bluuebunny/crossref_metadata_2025 huggingface dataset:
Oncologists’ receipt of pharmaceutical industry payments and use of non-recommended and low-value cancer care services.
Authors: Mitchell Aaron Philip , Dusetzina Stacie B , Mishra Meza Akriti , Trivedi Niti U. , Bach Peter Brian , Winn Aaron N
Published: June 2023

6639

Background: Personal payments from the pharmaceutical industry to US physicians are common and influence physician practice. Prior studies have found that industry payments sway physicians’ selection among effective, medically appropriate treatments. However, whether industry payments may be associated with non-recommended and low-value care has not been assessed. The objective of this study was to estimate the association between oncologists’ receipt of industry payments and use of non-recommended and/or low-value (NR/LV) interventions. Methods: Population-based cohort study using fee-for-service Medicare claims and Open Payments records of industry payments. We identified four NR/LV cancer interventions: 1) denosumab for castrate-sensitive prostate cancer; 2) GCSF for patients at low risk for neutropenic fever; 3) nab-paclitaxel instead of paclitaxel for breast and lung cancer 4) branded drug instead of a generic or biosimilar. Study sample: Medicare beneficiaries with an incident cancer diagnosis (identified by new occurrence of a cancer diagnosis code in proximity to claims for cancer treatment) from 2014-2019. We applied additional requirements as appropriate to identify four sub-cohorts, corresponding to patients at risk for each of the NR/LV treatments, and identified the treating oncologist using claims. The primary exposure was receipt, by a patient’s oncologist, of any industry payments for the corresponding NR/LV treatment of interest, within 365 days before the patient’s index cancer date. The primary outcome was receipt of the corresponding NR/LV treatment. We fit general linear models controlling for patient characteristics and calendar year. To assess robustness, we also accounted for physician-level fixed effects in separate models. Results: Cohort sizes were: denosumab N = 9,799; GCSF N = 271,485; nab-paclitaxel N = 86,394; branded drug N = 13,386. Controlling for patient characteristics and calendar year, industry payment was associated with an increase in the absolute prevalence of denosumab (+17.5% [95%CI:15.3 to 19.7%]), GCSF (+5.8% [95%CI:5.4 to 6.1%]), and nab-paclitaxel (+7.6% [95%CI:7.1 to 8.1%]) use, but lower branded drug use (-4.6 [95%CI:-5.8 to -3.3]). In physician-level fixed effects models, industry payment was associated with increased denosumab (+7.4% [95%CI:2.5 to 12.2%]) and nab-paclitaxel (+1.7% [95%CI:0.9 to 2.5%]) use, but not with GCSF (+0.4% [95%CI:-0.3 to 1.1%]) or branded drugs (+1.2% [95%CI:-5.8 to 8.3%]). Conclusions: Recent receipt of industry payments by physicians was associated with increased use of several forms of NR/LV cancer treatment. These findings raise quality-of-care concerns regarding physician-industry financial relationships. Additional work is needed to further explore the causal relationship between payments and non-recommended treatments, and between payments and patient outcomes.
The role of private insurance characteristics in the out-of-pocket costs of patients with multiple myeloma.
Authors: Gasoyan Hamlet , Rothberg Michael B.
Published: June 2023

6641

Background: Over the past two decades, the major advances in the treatment of multiple myeloma have improved overall survival considerably. High costs of novel medications and patient out-of-pocket costs were suggested to have a role in treatment disparities but available data on total- and patient-out-of-pocket costs are dated. We examined the costs in privately insured patients with newly diagnosed multiple myeloma in the first year after the diagnosis, based on insurance plan characteristics. Methods: This retrospective study used the IBM MarketScan Commercial Database for the years 2011–2019, which consists of medical and prescription medications data from 120+ large employers and 40+ health plans in the US. The primary outcome variables were total- and patient out-of-pocket costs during 1 year after the index diagnosis. Results: 5,487 privately insured adults with an index multiple myeloma diagnosis during 2012-2018 were identified. Approximately 41% (n=2,240) of the study population received bortezomib, 38.6% (n=2,117) received lenalidomide, and 5.7% (n=314) received carfilzomib during 1 year after the index diagnosis. The median total cost of care in the first year after multiple myeloma diagnosis increased from $133,938 (interquartile range, $19,770 – $292,501, expressed in 2018 USD) in patients diagnoses in 2012 to $252,559 ($33,089 – $380,662) in patients diagnoses in 2018. The median patient out-of-pocket costs were $3,147 (interquartile range $1,562 - $5,441, 2018 USD) in patients diagnosed in 2012 and $3,711 ($1,756 – $6,466) in patients diagnosed in 2018. Among patients diagnosed in 2018, the median patient out-of-pocket cost was $1,706 ($902 – $2,873) for patients with low out-of-pocket cost plans, $3,428 ($1,794 – $6,371) for those with average out-of-pocket cost plans, and $5,623 ($3,517 - $7,810) for patients with high out-of-pocket cost plans. Conclusions: While the total cost of care in the first year after multiple myeloma almost doubled during the study period, the patient out-of-pocket costs remained relatively stable. The protections imposed by the Affordable Care Act are likely key in preventing surges in patient out-of-pocket costs. Additional legislative action could help curb the price increases for multiple myeloma medications. [Table: see text]
Assessment of price variation in colorectal cancer screening procedures at US hospitals.
Authors: Paranjpe Ishan , Sharma Pranav , Wei Chen , Puram Vikram , Kamat Samir , Khaki Ali Raza
Published: June 2023

