bluuebunny/crossref_metadata_2025 huggingface dataset:
Electronic health record (EHR)-based machine learning (ML) to predict disease recurrence after surgical resection of early-stage non-small cell lung cancer (eNSCLC).
Authors: Pisano Steven , Honarvar Hossein , Parikh Ravi Bharat , Das Rahul K
Published: June 2023

6626

Background: Surgical resection (SR) is a guideline-recommended definitive therapy for patients (pts) with eNSCLC. However, 30–50% pts develop disease recurrence (DR) within the first 5 years (yrs) after surgery. ML applied to routinely collected EHR data could facilitate timely identification of pts at risk of DR who would benefit from enhanced surveillance or initial treatment (Tx) intensification. Methods: eNSCLC pts with stage IB-IIIA at the time of SR between Jan 2010 – February 2022 were identified from ConcertAI Patient360 oncology database comprising structured and curated records from US-based EHR. DR was defined as the human-curated earliest advanced/metastatic diagnosis date from SR. Gradient boosting (GB), random forest (RF), and logistic regression (LR) algorithms with 6-fold nested cross-validation were trained and compared to predict the risk of DR or death at 2 yrs from SR. Pts who did not experience DR and were lost to follow-up within 2 yrs from SR were removed. Feature importance was defined using Shapley Additive Explanation (SHAP)-derived odds ratios (OR). Due to low prevalence of DR at 2 yrs, AUPRC was used as performance metric. Pts in the 1st and 4th quartiles of predicted probabilities from XGB model were defined as low-risk vs. high-risk groups. Results: Among 3597 pts, median age was 68.3 yrs (IQR 12.5), 51.8% were female, and 8.6% were Black. 24.4% developed DR within 2 yrs. GB, RF, and LR models had similar ability to predict DR at 2 yrs with mean hold-out set AUPRC of 0.33. In GB model, DR prevalence at 2 yrs was 34% in the high-risk vs. 18% in the low-risk group in hold-out set. N0 stage, T stage < 3, receipt of adjuvant immune checkpoint inhibitor (ICI), and presence of EGFR mutations were protective against DR at 2 yrs, while history of anemia and congestive heart failure (CHF) were risk factors (Table). SHAP revealed a N stage-by-adjuvant therapy and a N stage-by-CHF interaction: benefit from adjuvant chemotherapy (CT) was limited to higher N stages, while adjuvant ICI was beneficial for all N stages. CHF was a risk factor for lower N stages but not for higher N stages. Conclusions: ML applied to structured and unstructuredEHRs identified predictors of risk of DR at 2 yrs after surgery in eNSCLC and may identify high-risk pts who would benefit from enhanced surveillance plans and Tx intensification in the eNSCLC setting. The model indicated favorable outcome from adjuvant targeted therapies in EGFR mutated pts. [Table: see text]
Evaluation of studies with commonly used real world data sources submitted to ASCO journals: Initial steps toward furthering transparent reporting.
Authors: Bates Benjamin , Kania Brooke , Ketelhut Ashley , Aneja Sanjay
Published: June 2023

6630

Background: Real world data (RWD) are used to understand treatment, care, and outcomes of patients with cancer. Reporting guidelines for observational studies, such as RECORD (health), RECORD-PE (treatment) and TRIPOD (prediction), were developed to increase the transparency of studies using RWD. These guidelines are not required for publication in ASCO Journals (JCO- Journal of Clinical Oncology, PO- Precision Oncology, OP- Oncology Practice, CCI- Clinical Cancer Informatics, GO- Global Oncology). Our objective was to describe the use of RWD among studies submitted to ASCO Journals and evaluate the applicability of guidelines and adherence to guidelines. Methods: ASCO submission system was used to identify all studies submitted to ASCO Journals between 2018-2022. Based on the abstract, the studies were categorized on whether selected RWD were used: SEER, Medicare, National Cancer Database [NCDB], Flatiron, CancerLinQ, IQVIA, Optum, MarketScan. Through manual review of the published manuscripts, we calculated positive predictive value (PPV) of our algorithm to identify the RWD. We estimated acceptance rate. For each study we evaluated the following: (1) linkages with other RWD; (2) applicability of reporting guidelines RECORD, RECORD-PE, TRIPOD; (3) use of flow diagram (RECORD) or study design figure for treatment and outcome assessment (RECORD-PE). Results: The PPV of our search algorithm was 79% (95%CI 73-84) but varied by journal (PPV 73-100; p=0.02). Based on our algorithm, among the 16,133 original reports submitted, 1,156 (7.2%) used one of the RWD sources. Overall acceptance rate among RWD sources was 18%. There was variability in submissions and acceptance rate of RWD by journal. OP and GO most and least frequently received a manuscript with the selected RWD 13% and 1%, respectively. GO accepted 77% of manuscripts that used selected RWD (88% of which were SEER). JCO accepted 3.5% of RWD manuscripts. Medicare, SEER, and NCDB were frequently identified data sources (61%, 31%, and 11%, respectively). SEER was linked to Medicare claims, surveys, or other sources in 77% of studies. The other data sources accounted for <5% each, although submission of EHR-linked to claims/registry increased over time (OR 1.26: 95%CI 1.07-1.49). RECORD, RECORD-PE and TRIPOD were applicable to 100%, 10% and 8% of the studies. RECORD-PE and TRIPOD were most applicable to PO/OP/CCI and CCI, respectively. A flow diagram demonstrating selection of participants was present in 31% of the studies. A figure to visualize study design was used in <5% of RECORD-PE relevant studies. Conclusions: RWD are commonly submitted and published within ASCO Journals. Reporting guidelines are applicable and particularly important when linkages occur. Studies using oncology RWD may benefit from reporting guidelines tailored to the unique qualities of these data sources and populations.
Real world data for venous thromboembolisms (VTEs) in patients with active cancer: Thromboprophylaxis pooled analysis from GMaT and ACT4CAT studies.
Authors: Tsoukalas Nikolaos , Christopoulou Athina , Timotheadou Eleni , Koumarianou Anna , Ardavanis Alexandros , Athanasiadis Ilias , Demiri Stamatina G , Bokas Alexandros , Samelis Georgios , Peroukidis Stavros , Papatsibas George , Andreadis Charalampos , Nikolakopoulos Achilleas , Psyrri Amanda , Kapodistrias Nikolaos , Papakostas Pavlos , Aravantinos Gerasimos , Athanasiadis Athanasios , Papakotoulas Pavlos , Boukovinas Ioannis
Published: June 2023

