bluuebunny/crossref_metadata_2025 huggingface dataset:
Reducing racial disparities in time to breast cancer diagnosis: Impact of immediate screening mammogram reads during the COVID pandemic.
Authors: Achibiri Janeiro , Dontchos Brian Nicholas , Mercaldo Sarah , Narayan Anand , Miles Randy C. , Lamb Leslie , Wang Gary X. , Lehman Constance Dobbins
Published: June 2021

6508

Background: During the COVID-19 pandemic, barriers to access screening mammography along with goals to reduce visits supported immediate reading of screening mammograms. Typically, screening mammograms are reported after patients have left the facility. If imaging is abnormal, then an additional visit is needed for diagnostic imaging, introducing delays and potential disparities .Thus, we implemented an immediate-read screening mammography program and measured its impact on racial/ethnic disparities in time to diagnostic imaging after an abnormal screening mammogram. Methods: Responding to the COVID-19 pandemic, we implemented an immediate read screening program in late May 2020. Patients were provided imaging results before discharge and if the exam was abnormal, efforts were made to perform diagnostic imaging during that visit. We identified consecutive screening mammograms performed weekdays 8:00am-4:30pm and Saturdays 9:00am-4:00pm pre-implementation (6/1/19-10/31/19) and post-implementation (6/1/2020-10/31/2020). Exams left unread while awaiting comparison studies, due to technical factors, or for more than 10 days were excluded. Patient demographics and time from screening exam completion to report finalized were obtained from the electronic medical record. Cancer detection rate (CDR), abnormal interpretation rate (AIR), and positive predictive value (PPV) were calculated. Multivariable linear and logistic regression models were used to compare time from screening exam to report, same-day diagnostic imaging, and screening performance metrics pre- and post-implementation overall and by patient subgroups. Results: After 963 exams met exclusion criteria, a total of 8,222 pre- and 7,235 post-implementation exams were included. Median time to report finalization decreased from 61minutes (interquartile range [IQR]:24, 152) to 4 minutes (IQR:2, 7) for pre- and post-implementation periods (p < 0.001). During the pre-implementation period, non-white patients had lower odds of having same-day diagnostic imaging after an abnormal screening exam (age-adjusted odds ratio: 0.28; 95% CI: 0.10, 0.78 p = 0.015). There was no evidence of this disparity post-implementation. AIR was higher in the pre- versus post-implementation period (6.3% versus 5.0%; p < 0.001). There was no evidence of a difference in CDR (5.8 versus 4.2 cancers/1,000 exams) and PPV (9.2% versus 8.4%) for pre- versus post-implementation periods. Conclusions: An immediate read screening mammography program reduces racial/ethnic disparities in time to diagnostic imaging after an abnormal screening mammogram, thus promoting equity in access to care.[Table: see text]
Racial and ethnic representation trends in United States oncology training programs.
Authors: Lombardi Conner , Lang Jacob , Issa Rochell , Ukaegbu Oke Oluchi , Reddy Krishna , Ekwenna Obi
Published: June 2021

6519

Background: Utilizing race and ethnicity data from the Accreditation Council for Graduate Medical Education (ACGME), this study aims to assess representation trends across American Society of Clinical Oncology (ASCO) participant specialties from the past five academic years in order to characterize current needs and effectively address these needs moving forward. Methods: Self-reported ethnicity/race data from the ACGME database books were collected from academic years 2015-16 to 2019-2020 for the following oncologic training programs: hematology and medical oncology, medical oncology, gynecologic oncology, pediatric hematology and oncology, radiation oncology, complex general surgical oncology. Summary statistics and chi-square analysis were conducted to compare underrepresented minority (URM) trends across programs. URM groups were cross-referenced with definitions provided by the AAMC and included those who identify as Hispanic, Latino or of Spanish origin, Black or African American, and Native American or Alaskan. Results: Over the study period, only 1,250 (9.0%) of 13,853 oncology trainees identified as URM. Chi-square analysis demonstrated no significant change in URM representation in all oncology specialties combined between 2015-16 and 2019-20 (8.9% [95% CI, 7.8%-10.0%] vs. 9.7% [95% CI, 8.7%-10.8%]; P=.31). Between 2015-16 and 2019-20, Hematology and oncology (+1.3%), pediatric hematology and oncology (+0.3%) all demonstrated insignificant increasing trends in representation while radiation oncology (-0.3%), complex general surgical oncology (-4.0%) had statistically insignificant decreasing trends in representation. Gynecologic oncology (+6.0%) demonstrated a significant increasing trend in representation. Conclusions: This is the first study to characterize the vast disparities in representation in oncologic training programs in the United States. There is a demonstrated lack of representation across all oncology training programs and a lack of significant improvement over the study period. A multiprong approach is needed to improve diversity and representation across the spectrum of the oncology workforce in the United States.
Investigating tumor molecular profiling as a possible contributor to racial/ethnic disparities in pancreatic cancer.
Authors: Walker Evan Justin , Piawah Sorbarikor , Griffin Ann , Carnevale Julia C. , Cinar Pelin , Collisson Eric Andrew , Tempero Margaret A. , Ko Andrew H.
Published: June 2021

