bluuebunny/crossref_metadata_2025 huggingface dataset:
Smoking and COVID-19 in patients with cancer: Novel analysis from CCC19 registry.
Authors: Kulkarni Amit , Hennessy Cassandra , Wilson Grace , Ramesh Vidhyalakshmi , Hwang Clara , Awosika Joy , Bakouny Ziad , Vilar-Compte Diana , Khan Hina , McKay Rana R. , Jani Chinmay , Puc Matthew , Kasi Anup , Berg Stephanie A. , Castillo Dan Ran , Hayes-Lattin Brandon M. , Hosmer Wylie , Flora Daniel Blake , Duma Narjust ,   COVID-19 and Cancer Consortium
Published: June 2022

e18766

Background: Patients (pts) with thoracic cancers have a high rate of hospitalization and death from COVID-19. Smoking has been associated with increased risk for severe COVID-19. However, there is limited data evaluating the impact of smoking recency on COVID-19 severity in pts with cancer. We aimed to characterize the clinical outcomes of COVID-19 based on the recency of smoking in pts with thoracic cancers (TC) and all other cancers (OC). Methods: Adult pts with cancer and lab-confirmed SARS-CoV-2 and smoking history recorded in the CCC19 registry (NCT0435470) were included. Pts were stratified by cancer type (TC or OC) and further stratified into subgroups based on the recency of smoking cessation: current smoker; former smokers who quit < 1 yr. ago; 1-5 yr. ago; 6-10 yr. ago; quit > 10 yr. ago; and never smoker. 30-day all-cause mortality was the primary endpoint. Secondary endpoints were any hospitalization; hospitalization with supplemental O2; ICU admission; and mechanical ventilation. Results: From January 2020 to December 2021, 752 pts from TC group and 8,291 pts from OC group met the inclusion criteria. 78% of patients in TC group ever smoked compared to 36% patients in the OC group. In both groups, the majority of never-smokers were females (70% and 60% in TC and OC respectively). The burden of smoking and the rate of pulmonary comorbidities (PC) was higher in the TC group (PC 22-69%) compared to OC group (PC 12-26%) across all smoking strata. Overall, 30-day all-cause mortality was 21% and 11% in pts with TC and OC respectively. Former smokers who quit < 1 year ago in TC group had the highest rate of mortality and severe COVID-19 outcomes. However, in the OC group, there was no consistent trend of higher mortality or severe COVID-19 outcomes in specific subgroups based on smoking recency. Conclusions: To our knowledge this is the largest study evaluating the effect of granular phenotypes of smoking recency on COVID-19 outcomes in pts with cancer. Recent smokers who quit < 1 year ago in TC group had the highest rate of mortality and severe COVID-19. Further analysis exploring the factors (e.g., smoking pack years) associated with severe outcomes in this subgroup is planned.[Table: see text]
A comparison of dosimetry and clinical outcomes in patients receiving photon external beam therapy to the pelvis: A two-year experience with 6MV and 10MV photon energies in cervical cancer patients at Parirenyatwa Radiotherapy Centre in Harare, Zimbabwe.
Authors: Banda Chimwemwe Moses , Ndlovu Ntokozo , Nyamhunga Albert
Published: June 2022

e18768

Background: Radiotherapy efficacy depends on the ability of the treatment machine to deliver optimal radiation dose to target volume while sparing normal tissue using different techniques. The photon energy determines penetrative power. Higher photon energies are generally preferred over low photon energies when treating deep tumours using 3-dimensional conformal radiotherapy (3DCRT). In most low income settings, availability of higher energies (≥10MV) is limited. Elsewhere protocols do not recommend use of lower energies for deep pelvic tumours. There is paucity of data comparing 10MV and 6MV photon energy plans and outcomes for treatment of pelvic tumours with 3DCRT. This study aimed to compare dosimetric and clinical tumour outcomes between the two photon energies which are available in our setting when treating locally advanced cervical cancer (LACC). Methods: We retrospectively analysed medical records for LACC patients who received definitive concurrent chemoradiotherapy (CCRT) at Parirenyatwa Group of Hospitals Radiotherapy Centre for the period between 1st January 2017 and 31st December 2018. Patient’s treatment plans were stratified into two arms according to the photon energies used (10MV and 6MV) and their respective dosimetric and clinical tumour outcomes at three months post-treatment were compared. Results: A total 875 cervical cancer patients were seen during the study period, of these 82 met the inclusion criteria and were evaluated. Out of these, 20(24.4%) and 62(75.6%) patients were planned and/or treated with 10MV and 6MV photon energy respectively. The differences in minimum doses to the planned target volume and dose homogeneity index between the two photon energies were statistically significant (p-values 0.027 and 0.028 respectively), whereas the other dosimetric parameters (maximum & average doses to the planned target volume, conformity index and maximum doses to rectum, bladder, femoral heads and bowel) were not statistically significant (p-values of 0.245, 0.309, 0.130, 0.19, 0.35 and 0.42, and 0.16 respectively). Complete clinical tumour response at 3 months post treatment was 95% in the 10 MV arm compared to 91% in the 6 MV arm. Conclusions: This study showed that the dosimetric and clinical tumour outcomes in LACC patients receiving 3DCRT definitive CCRT using 10MV or 6MV photon energy in our setting are comparable. Follow-up prospective studies to further characterise the application of these photon energies in resource constrained settings is recommended.
Methods used to generate safety-related evidence in real-world oncology settings: A systematic literature review.
Authors: Henderson Mackenzie , Cueto Jenilee , Yalamanchili Priyanka , Salas Maribel
Published: June 2022

