bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tolerability and efficacy of the first-in-class anti-CD47 antibody magrolimab combined with azacitidine in MDS and AML patients: Phase Ib results.
Authors: Sallman David Andrew , Al Malki Monzr , Asch Adam Steven , Lee Daniel Junseung , Kambhampati Suman , Donnellan William Bruce , Bradley Terrence James , Vyas Paresh , Jeyakumar Deepa , Marcucci Guido , Komrokji Rami S. , Van Elk Joanna , Lin Ming , Maute Roy , Volkmer Jens-Peter , Takimoto Chris H.M. , Chao Mark , Daver Naval Guastad 
Published: May 2020

7507 Background: Magrolimab (Hu5F9-G4) is an antibody blocking CD47, a macrophage immune checkpoint and don’t eat me signal on cancers. It induces tumor phagocytosis and eliminates leukemia stem cells. Azacitidine (AZA) synergizes with magrolimab by inducing eat me signals on leukemic cells, enhancing phagocytosis. We report Ph1b data including a potential MDS registration cohort. Methods: Magrolimab+AZA was given to untreated intermediate to very high risk IPSS-R MDS and intensive chemo unfit AML patients. A magrolimab priming/intrapatient dose escalation regimen (1-30 mg/kg QW, Q2W Cycle 3+) was used. AZA was dosed 75mg/m2 days 1-7. Efficacy was assessed by IWG 2006 (MDS) and ELN 2017 (AML) criteria. Results: 68 patients (39 MDS, 29 AML) with a median age of 72 were treated with magrolimab+AZA. 19% were intermediate cytogenetic risk with 68% poor risk (13% unknown). 27% were TP53 mutant. The combo was well-tolerated with safety similar to AZA alone. Common treatment-related AEs were anemia (38%), fatigue (21%), neutropenia (19%), thrombocytopenia (18%) and infusion reaction (16%). Treatment-related febrile neutropenia was 1.5%. Only 1 patient (1.5%) discontinued due to an AE. In RBC transfusion dependent patients, 58% of MDS and 64% of AML patients became transfusion independent. 30/33 (91%) efficacy evaluable MDS patients had an objective response (42% CR, 24% marrow CR (4/8 also with HI), 3% PR, 21% HI alone, 9% SD). MDS patient responses deepened on study, with a 56% CR rate in patients with ≥ 6 mo follow-up. In AML, 16/25 (64%) responded (40% CR, 16% CRi, 4% PR, 4% MFLS, 32% SD, 4% PD). In 12 TP53 mutant AML patients, 75% had a CR+CRi (42% CR, 33% CRi, 17% SD, 8% PD). Cytogenetic CR was seen in 35% and 50% of responding MDS and AML patients. 22% of MDS and 50% of AML patients with CR/CRi/marrow CR were MRD negative by flow cytometry. Median duration of response is not reached in either MDS or AML, including TP53 mutant AML, with a median follow-up of 5.8, 8.8 and 9.4 mos, respectively (range: 1.9 – 16.8 mos). 91% of MDS and 100% of AML responding patients are in response at 6 mos. The 6 mo overall survival estimate is 100% in MDS and 91% in TP53 mutant AML patients. Conclusions: Magrolimab is a macrophage targeting immunotherapy that with AZA is well tolerated with durable efficacy in MDS, AML, particularly TP53 mutant, a poor prognostic group. A potential registration single arm MDS cohort is ongoing (NCT03248479). ENHANCE, a randomized Ph3 MDS trial is planned. Additional patients/analyses will be reported. Funded by Forty Seven and CIRM. Clinical trial information: NCT03248479 .
Type of prior genotoxic insult determines the genomic characteristics of therapy-related acute myeloid leukemia.
