bluuebunny/crossref_metadata_2025 huggingface dataset:
Incidence of chronic graft versus host disease using post-transplant cyclophosphamide in HLA-matched versus haploidentical donors.
Authors: Hitt Mary Moses , Yimer Wondwosen , Milner Carter Payne , Herrin Vincent E. , Elkins Stephanie , Bigelow Carolyn L. , Hilal Talal
Published: June 2022

e19044

Background: Allogeneic hematopoietic cell transplant (allo-HCT) is the only potential cure for many hematologic cancers. Graft-versus-host disease (GVHD) is a significant cause of mortality after allo-HCT. Post-transplant cyclophosphamide (PTCy) in haploidentical HCT (haplo-HCT) has yielded survival outcomes similar to those seen in HLA-matched allo-HCT. Single center studies have demonstrated lower rates of chronic GVHD with the use of PTCy in HLA-matched allo-HCT. In this single center study, we analyzed the outcomes of HLA-matched and haplo-HCT in patients (pts) who received PTCy for GVHD ppx. Methods: Pts who received allo-HCT from matched related (MRD), matched unrelated (MUD), and haploidentical donors (Haplo) from Jan 2016 to July 2021 were identified. Pts who did not receive PTCy were excluded. Pts were divided into two groups – MRD/MUD and Haplo. Primary endpoint was cumulative incidence of chronic GVHD. Secondary endpoints were cumulative incidence of relapse, non-relapse mortality (NRM), and overall survival (OS) at 2-years. Comparisons were made based on log-rank test and a model for subhazard function of a failure event of primary interest with p < 0.05 used as cut-off point for statistical significance. Results: 62 pts (45 MRD/MUD,17 Haplo) were included. Baseline characteristics were similar. Median follow-up was 342 days post-transplant. Most had a diagnosis of AML (50%), high/very high DRI (48%), and received RIC (55%). Cumulative incidence of chronic GVHD was 11% overall (95% CI 5.8-21.3%); 6% for MRD/MUD and 27% for Haplo (p = 0.045). Cumulative incidence of relapse was 28% overall (95% CI 18-42%); 34% for MRD/MUD and 13% for Haplo (p = 0.09). Two-year OS was 55% overall (95% CI 39.1- 68.7%); 53% for MRD/MUD and 61% for Haplo (p = 0.043). There was no significant difference in incidence of grade 2-4 acute GVHD or NRM between groups. Conclusions: PTCy resulted in a significantly lower incidence of chronic GVHD in MRD/MUD group compared to Haplo group. Although cumulative incidence of relapse was not statistically different between groups, OS was worse in the MRD/MUD allo-HCT group after PTCy and most deaths were due to relapse.[Table: see text]
Efficacy and safety of bosutinib in later-line patients (pts) with chronic myeloid leukemia (CML): A sub-analysis from the phase 4 BYOND trial.
Authors: Gambacorti-Passerini Carlo , Brümmendorf Tim H. , Ernst Thomas , Leip Eric , Purcell Simon , Viqueira Andrea , Giles Francis J. , Rosti Gianantonio , Hochhaus Andreas
Published: June 2022

e19055

Background: Bosutinib (BOS) is approved for pts with Philadelphia chromosome-positive CML resistant/intolerant to prior therapy and newly diagnosed pts in chronic phase. Methods: The BYOND trial (NCT02228382) evaluated the efficacy and safety of BOS in 163 pts with CML resistant/intolerant to prior tyrosine kinase inhibitors (TKIs; Gambacorti-Passerini et al, Blood, 2021). We report a sub-analysis of 48 pts treated with 2 (3L) and 3 (4L) prior TKIs, categorized by resistance/intolerance to the last received TKI. This sub-analysis is based on the final Nov 23, 2020 database lock. Results: There were 18 and 30 pts resistant or intolerant to the last TKI who entered the study without complete cytogenetic response (CCyR) or major molecular response (MMR), respectively. Median (range) treatment duration was 10.6 mo (1.6–48.5) vs 28.3 mo (0.2–48.6) and median (range) dose intensity was 447.1 mg/d (131.3–520.4) vs 288.8 mg/d (79.7–500.0) for resistant vs intolerant pts. Prior TKIs included imatinib (88.9% vs 100.0%), dasatinib (88.9% vs 83.3%), and nilotinib (66.7% vs 63.3%) for resistant vs intolerant pts. Overall, 61.1% vs 66.7% of resistant vs intolerant pts discontinued BOS, mostly commonly due to adverse events (AEs) in 27.8% vs 16.7% pts; 16.7% vs 6.7% discontinued BOS due to insufficient clinical response. Rates of CCyR/MMR are shown in the table. Among responders (resistant vs intolerant pts), median (range) time to CCyR was 5.1 mo (2.8–8.8) vs 3.0 mo (2.7–6.1); median (range) time to MMR was 5.8 mo (2.8–9.4) vs 3.2 mo (2.8–9.3). In resistant vs intolerant pts, any grade treatment-emergent AEs (TEAEs) were reported by 100.0% vs 96.7% pts; grade 3/4 TEAEs were reported by 72.2% vs 83.3% pts. Grade 3/4 TEAEs > 10% in resistant pts were thrombocytopenia (22.2%) and neutropenia (11.1%), and in intolerant pts were increased alanine aminotransferase (26.7%), diarrhea (23.3%), pleural effusion (13.3%), and rash (13.3%). Conclusions: This sub-analysis of resistant/intolerant pts without baseline CCyR or MMR shows BOS was active in heavily pretreated pts with resistance/intolerance to the last TKI. Despite a difference between resistant/intolerant pts, efficacy outcomes, though lower than the overall BYOND population, are encouraging, and safety was generally consistent with previous reports. Clinical trial information: NCT02228382. [Table: see text]
Imatinib may not be the best choice for planning TFR in CML patients.
Authors: Alabdulwahab Amal S. , EL sayed Hussein E.G. , Sherisher Mohamed A. , Alghamdi Khalofa A.
Published: June 2022

