bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II study of the IDH2-inhibitor enasidenib in patients with high-risk IDH2-mutated myelodysplastic syndromes (MDS).
Authors: Venugopal Sangeetha , Dinardo Courtney Denton , Takahashi Koichi , Konopleva Marina , Loghavi Sanam , Borthakur Gautam , Dezern Amy Elizabeth , Masarova Lucia , Daver Naval Guastad , Short Nicholas James , Alvarado Yesid , Ravandi Farhad , Montalban-Bravo Guillermo , Sasaki Koji , Delumpa Ricardo , Sekeres Mikkael A. , Patel Bhumika J , Roboz Gail J. , Kantarjian Hagop M. , Garcia-Manero Guillermo 
Published: June 2021

7010 Background: Isocitrate dehydrogenase 2 ( IDH2) mutations occur in 5% of patients (pts) with MDS. Enasidenib (ENA) is a selective oral inhibitor of the mutant IDH2 enzyme with single-agent activity in relapsed/refractory acute myeloid leukemia (AML). We report the results of the open label phase II study designed to evaluate the efficacy and tolerability of ENA, as monotherapy or in combination with azacitidine (AZA) in pts with higher-risk IDH2-mutated MDS (NCT03383575). Methods: Pts with higher-risk [Revised International Prognostic Scoring System risk > 3 or high molecular risk (HMR)] MDS/CMML or LB AML naïve to hypomethylating agents (HMA) received ENA100 mg orally daily for 28 d of each 28-d cycle + AZA 75 mg/m2 IV or SC on d 1-7 of each cycle (ENA+AZA), and pts with refractory or progressive MDS to prior HMA therapy received ENA alone (ENA), in 28-d cycles until unacceptable toxicity, relapse, transformation to AML, or progression. The primary endpoint was overall response rate (ORR) [complete remission (CR), marrow CR (mCR), partial remission (PR) and hematologic improvement (HI)]. Other endpoints include safety, and survival outcomes. Results: 48 pts received ENA+AZA (n = 26) or ENA (n = 22). The median age was 73 yrs (range, 46-83). Most pts (72%) had HMR: ASXL1 (39%), and RUNX1 (17%). Median number Tx cycles was 4 (2–32) in the ENA+AZA, and 7 (1–23) in the ENA arm. Common Tx-related grade 3–4 AEs in the ENA+AZA arm were neutropenia (64%), thrombocytopenia (28%), and anemia (8%); these occurred in 10%, 0%, and 5%, in the ENA arm. Grade 3–4 infections occurred in 32% (ENA+AZA) and 14% (ENA). IDH differentiation syndrome occurred in 3 pts (12%) in the ENA+AZA and 5 pts (24%) in the ENA arm. Two deaths occurred during the initial 60 d, both unrelated to study and due to COVID. In response-evaluable pts (n=46), ORR was 84% (n = 21/25; 24% CR + 8% PR+44% mCR+ 8% HI] in the treatment naïve ENA+AZA and 43% (n = 9/21; 24% CR+5%PR+5% mCR+10% HI) in the HMA failure ENA arm (Table). Most common reason for Tx discontinuation was disease progression (ENA+AZA 20%, ENA 33%).5 pts (20%) received HCT in the ENA+AZA and 1 (5%) in the ENA arm. 7 pts in the ENA+AZA and 5 in the ENA arm were ongoing at data cutoff (Dec 31, 2020). After a median follow up of 12.6 mo, median OS was 32.2 mo in the ENA+AZA and 21.3 mo in the ENA arm. Conclusions: ENA is well tolerated and shows promising efficacy in IDH2-mutated higher risk MDS. Follow up and accrual is ongoing to better define duration and biomarkers of response. Clinical trial information: NCT03383575. [Table: see text]
Contemporary outcomes for adults with AML requiring ICU admission.
Authors: Hammond Danielle , Sasaki Koji , Geppner Alexis , Haddad Fadi , Mohamed Shehab , Rivera Daniel , Siddiqui Maria , Alwash Yasmin , Ramos Perez Jorge , Morita Kiyomi , Kim Kunhwa , Pierce Sherry , Gutierrez Cristina , Pemmaraju Naveen , Borthakur Gautam , Dinardo Courtney Denton , Ravandi Farhad , Garcia-Manero Guillermo , Kantarjian Hagop M. , Kadia Tapan M. 