6522

Background: A variety of biologic, socioeconomic, and treatment-related factors may contribute to the racial/ethnic disparities observed in pancreatic ductal adenocarcinoma (PDAC) outcomes. As tumor molecular profiling (TMP) is now recommended for patients (pts) with advanced PDAC to inform treatment selection, we hypothesized that rates of TMP, detection of actionable alterations (AA), and use of molecularly-targeted treatments differ across different racial/ethnic groups and may contribute to disparate outcomes. Methods: This retrospective analysis included all Non-Hispanic White (NWH), Asian, Hispanic/Latinx (H/L), and Black/African American (B/AfrAm) pts with PDAC who underwent TMP at UCSF over a 4-yr period. Medical records were reviewed for demographic and disease-specific data. Alterations classified as ‘pathogenic’ or ‘likely pathogenic’ in TMP clinical reports were included, and were categorized as ‘actionable’ if there was clinical or preclinical evidence of benefit from targeted therapy in any cancer. Associations between NHW and other groups were tested with Fishers exact test. Results: Between 1/2016-1/2020, 159/727 (22%) pts underwent PDAC TMP. 60 AA were detected in 54 pts. Rates of TMP or AA detection were not associated with racial/ethnic group (Table). Most AA (33/60, 55%) were associated with the Homologous Recombination DNA Damage Repair (HR-DDR) pathway ( ARID1A n = 15 , ATM n = 7 , and BRCA1 n = 5). Other common AA included PIK3CA alterations (n = 6), CDK4/6 amplifications (n = 5), AKT2 amplifications (n = 4) and KRAS G12C mutation (n = 4). Molecular targets differed between groups (HR-DDR genes comprised 55% AA in NHW vs 100% in H/L, p = 0.03). Regarding treatment, rates of platinum chemotherapy for HR-DDR gene-altered PDAC differed significantly between groups. Three NHW pts with HR-DDR alterations received a PARP-inhibitor +/- ATR inhibitor. Conclusions: To our knowledge, this is the first study to report PDAC TMP rates and therapeutic implications across racial/ethnic groups. Acknowledging the limitations of sample size and what defines AA, we observed no significant differences in rates of testing nor AA detection. Further study is needed to evaluate whether rates of molecularly-informed treatment selection contribute to racial/ethnic disparities in clinical outcomes. As therapeutic advances increase the likelihood of identifying AA, equitable access to both TMP and targeted treatments must be ensured for all pts with PDAC.[Table: see text]
Uptake of immunotherapy in patients with advanced cancer: A population-based study using health administrative data from Ontario, Canada.
Authors: Raphael Jacques , Richard Lucie , Lam Melody , Blanchette Phillip S. , Leighl Natasha B. , Rodrigues George , Trudeau Maureen E. , Krzyzanowska Monika K.
Published: June 2021

6529

Background: The introduction of immunotherapy (IO) in the treatment of patients with cancer has significantly improved clinical outcomes. Herein we report on IO uptake in Ontario, Canada, a publicly funded healthcare system. Methods: We conducted a retrospective cohort study using provincial health administrative data to: 1) assess IO uptake in adult patients with advanced melanoma, bladder, lung, head and neck (HN) and kidney cancers; and 2) identify predictors of IO usage between 2011 (pre-IO funding) and 2019. The datasets were linked using unique encoded identifiers and analyzed at ICES. IO uptake was captured between cancer diagnosis and last follow up and reported as a proportion of the entire cohort and by tumor site and drug type. A competing risk Fine and Gray regression model with death as competing risk was used to identify factors associated with IO use. Results: Among 59,510 patients with one of the five advanced cancers of interest, 7,660 (12.9%) received IO. Details of IO uptake are summarized in Table. IO uptake increased yearly from 2011 (2.7%) to 2019 (34.0%). Uptake was highest in melanoma (48.2%) and lowest in HN cancer (5.8%). The most commonly used drugs used were pembrolizumab (41.1%) and nivolumab (40.5%). In adjusted analysis, predictors of lower IO uptake included older age (hazard ratio (HR) 0.953, 95%CI 0.934-0.972 with every additional 10 years), female sex (HR 0.859, 95%CI 0.819-0.9), lower income quintile (HR 0.893, 95%CI 0.83-0.96), history of hospital admission (HR 0.768, 95%CI 0.734-0.805), female oncologist (HR 0.942, 95%CI 0.892-0.995), and de novo stage 4 cancer (HR 0.918, 95%CI 0.873-0.966). Predictors of higher IO uptake were low Charlson score (HR 1.118, 95%CI 1.01-1.236) and previous radiation therapy (HR 1.438, 95%CI 1.367-1.512). IO uptake was heterogeneous across cancer centres levels (1 to 4) and regions. Conclusions: While the use of IO for advanced cancer has steadily increased over time, uptake is associated with patient and physician characteristics, as well as system level factors. This variation suggests potential inequity in access to these potentially life-prolonging drugs and should be further investigated and addressed.[Table: see text]
Process redesign and daily management to improve cancer care access at the public healthcare system in Sao Jose dos Campos, Brazil.
Authors: Pinto Carlos Frederico , Stanzani Danilo , Pontes Elitania , Coelho Stela Maris , Correa Margarete , Benjamin Joana , Silva Messias Borges
Published: June 2021