e18769

Background: With the increasing availability of real-world data (RWD) as a valuable healthcare data source, there have been large shifts in how a drug’s properties can be evaluated over its life cycle. RWD can be used for many evidence generation purposes, including the evaluation of a drug’s safety in real-world settings outside of clinical trials. Traditional methods (e.g., cohort and case-control studies) are often used to analyze RWD, but novel methods have emerged as the field advances with access to more diverse data sources. The extent to which these newer methods are being used is unclear. The aim of this systematic review is to identify methods that have been used in recent years to generate safety-related evidence in real-world oncology settings. Methods: A search of literature published between 1/1/2016-8/10/2021 (Embase, Ovid) was performed to identify studies describing methods used to generate evidence related to the real-world safety of oncology products. Each article was independently screened by two researchers in two levels (title/abstract and full text screening). Data extracted included, but was not limited to, study design, cancer type, data source, and statistical methods. Results: Out of 845 publications identified, 44 were included for review (742 excluded after level 1 screening; 59 excluded after level 2 screening). The most common method used was the retrospective cohort study (n = 26), followed by prospective cohort study (n = 8), literature review (n = 4), cross-sectional study (n = 3), artificial intelligence (AI) methods (n = 3), data mining analysis (n = 2), case-series, and case-control study (n = 1 each). Some publications used multiple methods. While traditional methods (e.g., cohort study, literature review) were the most common throughout the search period, newer methods (e.g., AI methods) were identified in the latter part of the search period (2019-2020). The majority of studies that used traditional methods relied on medical records or claims data (e.g., Optum), which often provided structured RWD to evaluate physician-documented drug safety data. In contrast, articles that used newer methods like AI analyzed large amounts of patient-reported data (e.g., chatbot conversations; social networks), which allowed researchers to evaluate patients’ own experiences with drug safety. Conclusions: The most common evidence generation methods identified involved traditional methods, but novel methods were also identified, especially in recent years. This indicates a trend towards increased use of innovative methods like AI that allow for the analysis of data in ways not possible before. Taken together with more traditional methods and data sources, these findings can provide clinicians with a more comprehensive and patient-focused understanding of drug safety, which will ultimately improve patient care.
Breast density changes over time: Frequency, patterns, and practice implications.
Authors: Maloney Caitlin , Paul Shirlene , Lieberenz Jordan , Levy Mia Alyce , Stempel Lisa , Alvarado Rosalinda
Published: June 2022

e18772

Background: Dense breast tissue is known to obscure malignancy on mammography and is considered an independent risk factor for breast cancer. Because of its clinical significance, breast density has been incorporated into cancer risk assessment tools, supplemental screening recommendations, and patient notification laws. Changes in density—whether due to intrinsic changes in breast tissue over time or to inter-radiologist variability in interpreting mammographic results—can therefore have significant implications for patients. The purpose of this study was to quantify longitudinal patterns of breast density change. Methods: This retrospective cohort study tracked breast density changes among 37,156 patients who received multiple mammograms at a large academic medical center between October 1, 2015 and June 29, 2021. Breast Imaging-Reporting and Data System (BI-RADS) density categories A (least dense) through D (most dense), visually determined by radiologists at the time of screening, were abstracted from electronic medical records and dichotomized into one of two density statuses: non-dense (categories A and B) and dense (categories C and D). A sequence analysis of longitudinal changes between the two density statuses was performed using SQL. Results: The majority (91.3%, n = 33,920) of patients maintained the same density status (dense or non-dense) throughout the six-year study period, while 8.7% of participants (n = 3,236) experienced between one and six density status changes. Among patients who experienced any density status change, the vast majority (96.7%, n = 3,131) moved exclusively between BI-RADS categories B and C, the intermediate density categories (Table). Frequency of density status change was positively correlated with average number of mammograms performed per patient. Conclusions: Although most patients maintain a consistent breast density status, some will experience multiple status changes even over this relatively short timeframe (< 6 years), with more frequent changes being associated with more frequent mammograms. The overwhelming majority of patients whose density status changed moved exclusively between BI-RADS categories B and C, suggesting a role for inter-radiologist variability in visual assessments of intermediate-density tissue. These findings have implications for how density status changes are incorporated into patient education, risk assessment, and supplemental screening recommendations.[Table: see text]
Evolution of biomarker testing in advanced non-small cell lung cancer (aNSCLC) and metastatic breast cancer (mBC) in U.S. community practices.
Authors: Schwartzberg Lee S. , Yu Elaine , Meyer Craig S. , Shah Anuj , Price Richard , Szado Tania , Vaena Daniel A. , Daniel Davey B. , Slater Dennis , Staszewski Harry , Fang Bruno , Seneviratne Lasika , Ma Esprit
Published: June 2022