Published: June 2021

7025 Background: Patients (pts) with AML frequently encounter life-threatening complications requiring transfer to an intensive care unit (ICU). Methods: Retrospective analysis of 145 adults with AML requiring ICU admission at our tertiary cancer center 2018-19. Use of life-sustaining therapies (LSTs) and overall survival (OS) were reported using descriptive statistics. Logistic regression was used to identify risk factors for in-hospital death. Results: Median age was 64 yrs (range 18-86). 47% of pts had an ECOG status of ≥ 2 with a median of at least 1 comorbidity (Table). 117 pts (81%) had active leukemia at admission. 68 pts (47%) had poor-risk cytogenetics (CG) and 32 (22%) had TP53-mutated disease. 61 (42%), 27 (19%) and 57 pts (39%) were receiving 1st, 2nd and ≥ 3rd line therapy. 33 (23%) and 70 pts (48%) were receiving intensive and lower-intensity chemotherapy, respectively, and 77 pts (53%) were concurrently on venetoclax. Most common indications for admission were sepsis (32%), respiratory failure (24%) and leukocytosis (12%); Table outlines additional ICU admission details. Median OS from the date of ICU admission was 2.0 months (mo) for the entire cohort and 6.9, 1.6 and 1.2 mo in pts with favorable-, intermediate- and poor-risk CG. Median OS of pts receiving frontline vs. ≥ 2nd line therapy was 4.2 vs. 1.4 mo (P<0.001). Median OS in pts requiring 0-1 vs. 2-3 LSTs was 4.1 vs. 0.4 mo (P<0.001). OS was not different by age, co-morbidity burden nor therapy intensity. In a multivariate analysis that included SOFA scores, only adverse CG (OR 0.35, P = 0.028), and need for intubation with mechanical ventilation (IMV; OR 0.19, P = 0.009) were associated with increased odds of in-hospital mortality. Conclusions: A substantial portion of pts with AML survive their ICU admission with sufficient functionality to return home and receive subsequent therapy. In contrast to general medical populations, age, co-morbidities, and SOFA scores were not independently predictive of in-hospital mortality. Disease CG risk and the need for IMV were the strongest predictors of ICU survival. This suggests that many pts with AML can benefit from ICU care.[Table: see text]
Subcutaneous epcoritamab in patients with relapsed/refractory B-cell non-Hodgkin lymphoma: Safety profile and antitumor activity.
Authors: Clausen Michael Roost , Lugtenburg Pieternella , Hutchings Martin , Johnson Peter W. M. , Linton Kim M. , Lewis David John , Chamuleau Martine , Sureda Balari Anna , Cunningham David , Elliott Brian , DeMarco Dena , Chen Kuo-mei , Mous Rogier 
Published: June 2021

7518 Background: Epcoritamab is a CD20xCD3 bispecific antibody that induces T-cellmediated killing of CD20–positive malignant B-cells. We present updated data, including progression-free survival (PFS) from the dose escalation part of the first-in-human phase 1/2 study of epcoritamab in pts with relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL; NCT03625037). Methods: Adults with R/R CD20+ B-NHL received flat-dose 1 mL SC epcoritamab (step-up dosing approach) in 28-day cycles (q1w: cycles 1–2; q2w: cycles 3–6; q4w thereafter) until disease progression or unacceptable toxicity. Step-up dosing and standard prophylaxis were used to mitigate severity of cytokine release syndrome (CRS). Results: At data cut off (1/31/2021), 68 pts with B-NHL were enrolled across histologies including diffuse large B-cell lymphoma (DLBCL; n = 46 [67.6%]; de novo and transformed), follicular lymphoma (FL; 12 [17.6%]), mantle cell lymphoma (MCL; 4 [5.9%]), and others (6 [8.8%]). Majority were heavily pretreated (median [range] prior lines: DLBCL, 3 [1–6]; FL, 4.5 [1–18]); including prior CAR-T (n = 6) and prior ASCT (n = 10). At median follow-up of 14.1 mo (DLBCL, 10.2 mo; FL, 15.2 mo), treatment was ongoing in 15 (22%) pts. Most common treatment-emergent adverse events (AEs) were