6530

Background: Cancer is the second leading cause of death in Sao Jose dos Campos (SJC, a mid-sized city with 720,000 hab. in Sao Paulo state, Brazil) and the most relevant budget in tertiary care. The City Healthcare Authority created in October 2018 a team to manage and provide more effective and efficient cancer care and access to the public healthcare system by using process redesign and daily management tools (Previna Project). The aim was to guarantee access to cancer specialist and care up to 60 days form diagnosis, understanding that this can impact in cancer morbidity, mortality, and cost. Methods: The Previna was grounded in 4 major actions: (1) process redesign (2) escalated daily management system, (3) improve communication channels to all providers connecting primary care to specialized care, (4) and emergency access. (1) Process Redesign involved connecting and linking access to several providers and eliminating unnecessary steps or repeated orders in the system, it also involved alerts into the system for specific conditions like elevated PSA or CEA; positive fecal occult blood test; BIRADS 4-5 mammogram; abnormal PAP smears; and new screening protocols for prostate and colorectal cancer. (2) Daily Management involved internal daily discussions about capacity and review of system alerts or demands. Weekly discussions on specialized procedures including imaging, biopsies, chemo, radiation or surgery flows; and biweekly meetings with all providers (3 hospitals and 4 specialized practices). (3) Communication channels improvements involved a hotline to access flow managers for primary and secondary care units, specialist’s consultancy by phone, and (4) emergency access provided for units with special needs or urgent care requirements. All actions were connected by flow managers using alert systems, visual boards, kanban and similar tools to manage daily progress. Results: The access to cancer care and treatment up to 60 days improved from 2017 to 2020 almost two-fold with the Previna (Table). Cancer diagnosis also increased substantially, and it is expected to be related to previous periods underdiagnosed patients. Flow redesign also reduced median time to process Her2, ER and PR for breast cancer from 38 days in 2018 to 9 days in 2019 and 4 days in 2020, positively impacting treatment decisions. The hotline access reviewed and answered 2,389 demands from care providers between 2018 and 2020. Access to Cancer Care for ICD C00 – C97 (excl. C44 and C73) in SJC. Conclusions: The combined use of daily management, lean tools and flow redesign in the Previna was able to improve access and anticipate cancer diagnosis in a public healthcare system using simple and low-cost initiatives.[Table: see text]
High incidence of concurrent disease states detected during mobile lung cancer screening in an underserved population.
Authors: Carrizosa Daniel R. , Doege Darcy L. , Wheeler Mellisa S , Dungan Kia , Davis Lauren , Hickman Glenn , Weatherford Brooke , White Stephanie , Doty John D. , Mileham Kathryn Finch , Raghavan Derek
Published: June 2021

6540

Background: Studies such as the National Lung Screening Trial (NLST; N Engl J Med 2011;365:395-409) have shown a survival benefit to low-dose Lung CT screening in high-risk smokers. Levine Cancer Institute (LCI) initiated the first mobile low dose computerized tomographic (LDCT) lung screening program for underserved populations in 2017. In addition to being able to intervene early in the natural history of lung cancer, the project has also shown a previously unreported high incidence of incidental diseases in this population. We characterize these findings in 1198 patients. Methods: From May 2017, subjects with criteria eligible for NLST screening were identified and underwent LDCT for lung cancer detection. Patients screened in the program were all uninsured or underinsured, mean age 60.8 years, 18% were African American, 3% Latin-x and 78% were rural with an overall 47.1 mean pack-year smoking history. These patients were screened using a novel mobile LDCT (J Clin Oncol 37, 2019 suppl; abstr 6567) created for this program. By December 2020, 1198 patients completed their first screening. All CT scans were reviewed by two separate radiologists and were reviewed for quality assurance by a separate expert multidisciplinary team. Results: Of the 1198 subjects, 84% (1006 subjects) were found by LDCT to have a least one incidental disease. More than half of the subjects (645, 53.8%) had coronary atherosclerosis. Of those, 25% (183) were described to have at least moderate disease with 8% (96) described as severe. Overall, 42% (504) were found to have emphysema and 25% (299) had vascular atherosclerotic disease; 1.8% (22) of those screened had a detected aortic aneurysm. In total, thirty separate disease findings were found (listed from fourth to tenth most common finding: degenerative spine changes [205], cholelithiasis [59], hiatal hernia [52], pericardial effusions [38], fatty liver [32], kidney stone [3]), and cardiomegaly [30]). 3.5% (42) were found to have an undiscovered breast, adrenal, liver or kidney mass that required further workup. Conclusions: The number of incidental findings in our mainly rural underserved subject group was very high (84%). 35.5% of patients in the National Lung Screening Trial died from heart disease or respiratory disease. These numbers have not been overtly discussed and our study confirms the number of concerning incidental diseases that can lead to morbidity or mortality. In this high-risk, underserved population of heavy smokers, the opportunity for positive impact on other disease states can be increased by a mobile lung cancer screening program by increasing access to care.
Racial disparity in uterine cancer treatment and survival: A matter of Black women’s lives.
Authors: Balanean Alexandrina , Falkenstein Angelica , Zettler Marjorie E. , Klink Andrew J. , Savill Kristin M. Zimmerman , Kish Jonathan , Brown-Bickerstaff Cherrishe , Jeune-Smith Yolaine , Gajra Ajeet
Published: June 2021

