bluuebunny/crossref_metadata_2025_split huggingface dataset:
Treatment outcomes for newly diagnosed, untreated TP53-mutated acute myeloid leukemia: A systematic review and meta-analysis.
Authors: Daver Naval Guastad , Iqbal Shahed , Renard Camille , Chan Rebecca J. , Hasegawa Ken , Hu Hao , Tse Preston , Yan Jiajun , Zoratti Michael J. , Xie Feng , Ramsingh Giridharan 
Published: June 2022

e19020 Background: TP53 mutations are present in 10%–15% of patients with acute myeloid leukemia (AML) and are associated with resistance to therapy and poor outcomes. Currently available frontline therapies for TP53-mutated ( TP53m) AML include intensive chemotherapy (IC), hypomethylating agents (HMA), and venetoclax combined with HMA (VEN+HMA). This systematic review and meta-analysis evaluated outcomes associated with IC, HMA, and VEN+HMA in newly diagnosed, untreated TP53m AML. Methods: EMBASE and MEDLINE were searched May 20, 2021 to identify studies of interest. Single-arm data on complete remission (CR), CR with incomplete hematologic recovery (CRi), median overall survival (mOS), event-free survival (EFS), and duration of response (DoR) were extracted and pooled for each treatment. Response rates were pooled using random-effects models; the median of medians method was used for time-related outcomes. Results: Of 3006 abstracts identified, 17 publications describing 12 studies met the inclusion criteria: 6 were randomized clinical trials (RCTs), 2 were single-arm trials, and 4 were retrospective studies. Outcomes are displayed in the Table. CR rate was highest with IC at 43% (95% CI, 30%, 56%), followed by VEN+HMA, 33% (22%, 47%), and HMA alone 21% (7%, 49%). Rates of CR/CRi were 49% (37%, 60%) for VEN+HMA, 46% (39%, 53%) for IC, and 13% (2%, 48%) for HMA alone. mOS was similarly low across the 3 treatments: IC, 6.5 months (N=155; 5.1, 8.5); VEN+HMA, 6.2 (N=73; 5.2, 7.2); HMA, 6.1 (N=34; 4.9, 7.2). Conclusions: CR, CR/CRi, and mOS were low across all treatments for patients with newly diagnosed, untreated TP53m AML. Addition of venetoclax to HMA showed a trend toward improved response vs HMA alone but not for mOS. There is a significant unmet need for more effective treatment for this very difficult-to-treat population. [Table: see text]
Tisagenlecleucel for secondary CNS lymphoma, a case series.
Authors: Mann Shivtaj , Dhaliwal Armaan , Husnain Muhammad , Kumar Abhijeet , Persky Daniel O. 
Published: June 2022

e19507 Background: Secondary CNS lymphoma (SCNSL) in setting of relapsed, refractory (R/R) B cell lymphoma has unmet needs as this disease state has a poor prognosis with a reported median survival of 2 to 5 months. Historically, the mainstay of treatment for SCNSL in setting of R/R B cell lymphoma included high dose methotrexate, whole brain radiation (WBRT), and/or chemotherapy followed by autologous stem cell transplant. More recently, chimeric antigen receptor (CAR)-T cell therapy has gained attention as a new modality of therapy for patients with R/R SCNSL. The first two CAR-T cell products to gain FDA approval for R/R B cell lymphoma were Axicabtagene ciloleucel and Tisagenlecleucel. In the initial studies for these products, patients with SCNSL were excluded due to concerns for immune effector cell-associated neurotoxicity syndrome (ICANS) and cytokine release syndrome (CRS). Retrospective data has shown that patients with R/R SCNSL treated with Axicabtagene ciloleucel or Tisagenlecleucel could achieve high response rates; however, the data on the durability of response remains unclear. Recently, Lisocabtagene maraleucel, another CAR-T cell product, was approved for the treatment of R/R B cell lymphoma. The TRANSCEND trial which led to Lisocabtagene maraleucels approval did not exclude patients with SCNSL; however, only 3% of the patients had SCNSL. As such, literature on the durability of response of CAR-T cell therapy in R/R SCNSL still remains sparse. Here, we share our single institution experience of patients with R/R SCNSL treated with Tisagenlecleucel, an anti- CD19CAR-T cell therapy. Methods: For this observational study, patients with R/R SCNSL were identified and placed on a follow up list. Data was collected from May 2021 till December 2021. Data was analyzed for incidence of ICANS, CRS, and for duration of response. Results: A total of 3 patients with SCNSL were identified and treated at our center with Tisagelecleucel. One patient achieved complete response 30 days post CAR-T therapy but the day +100 imaging revealed progression of disease and was placed on subsequent line of therapy. One patient had partial response with progression of disease noted on day +60 imaging and died from complications of disease progression. One patient died from complications of CNS toxicity after receiving CAR-T therapy. Two patients had ICANS grade 4 and CRS grade 1 toxicities. One patient had no CNS or CRS toxicity. Conclusions: Our series is limited by the number of patients; however, suggests that though CAR-T therapy may result in disease response in R/R SCNSL the duration of response may be limited and that such patients may require other therapies such as autologous stem cell transplant to improve long term prognosis.