6637

Background: Venous Thromboembolisms (VTEs) lead to many negative consequences for patients with active cancer and are reported up to 20%. They affect anticancer treatment plan, increase morbidity, mortality, economic burden, and escalate psychological drain. Current guidelines recommend pharmacologic prophylaxis for thrombosis in ambulatory cancer patients with Khorana score ≥2. Methods: GMaT and ACT4CAT are prospective observational phase IV studies conducted by HeSMO in Greece. The aim was to record the clinical practice for ambulatory patients with active cancer who received thromboprophylaxis and enrolled after signing informed consent. Studies were approved by the bioethics committee. Results: 1157 patients from 26 oncology clinics enrolled who received thromboprophylaxis. Tumor types: gastrointestinal 38.5%, lung 24.8%, urological 12.2%, gynecological 6.9%, breast 6.1% and others 11.5%. Treatment lines: 1st 62.5%, 2nd 15.1%, 3rd 4%, adjuvant 9.7% and neoadjuvant 5.9%. Age ≥65 in 55.2%, BMI ≥30 in 17.8% and males 59.9%. High-Risk for Thrombosis Agents (HRTAs) received 82.3%: platinum agents (52.9%), antimetabolites (49.0%) and immunotherapy (10.2%). Notably, 52.7% of anticancer agents had potential drug-drug interactions (DDIs) with Direct Oral Anticoagulants (DOACs). High thrombotic risk factors presented in table. Thromboprophylaxis duration was 5.1±3.3 months with: tinzaparin 91.2%, fondaparinux 4.6%, bemiparin 2.3%, enoxaparin 1.2%, rivaroxaban 0.4% and apixaban 0.3%. Intermediate thromboprophylaxis doses of Low Molecular Weight Heparins (LMWHs) received 62% of patients; 50% in adjuvant setting & 72.6% in metastatic. 32 thrombotic events reported (efficacy: 97.2%, 95%CI: 96.3-98.2%) and 26 grade 1 or minor bleedings (2.2%, 95%CI:1.4-3.1%). Patients receiving intermediate doses of LMWHs had less risk for thrombosis (p=0.0308). Conclusions: VTEs prophylaxis in ambulatory patients with active cancer was found safe and effective. Apart from Khorana score, metastasis, HRTAs and DDIs seem to affect clinical decision for thromboprophylaxis mainly with LMWHs and often using intermediate doses irrelevant of clinical setting. Cancer Associated Thrombosis (CAT) is not negligible risk for patients and oncologists appeared to be aware about this. Clinical trial information: NCT03292107 , NCT03909399 . [Table: see text]
Cost of genetic testing, delayed care, and suboptimal treatment associated with polymerase chain reaction (PCR) versus next-generation sequencing (NGS) testing strategies in metastatic non-small cell lung cancer (mNSCLC).
Authors: Bestvina Christine M. , Waters Dexter , Morrison Laura , Emond Bruno , Lafeuille Marie-Hélène , Hilts Annalise , Lefebvre Patrick , He Andy , Vanderpoel Julie
Published: June 2023

6638

Background: NGS testing for genomic alterations has been found to expedite time to appropriate targeted therapy initiation compared to PCR testing in mNSCLC. This study assessed US payers’ costs of testing, delayed care, and suboptimal treatment initiation for PCR versus NGS testing in patients with mNSCLC. Methods: A decision tree model evaluated testing for guideline-recommended alterations (EGFR, ALK, ROS1, BRAF, KRAS, MET, HER2, RET, NTRK1/2/3) in patients with newly-diagnosed mNSCLC from first test until appropriate therapy initiation using 1) liquid or tissue NGS (60% [90% tissue, 10% liquid] of patients), 2) exclusionary KRAS test followed by sequential PCR tests (5%), 3) sequential PCR tests (5%), or 4) hotspot panel (30%) PCR tests. The proportion of patients testing positive for a targetable alteration and time to appropriate therapy initiation were evaluated. Cost components included genetic testing, testing-related medical services, delayed care (i.e., costs for medical services while waiting for test results), immunotherapy [IO]/chemotherapy [CTX] initiation prior to test results, and suboptimal treatment initiation after test results (i.e., costs of first-line IO/CTX in patients falsely testing negative for an actionable mutation). Results: In a modeled cohort of 1 million members (75% commercial, 25% Medicare), an estimated 1,119 patients had mNSCLC and were tested. The proportion of patients testing positive for a targetable alteration was 45.9% for NGS and 39.4% for PCR testing (Table). Total mean per patient costs were lower for NGS ($8,866) than for PCR ($18,252), driven by more rapid treatment with appropriate therapy (2.1 versus 5.2 weeks), resulting in lower delayed care costs and IO/CTX costs prior to test results. Conclusions: Results suggest that NGS testing may lead to better patient care and reduced costs to the health system relative to PCR testing. Costs of inappropriate IO/CTX initiation are an important component of increased costs of PCR-based approaches. [Table: see text]
Association between targeted cancer drug net health benefit and uptake, patient out-of-pocket spending, and total spending.
Authors: Lau-Min Kelsey S. , Wu Yaxin , Rochester Shavon E. , Bekelman Justin E. , Kanter Genevieve P. , Getz Kelly D.
Published: June 2023

