bluuebunny/crossref_metadata_2025_split huggingface dataset:
Linking insurance claims across time to characterize treatment, monitoring, and end-of-life care in metastatic breast cancer.
Authors: Caswell-Jin Jennifer Lee , Callahan Alison , Purington Natasha , Han Summer S. , Itakura Haruka , Sledge George W. , Shah Nigam , Kurian Allison W. 
Published: May 2020

7063 Background: Treatment and monitoring options for metastatic breast cancer (MBC) are increasing, but little is known about patterns or predictors of their use. Insurance claims are potentially informative, but tracking patient care timelines using episodic claims data has been cumbersome. Methods: We used an advanced cohort engine, implementing a temporal query language, to link IBM Marketscan claims over time for > 125 million US individuals from 2007-2014. To select the most common MBC subtype (ER+, HER2-), our criteria were: ≥2 MBC ICD codes, ≥1 year of follow-up, and ≥1 CPT or medication code for endocrine therapy and 0 for HER2-targeted therapy. We defined aggressive MBC as ≥1 ICD code for visceral or central nervous system metastasis < 1 year after the first MBC code. Geographic area was defined by 9 Census-Bureau designated regions. End-of-record was used as a surrogate for death in a Cox regression. We used multivariate logistic regression to determine correlation of factors, including disease aggressiveness and geography, with treatment, monitoring, and end-of-life events. Results: 7,335 women met criteria for ER+, HER2- MBC, with median age 59. Nearly half (46%) had aggressive disease, which correlated with shorter survival (hazard ratio (HR) 1.5 [1.4-1.6], P < 0.001). Treatment: first-line was endocrine therapy for 64% versus chemotherapy for 36%. Monitoring: 79% were imaged mostly by CT versus 21% by PET-CT, with median between-scan interval of 81 days; 63% received CA 15-3 serum tumor markers. End-of-life: 10% had a hospice code, of whom 19% had an ICU stay and 34% chemotherapy in the prior 3 months. Correlates of care: Disease aggressiveness correlated with first-line chemotherapy (odds ratio (OR) 2.0 [1.8-2.2], P < 0.001), PET/CT (OR 1.6 [1.4-1.8], P < 0.001), more frequent scans (OR 2.3 [2.1-2.6], P < 0.001), and chemotherapy < 3 months pre-hospice (OR 1.2 [1.1-1.4], P < 0.001), but not with CA 15-3 monitoring or ICU stay. Disease aggressiveness did not vary by region (χ2 P = 0.8), but region was significantly associated with treatment, monitoring, and end-of-life care (P < 0.001). Conclusions: Approximately two-thirds of ER+, HER2- MBC patients receive first-line endocrine therapy and are monitored with CA 15-3 serum tumor markers; 10% had evidence of hospice use, a likely underestimate due to differential follow-up. MBC care patterns vary by geography while disease aggressiveness does not, suggesting that care is not optimally tailored to individuals. These insights from claims data can inform quality improvement for MBC care.
Effect of enasidenib (ENA) plus azacitidine (AZA) on complete remission and overall response versus AZA monotherapy in mutant-IDH2 (mIDH2) newly diagnosed acute myeloid leukemia (ND-AML).
Authors: Dinardo Courtney Denton , Schuh Andre C. , Stein Eytan M. , Montesinos Pau , Wei Andrew , De Botton Stephane , Zeidan Amer Methqal , Fathi Amir Tahmasb , Quek Lynn , Kantarjian Hagop M. , Frattini Mark G. , Lersch Frederik , Gong Jing , Franovic Aleksandra , Vyas Paresh , Dohner Hartmut 
Published: May 2020

7501 Background: ENA and AZA each induce overall response rates (ORR) of ~30% and complete remission (CR) rates of ~20% in ND-AML. In vitro, combining ENA + AZA enhances cell differentiation. We report results of the phase II portion of an open-label, randomized phase I/II study of ENA + AZA (“E+A”) vs. AZA monotherapy (“A”) in patients (pts) with m IDH2 ND-AML (NCT02677922). Methods: Pts age ≥ 18 years ineligible for intensive chemotherapy, with ECOG PS ≤ 2 and intermediate- or poor-risk cytogenetics, were randomized 2:1 to E+A or A in 28-day (d) cycles. All pts received SC AZA 75 mg/m2/d x 7 d/cycle; pts randomized to E+A also received ENA 100 mg QD. The primary endpoint was ORR (CR, CR with incomplete recovery, partial remission, morphologic leukemia-free state). Other endpoints include duration of response (DOR), overall and event-free survival (OS, EFS), safety, and m IDH2 VAF. Results: 101 pts received E+A (n = 68) or A (n = 33). Median age was 75 years (57–85); most pts (83%) had intermediate-risk cytogenetics. 