e19059

Background: Treatment of chronic myeloid leukemia had been revolutionized by the use of Tyrosine kinase inhibitors. Recently, the strategy of treatment free remission had been introduced to ameliorate toxicity and reduce financial burden beside allowing patients who now have similar survival to normal people to achieve some goals as childbearing. Aim of this study: to check the suitability of imatinib as a first line treatment in potential patients in whom treatment free remission will be an ultimate goal. Methods: This study included patients with chronic myeloid leukemia, chronic phase who were treated in King Abdulla Medical city in the period between 2011 and end of 2019. Initial diagnosis was done by bone marrow, cytogenetics, molecular testing for BCR/ABL. Quantitative estimation of BCR-ABL1 was done on peripheral blood every 3 months to follow response which was assessed according to ELN criteria for follow up. Results: 140 patients were included in this study who received imatinib as first line therapy. The male to female ratio was 1.1 and the median age was 42 Y. 17 patients (12.1 %) were > 60 Y at start of treatment. The majority of patients were considered low risk (70.2%) as by EUTOS risk score. Breakpoint region was e13/a2 in 39.3%, e14/a2 in 38.3% and unknown in 22.7% of patients. 62% of patients were compliant with treatment. At the time of analysis, 79 patients (56%) remained on imatinib. 51/140 (36%) stopped it due to failure, 11 due to intolerance (7.9%). Favorable molecular responses were achieved in 67.4%, 53.9% and 50% at 3,6,12 months respectively. Compliance and risk scores were significantly affecting these responses. 54/70 (77%) of those who achieved MMR at 12 months achieved a deep molecular response (M4, M4.5) after a median period of 36 m. 40 patients (57%,74%) of those who achieved MMR, DMR respectively developed DMR lasting for more than 2 years (which is the requirement for TTF). This also reflects 28.5% of the whole group of patients. Conclusions: Although Imatinib continues to be the preferred first line in treating CML, CP yet it might be more suitable to use a second generation TKI if TFR is planned ahead.
Statins reduce mortality of patients with myelodysplastic syndromes.
Authors: Afzal Amber , Fiala Mark A. , Jacoby Meagan , Walter Matthew
Published: June 2022

e19063

Background: Statins can inhibit cholesterol synthesis through inhibition of mevalonic acid synthesis, and reduce prenylation of proteins involved in tumor growth. Their anti-neoplastic potential has been explored for many malignancies (e.g., multiple myeloma) with improvement in progression free- and overall- survival. Preclinical data support anti-neoplastic activity of statins for myeloid malignancies. In this study, we examined the effect of statins on mortality of patients with myelodysplastic syndromes (MDS) in this nationwide retrospective cohort study. Methods: We identified patients diagnosed with MDS through ICD-O-03 codes in the SEER-Medicare database between 2007 and 2017. Statins users were required to have at least one claim for a statin prescription within 6 months prior to MDS diagnosis. Propensity score matching was done to identify non-statin users with a similar cardiovascular risk profile. We analyzed the effect of statins on mortality (from any cause) in a Cox proportional hazards model that adjusted for demographics, SEER-Medicare MDS Risk Score ( SMMRS comprises of age, comorbidities, MDS histological subtype, cytopenias, transfusion-dependence and hospital admissions), treatments for lower risk MDS (growth factors or lenalidomide), and higher risk MDS (hypomethylating agents/stem cell transplant). Results: Our cohort of 6878 MDS patients (3439 statin users and 3439 non-statin users) had a median age of 80 years at diagnosis, and most were Caucasians. Non-statin users were more likely to have higher risk MDS (by SMMRS) at diagnosis. Statins users had a 33% {95% Confidence Interval (CI) 25%-40%; p <.001} lower risk of death than non-statin users. The beneficial effect of statins on mortality diminished over time (Table). Sub-group analysis (data not shown) showed a significant reduction in mortality with statin use in both patients with lower risk {low or intermediate-1 risk: Adjusted hazards ratio (aHR) 0.72; 95% CI 0.58-0.90; p = 0.003)} and higher risk {intermediate-2 or high-risk: aHR 0.67; 95% CI 0.59-0.76; p < 0.001)} MDS (categorized by SMMRS). Conclusions: Use of statins at time of MDS diagnosis is associated with reduced mortality among these patients. The beneficial effect of statins on death from cardiovascular events and myeloid malignancy should be further explored in clinical trials enrolling MDS patients.[Table: see text]
Preliminary safety and efficacy of relmacabtagene autoleucel (relma-cel) as second-line therapy for primary refractory Chinese patients with large B-cell lymphoma (LBCL): Results from an open-label, multicenter, single-arm phase I study.
Authors: Yan Zixun , Hu Yongxian , Sheng Lingshuang , Wang Li , Cheng Shu , Wu Wen , Xu Pengpeng , Zhang Muchen , Wang Chris , Zhou Zisong , Yang Su , Qin Yun , Huang He , Zhao Weili
Published: June 2022