e18778

Background: Biomarker testing has advanced from single-gene to NGS. This study examined aNSCLC and mBC biomarker testing ≤ 90d of advanced (adv) or metastatic (met) diagnosis (Dx) and treatment (tx) patterns at US practices. Methods: A retrospective observational study used Flatiron Health electronic health-record-derived de-identified database at OneOncology (OO) community and non-OO Flatiron Health nationwide (NAT) sites (̃90% community, ̃10% academic). Patients (Pts) ≥ 18y, with Dx of aNSCLC or mBC from 1/1/18 - 4/30/21, with ≥ 1 visit ≤ 90d after adv/met Dx and ≥ 90d follow-up were evaluated. Descriptive analyses and logistic regression were used. Results: A total of 16,882 pts with aNSCLC (2366 OO; 14,516 NAT), and 6500 pts with mBC (1026 OO; 5474 NAT) were included. Overall testing was high and stable (OO: 85% aNSCLC, 98% mBC; NAT: 84%, 97%) with higher NGS testing at OO (58% aNSCLC; 28% mBC) vs NAT (49%; 16%) (Table), which reflected more pts with aNSCLC tested for all 6 mutations (ALK, BRAF, KRAS, ROS-1, EGFR, PD-L1; 54% OO vs 50% NAT, p<0.001) and more pts with mBC tested for PIK3CA (27% OO vs 16% NAT, p<0.001). In aNSCLC, NGS testing increased similarly for OO and NAT over time (p>0.05); mBC NGS testing increased faster at NAT vs OO (p<0.05). Of pts tested and treated, 16% aNSCLC (1945 OO; 11,376 NAT) and < 3% mBC (14 OO; 108 NAT) received tx before test results were available. For pts with aNSCLC with ≥ 1 actionable mutation (ALK, BRAF, ROS-1, EGFR), 18% OO and 22% NAT had tx before test results. Cancer immunotherapy plus chemotherapy was the most common tx (36 % OO vs 40 % NAT); after test results, 33% vs 56% OO and 45% vs 44% NAT pts stayed on tx vs switched to targeted tx. For pts with aNSCLC with ≥ 1 aforementioned actionable mutations who waited until test results were available, 65% received targeted tx at OO and NAT. Conclusions: Biomarker testing has become standard of care in aNSCLC and mBC in US community settings. NGS rates increased over time and were higher at OO vs NAT. Differences in pts treated before test results reflects the need to wait for NGS results to inform initial tx in aNSCLC vs non-NGS results for mBC. This study shows NGS testing in US community practices has increased since 2018, particularly in mBC, but opportunities remain to optimize NGS results into tx decisions.[Table: see text]
Defendor: Real-world evidence of primary prolonged G-CSF prophylaxis by empegfilgrastim for relative dose intensity compliance in patients with solid tumors—The primary analysis.
Authors: Snegovoy Anton , Dergunov Alexander , Tatyanenko Anna , Yakuba Darya , Elkova Viktoriya , Shalina Anna , Komoza Yulia , Dmitrochenko Marina , Soroka Svetlana , Shegurova Margarita , Chapko Yana , Dmitriev Vadim , Timin Vladimir , Rossokha Elena , Gronskaya Yulia , Kononenko Inessa , Sorokina Irina
Published: June 2022

e18788

Background: Maintaining relative dose intensity (RDI) of chemotherapy is important to ensure optimal patient outcomes in a variety of solid cancers. RDI < 85% significantly decrease therapy efficiency (including overall survival) in almost solid tumors (ST). Chemotherapy-induced neutropenia (CIN) is the most common adverse event (AE) leading to low RDI. Proper administration of primary G-CSF prophylaxis (PP) allows to achieve optimal therapy efficiency. There are several trials and meta-analyses have shown a superior efficiency prolonged G-CSF vs short G-CSF. This multicenter prospective observational post-registration study of prolonged G-CSF empegfilgrastim (Extimia) was designed to evaluate the RDI of the cytotoxic therapy course under PP by empegfilgrastim in patients (pts) with ST receiving myelosuppressive therapy in the routine clinical practice. Methods: 2000 pts with ST receiving cytotoxic therapy (4-8 cycles per course are allowed) under PP with empegfilgrastim by investigator choice in the routine clinical practice. RDI of therapy course was primary endpoint and presented here for pts who completed the planned regimen. For each agent, both the planned and actual dose intensity were calculated by dividing the total cumulative dose by treatment duration in days. RDI was calculated for each single agent in chemotherapy-based (CTb) regimen and for CTb regimen in total. These descriptive analyses and RDI calculations were performed for the whole CT based regimen (chemotherapeutic agents, molecular target agents, monoclonal antibodies). Funded by JSC Biocad; Defendor ClinicalTrials.gov No NCT04811443. Results: At the data cut-off 1074 pts from 31 Russian sites underwent ≥ one cycle of CTb regimens combined with empegfilgrastim. Distribution of all-cancer types was in line with epidemiology data in Russia. 526 pts completed the planned CT course. 352 (66,9%) of them have at least onе of FN risk factor. RDI≥85% were achieved in 492 (93,5%) pts. RDI by key nosology is presented in Tab.1. 118 (22,4%) cases of interval prolongation and/or dose reduction was registered. The main reasons of RDI decrease were personal pts’s issues 69 (13,1%), COVID-19 pandemic 26 (4,9%), holidays 9 (1,7%) and others. Neutropenia was in 6 (1,1%) cases as a reason of RDI decrease. Treatment-related AEs of grade 1-2 occurred 12 (2,3%) pts (back pain, ossalgia, myalgia). Conclusions: Thus, PP with prolonged G-CSF empefilgrastim allows effectively maintain RDI in different nosology and treatment groups in pts with ST in the routine clinical practice.[Table: see text]
Economic impact of digital tumor board software: An evaluation of cost savings using real-world data.
Authors: Hammer Richard D. , Srinivas Sharan , Rajendran Suchithra , Guo Chaohui , Prime Matthew Stewart
Published: June 2022

