bluuebunny/crossref_metadata_2025 huggingface dataset:
Rates of adherence to bone health guidelines for women with breast cancer treated with anti-estrogen therapy.
Authors: Elliott Leighton Andrew , Vogel Victor G.
Published: May 2020

7051

Background: Long-term use of aromatase inhibitor (AI) therapy has been shown to decrease bone mineral density (BMD) and is associated with at least twice the fracture risk when compared to an age-matched healthy population. AI’s are a common treatment in hormone receptor-positive breast cancer for post-menopausal women. Similarly, tamoxifen has been shown to decrease BMD in premenopausal women. As a result, the National Comprehensive Cancer Network (NCCN) recommends BMD screening for women being treated with anti-estrogen therapy (AET), typically via Dual-energy X-ray absorptiometry (DEXA) scan. Previous studies have shown poor adherence to BMD screening with AI therapy, but no known study has evaluated compliance with tamoxifen therapy. Methods: We evaluated a retrospective cohort (December 2015 – July 2019) of all women with a breast cancer diagnosis initiating AET using data from the electronic health records of patients throughout a rural integrated health system. We assessed non-adherence to baseline and annual BMD screening using descriptive statistics along with preliminary data regarding fractures associated with AET therapy. Results: A total of 3,693 health records of women with a breast cancer diagnosis and documented prescription for AET were evaluated. In the year before AET initiation, 16% of women received BMD screening. Overall, 1,189 women treated with AET had a DEXA scan ordered at any point after drug initiation: 37% for AI’s and 12% for tamoxifen. Of those treated with AI, 84% had no DEXA ordered within 12 months of starting drug after a minimum of 9 months of continuous use; this value was 96% for tamoxifen use. Patients complied with the ordered DEXA scan within the first year 81% of the time. Repeat DEXA scans were ordered 34% of the time, and patient compliance decreased to 55%. There was no significant difference in the number of patient co-morbidities between patients who did and did not have a DEXA scan ordered. After starting an AI, 131 fractures were documented; 44% occurred within the first year following starting drug treatment with an average of 5 months from drug start to diagnosis. Conclusions: A significant proportion of breast cancer patients treated with AET did not receive guideline-recommended BMD screening. These findings should raise awareness of the importance of BMD screening by responsible providers, including oncologists, primary care physicians, care managers and insurance companies in order to decrease avoidable morbidity.
Factors associated with change in the magnitude of clinical benefit of anti-cancer drugs in the post-marketing period.
Authors: Bujosa Rodríguez Aida , Molto Consolacion , Hwang Thomas J , Vokinger Kerstin Noëlle , Tapia Jose Carlos , Gich Saladich Ignasi J. , Templeton Arnoud J. , Barnadas Agusti , Amir Eitan , Tibau Ariadna
Published: May 2020

7052

Background: Initial drug approval is often based on surrogate endpoints. Definitive outcomes like Overall Survival (OS) or Quality of life (QoL) may not be available. Here, we evaluate changes in the magnitude of clinical benefit using the American Society of Clinical Oncology Value Framework (ASCO-VF) and European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) comparing the time of approval to the most recent available data for cancer drugs approved by the US Food and Drug Administration (FDA) between 2006 and 2015. Methods: We examined data on trials supporting FDA accelerated (AA) and regular (RA) cancer drug approvals between January 2006 and December 2015. We performed a systematic search of Pubmed and ClinicalTrials.gov to identify updated OS and/or QoL data, with follow up through April 2019. For AA drugs we analysed initial and confirmatory trials as follow-up. ASCO-VF and ESMO-MCBS grades were applied for trials at approval and after marketing. We explored variables associated with improved clinical benefit scores using multivariable logistic regression. Results: We identified 102 trials supporting the approval of 59 drugs for 96 solid tumour indications. Of these indications, 22 (23%) were granted AA and 21 (95%) were converted to RA. At time of approval, 38% of trials showed improved OS and 17% improved QoL. Substantial clinical benefit was observed in 26% of initial approval trials using ESMO-MCSB and in 34% using ASCO-VF. After a median post-marketing period of 3.3 years, updated results changed substantial clinical benefit in 20 trials with ESMO-MCBS (19 upgrades, 1 downgrade) and in 23 trials using ASCO-VF (19 upgrades, 4 downgrades). For 25% of trials no updated information was found. In the palliative setting, multivariable analysis showed association between improved ASCO-VF scores and initial approvals based on single-arm trials (OR 9.21, 95%CI 1.36-62.29, P=0.023), drugs with companion diagnostics (OR 4.95, 95%CI 1.01-24.22, P=0.049) and second or later lines (OR 7.80, 95%CI 1.35-45.02, P=0.022) while for ESMO-MCBS, drugs with companion diagnostics (OR 6.86, 95%CI 1.82-25.86, P=0.004) and immunotherapy drugs (OR 6.42, 95%CI 1.27-32.59, P=0.025) were associated with greater clinical benefit. Conclusions: Drugs with companion diagnostic tests, immunotherapy as well as approved based on single-arm trials were associated with increased clinical benefit after marketing approval. For a quarter of trials there were no updated data in the post-marketing period.
Hyponatremia could be an important prognostic factor for oncology patients: Result of a retrospective study.
Authors: Das Prantik , Seneviratne Lalith , Gore Emma , Oo Zin Mar , Hulman Joshua , Sellahewa Luckni
Published: May 2020