e19509

Background: Relmacabtagene autoleucel (relma-cel) is a CD19-directed 4-1BB/CD3ζ chimeric antigen receptor T cell (CAR-T) product manufactured in China, it had been approved by NMPA for treatment of adults with r/r LBCL after ≥2 lines of systemic therapies based on the pivotal study (NCT04089215). Here, we report the results of relma-cel in patients with primary refractory disease after first-line standard of care (R-CHOP), an indication with poor clinical outcomes. Methods: This was an open-label, single-arm, multi-center, phase I study (NCT04812691). Eligible adults (≥18 years) met the criteria for primary refractory LBCL (not reach CR after first-line therapy). After screening and leukapheresis, patients received lymphodepletion [cyclophosphamide/fludarabine] followed by 100×106 CAR+ T cells. Results: High-risk disease characteristics were common in the study (Table). As of Nov 26, 2021, 14 patients had leukapheresis and 12 had relma-cel infusion. Among the efficacy-evaluable patients, the best ORR and CRR was 75.0% (95% CI: 42.8-94.5%) and 33.3% (95% CI: 9.9-65.1%), 3-month ORR and CRR were 41.7% (95% CI: 15.2-72.3%) and 33.3% (95% CI: 9.9-65.1%), respectively. With a median follow-up of 9.1 months, the median PFS was 10.0 months (95% CI: 0.85, NA), median DOR and OS were NA (95% CI: 2.2, NA) and NA (95% CI: 3.2, NA). Treatment-emergent adverse events (TEAE) were found in all patients. 10 (83.3%) patients had 1 or more study related Gr ≥3 TEAEs, the most common was cytopenia. 6 (50.0%) patients had Gr ≥3 prolonged cytopenia at Day 29. 6 (50.0%) patients had Gr ≤ 2 Cytokine Release Syndrome (CRS) with a median onset and duration of 6.0 and 11.0 days, no Gr ≥3 CRS observed. Neurotoxicity (NT) occurred in 2 patients (all Gr 1), the median onset and duration was 15.0 and 6.0 days. 2 deaths occurred in study due to disease progression. For 12 PK-evaluable patients, median Cmax was 36762.5 copies/μg DNA by qPCR with a median Tmax of 11 days and a median AUC1-29 of 333459.3 day×copies/μg. In 6 patients whose CAR-T cell had reached BLQ, 5 (83.3%) still had response with 4 (66.7%) patients for CR, 1 (16.7%) patients for PR. Univariate analysis did not indicate association between response and either exposure (AUC1–29) or peak concentration. Conclusions: Relma-cel was tolerable and showed promising ORR in Chinese patients with primary refractory LBCL. Evaluation of relma-cel in high risk second-line LBDL patients using a randomized trial design is planned. Clinical trial information: NCT04812691. [Table: see text]
CD20 and CD19 expression loss in relapsed or refractory b-cell non-Hodgkin lymphoma: A retrospective cohort.
Authors: Marshalek Joseph Patrick , Dragan Marcin , Tomassetti Sarah , LaBarbera Katie , Amaya Andy
Published: June 2022

e19537

Background: CD20-targeted therapies such as rituximab are widely used in the management of B-cell non-Hodgkin lymphoma (NHL). Re-treatment with anti-CD20 agents is common, however previous research has demonstrated loss of CD20 expression at time of relapse or refractory disease in a subset of patients. There is also amplified interest in alternative targets, specifically CD19, in the relapsed or refractory setting. Incidence of CD19 loss has been explored in post-CAR T cell therapy patients but not described elsewhere. We hypothesized that CD marker loss may be higher than previous reports due to expanded use of CD20- and CD19-targeted therapy. Methods: The present study is a retrospective cohort analysis of 229 patients with B-cell NHL from Harbor-UCLA Medical Center in Los Angeles, CA from 2006 to 2022. Charts were retrospectively reviewed for cases of B-cell NHL, and data was collected about demographics, diagnosis, treatment, and relapses. CD20 and CD19 expression analysis was performed by immunohistochemistry and / or flow cytometry at diagnosis and at each relapse whenever possible. The primary endpoint of the study was the rate of CD marker expression loss at time of relapse. Results: The cohort of 229 patients was composed of 54.1% diffuse large B-cell lymphoma (DLBCL), 14.4% follicular lymphoma (FL), 8.3% high-grade B-cell lymphoma (HGBCL), 7.0% marginal zone lymphoma (MZL), 4.8% mantle cell lymphoma (MCL), and 11.2% other. Overall, 28.8% (66/229) patients had relapsed or refractory disease. The rate of CD20 expression loss was 7.9% (5/63) across all relapses with two patients converting at first relapse (1 FL relapsing as HGBCL, 1 MZL), two patients at 2nd relapse (1 FL relapsing as DLBCL, 1 MZL relapsing as DLBCL), and one patient at 5th relapse (1 MZL). All five patients with CD20 phenotypic conversion received rituximab, and three patients received two or more rounds of anti-CD20 therapy. The median OS after CD20 expression loss was 4 months (95% CI 3.3 – 4.7 months). All patients (14/14) who had CD19 testing performed at relapse maintained CD19 positivity. Conclusions: This retrospective study demonstrates a rate of CD20 expression loss at relapse of 7.9%, which is less than previously reported rates ranging between 11-60%. CD20 expression loss seems to be associated with transformation to high-grade lymphoma, poor overall survival, and marginal zone histology. The conservation of CD19 expression across relapses supports the use of novel anti-CD19 targeted therapy in the relapsed or refractory setting. Whenever possible, repeat biopsy should be done at time of relapse prior to treatment with CD-targeted therapy. This study is of notable clinical relevance with expanded use of anti-CD20 agents and novel CD19-targeted therapies in the management of B-cell NHL.
Lymphopenia and outcomes of bendamustine-based therapy in follicular lymphoma.
Authors: Bakow Brianna R. , Muthiah Arun , Olszewski Adam J , Butera James N.
Published: June 2022