pyrexia (69%), CRS (59%), and injection site reaction (47%). CRS events were all grade 1 or 2 and most occurred in cycle 1; neurotoxicity was limited (6%; grade 1: 3%; grade 3: 3%; all transient). One case of tumor lysis syndrome was observed (1.5%; grade 3); there were no cases of febrile neutropenia or treatment-related death. Overall response is shown for DLBCL ≥12 mg and ≥48 mg and FL ≥12 mg, corresponding to the minimal efficacy threshold (Table). Responses deepened over time (PR converted to CR: DLBCL, 6 pts; FL, 3 pts). Median time to response was 1.4 mo (DLBCL) and 1.9 mo (FL). Among DLBCL pts achieving CR with ≥6 mg (n = 11), none relapsed while on treatment. The median PFS for pts with DLBCL ≥12 mg (n = 22) was 9.1 mo (95% CI: 1.6, NE; median follow-up 9.3 mo) and for pts with DLBCL ≥48 mg (n = 11) median PFS was not reached (median follow-up 8.8 mo). Updated analyses will be presented. Conclusions: With longer follow-up, SC epcoritamab demonstrated substantial single-agent activity, inducing deep and durable clinically meaningful responses, with a consistent safety profile. Notably no severe (grade ≥3) CRS events, no febrile neutropenia, and limited neurotoxicity was observed. Clinical trial information: NCT03625037. [Table: see text]
CNS relapse in DLBCL patients below 60 years treated with R-ACVBP, R-CHOEP, or R-CHOP: A joint analysis of LYSA and GLA/DSHNHL.
Authors: Thieblemont Catherine , Altmann Bettina , Casasnovas Olivier , Frontzek Fabian , Morschhauser Franck , Oberic Lucie , Poeschel Viola , Fitoussi Olivier , Renaud Loïc , Lenz Georg , Mounier Nicolas , Rosenwald Andreas , Ott German , Molina Thierry , Parrens Marie , Chartier Loic , Ziepert Marita , Tilly Herve , Schmitz Norbert 
Published: June 2021

7543 Background: Central nervous system (CNS) relapse occurs in 2-6% of DLBCL patients (pts) increasing to 10% or more in high-risk groups. Intrathecal (IT) or intravenous high-dose methotrexate (HD MTX) have limited if any prophylactic impact on CNS relapse. To address the role of systemic first-line therapy in pts tolerating intensified strategies (R-ACVBP, R-(Mega)CHOEP, R-CHO(E)P), we compared CNS relapses occurring in a large cohort of pts ≤60 years. Methods: We conducted a retrospective analysis including previously untreated pts with DLBCL by central review, age 18-60 years, from multicenter clinical trials conducted by LYSA and GLA/DSHNHL (Table). We assessed the risk of CNS relapse in matched cohorts based on the aaIPI. Results: A total of 2203 pts were included. Median age was 47 years (18-60). 455 pts were treated with R-ACVBP, 444 with R-(Mega)CHOEP, 1304 with R-CHOP. Distribution of CNS IPI was not significantly different comparing R-ACVBP to R-CHO(E)P groups within aaIPI categories (Table). PFS and OS were comparable according to treatment within aaIPI groups, also adjusted for prognostic factors. No CNS events occured during observation time of 3 years in pts with aaIPI 0. In pts with aaIPI 1, no CNS event occured in the R-ACVPB arm, the 3y-cumulative incidence of CNS relapse for pts treated with R-CHO(E)P group was 1.0% (95%CI 0.3-1.7). In pts with aaIPI 2,3 and intermediate/high CNS IPI, four (1.6%) treated with R-ACVBP experienced relapse in the CNS compared to 15 (3.9%) pts treated with R-(Mega)CHO(E)P (3y-cumulative incidence 1.6% (95%CI 0-3.2) vs. 4.0% (95%CI 2.0-6.0). Conclusions: CNS relapse was extremely rare in younger DLBCL pts with aaIPI 0 or 1; prophylactic measures are not warranted. In pts with aaIPI 2,3 (and intermediate/high CNS-IPI), only 4 (1.6%) CNS relapses were seen with the R-ACVBP while 15 (3.9%) relapses did occur after R-(Mega)CHO(E)P. This analysis underlines the important role of the systemic therapy in controling CNS relapse.[Table: see text]
MASS-FIX versus standard methods to predict for PFS and OS among multiple myeloma patients participating on the STAMINA trial.