6644

Background: Targeted cancer drugs (TCDs) have revolutionized oncology, but they are widely variable in their clinical benefit and are often accompanied by high patient-out-pocket (OOP) costs. The ASCO Value Framework uses published clinical trial data on survival, toxicity, and potential for symptom palliation to quantify the net health benefit (NHB) of any given cancer drug. We aimed to evaluate the association between NHB and uptake, patient OOP spending, and total spending for eight oral TCDs approved for the first line treatment of an advanced solid tumor based on one or more clinical trials comparing to a non-TCD control arm. Methods: We conducted a retrospective cohort study of incident pharmacy claims for oral TCDs prescribed to patients aged 18-64 years between 2012-2020 in the nationwide Health Care Cost Institute de-identified commercial claims dataset. NHB scores were calculated for each TCD of interest using the ASCO Value Framework and categorized as high (>60), medium (40-60), and low (<40) net health benefit. Distributions of incident 28-day TCD supplies were plotted over time by NHB category. The primary outcome was patient OOP spending (patient copay + coinsurance + deductible), whereas the secondary outcome was total spending (patient OOP spending + pharmacy reimbursement). Generalized linear models were used to evaluate the association between each outcome of interest and TCD NHB, adjusted for cancer indication. Results: We included 8,524 incident pharmacy claims for eight TCDs with nine indications in breast cancer, non-small cell lung cancer (NSCLC), melanoma, and pancreatic cancer. NHB scores ranged from 7 (erlotinib for pancreatic cancer) to 81 (crizotinib for ALK-rearranged NSCLC), with 1,145 (13%), 6,608 (78%), and 771 (9%) of pharmacy claims falling into low-, medium-, and high-NHB categories, respectively. Medium- and high-NHB TCDs accounted for the majority of incident TCD prescriptions throughout the study period. Median patient OOP spending was $18.78 for the first 28-day TCD supply (IQR $0.00-$87.57), with 45% of patients paying $0 and 8% paying >$1,000 OOP. Patient OOP spending was not significantly associated with TCD NHB category (difference $0.94, 95% CI -$49.99-$51.87 for medium vs low NHB; difference $58.86, 95% CI -$28.04-$145.75 for high vs low NHB). Median total spending was $10,118.79 (IQR $6,365.95-$10,600.37) for an incident 28-day TCD supply. There was a $1,083.56 increase in total spending for each 10-point increase in NHB score (95% CI $1,050.27-$1,116.84, p <0.01 for H0 = $0). Conclusions: Although TCDs are widely variable in their NHB, low-NHB TCDs are not prescribed as frequently as medium- and high-NHB TCDs. Total spending on TCDs is high and positively associated with NHB. Commercially insured patients are largely shielded from high OOP spending on TCDs.
Maxed out: Reaching the annual maximum out-of-pocket limit among insured patients diagnosed with cancer.
Authors: Banegas Matthew P. , Dickerson John F. , Petrik Amanda F , Anderson Melissa L. , Keast Erin , Ramaprasan Arvind , Wallace Jamie , Henrikson Nora B.
Published: June 2023

6646

Background: Patients with cancer face potentially high out-of-pocket costs associated with their medical care, which may lead to adverse medical and financial outcomes. Depending on their health insurance plan, patients may have to pay several thousands for medical care costs until they reach the annual maximum out-of-pocket [MOOP] spending limit; after which care costs are covered by insurance. The purpose of this study was to measure the proportion of adult patients who reach their health plan MOOP limit in the year of cancer diagnosis. Methods: Electronic health record data from 13,057 patients aged ≥18 years, diagnosed with cancer between Jan. 1, 2016–March 31, 2021 [index cancer], with ≥12 months of continuous health insurance coverage pre-cancer diagnosis were included. The primary outcome was defined as reaching the MOOP limit in the health plan benefit year of index cancer diagnosis (binary, yes/no). We additionally created a secondary outcome using 3 categories: (i) did not reach MOOP; (ii) reached MOOP prior to cancer diagnosis; (iii) reached MOOP after cancer diagnosis. Descriptive statistics were used to assess the distribution of outcomes across patient characteristics including health insurance type (e.g., commercial), high-deductible health plan (HDHP), cancer type, age at diagnosis, and Census-level household income was included. Multivariable logistic regression estimated the association between patient characteristics and the primary outcome. Complete case analyses were performed using Stata 16.1. Results: Patients’ mean age was 66 years (standard deviation [sd]: 13) and mean Census-level household income was $73,100 (sd: $24,000). Approximately 40% of patients had commercial health insurance and 62% had Medicare; 2% (n=283) had a HDHP. Breast (18%), lung (11%) and prostate (11%) cancers were most common. The mean annual MOOP limit was $3,040 for commercial plans and $2,688 for Medicare plans. Among patients with a commercial plan insurance, 46% reached their MOOP limit including 8% before and 37% after cancer diagnosis. For Medicare patients, 20% reached their MOOP limit, including 3% before and 17% after cancer diagnosis. Patients with a HDHP (adjusted Odds Ratio [aOR]: 2.61, 95% CI: 1.96-3.47), breast cancer (aOR: 2.29, 95% CI: 1.84-2.84), and lung cancer (aOR: 2.71, 95% CI: 2.04-3.61) had significantly greater odds of reaching the MOOP than those with a non-HDHP and other cancers. Household income was also significantly associated (aOR: 0.97, 95% CI:0.95-0.99) with reaching the MOOP. Conclusions: A substantial proportion of patients reach the annual MOOP limit during the year of cancer diagnosis, representing a population at high-risk for medical financial hardship. Future longitudinal studies are needed to assess the trajectory of OOP spending and implications on care utilization and health outcomes.
IMerge: Results from a phase 3, randomized, double-blind, placebo-controlled study of imetelstat in patients (pts) with heavily transfusion dependent (TD) non-del(5q) lower-risk myelodysplastic syndromes (LR-MDS) relapsed/refractory (R/R) to erythropoiesis stimulating agents (ESA).
Authors: Zeidan Amer Methqal , Platzbecker Uwe , Santini Valeria , Fenaux Pierre , Sekeres Mikkael A. , Savona Michael R. , Madanat Yazan F. , Diez-Campelo Maria , Valcarcel David , Illmer Thomas , Jonasova Anna , Belohlavkova Petra , Sherman Laurie Jill , Berry Tymara , Dougherty Souria , Shah Sheetal , Sun Libo , Wan Ying , Huang Fei , Komrokji Rami S.
Published: June 2023