7055

Background: Hyponatraemia is the most common electrolyte disorder encountered in clinical practice. Hyponatraemia in hospitalized people is associated with an increased morbidity, mortality and longer hospital stay compared with people with normal serum sodium concentrations. It is a negative prognostic indicator for survival in oncology patients. Incidence of hyponatremia in malignancy is largely underestimated. Methods: Retrospective analysis of patients admitted to oncology ward in our institution between August to September 2018 was conducted. Patients were identified from admission register and data were analysed from electronic medical records. Primary aim was to evaluate the incidence of hyponatraemia in oncology in-patients and impact on survival. Data were also analysed for patients demography, cancer types, grade of hyponatremia and treatment approach. Results: 119 patients were admitted to oncology ward during study period. Out of them 38% were identified to be Hyponatraemic and 51 % patients were male. Lung cancer was the predominant cancer type followed by breast, upper GI and ovarian respectively. Of hyponatraemic patients, 63% were asymptomatic, among symptomatic patients vomiting, confusion and headaches are common. According to severity, 42% patients had grade 1, 40% grade 2 and 18% grade 3 hyponatraemia respectively. When it comes to status of hydration, 62.2% were noted to be euvolaemic, 6.66% were hypervolaemic and 15.5% were hypovolaemic and the hydration status of the rest of 15.5% were not known. Considering mortality, 53% patients died within 30 days of diagnosis of hyponatremia compared to 17% deaths among non-hyponatraemic patients. Median survival of patients with grade 3, 2 and 1 hyponatremia were 29, 35 and 62 days respectively. Out of 45 patients 14 (31.1%) had acute onset hyponatraemia and they had considerably poorer survival compared to their chronic hyponatraemic counterparts. 80% of acute hyponatraemic patients have died within 30 days of diagnosis, compared to 140 days for chronic hyponatraemics with similar death rate. Out of 48% non-hyponatraemic patients who died within next 6 months, 31% developed hyponatraemia at some point before their death and amongst them, 5.7% had severe, 8.5% had moderate and 17% had mild hyponatraemia respectively. Conclusions: Our study indicated that hyponatremia is poor prognostic factor among oncology patients, with mortality being significantly higher when the grade is higher and when acute in onset. Identifying and early intervention could improve patient outcome.
The association of fitness and body mass index (BMI) on all-cause mortality in cancer survivors: The Henry Ford Exercise Testing Project (The FIT Project).
Authors: Marshall Catherine Handy , McAuley Paul A , Tsai Hua-Ling , Dardari Zeina , Al-Mallah Mouaz H , Brawner Clinton A , Lamerato Lois E. , Keteyian Steven , Ehrman Jonathan , Blaha Michael J
Published: May 2020

7060

Background: The obesity paradox –i.e. inverse associations between body mass index (BMI) and mortality – has been reported in patients with cancer, heart failure, and diabetes. However, the influence of cardiorespiratory fitness (CRF) on this relationship is not well established. This study assesses the association of BMI and CRF with all-cause mortality among cancer patients. Methods: The Henry Ford (HF) FIT Project is a retrospective cohort study of 69,885 consecutive patients who underwent physician-referred exercise stress testing from 1991 through 2009. Cancer diagnosis was identified through linkage to the HF tumor registry. We included patients 40-70 years old, with BMI recorded, at time of exercise test, with a history of cancer > 6 months prior. BMI was categorized as normal (18.5-24.9kg/m2), overweight (25-29.9kg/m2), or obese ( > = 30kg/m2). All-cause mortality was obtained from the National Death Index. Because of a significant interaction between BMI and cancer type, patients with breast or prostate cancer were excluded. Multivariable adjusted Cox proportional hazard models were used to evaluate the association of CRF andBMI with all-cause mortality; adjusted for age at exercise test, sex, diabetes, smoking, cancer stage, and time from cancer diagnosis to exercise test. Results: Included were 676 patients with a mean age of 58 years (SD 7.5), 51% female, 70% White, 25% Black, with a median of 4.8 years from diagnosis to exercise test and median follow up time of 10.3 years. Among patients achieving < 10 METs, those who are overweight and obese had a lower risk of mortality HR 0.47 (95% CI 0.25,0.86) and HR 0.44 (95% CI 0.26, 0.74, respectively), compared to those with normal BMI. Among patients with METs > = 10, those who were overweight had the lowest risk of all-cause mortality (HR 0.23, 95% CI 0.09-0.62) compared to normal weight, while no statistically significant different risk of mortality was observed when comparing those who are obese to normal weight (HR 0.37, 95% CI 0.13-1.06). In an analysis combining BMI and fitness groups (four categories), those with BMI > = 25 and METs > = 10 had the lowest risk of all-cause mortality (Table). Conclusions: In non-breast/non-prostate cancer patients, increased BMI is associated with improved overall survival in those with METs < 10, while a U-shaped relationship between BMI and all-cause mortality exists among those with METs > = 10. [Table: see text]
Perioperative chemotherapy versus adjuvant chemoradiation in resectable gastric cancer: A national cancer database analysis.
Authors: Malapati Sindhu Janarthanam , Singh Sunny R K , Kumar Rohit , Abdalla Ahmed , Hadid Tarik H.
Published: May 2020

7066

Background: In patients with resectable gastric cancer, the use of either perioperative chemotherapy (POC) or adjuvant chemoradiotherapy (CRT) are acceptable treatment options in addition to surgical resection. Both approaches improved overall survival (OS) compared to surgery alone. Randomized controlled trials comparing these two modalities are lacking. This study uses real-world data to compare the clinical outcomes of these two approaches. Methods: We identified gastric cancer patients in the NCDB who had definitive surgery between years 2004 and 2015. They were divided into two cohorts: POC and adjuvant CRT. We compared the OS and surgical outcomes in both groups. Kaplan-Meier method and multivariable Cox regression model were used to estimate survival. Results: Of 75,654 patients who underwent definitive surgical resection, 1,920 had POC and 9,161 had adjuvant CRT. Median OS was 56 months with POC and 38.5 months with CRT. After adjusting for age, gender, race, insurance status, comorbidity index, and treatment facility, patients who received POC had an 18% reduction in all-cause mortality compared to those who received adjuvant CRT (p <0.0001, 95% confidence interval 0.74- 0.88). Although, 30- and 90-day mortality was slightly higher with POC compared to CRT (0.047 vs. 0.03%, p<0.0001 and 1.46 vs. 0.45%, p<0.0001 for 30 and 90 day mortality, respectively). Length of hospital stay for primary tumor resection was similar between the two groups; but the 30 day readmission rate after surgery was higher with CRT compared to POC (12.74 vs. 8.33%, p<0.0001). Conclusions: Among patients undergoing definitive surgical resection for gastric cancer, our study shows an association between the use of POC (vs. adjuvant CRT) and improvement in OS. In the POC cohort, while there was a slight increase in postoperative mortality, this was surpassed by the benefit derived from use of POC, resulting in net improvement of survival. These interesting observations warrant confirmation in randomized clinical trials. [Table: see text]
The correlation between clinical benefit and financial cost of cancer drugs.
Authors: Mitchell Aaron Philip , Tabatabai Sara , Dey Pranammya , Ohn Jennifer , Curry Michael A. , Bach Peter
Published: May 2020