CAR T-cells effective for post-CART relapse: A new treatment paradigm.
Authors: Holland Elizabeth M. , Yates Bonnie , Silbert Sara K. , Foley Toni , Little Lauren , Fry Terry J. , Highfill Steven , Stroncek David , Shalabi Haneen , Shah Nirali N. 
Published: June 2022

e19508 Background: Chimeric antigen receptor T-cells (CART) induce remarkable responses in B-cell acute lymphoblastic leukemia (B-ALL), but relapse remains a challenge. Effective therapies for post-CART relapse are limited but may include infusion of a unique CART construct, a strategy distinct from reinfusion of the same CART product. Given limited data evaluating outcomes of a unique CART as salvage therapy for post-CART relapse, we report on the impact of prior CART constructs on subsequent CART responses. Methods: This was a retrospective review (NCT03827343) of children and young adults receiving CD19 and/or CD22 CART therapy for B-ALL between 7/1/12-12/30/21 at our center. Patients included received at least 2 unique CART constructs at some point in therapy, excluding interim CART reinfusions. CART-A was the first CART construct ever received and CART-B the second unique CART. The primary objective was to evaluate complete remission (CR) rates following CART-A versus CART-B. Results: Of 135 heavily pretreated patients, 54 (40%) received at least one prior CART. The majority (n=37, 68.5%) were male. Median age at CART-A and CART-B was 12.5 (range, 3.3-30.4) and 13.7 years (range, 4.5-30.7), respectively. In 42 (77.8%) patients, CART-B targeted a different antigen than CART-A, primarily due to loss of antigen target after CART-A. CR rate was substantially lower with CART-B (n=35, 64.8%) than with CART-A (n=48, 88.9%, p=0.006) (Table). Still, two (3.7%) patients with CART-A nonresponse attained CR with CART-B. Most CART-B responders (n=31, 88.6%) had CART-B targeting a different antigen than CART-A, suggesting limitations of same antigen targeting even with a unique CART construct. CART-B responses amongst 10 patients with interim hematopoietic stem cell transplantation (HSCT) after CART-A were similar to CART-B responses in those without interim HSCT (5 of 10, 50% vs. 30 of 44, 68.2%, p=0.3). In those where CRS grade was known for both CART infusions (n=40), CRS severity was milder with CART-B (≥grade 3, n=1, 2.5%) than with CART-A (≥grade 3, n=15, 37.5%, p=0.0001). Conclusions: Using an alternative CART for post-CART relapse is effective in a substantial proportion of patients, particularly when targeting a unique antigen. As post-CART relapse occurs more frequently and patients receive multiple CARTs, identifying optimization strategies for CART-B will be critical. Further investigation of indication for CART-B, role of interim HSCT, and optimal timing for sequential CART infusions is underway.[Table: see text]
A phase 2 expanded access study of zanubrutinib (ZANU) in patients (pts) with Waldenström Macroglobulinemia (WM).