21 pts in the E+A arm and 1 in the A arm were ongoing at data cutoff (Aug 2019). Most common reason for discontinuation was disease progression (E+A 31%, A 52%). Median number Tx cycles was 10 (1–26) in the E+A arm and 6 (1–28) in the A arm. 7 pts (21%) in the A arm received subsequent Tx with ENA. ORR, CR rate and DOR were significantly improved with E+A vs. A (Table). Median OS was 22 mo in both arms (HR 0.99 [95%CI 0.52, 1.87]; P = 0.97). Median EFS was 17.2 and 10.8 mo in the E+A and A arms, respectively (HR 0.59 [95%CI 0.30, 1.17]; P = 0.13). Maximal m IDH2 VAF change from BL was –83.4% with E+A vs. –17.7% with A ( P < 0.01). No baseline co-mutation predicted primary resistance. Common Tx-related grade 3–4 AEs in the E+A arm were thrombocytopenia (37%), neutropenia (35%), anemia (19%), and febrile neutropenia (15%); these occurred in 19%, 22%, 22%, and 16% in the A arm. Grade 3–4 infections occurred in 18% of E+A pts and 31% of A pts. IDH differentiation syndrome occurred in 12 pts (18%) in the E+A arm. 5 E+A pts (7%) and 1 A pt (3%) died in the first 60 d. Conclusions: Combining ENA + AZA resulted in significantly improved response rates and durations, and was generally well-tolerated in older patients with m IDH2 ND-AML. The impact of subsequent Tx on OS/EFS and new translational data will be presented at the meeting. Clinical trial information: NCT02677922 . [Table: see text]
Glasdegib (GLAS) plus low-dose cytarabine (LDAC) in AML or MDS: BRIGHT AML 1003 final report and four-year overall survival (OS) follow-up.
Authors: Heuser Michael , Robak Tadeusz , Montesinos Pau , Leber Brian , Fiedler Walter M. , Pollyea Daniel Aaron , Brown Andrew , O'Connell Ashleigh , Ma Wendy , Chan Geoffrey , Cortes Jorge E. 
Published: May 2020

7509 Background: In newly diagnosed AML or high-risk MDS, primary analysis of the randomized phase 2 BRIGHT AML 1003 trial (data cutoff Jan 2017) showed superior OS for GLAS+LDAC vs LDAC alone. The trial then continued to predefined completion 4 years from randomization of all patients (pts), reached in Mar 2019 and presented herein. Methods: Pts with newly diagnosed AML or high-risk MDS and unsuitable for intensive chemotherapy were randomized 2:1 to GLAS+LDAC (n=88) or LDAC alone (n=44). For these groups, median (range) treatment duration was 83 (3-1575) and 47 (6-239) days; median follow-up for survival 47.6 and 48.1 months; 4 (4.5%) and 1 pt (2.3%) completed ≥4 years’ follow-up. Results: Consistent with the primary findings (OS HR 0.51; 80% CI 0.39, 0.67 p=0.0004), GLAS+LDAC prolonged OS vs LDAC alone (table). Results were consistent in AML pts and cytogenetic risk/disease history subgroups (table), as were analyses by pt characteristics and baseline risk factors (not shown). Survival probability was 39.5% vs 9.5% at 1 year and 18.0% vs 2.4% at 2 years. GLAS+LDAC induced higher complete remission (CR) rates overall (16/88 vs 1/44; RR 8.12, 95% CI 1.05, 62.78, p=0.010) and across subgroups. Notably, fewer pts discontinued GLAS+LDAC due to AEs (38.1% and 46.3%) and there was no increased sepsis or bleeding vs LDAC alone despite longer glasdegib treatment. With GLAS+LDAC, SMO-inhibitor-associated AEs included dysgeusia (25.0%), muscle spasms (22.6%) and alopecia (10.7%), with only 1 pt discontinuing due to dysgeusia. Conclusions: Consistent with primary analyses, GLAS+LDAC continued to have an acceptable safety profile and improved OS vs LDAC alone. HRs were consistent across cytogenetic risk subgroups and support use of GLAS+LDAC in de novo and secondary AML. Clinical trial information: NCT01546038 . [Table: see text]
Evolving risk of therapy-related myelodysplastic syndromes and acute myeloid leukemia (tMDS/AML) following modern cancer therapies.