7071

Background: The cost of many cancer drugs is very high, but it is unclear if these costs are associated with commensurate improvement in outcomes. We aimed to assess the association between the cost of cancer treatments and their clinical benefit, using the NCCN Evidence Blocks value assessment framework. Methods: The NCCN Evidence Blocks include 4 measures of clinical benefit: Efficacy, Safety, Quality of Evidence, and Consistency of Evidence. The NCCN assigns scores on each measure ranging from 1 (least favorable) to 5 (most favorable). We obtained the NCCN Evidence Blocks scores as of December 31, 2018 for all recommended cancer treatments for the 30 most prevalent cancers in the US. For each treatment, we calculated total treatment costs (including drugs, administration fees, and supportive care medications) using Medicare reimbursement rates. We categorized treatments as either “time-limited” or “time-unlimited” according to whether their costs are best reflected as per full treatment course (often, adjuvant/neoadjuvant treatments) (time-limited) or per month of therapy (often, treatments for advanced disease) (time-unlimited). We used generalized estimating equations, with clustering within treatment indications, to estimate the association between Evidence Blocks scores and treatment costs, modeling the expected change in cost associated with a one-unit increase in the score on an Evidence Blocks measure. Results: There were 541 time-unlimited and 845 time-limited treatments. Among time-unlimited treatments, monthly treatment cost ranged from $4 to $64,630. Monthly treatment cost was positively associated with Efficacy ($3,036, 95%CI: $1,782, $4,289) and Quality of Evidence ($1,509, 95%CI: $171, $2,847) but negatively associated with Safety (-$1,470, 95%CI: -$2,790, -$151) and Consistency of Evidence (-$2,003, 95%CI -$3,420, -$586). Among time-limited treatments, cost per course of therapy ranged from $0 to $775,559, and no measure was significantly associated with cost. Evidence Blocks scores accounted for little of the variation in treatment cost (linear model R-squared = 0.10 for time-unlimited, and < 0.01 for time-unlimited). Conclusions: The association between NCCN Evidence Blocks measures and treatment cost was inconsistent, and accounted for little of the cost variation among treatments for the same indication. The clinical benefit of cancer treatments does not appear to be a primary determinant of treatment cost, suggesting that current pricing models may be inadequate to incentivize the development and utilization of high-value treatments.
Breast density notification with adjunctive digital breast tomosynthesis (DBT): A cost-effectiveness analysis.
Authors: Semprini Jason , Vaughan-Sarrazin Mary
Published: May 2020

7072

Background: Dense breasts increase a woman's risk of developing cancer while also raising the likelihood of a missed diagnosis from traditional mammography screening. Digital Breast Tomosynthesis (DBT) has been shown to identify positive breast cancer more accurately in women with dense breasts, but no study has estimated the cost-effectiveness of this screening mode under a notification requirement. Methods: Taking the perspective of a healthcare system, we estimated the incremental cost-effectiveness ratio (ICER) of providing DBT as an alternative to mammography for 40-year old women. Model parameters reflecting risk of breast cancer, detection rates, and costs were estimated from recent meta analyses, Tufts’ CEA registry, and Medicare Fee Schedules. We used probabilistic Markov Models to estimate the ICER under uncertainty, and a time-variant model in which breast density and cancer risk change over time. Additionally, a heterogeneity analysis included all women between the ages of 40-65, while also using 1st and 2nd degree family history to calculate cancer risk. Results: In the probabilistic model, adjunctive DBT has a cost differential of $12,203, with an increase of 0.0382 quality-adjusted life years (ICER = $319,491/QALY) compared to mammography. This result was most sensitive to the probability of a missed diagnosis for women with dense breasts. At a willing-ness to pay of $50,000, adjunctive DBT had a 57% chance of being more costly and less effective than standard mammography. Conversely, DBT only had a 20% chance of being cost-effective and a 9.9% chance of being less costly and more effective. The time-variant model reported an ICER of $174,218, but adjunctive DBT became even more cost-effective after expanding the population and including family history of cancer (ICER_All Ages = $157,146; ICER_FamHist = $153,388). Conclusions: Breast density notification laws which provide additional screening via DBT are not cost-effective at a willingness to pay of $50,000. Policymakers, however, should note that many modern cancer therapeutics also exceed this threshold. As an adjunctive screening technique, DBT would result in fewer deaths and increase quality of life, but the effect is minimal and carries a high cost. Including breast density within greater risk stratification protocols, however, may prove highly cost-effective, especially for older women with a family history of cancer.
Venous thromboembolism prophylaxis in ambulatory cancer patients initiating chemotherapy: A cost-effectiveness analysis.
Authors: Ryan Emma , Salinaro Julia , Havrilesky Laura J , Davidson Brittany Anne
Published: May 2020