Authors: Castillo Jorge J. , Kingsley Ed , Narang Mohit , Yimer Habte Aragaw , Dasanu Constantin A , Melear Jason M. , Coleman Morton , Farber Charles Michael , Gupta Mukul , Shulman Jonah , Mantovani Emily H. , Zhang Xiaowei , Cohen Aileen , Huang Jane 
Published: June 2022

e19522 Background: Bruton tyrosine kinase (BTK) inhibition is an emerging standard of care for WM. The next-generation BTK inhibitor ZANU (BGB-3111), designed to maximize BTK occupancy and minimize off-target inhibition of other kinases, is approved by the United States (US) Food and Drug Administration, Health Canada, and the European Union at a dose of 320 mg once daily (QD) or 160 mg twice daily (BID) for adult pts with WM. BGB-3111-216 is a single-arm expanded access study of ZANU in treatment-naïve (TN) pts who were unsuitable for standard chemoimmunotherapy or pts with relapsed refractory (R/R) WM. This study provides real-world experience with ZANU in pts with WM. Methods: Eligible pts with TN or R/R WM received ZANU 320 mg QD or 160 mg BID orally. Primary endpoint was the number of pts enrolled/treated and enrolling sites. Secondary endpoints included treatment-emergent adverse events (TEAEs) of special interest, disease response rate, progression-free survival (PFS), and overall survival (OS). Response was evaluated by investigator assessment according to the 6th International Workshop on WM ( Br J Haematol. 2013;160(2):171-6) every 6 mo at minimum. The study was closed by the sponsor in July 2021 and active pts were transitioned to commercial ZANU via a patient assistance program. Results: Fifty pts with WM (17, TN; 33, R/R) were enrolled between December 2019 and June 2021 across 10 academic and community medical centers in the US. Median age was 72 years, 54% had intermediate-, 40% had high-risk disease, and the median number of prior therapies for R/R pts was 2. Median treatment exposure was 9.2 mo (range, 1.4-20.0). Thirty-eight (76%) pts had ≥1 TEAE, and 36 (72%) had ≥1 TEAE of special interest. Grade ≥3 TEAEs of special interest were hypertension (8%), infection (8%), atrial fibrillation/flutter (2%), neutropenia (2%), and second primary malignancy (2%). No new safety signals were observed. In pts with ≥1 response evaluation, 39% achieved a best overall response (BOR) of very good partial response. Overall response rate was 85.4% and major response rate was 73.2% (Table). Of the 4 pts with BOR of progressive disease, 3 had IgM values that met partial response criteria before the 6-mo response assessment. PFS and OS were immature due to short follow-up, and the median was not met. Conclusions: These real-world expanded access study results were consistent with the established ZANU profile in WM or other B-cell malignancies when administered as oral monotherapy at 160 mg BID or 320 mg QD in pts with intermediate or high-risk R/R or TN WM. Clinical trial information: NCT04052854. [Table: see text]
Newly identified molecular and genetic characteristics of primary mediastinal large B-cell lymphoma.