6652

Background: Following the 2021 Hospital Price Transparency Final Rule, US hospitals were mandated to publish their insurer-negotiated prices. We identified factors contributing to price variability of colorectal cancer (CRC) screening procedures across the US. Methods: We compared prices of colonoscopy, flexible sigmoidoscopy, CT colonography, fecal occult blood test, fecal immunochemical test, and Cologuard across U.S. hospitals using the Turquoise dataset (N = 6,378). Psychiatric, rehabilitation, and pediatric hospitals were excluded. Prices in the top and bottom 1% were also excluded to minimize the effect of outliers. Prices were adjusted by the Medicare Geographic Price Index to account for regional variability. We then compared prices across several subgroups, including National Cancer Institute (NCI) designated hospitals, teaching hospitals, and investor owned hospitals. Significance was assessed using the Kruskal-Wallis test. To quantify price variability across insurance plans within a hospital, we defined the within-center-ratio as the 90th percentile rate at a hospital divided by the 10th percentile rate. To quantify variability across hospitals, the across-center-ratio was defined as the 90th percentile median rate across all hospitals divided by the 10th percentile median rate. Results: 1,460 hospitals reported commercial prices for colonoscopy with a median commercial price of $1,867 (IQR: $1,208 - $2,689). For colonoscopy, the within center ratio was 2.5 (IQR: 1.5 – 3.8) and the across-center ratio was 6.2. Prices for other procedures are provided in the table. Compared to non-investor owned hospitals, prices of colonoscopy ($2,082 vs $1,787, P <0.001) and flexible sigmoidoscopy ($2,022 vs $1,289, P <0.001) were significantly higher at investor owned hospitals. Furthermore, across investor classes, hospitals with >5% ownership from private equity firms had the highest median price for both colonoscopy ($2,898), and flexible sigmoidoscopy ($2,697). We did not find significant differences in price by NCI designation, academic teaching center affiliation, overall hospital mortality, overall hospital readmission rate, or urban/rural location. Conclusions: CRC screening procedure prices vary significantly both within and across hospitals. Private equity and other investor owned hospitals had significantly higher prices compared to non-investor owned hospitals. [Table: see text]
Specialty cancer care and survival in AYA ALL: A U.S. multi-state analysis.
Authors: Muffly Lori S. , Miller Kate , Maguire Frances Belda , Li Qian , Parsons Helen M. , Keegan Theresa
Published: June 2023

7008

Background: Unlike children with acute lymphoblastic leukemia (ALL) who receive cancer care almost exclusively from pediatric oncologists at specialized cancer centers (SCC; defined here as National Cancer Institute and/or Children’s Oncology Group designated cancer centers), adolescents and young adults (AYAs; 15-39 years) in the United States receive care in a variety of settings. Using state-wide population-based data, we sought to describe the health care delivery settings in which AYAs with ALL receive treatment and determine associations between front-line treatment at an SCC and leukemia-specific and overall survival (LSS/OS). Methods: We used data from the 2004-2018 California (CA), New York (NY), and Texas (TX) state cancer registries to identify front-line treatment setting of AYAs newly diagnosed with ALL. Multivariable logistic regression models evaluated characteristics associated with receiving treatment at an SCC. Cox proportional hazards regression models evaluated the associations with LSS/OS. All models were adjusted for gender, age, sex, race/ethnicity, socioeconomic status, insurance, and diagnosis year. Results: The cohort was comprised of 2283 (CA), 795 (NY), and 955 (TX) AYAs with ALL. Across all states, approximately 70% were ³18 years and 65% were male. Race/ethnicity varied by state: a majority in CA (63%) and TX (64%) were Hispanic, while most in NY were non-Hispanic White (NHW) (50%). Health insurance coverage also varied: most in CA were publicly insured (48%), while most in NY were privately insured (54%); TX had the highest rate of uninsured (18%). Treatment at an SCC occurred in 48.2% (CA), 44.4% (NY), and 19.5% (TX) of AYAs, increasing in CA and NY over time, but remaining unchanged in TX. Among all states, older age and uninsured status were significantly associated with lower odds of treatment at an SCC. In both CA (OR 0.58, 95% CI 0.45-0.74) and TX (OR 0.55, 95% CI 0.35-0.86), Hispanic patients had significantly lower odds of treatment at an SCC than NHW. In NY (OR 0.45, 95% CI 0.31-0.67) and TX (OR 0.49, 95% CI 0.3-0.8), publicly insured AYAs had significantly lower odds of receiving treatment at an SCC than those with private insurance. Front-line treatment at an SCC was significantly associated with both superior LSS (HR 0.73, 95% CI 0.63-0.85) and OS (HR 0.73, 95% CI 0.63-0.85) in CA and superior LSS (HR 0.70, 95% CI 0.51-0.94) and OS (HR 0.61, 95% CI 0.45-0.83) in TX; a non-significant association was seen in NY (LSS: HR 0.86, 95% CI 0.65-1.12; OS: HR 0.83, 95% CI .64-1.08). Conclusions: Only 20-50% of newly diagnosed AYA ALL patients receive front-line treatment at SCCs, with age, race/ethnicity, and insurance type independently influencing AYA ALL care setting. We show that the treatment of ALL at an SCC is associated with superior survival, highlighting the importance of statewide and national policy efforts to improve access and reduce inequities in AYA ALL.
Outcomes of 10-day decitabine with venetoclax for AML.
Authors: Coltoff Alexander , Baratam Praneeth , Green Kimberly Michelle , Davis James A. , Smith Deidra , Gaffney Kelly , Dougherty Elizabeth , Milligan Laura
Published: June 2023