7074

Background: Venous thromboembolism (VTE) is a major cause of morbidity and mortality among cancer patients. The Apixaban for the Prevention of Venous Thromboembolism in High-Risk Ambulatory Cancer Patients (AVERT) randomized controlled trial concluded that apixaban is a safe and effective option for VTE prophylaxis in high-risk ambulatory cancer patients initiating a new chemotherapy regimen. We performed a cost-effectiveness analysis from a health system perspective to determine if apixaban is a feasible prophylactic strategy for this population. Methods: A decision model was created from a third party payer perspective with a time horizon of 6 months, based on the treatment arms of the AVERT trial: (1) apixaban 2.5 mg twice daily for 6 months during active chemotherapy versus (2) placebo. Rates of VTE (4.2% apixaban vs 10.2% placebo), major bleeding (3.5% vs 1.8%) and clinically relevant nonmajor bleeding (CRNMB) (7.3% vs 5.5%) were modeled from the results of the AVERT trial. Cost estimates for treatments and events were obtained from wholesale drug costs, previously published studies and Medicare reimbursement data, and adjusted for inflation to 2018 dollars. Quality adjusted life years were calculated based on previously published utility values for the health states of advanced cancer, DVT, PE, and major bleeding events. An exploratory analysis was performed comparing prophylactic aspirin to no prophylaxis assuming a VTE rate of 7.2%, major bleeding rate of 3.5%, and CRNMB rate of 7.3%, based on the conservative assumptions that while aspirin may not be as effective at preventing VTE, the rate of clinically significant bleeding events would be similar or greater than that of apixaban. Results: In the base case model, apixaban is more costly and more effective than placebo (ICER = $5,013,190/QALY), and the cost per VTE prevented in the apixaban arm is $33,000. In one-way sensitivity analysis, if the cost of apixaban were reduced by 40% from $3,197 to $1,250 for a 6 month course, this could potentially be a cost-effective prophylaxis strategy with an ICER less than $100,000/QALY. In the alternative analysis, aspirin dominates placebo as it is both more effective and less expensive, and remains cost-effective even when the rate of clinically recognized bleeding with aspirin exceeds 15%. Conclusions: Further investigation into less costly prophylactic options such as generic direct oral anticoagulants (once available) and aspirin is warranted prior to broader implementation of a VTE prophylaxis strategy in this population.
Cost-effectiveness of genomic profiling in veterans with metastatic lung adenocarcinoma.
Authors: Poonnen Pradeep , Dong Olivia , Winski David , Reed Shelby D. , Vashistha Vishal , Bates Jill S. , Kelley Michael J. , Voora Deepak
Published: May 2020

7075

Background: Tumor profiling identifies patients who are eligible for targeted anticancer therapies. Common tumor profiling approaches include targeted gene panel testing (TGPT), which tests for common mutations in select genes, and multigene panel sequencing (MGPS), which tests for a broad range of mutations in a comprehensive set of genes. Our objective was to determine the lifetime cost-effectiveness of MGPS and TGPT compared to no tumor profiling for Veterans with metastatic lung adenocarcinoma from the Veterans Health Administration’s (VHA) perspective. Methods: A decision analytic model was developed to simulate outcomes for a closed cohort of hypothetical Veterans with metastatic lung adenocarcinoma considering anticancer therapy. OncoKB genes with levels of evidence 1 and 2 for guiding therapy were included. Three profiling strategies were studied: TGPT ( ALK, EGFR, ROS1), MGPS ( ALK, BRAF, EGFR, HER2, MET, NTRK1, NTRK2, NTRK3, RET, ROS1), and no tumor profiling. We assumed 95% of patients with actionable mutations received targeted therapies. Non-targeted therapy options included chemotherapy and/or immunotherapy, and no anticancer therapy. Model inputs were derived from randomized trials (progression-free survival), VHA and Medicare (drug costs), published studies (non-drug cancer-related management costs, health care utilities), and VHA National Precision Oncology Program and cBioPortal for Cancer Genomics databases (mutation prevalence). Costs (2019 US$) and quality-adjusted life years (QALYs) were discounted at 3%/year. Base-case scenario, one-way sensitivity analyses, and probabilistic sensitivity analyses (PSA) using 1,000 Monte Carlo simulations were completed. Results: Base-case results and corresponding 95% credible intervals from the PSA indicated the cost/QALY gained was $309,399 ($280,371-$343,161) for TGPT and $324,707 ($296,086-$359,778) for MGPS compared to no tumor profiling. Of the 3 strategies, MGPS resulted in the highest number of QALYs. One-way sensitivity analyses revealed the cost/QALY estimates were most impacted by changes in health state utility on a targeted therapy (quality of life), costs of alectinib, and non-drug cancer-related costs in patients receiving targeted therapy. Compared to no tumor profiling, cost-effectiveness ratios for both profiling approaches surpassed the $150,000/QALY threshold in 100% of PSA simulations. Conclusions: Tumor profiling (TGPT or MGPS) can optimize anticancer therapy selection in patients with metastatic lung adenocarcinoma and improve quality-adjusted survival, but compared to no tumor profiling, is not cost-effective.
Patient-reported out-of-pocket costs and financial toxicity during early-phase oncology clinical trials.
Authors: Huey Ryan , George Goldy , Phillips Penny , White Revenda , Fu Siqing , Janku Filip , Karp Daniel D. , Naing Aung , Piha-Paul Sarina Anne , Subbiah Vivek , Tsimberidou Apostolia Maria , Pant Shubham , Yap Timothy A , Rodon Ahnert Jordi , Meric-Bernstam Funda , Shih Ya-Chen T. , Hong David S.
Published: May 2020