7004

Background: Unmet needs remain for red blood cell (RBC) TD pts with LR-MDS R/R or ineligible for ESA. In P2 of the IMerge study (NCT02598661), heavily RBC TD ESA R/R non-del(5q) LR-MDS pts naive to lenalidomide and hypomethylating agents (len/HMA) treated with imetelstat, a telomerase inhibitor, achieved durable and continuous transfusion independence (TI). We report primary data from the P3 study of imetelstat in such pts. Methods: Heavily RBC TD ESA R/R non-del(5q) LR-MDS pts naive to len/HMAs were randomized 2:1 to receive imetelstat 7.5 mg/kg or placebo every 4 wks. Primary endpoint was 8-wk TI; subgroup analyses included IPSS risk, prior transfusion burden and ring sideroblast (RS) status. Secondary endpoints included 24-wk TI, TI duration and hematologic improvement-erythroid (HI-E). Variant allele frequency (VAF) changes were explored. Results: As of Oct 2022, 178 pts were randomized. The primary endpoint was met (Table); 39.8% vs 15.0% of pts receiving imetelstat vs placebo, respectively, achieved 8-wk TI. The rate of 8-wk TI was significantly higher with imetelstat vs placebo across subgroups, including RS negative pts. Median TI duration was significantly longer for imetelstat vs placebo, 51.6 vs 13.3 wks, P < 0.001. Pts receiving imetelstat had significantly higher mean hemoglobin (P < 0.001) and fewer transfusions (P = 0.042) over time than those on placebo. In 3 of 4 genes frequently mutated in MDS, VAF reduction was significantly greater in pts treated with imetelstat than placebo: SF3B1 (P < 0.001), TET2 (P = 0.032), DNMT3A (P = 0.019) and ASXL1 (P = NS). SF3B1 VAF reduction correlated with longer TI duration, P < 0.001. No new safety signals were identified. The most common Grade 3/4 AEs were thrombocytopenia and neutropenia, with similar rates of Grade ≥3 bleeding and infections on imetelstat and placebo. In pts treated with imetelstat, cytopenias were manageable, of short duration, and >80% were reversible to Grade ≤2 within 4 wks. Conclusions: For this LR-MDS pt population, imetelstat demonstrated statistically significant and clinically meaningful efficacy with high 8- and 24-wk TI rates, prolonged TI duration and increased hemoglobin. VAF reduction and its correlation to clinical endpoints support imetelstat’s disease-modifying potential. Safety results were consistent with prior reported experience. Clinical trial information: NCT02598661 . [Table: see text]
Updated efficacy and safety data from the AGILE study in patients with newly diagnosed acute myeloid leukemia treated with ivosidenib + azacitidine compared to placebo + azacitidine.
Authors: De Botton Stéphane , Montesinos Pau , Vives Polo Susana , Zarzycka Ewa , Wang Jianxiang , Riva Marta , Heuser Michael , Calado Rodrigo T. , Schuh Andre C. , Yeh Su-Peng , Hui Jianan , Gianolio Diego A. , Patel Prapti Arvind , Recher Christian , Dohner Hartmut
Published: June 2023

7012

Background: Ivosidenib (IVO) is a potent oral targeted inhibitor of mutant IDH1. In the AGILE study in patients (pts) with newly diagnosed IDH1-mutated acute myeloid leukemia, IVO plus azacitidine (AZA) significantly improved event-free survival (EFS), overall survival (OS), complete remission (CR), and CR or CR with partial hematologic recovery (CR+CRh) rates v placebo (PBO) plus AZA. As of March 2021, median OS (mOS) was 24 months (IVO+AZA) v 7.9 months (PBO+AZA; HR: 0.44; p=0.0005). Long-term follow-up data are presented. Methods: In the double-blind AGILE study, pts were randomized 1:1 to IVO 500 mg QD + AZA 75 mg/m2 SC or IV for 7 days in 28-day cycles, or PBO+AZA. Long-term follow-up data (June 2022) for OS, blood count recovery, transfusion independence and safety are described here. Results: 148 pts were randomized: 73 to IVO+AZA; 75 to PBO+AZA. Median treatment duration was 10.8 months (IVO+AZA) v 3.2 months (PBO+AZA). Five PBO+AZA pts crossed over to IVO+AZA after March 2021 (Table), and no adjustment was made for crossover in the updated OS analysis. At a median follow-up of 28.6 months, mOS was 29.3 months (95% CI 13.2, not reached) for IVO+AZA v 7.9 months (95% CI 4.1, 11.3) for PBO+AZA (HR 0.42 [0.27, 0.65]; p<0.0001). OS rates were 62.9% and 38.3% at 12 months and 53.1% and 17.4% at 24 months, with IVO+AZA and PBO+AZA, respectively. In the IVO+AZA arm, hemoglobin levels steadily increased from baseline (BL; 88.8 g/L) to cycle 8, and then stabilized; mean platelet count recovered from BL values (72.7 x 109/L) as early as week 8 (171.9 x 109/L) and remained stable; and mean neutrophil counts rapidly increased from BL (0.98 x 109/L) to week 3 (3.99 x 109/L) and week 4 (4.36 x 109/L), and then stabilized to within the normal range. Conversion from BL transfusion dependence (red blood cell and/or platelet transfusion dependence) to post-BL transfusion independence was significantly higher with IVO+AZA than PBO+AZA (53.8% v 17.1%, respectively; p=0.0004). There were fewer neutropenic fever events (27.8% v 33.8%) and infections (34.7% v 51.4%) with IVO+AZA than with PBO+AZA. TEAEs led to discontinuation of IVO+AZA or PBO+AZA in 26.4% and 25.7% of pts, respectively. Conclusions: Updated data on OS (>5 months longer mOS and a greater risk reduction in deaths compared to the initial analysis), transfusion independence, blood count recovery and safety confirms the clinically and statistically robust benefit in favor of IVO+AZA at long-term follow up. Patient disposition. Clinical trial information: NCT03173248 . [Table: see text]
Outcomes of 3- versus 5-day administration schedule of consolidation cytarabine in adults with acute myeloid leukemia (AML).
Authors: Diebold Kendall , Bachiashvili Kimo , Jamy Omer Hassan , Vachhani Pankit , Godby Kelly Nicole , Bhatia Ravi , Diamond Barry , Oliver Josh D , Moulton Kaitlin R , Rangaraju Sravanti
Published: June 2023