e19540

Background: Bendamustine plus rituximab (BR) is the preferred first-line immunochemotherapy for follicular lymphoma (FL) due to its efficacy and generally favorable adverse effect profile. However, it often causes prolonged lymphopenia, and impaired lymphocyte recovery after BR therapy has been recognized as a risk factor for opportunistic infections. On the other hand, little is known about the impact of profound lymphopenia on the overall treatment outcomes of BR. We examined the relationship between lymphopenia and treatment response in patients with FL who received BR at our institution. Methods: We retrospectively identified patients who received BR as first-line therapy for FL at the Lifespan Cancer Institute between October 2008 and November 2020. We used log-transformed absolute lymphocyte count (ALC) as the potential prognostic variable, integrated as the area under curve based on all available laboratory tests over the typical duration of BR (6 months). Outcomes included complete response to BR determined by post-treatment positron emission tomography or computed tomography, survival, and occurrence of hospitalization or herpes zoster on therapy. The association between ALC and survival or binary endpoints was examined using Cox or logistic models, respectively, adjusting for age, sex, cumulative bendamustine dose, and baseline ECOG performance status (PS). Results: We included 53 patients followed for a median of 69 months from start of BR. At treatment initiation, most patients had a PS of 0-1, stage III or IV disease, and high-risk lymphoma as defined by the Follicular Lymphoma International Prognostic Index (FLIPI) (Table). We observed an association between higher ALC during treatment and increased rates of CR (adjusted odds ratio, 2.50, 95% CI 1.04 – 6.00; p = 0.040), longer progression free survival (PFS) (adjusted hazard ratio [HR], 0.53, 95% CI 0.31 – 0.92, p = 0.023), and overall survival (OS) (HR, 0.45, 95% CI 0.23 – 0.87, p = 0.018). Higher ALC values during treatment and 1 month after treatment initiation were also associated with lower probability of hospitalization (p = 0.048 and p = 0.028, respectively). We did not find a statistically significant association between ALC and rates of zoster infection, but the number of observed events was low (n = 6). Conclusions: Our results suggest an association between higher ALC values during bendamustine therapy and improved treatment outcomes. Improvement in PFS, OS, and hospitalization rates with higher ALC values may be due relative preservation of nutritional balance and immune reserve. The association with survival should be confirmed in larger datasets and its potential mechanism elucidated.[Table: see text]
Prompt assessment of tumor load and treatment response in patients with lymphoma by a blood-based multiomics approach.
Authors: Wang Xinhua , Li Zhi-Ming , Chang Yu , Chang Yinyin , Chang Fangyuan , Zhu Dandan , Wu Wei , Li Shiyong , Zhang Mingzhi , Mao Mao
Published: June 2022

e19547

Background: Lymphomas represent a diverse group of diseases that arise from a clonal proliferation of lymphocytes. Periodic imaging is the current standard of care for clinical evaluation of treatment response for lymphoma patients, but It bears obvious shortcomings. Therefore, more accurate method is needed to evaluate treatment effect of Lymphoma. Methods: We present a real-time blood-based treatment response monitoring assay SeekInClarity to assess tumor load and response to varied treatment protocols in patients with lymphoma. A novel multidimensional molecular tumor burden (MTB) model was utilized. Copy number aberrations (CNAs) and fragment size (FS) patterns across the genome from sWGS data and levels of 7 PTMs (AFP, CEA, CA153, CA125, CA199, CYFRA21-1, CA724) are exploited to establish the MTB model. Patients with lymphoma were radiological assessed at baseline and reassessed regularly after treatment. The patients also had 10 ml venous blood samples collected for SeekInClarity at baseline and every two treatment cycles. Results: At baseline, 64.5% (80/124) patients were tested positive by SeekInClarity, implying the high MTB. In particular, genome-wide or focal CNA patterns were observed in 45.2% patients, and FS profile abnormality was witnessed from 42.5% patients, indicating both features are fundamental and ubiquitous surrogates of tumor burden. Elevated level of PTMs was also reported from 23.4% patients. All patients received various combination therapies with chemotherapies or immunotherapies as the backbone, and evaluated efficacy by clinical imaging. MTB evaluations of patients who underwent the follow-up SeekinClarity were compared with clinical imaging results. For the 44 patients who had negative MTB at baseline, 33 of them were performed following SeekinClarity and kept negative after treatment, and their imaging evaluations all showed remarkably curative effect. Furthermore, in the 80 patients with positive MTB, 57 patients were performed subsequent SeekinClarity tests, and a concordance of 81.6% was achieved with clinical evaluation. In addition, there was an 18.8% discordance between imaging evaluation and SeekinClarity. For these who had clinical partial response but unchanged or higher MTB, more tests and clinical evaluations are needed to assure the true clinical outcomes. Conclusions: This proof-of-concept study demonstrated SeekInClarity, a non-invasive, multidimensional multi-omics blood-based assay, can promptly evaluate the treatment response of patients with lymphoma. By implementing this assay, the dynamic change of MTB can help physicians to make well-informed decisions on the upcoming therapeutic strategies for each patient in conjunction with imaging. This study is still ongoing, and more cases and more time points are included to demonstrate the clinical performance of the assay.
Predictive value of TGFβ1/TGFBR2 ratio for evaluating the effectiveness of treatment in patients with diffuse large B-cell lymphoma (DLBCL).
Authors: Bandovkina Valeria A. , Frantsiyants Elena M. , Kushtova Luiza B. , Kozel Yuliya Yu. , Snezhko Aleksandr V. , Dmitrieva Viktoria V. , Kozyuk Olga V. , Malinin Sergey A. , Chalkhakhyan Lusegen Kh. , Kaminskiy Gennadiy V. , Lysenko Irina B. , Nikolaeva Nadezhda V. , Kit Oleg I.
Published: June 2022