7082

Background: Clinical trials are an important therapeutic option for cancer patients (pts). Although financial burden in cancer treatment is well-documented, the financial burden associated with clinical trials is not well understood, especially for pts with lower income. Methods: We conducted a survey regarding economic burden and financial toxicity in cancer pts who had been on Phase I clinical trials for ≥1 month. Financial Toxicity Score (FTS) was assessed using the validated COmprehensive Score for Financial Toxicity (COST) survey (scale 0-44, lower scores indicate worse toxicity). Pts also reported monthly out-of-pocket (OOP) medical and non-medical expenses. We applied multivariable logistic regression to analyze risk of financial toxicity, and unanticipated expenses. Results: Early-phase clinical trial pts (N = 213, median age = 59y; 59% female; 74% White, 45% w/ annual income ≤$60K; 50% lived > 300 miles from the clinic; 40% required air travel; 37% had Medicare, 54% had employer sponsored insurance) had a median FTS of 20, with interquartile range of 12. Median monthly OOP costs for non-medical expenses was $1075, and for medical expenses was $475. Median total monthly OOP costs was $1750. 55% and 64% of pts reported that actual medical and non-medical expenses were higher than expected, respectively. Worse financial toxicity (≤ median FTS) in pts was associated with yearly household income < $60K (OR: 2.7, P = 0.008), having medical costs higher than expected (OR: 3.2, P = 0.024), participation on ≥1 Phase I clinical trial prior to their current trial (OR: 2.2, P = 0.028), and living > 100 miles away from the clinical trials hospital (OR: 2.3, P = 0.043). However, 34% of pts who lived > 100 miles away received partial/full reimbursement of clinical trial-related travel costs from study sponsor/other/insurance. Racial/ethnic minority (OR: 2.6, P = 0.008) and pts who were unemployed or not working outside the home (OR: 2.4, P = 0.023) were more likely to report that actual medical costs were much higher than expected. 53% of pts used savings and 18% retirement accounts to pay for treatment. Conclusions: Among cancer pts participating on clinical trials, economic burden is high, and most of pts’ OOP costs were on non-medical expenses. Financial toxicity is disproportionally higher in pts with lower income. OOP costs can be substantial and are often unexpected for pts. Furthermore, prior participation in ≥1 Phase I clinical trial and living far away from the clinical trials hospital seem to increase risk of financial toxicity.
Escalated dosing schedules of CC-486 for patients experiencing first acute myeloid leukemia (AML) relapse: Results from the phase III QUAZAR AML-001 maintenance trial.
Authors: Dohner Hartmut , Wei Andrew , Montesinos Pau , Dombret Hervé , Ravandi Farhad , Sayar Hamid , Porkka Kimmo , Sandhu Irwindeep , Passamonti Francesco , Pane Fabrizio , Robak Tadeusz , Falantes Jose F. , Schuh Andre C. , Ossenkoppele Gert J. , La Torre Ignazia , Skikne Barry , Kumar Keshava , Dong Qian , Beach C. L. , Roboz Gail J.
Published: May 2020

7513

Background: A goal of AML maintenance therapy is to decrease the risk of relapse by suppressing growth of residual leukemic cells post-induction. CC-486 is an oral hypomethylating agent that allows for extended dosing schedules ( >7 days [d]/28d cycle) to sustain therapeutic activity. In the QUAZAR AML-001 trial (NCT01757535), CC-486 maintenance treatment (Tx) significantly prolonged overall (OS) and relapse-free survival vs. placebo (PBO) in pts with AML in first remission following induction chemotherapy (IC), who were not candidates for hematopoietic stem cell transplant (HSCT). Pts initially received CC-486 or PBO for 14d/cycle, but pts who relapsed with 5–15% blasts could receive escalated 21d/cycle dosing. We review outcomes of pts who received 21d dosing in QUAZAR AML-001. Methods: Pts were aged ≥ 55 years, with intermediate- or poor-risk cytogenetics and ECOG PS ≤ 3, and had achieved first CR/CRi after IC ± consolidation. Within 4 mo of CR/CRi, pts were randomized 1:1 to CC-486 300 mg or PBO QD on d 1–14 of 28d Tx cycles. CR/CRi status was assessed every 3 cycles. Pts relapsing with 5%–15% blasts in blood or bone marrow could receive study drug for 21d/cycle at the investigator’s discretion. Tx could continue until > 15% blasts, unacceptable toxicity, or HSCT. Results: 91 patients (CC-486, 51/238 [21%]; PBO, 40/234 [17%]) were assigned to ≥ 1 21d/cycle dosing schedule. Median time to dose escalation was 9.2 mo (range 1.0-52.7) for CC-486 and 6.0 mo (0.5-19.3) for PBO. Median number of 21d dosing cycles was 2.0 (range 1-45) in the CC-486 arm and 2.0 (1-16) in the PBO arm; 43% and 18% of pts, respectively, received > 3 cycles of 21d dosing. Among 78 evaluable pts, 10/43 (23%) CC-486 pts and 4/35 (11%) PBO pts regained CR/CRi (central review) during dose escalation. Median OS from randomization was 22.8 mo vs. 14.6 mo with CC-486 vs. PBO, respectively (HR 0.66 [95%CI 0.42, 1.0]; P = 0.073), and 1-year survival rates were 80.4% vs. 59.5% (+20.9% [95%CI 2.1%, 39.7%]). The most common AEs with first onset during 21d dosing were febrile neutropenia (CC-486 24%, PBO 3%), thrombocytopenia (22%, 23%), anemia (22%, 20%), and neutropenia (20%, 10%). Conclusions: Escalated 21d CC-486 dosing was well tolerated and resulted in prolongation of OS and restoration of remission in approximately one-fourth of pts. Hematologic AEs first reported during escalated dosing in both Tx arms may be due in part to disease relapse. A 21d dosing schedule should be considered for pts receiving CC-486 who experience relapse with 5–15% blasts. Clinical trial information: NCT01757535 .
CC-486 is safe and well-tolerated as maintenance therapy in elderly patients (≥75 years) with acute myeloid leukemia (AML) in first remission following induction chemotherapy: Results from the phase III QUAZAR AML-001 trial.
Authors: Ravandi Farhad , Wei Andrew , Dohner Hartmut , Dombret Hervé , Ossenkoppele Gert J. , Pfeilstöcker Michael , Thol Felicitas , Feldman Georg , Voso Maria Teresa , Marlton Paula , Harvey Michael , Santini Valeria , Fianchi Luana , Candoni Anna , La Torre Ignazia , Skikne Barry , Kumar Keshava , Dong Qian , Beach C. L. , Roboz Gail J.
Published: May 2020