Authors: Dispenzieri Angela , Krishnan Amrita Y. , Arendt Bonnie , Dasari Surendra , Efebera Yvonne Adeduni , Geller Nancy , Giralt Sergio , Hahn Theresa , Kohlhagen Mindy C. , Landau Heather Jolie , Hari Parameswaran , Pasquini Marcelo C. , Qazilbash Muzaffar H. , McCarthy Philip L. , Shah Nina , Vesole David H. , Vogl Dan T. , Wallace Paul K. , Stadtmauer Edward A. , Murray David L. 
Published: June 2021

8009 Background: Measuring response among patients with multiple myeloma is essential for the care of patients. Deeper responses have been associated with better progression free survival (PFS) and overall survival (OS). Serum (SIFE) and urine immunofixation are the currently used markers for biochemical documentation of CR after which marrow is tested for plasma cell clearance. Next generation flow cytometry and sequencing are used to document the presence of minimal residual disease (MRD). Mass spectrometry of blood by MALDI (Mass-Fix) is a new simple, inexpensive, sensitive, and specific means of detecting monoclonal immunoglobulins. To better test the hypothesis that Mass-Fix is superior to existing methodologies to predict for survival outcomes—especially SIFE-- samples from the STAMINA trial (NCT01109004), a trial comparing 3 transplant approaches among patients who have already received induction, were employed. Methods: Five-hundred and seventy-five patients were included. Samples from enrollment post-induction (post-I) and 1-year post enrollment (1YR) were tested when available. Four response parameters were assessed univariately: Mass-Fix, SIFE, complete response, and MRD by next generation flow cytometry. Mass spectrometry spectra were evaluated in a blinded fashion. Complete response was according to the 2006 International Myeloma Working Group criteria. Multivariate Cox proportional hazard models using stepwise regression were developed to explore the independent effect of the different response parameters on PFS and OS and interactions with other risk factors. Results: Of the 4 response measures, only MRD and Mass-Fix predicted for PFS and OS at multiple testing points on multivariate analyses (Table). Of the 4 post-I measurements, only MRD predicted for PFS; however, Mass-Fix was the only post-I measurement to predict for OS. Of all the 1-year measures, both 1YR Mass-Fix and 1YR MRD positivity predicted for inferior PFS and OS. In models including MRD and Mass-Fix, SIFE and CR were not prognostic for PFS or OS. Conclusions: Mass-Fix is a powerful means to track monoclonal proteins. The full utility of Mass-Fix was not exploited given the absence of a diagnostic sample and the fact that only serum (and not urine) was tested. Despite these limitations, it performed well at pre-induction and at 1 year. Mass-Fix provides a convenient and non-invasive means of predicting for myeloma outcomes. Clinical trial information: NCT01109004. [Table: see text]
Updates from ICARIA-MM, a phase 3 study of isatuximab (Isa) plus pomalidomide and low-dose dexamethasone (Pd) versus Pd in relapsed and refractory multiple myeloma (RRMM).