e18794

Background: Multidisciplinary tumor boards (MTB) provide an interdisciplinary approach for decision-making in cancer care and are an integral part of cancer treatment plans. MTBs are widely considered the “gold standard” in cancer care delivery and are required for accreditation by the American College of Surgeons on Cancer Program. Preparing for MTBs is time-consuming and labor-intensive. We have previously published the largest real-world study of a digital solution (NAVIFY), showing significant decreases in the case preparation time compared to traditional methods.1 We now extend that study to evaluate the economic impact on costs of MTBs in an academic setting. Methods: The NAVIFY Tumor Board solution was introduced at the University of Missouri Health Care (MU) in 2018. Data was collected in three tumor boards (Breast, ENT, and GI) for pre- and post- NAVIFY implementation as previously published1 . For the current study, raw data was collected and preprocessed to obtain eight pertinent variables. A retrospective pre-post analysis was used to evaluate the economic effectiveness of NAVIFY. Using the salary data collected from publicly available sources, the average personnel cost/case (nurse navigator, radiology, pathology and genetic counseling) was analyzed for each tumor board for pre and post stable integration of NAVIFY. In addition, a system-wide cost projection study and payback analysis were also performed based on 12 tumor boards. Results: The average personnel cost/case after integration of NAVIFY showed a savings of 40% in breast MTB, 52% for ENT MTB, and 6% for GI MTB. Both Breast and ENT were considered to be the optimal use of the software after implementation. Using these two tumor boards, the average total personnel cost/case pre-NAVIFY was $93.20 and $49.55 post integration. Annual system-wide cost projections showed an annual savings of $299,614. Discounted payback period analysis showed a payback period of 0.17 years. Conclusions: Implementation of NAVIFY digital tumor board solution showed a significant impact on the total cost of tumor board preparation with overall a decrease in personnel cost/case of 53% with ideal implementation. The comparatively slight decrease in GI could be explained by an increase in cases reviewed from an average of 8 to 11 pre vs post NAVIFY requiring increased radiologist time, and poor user adoption by surgeons. In conclusion, implementation of a digital tumor board software provides significant savings in case preparation costs, second to decreased time costs of personnel. While not evaluated in this study, these cost savings do not take into account the increased potential clinical revenue that may also accompany the improved efficiency on provider time. References 1. Hammer RD, etal. Digital Tumor Board Solutions Have Significant Impact on Case Preparation. JCO Clin Cancer Inform. 2020 Aug;4:757-768.
The incidence of atrial fibrillation shortly following radiation therapy in patients with lung cancer: A population-based study.
Authors: Nikita Nikita , Lu Bo , Gandhi Krupa , Keith Scott W. , Lu-Yao Grace L.
Published: June 2022

e18796

Background: Lung cancer is the third most common cause cancer in the US. Although radiation therapy (RT) is one of the most common treatment modalities for lung cancer. RT-induced atrial fibrillation (AFib) is understudied. We examined the relationship between different types of RT and AFib incidence. Methods: Lung cancer patients receiving RT were identified from the SEER-Medicare linked data between 2010 and 2015. Patients with 12 months continuous Part A and B coverage prior to RT were included. Patients were excluded if they lost coverage, were enrolled in HMOs, aged < 65 years old, or diagnosed at death, had malignant effusion or pre-existing AFib. RT was identified as IMRT (HCPCS: 77301, 77418, G0174, G0178, 0073T), or non-IMRT related external beam radiation (HCPCS: 77290, 76370, 77014, 77295, 77280, 77285, CPT: 77402–77416, 77427). AFib was identified within 30 days of initiating RT using ICD-10 codes. Continuous variables were summarized by mean and standard deviation; categorical variables by frequency and percentage. Student’s t-test was used to compare continuous data between groups. Pearson’s chi-square test was used to compare categorical data between groups. Results: We identified 3,499 lung cancer patients receiving radiation. Of these, 830 were diagnosed with AFib after RT. The type of RT (IMRT vs non-IMRT) and type of hilar involvement were both associated with the incidence of AFib in these patients (Table). Conclusions: This is the first population based study to identify factors associated with increased AFib incidence in lung cancer patients receiving radiation. Further studies are warranted to better understand these associations.[Table: see text]
Health outcomes modelling of RNA-based versus DNA-based detection of driver gene rearrangements in non-small cell lung cancer.
Authors: Jun Tomi , Oh William K. , Schadt Eric , Higashi Mitchell
Published: June 2022

e18837

Background: There are several FDA-approved targeted therapies for NSCLC with driver gene rearrangements (DGRs) involving ALK, ROS1, RET, NTRK1-3, and MET exon 14. DNA-based sequencing panels miss 15-20% of DGRs compared to RNA-based methods (Benayed et al., 2019; Solomon et al., 2020). We modelled the years of life gained by using RNA- instead of DNA-based methods for DGR detection. Methods: We used the IVI-NSCLC open-source model to analyze the relationship between stable disease, progression, and death as previously described in a multi-state model. Previously reported PFS hazard ratios for targeted therapies (versus chemotherapy) treating DGRs range from 0.17 to 0.52 (Hoang et al., 2020). Therefore, we assumed that the HRs corresponding to the parameter estimates for the targeted therapy option built into the model would approximate treatment-specific relative effects of targeted therapies for DGRs (PFS = 0.3; OS = 0.8). We simulated life-years and quality-adjusted life years (QALYs) for a cohort of 1,000 patients with DGRs matched to appropriate targeted therapies over a 5-year time horizon. We used population-level prevalence data to estimate the number of patients with metastatic NSCLC and DGRs. We then estimated the number of false negatives generated by DNA-only sequencing and calculated the additional life-years gained if RNA-based methods were used instead. Results: In a simulated cohort of 1,000 patients with DGRs detected through RNA sequencing and receiving targeted therapy, median PFS and OS were 1.8 and 3.7 years, respectively. The use of targeted therapy (instead of chemotherapy) in these patients increased life-years by 3.46 years (95% CI, 3.04-3.90) and QALYs by 2.27 years (95% CI 1.91-2.71) on average per patient. There were approximately 235,768 new lung cancers in the US in 2021, 56% of which were metastatic at diagnosis (SEER). Approximately 50% of lung cancers are adenocarcinomas, and approximately 12% of adenocarcinomas have DGRs: ALK (5%) , MET (4%) , ROS1 (2%) , RET (1%) , and NTRK1-3 (< 1%). Thus, there were approximately 7,922 new metastatic NSCLC cases with DGRs in 2021. Prior studies have shown that DNA-only methods have a sensitivity of 80-85% for DGRs compared to RNA-based methods. At the level of the US population, this implies 1,188-1,584 false negative cases in 2021. The clinical impact of eliminating these false negatives by using RNA- instead of DNA-based methods to identify DGRs amounts to 4,110–5,480 life-years or 2,696–3,595 QALYs gained by appropriately matching patients with DGRs to targeted therapy over chemotherapy. Conclusions: DNA-only sequencing methods have limited sensitivity for DGRs in lung cancer, leading to false negatives and missed opportunities for targeted therapy. This modeling study suggests that the elimination of such false negatives using RNA-based detection methods would lead to meaningful gains in patient outcomes.
A phase 1b study of blinatumomab with the anti-programmed cell death (PD)-1 antibody AMG 404 in adults with relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (ALL).
Authors: Papayannidis Cristina , Borlenghi Erika , Yeung David , Machherndl-Spandl Sigrid , Bellido Mar , Sandhu Karamjeet , Wong Hansen , Rasmussen Erik , Zugmaier Gerhard , Markovic Ana , Gordon Paul R. , Jabbour Elias
Published: June 2022