e19559

Background: About 30-40% of patients with diffuse large B-cell lymphoma (DLBCL) do not respond to treatment, they subsequently relapse or remain refractory, so the search for predictive factors for the treatment effectiveness is relevant. TGF-β is a pleiotropic regulator of many pathophysiological processes, including carcinogenesis and immune responses, and its signals are initiated via its binding with proteins, including TGF-β receptor type 1 and type 2 (TGFBR2). The purpose of this study was to analyze the TGFβ1 and TGFBR2 blood levels and their ratio in patients with DLBCL depending on the treatment efficacy. Methods: The study included 63 patients (32 men and 31 women aged 23-88 years, median age 55.6 years) diagnosed with DLBCL. Blood levels of TGFβ1 and TGFBR2 were determined by ELISA before and after treatment. Stage I DLBCL was registered in 6 (9.5%) patients, stage II in 25 (39.7%), stage III in 5 (7.9%), stage IV in 27 (42.9%). All patients received standard treatment with R-CHOP, R-CHOEP, R-EPOCH. Direct results of the treatment were assessed by Cheson’s criteria. By their response to the therapy, patients were divided into 3 groups: group 1 (25.4%) – relapsed disease, group 2 (25.4%) – refractory disease, and group 3 (49.2%) – remission. A group of healthy donors included 20 men and women. All patients gave their informed consent to the study. Results: Blood levels of TGF-β1 in all patients before the treatment were higher than in donors by 2.1 times, and after the treatment by 2.4, 1.9 and 1.9 times, respectively, in groups 1, 2 and 3. The values between the groups did not differ significantly. Levels of TGFBR2, on the contrary, were lower in patients before treatment than in donors by 3 times, and after treatment by 3.5 in group 1, by 4 times in group 2, and similar to the norm in group 3. The TGFβ1/TGFBR2 ratios in patients before treatment were 6.1 times higher than the norm. After treatment, the ratio in patients of groups 1 and 2 were 8.6 and 7.2 times higher than in healthy donors. The ratio in patients of group 3 was 2.3 times higher than in healthy donors, and the value differed significantly from the values in groups 1 (3.8 times lower) and 2 (3.2 times lower). Conclusions: Monitoring the TGFβ1/TGFBR2 ratio in DLBCL patients before and during the treatment will allow promptly determination of adverse outcomes and changing the treatment regimen.
Observational study evaluating wait time and clinical outcomes in patients (pts) with diffuse large B-cell lymphoma (DLBCL) who received chimeric antigen receptor (CAR) T-cell therapy (T-CT).
Authors: Chun Danielle , Yin Yu , Bernhardt Alf , Sanders Lynn , Brouwer Emily
Published: June 2022

e19577

Background: 5-year survival rates for DLBCL pts in the first-line setting range from 60% to 70%. Up to 50% of pts become refractory to or relapse (r/r) after treatment. Autologous CAR T-CT has shown efficacy in r/r DLBCL in ≥2 lines of treatment but faces significant challenges with cell collection and manufacturing that may delay pt treatment. This study assessed the impact of wait time for CAR T-CT (time between apheresis and CAR T-CT administration) on progression-free survival (PFS) in DLBCL pts. Methods: Data from pts in the electronic health record-derived de-identified US-based Flatiron Health database, who had a DLBCL diagnosis after Jan 1, 2011, and a documented CAR T-CT administration date, were included. Pts missing a documented apheresis date were excluded. Demographic and clinical characteristics were assessed within 6 months (mos) prior to index date (CAR T-CT administration). Pts were followed from index date to the first of pt death or end of data availability. Given no established clinically relevant cut points, short wait time was defined as < median time between apheresis and index date. Long wait time was defined as ≥ median time. 3-, 6-, and 12-mo PFS probabilities (95% confidence intervals [CIs]) by wait time were reported. Results: 91 DLBCL pts received CAR T-CT; 78 had a documented apheresis date. Median time from apheresis to index date was 37 days (interquartile range: 25, 116). 55% of pts experienced longer wait times (≥37 days). 45% experienced shorter times (<37 days). Pts were mostly white (80%–84%), male (57%–65%), and older (median: 60–67 years), with similar median follow-up time from index (4.0–4.7 mos). More pts with short wait times had stage 4 disease than those with long wait times (51% vs 28%). 71% of pts with shorter wait times received axicabtagene ciloleucel. Among those with long wait times, 72% received tisaggenlecleucel. More pts with long wait times received bridging therapy (66% vs 74%). Pts with short wait times had a higher 3-mo PFS probability than pts with long wait times. The 6- and 12-mo PFS probabilities were lower in those with shorter wait times (Table). No statistical comparisons were made due to small sample size. Conclusions: This real-world study showed no meaningful differences in PFS between wait times in DLBCL pts in the United States. Results from this study show evidence of channeling bias which is an important consideration for evaluating real-world data to construct external control arms. Future studies are needed to further evaluate the impact of delayed treatment in pts with r/r DLBCL. Funding: Takeda Development Center Americas, Inc.[Table: see text]
Economic evaluations of adjunctive osimertinib treatment in surgically resected epidermal growth factor receptor positive (EGFR+) non-small cell lung cancer (NSCLC): Analysis for stage 1B disease.
Authors: Choi Briana M , Abraham Rachel B , Aqel Osama , Agu Uche S , Gregory Kristen C. , Obeng-Kusi Mavis , Calamia Matthias , Halawah Hala , Tugay Deniz , Alamer Ahmad , McBride Ali , Abraham Ivo
Published: June 2022