Authors: Ozga Michael , Blachly James Stewart , Grieselhuber Nicole Renee , Larkin Karilyn T.M. , Walker Alison R. , Bhatnagar Bhavana , Behbehani Gregory , Long Meixiao , Haque Tamanna Zohra , Vasu Sumithira , Zhao Weiqiang , Jones Daniel , Byrd John C. , Mims Alice S. , Saygin Caner 
Published: May 2020

7515 Background: Therapy-related AML (tAML) is a long-term complication of cytotoxic cancer therapy. It is characterized by adverse genetics and inferior survival outcomes when compared to de novo AML. A proposed mechanism in tAML pathogenesis includes treatment-induced selection of clones harboring pre-existing mutations (i.e. clonal hematopoiesis, CH). We hypothesize that genotoxic therapies used to treat prior malignancy drive leukemogenesis through different mechanisms leading to unique clonal compositions. Methods: AML patients (pts) treated at The Ohio State University between 2015-2018 were included. Genetic profiling was performed using Miseq Illumina platform with a 49-gene targeted sequencing panel at our clinical laboratory. Results: We studied 337 AML pts (Table), of whom 53% had smoking history. Mutations involving ASXL1 were more common in smokers vs non-smokers (14% vs 5.8%, p= .001), while JAK2 mutations were more common in non-smokers (8% vs 1.2%, p= .003). Regarding specific genotoxic therapies and mutations in tAML, we investigated common CH-associated mutations including DNMT3A, TET2, and ASXL1 (DTA mutations). In tAML pts, those exposed to radiotherapy experienced a higher frequency of DTA (52% vs 27%, p= .05), NPM1 (21% vs 0%, p= .002), and SRSF2 (15% vs 0%, p= .01) mutations, and conversely, a lower incidence of TP53 mutations (21% vs 46%, p= .04). Pts with history of cytotoxic chemotherapy had a lower incidence of DTA mutations, including those who received platinum agents (8% vs 49%, p= .005) and taxanes (7% vs 52%, p< .001), but had a higher incidence of TP53 mutations (75% vs 25%, p< .001 for platinum; 53% vs 25%, p= .04 for taxanes). Similarly, alkylators and anthracyclines were associated with lower incidence of DNMT3A (0% vs 20%, p= .009) and ASXL1 (0% vs 12.5%, p= .04) mutations. Conclusions: Different genotoxic agents demonstrate unique effects in leukemia development. Our data suggest that CH clones with DTA mutations may be enriched with smoking and radiotherapy, while cytotoxic chemotherapy may confer a higher incidence of TP53 mutations. Given the adverse prognosis of TP53 mutated AML, identification of pre-existing CH clones might influence treatment selection in solid tumor pts receiving anticancer therapy. [Table: see text]
Longer-term RBC transfusion reduction in the phase III MEDALIST study of luspatercept in patients (pts) with lower-risk MDS with ring sideroblasts (RS).
Authors: Komrokji Rami S. , Sekeres Mikkael A. , Zeidan Amer Methqal , Fenaux Pierre , List Alan F. , Dezern Amy Elizabeth , Greenberg Peter L. , Savona Michael R. , Jurcic Joseph G. , Verma Amit , Mufti Ghulam J. , Buckstein Rena , Santini Valeria , Laadem Abderrahmane , Ito Rodrigo , Zhang Jennie , Louis Chrystal Ursula , Linde Peter G. , Garcia-Manero Guillermo 
Published: May 2020

7518 Background: MEDALIST (NCT02631070) is a randomized, placebo (PBO)-controlled, phase 3 trial evaluating the efficacy and safety of luspatercept, a first-in-class erythroid maturation agent, in pts with anemia due to lower-risk MDS (LR-MDS) with RS (Fenaux & Platzbecker et al. NEJM. 2020;382:140-51). Methods: Pts were aged ≥ 18 years; had IPSS-R-defined Very low-, Low-, or Intermediate-risk MDS with RS; were refractory, intolerant, or unlikely to respond to ESAs; and required RBC transfusions (≥ 2 units/8 weeks in the 16 weeks prior to randomization). 