bluuebunny/crossref_metadata_2025 huggingface dataset:
Receipt of financial drug assistance for oral targeted therapy among older adults with advanced non-small cell lung cancer (NSCLC).
Authors: Kumar Anika , Ragavan Meera Vimala , Zeng Sandra , Wong Melisa L.
Published: June 2023

e18916

Background: Financial drug assistance programs are a critical resource to mitigate financial toxicity for oral targeted therapy but can be challenging to access and navigate. Older adults with cancer frequently face high copayments for oral targeted therapy, yet they may be less able to navigate assistance programs due to functional and cognitive impairments. To identify potential barriers to receipt of assistance among older adults with advanced NSCLC, we evaluated associations between demographic, clinical, and geriatric assessment characteristics and receipt of financial drug assistance. Methods: We conducted a prospective cohort study at a Comprehensive Cancer Center where thoracic oncology nurses and pharmacists are available to help patients navigate financial drug assistance applications. We enrolled adults age > 65 with advanced NSCLC starting a new chemotherapy, immunotherapy, and/or oral targeted therapy regimen with non-curative intent. For this analysis, we included only older adults who received oral targeted therapy. Patients completed a pretreatment geriatric assessment to evaluate function, cognition, social support, comorbidities, mood, and nutrition. Receipt of financial drug assistance was abstracted from the medical record. We used Fisher’s exact tests to evaluate for differences in demographic, clinical, and geriatric assessment characteristics between those who did and did not receive financial drug assistance. Results: Of the 168 older adults with advanced NSCLC in the parent cohort study, 45 received oral targeted therapy and were included in this analysis. Median age was 74 (range 65-94); 56% were White, 40% Asian, 2% Black, and 2% Hispanic. The majority had Medicare (76%) followed by private insurance (18%), Medicare and Medicaid (4%), and Medicaid alone (2%). On the geriatric assessment, 60% were dependent in instrumental activities of daily living, 20% were dependent in basic activities of daily living, 51% had an abnormal Montreal Cognitive Assessment, and 42% had poor tangible social support. Overall, 9 older adults (20%) received financial drug assistance for their oral targeted therapy. Older adults with a lower household income were more likely to receive financial drug assistance (p = 0.007). There were no statistically significant differences in receipt of financial drug assistance according to other demographic, clinical, or geriatric assessment characteristics including function, cognition, and social support. Conclusions: Older adults with advanced NSCLC on oral targeted therapy with lower household incomes were appropriately more likely to receive financial drug assistance. The lack of associations between receipt of financial drug assistance and function, cognition, and social support suggests that thoracic oncology staff are successfully helping older adults navigate financial drug assistance programs.
Cost of breast cancer screening in the USA: Comparison of current practice, advocated guidelines, and a personalized risk-based approach.
Authors: Badal Kimberly , Staib James , Tice Jeffrey , Kim Mi-Ok , Eklund Martin , DaCosta Byfield Stacey , Catlett Kierstin , Wilson Leslie , Maffey Liz , Soonavala Rashna , Stover-Fiscalini Allison , Esserman Laura
Published: June 2023

e18917

Background: Several clinical trials are comparing the safety and efficacy of risk-based and age-based breast cancer screening. This study aimed to estimate the aggregate yearly cost of screening in the USA for 2019 to 2021 and to project cost of four strategies: annual, biennial, hybrid, and the WISDOM (Women Informed to Screen Depending on Measures of risk) clinical trial’s risk-based strategy. An assessment of screening costs under different strategies can inform policy decisions. Methods: Total cost was estimated for each strategy by summing screening and recall cost for eligible women from a national payer perspective. Data from the FDA Mammography Quality Standards Act and Program was used to estimate the number of screening mammograms in 2019 to 2021. Data from the Optum Labs Data Warehouse (OLDW) was used to estimate utilization of 2D and 3D mammograms, MRI and mammogram costs, recall costs and rates. OLDW contains longitudinal de-identified administrative, medical, and pharmacy claims for over 200 million commercial and Medicare Advantage (MA) enrollees and patients. Study subjects were continuously enrolled for approximately three years to capture all encounters. Medicare Advantage claims were used to approximate public payer costs and rates. We assumed 100% adherence to all strategies. The risk-based strategy used a cost of $270 for genetic testing and risk assessment. Probabilistic sensitivity analysis was used to estimate uncertainty in the estimated aggregate cost. One-way deterministic sensitivity analysis was used to determine the impact of each input on the aggregate cost. Results: Median mammogram costs ranged from $139-$360, MRI costs ranged from $545-$2,439, while recall rates ranged from 9.2%-20.9%. The annual cost of screening 50% of eligible women in 2019 was $11.5B ($10.37-13.94B) and cost $77,824 per breast cancer detected. The estimated yearly aggregate cost of screening 100% of eligible women was: $26.71B ($24.61-32.82B) for annual; $18.09B ($16.03-21.16B) for hybrid; $7.57B ($6.97-9.29B) for biennial; and $9.60B ($8.88-11.70B) for risk-based strategies. The estimated average cost per woman screened until 74 years was: $22,315 for annual; $16,552 for hybrid; $4,133 for biennial; and $6,878 for risk-based. The yearly aggregate cost of screening was most sensitive to variations in commercial 3D mammography cost. Conclusions: Biennial and risk-based screening can reduce cost substantially. Risk-based screening reduced cost even with the cost of population genetic testing included while maintaining intensive screening for the highest-risk women. The resources saved can be used to improve screening for women at high-risk of fast-growing disease who are often identified between screens and for improving overall adherence.
Excess testing after diagnosis of incidental pulmonary nodules (IPNs) in the Medicare population.
Authors: Osarogiagbon Raymond U. , Pinsky Paul
Published: June 2023