7022

Background: Venetoclax (VEN) + a hypomethylating agent (HMA) has improved outcomes for patients with acute myeloid leukemia (AML). VIALE-A showed improved overall response rate (ORR) and overall survival (OS) with VEN + HMA in newly diagnosed AML (ND AML); the complete remission (CR) rate was 36.7% and the median OS was 14.7 months. Later, DiNardo et al. reported a trial of 10-day decitabine (DEC10) + VEN with a CR rate of 65.7% and a median OS of 18 months in a ND AML cohort. We report real world outcomes of VEN + DEC10 for AML induction. Methods: We reviewed 82 adult patients treated with VEN + DEC10 at our institution. Patients received 1 or 2 cycles of VEN + DEC10 followed by additional cycles of VEN + 5-day decitabine (DEC5) per physician discretion. Results: Twenty-four patients had ND AML, 28 had secondary AML (sAML) and 30 had relapsed/refractory (R/R AML) with a median age (years) of 72, 70, and 59 in each group, respectively. Cytogenetics were poor-risk in 13 ND patients (54.2%), 14 sAML patients (50%), and 17 R/R patients (56.7%). Twenty-two patients (26.8%) had TP53 mutations. Six patients (7.3%) received rasburicase. Neutropenic fever was seen in 46 patients (56.1%), and 34 (41.5%) had documented infections. Thirty-eight patients (46.3%) were re-hospitalized during cycle 1 (C1), at a median of 22 days after starting. The median time from the start of C1 to C2 was 41 days. Thirty-day mortality was 7.3%. In ND AML, ORR was 91.7% and composite CR rate (CRc; CR + CR with incomplete hematologic recovery[CRi]) was 75%. Nine of 15 patients (60%) in CR were negative for measurable residual disease (MRD-). In sAML, ORR was 53.6% and CRc rate was 50% (35.7% MRD- CR). CRc was achieved by eight of 16 (50%) untreated sAML patients vs six of 12 (50%) who were previously treated. In R/R AML, ORR was 56.7% and CRc rate was 43.3% (53.8% MRD- CR). TP53-mutated AML had an ORR of 59% and a CRc of 50%. Median OS was 5.5 months in TP53-mutant AML, 7.4 months in R/R AML, and was not reached in ND AML or sAML. Fifteen patients (18.3%) received an allogeneic transplant (3 ND, 3 sAML and 9 R/R) in MRD- CR (n = 11), MRD+ CR (n = 2) and CRi (n = 2). At a median of 263 days post-transplant, there were 3 relapses and the median OS was not reached. Conclusions: VEN + DEC10 compared favorably with published data, yielding high ORR, CR, and MRD- CR rates in ND AML. CR rate for R/R AML with VEN + DAC10 was similar to that for ND AML in the VIALE-A trial. These results warrant a prospective, randomized trial of VEN + DEC10 vs VEN + DEC5 in AML. [Table: see text]
BOS-371, a monoclonal antibody against IL1RAP: Characterization in preclinical models of AML.
Authors: West Kip A , Kumar Sanjay , Scott Martin , Emery John G , Steidl Ulrich G , Narayanagari Swathi-Rao , Mitchell Kelly , Ren Fang , Ying Hua , Fei Qi , Yang Teddy , Svensson Eric , Rosen Galit
Published: June 2023

7030

Background: IL1 receptor accessory protein (IL1RAP) is a cell surface protein overexpressed on leukemia stem cells (LSC) and progenitors in AML, CML and high-risk MDS. It is an indispensable co-receptor for the IL1 superfamily, but its role reaches beyond anti-apoptotic pathways. IL1RAP directly interacts with and potentiates signaling of FLT3 and c-KIT which have significant roles in AML pathogenesis. High IL1RAP is correlated with poor prognosis and IL1 blockade attenuates expansion of LSCs. Thus, targeting IL1RAP has emerged as a promising immunotherapeutic approach for myeloid malignancies. BOS-371 is a humanized monoclonal antibody targeting IL1RAP that has been Fc-engineered to enhance its capacity to induce antibody directed cell cytotoxicity (ADCC) and deplete IL1RAP-expressing AML cells. Methods: The preclinical activity of BOS-371 was characterized using multiple assays. In vitro analysis included: binding affinity in IL1RAP-expressing cell lines; inhibition of IL1-dependent signaling as measured by IL1a -stimulated secretion of IL6 from MRC5 lung cancer cells; measurement of ADCC in co-cultures of human NK cells with either IL1RAP-expressing cell lines or primary AML cells; and cell growth by monitoring metabolic activity of primary AML cells. In vivo efficacy of BOS-371 was determined in AML models: MV4-11 and ML2 cells (CDX) implanted in NOG and NOD-SCID mice, respectively, and patient-derived (PDX) leukemia cells implanted in NOG mice. Results: BOS-371 binds with high affinity to IL1RAP-expressing cells (average EC50 337pM) leading to potent inhibition of IL1 signaling (IC50 600pM). Co-culture assays in the presence of BOS-371 showed potent induction of ADCC with an EC50 of 60-70pM (cell lines) or 4-11pM (primary cells) and 80-100% cell lysis (both cell lines and primary cells). The ability of BOS-371 to impact AML cell growth exclusively through inhibition of IL1 signaling was measured in a panel of 15 primary AML samples. Incubation with BOS-371 led to IC50s ranging from 20-700nM in responsive samples. Evaluation of BOS-371 activity in vivo showed that administration of BOS-371 resulted in significant anti-leukemic activity. In CDX studies, BOS-371 treatment led to > 50% decrease in systemic disease and engraftment in bones and organs. The results observed in CDX AML models were reproduced in PDX mouse models of AML, where decreases in both peripheral ( > 70%) and bone marrow ( > 50%) disease burden in response to BOS-371 were observed. Conclusions: These findings demonstrate that BOS-371 binds with high affinity to IL1RAP, potently inhibits IL1 signaling and induces ADCC, leading to anti-leukemic activity in vitro and in vivo. The preclinical results support the clinical investigation of BOS-371 for the treatment of myeloid malignancies. A Phase 1 trial is currently in development.
Shattering myths regarding Hispanic ethnicity and survival in acute myeloid leukemia: Insights from the National Cancer Database.
Authors: Premnath Naveen , Khan Adeel , Pandey Mohak , Pandey Urvashi , Hoff Fieke W , Chung Stephen , Ramakrishnan Geethakumari Praveen , Collins Robert , Paulk Elizabeth , Sweetenham John W. , Madanat Yazan F
Published: June 2023