7530

Background: About 40-50% of older patients (pts) with AML attain complete remission (CR) with induction chemotherapy (IC) but relapse is common.Effective, well-tolerated maintenance treatment (Tx) is needed for older pts in remission who are not eligible for hematopoietic stem cell transplant (HSCT). CC-486 is an oral hypomethylating agent that allows for extended dosing schedules ( >7 days [d]/cycle) to sustain therapeutic activity. In the phase III placebo (PBO)-controlled QUAZAR AML-001 trial (NCT01757535), CC-486 maintenance therapy in pts with AML in first remission following IC produced significant improvements in overall and relapse-free survival. Here we report safety and tolerability findings among pt subgroups defined by age at study entry. Methods: Eligible pts were ≥ 55 yrs of age, with de novo or secondary AML, intermediate or poor risk cytogenetics, and ECOG PS ≤ 3; had achieved first CR or CRi after IC ± consolidation; and were not candidates for HSCT. Within 4 mo of CR/CRi, pts were randomized 1:1 to CC-486 300 mg or PBO QD on d 1–14 of repeated 28d Tx cycles. Safety was assessed across 3 age subgroups (≥ 55 to < 65, ≥ 65 to < 75, and ≥ 75 yrs) in pts who received ≥ 1 dose of study drug. Adverse events (AEs) were coded using MedDRA v. 22.0 and graded by NCI-CTCAE v. 4.0. Results: 469 pts ( >99% of all enrolled pts) were evaluable for safety (CC-486 n = 236; PBO n = 233). Median age was 68 yrs (range 55-86). Age distribution was similar between the two Tx arms (Table). Between Tx arms, AE rates within each age stratum were similar to rates in the overall study population. The most common AEs (any grade) with CC-486 were GI events, which were more frequent than in the PBO arm across age groups. Within the CC-486 arm, AE rates were generally consistent across age groups, except for constipation, which was > 20% more frequent in pts aged ≥ 75 yrs, and thrombocytopenia, which was ≥ 20% less frequent in this group (Table). Overall, 13% and 4% of pts in the CC-486 and PBO groups discontinued Tx due to AEs. Conclusions: In QUAZAR AML-001, CC-486 was generally well tolerated in all age groups, including elderly pts aged ≥ 75 yrs. Clinical trial information: NCT01757535 . [Table: see text]
FACT physical wellbeing to independently predict overall survival in patients with acute myeloid leukemia.
Authors: Peipert John , Efficace Fabio , Pierson Renee F. , Yount Susan , Loefgren Christina , Cella David , He Jianming
Published: May 2020

7532

Background: Patient-reported outcomes (PROs) predict overall survival (OS) in solid cancer populations, but little evidence exists around the prognostic value of PROs in patients with hematologic malignancies. We investigated whether scales from the Functional Assessment of Cancer Therapy – Leukemia (FACT-Leu) predicted OS beyond established prognostic factors. Methods: Data were from 317 AML patients unfit for intensive therapy from a clinical trial comparing Dacogen (decitabine) plus Talacotuzumab versus Dacogen (decitabine) alone (AML2002; NCT02472145). We used ridge-penalized Cox models to determine whether baseline (1st cycle) FACT-Leu scales predicted OS. FACT-Leu scales significant in these models and factors from a validated prognostic model, the AML composite model (AML-CL; covariates listed in Table), were entered into Cox proportional hazard models. Lastly, model selection procedures were run with 1000 bootstrapped samples using all variables. The inclusion frequency of each FACT-Leu scale in the final models was examined to evaluate prognostic value for OS (i.e., higher the % of inclusion, higher importance of the variable). Results: In the ridge-penalized Cox models, the Physical Wellbeing Scale (PWB), Trial Outcome Index (TOI), and FACT-Leu Total scales were significant predictors of OS. After adjusting for the AML-CL factors, an important difference (2 pts) in PWB score was associated with a 9% decline in OS. (Table) Model validity was evidenced as the PWB scale appeared in a large majority of selected models (90%-97%), while the TOI (45%-73%) and FACT-Leu Total (41%-71%) appeared less often. Conclusions: FACT-Leu scales, especially the PWB, were significant prognostic factors for OS among AML patients not suitable for intensive therapy. These results may indicate PROs' value as stratification factors in trials with AML patients and underscore the need to more systematically collect PRO data in routine care practice with AML patients. Clinical trial information: NCT02472145 . [Table: see text]
Meta-analysis of case-control studies to examine the relationship between occupational pesticide exposure and risk of acute myeloid leukemia.
Authors: Vallet Nicolas , Foucault Amélie , Picou Frederic , Gyan Emmanuel , Herault Olivier
Published: May 2020