7014

Background: Consolidation therapy with intermediate to high-dose cytarabine is critical to prevent relapse in AML. Cytarabine is typically administered every 12 hours on days 1, 3, 5. Two large studies have examined a condensed 3-day administration schedule in patients <60 years and demonstrated a shorter time to absolute neutrophil count (ANC) recovery without compromising long term outcomes. However, use of this regimen in patients ≥60 years has not been evaluated. Here we report our experience with the condensed administration schedule compared with the standard schedule in patients over and under 60 years. Methods: All patients with AML in first complete remission (CR) following intensive induction chemotherapy receiving consolidation at our institution between 1/1/2020 to 12/31/2021 were included in the study. Patients received cytarabine every 12 hours on days 1, 3, 5 (AC135) from 1/1/2020 – 12/31/2020 and cytarabine every 12 hours on days 1, 2, 3 (AC123) from 1/1/2021 – 12/31/2021. All patients received peg-filgrastim support. Data was collected to determine time to ANC recovery >1,000/µL, hemoglobin (Hb) >8g/dL, and platelets >75,000/µL. Comparison of continuous variables between two groups was done using multiple t-tests. Results: Between 1/1/2020 - 12/31/2021, 91 patients received at least one cycle of consolidation with 212 individual encounters. 38 patients received all cycles with AC135, 45 received AC123, and 8 received at least one cycle each of AC123 and AC135. Median age of the AC123 cohort was 50.2 years (range 19-72 years) and 54.3 years for the AC135 cohort (range 22-72 years). For patients ≥60 years of age, 33% (71/213) of the encounters were in the AC123 cohort and the rest in AC135 cohort. Median dose of cytarabine was 5,100 mg/dose in AC123 and 4,600 mg /dose in AC135 (p=0.02). Median time to ANC recovery, hemoglobin, and platelets as well as hospital-related outcomes are described in the table. In patients ≥60 years, median time to ANC recovery was 16.5 vs. 18.6 days (p = 0.03) and platelet recovery was 17.4 vs. 19.7 (p = 0.0008) in AC123 vs AC135 respectively. No neurotoxicity events were noted. Complication rates were similar in both arms. Conclusions: Our study demonstrates that AC123, as compared to AC135, is safe and leads to earlier hematopoietic recovery in adults under and over 60 years. AC123 should be considered the preferred schedule of consolidation therapy administration. [Table: see text]
Pelabresib (CPI-0610) monotherapy in high-risk essential thrombocythemia refractory or intolerant to hydroxyurea: Preliminary results from MANIFEST study.
Authors: Passamonti Francesco , Patriarca Andrea , Knapper Steven , Rivera Candido , Scandura Joseph , Devos Timothy , Granacher Nikki , Mead Adam J. , Oh Stephen , Palmer Jeanne M. , Rampal Raajit , Teichmann Lino , Cui Jie , Klein Sandra , Colak Gozde , Harrison Claire
Published: June 2023

7019

Background: High-risk essential thrombocythemia (HR ET) is characterized by thrombocytosis, thrombohemorrhagic events and systemic symptoms. Pts can experience intolerance, inadequate response or loss of response to first-line cytoreductive therapies (hydroxyurea [HU] or interferon alfa-2a). BET protein inhibition is a novel therapeutic strategy that downregulates inflammatory cytokines and may inhibit differentiation and proliferation of abnormal megakaryocytes involved in ET pathogenesis. Results from the Phase 2 MANIFEST study (NCT02158858) suggested potentially encouraging clinical efficacy in pts with myelofibrosis treated with Pelabresib (PELA), an oral, small-molecule, investigational BET inhibitor. Here we present preliminary results from MANIFEST Arm 4 investigating PELA monotherapy in HR ET refractory or intolerant to HU. Methods: Eligible pts had platelets > 600 x 109/L and ≥ 2 symptoms (average score ≥3/ TSS≥15). Pts received PELA monotherapy 225 mg QD. The primary endpoint was complete hematologic response (CHR; normalization of platelet count (≤400 x 109/L), WBC count (≤10 x 109/L) confirmed after one cycle [after 3 weeks]) and normal spleen size. Secondary endpoints included partial HR (PHR; platelets 400–600 x 109/L and WBC ≤10 x 109/L), symptom improvement (≥50% TSS reduction) and safety. Results: As of July 2022, 20 pts with HR ET were treated: median age 64 yrs (42–83), median Hgb 13 (10–16) g/dL, median platelet count 772 (418–1255) x 109/L and median TSS 32.7 (6.9–123). The majority of pts had a hematologic response (90% [18/20] unconfirmed CHR or PHR); confirmed CHR was observed in 40% (8/20) (Table). Median platelet and WBC count at Wk 12 was 446 x109/L and 8.2 x 109/L, respectively. TSS reduction was reported in 86% (12/14 pts); median TSS reduction at Wk 12 was –31%. Hgb levels remained stable through Wk 24. The most common nonhematologic AEs were nausea (60%; 10% Gr 3), diarrhea (35%; 5% Gr 3) and dysgeusia (35%; no Gr 3). Hemorrhagic or thromboembolic events were reported in 30% pts (15% Gr 3). No events of thrombocytopenia and no Gr 4 events or higher were reported. Conclusions: Preliminary results from Arm 4 of the MANIFEST study suggest potential clinical benefit with PELA monotherapy in pts with HR ET refractory or intolerant to HU as supported by hematologic responses and symptom improvement. Safety results are consistent with the known safety profile of PELA and as expected in the underlying study population. Clinical trial information: NCT02158858 . [Table: see text]
Implications for acute myeloid leukemia (AML) treatment and care during the COVID-19 pandemic: A Connect Myeloid Registry study.
Authors: Scott Bart L. , Sekeres Mikkael A. , Garcia-Manero Guillermo , Grinblatt David L. , DeGutis Irene S. , Kiselev Pavel , McBride Ali , Heydendael Willem , Yu Edward , Roboz Gail J.
Published: June 2023