e20502

Background: Patients with stage 1B non-small cell lung cancer (NSCLC) who receive surgical resection are at continued risk of disease recurrence and death after the surgery. Osimertinib, a tyrosine kinase inhibitor indicated for epidermal growth factor receptor positive (EGFR+) NSCLC, has been used post-operatively as adjunctive therapy to improve clinical outcomes in surgically resected EGFR+ stage 1B NSCLC. We evaluated the cost effectiveness/utility of adjunctive osimertinib treatment post-surgically in stage 1B. Methods: A two state partitioned survival model with disease free survival (DFS) and disease recurrence or death was specified (US payer perspective). Kaplan-Meier DFS curves were fitted to parametric functions. A 5 year time horizon was adopted and a 3% discount rate was applied to costs and utilities after year 1. Wholesale acquisition costs for treatments were sourced from Redbook, adverse event costs (grade 3/4; all grades for immunotherapy related AEs) utilized published data, and monitoring costs were based on Physician Fee Schedules (US $2021). We estimated incremental costs, DFS life years (DFSLY), and DFS quality adjusted life years (DFSQALY). Based on DFSLY and DFSQALY gained (g), incremental cost effectiveness/utility ratios (ICER/ICUR) were determined in base case analyses (BCA) and probabilistic sensitivity analyses (PSA). Results: Exponential regression was utilized to extrapolate the osimertinib DFS Kaplan-Meier curve, while Weibull regression was applied for extrapolation of the placebo DFS curve. Shown in the table below, the BCA (PSA) revealed incremental cost of $774,710 ($775,941) and ncremental DFSLY of 0.813 (0.954), yielding an ICER of $952,797/DFSLYg ($813,162/DFSLYg); and incremental DFSQALY of 0.576 (0.676), yielding an ICUR of $1,345,340/DFSQALYg (1,147,793/DFSQALYg). Conclusions: In surgically resected stage 1B EGFR+ NSCLC, the model estimated incremental benefits of 0.813 (0.954) LYg and 0.576 (0.676) QALYg, however at marked incremental cost. As adjunctive osimertinib treatment is indicated in EGFR+ NSCLC disease stages 2 and 3A, the present stage 1B cost effectiveness/utility results should be compared to those for stages 2 and 3A.[Table: see text]
A survey on gene mutations of PD-1/PD-L1 treatment in Chinese lung cancer patients.
Authors: Long Fang Fang , Huang Wen Chuang , Peng Bo , Zhang Jing , Peisu Suo , Chen Shifu , Wu Fa Sheng
Published: June 2022

e20503

Background: The expression of PD-L1 is closely related to the curative effect. Here, we want to study the details of gene mutation in expression and dig out some relevant information from Chinese LC patients. Methods: LC patients with both genomic information and PD-L1 expression status were screened from HapLab database. PD-L1 expression was detected by immunochemistry. R packages ClusterProfiler was used for gene enrichment analysis. Results: LC Patients were divided into two groups by tumor proportion score (TPS):1039 PD-L1 negative patients (TPS < 1%) and 1669 PD-L1 positive patients (TPS > = 1%). The overall mutation frequency of 51 genes were significantly different between PD-L1 negative patients and PD-L1 positive patients (Chi-Squared test, Pvalue < 0.05). 6 genes were mutated at high frequencies in patients with high TPS, and 45 genes were mutated at high frequencies in patients with low TPS. Among these genes, FGFR3, MDM2 and SKT11 have been reported to be associated with HPD, showing significantly higher mutation frequencies in PD-L1 negative patients (Pvalue < = 0.001). Two sets of genes were enriched respectively, both of which were enriched in MAPK and PI3K-Akt related pathways, while the enrichment results of EGFR tyrosine kinase inhibitor resistance only existed in PD-L1 negative. Conclusions: Our study investigated the genomic alterations associated with PD-L1 expression status in Chinese LC patients. From the data of Chinese lung cancer patients, we found 55 genes related to PD-1/PD-L1 treatment. These genes contain HPD related genes. Perhaps PD-L1 expression is associated with HPD.
Intratumor heterogeneity analysis in lung adenocarcinoma by single-cell RNA sequencing and construction of a prognostic gene signature.
Authors: Huang Haifu , Wang Weiyu , Mu Tianhao , Fu Biqian
Published: June 2022

e20521

Background: Lung adenocarcinoma (LUAD), at the cellular level, has a high degree of intratumor heterogeneity. Advanced single-cell sequencing technologies have offered tools to analyze intratumor heterogeneity and identify the biomarkers, thereby aiding cancer diagnosis and prediction of the patient prognosis. Methods: From the Gene Expression Omnibus (GEO) (www.ncbi.nlm.nih.gov/geo) database, the single-cell RNA sequencing (scRNA-seq) data from two LUAD and two para-cancerous tissue samples were obtained. We performed a dimensionality reduction and unsupervised clustering to identify the different cell clusters within the tumor tissues. To identify the most relevant modules and important cell subpopulations (clusters) in LUAD tissues, a weighted gene co-expression network analysis (WGCNA) was performed. Subsequently, we classified the LUAD molecular subtypes according to the marker genes of these clusters. The Limma package ( www.bioconductor.org/packages/release/bioc/html/limma ) was used to screen for the differentially expressed genes (DEGs) between the subtypes. Using univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses, the gene signature most significantly associated with the prognosis of LUAD patients was determined. Results: A total of 14 cell clusters belonging to 10 cell types in LUAD was identified. The turquoise module was found to be the most relevant to LUAD among all the modules; cluster 10 (C10) was found to be the most strongly associated with the turquoise module. In The Cancer Genome Atlas (TCGA), patients with LUAD were divided into two groups of distinct molecular subtypes. Based on the 165 shared genes between the turquoise module and C10, 511 DEGs between the two molecular subtypes were obtained, and five of them were selected to construct the gene signature, which was validated to be an independent prognostic marker of LUAD. Conclusions: 14 cell clusters co-existed in LUAD, which contributed to its intratumor heterogeneity. In addition, two molecular subtypes of LUAD were identified and a five-gene signature was developed and validated to be significantly associated with prognostic and clinical characteristics of LUAD patients. Keywords: single-cell RNA sequencing, lung adenocarcinoma, intratumor heterogeneity, molecular subtypes, prognosis, five-gene signature.
Construction of a diagnostic model through the gene expression profile of the patients’ peripheral blood mononuclear cells and clinical characteristics for malignant lung nodules diagnosis.
Authors: Cai Yi , Li Zhuoqi
Published: June 2022