229 pts were randomized 2:1 to luspatercept (1.0 mg/kg, titration to 1.75 mg/kg) or PBO subcutaneously every 3 weeks. This analysis evaluates long-term transfusion burden reduction with luspatercept in all pts in the MEDALIST trial. Results: As of July 1, 2019, 77/153 (50.3%) and 11/76 (14.5%) pts in the luspatercept and PBO arms, respectively, achieved ≥ 50% RBC transfusion burden reduction for ≥ 24 weeks ( P < 0.0001). The median longest single response episode was 131.6 weeks with luspatercept, and not estimable with PBO due to pts stopping treatment. In Weeks 9–24, mean change from baseline in RBC units transfused was −3.0 (95% CI −3.9, −2.1) vs +0.4 (95% CI −0.6, 1.4) in the luspatercept vs PBO arms. In Weeks 33–48, mean change in RBC units transfused in the luspatercept arm was −4.9 (95% CI −5.9, −3.9). In Weeks 1–24, mean number of transfusion visits was 5.9 vs 9.5 in the luspatercept vs PBO arms. Risk of recurrent transfusion visits in Weeks 1–24 for luspatercept vs PBO was 0.699 (95% CI 0.597, 0.819; P < 0.0001). Mean number (least squares [LS] mean) of RBC units transfused/48 weeks during Weeks 1–48 was 22.89 (23.28) vs 35.98 (35.20) in luspatercept vs PBO arms (LS mean difference −11.92 [95% CI −15.55, −8.28]; P < 0.0001). The mean number (LS mean) of RBC transfusion events over 48 weeks was 12.95 (13.14) vs 19.54 (19.15) in the luspatercept vs PBO arms (LS mean difference −6.00 [95% CI −8.16, −3.85]; P < 0.0001). LS mean change from baseline in serum ferritin was −2.7 µg/L vs +226.5 µg/L in luspatercept vs PBO (LS mean difference −229.1 µg/L; P = 0.0024) in Weeks 9–24; and −72.0 µg/L vs +247.4 µg/L in Weeks 33–48 (LS mean difference −319.5 µg/L; P = 0.0294). In Weeks 1–24, 38/127 (29.9%) vs 5/65 (7.7%) pts ( P = 0.0005) achieved major HI-E response per IWG 2018 criteria in luspatercept vs PBO arms, respectively. Conclusions: Luspatercept demonstrated clinical efficacy in pts with LR-MDS with RS and was associated with significant reductions in RBC transfusions (≥ 50%) and serum ferritin. Clinical trial information: NCT02631070 .
Activity of decitabine as maintenance therapy in core binding factor acute myeloid leukemia.
Authors: Shoukier Mahran , Kantarjian Hagop M. , Garcia-Manero Guillermo , Patel Keyur P. , Kadia Tapan M. , Ravandi Farhad , Ohanian Maro , Daver Naval Guastad , Issa Ghayas C. , Aldrich Jeffrey , Borthakur Gautam 
Published: May 2020

7522 Background: Real-time quantitative (RTPCR) based minimal residual disease (MRD) monitoring provides prognostic information in core binding factor acute myeloid leukemia (CBF-AML). Earlier we reported on the activity of decitabine (DAC) as maintenance therapy in a smaller cohort of patients with CBF AML. Methods: We have summarized the results in patients (pts) with CBF who received DAC maintenance for persistent RTPCR positivity or because of inability to complete all planned consolidation in a fludarabine, GCSF, cytarabine (FLAG) based regimen. The planned number of DAC cycles was 12 but could be adjusted at the discretion of the treating physician based on RTPCR response. Serial RTPCR was obtained approximately every 2-3 months. Results: Thirty-four pts with CBF-AML [t(8;21)=14 and inv(16)=20] received DAC as maintenance. Eighteen pts (53%) completed a full course (7 cycles) of FLAG based regimen before DAC for persistent PCR positivity (group 1). Sixteen pts (47%) were switched to DAC as they did not complete planned consolidation (group 2). In group 2, 9 pts (56%) had negative PCR (group 2A) and 7 pts (46%) had positive PCR (group 2B) prior to starting DAC. Patient characteristics are summarized in table. The median follow up was 59.2 [15.4-107.2] and 32.47 [8.5-86.3] months for group 1 and 2, respectively. In Group 1 and group 2A only 1 patient each had relapse, while 5 pts (72%) from group 2B had relapse. All the patients in group 2B with relapse were at suboptimal RTPCR response (>0.1%). Conclusions: Our study shows DAC is an effective maintenance for CBF-AML pts who have persistent PCR positively after FLAG based induction consolidation and those unable to tolerate a full course, but have negative PCR. However patients with high levels of MRD persistence should be considered for stem cell transplant. [Table: see text]
Comparative study of therapy-related (tALL) and de novo adult acute lymphoblastic leukemia (dnALL): Contemporary Mayo Clinic ALL cohort.