6550

Background: Despite similar incidence rates of uterine cancer (UC) in Black and White women, the former have worse prognosis and survival. Absence of denominator correction for UC hysterectomy (prevalence varies within the United States [US] by race/region) may underestimate incidence. The objective of this study is to compare treatment and survival of patients with UC by race in a large, contemporary, population-based study with at least 5 years of follow-up. Methods: With the latest available data from the Surveillance, Epidemiology, and End Results database, comparisons between Black and White patients were made using chi-square and Mann-Whitney tests. Cox proportional hazards regression estimated the adjusted risk of mortality by including age at diagnosis, race, US region, tumor histology/stage/grade, and receipt of hysterectomy as covariates. Results: A total of 105,036 women (11,028 Black and 94,008 White) newly diagnosed with UC in 2000-2013 and followed through 2018 were identified. Median age at diagnosis was 62 years, and more patients in the South were Black (41% vs 17%, P<.0001). Higher rates of type 2 (15% vs 6%), late-stage (44% vs 28%), and high-grade (48% vs 25%) tumors at diagnosis were also found in Black women (all Ps<.0001; Table). Compared with White women, Black women had lower 5-year survival rate (18% vs 37%, P<.0001), shorter survival (median 49 vs 78 months, P<.0001), and higher adjusted mortality risk (hazard ratio [HR]: 1.3, 95% CI: [1.3, 1.4], P<.0001). Lack or unknown status of hysterectomy was also associated with higher death risk (HR: 3.6, 95% CI: [3.4, 3.9], P<.0001). Conclusions: Correcting for hysterectomy attenuates racial disparity in incidence; however, black women have inferior outcomes primarily due to increased aggressive histology, late-stage, and high-grade tumors as well as decreased use of hysterectomy. Underestimation of at-risk populations may be misdirecting cancer control efforts, highlighting the importance of accurate reporting to inform potential treatment adaptations. Next steps are to assess cancer-specific mortality with Fine-Gray competing risk models.[Table: see text]
Characteristics of patients hospitalized through the emergency department with an oncology drug-related side effect.
Authors: Avalos-Reyes Elisea , Parke Darren , Wallace Kirsten , Freeman Allison , Johnson Kjel Andrew
Published: June 2021

6557

Background: Recent advances in oncology treatment present an expanding spectrum of cancer-treatment-related emergencies.Many aspects of healthcare utilization, specifically emergency department (ED) visits, are not well studied in this population. The purpose of this study is to determine (1) what proportion of cancer patients visit the ED with an oncology drug-related side effect and are admitted and (2) what factors impact the probability of inpatient admission among these patients. Methods: This study evaluated ED visits by adult patients undergoing active drug treatment for cancer insured by a large commercial and Medicare health plan in the United States between January 1, 2018, and September 30, 2019. Among cancer-related ED visits, logistic regression was used to determine the marginal effect of demographic and clinical characteristics of patients on acute inpatient admission. Results: There were 39,921 total ED visits among patients undergoing drug treatment for cancer; of these, 76% presented with an oncology drug-related side-effect. 36% of all ED visits resulted in admission, 5% resulted in an observation stay. After adjusting, age was not a significant predictor of inpatient admission. Being male (p < 0.01) and living in urban (p < 0.01) or suburban (p < 0.01) zip codes significantly increased the likelihood of admission. Patients with colorectal (p = 0.019), gastrointestinal (p < 0.01), blood (p < 0.01), lung (p < 0.01), metastatic (p < 0.01) cancers, or Hodgkin’s lymphoma (p < 0.01) had significantly increased risk of admission. Patients with prostate (p < 0.01) cancer had a significantly reduced risk of admission. The primary complaint upon presentation to the ED was the most important predictor of inpatient admission; sepsis, pneumonia, medical complications, white cell disorders, metastatic cancer, and fractures were all associated with a significantly higher (all p < 0.001) risk of admission. Patients with comorbid heart failure (p < 0.001), those taking ulcer medications (p < 0.01), or inflammatory bowel disease (p = 0.03) had a significantly increased risk of admission. Results were consistent regardless of payer (Medicare or commercial health plan). Conclusions: This study identified cancer patients for whom acute inpatient admission from an ED presentation is more likely. Future studies identifying cancer patients who may be at risk of making an ED presentation based on demographic, clinical and disease-related characteristics are needed and may help inform targeted follow up of patients to mitigate potentially avoidable ED presentation and subsequent inpatient admission.
The landscape of mortality during or within 30 days after non-palliative radiotherapy across 11 major cancer types.
Authors: Xiang Michael , Raldow Ann C. , Pollom Erqi L. , Steinberg Michael L. , Kishan Amar Upadhyaya
Published: June 2021

6570

Background: The rate of peri-RT mortality (death that occurs during or within 30 days after non-palliative radiotherapy) has not been previously characterized. Risk factors and predictors for peri-RT mortality are unknown. Methods: Adult and pediatric patients with non-metastatic cancer who received non-palliative external beam radiation between 2004-2016 were identified in the National Cancer Database for 11 cancer types: breast, prostate, genitourinary (non-prostate), bone/soft tissue, gynecological, head/neck, lymphoma, gastrointestinal, small cell lung, non-small cell lung, and central nervous system (CNS). Multivariable logistic regression was used to identify predictors of peri-RT mortality while controlling for 16 covariates, including patient, tumor, and treatment factors. Results: Approximately 1.32 million patients were identified. Peri-RT mortality was 2.8% overall but spanned 2 orders of magnitude depending on cancer type, ranging from 0.1% for breast cancer to 8.6% for CNS malignancies. Other cancers with > 5% peri-RT mortality were non-prostate genitourinary, small cell lung, and non-small cell lung. Peri-RT mortality steadily improved from 3.5% in 2004 to 2.0% in 2016 ( P <.0001). Major predictors of peri-RT mortality were cancer stage, older age, baseline comorbidity, and lack of private insurance, while male sex, Black race, and geographical region were associated with modestly increased risk (all P <.0001). Conversely, treatment at an academic center, higher patient volume at the treating facility, concurrent chemotherapy, and intensity-modulated radiotherapy were associated with modestly decreased risk (all P <.0001). Among patients receiving stereotactic radiotherapy, peri-RT mortality was 1.0% (adjusted odds ratio 0.27, 95% confidence interval 0.24-0.30, P <.0001), underscoring the excellent safety record of this treatment approach. Conclusions: Peri-RT mortality varied considerably as a function of multiple disease-specific and sociodemographic differences, which highlight potential areas of health disparities. Early recognition of patients at increased risk may facilitate closer monitoring or other prophylactic interventions.
Patient and treatment characteristics of emergency presentations due to immune-mediated toxicities.
Authors: Nahm Sharon Hyo-Eun , Heywood Richard , Callaghan Sophia , Serra-Bellver Patricio , Gupta Avinash , Cooksley Tim , Lorigan Paul
Published: June 2021