e19003

Background: Preclinical data indicate that anti-PD-1 agents can facilitate activity of bispecific T-cell engager (BiTE) molecules. Here we assess the combination of the anti-CD19 BiTE molecule blinatumomab with the anti-PD-1 antibody AMG 404 in adults with R/R ALL (NCT04524455). Methods: Eligible adults with R/R ALL (Ph+ disease included) received 2-5 treatment cycles. Each cycle was 42 days, consisting of 4 weeks of cIV blinatumomab and a 2-week treatment-free interval as per label. In Cohort 1, AMG 404 was dosed IV at 240 mg every 4 weeks (Q4W); first dose was Day (D) 11 of Cycle (C) 1. Primary endpoints were dose-limiting toxicities (DLTs) and other adverse events (AEs). Results: As of 20 Dec 2021, patients (pts) from Cohort 1 (n=8) had median age of 57 (range: 24-73) y, 6/8 male, 6/8 Caucasian, 1 with extramedullary disease (duodenum), 2 with prior blinatumomab, and a median of 5 (2-15) prior treatment lines. Two pts remain on study and 2 completed the study; 4 pts discontinued the study due to death (n=3) or consent withdrawn (n=1). No DLTs were reported for the 3 evaluable pts. Of the 5 pts not evaluable for DLTs, in C1, 4 had disease progression and 1 an unrelated fatal pneumonia. Treatment-related grade (Gr) ≥3 and/or serious AEs in all 8 pts included cytokine release syndrome (CRS) (1 pt Gr 2, 1 pt Gr 1 and 3), Gr 3 increases in ALT and AST, Gr 3 fever, Gr 3-4 neutropenia, Gr 4 neutropenia/Gr 3-4 thrombocytopenia (same pt), Gr 2 sensorimotor polyneuropathy, Gr 3 hypertension, Gr 3 encephalopathy, and in 1 pt Gr 3-4 decreases in white blood cells, lymphocytes, and neutrophils. One pt developed Gr 3 SARS-COV-2 pneumonia on C2D25, resolving without clinical sequelae. C3 start was delayed by 12 days but protocol treatment resumed uneventfully. All 3 DLT-evaluable pts had a complete response (CR) or CR with partial hematologic recovery (CRh), 2/3 without measurable residual disease (MRD), within 2 cycles; the 3rd pt had an MRD response at the end of C3. Preliminary pharmacokinetic results for the combination of blinatumomab and AMG 404 demonstrated that their exposures were consistent with those observed for each as monotherapy and did not indicate any drug-drug interactions. To date, all samples tested for anti-blinatumomab antibodies have been negative. Conclusions: In this ongoing phase 1b study, the combination of blinatumomab with AMG 404 was tolerated with a manageable safety profile. No DLTs were reported. Enrollment continues in Cohort 2 in which AMG 404 is dosed Q4W at 480 mg starting on C1D1, 48 hours prior to blinatumomab. Clinical trial information: NCT04524455. [Table: see text]
Evaluating asparaginase toxicity in Hispanic patients with acute lymphoblastic leukemia in a large safety-net hospital.
Authors: Abdelmeseeh Elijah , Dragon Marcin , Tomassetti Sarah
Published: June 2022