Authors: Abdel Rahman Zaid , Parrondo Ricardo Daniel , Heckman Michael , Spiegel Matthew , Miller Kevin Charles , Sproat Lisa Ostrosky , Jiang Liuyan , Murthy Hemant S. , Alkhateeb Hassan , Litzow Mark Robert , Greipp Patricia T. , Foran James M. 
Published: May 2020

7523 Background: tALL is a recently appreciated but poorly defined clinical entity. We define tALL as any prior exposure to cytotoxic chemotherapy and/or radiation for another malignancy, and we report a comparative analysis of characteristics, cytogenetics and outcomes for this subset among a modern unselected ALL cohort from the Mayo Clinic Cancer Center (MCCC). Methods: We performed a systematic search in the 3-site MCCC registry and included all patients (pts) diagnosed and received at least 1 cycle of ALL-directed therapy and/or underwent allogeneic transplantation (AlloHCT) between 2008-2018. Comparisons of characteristics between tALL and dnALL were made using a Wilcoxon rank sum test (continuous variables) and Fisher’s exact test (categorical variables). Time-to-event variables were compared using unadjusted Cox proportional hazards regression models. Results: 431 ALL pts were identified during the study period, including n = 69 (16%) classified as tALL. Median follow-up from diagnosis was 2.3 years (range 0-18 years). The most common prior malignancies among tALL pts were Breast (24.6%), Lymphoma (15.9%), Myeloid (15.9%), GU/GYN (14.5%) and Myeloma (11.6%). In comparison to dnALL, pts with tALL were significantly older (63.2 vs 45.2 years, P < 0.001), more often female (65.2% vs 39.8%, P < 0.001), less frequently Hispanic (3.5% vs 13.1%, P = 0.042); more often of B-lineage (92.8% vs 81.8%, P = 0.022). On review of cytogenetics, tALL pts more often had hypodiploidy/near triploidy (Ho/Tr) (21.7% vs 4.1%, P < 0.001), more often had monosomal (MDS-like) (33.3% vs 12.4%, P = 0.0047) and complex karyotype (38% vs 17.3%, P = 0.0069). Importantly, incidence of BCR/ABL-positive (Ph+) ALL was not significantly different. Latency period between exposure to prior cancer therapy and development of tALL was significantly longer for Ph+ compared to Ph-negative ALL (median 9 vs. 4 years, P = 0.007). Patients with tALL had a 3-year OS after diagnosis of 37% [vs 59.7% for dnALL (HR death 1.86, 95% CI 1.31-2.65, P < 0.001)]. However, the two groups did not differ significantly regarding occurrence of AlloHCT (HR = 0.91, 95% CI 0.63-1.31, P = 0.61) or post-AlloHCT survival (HR = 1.29, 95% CI 0.75-2.23, P = 0.35). Conclusions: Therapy-related ALL represents an important & unique clinical entity with poor prognosis & adverse cytogenetic features. Ph+ tALL has a longer latency and similar frequency in both tALL and dnALL. AlloHCT appears to be an appropriate treatment strategy, possibly abrogating the poor prognosis of tALL.
Effect of early blood counts on overall survival (OS) following glasdegib + LDAC in newly diagnosed AML: BRIGHT AML 1003 post hoc analysis.
Authors: Wang Eunice S. , Heuser Michael , Sekeres Mikkael A. , Papayannidis Cristina , Candoni Anna , Merchant Akil , Brown Andrew , O'Connell Ashleigh , Ma Wendy , Chan Geoffrey , Cortes Jorge E. 