Authors: Kamaeva Inna A. , Novikova Inna A. , Lysenko Irina B. , Timoshkina Natalya N. , Nikolaeva Nadezhda V. , Kapuza Elena A. , Gaysultanova Yakha S. , Pushkareva Tatiana F. , Tishina Anna V. , Samaneva Natalia Yu. , Vladimirova Liubov Yu 
Published: June 2022

e19580 Background: Many studies have been devoted to the molecular profile of diffuse large B-cell lymphoma; however, a clear molecular and genetic picture of primary mediastinal large B-cell lymphoma (PMBLC) has not yet been described. Studies have reported various signaling pathways involved in PMBCL pathogenesis, with the best known JAK-STAT and NF-kB. This study was aimed at the detection of previously undescribed mutations, as well as the identification of signaling pathways that may be of interest in the search for new therapeutic targets for PMBCL. Methods: Tumor biopsy specimens from 23 PMBCL patients were examined by next-generation sequencing (NGS) on the Illumina NextSeq 550 system with an average coverage of at least 100x using the AVENIO Tumor Expanded Panel (Roche, USA) containing 77 genes. Analytical sensitivity of mutation detection was 5%. The pathogenicity of the identified nucleotide substitutions was assessed according to ACMG (American College of Medical Genetics and Genomics) and AMP (Association of Molecular Pathology) recommendations. Genomic DNAs were extracted from FFPE blocks using the Gene Read DNA FFPE Kit panel (Qiagen, USA) according to the standard protocol. DNA concentrations were measured fluorimetrically on the Qubit 2.0 fluorometer (Life Technologies, USA). The AVENIO Oncology Analysis Software was used to process the data and to search for clinically significant mutations. The genetic material was analyzed for clinically significant mutations among well-known databases: COSMIC: V83, TCGA 9.0, Exac: 1.0, DBSNP: 150, 1000 Genomes: phase_3_v5b, Snpeff: 4.2. Results: The targeted high-performance sequencing of PMBLC samples showed a newly revealed range of polymorphisms in 9 genes in patients with PMBLC (Alk, TP53, CCND3, RNF43, PIK3CA, FGFR3, SMO, MET, EZH2), previously not described for this cancer. We also interpreted signal pathways related to the mutated genes. Conclusions: The identified polymorphisms and the relationship of mutated genes with PMBLC signaling paths can serve as new therapeutic targets for patients with PMBLC.
Retrospective analysis of responses to second-line treatments of multiple myeloma after disease progression in patients who underwent ASCT.
Authors: Awada Hussein , Hajj Ali Adel , Ali Muhammad Faizan , Adroja Shubham , Mahalwar Gauranga , Kumar Ashish , Babar Arslan , Anwer Faiz 
Published: June 2022

e20004 Background: Most Multiple Myeloma (MM) patients who respond to initial treatment ultimately progress. Data regarding 2nd line treatment remains scarce, but in general treatment relies on whether the disease is refractory to Lenalidomide (R) or not. Here, we report responses to 2nd line treatments of MM patients in with disease progression (PD) following Autologous Stem Cell Transplant (ASCT). Methods: We retrospectively reviewed MM patients with PD after ASCT at Cleveland Clinic during the period of April 1, 2016 till December 31, 2021. Baseline demographic, clinical and cytogenetic features were obtained from electronic records. Patients who had PD after ASCT, as defined by IMWG criteria, were divided into two smaller subcohorts: R-refractory and R-sensitive. Outcomes were compared among treatment groups within each subcohort. Continuous variables are reported as means with standard deviations, while categorical variables are presented as percentages. Categorical variables were compared using the chi-squared test while the t test and ANOVA were used for continuous variables. Results: 127 patients who had PD following ASCT were identified (Table). Most common cytogenetic aberrancies were del(13) (RB) 34.6%, t(11;14) 18.9% and gain(1q) 15%. Pre-PD maintenance included R 58.3%, Bortezomib (V) 7.1%, RV combination 8.7% and other R-based regimens 9.4%, with no difference in time to disease progression (TTPD) between them (p = 0.82), and an average of 15.5 months TTPD among all patients. ISS III patients were likely to progress earlier than ISS II or I (10.91 vs 14.56 vs 20.33 months; p = 0.008), while high and standard-risk cytogenetics did not predict TTPD (12.62 vs 16.85 months; p = 0.092). Patient who achieved CR either pre or post-ASCT were less likely to progress compared to others with weaker responses (p = 0.032; p = 0.002). Patients who did not achieve CR post-ASCT progressed earlier than those with CR (12.37 vs 16.53 months; p = 0.041). In R-sensitive patients (n = 25), PD was not significantly different in patients on 2nd line Daratumumab (D), R and dexamethasone (d) vs RVd (45.5% vs 60%; p = 0.505). In R-refractory patients (n = 57), PD was also not significantly different in DVd, Dd with Pomalidomide, or Carfilzomib (C)-based regimens (81.3% vs 68.2% vs 60%; p = 0.426). Time to 2nd PD was significantly longer in DRd vs RVd (12.4 vs 3 months; p = 0.026) but similar in DVd vs DPd vs C-based regimens (6.75 vs 8 vs 5.89 months; p = 0.711). Conclusions: TTPD in MM post-ASCT is determined by the ISS stage and achieving CR but not by cytogenetic risk or maintenance choice. Current regimens used as 2nd line in R-refractory patients are statistically indifferent, but DRd delays further PD compared to RVd in R-sensitive patients.[Table: see text]
miR-6124: A potential new prognosis biomarker for lung squamous cell carcinoma through m5C regulating mechanism.