e19012

Background: Asparaginase has been a common component of induction therapy for acute lymphoblastic leukemia (ALL) patients for decades. The use of asaparaginase in the treatment of ALL has shown significant efficacy leading to improved outcomes when used in combination with chemotherapy in children. Despite these results, this medication is not used ubiquitously due to its toxicity profile in adults that includes hepatotoxicity, thrombosis, pancreatitis, and allergic reactions. Established risk factors for increased toxicity are increased age, obesity, and higher doses. Our study aims at reviewing the toxicity profile of this medication in Hispanic patients. We suspected that our patient population will have a higher incidence of various toxicities due to the higher prevalence of obesity and liver disease in this population. Methods: We performed a retrospective chart review of all patients aged greater than 18 years who presented to Harbor-UCLA Medical Center between 2015 and 2021 and were diagnosed with ALL who were given a treatment regimen that included asparaginase. We collected information about demographics, laboratory parameters on diagnosis, treatment details, and information on complications related to the treatment. Results: A total of 14 patients diagnosed with ALL and treated with asparaginase at Harbor-UCLA Medical Center from January 2016-November 2021 were included in this study. Our cohort consists of 53% males and 46% females, with an average age of 31 (SD 9.4). Our patient population had an average of BMI of 34 (SD 8.7), with the majority, 9 out of 14, being classified as obese. The majority of the cohort was Philadelphia chromosome negative (80%). In our study, the incidence of grade 3 to 4 hyperbilirubinemia was 6 out of 14 patients (42%). Half of our patients who suffered from hyperbilirubinemia suffered from class III obesity. The incidence of grade 3 to 4 transaminitis was 13 out of 14 patients (93%). A total of 5 out of 14 patients (36%) also suffered from thrombosis. One patient (7%) had a hypersensitivity reaction. Conclusions: Our incidence of hyperbilirinemia is higher than previously published incidence values. Various studies have shown different incidence rates ranging between 14-40%. Our patient population did experience severe transaminitis in a much higher rate than previously reported rates of around 50%. The higher incidence noted in our patients with class III obesity is in line with recent expert recommendations for dose reduction of asparaginase in patients with severe obesity. We have concluded from our study that our Hispanic population is at higher risk for developing hepatotoxicity after asparaginase use but could be related to the high prevalence of obesity in our population. This is important for future patient care to appropriately select candidates for this intensive therapy and reduce the risk of severe adverse events.
Impact of TKI combination therapy and MRD negativity on outcomes in Philadelphia chromosome-positive ALL: A retrospective, single-center experience.
Authors: Tran Valerie , Bouligny Ian Michael , Alnimer Yanal Mufeed , Zacholski Kyle , Venn Chad Michael , Ho Thuy , Maher Keri Renee
Published: June 2022

e19052

Background: Presence of the Philadelphia chromosome (Ph+) in newly diagnosed B-cell acute lymphoblastic leukemia (ALL) conveys high-risk disease and a poor prognosis. Hematopoietic stem cell transplant (HSCT) following induction and achievement of remission remains the standard of care. In the era of TKIs targeting BCR-ABL1 in addition to newer combination strategies, the impact of HSCT in the first complete remission (CR) remains unclear, particularly in the context of measurable residual disease (MRD) negativity. We present the outcomes of Ph+ B-ALL patients with and without HSCT, stratified with respect to MRD negativity. Methods: We identified 32 patients with Ph+ B-cell ALL from January 2015 to January 2021 at our institution who were treated with TKIs and received HSCT with evaluable MRD prior to transplant. Baseline patient demographics were obtained, including labs, performance status at diagnosis, comorbidities, molecular profiling by NGS, doses of induction, toxicities, response, MRD analysis by PCR, HCT-CI scores, and HSCT outcomes. The event for calculating the overall survival (OS) was the date of death. Patients were otherwise censored at the date of last contact. Results: Of the 25 patients who underwent HSCT, the median age was 46 years and 48.0% were male. TKIs in combination with high-intensity regimens were given in 88.0% of patients at induction. There were no deaths within 60 days following induction. Twenty (80.0%) patients achieved CR or CRi, and of those, 56% were MRD-negative by the time of HSCT. At a median follow-up time of 4.74 years, the OS of patients that achieved CR following induction and HSCT was not reached, and there were no significant differences between the two groups (p = .1326). We then compared the 14 MRD-negative patients undergoing HSCT to 7 MRD-negative patients who did not undergo transplant aged ≤65 years with ECOG ≤2. There was no difference in age (p = .5353), ECOG score (p = .6364), or Charlson Comorbidity Index score (p = .7018) between the two groups. The median OS in the MRD-negative HSCT group was not reached and the median OS in the MRD-negative non-HSCT was 5.45 years (p = .0210). Conclusions: In the era of combination chemotherapy with TKIs, MRD positivity at the time of allogenic HSCT does not appear to impact survival at 5 years in this small retrospective cohort. Post-transplant TKI maintenance may abrogate MRD implications at the time of HSCT. Our findings demonstrate that Ph+ ALL patients benefit from HSCT when candidates, regardless of MRD status, as those undergoing HSCT demonstrated a statistically superior survival. HSCT appears to remain the standard of care despite newer combination strategies and MRD-driven treatment.
Trends in Medicare oral anticancer drug utilization among relapsed and refractory chronic myeloid leukemia patients.
Authors: McBride Kaitlyn , Snyder Sophie
Published: June 2022

e19058

Background: The treatment landscape for patients with relapsed and refractory (RR) chronic myeloid leukemia (CML) has changed significantly in recent years, with the introduction of targeted oral anticancer therapies. Current guidelines from the National Cancer Comprehensive Network (NCCN) recommend tyrosine-kinase inhibitors (TKIs) for second line and subsequent therapy. Recent real-world data evaluating treatment patterns in RR CML is limited. Study objective was to evaluate treatment patterns and trends in utilization of oral anticancer agents among Medicare beneficiaries diagnosed with RR CML, from 2017-2019. Methods: Retrospective study using Medicare Part D Prescription Drug Event Files, which contain records on prescription drug fills among Medicare beneficiaries enrolled in Fee-for-Service and Medicare Advantage plans. Beneficiaries diagnosed with RR CML (C9212 ICD-10) and prescribed oral anti-cancer therapy (Bosutinib, Dasatanib, Nilotinib, Ponatinib or Imatinib Mesylate) were identified and followed for at least 12 months, from index diagnosis until end of study period (December 31, 2019) or death. Trends in utilization by oral therapy, by number of beneficiary utilizers and prescription drug claims, were evaluated from 2017 to 2019. Results: Overall, 327 Medicare beneficiaries with a diagnosis of RR MM were prescribed an oral TKI therapy (Bosutinib, Dasatanib, Nilotinib, Ponatinib or Imatinib Mesylate) throughout the study period (2017-2019). The number of beneficiaries prescribed at least 1 oral therapy increased between 2017 and 2019, from 154 to 212 (Table). Total utilization also increased: from 210 prescription drug claims in 2017 to 296 in 2019. Throughout the study period, Imatinib Mesylate had the largest market share among all oral therapies, however the share decreased over time (from 35.7% in 2017 to 30.7% in 2019). Nilotinib had the largest gain in market share during this period, from 15.7% to 20.9%. Conclusions: Study findings suggest utilization of oral therapies are increasing over time, and shifting from Imatinib Mesylate to newer therapeutic agents. Given the high costs for these novel therapies, future research should examine trends in patient out-of-pocket spending, as well as factors impacting patient adherence.[Table: see text]
Antibody seroprevalence against SARS-Cov-2 among chronic myeloid leukemia patients.
Authors: Miranda Marisol , Bradshaw Danielle , Farmaha Jaspreet , Patel Reeya , Jones Kimya , Singh Harmanpreet , Vashisht Ashutosh , Sahajpal Nikhil Shri , Kohle Ravindra , Cortes Jorge E.
Published: June 2022