e18922

Background: Management of IPNs re-distributes lung cancer to earlier stages at diagnosis, but most people with IPNs will not develop lung cancer. We assessed the rate of diagnostic procedures related to suspected lung cancer in people on Medicare who had IPNs. Methods: We analyzed the 5% SEER-Medicare database for IPNs, diagnostic procedures, and lung cancer status. We analyzed two cohorts: persons with chest CT scan procedure codes accompanied by ICD-9 code 793.11 or ICD-10 code R91.1 during 2014-2017 (IPN cohort) and persons with CT scan procedure codes without the IPN codes during that period (control cohort). We computed rates of lung cancer-related diagnostic procedures (per 100 person-years [PY]) during the 2-year follow-up period, including chest CT, PET/PET-CT, bronchoscopy, needle biopsy, and surgical procedures. We used multivariable Poisson regression to estimate procedure rate ratios (RRs) across cohorts, controlling for demographics and COPD status. Using the regression RRs, we estimated excess procedures in the IPN cohort over the 2-year follow-up period by subtracting the control cohort (background) rate. Based on prior data on the reduced proportion (by 36%) of late-stage disease associated with follow-up of IPNs, we computed a metric of excess procedures per late-stage case avoided by IPN follow-up. Results: Of 19,009 (IPN) and 60,985 (control) persons, 3.6% and 0.8%, respectively, had lung cancer diagnosed during 2-year follow-up. Among IPN cohort without lung cancer, rates per 100 PY were 73.1, 9.4, 4.0, 3.2 and 1.0 for chest CT, PET/PET-CT, bronchoscopy, needle biopsy, and surgical procedures, respectively (Table). Poisson regression showed significantly elevated RRs for the IPN versus control cohort for all procedures, with RRs ranging from 1.27 (bronchoscopy) to 2.03 (Chest CT). Excess procedures in the IPN cohort (per 100 persons) ranged from 63 for chest CT to 0.9 for surgical procedures (Table). Excess procedures per late-stage case avoided ranged from 48 for chest CT to 0.7 for surgical procedures. Conclusions: The burden of diagnostic procedures following reported IPNs is modest relative to the yield of early-stage lung cancer. [Table: see text]
Cost effectiveness of a personalized approach for lung cancer screening with LDCT based on the use of blood-based biomarker test.
Authors: Irajizad Ehsan , Fahrmann Johannes , Vykoukal Jody , Do Kim-Anh , Dennison Jennifer , Ostrin Edwin J. , Hanash Samir M
Published: June 2023

e18927

Background: We previously reported that a circulating panel of protein biomarkers together with a risk model based on subject characteristics improves lung cancer risk assessment for lung cancer screening compared to current screening eligibility criteria (JCO 2022 PMID 34995129). The goal of this study is to assess cost-effectiveness of a personalized approach to lung cancer screening with LDCT. Methods: We conducted retrospective analyses using data from the US Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial and protein biomarker data measured on prospectively collected pre-clinical sera from the PLCO biorepository. For determination of cost-effectiveness of using the biomarker test for risk based referral for LDCT, we assumed screening of 27.0 million US ever smokers. The reference scenario assumed eligibility using the risk-based smoking approach with no cost. We predicted that the proportion of upcoming lung cancer cases categorized as screening eligible will increase as a result of biomarker-informed eligibility. We used direct NLST costs using 2009 Medicare prices for screening (per person screened), workup (per positive screen), and treatment (per lung cancer case) and evaluated the effectiveness at different biomarker costs. We used life year gained for cases and non-cases, with and without screening. Results: With 80.4% sensitivity at 66.9% specificity; performance of our previously established lung panel, assuming a willingness-to-pay threshold of $70 000 per life-year gained, the biomarker test for referral to screening is cost-effective up to 300$. At a willingness-to-pay threshold of $100,000 per life-year, the biomarker test is cost-effective up to $500. Conclusions: A cost effective blood-based biomarker test has been developed for referral for lung cancer screening with LDCT.
Cost-utility analyses of later-line treatments for metastatic colorectal cancer (mCRC) by network meta-analysis (NMA) approach: Conventional constant hazard ratio vs novel survival curves methodologies.
Authors: Obeng-Kusi Mavis , Erstad Brian L , Roe Denise , Abraham Ivo
Published: June 2023

e18928

Background: Cost-utility analyses of later-line treatments for metastatic colorectal cancer (mCRC) differ based on network meta-analysis (NMA) approach: conventional constant hazard ratio vs novel survival curves methodologies. Methods: We conducted a CUA estimating the incremental cost utility ratio (ICUR) over a 5-year time horizon from the US payer perspective. The 3-state partitioned survival models included efficacy inputs from a novel one-step multivariate NMA of progression-free and overall survival curves and from a conventional constant hazard ratio NMA. Utilities, as well as drug acquisition, administration, adverse event, monitoring and end of life costs were sourced from literature. We compared results and examined statistical factors in either approach that may explain the observed results. Results: The multivariate NMA produced lower estimates of survival benefits over placebo compared to the NMA based on constant hazard ratios, at the same incremental costs (Table). This reduction in incremental benefits led to higher estimates of cost-effectiveness and cost-utility when using the multivariate NMA. Probabilistic sensitivity analyses showed greater uncertainty in the model based on the constant hazard NMA. Conclusions: The multivariate NMA produced lower estimates of survival benefits over placebo compared to the NMA based on constant hazard ratios, at the same incremental costs (Table). This reduction in incremental benefits led to higher estimates of cost-effectiveness and cost-utility when using the multivariate NMA. Probabilistic sensitivity analyses showed greater uncertainty in the model based on the constant hazard NMA. [Table: see text]
Novel RNA epigenetics-driven technologies for rapid prediction of cancer drug resistance.
Authors: Wood Shaun , Willbanks Amber , Tang Derrick , Arber Daniel A , Oakes Scott , Shammo Jamile M. , Odenike Olatoyosi , Stock Wendy , Larson Richard , Cheng Jason X
Published: June 2023

