid chromatography-tandem mass spectrometry, we assessed trough plasma imatinib concentrations at steady state (Cmin) in more than 150 CML patients. Major molecular response (MMR) was defined as a 3 logarithm reduction of BCR-ABL transcripts, quantified from peripheral blood using Q-RTPCR. In addition, suboptimal response criteria defined by the European Leukemianet were used to increase doses of imatinib. Results: i) we assessed Cmin in 85 CML patients and demonstated a correlation with imatinib doses (median values 813, 1,135, 1,709 ng/ml for respectively 300,400, 600 mg/day). ii) for 68 patients after at least one year's treatment mean Cmin were significantly higher in the group with MMR (34 patients) than in the group without (1,452.1±649.1 ng per milliliter vs. 869.3±427.5 ng per milliliter, P<0.001) whereas there was no difference in the imatinib daily dose. For Cmin and their discrimination potential for MMR, the area under receiver-operating characteristic curve was 0.775, with best sensitivity (76.5 percent) and specificity (70.6 percent) at a plasma threshold of 1,002 ng per milliliter. iii) dose escalation of imatinid, 400mg up to 600mg was proposed in 8 patients in suboptimal response (3 according to cytogenetic criteria and 5 according to molecular criteria). The median Cmin increase from 573 ng/ml [181–1,376] to 1,139 ng/ml [733–2,262] and 5 patients had a cytogenetic (n=3) or a molecular (n=2) response. Conclusions: Monitoring of imatinib plasma levels could be very useful for the management of CML patients, or should at least be checked in the case of treatment failure or suboptimal response or in patients nonadherent with imatinib or with a drug-drug interaction suspicion. No significant financial relationships to disclose.
Beta-2 microglobulin (B2M) is an independent prognostic factor for clinical outcomes in patients with CLL treated with frontline fludarabine, cyclophosphamide, and rituximab (FCR) regardless of age, creatinine clearance (CrCl)
Authors: Tsimberidou A. M. , Tam C. , Wierda W. , O' Brien S. , Lerner S. , Keating M. J. 
Published: March 2020

7034 Introduction: High β2M levels are a risk factor in CLL. PCR therapy has been reported to be better tolerated than FCR in older or with decrease renal function pts (Shanafelt, Blood 108:15a). We assessed the association between age, CrCl, PS, β2M and outcomes in pts treated with FCR. Methods: From 7/99 to 1/04, 300 pts received rituximab 375 mg/m2 D1; fludarabine 25 mg/m2/d D2–3; and cyclophosphamide 250 mg/m2/d D2–3. Serum β2M levels were measured by radioimmunoassay. CrCl was calculated (Cockcroft-Gault equation). Results: The median age was 57 yrs (≥70, 14%). Age ≥70 was associated with fewer FCR courses (p<.0001); lower rates of CR (p=.001), overall response (OR; p=.04), survival (OS; p<.0001), and FFS (p=.008); and higher rates of G3–4 thrombopenia (p<.0001) or anemia (p=.002) compared with age<70. The median CrCl was 90 mL/min (CrCl <70, 27%). Pts with CrCl <70 had higher rates of G3–4 thrombopenia (p=.006) or anemia (p=.01) than others. There were no differences between the 2 groups in the other outcomes. PS was 0 in 40%, 1 in 57%, and 2 in 3% of pts. Better PS was associated with higher rates of CR (p=.007) and FFS (p=.02) but did not affect OR or OS. The median β2M level was 3.7 mg/L (β2M ≥ 4, 43%). The rates of CR, survival, and FFS were lower in pts with β2M ≥ 4 compared with others (p<.0001 each). High β2M levels were associated with older age, lower CrCl levels, poorer PS (p<.0001 each), higher rates of G3–4 neutropenia (p=.005), thrombocytopenia (p=.01), and infections (p=.03), and fewer FCR courses (p=.004). The median follow-up was 5 yrs. The rates of CR, 3-yr OS and 3-yr FFS were 72%, 87% and 76%, respectively. Independent factors predicting response were lower β2M (p=.0004) and lower WBC counts (p=.02). Independent factors predicting longer OS were younger age (p=.001), lower β2M (p=.003) and lower WBC (p=.03). Independent factors predicting longer FFS were lower β2M levels (p=.0006), and lower WBC counts (p=.005). Conclusion: Age ≥70 yrs and poor PS, but not CrCl level were associated with poor clinical outcomes. High β2M levels are an independent adverse prognostic factor for CR, OS, and FFS in the context of other prognostic factors. No significant financial relationships to disclose.