7032

Background: Previous smaller studies suggest that despite younger age at presentation, Hispanic patients (HP) with acute myeloid leukemia (AML) have worse prognosis than non-Hispanics patients (NHP). Methods: We queried the National Cancer Database (NCDB) between 2004 to 2017 for adults aged ≥18 years for a diagnosis of AML using the ICD-O-3 diagnosis code. Baseline characteristics and outcomes were compared. Results: A total of 144,146 patients with AML were identified during the study period of which 9173 were Hispanic (6.4%). The median age at diagnosis was 66 years overall. Hispanics were younger at presentation with median age 55 compared to 67 in non-Hispanics ( p< 0.001). A higher proportion of HP were uninsured and in the lowest income quartile compared to NHP across all AML subtypes. HP had statistically significant longer survival across AML subtypes except for tAML. When adjusted for age, sex, Charlson Deyo Comorbidity Index, insurance, chemotherapy, transplant, and income status using a multivariate Cox regression analysis, HP had non-inferior survival to NHP. Conclusions: We present the largest study to date in Hispanics with AML. Hispanics presented at younger ages and had worse socioeconomic factors compared to NHP and when adjusted for multiple variables, did not have worse outcomes as reported in prior data. We believe previous studies in HP demonstrating worse prognosis may reflect bias and confounding given smaller patient numbers and are suggestive of disparities in access to health care and present opportunities for improvement. [Table: see text]
Clinical outcomes of patients with newly diagnosed acute myeloid leukemia receiving treatment in a safety-net hospital system.
Authors: Lu Jason , Bhakta Preeya , Lachowiez Curtis Andrew , Apostolidou Effie
Published: June 2023

7035

Background: Standard induction therapy for acute myeloid leukemia (AML) results in 5-year overall survival (OS) rates of 30-45%. Further risk stratification and novel therapeutic options have improved 5-year OS rates to 75-80% in certain subgroups. Despite these advances, many patients lack proper socioeconomic resources, leading to limited access to new therapies, clinical trials, and hematopoietic cell transplantation (HCT), which remains the only curative therapy for AML. Many of these patients receive care within publicly funded ‘safety net’ institutions designed to serve all individuals, regardless of ability to pay, insurance status, or immigration status. Outcomes of historically underserved patients with AML treated within a large county hospital system remain unknown. Methods: This retrospective cohort analysis evaluated clinical outcomes of patients aged ≥18 years with newly diagnosed AML (ND-AML) treated in the Harris County Health System, Houston, TX, from January 2005 to July 2019. Results: One hundred ninety-two patients with ND-AML were included (de novo AML [n = 140], secondary AML [n = 45], and therapy-related AML [n = 7]). Median age was 52 years (range: 19-89) at diagnosis, and 102 (52.3%) were male. Most patients identified as Hispanic (n = 110). Sixty-two percent of patients were uninsured or indigent, receiving care under the county’s financial assistance programs. The majority had adverse risk 84 (44.3%), while 78 were intermediate (40.6%), and 26 favorable risk (13.5%). Standard induction therapy was administered in 172 (88%) of patients. Cytarabine and Anthracycline (7+3) based regimens were most commonly used (72.8%). 192 patients were evaluable for response. 139 (72.4%) achieved composite complete remission (CR/CRi) and 41 (21.4%) had primary refractory disease. For those who achieved CR after first or second induction, the median duration of CR was 16.7 months. with 25 (13.7%) ultimately receiving HCT. Common reasons for not receiving HCT included lack of insurance (19.2%) or non-citizen status (23.1%) (n = 77). 82 of the 139 patients who achieved CR relapsed. After a median follow up of 16 months, five-year OS rates were 20.7% from our entire cohort of patients. Conclusions: In this cohort of patients treated in a safety-net system, median OS and EFS were lower than reported outcomes in the past decade. In addition, only 13.7% received HCT, one of the only curative treatments for AML. Some barriers included inability to refer to transplant center due to lack of financial support or immigration status. Addressing socioeconomic and institutional barriers to AML therapy and HCT will advance care for disadvantaged patients, thereby improving outcomes of patients AML.
A step toward genomic equity: Mutational profiling of patients with myeloid neoplasm in the largest minority-serving hospital in metropolitan Chicago.
Authors: Elsebaie Maha AT , Turk Ekrem , Deenadayalan Vaishali , Obeidat Khaldun , Nanaa Ahmad , Zia Maryam , Birch Noah W.
Published: June 2023