Authors: Wang Qian , Zou Yuqing , Xiao Shanshan , Wang Tao ,   Hangzhou Repugene Technology Co,.Ltd
Published: June 2022

e20568 Background: RNA methylation is an important epigenetic modification that can act as tumor prognosis biomarkers, and which is regulated by methyltransferase, RNA binding protein, and demethylase. 5-Methylcytosine (m5C) is a well-known post-transcriptional modification that plays an important role in cell differentiation and apoptosis. Although gene mutations in those regulator genes are associated with various cancers, the m5C regulating mechanism and its roles in cancer prognosis largely remains unknown. This study aimed to find new microRNA biomarkers associated with prognosis of clinical outcomes through m5C regulating mechanism in lung squamous cell carcinoma (LUSC). Methods: The RNA-seq expression data of LUSC were collected from the The Cancer Genome Atlas (TCGA). In total, we obtained 501 LUSC tumor samples and 49 normal samples from 502 LUSC patients. We firstly identified differential expressed genes of the 13 previously reported m5C regulators between the tumor tissues and adjacent normal tissues. Then miRNAs were identified using Pearson correlation analysis between the microRNA expression and the differential expressed m5C regulator genes. Pathway enrichment analysis of the miRNAs was performed using clusterProfiler to examine their cancer development roles. Furthermore, cox regression analysis was used to evaluate the risk factor for overall survival. Targeted relationship between miRNA and genes were confirmed by miRTarBase. Results: Differential analysis revealed 4 significantly up-regulated (NOP2, NSUN2, DNMT3B and ALYREF) genes in tumor among 13 interested m5C regulators. Pearson correlation analysis identified 39 correlated miRNAs. After cox regression, we found out one micro-RNA miR-6124, which is highly correlated with DNMT3B gene and is significantly associated with worse overall survival (OS, p < 0.01). We then identified the regulatory targets of miR-6124 using miRTarBase database. In total we identified 181 target genes. Among them, H3F3A which encode histone H3 synergistically work with DNMT3B gene as showed in the previous studies and promote DNA methylation of the oncogenes. Such preliminary results showed miR-6124 may be involved in cancer pathway regulating and was a potential prognosis biomarker candidate in LUSC. Conclusions: We identified a potential new prognosis biomarker in lung squamous cell carcinoma. The identified miR-6124 is involved in DNMT3B and m5C regulating mechanism. Further evidences are needed to study its’ role in clinical applications.
Pathological response to neoadjuvant chemoimmunotherapy in resectable non-small cell lung cancer (NSCLC): A systematic review and meta-analysis.