e19061

Background: The rapid spread of SARS-CoV-2 has elicited an equally rapid development of effective vaccines, leading to a reduction of COVID-19 severity and deaths. There is limited data on COVID-19-related immunity in chronic myeloid leukemia (CML) patients. Methods: SPARTA (SARS2 SeroPrevalence And Respiratory Tract Assessment) is an ongoing observational study for participants age ≥18 years to investigate immunity to SARS-CoV-2 after infection and/or vaccination. We included patients with CML and compared them with a non-cancer group. We collected saliva and peripheral blood to measure antigen levels by RT-PCR and antibodies (secretory IgG antibodies and neutralizing antibodies). Results: From October 1, 2021, to February 4, 2022, we prospectively enrolled 49 participants (23 CML, 26 non-cancer). Most were male (56.5%) in the CML group and female in the control group (61.5%), mean age 56.39 y vs. 51.96 y, respectively, and self-identified as white (87% vs. 76.9%). In the CML group, 11 (47.8%) had ≥1 comorbidities, vs 13 (50%) in the control group. Twenty-one (91.3%) CML patients were receiving tyrosine-kinase inhibitors; 4 (18.2%) non-cancer subjects reported taking any medication. Most participants in both groups had received at least one dose of COVID-19 vaccine (73.9% vs. 73.1%); 100% of CML patients received two doses vs. 84.2% of controls; the CML group had a higher percentage of subjects fully vaccinated (66.7% vs. 25%). The CML group had a lower percentage of patients previously diagnosed with COVID-19 (8.8% vs. 57.7%). However, there was no difference in the detection of SARS-CoV-2 antigen at the time of enrollment (0% vs. 4%). SARS-CoV-2 IgG antibodies were detected in most of the participants regardless of cancer status (78.3% in the CML cohort and 88% in the non-cancer cohort), and neutralizing antibodies were detected in 82.6% and 95.6%, respectively. The two groups had comparable IgG (mean 146.3 Ru/ml vs. 148.9 Ru/ml) and neutralizing (mean 1329.1 ng/ml vs. 1112 ng/ml) antibody levels. Conclusions: Our preliminary data comparing concomitant cohorts with similar socio-demographic characteristics and medical history indicate that a diagnosis of CML did not impact the development of antibodies against SARS-CoV-2. We are conducting continuous analysis of antibodies levels over time to assess the evolution of antibody immunity and functional studies including cellular immunity assessments.[Table: see text]
Impact of SF3B1 mutation on outcomes in myelofibrosis.
Authors: Bose Prithviraj , Senapati Jayastu , Masarova Lucia , Pemmaraju Naveen , Bravo Guillermo Montalban , Pierce Sherry , Zhou Lingsha , Garcia-Manero Guillermo , Kantarjian Hagop M. , Verstovsek Srdan
Published: June 2022

e19080

Background: Splicing factor 3B subunit 1 ( SF3B1) mutations have been shown to confer a unique phenotype in MDS and MDS/MPN overlap syndromes, with ring sideroblasts, thrombocytosis and favorable prognosis. In myelofibrosis (MF) the frequency of SF3B1 mutation is <10% and may play a less important role in disease outcomes (Lasho et. al, Leukemia, 2011). Methods: We retrospectively analyzed all patients (pts) with WHO-defined MF (primary, including pre-fibrotic MF, or progressed from PV or ET) seen at our center from Jan. 2017 through Jul. 2021. We compared disease phenotypes, MPN driver and co-occurring mutations, cytogenetics, dynamic IPSS (DIPSS) score, transfusion requirements, treatment characteristics and survival outcomes between patients with SF3B1-mutated ( SF3B1+) and -wild type ( SF3B1-) MF. Results: A total of 381 pts were identified, 29 (8%) of whom were SF3B1+. There were similar frequencies of JAK2, CALR, MPL mutations and “triple negative” MF in the 2 groups (Table). The median number of SF3B1 mutations was 1 (range, 1-2); K666N being the most common (52%). The 2 groups were similar in regard to their baseline hemoglobin, white blood cell counts, platelets, co-occurring mutations, symptom burden and DIPSS but more SF3B1+ pts were PRBC transfusion-dependent at presentation than SF3B1- pts (38% vs. 15%, p=0.003). At a median follow up of 17.2 months for the entire cohort (range, 0.1- 52.2 mos., 22.6 mos. for SF3B1+ and 16.8 mos. for SF3B1-), 41 pts had died [14% SF3B1+ and 10% SF3B1-, p=0.5] and 7 pts (1 SF3B1+ and 6 SF3B1-) had leukemic transformation. The median estimated OS was 230 months for SF3B1- vs. not reached for SF3B1+ pts (p = 0.6). Conclusions: SF3B1 mutation is an uncommon event in MF and does not substantially affect disease phenotype and outcomes. MF pts with SF3B1 mutation are more likely to be PRBC transfusion dependent.[Table: see text]
Venetoclax combined with cladribine in patients with relapsed/refractory (R/R) T-cell prolymphocytic leukemia (T-PLL).
Authors: Arani Naszrin , Jammal Nadya , Geppner Alexis , Kim Kunhwa , Borthakur Gautam , Jain Nitin , Konopleva Marina , Garcia-Manero Guillermo , Ferrajoli Alessandra , Jabbour Elias , Kantarjian Hagop M. , Kadia Tapan M.
Published: June 2022