7037

Background: Information on genomic landscape of myeloid neoplasms comes from large studies of patients with predominantly European ancestry. Minority-serving hospitals offer unique opportunities to study ethnically diverse populations. Methods: In this retrospective study at the Stroger Hospital of Cook County, we included patients ≥18 years old with myeloid neoplasms or premalignant conditions who underwent mutational profiling via next generation sequencing (NGS). We utilized two commercially available myeloid panels: “ FoundationOneHeme” (406 gene panel) and “ Tempus” (648 gene panel) . Patient demographics were collected, including self-reported race/ethnicity. We compared data distribution using Kruskal-Wallis, Pearson’s χ2, or Fisher’s exact tests. Overall survival (OS) probabilities were compared using the log-rank test. Results: Ninety-four patients underwent NGS between 04/01/2020 and 12/31/2022, including 45 females (47.9%). 38 patients (40.4%) identified as Black, 28 (29.8%) as White, and 28 (29.8%) as Other (10.6% Asian, 9.6% Mexican/South American, and 9.6% undetermined). 30 patients (32%) identified as Hispanic and 64 (68%) as Non-Hispanic. Diagnoses included Acute myeloid leukemia (AML, 32%), Myelodysplastic syndromes (MDS, 13%), MDS/MPN overlap syndrome (7%), and Clonal Hematopoiesis of Indeterminate Potential (7%). Eighty-eight patients had at least one pathogenic variant and harbored 259 mutations in 74 genes. Commonly mutated genes were ASXL1 (23%), JAK2 (17%), DNMT3A (14%), and TET2 (13%).Non-White patients were more likely to have IDH2 mutations (5% Black vs. 0% White vs. vs. 14% Other races, p=0.011). Mutation count didn’t differ between racial p=0.525 or ethnic groups p=0.345. AML & MDS patients were more likely to have TET2, RUNX1, TP53, and IDH2 mutations. In addition, 24% of AML & MDS patients had mutated ASXL1. TET2, SRSF2, and RUNX1 mutations were common among MDS/MPN patients (Table). AML & MDS patients had poor OS, but OS didn’t differ between racial/ethnic groups. Conclusions: Premalignant mutations (e.g., ASXL1, TET2) predominated in our patients and tended to co-occur, increasing the overall mutational burden. Non-White patients were more likely to have IDH2 mutations. Adverse markers were common among AML & MDS patients, likely contributing to their dismal survival. Studies inclusive of ethnically diverse patients are needed to accurately translate genetic findings into clinical practice. This report from a large, minority-serving hospital represents a step toward promoting genomic and healthcare equity. [Table: see text]
Evaluation of cardiac failure and recovery in acute myelogenous leukemia.
Authors: Wu Matthew , Russell Katie , Shaw Carole , Halpern Anna B. , Ghiuzeli Cristina Maria , Appelbaum Jacob , Hendrie Paul , Walter Roland B. , Percival Mary-Elizabeth M.
Published: June 2023

7038

Background: Cardiac failure causes significant comorbidity and death in acute myeloid leukemia (AML) patients, with incidence estimated at 10-15% (Neuendorff N Blood Adv. 2020). We sought to describe the post-treatment cardiac experience in AML survivors including factors associated with onset, persistence, and outcome of cardiac dysfunction during and following treatment. Methods: 86 patients with AML or other high-grade myeloid neoplasms treated with induction chemotherapy with or without allogeneic hematopoietic cell transplant were identified at the University of Washington/Fred Hutchinson Cancer Center from 1/2000-1/2022. All patients sustained cardiac dysfunction, defined as left ventricular ejection function (LVEF) decline of 10% with absolute LVEF below 50% during chemotherapy. A multivariable analysis was performed to compare those who recovered (LVEF recovery) and those who did not (LVEF non-recovery), examining baseline health factors, disease risk (ELN 2017), time to dysfunction and recovery, most probable cause of cardiac dysfunction based on cardiologist evaluation, and goal-directed medical therapy (GDMT) use and dosage. Results: 48% (41 out of 86) failed to recover following LVEF decline. This cohort tended to be older, male, and had more ASCVD risk factors ( p < 0.05). Neither the choice of chemotherapy regimen ( p= 0.43) nor the cumulative anthracycline dose ( p= 0.44) was significantly different between the LVEF recovery and non-recovery groups. Onset of cardiac dysfunction tended to occur later in the LVEF recovery cohort (median 72 vs. 48.5 days, p= 0.660). In subjects who recovered, the median time to recovery was 87 days (range 2-268 days). When chemotherapy was identified as the probable cause, it was associated with greater likelihood of eventual recovery ( p= 0.014), whereas ischemic coronary etiology was associated with non-recovery ( p= 0.005). Failing to recover from cardiac dysfunction correlated with shorter survival (median 229 vs 650 days, p = 0.005). Multivariable analysis is shown in the Table below. Importantly, the use of GDMT with higher doses of renin-angiotensin inhibitor medications (RAASi) were associated with higher probability of recovery (not shown, p < 0.05). Conclusions: The present study demonstrates recovery occurring in over half of AML patients who experienced cardiac dysfunction during their chemotherapy. Recovery was more common in patients whose cardiac dysfunction is precipitated by chemotherapy and in patients who received GDMT with aggressive use of RAASi. Since cardiac recovery was associated with improved survival, next steps include establishing a cardiac monitoring algorithm to initiate early and aggressive GDMT. [Table: see text]
Analysis of short-term efficacy and safety of mitoxantrone hydrochloride liposome regimen therapy in adult acute myeloid leukemia.
Authors: Ma Jun , Hu Junbin , Liu Li , Chen Yuqing , He Aili , Lou Shifeng , Ge Jian , Qi Kunming , Yang Yanli , Ye Jingjing , Cheng Hai , Lu Yinghao , Wang Linhui , Cai Huili , Wei Xudong , Yang Xiangdong , Xue Hua , Wang Hongxiang
Published: June 2023