6586

Background: The prevalence of immune-mediated toxicities from immune checkpoint inhibitors (ICIs) is well described. However, the characteristics and treatment patterns for patients with emergency presentations due to immune-mediated toxicity are less well known. Methods: This study of all emergency presentations in patients treated with ICIs was performed at The Christie NHS Foundation Trust, Manchester, United Kingdom from May 2018-February 2020. The aims were to describe the patient and treatment characteristics of those diagnosed with an immune-mediated toxicity. Results: In total, 597 patients receiving ICIs had an emergency presentation and 191/597 (32%) were diagnosed with an immune-mediated toxicity. Of these patients, the median age was 64 years and 127/191 (67%) were male. The most common tumour types were melanoma (53%) and lung (22%) and the most common ICI received was ipilimumab + nivolumab combination immunotherapy (42%), followed by pembrolizumab monotherapy (21%) and nivolumab monotherapy (20%). The median number of cycles received was 3 (range 1-54), and 73/191 (38%) previously had ≥ grade 2 immune-mediated toxicity. The most common diagnoses were colitis (38%), hepatitis (15%), and pneumonitis (14%). The majority, 180/191 (94%) received steroids and 52/180 (29%) patients required second-line immunosuppression. The most common second-line immunosuppressants used were mycophenolate mofetil (58%) and infliximab (50%). Eleven patients (22%) required more than one second-line immunosuppressant. Conclusions: The majority of patients with emergency presentations due to immune-mediated toxicity were being treated with combination immunotherapy for melanoma. More than a third of patients had previous ≥ grade 2 immune-mediated toxicity. Over one quarter of patients treated with steroids required second-line immunosuppression. Identifying these characteristics can help inform which patients receiving ICIs seeking medical review need admission to a center with experience in managing immune-mediated toxicity.
Leveraging the electronic medical record (EMR) to predict patient reported financial hardship in cancer patients.
Authors: Voleti Sandeep Sai , Ailawadhi Sikander , Mead-Harvey Carolyn , Warsame Rahma M. , Fonseca Rafael , Griffin Joan M. , Khera Nandita
Published: June 2021

6594

Background: Patient reported financial hardship (FH) in cancer care is a growing challenge for patients, their caregivers and healthcare providers. As treatment costs escalate, it is imperative to develop effective strategies to proactively recognize and mitigate FH within oncology practice. Using automated processes to screen and refer patients to appropriate resources is a potential option. At Mayo Clinic, screening for FH involves using a single financial strain question ‘ How hard is it for you to pay for the very basics like food, housing, medical care, and heating?’ completed by all cancer patients annually as part of the Social Determinants of Health (SDOH) assessment. In this study, we describe the prevalence and predictors for FH (denoted by the answer ‘hard and very hard’) in our patient population. Methods: Patients receiving cancer care at the three Mayo Clinic sites (Minnesota, Arizona, and Florida) who completed the FH screen at least once were included in this study. Demographics (age, gender, race/ ethnicity, insurance, employment status, marital status, and zip code) and disease state data for included patients was extracted from the EMR and Mayo Clinic Cancer Registry. Disease state was categorized by type of cancer (hematological or solid malignancy) and cancer stage. Zip code was used to derive median income, rural/urban residence and distance from the cancer center. Multivariable logistic regression models were utilized to examine factors associated with FH. Results: The final study cohort included 31,969 patients with median age 66 years (IQR 57,73), 51% females, and 76% married. Race/ethnicity composition was 93% White, 3% Black, and 4% Hispanic. 52% of patients had Medicare and 43% had commercial insurance. Other notable factors included 48% retired, 41% working/ students, 76% married, and 72% urban residents. Median time from cancer diagnosis was 1.1 year (IQR 0.1, 3.8) and median income was $64,406 (IQR 53,067, 82,038). 31% of patients had hematological malignancies, 20% of the cancers for which staging information was available were metastatic. FH was reported by 4% (n = 1194) of the patients. A significantly higher likelihood of endorsing FH (p < 0.001 for all) was noted in Hispanic (OR 1.64), Black (OR 1.84), American Indian/Alaskan native (OR 2.02), below median income (OR 1.48), rural (OR 1.17), self-pay (OR 2.77), Medicaid (OR 2.29), Medicare (OR 1.43), unemployed/disabled (OR 2.39), single (OR 2.07), or divorced (OR 2.43) patients. Older age, being retired, and living farther from the cancer center were associated with significantly less likelihood of endorsing FH. Conclusions: Our study successfully leveraged the EMR to identify key sociodemographic groups more likely to report FH. An electronic trigger to flag such patients at high-risk of FH and proactively address FH is currently being developed.
Prognostic factors of overall (OS) and relapse-free survival (RFS) for patients with acute myeloid leukemia (AML) in remission after intensive chemotherapy (IC): Multivariate analyses from the QUAZAR AML-001 trial of oral azacitidine (Oral-AZA).
Authors: Roboz Gail J. , Wei Andrew H. , Ravandi Farhad , Pocock Christopher , Montesinos Pau , Dombret Hervé , Porkka Kimmo , La Torre Ignazia , Skikne Barry , Zhong Jianhua , Beach C. L. , Dohner Hartmut
Published: June 2021