7540

Background: Occupational pesticide exposure (OPE) is associated with the risk of developing lymphoid malignancies, but less information is available on large cohorts about the risk of occurrence of acute myeloid leukemia (AML). To answer this question, we performed a meta-analysis including relevant adult case-control studies which reported OPE. Methods: Following PRISMA and MOOSE guidelines, two investigators performed a systematic search in PubMed and Cochrane databases for case-control studies evaluating the association between OPE and AML between 1946 and August 28, 2018. In order to identify the maximum number of studies, keywords related to demographical, pesticides and chemicals data exposures were used. Studies reporting AML diagnosis based only on death certificates, controls from cancer databases and pediatric cases (<15 years-old) were not included. Statistical analyses were performed with R software and the ‘mefafor’ package. Results: Fifteen studies which included 4,068 AML patients and 250,975 control subjects were included. Using a random effects model, the overall analysis showed a significant adverse association between OPE and AML with OR=1.49 (95%CI: 1.10-2.01), and a significant heterogeneity between studies ( I² =0.73, p<0.001). The robustness was checked after sequential exclusion of one study at a time which did not influence the overall OR estimate. A publication bias underestimating the OR was suggested by an asymmetrical funnel plot. Using trim-and-fill method, hypothetical missing studies were added studies in order to adjust the OR (OR=1.76 [95%CI: 1.30-2.38]. A stratified analysis showed that the association was significant in Asian populations (OR=1.74; 95%CI: 1.32-2.30) and upon exposure to insecticides (OR=1.45; 95%CI: 1.16-1.81), yet partly influenced by other factors, since most of the studies reported unadjusted results (n=8, 53%). Data on biological characteristics were unavailable to stratify patients according to AML molecular or cytogenetic characteristics. Conclusions: From this new extensive review and analysis, it clearly appears that AML should be considered as occupational illness in patients with demonstrated OPE. Further studies will have to focus on the biological effects of individual and pesticides cocktails in order to determine the pathogenesis mechanisms involved in leukemogenesis, and to improve individual protection.
Phase I study of the Bcl-2 inhibitor venetoclax with DA-EPOCH-R as initial therapy for aggressive B-cell lymphomas.
Authors: Rutherford Sarah C. , Abramson Jeremy S. , Bartlett Nancy L. , Barta Stefan K. , Khan Nadia , Joyce Robin , Maddocks Kami J. , Yuan Ying , Ali-Shaw Trisha , Senese Silvia , Westin Jason , Leonard John Paul
Published: May 2020

8003

Background: Dose-adjusted (DA) EPOCH-R is a frontline treatment for aggressive B-cell lymphomas. Bcl-2 is associated with chemoresistance due to BCL2 gene rearrangement or protein overexpression in lymphomas and is antagonized by BH3 mimetic venetoclax (ven). We conducted a phase I study combining ven with DA-EPOCH-R in aggressive B-cell lymphomas. Methods: This phase 1 study used Bayesian optimal interval design with dose expansion. Eligible patients (pts) were 18 years with newly diagnosed diffuse large B-cell (DLBCL), primary mediastinal, and high grade B-cell lymphoma (HGBCL) with double hit (DHL) or not otherwise specified (NOS). Ven was dosed at 400 mg (DL1), 600 mg (DL2), and 800 mg (DL3) daily for 10 days with 6 cycles of DA-EPOCH-R. A subsequent cohort received ven 600 mg daily for 5 days (DL2B). Toxicities were graded by CTCAE v4.0 and response assessed by Lugano criteria. Dose limiting toxicity (DLT) period was cycle 1 and primarily included grade (gr) ≥3 neutropenia on cycle 2 day 1, gr ≥4 febrile neutropenia/thrombocytopenia, and gr ≥3 nausea, vomiting, diarrhea despite supportive care. Results: 30 pts enrolled with median age 64 (24-79), and 50% female. Ann Arbor stage was III-IV in 23. IPI was high risk in > 50%. Diagnosis was DHL (15), DLBCL NOS (13), and HGBCL NOS (2). 18 had MYC and 14 had BCL2 rearrangements. Bcl-2 was expressed ≥50% by IHC in 21/26 with data. There were no DLTs in DL1 (3 pts) or DL2 (9 pts). 1/6 had DLT in DL3 (gr 4 thrombocytopenia). Ven dose reductions occurred in subsequent cycles in 4 (2 in DL2; 2 in DL3). Of 18 in DL1-3, EPOCH was escalated above level 1 in 1 and de-escalated below level 1 in 7. Because of delays and ven dose reductions in DL2-3 due in part to cytopenias, infections and GI toxicities, we accrued DL2B. In DL2B, 0/12 pts had DLTs or ven dose reductions. EPOCH was escalated above level 1 in 4 and de-escalated below level 1 in 3. 1 died of sepsis during cycle 3. Most common gr 3-4 toxicities across all dose levels were cytopenias; febrile neutropenia occurred in 57%. Most common non-hematologic toxicities of all grades were hypocalcemia, nausea, diarrhea, hypokalemia and fatigue. ORR (N = 30) ITT was 97% with 27 (90%) complete and 2 (7%) partial responses; 1 was not evaluable. Follow up is ongoing. Of 15 DHL, ORR and CRR were 93% and 80%. Conclusions: We identified ven 600 mg for 5 days per cycle as RP2D with DA-EPOCH-R. DL2B was well tolerated and required no ven dose reductions. Further efficacy and safety is being evaluated in Alliance 51701, DA-EPOCH-R/R-CHOP in DH/double expressor lymphomas, using the dosing regimen defined by this study. Clinical trial information: NCT03036904 .
Phase II, multicenter trial of nivolumab (Nivo) and brentuximab vedotin (BV) in patients (Pts) with untreated Hodgkin lymphoma (HL) over the age of 60 years or unable to receive standard ABVD chemotherapy: Results of a study of Academic and Community Cancer Research United (ACCRU) RU051505I.
Authors: Cheson Bruce D. , Bartlett Nancy L. , LaPlant Betsy , Lee Hun Ju , Advani Ranjana H. , Christian Beth , Magid Diefenbach Catherine S. , Feldman Tatyana , Ansell Stephen M.
Published: May 2020