7039

Background: Acute myeloid leukemia (AML) is highly heterogeneous, and more than half of patients (pts) will experience refractory or relapse, with poor prognosis. Currently, chemotherapy and hematopoietic stem cell transplantation (HSCT) are the main treatments for AML. Mitoxantrone is a synthetic anthracenedione anti-cancer drug that is effective in lymphoma, leukemia, and other solid tumors. Mitoxantrone hydrochloride liposome (PLM60) is the first approved mitoxantrone nano-drug, which has shown favorable pharmacokinetic characteristics and significantly prolong the survival time of animals compared with the same dose of mitoxantrone (Li 2008). However, there is still a lack of systematic reports about the real-world application of PLM60 in AML. Methods: We performed a multicenter retrospective analysis of 82 pts with newly diagnosed AML and relapsed/refractory (R/R) AML, who received at least one cycle of PLM60 regimen between January 2022 and November 2022. Pts aged 18 years and above with confirmed diagnosis of AML according to the 2016-revised WHO criteria were eligible for inclusion, except acute promyelocytic leukemia (APL). The median dose of PLM60 in the regimen was 20.0 (range 10.3–31.6) mg/m2. Efficacy was assessed by composite complete remission (CRc) rate and overall response rate (ORR), and logistic regression analysis was performed to analyze factors affecting the curative effect. Adverse events were assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Results: 82 pts were enrolled with a median age of 50.5 (range 20-83) years. There were 71 cases of de novo AML and 11 cases of secondary AML. Targeted sequencing was performed on 86.6% of pts (71/82). FLT3 was the most commonly mutated gene found in 22.5% (16/71), followed by ASXL1 mutated in 12.7%, NPM1 in 11.3%, and TP53 in 11.3%. 4.9% (4/82) of pts underwent HSCT. Among the 25 newly diagnosed pts, CRc rate was 72.0% (18/25) and ORR was 92.0% (23/25). Among the 57 R/R pts, CRc rate was 24.6% (14/57) and ORR was 40.4% (23/57). The courses of induction failure ( OR= 16.617, P= 0.026), and the duration of the first complete remission (CR1) ( OR= 20.647, P= 0.007) were independent influencing factors of the efficacy. Common grade 3/4 AEs included decreased neutrophil count (84.1%), thrombocytopenia (76.8%), anemia (73.2%), febrile neutropenia (47.6%), pulmonary infection (11.0%) and upper respiratory tract infection (2.4%). The overall safety was acceptable and controllable. Conclusions: The PLM60 regimen had an encouraging efficacy and showed a manageable safety profile with the most adverse events being hematologic toxicities.
Comparison of characteristics and prognostic impact of FUS-ERG and AML1-MTG16 fusion genes in adult AML patients: A retrospective study from 1988 to 2022 with a medical database.
Authors: Zhou Ziyue , Zhou Yile , Yao Yiyi , Mao Liping , Zhang Yi , Hong Qing , Zhuo Nanfang , Pan Peifeng , Tong Hongyan , Jin Jie , Wang Huafeng
Published: June 2023

7042

Background: AML1-MTG16 and FUS-ERG are two rare fusion genes in acute myeloid leukemia (AML). Their clinical characteristics and factors influencing prognosis have been summarized in a cohort of pediatric patients, but no systematic review is approached in adult. Methods: We retrospectively analyzed the clinical data of adult AML patients with AML1-MTG16 or FUS-ERG fusion genes, who were reported on Mitelman Database, PubMed and China national knowledge infrastructure (CNKI) from 1988 to 2022 or have received treatment in the First Affiliated Hospital, Zhejiang University School of Medical, and compared them with patients with RUNX1-RUNX1T1, exploring their clinical features and prognosis. Results: 314 patients were totally included for analysis. In comparison of RUNX1-RUNX1T1 group (n = 209), FUS-ERG-positive patients (n = 108) significantly exhibited a younger onset age (34.5y vs. 41y), higher WBC count (16.7 ×109/L vs. 10.4×109/L), higher recurrence rate (61.8% vs. 30.4%), and a worse response to chemotherapy (complete remission rate: 71.6% vs. 91.8%), while patients with AML1-MTG16 (n = 24) presented primarily as the secondary AML (83.3%) with a significantly elder age (56y vs. 41y). The FUS-ERG patients had a worse median overall survival (OS) of 13 months (95%CI: 11.6-14.4, P < 0.01) and a worse median disease free survival (DFS) of 7.5 months (95%CI: 6.5-8.5, P < 0.05) than control group, which also occurred in those had AML1-MTG16 gene with a median OS of 18.5 months (95%CI: 12.4-24.6, P < 0.01) and a median DFS of 14 months (95%CI: 3.7-24.3, P = 0.10). As shown in the table below, CR after induction chemotherapy, hematopoietic stem cell transplantation (HSCT), trisomy, monosomy and age of patients were associated with the prognosis of FUS-ERG group. Unlike pediatric patients, the adult AML1-MTG16 patients did not perform a better outcome (OS: HR = 0.90, P = 0.83; DFS: HR = 0.54, P = 0.34) in contrast with FUS-ERG patients. Conclusions: The retrospective study summarized the clinical characteristics of AML1-MTG16 and FUS-ERG, identifying their distinctions on multiple aspects such as prior disease, recurrence rate, response to chemotherapy and cytogenetics. AML1-MTG16 exhibited extremely bad prognosis like FUS-ERG in adult population, which varied from the results in pediatric cohort. Several factors including age, CR after induction chemotherapy, HSCT, trisomy and monosomy were relevant to the prognosis of FUS-ERG. [Table: see text]
Real-world (RW) use of venetoclax (VEN) in patients (pts) with acute myeloid leukemia (AML) in a US RWE database (COTA).
Authors: Zeidan Amer Methqal , Hernandez Donoso Leyla , Hodzic Sejla , Owusu Henry F , Pathak Dhrubajyoti , Zhou Summera Qiheng , Stein Eytan
Published: June 2023