e19001

Background: The human genome comprises ~99% non-coding DNA sequences (ncDNAs), most of which are actively transcribed into various forms of non-coding RNAs (ncRNAs) that undergo extensive chemical modifications to regulate various functions of the subcellular organelles in human cells ( Statello, et al. Nat Rev Mol Cell Biol 2020). However, the clinical potential of RNA modifications and RNA modifying proteins, i.e., RNA epigenetics, is largely unexplored. In a recent study ( Cheng et al. Nat Commun 2018), we first demonstrated that specific RNA cytosine methyltransferases (RCMTs), namely NSUN1 and NSUN2, directly interact with elongating RNA polymerase II (eRNAPII) and the bromodomain-containing protein 4 (BRD4) to form distinct active chromatin structures (ACS) that regulate drug resistance in leukemia cells. This proof-of-concept study enabled us to develop the first-generation of RNA epigenetics-driven drug-predictive system. The primary goal of this study is to validate and optimize this novel drug-predictive system with clinical myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Methods: We developed new technologies, including 5-ethynyl uridine click chemistry (EC) and proximity ligation rolling cycle amplification (PL-RCA)-coupled confocal microscopy (CM), flow cytometry (FCM) and RNA sequencing (RNA-seq). Immunohistochemistry (IHC), western blot (WB), co-immunoprecipitation (co-IP), and dot blot were also used in this study. Results: Our data demonstrated significantly increased expression of the NSUN1, NSUN2 and other key components of the drug-resistant ACS in MDS/AML, which is correlated with disease progression and drug resistance in MDS and AML. We have developed novel technologies, i.e., EC- and PL-RCA-coupled CM and FCM (EC-/PL-RCA/CM & FCM) to visualize and quantify RCMTs-mediated ACS and nascent RNA synthesis in MDS/AML. We discovered nascent RNA synthesis as a highly sensitive and super-fast drug-predictive marker that is independent of cell death and apoptosis. Our data demonstrated that PL-RCA/FCM and EC-/CM have a very high sensitivity to detect the NSUN1/2-mediated ACS in leukemia cell lines and clinical MDS/AML specimens. Our preliminary data demonstrated that increased levels of NSUN1/2-mediated ACS detected by PL-RCA/FCM in pre-treatment MDS/AML can rapidly predict the responses to venetoclax and/or azacitidine. We are actively pursuing RNA-seq targeting NSUN1/2-associated nascent RNAs and ACS, which provides a novel strategy to dissect the functional genomics and RNA epigenetics underlying cancer drug resistance. Conclusions: We have developed a novel RCMTs/NSUN1/2-targeting system for rapid prediction and in-depth analysis of drug resistance in MDS/AML. A large sized clinical study is needed to further validate its usefulness in clinical settings.
Defining risk of central nervous system relapse in acute myeloid leukemia following allogeneic stem cell transplantation.
Authors: Nicchi Vincent , Roloff Gregory , Gomez Kayeromi , Campo Loredana , Badami Ami , Tsai Stephanie , Stiff Patrick J. , Hagen Patrick
Published: June 2023

e19009

Background: Relapse following allogeneic stem cell transplant (AlloSCT) for acute myeloid leukemia (AML) remains the commonest cause of death post-transplant. Central nervous system (CNS) relapse is a devastating complication. With an estimated incidence of 2-8%, defining those patients at high risk and the management following CNS relapse remains controversial. We sought to identify demographic, clinical, molecular, and laboratory risk factors that would predispose AML patients to CNS relapse. Methods: This was a single institution retrospective study at Loyola University Medical Center. Inclusion criteria were adult patients with AML undergoing first AlloSCT from January 2012 to June 2021. Diagnosis of CNS relapse following AlloSCT was defined as leukemic blasts detected in spinal fluid analysis in accordance with established criteria. Chi-square tests were used to test the association between the experiencing of relapse and the categorical variables recorded. Wilcoxon Rank Sum test were used to assess the relationship between relapse experience and each of the demographic variables. Due to the low count of patients with CNS relapse and in order to avoid a poor estimation of confidence limits of any effect size, we limited our analyses to descriptive statistics and univariable analyses. Results: 198 patients met inclusion criteria with 8 cases (4.0% total) identified with CNS relapse following AlloSCT. Our analysis initially characterized 44 variables including age, race, HCT-CI risk, and day 100 chimerism. Univariate analysis is shown in the table below. Of note, it revealed that 62.50% of patients with CNS relapse had a chimerism value ≤98% at day 100 post-transplant as compared to 22.58% of patients without CNS relapse (p-value 0.02). Additionally, 87.50% of the CNS relapse group versus 51.38% of the group without relapse had favorable to intermediate AML risk scores (p-value 0.07). Conclusions: We observed a 4.0% rate of CNS relapse, which is consistent with what has been repored in the literature. Our results suggest that day 100 chimerism and disease risk index may be predictive of CNS relapse. Since there is a 10.6% incidence (5/47) of eventual CNS relapse amongst those with ≤98% chimerism at day 100, these patients could be considered for a lumbar puncture and bone marrow biopsy to prevent full relapse. Further research in this topic would be valuable to provide additional AML guidance in managing this uncommon complication, such as which patients may benefit from prophylactic strategies. [Table: see text]
Responses in patients with AML and treated with entospletinib monotherapy.
Authors: Lin Tara L. , Cutler Richard E. , Olek Elizabeth , Carvajal Luis A. , DiMartino Jorge F. , Walker Alison R.
Published: June 2023