Published: May 2020

7525 Background: Addition of glasdegib (GLAS) to LDAC approximately doubled OS without significant worsening of myelosuppression-related complications, ostensibly by targeting leukemic stem cells dependent on the hedgehog pathway, which is not involved in normal adult hematopoiesis. We assessed potential association of early blood counts and OS. Methods: In BRIGHT AML 1003, patients (pts) with newly diagnosed AML were randomized to GLAS + LDAC (n = 78) or LDAC alone (n = 38). GLAS was given once daily continuously and LDAC on days 1–10 of a 28-day cycle. We evaluated peripheral blood counts measured early in the study (cycle 2 day 1 [C2D1]), approximately 1 month before the first bone marrow assessments. OS was compared for GLAS+LDAC vs LDAC alone subgroups meeting thresholds of absolute neutrophil count (ANC; ≥1000 or 500/µL), hemoglobin (Hb; ≥10 or 9 g/dL) or platelets (≥100,000 or 50,000/µL). Data cut-off was Apr 2019. Results: Among all pts regardless of baseline values, achievement of ANC, Hb and platelet thresholds at C2D1 was associated with improved OS with GLAS+LDAC (table, left side). Notably, in pts who did not meet ANC, Hb or platelet thresholds (table, right side), OS benefit with GLAS+LDAC was also observed (table, all p≤0.05). Among pts below threshold at baseline, C2D1 recovery of platelets ≥50,000 or 100,000 and Hb ≥9 or 10 was associated with improved OS (not shown). Clinical trial information: NCT01546038 . Conclusions: In pts with newly diagnosed AML, improved OS was associated with various blood count thresholds after 1 cycle of GLAS+LDAC vs LDAC alone. In pts with baseline measurements below threshold, recovery of specific thresholds was associated with improved OS. These exploratory results are consistent with the hematopoiesis-sparing mechanism of GLAS, and merit further evaluation. [Table: see text]
Health-related quality of life (HRQoL) in patients with untreated higher-risk myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and chronic myelomonocytic leukemia (CMML) receiving glasdegib + azacitidine (AZA).
Authors: Wang Eunice S. , Bell Timothy , Zeidan Amer Methqal , Bhattacharyya Helen , Kudla Art , Chan Geoffrey , Sekeres Mikkael A. 
Published: May 2020

7527 Background: Glasdegib + AZA showed promising remission rates and overall survival in an analysis of BRIGHT MDS & AML 1012 in patients (pts) with MDS, AML and CMML. Here we assess the impact of glasdegib + AZA on HRQoL in this ongoing Phase Ib study. Methods: Untreated pts with MDS, AML and CMML ineligible for intensive chemotherapy received glasdegib (100 mg QD) + AZA (75 mg/m2/D on D1–7 q28D). Pt-reported outcomes (PRO) that characterize HRQoL were measured using the MD Anderson Symptom Inventory (MDASI)-AML/MDS, Pt Global Impression of Severity (PGI-S), and Pt Global Impression of Change (PGIC) tools. PRO were assessed at baseline (BL; except the PGIC), D7 and D15 of cycle (Cyc) 1, D1 of each subsequent Cyc and at end of treatment. Data cutoff: Sept 11, 2019. Results: For the MDS (n=30, including 3 with CMML) and AML (n=30) cohorts, median (range) number of Cyc started was 5 (1–14) and 5 (1–15), respectively. HRQoL over time, as determined by MDASI-AML/MDS, is shown in the Table, with mean scores indicating low symptom burden over time. For the PGI-S, both cohorts showed similar trends in pt’s impression of current leukemia symptoms remaining constant over time (i.e. absent to mild). For the PGIC, pt’s impression of change of leukemia symptoms since starting study medication remained constant over time (i.e. no to minimal change) for the MDS cohort and showed improvement in the AML cohort (i.e. minimal change to much improved). Conclusions: Glasdegib + AZA is a promising first-line treatment option that does not negatively impact the HRQoL of pts with MDS, AML and CMML ineligible for intensive chemotherapy. Clinical trial information: NCT02367456 . [Table: see text]
Pre-transplant molecular minimal residual disease (MMRD) is associated with inferior outcomes in patients with acute myeloid leukemia undergoing allogeneic stem cell transplantation.