7044

Background: VEN + hypomethylating agents (HMAs)/low-dose cytarabine was approved for the treatment (tx) of pts with AML who are ≥75 y or ineligible for intensive chemotherapy (CT) in 11/2018. To understand the use, safety, and efficacy of VEN in clinical practice, the COTA AML database, using pt-level curated electronic health record data from centers across the US, was analyzed. Methods: This is a retrospective, descriptive analysis of deidentified secondary data from the COTA AML database in the US. Data was abstracted for adults diagnosed with AML who initiated first-line (1L) tx on or after 01/01/2018 and received ≥1 VEN tx at any point. Pts with no diagnosis date or with concurrent primary malignancies were excluded. Follow-up was until the last recorded event (last visit or death). The study period for this analysis was 01/2018 to 09/2022. Results: Of 3836 pts with AML in the database, 1163 pts initiated 1L tx in or after 2018; of these, 636 received ≥1 VEN tx at any point. See Table for baseline demographic data. Most VEN-treated pts were seen by community healthcare providers (407/636, 64%). Genetic/molecular data were limited. Of the most frequently tested mutations, the most common were TP53 (129/461, 28%), RUNX1 (109/444, 25%), TET2 (101/414, 24%), ASLX1 (92/417, 22%), and DNMT3A (91/424, 22%). Of pts who received VEN, 47% (299/636) received 1L VEN, and the majority (269/636, 42%) received VEN + HMAs. For pts with tx prior to VEN (pretreated), 262/337 (78%) were previously treated with CT. 1L pts were more often treated in community centers than pretreated pts (73% vs 56%), had more comorbidities (56% vs 40%), and TP53 positivity (19% vs 10%) at baseline. Of 284 VEN-treated pts with available response data, 180 (63%) had a complete response (CR). Median OS (mOS) of VEN-treated pts was 14.4 mo from 1L tx initiation (de novo AML, 17 mo; secondary AML, 14 mo). mOS from diagnosis was 14 mo for newly diagnosed and 18 mo for pretreated pts. Toxicity was the main cause of dose reduction and discontinuation. Median duration of VEN tx was 78 d. Dose reduction was reported in ~30% of VEN-treated pts. Of VEN-treated pts, 53% (338/636) discontinued at least 1 VEN regimen, with a median time to discontinuation of 49.5 d. Conclusions: This study provides an overview of the RW use of VEN in pts with AML in the US since its approval in 11/2018. Despite the study period starting earlier than VEN approval, almost half of pts with AML who initiated tx after 2018 received 1L VEN. The RW CR rate in VEN-treated pts with available data was 63%, but over half of VEN-treated pts had VEN tx discontinuation. [Table: see text]
Preliminary results of a phase 1, first-in-human study of INA03, an anti-CD71 antibody-drug conjugate, in patients with relapsed or refractory (R/R) acute leukemias.
Authors: Garciaz Sylvain , Bories Pierre , Lopez Almeida Leonor , Boher Jean-Marie , Belanger Coralie , Recher Christian , Hermine Olivier , Vey Norbert , Launay Pierre
Published: June 2023

7045

Background: R/R acute leukemias (AL) represent major therapeutic challenges. Several reports have highlighted the role of iron metabolism in various proliferative tumor models including AL including the over-expression of the transferrin receptor (TfR1/CD71). Our strategy is thus to harness CD71 overexpression to specifically target cytotoxic agents to leukemic cells. INA03 is an antibody drug conjugate (ADC) constituted of a humanized monoclonal IgG4 against CD71 and the microtubule disrupting agent monomethyl auristatin E (MMAE). We herein report the preliminary safety and efficacy data of INA03 from a phase 1/2 trial in patients (pts) with R/R AL (NCT03957915). Methods: INA03 is given as 30 minutes IV infusion on days 1 (Loading dose (LD)) followed by maintenance injections on D15 for cycle 1 and on D1 and D15 of cycle 2 and beyond. Eligibility criteria are: R/R AL after at least one line of treatment including high dose chemotherapy and/or Vidaza and Venetoclax, AlloSCT > 18y, with FEVG > 50%, Creatinine Clearance > 30ml/min, normal liver function, ECOG < 2. The study design is based on a continuous reassessment method and includes 2 parts: a LD Titration study (Part 1, completed), followed by a Dose Escalation Part 2. During Part 1, sequential cohorts of 2 pts were included to receive ascending LD of INA03 followed by subsequent fixed dose of INA03 to deal with a potential sink effect related to the high expression of CD71 in normal erythroblasts. During Part 2, sequential cohorts of 3 pts received escalating doses of INA03 Q2 weeks in 28-day cycles. The objectives were to establish the MTD for subsequent administration and both safety/tolerability and anti-leukemic activity. Results: With a cutoff date of January 18, 2023, 22 pts across 8 cohorts were included in the study. The median age was 73 (range: 39 – 83), 20 (91%) pts had AML and two (9%) had ALL. Three (13.6%) pts had a prior allo-SCT and 12 (54.5%) had prior VEN exposure. Pts received escalating doses of INA03 of 0.02 mg/kg to 2 mg/kg. MMAE pharmacokinetics (PK) appears dose-proportional with a small accumulation after repeated IV, while INA03 PK exhibits target-mediated drug disposition without accumulation. No DLT was observed among the 18 DLT-evaluable pts, up to the highest dose of 2 mg/kg. No grade 2-4 TEAEs were observed. One related grade 1 TEAE (hyperkalemia/phosphatemia) was reported. Transient decrease of reticulocyte count and erythroblasts percentage were observed at 0.5 mg/kg and above. Blasts reductions were seen in 3/18 evaluable pts at dose > 1 mg/kg including two partial responses. Conclusions: INA03 is well tolerated up to the dose of 2 mg/kg with some efficacy signals in R/R AL. The trial continues to accrue patients. Clinical trial information: NCT03957915 .
Treatment outcomes in adults with newly diagnosed B-cell acute lymphoblastic leukemia: A comparison between pediatric-inspired regimens and HyperCVAD at a Hispanic-serving cancer center.
Authors: Griffin Shawn Patrick , Lee Benjamin , Pannunzio Nicholas , Doh Jean , Chan Alexandre , Ciurea Stefan , Jeyakumar Deepa , O'Brien Susan Mary , Fleischman Angela G , Naqvi Kiran , Kongtim Piyanuch
Published: June 2023