7021

Background: For patients (pts) with AML, timely treatment is critical. The COVID-19 pandemic broadly disrupted healthcare (eg, decreased blood donations), possibly causing delays in AML treatment and care. To determine the extent of the COVID-19 impact on AML, this analysis examines the effect of the pandemic on managing pts with AML in the Connect Myeloid Registry (NCT01688011). Methods: The Registry is a large, US, multicenter, prospective, observational cohort study that includes newly diagnosed pts with AML aged ≥55 y. Pt characteristics (including assessment for transplant) were analyzed from December 2013 to March 2020 (from Registry opening to the start of the pandemic; Period 1), from March 2020 to May 2021 (during major healthcare disruptions; Period 2), and from May 2021 to January 2022 (resource stabilization and increased vaccine availability; Period 3). Monthly COVID-19 incidence was calculated per weekly US government data (CDC COVID Data Tracker; 2023). Rates of visits (office, remote) and transfusions were calculated by monthly events/person-year. Overall survival (OS) was estimated using the Kaplan-Meier method. Results: In this analysis, 650 pts were included in Period 1, 87 pts in Period 2, and 36 pts in Period 3; demographics and baseline characteristics were balanced across periods. Prior to the COVID-19 pandemic (Period 1), 25.1% of pts were not assessed for transplant; however, after the onset of the pandemic, this increased (45.5% and 44.4% in Periods 2 and 3, respectively). When monthly US COVID-19 cases increased, in-person visits and transfusion rates generally decreased in the Registry (Table). The proportion of pts receiving oral-containing induction regimens was 49.4% (40/81) in Period 1 (starting in January 2019, due to FDA approval of venetoclax in November 2018) and 50.6% (44/87) in Period 2, with a slight increase to 63.9% (23/36) in Period 3. No significant differences in OS by period were observed. Conclusions: In this analysis of pts with AML in the real-world setting, a pattern of increased COVID-19 cases in the US was accompanied by fewer transfusions, fewer in-person visits, and fewer assessments for stem cell transplantation, without a significant impact on OS. Clinical trial information: NCT01688011 . [Table: see text]
Examining safety and durable disease remission in R/R B-ALL after autologous CD19-directed CAR T cells produced by novel PRIMCAR manufacture platform.
Authors: Yang Zhi , Li Shiqi , Li Yu , Liu Lin , Yuan Zhongtao , Zhang Yingzi , Luo Le , Zhang Lihua , Chen Yingnian , Zhang Qianzhen , Shen Junjie , Li Yunyan , Wang Linling , Wang Meiling , Zhu Wei , He Xiao , Wang Youcheng , Dong Yancheng , Wang Sanbin , Qian Cheng
Published: June 2023

7026

Background: CD19 chimeric antigen receptor (CAR) T cell therapy has shown promising efficacy in the r/r B-ALL. However, the life-threatening side effect and disease relapse limited its wide application. To overcome these limitations, we established a novel PrimeCAR platform (PRIMCAR) and reported the preliminary safety and effectiveness data of MC-1-50 CAR-T cells before (Shiqi Li, et al. J Clin Oncol 2022; 40 [suppl 16]. Abstract 7008). Here, we present updated data. Methods: In this Phase I /II study (NCT04271410), MC-1-50 CAR T cells were manufactured by the PRIMCAR platform, which reduces manufacture periods to about 2 days. Patients (pts) received single-dose of MC-1-50 at dose ranged 1-5×105 CAR+/kg (Level 1, 1×105 CAR+/kg; Level 2, 2×105 CAR+/kg; Level 3, 3×105 CAR+/kg; Level 4, 5×105 CAR+/kg). Pts were pre-conditioned with fludarabine (25-30 mg/m2) and cyclophosphamide (200-300 mg/m2) daily for 3 days. Toxicity was graded by CTCAE, CRS and ICANS were graded by ASTCT criteria. Results: 19 pts with r/r B-ALL were infused. Disease characteristics and outcomes are shown in the table. No DLTs were reported. 18 pts (94.7%) experienced CRS, including 10 (52.6%) at grade 1, 7 (36.8%) at grade 2, 1 (5.3%) at grade 3, and no ≥ 4 CRS were observed. Three pts (15.8%) experienced ICANS, including 2 (10.5%) at grade 1, 1(5.3%) at grade 2, and no ≥ 3 ICANS occurred. All patients achieved CR/CRi (BM MRD-) in the first month. All patients received no other anti-tumor therapy until relapse was confirmed. The median DOR was not reached. 6 patients confirmed relapse, including 4 were CD19 negative and 2 were CD19 positive but with CD19 gene mutation at the time of relapse. All patients in 4 dose levels had good CAR-T expansion and exhibited long persistence features. Only 3 patients experienced the loss of CAR-T. Conclusions: Treatment of r/r B-ALL at a very low dose resulted in excellent safety profiles while exhibiting a high and durable efficacy. That makes this PRIMCAR platform potential for outpatient administration in the future. Clinical trial information: NCT04271410 . [Table: see text]
Survival outcomes with CPX-351 vs 7+3 by baseline bone marrow blast percentage in older adults with newly diagnosed high-risk or secondary acute myeloid leukemia: A 5-year follow-up study.
Authors: Ritchie Ellen K. , Lin Tara L. , Newell Laura F. , Stuart Robert K. , Solomon Scott R. , Stone Richard M. , Schiller Gary J. , Wieduwilt Matthew Joseph , Ryan Eileen A. , Dronamraju Nalina , Lancet Jeffrey E. , Cortes Jorge E.
Published: June 2023

