bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of type of salvage therapy (ST) and response to bridging therapy (BT) on CAR-T therapy outcomes for relapsed/refractory aggressive B-cell non-Hodgkin lymphoma (NHL).
Authors: Khurana Arushi , Al Saleh Abdullah S. , Gandhi Sangeetha , Truong Tuan , Brandes Eva , Estby Breanna , Lange Gina , Villasboas Jose Caetano , Paludo Jonas , Bennani N. Nora , Ansell Stephen M. , Johnston Patrick B. , Lin Yi 
Published: May 2020

e15020 Background: Durable responses were seen in registration trials for CAR-T in NHL across poor prognostic groups including early relapse post stem cell transplant (ASCT). Multi-center reports of real-world practice noted patients who received BT prior to CAR-T had decreased survival. The impact of last ST and response to BT on clinical outcome are examined here. Methods: Retrospective chart review was performed on 47 patients who received axicabtagene ciloleucel from June 2016 – September 2019 at Mayo Clinic, Rochester. ST was defined as last therapy prior to leukapheresis and grouped into categories – non-ASCT (chemotherapy, and immunotherapy), and ASCT. BT was defined as therapy given between leukapheresis and CAR-T. Response to therapy was evaluated using 2014 Lugano criteria. Event free survival (EFS) was defined as time from CAR-T infusion to progression, next treatment, or death. Results: The ST distribution was 77% non-ASCT [chemo 66% (31), and immunotherapy 11% (5)], and 23% (11) ASCT. EFS was significantly prolonged for the ASCT (median not reached) vs non-ASCT (median 3.8 months, p = 0.03) despite no difference in median prior lines of therapy. This may reflect more aggressive disease in the non-ASCT arm, as time from start of ST to leukapheresis was shorter (median non-ASCT 2.2 months vs. ASCT 4.4 months, p = 0.0008). Patients received BT if there were concerns for symptomatic progression during CAR-T manufacturing that would reduce the likelihood to receive CAR-T. Sixty-two percent (29) patients received BT (11 chemo, and 18 immunotherapy). The EFS did not differ between the type of BT. However, patients who progressed after BT had worse EFS than those who achieved stable disease or partial response (median 2.8 vs 8.7 months, p = 0.03). Conclusions: Patients who received CAR-T as the next treatment after ASCT had better EFS than those after other types of ST. While patients who received BT have worse survival than those who didn’t, having some control of lymphoma progression with BT was associated with better EFS than those who continued to have progressive disease.
Correlation between JAK1/2 expression and immune-related genes and JAK2 gene variants: A pan-cancer analysis.
Authors: Xu Lichao , Zhang Ding , Wang Guoqiang , Chen Chao , Wang Ying , Huang Haozhe , Zhang Zhenghua 
Published: May 2020

e15057 Background: Loss of function mutations for Janus kinases 1/2 (JAK1/2) have shown to be the underling mechanism of primary resistance to immune checkpoint inhibitors (ICIs). However, the correlation between JAK1/2 expression and immune-related genes have not been studied. Methods: Survival, mRNA expression and whole-exome sequencing data from 32 pan-cancer atlas studies were obtained from The Cancer Genome Atlas (TCGA). Correlations between JAK1/2 expression and immune-related genes were depicted in heatmaps. We also analyzed the association between JAK2 gene variants and JAK2 expression. Results: In total, 10071 samples with mRNA expression data were included for analysis. Expression of 46 immune-related genes were positively correlated with JAK2 expression in 25 tumors instead of JAK1 expression. Patients with higher expression of JAK2 had better prognosis than patients with lower expression of JAK2 in 13 tumors. Among 10071 patients, 363 (3.60%) patients harbored JAK2 variants, including 8 with frame shift mutations, 44 with nonsense mutations, 142 with missense mutations, 11 with splices, 8 with fusions, 90 with copy-number reduction and 116 with copy-number amplification. There was no difference in JAK2 expression between patients with JAK2 variants and those without JAK2 variants. However, JAK2 fusion (2.20%, 8/363) and amplification (31.96%, 116/363) were associated with higher JAK2 expression. Conclusions: Our pan-cancer analysis found that JAK2 expression was correlated with immune-related genes and the prognosis of cancer patients. JAK2 fusion and amplification increased the expression of JAK2. Altogether, patients with high JAK2 expression may benefit from ICIs.
A prospective cohort study of HLA-B44 supertype as predictor of response to novel immune checkpoint combinations.
Authors: Hernandez-Guerrero Tatiana , Doger Bernard , Morillo Daniel , Casado Victoria , Domine Manuel , García Foncillas Jesús , Moreno Victor 
Published: May 2020