Authors: Singh Abhay , Mrad Chebli , Faber Mark G , Hahn Theresa , Wang Eunice S. , Herr Megan , Thota Swapna 
Published: May 2020

7516 Background: Data describing risks of tMDS/AML after targeted and immunotherapy (IO) agents are lacking. Melanoma (Mel) and renal cell carcinoma (RCC) are considered chemotherapy insensitive and have been treated with IO (interferon and interleukin) since the 1990s. In 2004, use of tyrosine kinase inhibitors (TKIs) began in non-small cell lung cancer (NSCLC) and expanded to RCC in 2005 and Mel trials in 2011. Checkpoint inhibitor (CPI) use began in 2011 for Mel, 2012 for NSCLC in trials and later for RCC. For multiple myeloma (MM), use of lenalidomide has been increasing since 2007. All these modern therapies have well described immunomodulatory functions. Methods: Using 17 population-based SEER cancer registries, we studied 565,149 patients diagnosed from 2000-2015 with Mel, RCC, NSCLC, or MM who survived ≥1 year and assessed risk of tMDS/AML across periods P1 (2000-2005), P2 (2006-2010) and P3 (2011-2015). Censoring occurred at 5 years of follow up to limit bias and assess risk alteration across approval and utilization periods of these modern therapies. Results: tMDS/AML risk was significantly elevated after RCC in P1 [standardized incidence ratio (SIR): 1.61, possibly from chemo exposure that was still prevalent to some extent in P1 period] and a downtrend noted in P2 (SIR: 1.11) and P3 (SIR: 0.60). tMDS/AML risk after Mel showed similar downtrend, not statistically significant. In contrast, risk for tMDS/AML after MM increased across all periods ( SIRs 4.51 > 5.05 > 5.23), and risk after NSCLC increased from P1 to P2 but decreased thereafter, pattern most pronounced in stage I-III NSCLC ( 1.64 > 3.15 > 1.92). Conclusions: Periods when TKI and CPI use became standard in Mel and RCC, we observed a decrease in tMDS/AML risk. Similar decrease in the most recent period for stage I-III NSCLC was observed, possibly due to progression of these earlier staged cancers resulting in receipt of TKIs and CPI for stage IV disease. tMDS/AML risk after MM increased contradicting the decline in risk previously reported in the literature. Discordance may be due to survival bias as MM patients are now living longer (SEER 5-yr survival in ‘00 was 35% and 53% in ‘15) with more time to develop tMDS/AML. Overall, aside from better efficacy and/or tolerability of modern therapies, another observed benefit was lower tMDS/AML risk. This risk was lower than general population in Mel/RCC, suggesting a possible protective effect of these therapies. SIR tables/graphs with updated SEER data (available 04/2020) with follow up through 2018 will be presented.
Glasdegib in combination with azacitidine (AZA) in patients (pts) with untreated higher-risk myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML): Effects on marrow recovery and transfusion independence.
Authors: Zeidan Amer Methqal , Schuster Michael , Joris Magalie , Krauter Jurgen , Maertens Johan , Gyan Emmanuel , Kovacsovics Tibor , Verma Amit , Vyas Paresh , Wang Eunice S. , Ma Wendy , Zeremski Mirjana , Kudla Art , Chan Geoffrey , Sekeres Mikkael A. 
Published: May 2020

7526 Background: Glasdegib, an oral inhibitor of the Hedgehog signaling pathway, is approved in the USA in combination with low-dose cytarabine to treat pts with newly diagnosed AML unable to receive intensive chemotherapy due to comorbidities or age (≥75 years). Glasdegib + AZA showed promising remission rates and overall survival with a generally well-tolerated and manageable safety profile in an analysis of BRIGHT MDS & AML 1012 in pts with MDS, AML and CMML. Here we evaluate early hematopoietic recovery and transfusion independence with glasdegib + AZA 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). Data cutoff: Sept 11, 2019. Results: Among pts with MDS (n=30; including 3 with CMML), median duration of treatment was 5.0 months (range, 0.4–15.5). Recovery of absolute neutrophil count (ANC), hemoglobin (Hb) and platelets at 2 thresholds started in cycle (Cyc) 1 (Table). Early platelet recovery correlated with response to treatment; 54% (7/13) of pts with platelets ≥100,000/µL at Cyc 2, D1 achieved complete or partial remission vs 0% (0/13) of pts with <100,000/µL, P=0.002. Start of Cyc 2 was delayed due to AEs in 8% (2/26) of pts. 54% (7/13) of evaluable pts transfusion dependent at baseline (BL) became transfusion independent. Among pts with AML (n=30), median duration of treatment was 5.0 months (range, 0.3–14.9). ANC, Hb and platelet recoveries started in Cyc 1 (Table). 9% (2/23) of pts had Cyc 2 dose delays due to AEs. 64% (9/14) of evaluable pts transfusion dependent at BL became transfusion independent. Clinical trial information: NCT02367456 . Conclusions: Glasdegib + AZA shows promising rates of survival with early marrow recovery in the up-front treatment of pts with MDS, AML and CMML ineligible for intensive chemotherapy. The association between early hematopoietic recovery and efficacy in the MDS cohort merits further study. [Table: see text]
Post-remission clonal hematopoiesis; Practical implications for measurable residual disease assessment in acute myeloid leukemia (AML).