Authors: Syaj Sebawe , Akhdar Marah , Ababneh Obada Ehab , Hamouri Shadi 
Published: June 2022

e20582 Background: The advantage of combining chemotherapy and immune checkpoint inhibitors (ICIs) in resectable non-small cell lung cancer (NSCLC) patients has recently been studied in clinical trial settings. We aim to systematically revise the evidence of efficacy and safety of neoadjuvant chemoimmunotherapy treatment. Methods: We carried out a systematic search on MEDLINE, Scopus, Cochrane, and ASCO meetings library. Screening was done to include clinical trials of stage I-IIIA NSCLC patients who underwent any combination of ICIs and chemotherapy. The primary outcomes were major pathological response (MPR) and pathological complete response (pCR), and the secondary outcomes were 24-month overall survival (OS) and safety measured by adverse events (AEs). A meta-analysis was conducted for intention-to-treat MPR and pCR outcomes, in addition to a mixed-effects meta-regression model to investigate the effect of PD-L1 expression, tumor mutational burden (TMB), N stage (AJCC 8th), tumor size and tumor histology on MPR and pCR. PD-L1+ patients were defined to have a tumor proportion score of more or equal to 1%. Results: We included 9 phase II clinical trials and 1 phase III trial, all consisting of 471 patients. Trials administered neoadjuvant chemotherapy agents like carboplatin (N = 6 studies), cisplatin (N = 5), nab-paclitaxel (N = 4), pemetrexed (N = 2), and others, either as a doublet- or a triplet-agent regimen. ICIs used were anti-PD-1 (N = 5), anti-PD-L1 (N = 3), or anti-CTLA-4 agents (N = 2). Meta-analysis of 447 patients from 9 trials showed a pooled MPR of 49.2% (95% CI: 34.8 to 63.7%) with high heterogeneity (I2 = 87%, p < 0.01). Pooling the pCR from 10 trials including 471 patients results in an estimate of 27.5% (95% CI: 17.2 to 38.2%) with significant heterogeneity (I2 = 80%, p < 0.01). Meta-regression has found a significant association between being PD-L1+ and achieving MPR (odds ratio = 3.82, 95% CI: 1.55 to 9.58). However, this effect diminished in the multiple meta-regression that included age, tumor histology, in addition to PD-L1 status. None of these factors was correlated to achieving a pCR. Investigating the effect of tumor size, T stage, N stage, or TMB on MPR or pCR was not possible due to underreported data. Three trials of 137 patients reported a 24-month OS of 84.4% (95% CI: 77.6 to 90.2%) with low heterogeneity (I2 = 11%, p = 0.33). The most prevalent grade 3/4 AEs from the neoadjuvant treatment were neutropenia in 7.2% of patients, diarrhea in 3.2%, fatigue in 3.0%, and anemia in 2.1% of patients. The commonest any-grade AEs were fatigue (43.9%), alopecia (38.4%), diarrhea (31.6%), anemia (23.8%) and neutropenia (17.0%). Conclusions: The addition of ICIs to chemotherapy in neoadjuvant settings is an effective and feasible option. Effect of tumor size, PD-L1 status and TMB on MPR and pCR should be further investigated for better selection of treatment candidates.
Real-world data of durvalumab plus chemotherapy for extended stage small cell lung cancer patients: A Chilean experience.
Authors: Samtani Suraj Rajesh , Rojas Carlos , Gonzalez Jaime , Godoy Luis , Burotto Mauricio 
Published: June 2022

e20600 Background: Immunotherapy has changed the landscape for small cell lung cancer treatment. The aim of this study was to evaluate the efficacy of durvalumab plus chemotherapy in small cell lung cancer (SCLC) patients in real world experience. Methods: Eligibility criteria included, histologically confirmed extended stage SCLC (ES-SCLC), evaluable disease and no prior therapy. Patients received durvalumab plus chemotherapy until progressive disease (PD) or unacceptable toxicity. The main aim of the study was to report the efficacy and safety profile of durvalumab plus chemotherapy in patients with SCLC of our everyday clinical practice. The secondary aim was to perform subgroup analysis by clinical features. Results: From May 2020 to January of 2022, 15 patients were enrolled. The patients demographics were: median age 62 years, 67% male; 93,3% former/current smoker; 100% of patients presented with extended stage SCLC at diagnosis and 26,6% had brain metastasis at diagnosis. The most frequent sites of metastasis were distant lymph nodes 67%, liver metastasis 40% and bone metastasis 33%. Number of average cycles was 16,5. The median overall survival was 11,43 months and overall response rate (ORR) was 46%. In terms of safety profile, 73% developed treatment related adverse effects, 40% were grade 2 and 20% were grade 3. No treatment adverse effects leading to deaths were observed in our cohort of patients. Conclusions: This study represents one of the first real word experience with durvalumab plus chemotherapy in ES SCLC and the results are consistent with previously reported in clinical trials.