7048

Background: It is unknown if HyperCVAD is more favorable than pediatric-inspired regimens (PIRs) among adult Hispanic patients with newly diagnosed B-cell acute lymphoblastic leukemia. This analysis aims to determine the interaction of Hispanic ethnicity and treatment regimen on outcomes. Methods: Records of adults (≥ 18 years) treated with a PIR or HyperCVAD from January 2011 to November 2022 at our institution were reviewed. Patients were excluded if they received treatment modifications in a clinical trial or were lost to follow-up prior to 6 months. The primary endpoint was event-free survival (EFS) comprised of relapse, death, secondary malignancy, or failure to achieve complete remission. Secondary endpoints included overall survival (OS). Ph+ disease was not grouped into the poor-risk category. Results: 100 patients were included. Median age was 39 years, 57% were male, and 61% self-identified as Hispanic. 48 were included in the PIR and 52 in the HyperCVAD groups. 37 in the PIR group received CALGB 10403. There was no difference in race, ethnicity, rituximab use, WBC, LDH, bone marrow blast %, presence of CNS disease at diagnosis, or poor-risk genetics (Table) between the PIR and HyperCVAD groups. However, a lower rate of Ph+ disease (8.3% vs 58%) and younger median age (31 years vs 49 years) was observed in the PIR group. Allogeneic stem cell transplantation (ASCT) was pursued in 48% of PIR and 37% of HyperCVAD-treated patients. EFS at 5-years was lower among patients receiving a PIR compared to HyperCVAD (28% vs 41%; hazard ratio [HR], 1.89; P = .022). After censoring for ASCT there was no change (P = .03). Treatment group was the only significant predictor for EFS although a treatment-by-subgroup interaction (P < .10) with Hispanic ethnicity was found. OS at 5-years was 61% in PIR and 64% in HyperCVAD-treated patients (HR, 1.54; P = .25). In multivariable Cox regression analysis, Hispanic ethnicity (HR, 2.56; P = .041) and male sex (HR, 2.62; P = .027) were predictors for worse OS. Hispanic patients demonstrated worse EFS with a PIR compared to HyperCVAD (HR, 2.52; P = .008), which remained significant when evaluating only Ph- patients (HR, 2.20; P=.048). Non-Hispanics did not experience the same difference in EFS (HR, 0.88; P=.81). Conclusions: Treatment with a PIR resulted in worse EFS over HyperCVAD in adult Hispanic ALL patients. Future studies focusing on regimen intensity, adherence, and toxicities are needed to explore potential causes for this disparity. [Table: see text]
Mortality rate and social disparity trends with tyrosine kinase inhibitory availability in chronic myelogenous leukemia: An analysis in the US from 1999 to 2020.
Authors: Varughese Tony , Koprivnikar Jamie
Published: June 2023

7055

Background: We analyzed CML mortality from 1999 to 2020 in the US in relation to FDA approval of tyrosine kinase inhibitors (TKIs). These agents were introduced in the 2000s, revolutionizing the treatment of CML and providing a paradigm for targeted therapy in oncology. Starting with imatinib in 2001, followed by dasatinib (2006), nilotinib (2007), and bosutinib (2012). TKIs have increased tolerability and efficacy for the treatment of CML as compared to previous treatment modalities. We investigated age-adjusted mortality rates (AAMR) and annual percent change (APC) in this population in relation to TKI approval. Methods: Using the CDC WONDER database, we examined mortality trends from 1999 to 2020 for CML in the US. AAMRs were calculated per 100,000 people and stratified by sex, race/ethnicity, and census region. AAMR groups were listed as pre-TKI era and 1 year post-FDA approval of different TKI agents. We computed the APC trends for the respective stratification with Joinpoint, a regression analysis program. Results: Between 1999 and 2020 there were 35,268 deaths from CML. In 1999, overall AAMR initially was 0.8, which improved to 0.5 by 2020 with a respective APC of -2.5%. In our subgroup analysis there was a consistent and significant decrease in AAMR since the introduction of Imatinib in 2001. With additional TKI releases, AAMR continued to decline in all subgroups. APC for mortality rates was similar between all subgroups [-2.0 to -2.8%] indicating a similar benefit regardless of subgroup. Male AAMR was consistently higher than female AAMR. Black and white patients (0.5, 2020) have a 2.5x higher AAMR (0.2, 2020) compared to Asian patients. Census region did not show a significant difference between each other. Conclusions: Since the FDA approval of imatinib in 2001 and the subsequent release of TKIs there has been a significant impact on reducing AAMR for patients with CML. The decline was seen in sex, race, and census region. The APCs were similar between all subgroups indicating a consistent improvement in survival. Possible etiologies of disparities in AARM for males in comparison to females and for black and white patients in comparison to Asian patients include gender and race-associated gene polymorphisms possibly inducing differences in drug metabolism. Further gender and race specific pharmacokinetic studies would be useful to further elucidate etiology of the disparity and may lead to changes in TKI dosing strategies. [Table: see text]