Authors: Richardson Paul G. , Perrot Aurore , F. San-Miguel Jesús , Beksac Meral , Spicka Ivan , Leleu Xavier , Schjesvold Fredrik , Moreau Philippe , Dimopoulos Meletios A. , Huang Jeffrey SY. , Minarik Jiri , Cavo Michele , Prince H. Miles , Zheng Cheng , Dubin Franck , Van De Velde Helgi , Anderson Kenneth Carl 
Published: June 2021

8017 Background: Isa is an approved monoclonal antibody that binds to a specific epitope on the CD38 receptor. The Phase 3 ICARIA-MM study (NCT02990338) demonstrated significantly improved progression-free survival (PFS) with Isa-Pd vs Pd ( P= 0.001) and a manageable safety profile (Attal M, et al. Lancet 2019;394:2096-2107). Here we report updated ICARIA results. Methods: Pts with RRMM (N = 307) who have received ≥2 prior therapies, including lenalidomide (Len) and a proteasome inhibitor (PI), were randomized to Isa-Pd (n = 154) or Pd (n = 153). Isa was administered intravenously at 10 mg/kg weekly for 4 weeks, and every other week thereafter. This preplanned second interim analysis assessed longer term outcomes, including time to next treatment (TTNT), overall survival (OS), time from randomization to disease progression on first subsequent therapy or death (PFS2), and safety. Results: Pts had a median of 3 prior lines of therapy (IQR 2–4; table). As of Oct 1, 2020 (median follow-up, 35.3 months [mo]), 27 Isa-Pd pts (18%) vs 12 Pd pts (8%) were still on treatment; 60% vs 72% had proceeded to subsequent therapy. Median TTNT was 15.5 mo with Isa-Pd vs 8.9 mo with Pd (hazard ratio [HR] 0.56; 95% confidence interval [CI] 0.42–0.74; P< 0.0001); 24% vs 58% of pts with subsequent therapy received daratumumab (dara). Overall response rate (ORR) in subsequent treatment with dara monotherapy was higher after Pd (38%) than Isa-Pd (14%), but was similar (32% vs 31%) with dara combination therapy (table). Median PFS2 in the intent-to-treat population was 17.5 mo with Isa-Pd vs 12.9 mo with Pd (HR 0.76; 95% CI 0.58–0.99; P= 0.0202). Median OS was 24.6 mo with Isa-Pd vs 17.7 mo with Pd (HR 0.76; 95% CI 0.58–1.01; one-sided P= 0.0280). Median treatment duration was 47.6 weeks (range 1.3–171.6) with Isa-Pd vs 24.0 weeks (range 1.0–168.6) with Pd. Serious treatment-emergent adverse event (TEAEs) were seen in 73% of Isa-Pd pts vs 60% of Pd pts. Most frequent non-hematologic TEAEs (any grade) with Isa-Pd were infusion reaction (38%), upper respiratory tract infection (34%), and diarrhea (30%). Grade 3–4 neutropenia (85% vs 71%) and thrombocytopenia (34% vs 25%) were more frequent with Isa-Pd than with Pd. Conclusions: Isa-Pd demonstrates a significant improvement in TTNT and PFS2 compared with Pd. A strong trend in OS benefit was also seen in the Isa-Pd arm, with approximately 7 mo improvement in median OS. The overall safety profile remains unchanged from prior analyses. Funding: Sanofi. Clinical trial information: NCT02990338. [Table: see text]
Updated overall survival (OS) and exploratory analysis from the randomized, phase II EVAN study of erlotinib (E) versus vinorelbine plus cisplatin (NP) as adjuvant therapy in Chinese patients with stage IIIA EGFR+ NSCLC.