e19010

Background: AML is a disease defined by the acquisition of genetic lesions in normal hematopoietic stem cells and progenitors resulting in poorly differentiated and highly proliferative leukemic blasts. Spleen tyrosine kinase (SYK) is a nonreceptor tyrosine kinase that maintains de-differentiation and leukemogenesis. MLL rearrangements (MLL-r) occur in up to 10% of adult AML and are associated with upregulated expression of the transcription factors HOXA9 and MEIS1 and worse clinical outcomes. Entospletinib (ENTO), an oral, selective inhibitor of SYK, has been studied in clinical trials for unselected AML patients as well as MLL-r patients. ENTO plus standard induction chemotherapy in front line had a 76% (13/17) composite complete response (CR) in AML patients with high HOXA9 and MEIS1. We have 3 patients that achieved CRs with ENTO monotherapy; one patient achieved CR to 14 days of ENTO monotherapy prior to initiation of chemotherapy; 2 patients with relapsed/refractory AML with MLL-r treated with ENTO monotherapy achieved CRs. Methods: This was part of an international multicenter phase Ib/II study (NCT02343939) which evaluated the efficacy, safety, and tolerability of ENTO in subjects with AML. During dose escalation, ENTO was administered in combination with induction chemotherapy (Group A) or with a hypomethylating agent (Group B). ENTO was administered as monotherapy for R/R AML in Group C. This report includes one patient from group A (newly diagnosed AML, MLL-r, 14-day monotherapy lead-in with ENTO) and two patients from group C monotherapy (relapsed/refractory AML, MLL-r). Results: Three patients receiving ENTO monotherapy had CRs. 18-year-old male from group A, that was MLL-r, NPM1-mutant (-). Patient treated at 400 mg PO, BID, achieved a cytogenetic CR with incomplete count recovery after cycle 0 (before chemotherapy); the patient continued study with induction chemotherapy and ultimately received ASCT in CR. Two additional patients in group C (with multiple therapies), both at 400 mg bid: (i) 37-year-old male, MLL-r, NPM1(-), was on study for 28 days, achieved CR; (ii) 28-year-old female, MLL-r, NPM1(-) on study for 60 days, achieved CR, both proceeded to SCT. Conclusions: Based on the results from these three patients, the clinical activity of SYK inhibition should be explored further in AML. We are testing Lanraplenib, a next-generation SYK inhibitor with enhanced selectivity, and more favorable pharmacologic properties in combination in genetically defined subsets of AML (NCT05028751). Clinical trial information: NCT02343939 .
A phase II trial of ponatinib and blinatumomab in adults with newly diagnosed Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL).
Authors: Short Nicholas James , Jabbour Elias , Jain Nitin , Macaron Walid , Huang Xuelin , Montalban-Bravo Guillermo , Kadia Tapan M. , Daver Naval Guastad , Haddad Fadi , Zoghbi Marianne , Nasnas Cedric Christophe , Nasr Lewis Fady , Mayor Ejiroghene , Deen Wuliamatu , Thankachan Jennifer , Loiselle Christopher , Garris Rebecca , Konopleva Marina , Ravandi Farhad , Kantarjian Hagop M.
Published: June 2023

e19013

Background: Ponatinib and blinatumomab are both active in Ph+ ALL. A combination of these agents may lead to durable remissions when given in the frontline setting and may eliminate the need for chemotherapy or stem cell transplant (SCT). Methods: In this phase II study, patients (pts) with newly diagnosed Ph+ ALL received up to 5 cycles of blinatumomab in combination with ponatinib, followed by ponatinib maintenance for at least 5 years. Ponatinib 30mg daily was given during cycle 1 and decreased to 15mg daily once a complete molecular response (CMR) was achieved. Pts also received 12 doses of prophylactic IT chemotherapy. Results: Between 2/2018 and 1/2023, 54 pts were with newly diagnosed Ph+ ALL were treated. Baseline characteristics are shown in the table. Among 35 pts evaluable for hematologic response, 23 (97%) achieved CR/CRi; 1 pt had early death. Among 48 pts evaluable for molecular response, 34 (71%) achieved CMR after 1 cycle, and 43 (90%) achieved CMR at any time. After 2 weeks of therapy, 18/35 tested pts (51%) achieved CMR in the peripheral blood. 34/38 tested pts (89%) achieved MRD negativity by next-generation sequencing at a level of 10-6. Four of these pts who were MRD-negative by NGS had detectable low-level BCR:ABL1 transcripts by PCR at the same time (ranging from 0.01% to 0.05%). The median follow-up is 16 months (range, 1-55 months). Three patients relapsed after a median of 9 months of remission (range, 8-23 months), 1 in bone marrow with new E225V mutation and 2 extramedullary-only. Three pts have died (1 from intracranial hemorrhage, 1 from post-procedural hemorrhage, and 1 from brain aneurysm). There have been no leukemia-related deaths, the estimated 2-year EFS and OS are both 90%. Only 1 pt underwent SCT in first remission; this pt was transplanted due to persistently low-level BCR:ABL1 positivity. Among the 47 pts in ongoing remission without SCT, the median duration of response is 15 months. Most side effects were grade 1-2 and were consistent with the known toxicity profile of the two agents. Ponatinib was discontinued in 2 patients due to possibly related adverse events (CVA and coronary stenosis in 1 pt each). Conclusions: The chemotherapy-free combination of ponatinib and blinatumomab is safe and effective in newly diagnosed Ph+ ALL, with high rates of MRD negativity. Encouraging duration of remission and OS has been observed without the need for SCT. Clinical trial information: NCT03263572 . [Table: see text]
Optical genome mapping for cytogenomic analysis of hematological neoplasms.
Authors: Tang Guilin , Tang Zhenya , Kanagal-Shamanna Rashmi , Kantarjian Hagop M. , Garcia-Manero Guillermo , Cuglievan Branko , McCall David , Jain Preetesh , Robinson Melissa , Reynolds Alex , Danos Christopher P , Cardona Griselda Jazmin , Geiger Christopher P , Yang Su , Medeiros L Jeffrey , Toruner Gokce A
Published: June 2023