Authors: Husnain Muhammad , Komanduri Krishna , Ramdial Jeremy , Lekakis Lazaros J. , Wang Trent Peng , Goodman Mark , Pereira Denise L. , Beitinjaneh Amer , Carollo Douglas , Ali Robert , Mohammed Yaqub Nadeem , Arshad Junaid , Byrnes Diana , Saul Eduardo Edelman , Aguirre Luis E. , Jimenez Antonio Martin 
Published: May 2020

7547 Background: Allogeneic Stem Cell Transplant (alloSCT) continues to be the optimal consolidation strategy for many patients with AML; cytogenetic and molecular abnormalities are known predictors of post-transplant outcomes. There is increasing evidence that Molecular Minimal Residual Disease (MMRD) following induction has important prognostic implications and its value in the prediction of post-transplant relapse continues to be elucidated. We aim to evaluate the impact of genetics and pre-transplant MMRD on clinical outcomes following alloSCT. Methods: We retrospectively evaluated eighty-nine patients, ≥18 years with a diagnosis of AML in complete morphologic remission (i.e. < 5% BM blasts by morphologic assessment) who received alloSCT between 01/2012-05/2018 at the University of Miami and for whom cytogenetic and comprehensive molecular data was available prior to transplantation. Patients were stratified into favorable, intermediate and poor-risk categories based on 2017 ELN criteria. MMRD was defined as persistent leukemia-specific mutations prior to transplantation (i.e. NPM1, FLT3, CEBPA, IDH1-2, RUNX1 and TP53). Persistence of DTA mutations (DNMT3A, TET2 and ASXL1) was not considered MMRD, patients with unavailable cytogenetic/molecular data at diagnosis were excluded. Results: Seventy-four (83%) patients were transplanted in CR1, myeloablative conditioning was used in 72% of patients. Two-year OS and LFS were 69.4% and 78.2%, respectively. Stratification by ELN criteria resulted in prognostic separation for patients transplanted in CR1: 2-year OS for favorable (87%), intermediate (68%) and adverse risk (51%) patients (p = 0.0417). The presence of MMRD was the strongest predictor of post-transplant outcomes for the whole cohort with 2-year OS and LFS of 29.4% and 37.1% (HR 5.45 [95%CI 2.43-12.3] p = 0.0001; HR 12.4 [95%CI: 3.76 to 39.8] p = 0.0001); respectively. Subgroup analysis confirmed that MMRD was associated with significantly inferior LFS for IM/favorable and adverse risk patients (HR: 6.76 [95% CI 1.12 to 40.9], p = 0.038). Conclusions: Pre-transplant MMRD was the most important prognostic factor for relapse and survival in our cohort of AML patients undergoing alloSCT. Correlation of MMRD with other transplant variables such as conditioning intensity, MRD status by MFC and the impact of pre-emptive/therapeutic strategies in high-risk patients continues to be explored.
Disparities in receipt of complete diagnostic evaluation to confirm myelodysplastic syndromes.
Authors: Mukherjee Sudipto , Dong Weichuan , Statler Abby , Koroukian Siran M. 
Published: May 2020

7555 Background: A complete diagnostic evaluation (CDE), including bone marrow (BM) biopsy, cytogenic testing, FISH panel, and/or flow cytometry, is widely accepted as a prerequisite for histopathologic confirmation of MDS. Earlier reports have raised concerns regarding accuracy of MDS diagnosis in population registries that do not require confirmatory tests for disease reporting. We queried Medicare files to analyze the extent of use of, and factors associated with CDE for diagnosing MDS. Methods: The study population included Medicare patients with at least one inpatient or two outpatient claims for MDS within a 12-month period during the years 2012 and 2013. Variables included age, sex, race, morphologic MDS categories, cytopenias (isolated or any combination), transfusion burden, comorbididities, as well as county-level characteristics (income, educational attainment, rurality, and availability of internal medicine subspecialists). Classification and regression tree (CART) and multivariable logistic regression analysis were used to identify combinations of factors associated with receipt of CDE. Results: Our study population included 45,067 MDS patients, of whom only 68.6% received CDE that included BM biopsy and/or chromosomal studies. The percent of patients undergoing CDE was significantly lower among those 85 years of age or older (56.1%); women (63.7%); Blacks (64.2%); patients with isolated anemia (60.3%); and those who were transfusion independent (p < 0.001 for all comparisons). On the other hand, CDE was significantly higher among patients with the category of MDS with excess blasts (89.4%); those presenting with pancytopenia (92.2%); and those with high transfusion burden (80%). There was little variation by comorbidity burden, county level characteristics, or availability of subspecialists. In CART analysis, 80% of patients presenting with any two or more cytopenias received CDE. In multivariable analysis, advanced age, female sex, Black race, higher comorbidity burden and availability of subspecialists were associated with a lower likelihood to receive CDE, while patients with MDS with excess blasts, and with any > 2 cytopenias were more likely to receive CDE ( P< .0001). Conclusions: Nearly one third (31%) of MDS patients in the Medicare database lack CDE especially BM biopsy. Disparities in CDE can be corrected through proper physician education and stringent registry reporting to avoid such high diagnostic inaccuracies, leading to potential missed treatment opportunities.