Authors: Loghavi Sanam , Tanaka Tomoyuki , Furudate Ken , Wang Sa A , Takahashi Koichi 
Published: May 2020

7529 Background: Clonal Hematopoiesis may persist following complete remission (CR) in patients with acute myeloid leukemia (AML) but does not necessarily indicate residual AML and may represent persistence of pre-leukemic stem cells. Post-remission CH identified by NGS has not been systemically studied in parallel with measurable residual disease (MRD) detection by flow cytometric immunophenotyping (FCI). Methods: We studied bone marrow sample from AML patients at baseline and CR by targeted deep NGS of 295 genes (median 403x depth) and compared the results to FCI. Measurable residual disease (MRD) detection by FCI was performed by comparing the phenotype at CR to baseline and by detection of leukemia associated immunophenotype (LAIP) and derivation from normal (DFN) (sensitivity: 0.1%). Post-CR CH was defined as presence of mutations originally detected in AML with variant allele frequency > 2.5%. FCI results were categorized into 4 groups: a) AML MRD negative by LAIP or DFN b) AML MRD+ (similar to baseline) c) AML MRD+ (different from baseline), d) Negative for AML MRD, but aberrant phenotype suggestive of pre-leukemic cells. We correlated FCI and NGS results. Results: 101 patients were included in the study. 45 (45%) had persistent post-CR clonal hematopoiesis; 23 (51%) had phenotypic alterations detected by FCI including AML MRD+ in 18 (40%) and pre-leukemic cells in 5 (10%). Among patient with no detectable mutations by NGS (n = 56; 55%), 14 (25%) had FCI aberrancies including AML MRD+ in 4 (7%) and pre-leukemic cells in 10 (18%). CH was significantly more common in samples with residual phenotypic aberrancies detected by FCI (p = 0.004). There was no significant correlation between FCI group d and persistent CH (p = 0.4). Persistent ASXL1 (p = 0.024, OR = 7.2 ) and RUNX1 (p = 0.016; OR = 17.3) mutations were significantly associated with FCI abnormalities. The correlation coefficient between FCI abnormalities and RUNX1 mutations inferred from a Bayesian network structure was 0.66. Conclusions: NGS and FCI are complementary in evaluating post treatment disease status in AML. Post CR-CH is associated with phenotypic abnormalities that either represent residual AML or pre-leukemic cells. The latter may not have the same prognostic implications as AML MRD; however, the association with outcome needs to be elucidated. Single cell DNA sequencing technologies may be helpful in more accurately deciphering the association of individual gene mutations and their contribution to phenotypic aberrations.
Health-related quality of life (HRQoL) in the phase III QUAZAR-AML-001 trial of CC-486 as maintenance therapy for patients with acute myeloid leukemia (AML) in first remission following induction chemotherapy (IC).