e20527

Background: Low dose computed tomography (LDCT) is widely accepted for detecting early-stage lung cancer. However, it remains a great challenge for it to distinguish malignant lung tumors from benign lung nodules because of the high false positive rate. Therefore, a better non-invasive diagnostic tool is needed to improve the specificity. Methods: Two GEO datasets of expression profiling by array of peripheral blood mononuclear cells (PBMC) from patients with malignant lung nodules or non-malignant lung conditions, as well as relevant clinical information were downloaded and disposed. R package edgeR was applied to screen out the differentially expressed genes with |log2-fold change (FC)| ≥ 0.25 and p≤0.05. Logistic regression model was constructed based on GSE135304 dataset in order to find which factors contribute to the distinguishing of malignant lung nodules from non-malignant lung conditions, and this model was then validated in GSE108375 dataset. Results: 23 differentially expressed genes from the PBMC between patients with lung cancer and non-malignant lung conditions, and the patients’ lung nodule size and age were included in the diagnostic model through the logistic regression analysis. And in the training dataset GSE135304, the ROC curve shows the specificity of the model is 0.866 and sensitivity is 0.848, and the AUC value is 0.857. In the meantime, the specificity and sensitivity of the validation dataset GSE108375 are 0.865 and 0.893 respectively, and the AUC value comes to 0.879. Conclusions: This diagnostic model shows high sensitivity and specificity in both training group and validation group, so it may be a good tool for the mini-invasive diagnosis of malignant lung nodules.
Systematic analysis the genomic and microenvironment characteristics with the status of human leukocyte antigen (HLA) and the integration of HLA LOH, TMB and PD-L1 could further distinguish the responders to immunotherapy.
Authors: Zhang Xiaotao , Wang Jun , Chen Jun , Zhang Linlin , Guan Yaping , Chu Huili , Yu Haiming , Yu Lan , Lu Huiping , Jin Haoxuan , Gu Tiantian , Wang Xiuyan
Published: June 2022

e20529

Background: Although studies have shown that loss of heterozygosity (LOH) at the human leukocyte antigen (HLA) locus is one of the mechanisms of immune escape, the effect of HLA LOH on the immune checkpoint inhibitors (ICIs) treatment is still need to be further investigated, especially for the patients with positive programmed cell death-Ligand 1 (PD-L1) expression and high tumor mutation burden (TMB). Methods: 425 sample of Chinese lung cancer patients who received PD-L1 immunotherapy were performed with targeted panel sequencing to analyzed the genomic characteristics with HLA status. 994 non-small cell lung cancer (NSCLC) sample from The Cancer Genome Atlas (TCGA) were used to analyze the impact of HLA LOH on the tumor microenvironment. In addition, 89 samples from previous study were used to analyze the association of HLA status with the ICIs treatment in NSCLC. Results: The genomic characteristics from 425 sample of Chinese lung cancer patients who received PD-L1 immunotherapy were analyzed. We found that mutation frequency of driver genes and TMB in the HLA LOH high group were significantly increased. Transcriptome analysis revealed HLA LOH played a critical role in the tumor immune microenvironment in PD-L1+/TMB-H population and the impact on lung adenocarcinoma was greater than that on lung squamous cell carcinoma. Progression-free survival of PD-L1+/TMB-H population was significantly decreased in HLA LOH group which suggest that comprehensive considering HLA LOH as a biomarker may improve clinical response to immunotherapy. Conclusions: This work showed the genomic and immune microenvironment characteristics of HLA LOH and demonstrated HLA LOH as a significant negative predictor of outcomes after ICIs treatment, especially in PD-L1+/TMB-H population. These data suggested that comprehensive considering HLA LOH as a biomarker may improve clinical response to immunotherapy.
Characterization of MET exon 14 skipping in pancancer.
Authors: Li Fei , Chen Jing , Zhang Xiaoyan , Yang Dongxiao , Xia Liang , Wang Dazhong , Jin Kai , Zhu Jianhua , Fang Yu , Wang Chunyang , Ma Tonghui , Pu Xingxiang
Published: June 2022