e19087

Background: T-cell prolymphocytic leukemia (T-PLL) is an ultra-rare and aggressive mature T-cell leukemia associated with a poor prognosis. First-line therapy is with CD52 monoclonal antibody alemtuzumab and allogenic stem cell transplant (SCT), but treatment is rarely curative. There is a critical need for more active therapies to improve outcomes. The BCL-2 inhibitor venetoclax (VEN) has demonstrated activity in T-PLL. We studied a combination of cladribine plus VEN in 5 patients (pts) with R/R T-PLL to investigate the safety and efficacy of this combination. Methods: We retrospectively analyzed pts ≥ 18 years with R/R T-PLL treated with a backbone of cladribine 5 mg/m2 intravenous (IV) for 5 days with VEN at a target dose of 600-800 mg orally daily (reduced for concomitant drug interactions) on a 28-day cycle. Two pts concomitantly received alemtuzumab, 1 received ruxolitinib, and 2 pts received both. Baseline demographics, cytogenetics and mutations were collected and summarized using descriptive statistics. Response criteria were defined according to the T-PLL consortium and survival analyzed by Kaplan-Meier method. Results: Five pts with a median age of 64 years (range, 59-66) were treated with cladribine + VEN. Pts had a median of 1 prior therapy (range, 1-3), including 3 (60%) with prior SCT. Overall response rate was 100%, including 2 (40%) complete remission with incomplete count recovery (CRi) (with 1 MRD negative CR), and 3 (60%) partial response (PR). A median of 2 cycles were given (range, 1-4). Baseline characteristics are summarized in Table. All five pts had abnormalities of chromosomes 8, 14, and TCL-1 (positive by FISH); 3 had a STAT5B mutation and 1 each had mutations in JAK1, JAK3, and IL7R. Pts had rapid reductions in all T-PLL-related symptoms and signs (i.e., WBC, splenomegaly, effusions, skin lesions, nodes) within the 2 weeks of starting. The regimen was well-tolerated. Two pts had transient grade 1 creatinine elevations and 4 had grade 4 neutropenia that returned to baseline in a median of 67 days (range, 2-93 days). At the time of data review, 1 patient was alive at 8.3 months. The median overall survival (OS) was 5.8 months. Conclusions: The combination of cladribine and VEN in patients with T-PLL refractory to first-line alemtuzumab was well-tolerated and effective. It was associated with rapid disease control, including splenomegaly, fatigue, pleural infiltrates, and skin infiltration. Staging studies to be presented. This encouraging experience should prompt further study as salvage therapy for T-PLL.[Table: see text]
Survival outcome of patients with relapsed or refractory classical Hodgkin lymphoma who achieved remission during immune checkpoint inhibitors treatment.
Authors: Liu Weiping , Lin Ningjing , Xie Yan , Wang Xiaopei , Song Yuqin , Zhu Jun
Published: June 2022

e19531

Background: Immune checkpoint inhibitors (ICIs) showed strong activity and tolerable toxicity in those patients with relapsed or refractory classical Hodgkin lymphoma. However, there was limited data on the long-term survival outcome of those patients after remission due to ICIs treatment. Methods: The data was collected from 4 pivotal phase 2 clinical trials: AK105-201 (penpulimab, NCT03722147), BGB-A317 (tislelizumab, NCT03209973), SHR-1210 (camrelizumab, NCT03155425), GLS-010 (zimberelimab, NCT03655483). The key inclusion criteria included age ≥18 years, relapsed or refractory classical Hodgkin lymphoma, lines of prior chemotherapy ≥ 2, treated with ICIs monotherapy, achieving complete remission (CR) or partial remission (PR). The progression-free survival (PFS) and overall survival (OS) were estimated from the time of registration. Results: Among 324 screened patients, 260 patients (140 with CR, 120 with PR) were enrolled. The median age was 32 years with a male/female ratio of 1.3:1. The median lines of prior chemotherapy was 3 (range, 2-11). Additionally, 184 patients had refractory disease, and 54 patients received autologous stem cell transplantation (n = 45) or brentuximab vedotin (n = 9). With a median follow-up period of 31.1 months, 116 (44.6%) patients underwent disease progression and 18 (6.9%) patients died. The 3-year PFS and OS rates of 55.1% and 89.7% for all patients, respectively. Compared with those with CR, patients with PR had inferior survival outcome (3-year PFS, 29.5% vs. 72.3%, P < 0.001; 3-year OS, 81.5% vs. 94.4%, P = 0.017). In terms of duration of treatment, the 3-year PFS and OS rates were 28.6% and 71.6%, and 74.5% and 98.5% for patients with duration of treatment < 24 and > 24 month, respectively ( P values were both < 0.001). Among patients with CR, longer duration of treatment (> 24 month) remained positive impact on the survival outcome (3-year PFS, 81.3% vs. 47.1%, P < 0.001; 3-year OS, 98.1% vs. 82.9%, P < 0.001). Conclusions: Deeper remission and longer duration and led to favorable survival outcome for patients with relapsed or refractory classical Hodgkin lymphoma who achieved remission during ICIs treatment.