e19016

Background: Optical genome mapping (OGM) provides a genome-wide analysis for structural variants and copy number changes in one-assay. Compared with conventional G-banded karyotyping (GBK), OGM provides significantly higher resolution and does not require metaphase cells. In this study, we assessed the added value of OGM for cytogenomic analysis of hematological neoplasms. Methods: OGM was performed on blood or bone marrow using Saphyr from Bionano Genomics on 63 patients diagnosed with various types of hematological malignancy (see Table). Variant calling was made by the Rare Variant Analysis pipeline on Bionano Access after applying recommended filters. Each patient had karyotype and/or fluorescence in situ hybridization (FISH) results available for comparison and confirmation. Only Tier 1 (pathogenic) and Tier 2 (likely pathologic) abnormalities were included for comparison purposes in this study. Results: The results were completely concordant between GBK/FISH and OGM in 30 (47.6%) patients, including 10 patients who showed no cytogenetic abnormality (normal). Fully discordant results were found in 8 (12.7%) patients: 2 had an abnormal karyotype but normal OGM, the discrepancy was mainly due to the clonal size (<20%) below the limitation of detection of OGM; 6 had a normal karyotype but cytogenetic abnormalities were detected by OGM, the discrepancy was mainly due to failure of tumor cells growth (n=5) or subtle cytogenetic abnormality undetectable by GBK (n=1). Partially concordant results between karyotype/FISH and OGM were observed in 25 (40%) patients, some abnormalities were detected by both, some were detected by GBK alone (n=4) or by OGM alone (n=25), the latter group included 10 cases with chromothripsis which only be detected by OGM. Overall, OGM provided clinically significant information in 14 (22%) patients regarding diagnosis, risk stratification, and/or identifying therapeutic targets. The added value was more common in lymphoid neoplasms (9 of 27 patients, 33%). Conclusions: OGM provides additional clinically relevant cytogenetic information in the workup of hematological neoplasms. This added value is more apparent in lymphoid neoplasms. These improvements are largely contributable to the higher resolution provided by OGM and analysis independent of metaphase cells. A major limitation of OGM usage is the need for a clonal size of at least 20%. [Table: see text]
Clinical spectrum and outcomes of carbapenem resistant infections in patients with acute leukaemia: A clinical study from a tertiary oncology centre in India.
Authors: Hari Vishnu , Prakash N.P. , Nath Swapna R.
Published: June 2023

e19020

Background: The prevalence of carbapenem resistant organisms (CRO) are increasing worldwide and associated with grave implications in patients with hematological malignancies. Data on such infections in patients with acute leukemia are scarce, especially from the developing world. The aim of this study was to evaluate characteristics and outcomes of bacteremia with CRO in patients treated for acute leukemia with aggressive chemotherapy regimens. Methods: This prospective observational study was conducted in a tertiary oncology centre in South India. Data on Carbapenem resistant bloodstream infection (CRBSI) in patients with acute leukemia (ALL and AML) aged 14-60 years, from March 2017 to February 2018 were prospectively collected. The final outcome was determined as survival and all-cause death due to CRBSI. Results: Out of 334 patients treated for acute leukemia, 49 patients developed infections with CRO (14.6%). The patients included 27 males (55%) and 22 females (45%), with age ranging from 14 year to 58 years (median age: 42 years). The most common isolates were Klebsiella species (63%) and E.coli (25%). All carbapenem resistant isolates were sensitive to Colistin and 74% were sensitive to Tigecycline. The case-fatality rate was 69% (34/49) in our cohort. Acute kidney injury, shock, septicemia and an initial procalcitonin value > 1mcg/L were predictor of mortality. Disease in remission and neutrophil count recovery post chemotherapy were favorable factors associated with the outcome. There was no statistically significant difference in mortality in patients treated with single agent antibiotics versus combination antibiotics sensitive against CRO. Conclusions: Carbapenem resistant infections in patients with acute leukaemia are associated with a high mortality rate. The factors associated with improved outcome were disease in remission and neutrophil count recovery, post chemotherapy. The presence of acute kidney injury, shock, sepsis and a procalcitonin value more than 1 mcg/L were significant predictor of mortality.
A demographic study of acute megakaryoblastic leukemia using the national cancer database.
Authors: Juang Eric , Furtado Nikhil , Keirns Darby , Wu Xinxin , Silberstein Peter T. , Hsia Beau
Published: June 2023