e20530

Background: MET exon 14 skipping ( METex14) is characterized oncogenic that possesses susceptibility to targeted inhibitors. We retrospectively investigated a Chinese Pan-cancer cohort to characterize METex14 alterations and co-mutation. Methods: We screened tumor tissues or body fluids of a pan-cancer patients by DNA-based next-generation sequencing assay (Genetron Health) from 2017 to 2020. And distribution of co-mutation with METex14 was analyzed. Results: 233 samples from 187 patients (190 tissues and 43 circulating tumor DNA) were identified with METex14. Average age of these METex14 patients was 67.84 ± 12.19 years old, indicating they were characterized by advanced age. The cancer distribution involved METex14 was 95.72% of lung cancer (179 cases), 3.21% of brain tumors (4 glioma blastoma, 1 anaplastic astrocytoma and 1 ependymoma), 0.535% of gastrointestinal stromal tumor (1 case) and 0.535% of sarcoma (1 case). Referring to different transcripts (NM_001127500.1/2 or NM_000245.2), a total of 68 distinct sequence variants of METex14 were identified spanning functional regions: 31 forms in splice donor site (SD, 148 cases, including 1 case of D1010H), 5 in splice acceptor site (SA, 5 cases), 13 in poly-pyrimidine tract (PPT, 15 cases), 19 cover PPT and SA (19 cases). In non-lung cancers, 5 of 8 cases were detected of METex14 variation in SD site. Among the driver coexisting cases of lung cancer, METex14 samples mainly coexisted with MET amplification, EGFR driver mutations and functional fusions. Co-mutation cases with MET amplification (13) and SEMA3D-MET fusion (1) may benefit from MET inhibitors, which may be the same as the samples of METex14 alone. 13 of METex14 cases occurred with MDM2 and 9 of CDK4 amplification, respectively. There were 2 of METex14 cases coexisted with EGFR 19del or L858R, which may benefit from combination or sequential therapies of MET inhibitor and EGFR TKIs. In addition, 2 of METex14 cases were detected with functional fusions (1 ALK-EML4, 1 KIFI5B-RET), resulting in potential benefit from combination of corresponding targeted agents. Among non-lung cancer cases, 2 of 8 case had coexistence of METex14 and MET amplification, 6 of 8 patients had coexistence of METex14 and TP53, similar phenomenon was also observed in lung cancer samples. Conclusions: Here we reported diverse METex14 alterations in a Chinese pan-cancer cohort that contribute to oncogenic transformation. METex14 mutations of pan-cancer mainly occurred in SD site. TP53 was its main co-mutant gene among pan-cancers, and MET amplification was also observed.
Characterization of patients with lung adenocarcinoma treated at a reference oncology center in northeastern Brazil and submitted to EGFR gene mutation research.
Authors: Silva-Fernandes Isabelle Joyce de Lima , Andrade Letícia Macedo Nicácio , Lima Arthur Ernani Saldanha e Oliveira , Bezerra Maria Júlia Barbosa , Luciano Maria Claudia dos Santos , Lima Valeska Portela , Neto José de Brito Vieira , Soares Bruno Marques , Rodrigues Aline Kimberly Almeida , Oliveira Samara Regia , Cunha Maria do Perpétuo Socorro Saldanha , Hirth Carlos Gustavo , Bitencourt Flávio da Silveira , Sant'Ana Rosane Oliveira , Silva Paulo Goberlânio de Barros
Published: June 2022

e20548

Background: Lung cancer has the highest incidence and mortality worldwide. In Brazil, it is the second most common, and individualized therapy, although more efficient than traditional chemotherapy, is still a challenge for health services, especially in developing countries, as socioeconomic disparities make access to genetic testing difficult or treatment. Thus, it is understood that greater knowledge about the genetic profile and therapeutic response of different populations can contribute to policy changes that guarantee expanded access to individualized therapy. Methods: the EGFR gene mutation status was correlated with clinical-epidemiological, socioeconomic, treatment, and survival parameters of patients with lung adenocarcinoma treated from 2014 to 2021 at an oncology referral center in northeastern Brazil. Data were obtained retrospectively from the patient's charts at the Hospital Haroldo Juaçaba/Instituto do Câncer do Ceará. The X²/Fisher and Log-Rank Mantel-Cox tests were used to associate clinical variables and overall survival curves. The Research Ethics Committee approved the research under protocol number 3.544.754. Results: 586 patients tested, 157 (26.8%) had an EGFR mutation, with exon 19 deletion (n = 83, 52.9%). the most frequent followed by L858R (n = 54, 34.4%) and others (n = 30, 12.8%). The EGFR mutation was inversely associated with smoking history (p < 0.001) and previous use of carboplatin plus paclitaxel (p < 0.001). The median overall survival was 33 (95%CI = 25-41) months, and the presence of a mutation was not associated with a worse outcome (p = 0.146). Interestingly, patients with sensitivity mutation who used gefitinib (64.1%) did not show a significant difference in overall survival (p = 0.218). However, when stratifying analyzes according to mutation type, it was observed that patients with exon 19 deletion treated with gefitinib had greater median overall survival (32, 95%CI = 27-37 months) than patients with this mutation not treated with gefitinib (median = 15, 95%CI = 2-25 months) (p < 0.001). Patients with the L858R type sensitivity mutation (p = 0.523) or other mutations (p = 0.439) did not experience significant benefits from gefitinib use. Conclusions: In the population studied, the exon 19 deletion was the most frequent and the only one associated with a substantial benefit from using gefitinib.
Using multiomics analysis to examine prognostic biomarkers for patients with squamous cell lung carcinoma treated with neoadjuvant therapy of camrelizumab combined with Apatinib.
Authors: Wang Jinliang , Lu Di , Zhai Jinzhao , Zhang Zhibo , Yan Xiang , Zhang Fan , Wang Lijie , Haitao TAO , Yuan Fang , Li Xiaoyan , Zhi Xiaoyu , Ge Xiangwei , Hu Yi , Zhou Wenhao , Luo Haitao
Published: June 2022

e20563

Background: Immune checkpoint inhibitor (ICI) combined with targeted therapy as a neoadjuvant therapy has been applied to the treatment of squamous cell lung carcinoma (SCLC). However, biomarkers to predict the response are unclear. Methods: 26 SCLC patients treated with neoadjuvant therapy of camrelizumab combined with apatinib were enrolled. Pretreatment samples of these patients were performed with whole-exome sequencing, RNA sequencing, TCR sequencing and IHC of PD-L1 expression. Peripheral blood at different timepoints were collected and analyzed with ctDNA sequencing. Results: At baseline, tumor mutation burden was found to be associated with clinical benefit. For patients with HLA intact, tumor neoantigen burden are significantly increased in the benefited group compared with non-benefited group. Transcriptome analysis revealed that regulatory T cells were significant higher in non-benefited group. In addition, diversity of dominate T-cell receptor repertoire was found to be associated with clinical benefit. Post-treatment, the levels of ctDNA decreased in the benefited group. Conclusions: In this study, we comprehensively analyzed the genomic, tumor microenvironment and serum biomarkers in SCLC patients treated with ICI combined with targeted therapy, and found that TMB, regulatory T cells and change of ctDNA levels were associated with the clinical benefit. In addition, the combination of HLA status and TNB could further distinguish responders.