7027

Background: CPX-351, a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio, is approved for newly diagnosed therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes in the US and Europe following positive efficacy and safety data from the pivotal phase 3 clinical trial (NCT01696084). A previous exploratory analysis of the trial data (median follow-up 20.7 months) showed improved survival outcomes with CPX-351 vs conventional 7+3 chemotherapy in adults with newly diagnosed high-risk or secondary AML (sAML) irrespective of baseline bone marrow (BM) blast percentage. Here we report 5-year follow-up data (median follow-up 60.9 months) to provide insights into the longer-term efficacy and safety of CPX-351 in these patient subgroups. Methods: Patients (60–75 years) with a pathologic diagnosis of AML (high-risk/sAML) per the WHO 2008 criteria (≥20% blasts in peripheral blood or BM) and an ECOG PS of 0–2 were randomized to receive CPX-351 or 7+3 chemotherapy. In these post hoc subgroup analyses at 5 years follow-up, overall survival (OS), event-free survival (EFS) and complete remission (CR) were assessed by baseline BM blast percentage. The analysis included patients with low ( < 20%) BM blasts to account for changes in blast count thresholds in the updated WHO AML classification. Results: Overall, median OS and EFS were longer with CPX-351 vs 7+3 in each subgroup; median OS was greatest in low blast subgroups for both treatments (Table). Higher CR rates were observed with CPX-351 vs 7+3 irrespective of baseline BM blasts. Median Kaplan-Meier (KM)-estimated survival rates increased with CPX-351 vs 7+3 across BM blast subgroups. The CPX-351 safety profile was comparable across BM blast subgroups and consistent with the known safety profile of 7+3. Conclusions: These 5-year follow-up data suggest that CPX-351 results in improved outcomes irrespective of baseline BM blast percentage vs conventional 7+3 chemotherapy in older adults with AML. Clinical trial information: NCT01696084 . [Table: see text]
Identification of factors to predict low risk febrile neutropenia admissions in patients with acute myeloid leukemia (AML) following intensive chemotherapy.
Authors: Pal Khushboo , Ali Zahra , Othus Megan , Russell Katie , Shaw Carole , Percival Mary-Elizabeth M. , Hendrie Paul , Walter Roland B. , Halpern Anna B.
Published: June 2023

7031

Background: Febrile neutropenia (FN) is the most common reason for hospital readmission following chemotherapy for AML. Standard practice for FN in AML is hospitalization for rapid administration of IV antibiotics, thus FN is a major driver of healthcare resource utilization and cost. Whether this approach is justified in all situations is unknown. While FN risk models have been developed focusing on solid tumors, factors predicting uncomplicated courses of FN in AML, which may allow identification of patients suitable for outpatient management, have not been studied. We therefore examined whether baseline clinical characteristics could predict which AML patients with FN have a lower risk of progression to severe illness. Methods: We retrospectively reviewed medical records from 7/29/2014-12/24/2022 to identify adults with FN (fever >38.3C and white blood count <1000/µL). Included were patients with high-grade myeloid neoplasm (>10% blasts in blood/marrow) who received intensive chemotherapy (cytarabine dose >=100 2 /day) within 8 weeks. We collected baseline clinical and disease variables. Outcomes were: infections identified, hospital length of stay (LOS), intensive care unit (ICU) admission, and survival. A “low-risk [LR]” outcome was defined as a LOS <72hrs without ICU admission or inpatient death. Univariate and multivariable (MV) logistic regression models were used to assess covariate associations with outcomes. Results: We identified 350 FN admissions in 198 patients with a median age 62 (range: 21-87) yrs. 63% were newly diagnosed and 37% relapsed/refractory. 12% had prior transplant. Median duration of neutropenia prior to fever was 12 (1-287) days. 46% had transfusion <24 hours prior to fever. The median LOS was 5 (1-56) days. 9% of patients went to ICU and 6% died inpatient.Overall, 15% of admissions were classified as LR. 57% had an infection identified. The table shows factors in MV analysis that predicted an infection identified or high-risk (HR) admission. Conclusions: Only 15% of AML admissions for FN were LR. Factors that predict HR outcomes in standard FN models such the MASCC score—e.g. age, prior fungal infection —were not predictive of HR outcomes in AML. As a next step, we will compare our model to other published models used to predict poor outcomes after FN, which have not been developed or validated in AML. [Table: see text]
Comparison of next-generation sequencing and flow cytometry in detecting minimal residual disease in adult acute lymphoid leukemia: Evaluating clinical outcomes in a single-center study.
Authors: Nittur Vinay , Ashouri Karam , Adnani Blake , Hwang Jennifer , Chen Denaly , Schiff Kimberly , Savitala-Damerla Lakshmi , Ladha Abdullah , Woan Karrune , Tam Eric Leon , Chaudhary Preet , Yaghmour George
Published: June 2023

7033

Background: Detection of measurable residual disease (MRD) is an important biomarker to direct treatment for adult patients with acute lymphoblastic leukemia (ALL). Currently, multiparameter flow cytometry (MFC) is standard of care and can detect residual leukemia cells in 1 out of 100,000 cells (1 × 10−5). Routine use of next-generation sequencing (NGS) assays with higher levels of sensitivity may improve disease-free survival and overall survival in adult ALL patients. The clonoSEQ MRD assay (Adaptive Biotechnologies Corporation, USA) can detect MRD at a sensitivity of 1 × 10−6 . In this study, we compare the detection of MRD by clonoSEQ assay and MFC in adult ALL patients at a single institution. Methods: We performed a retrospective study evaluating 92 adult patients with B- or T-ALL admitted to Norris Comprehensive Cancer Center between 2014 and 2022. Patients were excluded if they did not achieve complete remission (N=9) or if they presented with prior relapse (N=27). Median time to first complete remission (CR1) was 2.38 months. Among our cohort (N=56 patients), all patients underwent pre-treatment bone marrow sampling which was used for Clonoseq assay. 52 patients had contemporaneous MFC which was used for comparative analysis. MRD on MFC was defined as residual leukemia cells at a sensitivity of 1 × 10−5. MRD on Clonoseq assay was evaluated at 1 × 10−6; residual cells under this limit were considered MRD−. Results: Demographics are summarized in the table. Median time to follow-up from MRD assessment was 18.0 months. 10 patients relapsed (17.9%), 3 patients died (5.4%), and 20 patients (35.7%) underwent allogeneic transplant during first remission. Among 52 patients analyzed by both MFC and NGS at CR, 26 (50%) were concordantly MRD− by NGS and NGF, 13 (25%) were discordantly MRD− by NGF but MRD+ by NGS, and 13 (25%) concordantly MRD+ by NGS and NGF. Residual cell levels between NGS and NGF were strongly correlated (R-Squared = 0.6744, p<0.001), however, MRD status was significantly different between NGS and NGF (p<0.001 using Fisher’s Exact Test). This difference was likely driven by disparities in the limits of detection between both methods. Conclusions: Assessment of MRD using the clonoSEQ assay over a standard MFC-based approach adds crucial prognostic information among adult ALL patients who achieved CR. [Table: see text]
Results from a phase (Ph) 1 clinical study of the all-oral regimen of CC-486 and venetoclax for acute myeloid leukemia (AML).
Authors: Amaya Maria , McMahon Christine , Gutman Jonathan Aaron , Stevens Brett , Sohalski Connor , Tobin Jennifer , Smith Clayton , Jordan Craig , Pollyea Daniel Aaron
Published: June 2023