e19023

Background: Acute megakaryoblastic leukemia (AMKL) is a rare subtype of acute myeloid leukemia that, based on past studies, primarily affects children. Patients with Down syndrome (DS) have a higher risk of developing AMKL. While DS-associated AMKL has an overall survival rate of 80%, the prognosis of adult AMKL is much poorer (overall survival rate of < 40%). The prognostic heterogeneity of AMKL warrants an investigation of its diagnostic trends in order to gain epidemiological insights. In this study, demographic data of AMKL patients was obtained from the National Cancer Database (NCDB) and analyzed to determine factors that affect the outcome of AMKL patients. Methods: In this retrospective cohort study, data from the 2004-2020 NCDB was analyzed to identify cases of AMKL with ICD-O-3 code 9910. Demographic data attached to the identified cases assessed included age, sex, race, Hispanic status, insurance status, facility type, surgery status, palliative care status, and Charlson-Deyo score. Descriptive statistics were obtained, and the incidence trends of AMKL were interpreted using regression analysis. Results: A total of 765 patients diagnosed with AMKL were identified in the database between 2004 – 2020 with a decreasing incidence of patients diagnosed per year (64 cases in 2004 and 11 cases in 2020; R^2 = 0.86). The average age of diagnosis was 40.3 years (SD = 32.4, range = 0 – 90 years, median = 51 years). AMKL exhibits slight male prevalence (55.2% vs 44.8% for females). The majority of the patients were Non-Hispanic White (77.6%). Most individuals had Charlson-Deyo comorbidity scores of 0 (79.1%). The incidence rates were similar across household income quartiles. 72.8% of AMKL cases were diagnosed in urban areas with a population of > 250,000. Fewer cases were treated at community cancer programs as compared to either academic/research programs (45.1%) or integrated network cancer programs (20.6%). Private insurance (38.6%), Medicare (30.6%), and Medicaid (22.0%) were the most common insurance types. All patients received surgical intervention of the bone marrow and 3.2% of patients received palliative care. Conclusions: This NCDB-based demographic analysis on AMKL serves to improve the general understanding of AMKL. Surprisingly, the average and median ages of diagnosis are 40.3 and 51 years, respectively, which contradicts prior reports of AMKL being primarily a pediatric disease. Our analysis of the socioeconomic factors of AMKL patients showed that most AMKL patients were non-Hispanic Whites and diagnosed and treated in urban settings. In addition, the majority of AMKL patients had government insurance (54.6%; Medicare, Medicaid, and others). While this study provides initial insight into the role demographics play in the diagnosis and treatment of AMKL patients, further studies on how these factors contribute to their outcome would provide great value in understanding the social disparity in AMKL.
Mini-hyper-CVD plus inotuzumab ozogamicin (InO), with or without blinatumomab (Blina), in older patients with newly diagnosed Philadelphia chromosome (Ph)-negative B-cell acute lymphoblastic leukemia (ALL): Updates from a phase II trial.
Authors: Nasnas Cedric Christophe , Jabbour Elias , Haddad Fadi , Short Nicholas James , Nasr Lewis Fady , Macaron Walid , Zoghbi Marianne , Ravandi Farhad , Jain Nitin , Kadia Tapan M. , Daver Naval Guastad , Borthakur Gautam , Dinardo Courtney Denton , Jacob Jovitta , Roy Edith , Loiselle Christopher , Milton Anna , Rivera Juan , Garris Rebecca , Kantarjian Hagop M.
Published: June 2023

e19025

Background: The overall survival (OS) of patients (pts) with relapsed/refractory B-ALL has improved with the introduction of InO and Blina. Compared to conventional chemotherapy, the incorporation of these agents into the frontline setting of older pts with ALL may allow the use of less chemotherapy and potentially improve outcomes. Methods: Adults ≥60 yrs with newly diagnosed Ph-negative B-ALL received mini-Hyper-CVD (mini-HCVD) for up to 8 cycles. Initially, InO was given at 1.3-1.8mg/m2 on Day (D) 3 of Cycle (C) 1 and 0.8-1.3mg/m2 on D3 of C2-4. Rituximab (if CD20+) and prophylactic IT chemotherapy were given for the first 4 cycles. Responders received POMP maintenance for up to 3 yrs. Beginning with pt #50, InO was given in fractionated doses each cycle (0.6 mg/m2 on D2 and 0.3 mg/m2 on D8 of C1; 0.3 mg/m2 on D2 and 8 of C2-4) and 4 cycles of Blina were given following 4 cycles of mini-HCVD plus InO. Maintenance was with 12 cycles of POMP and 4 cycles of Blina (1 cycle of Blina after 3 cycles of POMP). Results: 83 pts were treated, of whom 6 were in complete remission (CR) at enrollment(Table 1). Among 77 evaluable pts, 76 (99%) responded (CR, 90%). Among responders, the rates of MRD negativity by flow cytometry were 79% and 94% after C1 and overall, respectively. No early death was observed. Among 82 pts in remission, 11 (13%) relapsed, 4 (5%) underwent ASCT, 34 (41%) remain in ongoing continuous remission, 33 (41%) died in remission, of whom 9 died after developing MDS/AML. Three pts (4%) developed veno-occlusive disease, 2 after subsequent ASCT. After a median follow-up of 65 months (range, 6-126), the 5-yr continuous remission duration and OS rates were 78% and 48%, respectively. Age ≥70 and adverse cytogenetics were associated with worse outcomes. The inferior outcome in pts ≥70 yrs was primarily attributed to higher rates of death in CR. The 5-yr OS for pts age 60-69 yrs without adverse cytogenetics (n=40), age 60-69 with adverse cytogenetics (n=15), age ≥70 without adverse cytogenetics (n=24) and age ≥70 with adverse cytogenetics (n=4) were 72%, 27%, 38% and 0%, respectively. Conclusions: Favorable outcomes were observed in older pts with newly diagnosed Ph-negative ALL treated with mini-HCVD plus InO, with or without Blina. The 5-yr OS was 48%. Clinical trial information: NCT01371630 . [Table: see text]
Demographic factors affecting patients with AML with myelodysplasia-related changes.
Authors: Stewart Laura , Keirns Darby , Wu Xinxin , Silberstein Peter T. , Hsia Beau
Published: June 2023