Authors: Yue Dongsheng , Xu Shi-Dong , Wang Qun , Li Xiaofei , Shen Yi , Zhao Heng , Chen Chun , Mao Weimin , Liu Wei , Liu Junfeng , Zhang Lan-Jun , Ma Haitao , Li Qiang , Yang Yue , Liu Yongyu , Chen Haiquan , Zhang Zhenfa , Zhang Bin , Gong Fuyu , Wang Changli 
Published: June 2021

8520 Background: The EVAN study of E vs NP in stage III EGFR+ NSCLC has met its primary endpoint and been previously published: 2-year disease-free survival was 81.4% (95% CI, 69.6–93.1) in E group vs 44.6% (95% CI, 26.9-62.4) in NP group (HR, 1.823; 95% CI, 1.194–2.784; P=0.0054). We report 5-year OS and exploratory results from EVAN with a further 43 month follow up (cutoff date: Jan 6, 2021). Methods: Patients with stage IIIA EGFR+ NSCLC were randomized assigned (1:1) into either E arm (n=51, 150mg/day) or NP arm (n=51, vinorelbine 25mg/m2 on day 1, 8 and cisplatin 75mg/m2 on day 1 of a 21-day cycle). In order to explore the relationship between patient benefits and co-occurring variants, 47 patients received whole exome sequencing (WES) analysis (E, n=24; NP, n=23). Results: Median follow-up time was 54.8 months for E and 63.9 months for NP. E improved OS and 5-year survival rate compared with NP in ITT population. The median OS was 84.2m (95% CI, 78.1,-) with E vs 61.1m (95% CI, 39.6-82.1) with NP (HR, 0.318; 95% CI, 0.151-0.670). The 5-year survival rates were 84.8% (95%CI, 72.0-97.6) and 51.1% (95% CI, 34.7-67.5), respectively. In the WES analysis, we found that the most frequent genes with co-occurring variants at baseline were TP53, MUC16, FAM104B, KMT5A and DNAH9, and additional EGFR variants, each with similar prevalence regardless of EGFR-activating mutation subgroup. Moreover, in the erlotinib-treated patients, the SNP mutation of UBXN11 was associated with significantly worse DFS (P=0.0111). Conclusions: This is the first randomized study of EGFR-TKI to demonstrate a clinically meaningful improvement in OS vs chemotherapy in stage III EGFR+ NSCLC (5-year survival rate 84.8% in E vs 51.1% in NP). The co-occurring variants at baseline may be associated with reduced DFS. Further studies are required to confirm our results (EVAN, NCT01683175). Clinical trial information: NCT01683175.
Deep learning to predict subtypes of poorly differentiated lung cancer from biopsy whole slide images.
Authors: Toyokawa Gouji , Kanavati Fahdi , Momosaki Seiya , Tateishi Kengo , Takeoka Hiroaki , Okamoto Masaki , Yamazaki Koji , Takeo Sadanori , Iizuka Osamu , Tsuneki Masayuki 
Published: June 2021

8536 Background: Lung cancer is the leading cause of cancer-related death in many countries, and its prognosis remains unsatisfactory. Since treatment approaches differ substantially based on the subtype, such as adenocarcinoma (ADC), squamous cell carcinoma (SCC) and small cell lung cancer (SCLC), an accurate histopathological diagnosis is of great importance. However, if the specimen is solely composed of poorly differentiated cancer cells, distinguishing between histological subtypes can be difficult. The present study developed a deep learning model to classify lung cancer subtypes from whole slide images (WSIs) of transbronchial lung biopsy (TBLB) specimens, in particular with the aim of using this model to evaluate a challenging test set of indeterminate cases. Methods: Our deep learning model consisted of two separately trained components: a convolutional neural network tile classifier and a recurrent neural network tile aggregator for the WSI diagnosis. We used a training set consisting of 638 WSIs of TBLB specimens to train a deep learning model to classify lung cancer subtypes (ADC, SCC and SCLC) and non-neoplastic lesions. The training set consisted of 593 WSIs for which the diagnosis had been determined by pathologists based on the visual inspection of Hematoxylin-Eosin (HE) slides and of 45 WSIs of indeterminate cases (64 ADCs and 19 SCCs). We then evaluated the models using five independent test sets. For each test set, we computed the receiver operator curve (ROC) area under the curve (AUC). Results: We applied the model to an indeterminate test set of WSIs obtained from TBLB specimens that pathologists had not been able to conclusively diagnose by examining the HE-stained specimens alone. Overall, the model achieved ROC AUCs of 0.993 (confidence interval [CI] 0.971-1.0) and 0.996 (0.981-1.0) for ADC and SCC, respectively. We further evaluated the model using five independent test sets consisting of both TBLB and surgically resected lung specimens (combined total of 2490 WSIs) and obtained highly promising results with ROC AUCs ranging from 0.94 to 0.99. Conclusions: In this study, we demonstrated that a deep learning model could be trained to predict lung cancer subtypes in indeterminate TBLB specimens. The extremely promising results obtained show that if deployed in clinical practice, a deep learning model that is capable of aiding pathologists in diagnosing indeterminate cases would be extremely beneficial as it would allow a diagnosis to be obtained sooner and reduce costs that would result from further investigations.