7034

Background: Venetoclax (Ven) with azacitidine (Aza) is the standard of care for newly diagnosed AML patients who are unfit for intensive induction chemotherapy. It is well known that this treatment also has activity in the relapsed and refractory (R/R) setting. However, this regimen requires seven consecutive daily SQ or IV doses of Aza each month. The relative inconvenience of this, and its negative impact on quality of life, may lead to its early discontinuation, possibly decreasing the overall efficacy of this regimen. An all-oral regimen may decrease infusion center visits, and potentially increase the efficacy of the regimen due to improved compliance. CC-486 is the oral formulation of Aza that is currently approved for post-induction chemotherapy maintenance in AML. Methods: This is a single center open label, Ph 1 study investigating CC-486 and Ven in R/R AML patients. In the dose escalation phase, subjects received CC-486 at one of two cohorts (200 mg PO days 1-14 and 300 mg PO days 1-14). Ven was given at the 400 mg/day PO regimen, for 28 days, after an initial intra-patient dose escalation per the standard of care. Using a 3+3 study design for the two cohorts, we aimed to determine the maximum tolerated dose (MTD) of CC-486 in combination with Ven. An expansion cohort is planned for 10 patients treated at the MTD. Results: As of February 1, 2023, 8 patients have been accrued. The average age at the time of enrollment was 64, and median prior treatment regimens was 1 (range 1-3). Four patients had received Ven in prior treatments. In cohort 1, there were no DLT events. There have been no DLT events in 5/6 patients enrolled in cohort 2. The most common hematologic toxicities were Gr 3-4 neutropenia (n = 7, 88%), Gr 3-4 anemia (n = 6, 75%), and Gr 3-4 thrombocytopenia (n = 4, 50%). The most common non-hematologic toxicities were Gr 1-2 nausea (n = 4, 50%), Gr 1-2 fatigue (n = 2, 25%), and Gr 1-2 diarrhea (n = 2, 25%). Best responses were complete remission (CR) (n = 2, 25%), partial remission (PR) (n = 1, 13%), and stable disease (SD) (n = 2, 25%). Three patients proceeded to an allogeneic stem cell transplant. Conclusions: CC-486 and Ven is an all-oral regimen being investigated for the treatment of R/R AML. Our Ph 1 dose escalation thus far has demonstrated a favorable safety profile for this regimen. Full Ph 1 findings and the MTD will be presented at the meeting. Responses have been seen in both dose cohorts, and patients have been bridged to hematopoietic stem cell transplant. Clinical trial information: NCT05287568 . [Table: see text]
Clinical and molecular characteristics of patients with AML with an exceptional response to ivosidenib.
Authors: Watts Justin M. , Patel Prapti Arvind , Choe Sung , Bai Xiaofei , Marchione Dylan M. , Stein Eytan M.
Published: June 2023

7036

Background: Ivosidenib (IVO) twas approved based on a CR/CRh rate of 31.8% in IDH1 mutant (IDH1m) R/R AML; median duration of CR/CRh (DOR) was 8.2 months (mo). The purpose of this study is to elucidate the clinical and molecular characteristics of exceptional responders to single agent IVO. Methods: We analyzed all patients (pts) with IDH1m R/R AML who received IVO 500mg QD on the phase 1 dose escalation/expansion study and had a DOR of >12 mo. Results: Of 179 pts who received IVO 500 mg QD, 57 (31.8%) achieved a CR/CRh. Of these, 20 (35.1%) had a DOR >12 mo. After excluding 7 pts who went to HSCT, 13 (22.8% of responders, 7.3% of cohort) had DOR >12 mo (exceptional response) and 8 (14% of responders, 4.5% of cohort) had DOR >24 mo. The 13 exceptional responders all achieved CR as best response, and median DOR was 42.6 mo. Median OS was not reached; estimated OS at 48 mo was 67.1%. Median EFS was 44.4 mo. Reasons for discontinuing treatment included relapse (n=4), adverse event unrelated to IVO (n=3), and patient (pt) decision (n=3). Three pts remain on treatment. All pts who relapsed had DOR between 1-2 years; none of the 8 pts with DOR >2 years relapsed. Baseline characteristics are in the table. The most common co-mutations were DNMT3A, ASXL1, SRSF2, and JAK2 (3 each, 23%). Five pts (39%) had a splicing factor mutation. No pts had FLT3 or RTK pathway mutations other than JAK2. Only 1 pt with NPM1 had an exceptional response, and 1 pt had TP53 (VAF 3.6%). Six pts (46%) had an abnormal karyotype, 6 normal (46%), and 1 missing (8%). Most pts had intermediate-risk cytogenetics (10 pts, 77%), 2 poor-risk, and 1 missing. The median IDH1 VAF was 25% (range 10-50%). The median number of co-mutations was 1 (range 0-6). Having 0-1 co-mutations was associated with a longer response. Eleven pts (85%) had an IDH1 R132C mutation; 1 each (7.7%) had R132H and R132L mutations. Mutation clearance of IDH1 was noted in 8 pts (61.5%). Conclusions: A subset of pts with IDH1m R/R AML have prolonged CR on single agent IVO without HSCT (22.8% of CR/CRh responders) and no pts in CR for >2 years (14% of CR/CRh responders) relapsed. A low mutational burden, lack of RTK pathway mutations and canonical AML drivers, and co-occurrence of mutations associated with clonal hematopoiesis appear to be associated with exceptional response. Clinical trial information: NCT02074839 . [Table: see text]