e19027

Background: Acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) is a rare and aggressive form of acute myeloid leukemia (AML) that makes up about 25-34% of its annual cases. The subtype includes a varied group of tumors with clinical, genetic, and morphological characteristics that confer poor outcomes. AML-MRC is commonly treated with intensive chemotherapy, but the median survival is only 9-12 months. Given the poor outcomes, gaining a better understanding of epidemiologic factors could reveal opportunities for earlier diagnosis and improved treatment planning. Demographic characteristics of AML-MRC patients were identified and examined using the National Cancer Database (NCDB). Methods: Individuals with a confirmed diagnosis of AML-MRC (N = 14,536) were identified using the NCDB for a retrospective analysis from 2004 to 2020. Patient sex, age at diagnosis, race, household income, insurance status, urban/rural residence, and Charlson-Deyo score were examined by descriptive statistics, and diagnostic trends by year were identified and calculated with regression analysis. Results: A total of 14,536 patients diagnosed with AML-MRC between 2004 – 2020 were identified in the NCDB. Within this timeframe, there was an increasing incidence of diagnosis per year (R2 = 0.9). AML-MRC was more common in males (61.1%) than females (38.9%), and the average age at diagnosis was 68.9 years (SD = 13.0, range = 0 – 90 years). The majority of patients (87.3%) were White. Patients were most likely to be a part of the highest median household income quartile (33.6%) and least likely to be a part of the bottom quartile (13.2%). A higher percentage of patients were insured by Medicare (63.0%) compared to private insurance (25.3%). Most patients lived in counties in metro areas of 1 million population or more (51.4%). Most individuals had Charlson-Deyo comorbidity scores of zero (68.1%). The most common type of treatment facility was academic/research programs (55.1%) followed by comprehensive community cancer programs (23.3%). Conclusions: AML-MRC is a common subtype of AML with a poor prognosis. Previous studies have found that most individuals with AML-MRC are older-aged, White males. Our study corroborated this finding and examined additional demographic factors. We found that these patients were more likely to hold insurance through Medicare, likely reflecting the older average age at diagnosis. Additionally, patients were most commonly in the highest household income quartile and living in a metropolitan area with the highest population density. This could suggest that better access to healthcare improves rates of diagnosis of AML-MRC. Especially given that more people are being diagnosed each year, further research should work to understand the effects of these, and other, socioeconomic factors on the diagnosis, treatment, and prognosis of patients with AML-MRC.
Comparison of time of onset of leukemia with patients receiving adalimumab vs other TNF α inhibitors.
Authors: Devarkonda Vishal , Balmuri Shravya , Gaddam Shiva Jashwanth , Keerty Dinesh , Akabane Hugo
Published: June 2023

e19034

Background: TNF α (Tumor necrosis factor alpha) inhibitors were first approved by US FDA (Food and drug administration) in the late 1990s to manage several inflammatory conditions. Theoretically, TNF α inhibitors have an elevated risk of malignancies as TNF plays a role in cell apoptosis. The development of newer human monoclonal TNF α antibodies like Adalimumab has been approved for a broader clinical spectrum of activity. However, any increase relative risk of malignancies associated with these drugs is highly debatable, with many post-marketing surveillance studies showing no significant increases in the relative risk of malignancies receiving these drugs. We hypothesize with the null hypothesis stating that there is no significant difference in the time of onset of acute leukemia in the patients receiving Adalimumab in comparison with other TNF α inhibitors. Methods: A comprehensive literature search of PubMed, Embase, and Cochrane was conducted. A total of 19 cases of acute leukemia were reported in association with TNF α inhibitors receiving it for various inflammatory conditions. Of nineteen patients, ten received Adalimumab as the last TNF α inhibitor, while nine received other TNF α inhibitors for various inflammatory etiologies. These patients received multiple lines of treatment with steroids, Thiopurines, Methotrexate, and TNF α inhibitors with varying duration of disease activity. We performed a one-way ANOVA analysis comparing the mean duration of the last TNF inhibitor with the time to diagnosis of leukemia. Results: The results indicate a significant effect [F (1, 17) = 5.652, p=0.029 < 0.05]. The comparison revealed a significant difference between the patients who took Adalimumab (M=5.650; SD=3.8733) and other TNF α inhibitors (M=23.333; SD=23.2379) as the last drug. We, therefore, reject the null hypothesis as there is a significant difference in the time of onset of acute leukemia in the patients receiving Adalimumab in comparison with other TNF α inhibitors. Conclusions: In this limited study of the cases of acute leukemia reported in the literature receiving TNF inhibitors for various inflammatory conditions, patients receiving Adalimumab would have the early time of onset of leukemia in comparison with the other TNF α inhibitors. [Table: see text]
Trajectories of physical well-being among adults with acute myeloid leukemia.
Authors: Jensen-Battaglia Marielle , Sohn Michael , Wang Ying , Consagra William , LoCastro Marissa , Davis Jenae N. , Buettner Kathryn , Mortaz Soroush , El-Jawahri Areej , Loh Kah Poh
Published: June 2023