7014

Background: Demographic and disease factors influence outcomes for patients (pts) with AML. In the phase 3 QUAZAR AML-001 trial, Oral-AZA significantly prolonged OS and RFS vs. placebo (PBO) for pts with AML in first remission after IC (Wei, NEJM, 2020). Univariate analyses showed OS and RFS benefits with Oral-AZA vs. PBO across pt subgroups defined by baseline (BL) characteristics. MV analyses were performed to identify BL characteristics independently predictive of OS/RFS in QUAZAR AML-001, and to assess Tx effects of Oral-AZA vs. PBO on survival when adjusted for BL factors. Methods: Pts were aged ≥55 yrs with AML in complete remission (CR) or CR with incomplete count recovery (CRi) after induction ± consolidation. Within 4 months of CR/CRi, pts were randomized 1:1 to receive Oral-AZA 300 mg or PBO for 14d/28d cycle. Cox proportional hazards models were used to estimate Tx effects of Oral-AZA vs. PBO on OS and RFS, adjusting for BL age, sex, ECOG PS score, cytogenetic risk at diagnosis (Dx), prior MDS, geographic region, CR/CRi after induction (per investigator) and at BL (per sponsor), MRD status, receipt of consolidation, number of consolidation cycles, platelet count, and ANC. In a stepwise procedure, randomized Tx and BL variables were selected incrementally into a Cox model if P ≤ 0.25. After each addition, the contribution of the covariate adjusted for other covariates in the model was evaluated and retained in the model if P ≤ 0.15. Results : Oral-AZA Tx remained a significant independent predictor of improved OS (HR 0.70) and RFS (HR 0.57) vs. PBO after controlling for BL characteristics (Table). MRD status, cytogenetic risk, and pt age were each also independently predictive of OS and RFS. Response after induction (CR vs. CRi) and BL ANC were predictive of OS but not RFS, whereas prior MDS, CR/CRi at BL, and number of consolidation cycles were only predictive of RFS. Conclusions: Tx with Oral-AZA reduced the risk of death by 30% and risk of relapse by 43% vs. PBO independent of BL characteristics. Cytogenetic risk at Dx, MRD status, and pt age also independently predicted survival outcomes. Clinical trial information: NCT01757535. [Table: see text]
Predictive phosphoproteomic signatures for midostaurin plus chemotherapy response in FLT3 mutant positive acute myeloid leukaemia.
Authors: Dokal Arran David , Arruda Andrea , Smith Ryan , Greenhalgh Calum , Patella Francesca , Casado-Izquierdo Pedro Maria , Wrench Bela , Theaker Jane , Thompson Andrew , Minden Mark D. , Gribben John G. , Britton David James , Cutillas Pedro Rodriguez
Published: June 2021

7019

Background: Midostaurin is approved for FLT3 mutant-positive (FLT3+) acute myeloid leukemia (AML), however efficacy has also been observed in a subpopulation of FLT3 mutant-negative AML, suggesting that FLT3 mutation is not the only determinant in conferring midostaurin sensitivity. We previously described a phosphoproteomic signature significantly elevated in primary AML blasts that responded to midostaurin ex vivo (Casado et al Leukaemia 2018). This signature includes phosphorylation sites on protein kinase C delta (a midostaurin off-target) and its substrate GSK3A. In this study, we tested whether these phospho-signatures could group FLT3+ patients based on clinical responses to midostaurin plus chemotherapy. Methods: We obtained FLT3+ bone marrow (BM) and peripheral blood (PB) diagnosis specimens (n=56 cases) from the Leukemia Tissue Bank at Princess Margaret Cancer Centre. These patients were treated with standard chemotherapy plus midostaurin. Phospho-signatures quantified using mass spectrometry were analysed with a classification machine learning algorithm to group patients based on response to treatment as a function of phospho-signature status. Other features (e.g. genetic mutations, HSC-transplant) were also analysed. Differential survival analysis was carried out with Kaplan-Meier and Log Rank test methods. Phospho-signatures for BM and PB samples were analysed independently. Results: A first ML model was developed based on the signature described in the Casado et al study. Patients positive for this signature exhibited a survival probability of 243 weeks, compared to 126 weeks in signature negative patients (averages by geometric mean, Log Rank p = 9.88e-05). As the patients in the current study received chemotherapy, in addition to midostaurin, we also identified a new signature consisting of 26 phospho-sites (model 2), which partially overlapped with the first model. Patients positive for model 2 signature showed a markedly longer survival time than negative patients (269 vs 76 weeks, Log Rank p = 1.30e-05 for PB and 241 vs 56, Log Rank p = 2.13e-09 for BM specimens, Table). No other features separated survival as clearly as model 2. Conclusions: We have identified phospho-signatures with the potential to further stratify FLT3+ AML for midostaurin treatment. The presence of PRKCD signalling components in signatures provides a rationale for midostaurin activity in sensitive cases. Analysis will also be performed on FLT3 mutant-negative cases to validate the signature in this group.[Table: see text]
High dimensional mapping of temporal evolution within the marrow microenvironment in response to FLT3 inhibitor therapy.
Authors: Newman Matthew , Joshi Sunil K. , Bottomly Daniel , McWeeney Shannon , Druker Brian J. , Lind Evan , Traer Elie A.
Published: June 2021