Authors: Roboz Gail J. , Dohner Hartmut , Pocock Christopher , Dombret Hervé , Ravandi Farhad , Jang Jun Ho , Selleslag Dominik , Mayer Jiri , Martens Uwe Marc , Liesveld Jane , del Castillo Teresa Bernal , Wang Ming-Chung , La Torre Ignazia , Skikne Barry , Kumar Keshava , Dong Qian , Braverman Julia , Abi Nehme Salem , Beach C. L. , Wei Andrew 
Published: May 2020

7533 Background: Effective AML maintenance treatment (Tx) should decrease the risk of relapse and prolong survival without compromising HRQoL. In the placebo (PBO)-controlled phase III QUAZAR AML-001 trial (NCT01757535), CC-486, an oral hypomethylating agent, provided significant improvements in overall (OS) and relapse-free survival (RFS) in patients (pts) with AML in first remission following IC. Here we present pt-reported HRQoL outcomes from that study. Methods: Eligible pts were ≥ 55 yrs of age with intermediate- or poor-risk cytogenetics and ECOG PS ≤ 3, and in CR/CRi after IC ± consolidation. Pts were randomized 1:1 to CC-486 300 mg or PBO QD on days (d) 1–14 of 28d Tx cycles. HRQoL was assessed by FACIT-Fatigue scale and EQ-5D-3L health utility index, completed on d1 of each cycle and at end of Tx (EOT). Endpoints include Tx differences in mean changes from baseline (BL), and proportions of pts with clinically meaningful change from BL (improvement, no change, deterioration). Evaluable pts had an HRQoL assessment at BL and ≥ 1 post-BL visit. Stratified ANCOVA models included Tx and BL scores as covariates. Results: In all, 225/238 pts (95%) in the CC-486 arm were evaluable for FACIT-Fatigue and EQ-5D-3L, and 219/234 pts (94%) in the PBO arm were evaluable for FACIT-Fatigue and 217 (93%) for EQ-5D-3L. Pt characteristics were comparable between Tx arms. Most pts (61%) were 65-74 yrs of age. Median number of CC-486 Tx cycles was 12 and PBO cycles was 7. Compliance rates were > 95% at BL and remained high ( > 85%) at all post-BL visits except for EOT. At BL, pts in both Tx arms had comparable low levels of fatigue and generally good HRQoL relative to an age-matched general population. There were no meaningful differences between CC-486 and PBO in mean changes from BL in FACIT-Fatigue or EQ-5D-3L scores at any post-BL visit. There was no statistically significant difference between Tx arms in proportion of pts with a clinically meaningful deterioration in FACIT-Fatigue score at any post-BL visit except at cycle 29 (likely due to chance; no adjustment made for multiple testing), or in EQ-5D-3L at any visit. Median time to deterioration was not significantly different between CC-486 and PBO on the FACIT-Fatigue scale (41 vs 44 weeks, respectively; P = 0.70) or the EQ-5D-3L (200 vs 164 weeks; P = 0.63). Conclusions: HRQoL and low levels of fatigue were preserved with CC-486 maintenance Tx. CC-486 significantly improved OS and RFS while maintaining HRQoL comparable to PBO. Clinical trial information: NCT01757535 .
Relation between measurable residual disease and morphologic relapse in AML.
Authors: Shih Lauren , Othus Megan , Gardner Kelda , Shaw Carole , Halpern Anna B. , Becker Pamela Sue , Walter Roland B. , Estey Elihu , Percival Mary-Elizabeth M. 
Published: May 2020

7535 Background: Measurable residual disease (MRD) in AML portends a poor prognosis. The outcomes and treatments of MRD after an initial MRD negative complete remission (MRD- CR) are unclear. Methods: We retrospectively identified 432 patients ≥ 18 years of age treated for AML or high grade myeloid neoplasm (10-19% blasts in blood and/or marrow) at University of Washington/Seattle Cancer Care Alliance from 2008-2017 who achieved MRD- CR after initial treatment. Next disease recurrence was recorded, with patients either developing MRD ( < 5% blasts via multiparameter flow cytometry; n = 44) or developing morphologic relapse (≥5% blasts; n = 100). The remaining patients remained in MRD- CR (n = 288, median follow up time 3.7 years). A landmark analysis at one year was performed to compare overall survival (OS). Results: Patients who developed MRD tended to be older (p = 0.009), but baseline characteristics were otherwise similar. Therapies for MRD included allogeneic transplant, low intensity chemotherapy, and high intensity chemotherapy; no significant associations were found between type MRD directed therapy and survival. Landmark OS at 1 year after MRD- CR was significantly different for patients without relapse at 1 year compared to those with MRD or morphologic relapse (median OS was 8.5 years for no relapse, 2.2 years for MRD, and 1.0 years for morphologic relapse). A multivariable Cox regression model among patients alive at 1 year showed patients without relapse had significantly improved OS compared to those with morphologic relapse [HR 0.18 (95% CI 0.1-0.31)]. Although there was a trend towards improved OS, we did not identify a significant difference between patients with MRD relapse compared to morphologic relapse [HR 0.54 (95% CI 0.27-1.11)]. There were no significant differences in patient characteristics for patients with MRD vs morphologic relapse matched by time of relapse (days 30-90, 90-150, 150-210). Conclusions: Following MRD- CR, development of either MRD or morphologic relapse were both associated with decreased OS. Notably, no significant differences in terms of survival were seen between patients who presented with MRD as opposed to morphologic relapse. No clear predictors were identified for MRD vs morphologic relapse. In this cohort, development of MRD carried a poor OS prognosis, similar to the prognosis of developing morphologic relapse. Future clinical trials should focus on MRD directed therapies, as no consensus exists about optimal treatment of MRD.