8014

Background: HL is highly curable with > 90% of pts with limited and > 80% with advanced stage disease experiencing long-term disease-free survival. HL typically occurs in younger pts, yet 15-35% are > 60 yrs and experience a lower response rate, shorter survival, and greater toxicity. BV and checkpoint inhibitors have impressive activity in pts with relapsed and refractory HL. Thus, we initiated a phase II trial of BV-nivo in untreated pts with HL >60 yrs of age or considered unsuitable for standard ABVD therapy. Methods: Inclusion criteria: previously untreated pts with classical HL > 60 yrs or < 60 yrs but considered unsuitable for standard chemotherapy because of a cardiac ejection fraction of < 50%, diffusion capacity < 80%, or creatinine clearance > 30 but < 60 mL/min, or refused chemotherapy; ECOG PS 0-2, ANC >1500/mm3, platelets > 100,000/mm3, hemoglobin > 9 g/dl, bilirubin <1.5 x upper limits of normal (ULN), aspartate/alanine transaminases < 2.5 x ULN, amylase and/or lipase < 1.5 x ULN, and serum creatinine < 2.0 mg/dl. Pts received BV at 1.8 mg/kg (cap at 180 mg) and nivo 3 mg/kg every 21 days for 8 cycles. Response was assessed per the Lugano Classification. Results: The study accrued 46 pts between May 13, 2016-January 30, 2019. Median age of 71.5 yrs, 69.5% had ECOG PS 1 or 2; 64% stage III or IV; 39.1% with B symptoms; 4.3% were < 60 years. Median follow-up was 21.2 months (range 2.9, 38.5), and 35 pts (76.1%) completed all 8 cycles of therapy. At the interim analysis (1st 25 pts) ORR was 64% (52% mCR, 12% pMR) which was lower than the projected 80%. In all 46 pts, 45.7% achieved mCR and 15.2% mPR (ORR 60.9%); in evaluable pts, best ORR was 95% with 68% mCR. No clinical factors predicted response. Neither median duration of response nor median survival has been reached. Median PFS is 21.8 months (17.8, Not reached). 22 pts experienced 33 treatment delays, primarily due to BV. 22 pts experienced peripheral neuropathy (5 grade 3). Grade 4 toxicities included increased transaminases (n = 1), increased lipase and/or amylase (n = 2), pancreatitis (1). One pt died from cardiac arrest, possibly treatment-related. Conclusions: BV-nivo is active in untreated older HL pts with comorbidities. However, efficacy and response durability did not meet pre-specified criteria. Future trials based on these drugs, selecting pts most likely to benefit, may lead to a chemo-free approach for pts with HL. Clinical trial information: NCT02758717 .
Results of a completed phase I study of LAM-002 (apilimod dimesylate), a first-in-class phosphatidylinositol-3-phosphate 5 kinase (PIKfyve) inhibitor, administered as monotherapy or with rituximab or atezolizumab to patients with previously treated follicular lymphoma or other B-cell cancers.
Authors: Magid Diefenbach Catherine S. , Cohen Jonathan B , Harb Wael A. , Ansell Stephen M. , Nastoupil Loretta J. , Abramson Jeremy S. , Lakhani Nehal J. , Schreeder Marshall T. , Sher Taimur , Patel-Donnelly Dipti , Aboulafia David Michael , Fuchs Candace A. , Nix Darrell , Landrette Sean , Graham Patricia S , King Lydia B , Young Peter L. , Miller Langdon L. , Lichenstein Henri , Rutherford Sarah C.
Published: May 2020

8017

Background: LAM-002 is a selective inhibitor of PIKfyve that disrupts lysosomal homeostasis, inducing cytotoxicity in B-cell lymphoma models as monotherapy or with anti-CD20 or anti-PDL1 antibodies (Gayle et al., Blood 2017;129(13):1768). Methods: In this study, patients received LAM-002 orally 2-3 times per day (BID or TID) in a 3+3 escalation. Additional patients received LAM-002 125 mg BID as monotherapy; with rituximab 375 mg/m2 intravenously (IV) and or subcutaneously weekly (Q1W) x 4 → Q8W x 4; or atezolizumab 1200 mg IV Q3W until disease progression or unacceptable toxicity. Pharmacokinetics (PK) were assessed for 8 hours postdose on Days 1 and 8. Efficacy was evaluated Q6-12W. Results: The study enrolled 62 patients (M:F n = 32/30); median [range] age = 69 [46-89] years; with diagnoses (n) of diffuse large B-cell lymphoma (25), follicular lymphoma (19), marginal zone lymphoma (8), mantle cell lymphoma (5), or chronic lymphocytic leukemia (5) to receive LAM-002 alone (n) at 50 mg BID (3), 100 mg BID (8), 150 mg BID (8), 75 mg TID (4), or 125 mg BID (20); LAM-002/rituximab (12); or LAM-002/atezolizumab (7). During LAM-002 dose-ranging (50 mg BID → 100 mg BID → 150 mg BID → 75 mg TID → 125 mg BID) transient, reversible nausea and/or diarrhea occurred at 150 mg BID and 75 mg TID, resulting in a LAM-002 recommended Phase 2 dosing regimen (RP2DR) of 125 mg BID. Among 39 patients receiving LAM-002, 125 mg BID, alone or in combination for up to 22 cycles (1.9 years), adverse events were typically low-grade. LAM-002 PK showed rapid absorption, dose proportionality, minimal accumulation, and no substantive changes with rituximab or atezolizumab coadministration. In patients with follicular lymphoma and median [range] prior therapies = 3 [1-9] treated with the RP2DR, objective response rates were 2/7 (29%; 1 complete response [CR], 1 partial response [PR]) with LAM-002, 5/8 (63%; 1 CR, 4 PRs) with LAM-002/rituximab, and 2/2 (100%; 2 PRs) with LAM-002/atezolizumab. Conclusions: LAM-002, the first clinical PIKfyve inhibitor, is safe alone or with full-dose anti-CD20 or anti-PD-L1 inhibition. LAM-002 does not cause the myelosuppressive or immune adverse events associated with lenalidomide or PI3K inhibitors. Promising efficacy supports registration-directed Phase 2/3 testing of LAM-002 monotherapy and combination therapy for patients with previously treated follicular lymphoma. Clinical trial information: NCT02594384 .