7020

Background: The advent of genomic sequencing technologies has revealed underlying genetic alterations, such as FLT3 mutations, that can be targeted in acute myeloid leukemia (AML). However, development of resistance limits the durability of response. Recent data has implicated that factors from the bone marrow microenvironment mediate initial resistance to FLT3 inhibitors (FLT3i) in AML. We combined high dimensional characterization techniques, time-of-flight mass cytometry (CyTOF) and RNA sequencing, to examine sequential marrow stromal samples from a subset of patients with FLT3 mutated AML treated with the FLT3i gilteritinib. Here, we report on the heterogeneity and evolution of cell surface and secreted factors over time. Methods: RNA sequencing of primary FLT3-ITD stromal samples (N = 29) from pre-study and on-treatment patients enabled prioritization of candidate targets for CyTOF. Target-specific purified antibodies were purchased pre-conjugated to metal lanthanides or conjugated in house according to manufacturer protocols (after validation via traditional flow cytometry). Primary stromal cells were cultured ex vivo until confluent and were harvested and stained according to a standardized protocol, and subsequently run on a Helios (Fluidigm) mass cytometer. A computational approach was employed to compensate and visualize data via the CATALYST R package. A total of four pre-treatment and four post-gilteritinib timepoint isolates (N = 8) were analyzed. Results: A 36-target mass cytometry panel revealed protein level differences in patients before and after gilteritinib therapy. Dimensional reduction techniques such as MDS and UMAP showed that samples taken from later timepoints clustered together compared to their earlier counterparts with respect to global protein expression. Inflammatory mediators such as IL1-beta and MCP-1 were upregulated in patient stroma soon after gilteritinib treatment and therefore potentially contribute to early resistance. Novel markers previously implicated in early resistance to targeted therapies in AML such as FGF2 and FGFR1 similarly peaked earlier in treatment, mimicking the clinical course of expression observed in marrow stroma of patients treated with another FLT3 inhibitor quizartinib (Traer et al. Cancer Res. 2016). Conclusions: Our findings show that primary marrow stroma evolves during gilteritinib treatment, and that stromal proteins previously reported to promote early resistance to FLT3i are also upregulated during gilteritinib resistance. The heterogeneity of stromal cell isolates detected by mass cytometry highlights the utility of high dimensional tracking of disease course in patients, and may enable a better understanding of how the temporal evolution of the marrow microenvironment contributes to development of resistance to targeted therapies such as gilteritinib and other FLT3i over time.
Preliminary results of V-FAST, a phase 1b master trial to investigate CPX-351 combined with targeted agents in newly diagnosed AML.
Authors: Pullarkat Vinod , Levis Mark J. , Mannis Gabriel N. , Strickland Stephen Anthony , Lin Tara L. , Faderl Stefan , Chakravarthy Divya , Chandrasekaran Vijayalakshmi , Cheung Ronald , Erba Harry Paul
Published: June 2021

7026

Background: CPX-351 (US: Vyxeos; EU: Vyxeos Liposomal), a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar drug ratio, is approved by the US FDA and EMA for adults with newly diagnosed t-AML or AML with myelodysplasia-related changes. Preclinical data suggest CPX-351 may exert synergistic activity when combined with agents such as the BCL-2 inhibitor venetoclax (VEN) or FLT3 inhibitor midostaurin (MIDO). Methods: V-FAST (Vyxeos – First Phase Assessment With Targeted Agents) is an open-label, multicenter, phase 1b master trial (NCT04075747) to evaluate safety and establish the recommended phase 2 dose (RP2D) of CPX-351 combined with targeted agents in patients (pts) aged 18-75 y with untreated AML who are fit for intensive chemotherapy. The study includes a dose-exploration phase (3+3 design) and subsequent expansion phase. Pts received CPX-351 (dose level 1 for first induction [DL1]: 100 units/m2 on Days 1, 3, and 5) plus VEN (Arm A; DL1: 400 mg on Days 1-14), MIDO (Arm B; DL1: 50 mg BID on Days 8-21), or the IDH2 inhibitor enasidenib ([ENA] Arm C; DL1: 100 mg on Days 8-28) based on mutation testing. Results: Among 21 pts with available data enrolled by 11/06/20 (24 pts enrolled total; data cut-off: 01/19/21), the median age was 54 y (range: 35, 69). In Arm A (n = 17), 11 (65%) pts had de novo AML, 5 (29%) had an antecedent hematologic disorder (2 [12%] had myelofibrosis), and 2 (12%) had t-AML; 12 (71%) had adverse-risk AML; and 6 (35%) had mutated TP53. In Arms B (n = 3) and C (n = 1), all pts had intermediate-risk de novo AML. DL1 was the RP2D in Arms A and B; the RP2D in Arm C is still under investigation. In Arm A, 1/6 pts in the dose-exploration phase had 2 dose-limiting toxicities (DLTs) of grade 4 neutropenia and thrombocytopenia that extended beyond 49 days; no DLTs have occurred for Arms B and C. The combinations exhibited manageable safety profiles (Table). Of pts with available response data, complete remission (CR) or CR with incomplete platelet or neutrophil recovery was achieved by 6/14 (43%) pts in Arm A, including 4 (29%) with CR. All pts in Arms B and C achieved CR. Conclusions: These preliminary results suggest CPX-351 can be combined with VEN and MIDO with manageable toxicities in newly diagnosed AML pts, with DL1 determined to be the RP2D. The study is ongoing and actively enrolling pts; updated results will be presented at the meeting. Clinical trial information: NCT04075747. [Table: see text]
Characterizing advance care planning, palliative care utilization, and location of end-of-life for adult allogeneic hematopoietic stem cell transplant recipients.
Authors: Hoffman Stephanie , Reddy Pavan , Magenau John Martin , Pawarode Attaphol , Parkin Brian , Anand Sarah Marie , Ghosh Monalisa , Maciejewski John Joseph , King Darren Patrick , Riwes Mary
Published: June 2021