e19040

Background: Adults with acute myeloid leukemia (AML) commonly experience physical decline related to their disease and treatment which is associated with negative outcomes. However, physical trajectories differ among patients. Identifying distinct physical trajectories may help guide clinical decision making and supportive care interventions. In this secondary analysis, we examined physical trajectories of patients with AML and factors associated with these trajectories. Methods: We used data from patients with newly diagnosed AML in four clinical trials. Functional Assessment of Cancer Therapy Physical Well-Being sub scale (FACT-PWB, range 0-28) was measured from baseline to day 200, up to 5 timepoints per patient. We used group-based trajectory models (GBTM) weighted for mortality-related drop out to identify groups of patients with similar trajectories of change in FACT-PWB and estimate the association of baseline demographics (age, marital status, education) and clinical factors (AML risk, baseline FACT-PWB, depression, anxiety) with group membership. The number of groups was selected based on clinical interpretability and model fit statistics. Results: We included 343 patients with ≥ 1 FACT-PWB score during up to 200 days of follow-up. Mean age was 65 (SD 12.7), most had intermediate risk AML (178, 52%), received intensive treatment (244, 71%), and died during the follow up period (199, 58%). The GBTM with 4 patterns of change in FACT-PWB showed the best fit for our data (Table). The largest group (Group 2: N = 188, 55%) declined slightly in the first month, then stabilized, while those in the smallest group (Group 1: N = 16, 5%) declined steadily in the first 3 months before improving and stabilizing. Lower baseline FACT-PWB was associated with membership in Group 3: Slight improvement then stable (115, 34%) and Group 4: Steep improvement then stable (24, 7%)), relative to Group 2 (p < .001). Other variables were not associated with group membership. Conclusions: Adults newly diagnosed with AML show distinct patterns of change in their physical well-being after starting treatment. Future studies should measure self-reported and objective physical function in addition to physical well-being in patients with AML, especially with recent change in treatment landscape, to better understand their trajectories. [Table: see text]
A phase 2 study of the combination of decitabine (DAC), venetoclax (VEN), and ponatinib in patients (Pts) with chronic myeloid leukemia (CML) in accelerated phase (AP)/myeloid blast phase (MBP) or Philadelphia-chromosome positive (Ph+) acute myeloid leukemia (AML).
Authors: Senapati Jayastu , Ravandi Farhad , Dinardo Courtney Denton , Issa Ghayas C. , Sasaki Koji , Konopleva Marina , Macaron Walid , Nasr Lewis Fady , Zoghbi Marianne , Nasnas Cedric Christophe , Pemmaraju Naveen , Chien Kelly Sharon , Ohanian Maro , Jabbour Elias , Maiti Abhishek , Kantarjian Hagop M. , Short Nicholas James
Published: June 2023

e19044

Background: CML-AP/MBP and Ph+ AML are therapeutic challenges. Based on published pre-clinical data of synergism (Leonard et.al., Sci Transl Med 2016), we hypothesized that combining ponatinib with DAC and VEN might lead to high rates of response and facilitate allogeneic stem cell transplantation (SCT). Methods: The study (NCT04188405) enrolled pts ≥ 18 years of age with CML-AP, CML-MBP or Ph+ AML with ECOG PS ≤ 3 and adequate liver/renal function. Pts with significant uncontrolled cardiovascular comorbidities were excluded. Therapy was with DAC (20 mg/m2/day) x 5 days, VEN (400 mg equivalent dose/day) x 21 days, and ponatinib (45mg/day) x 21 days in cycle 1 and then continuously in cycles 2-24. Each cycle was for 28 days. Ponatinib was reduced to 30mg/day for pts in CR/CRi and to 15 mg/day for pts in CMR. Intrathecal prophylaxis with 4 doses of cytarabine was recommended. The primary objective was to determine the overall response rate (ORR) with the regimen. Results: From Jul 2020 to Jan 2023, 15 pts were treated, 4 with CML-AP, 10 with CML-MBP and 1 with Ph+ AML (Table). 11 pts (73%) had prior TKI exposure, including 4 pts with prior ponatinib. 5 of 13 tested pts (38%) had an ABL1 kinase domain mutation (T315I, Q252H, L384M in 1 pt each and E255K in 2 pts). The median number of cycles received was 3 (range, 1-7). 11 pts (73%) responded; 6 pts (40%) with CR/CRi and 5 (33%) with MLFS. Best response was achieved after cycle 1 in 9 of 11 (82%) responders. All 4 pts with CML-AP responded, and 9 of 11 pts (82%) with prior TKI exposure responded. Four pts underwent subsequent SCT. At a median follow-up of 9.8 months, the median overall survival (OS) was 11.0 months, and the estimated 10-month OS was 63%. The median relapse-free survival was 5.7 months. Among the 11 responders, 5 relapsed (one after SCT), and 6 are in ongoing response (3 after SCT). One pt had a related grade 3 mucositis. No grade 4-5 related non-hematological adverse events were observed. Of the 10 pts who received > 1 cycle of therapy, 5 pts had delay (>1 week) in initiation of subsequent cycles due to cytopenias. The 60-day mortality rate was 0%. Two pts died on study, one from leukemia and one from infection while in MLFS. Conclusions: A triplet combination of DAC, VEN and ponatinib was well-tolerated and resulted in an ORR of 73% in this poor-risk population of pts with advanced Ph+ leukemias. Clinical trial information: NCT04188405 . [Table: see text]