7034

Background: The impacts of advance care planning (ACP) on end-of-life (EOL) outcomes in allogeneic hematopoietic stem cell transplant (allo HCT) recipients are not well known. ACP includes advance directive (AD) completion, and palliative care (PC) consultation. Using these two components, we aimed to explore the current state of ACP and its impact on EOL outcomes in allo HCT recipients to provide the groundwork for future prospective studies. Methods: We performed a retrospective study of deceased adult patients who underwent allo HCT between December 2015-December 2019. We summarized patient characteristics, the rate of AD completion, PC consultation, and location of end-of-life (EOL). Univariate and multivariate analyses were performed to evaluate patient characteristics that may be associated with AD completion, PC consultation and assess the impact of these two factors on location of EOL. Results: See Table for summary of patient characteristics. Of the 125 patients included, we found that 66% (n = 82) completed ADs. All patients with ADs completed them prior to undergoing transplant and never modified them. The majority of patients (84%) with an AD expressed the desire to avoid life-sustaining treatment in the event of terminal illness or irreversible coma. PC was consulted for 46% (n = 58) of patients within 6 months prior to time of death (TOD). Regarding location of EOL, 30% of all patients died in the hospital (non-ICU), 20% in the ICU, 38% at home with hospice, and 10% in a hospice facility. Patients with ADs appeared more likely to die outside of the hospital compared to those without (53% vs. 44%, p = 0.4506). By multivariate analysis, there were no significant patient characteristics associated with the presence of an AD or PC consultation. After adjusting for age and comorbidity index, we found that patients with an AD were significantly more likely to die outside of the ICU (OR 3.0, 95% CI 1.2-7.5, p = 0.02), an effect that was further amplified in patients who both had an AD and received PC consultation at any point (n = 30, p = 0.0077). Conclusions: Our findings highlight the importance of ACP for EOL outcomes in the allo HCT population. While the rate of AD completion in our study population is higher than that of prior studies, future prospective studies aimed to improve the rate of ACP are needed.[Table: see text]
Model-based analysis to support dose selection of pevonedistat (PEV) combined with azacitidine (AZA) in patients (pts) with higher-risk myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML).
Authors: Zhou Xiaofei , Mould Diane R. , Zhao Dan , Sekeres Mikkael A. , Adès Lionel , Swords Ronan T. , Handa Hiroshi , Fram Robert J. , Faller Douglas V. , Tsukurov Olga , Gupta Neeraj
Published: June 2021

7042

Background: PEV+AZA has been studied in higher-risk MDS/CMML and AML, with encouraging efficacy and an acceptable safety profile without added myelosuppression. This pooled analysis was performed to evaluate the impact of PEV exposure on safety and efficacy. Methods: Data from three studies (NCT01814826, NCT02782468 and NCT02610777) were used in the PEV exposure–safety analyses, including ≥ grade 3 neutropenia (NEU3), febrile neutropenia (FN), ≥ grade 3 thrombocytopenia, ≥ grade 3 alanine aminotransferase elevation, ≥ grade 3 aspartate aminotransferase elevation and ≥ grade 3 treatment-emergent adverse event (TEAE3), in pts with higher-risk MDS/CMML and AML who received PEV+AZA. Data from NCT02610777 were used for exposure–efficacy analyses, including overall survival (OS), event-free survival (EFS), complete response (CR) and CR+partial response (PR), in pts with higher-risk MDS/CMML who received PEV+AZA. The exposure metrics for individual pts were derived from a previously developed population pharmacokinetic model with pooled data from eight phase 1/2 studies. PEV exposure–safety relationships for the toxicity endpoints, exposure–CR and exposure–CR+PR, were estimated by logistic regression. Age, sex, race, baseline Eastern Cooperate Oncology Group (ECOG) Performance Status score and disease type were evaluated as covariates. Cox proportional-hazards models were used to evaluate the PEV exposure–survival for higher-risk MDS/CMML, with age, sex, baseline ECOG PS score, Revised International Prognostic Scoring System score (IPSS-R) and disease type as potential covariates. Results: In total, 135 pts (median age, 74 years; male, 64%; Caucasian, 82%) and 41 pts (median age, 74 years; male, 76%; Caucasian, 90%; median IPSS-R, 5.5) were included in PEV exposure–safety and exposure–efficacy analyses, respectively. PEV exposure was significantly related to the incidence of NEU3 ( p = 0.003), FN ( p = 0.02) and TEAE3 ( p = 0.02), supporting PEV dose reductions for pts with treatment-related toxicities. Relationships between PEV exposures and CR, CR+PR, EFS or OS indicated consistent clinical benefit across ranges of PEV exposure following a starting dose of 20 mg/m2. Conclusions: The association between exposure and safety supports PEV dose reductions for pts with treatment-related toxicities. The exposure–efficacy analyses indicated consistent clinical benefit across ranges of PEV exposure following a starting dose of 20 mg/m2. These results support a favorable benefit–risk profile of the 20 mg/m2 PEV dose on days 1, 3 and 5 in combination with AZA 75 mg/m2 for 7 days in 28-day cycles. Clinical trial information: NCT01814826 , NCT02782468 , NCT02610777.