e15071 Background: To date there are no clear predictors of response to novel immune checkpoint inhibitor (ICI) combinations. Recent reports suggest that HLA-I (Human Leukocyte Antigen Class I) supertype B44 may predict survival to PD1(L)1 inhibition in patients with melanoma and non-small cell lung cancer (NSCLC) ( Chowell et al, Science 2018). We sought to study if this effect is exclusive for PD(L)1 inhibition alone and the impact of HLA-B44 on ICI combinations with new immunotherapeutic agents. Methods: Between 2017 and 2019, 77 patients treated across 11 different early phase clinical trials (NSCLC: 64: (83,1%); melanoma: 4: (5,2%), bladder 8 (10,4%); and one nasopharynx carcinoma), ICI-naive were prospectively evaluated for HLA-I subclass. All patients were ECOG 0 or 1 (50 and 27 respectively). Most patients had ≤ 2 metastatic sites (55: 71,4%); 24 (31,2%) patients were treated with PD(L)1 inhibitors as monotherapy, and 53 (68.8%) with PD(L)1-containing combinations including ICI and agonists such as ICOS, OX40 or GITR monoclonal antibodies. HLA-I was classified for supertypes and the variables of progression-free survival (PFS) and overall survival (OS) were compared for patients with HLA-B44+ and B44-, in both groups (monotherapy and combinations). Results: 44 patients were HLA-B44+ and 33 were negative. For patients treated with anti-PD(L)1 agents as monotherapy, those that were HLA-B44+ had a longer PFS: [medianPFS: 22,38 months (m) (95% CI: 13,39 – 31,37); vs 3,8m (95% IC: 2,05 – 5,65); p: 0,002] and OS: [median: 33,2 m (95% CI: 23,7 – 42,6) vs 14,46 m (95% IC: 7,86 – 21,1); p: 0,13]. In contrast, these marked differences were not evident in patients receiving PD1 combination therapies [HLA-B44+ mPFS: 7,17m (95% CI: 4,41 - 9,93) vs 9,46 m (IC95% 6,8 m – 12,07); p:0,290], and OS: 11,53m (95% IC: 8,33 – 14,7) vs 18,9 m (IC 95% 13,3 – 24,5) p: 0,24. Lastly, response rate was also better for patients with HLA-B44 positive treated with PD1 monotherapy (66,7% vs 16,7% in HLA-B44 negative patients) p: 0,048, whilst when administering ICI combinations, HLA-B44 negative patients seemed to have a better response rate (44% vs 27% in HLA-B44 positive patients; p = 0,148). Conclusions: These results confirm in a prospective cohort the predictive impact of HLA-B44 supertype for patients treated with anti-PD(L)1 agent and suggest a potential benefit of combining checkpoint inhibitors in patients with other HLA supertypes (non-HLA-B44+).
Immortal time bias in the association between toxicity and response for immune checkpoint inhibitors: A systematic review and meta-analysis.
Authors: Dall'Olio Filippo G. , Rizzo Alessandro , Mollica Veronica , Massucci Maria , Maggio Ilaria , Massari Francesco 
Published: May 2020

e15080 Background: A number of studies have addressed the association between Immune related Adverse Events (IrAE) and outcome in patients treated with Immune Checkpoint Inhibitors (ICI). Only a minority of them considered the effect of immortal time bias (ITB), and results of these papers are conflicting. The aim of our meta-analysis was to assess the relationship between IrAE and outcomes for patients treated with ICIs, with a focus on ITB in weighing the role of this association. Methods: PubMed, Embase (Ovid), and Scopus were searched through January 2, 2020. Studies reporting the prognostic impact of IrAE development on outcome in advanced cancer patients treated with anti PD-1 or PD-L1.Two investigators independently extracted data from each study following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guideline. Author name, cancer type, PD-1 and PD-L1 inhibitor used, number of patients, number and type of all adverse events, presence of a landmark analysis, median OS and PFS and difference between patient with or without IrAE in terms of OS and PFS (Hazard Ratio) and ORR (Odds Ratio) were extracted. Data were pooled using a random-effects model. Main outcome were Overall Survival (OS), Progression Free Survival (PFS) and Overall Response Rate (ORR). Analysis was performed with dedicated software (R studio version 1.2.1335, metafor package). Results: A total of 29 articles comprising 7430 patients were included. 7 papers published the results of survival analysis according to landmark analysis, 2 papers published only the naïve analysis while stating that a landmark analysis resulted non significant, and the others did not perform a landmark analysis. IrAEs were associated with improved outcomes with high heterogeneity ( I2 70.8%, p < 0.001 for OS; 65.7%, p 0.002 for PFS; 62.1%, p 0.001 for ORR). When subgroup analysis was performed according to the adoption of a landmark approach, the association between IrAE and outcome remains significant for OS, PFS and ORR but the effect size was smaller ( HR 0.61 vs 0.41 for OS, ANOVA Q-test for difference between subgroup p = 0.015; HR 0.66 vs 0.47 for PFS, ANOVA Q-test p 0.029; OR 2.59 vs 6.77 for ORR, ANOVA Q-test p < 0.001) while heterogeneity was substantially reduced (I2 for papers using LM 43% for OS, p 0.115; 9.7% for PFS, p 0.355; 0.0% for ORR, p 0.556). Conclusions: Our analysis suggests a significant confounding effect of ITB as well as a real effect of IrAE development on outcome.
A rational approach to nivolumab dosing using cost analysis.
Authors: Renner Alex , Samtani Suraj Rajesh , Salinas Carlos , Rojas Carlos , Burotto Pichun Mauricio Emanuel 
Published: May 2020

e15101 Background: Immune checkpoint inhibitors have changed the landscape in oncology, offering durable responses and improved survival across several tumor types. A significant problem in many countries is access to these drugs, as the yearly treatment cost can exceed $100,000. One of the alternatives to reduce the total cost of therapy is to optimize the dosing strategy. Nivolumab was initially approved with a 3mg/kg Q2W dosage, later fixed dose nivolumab 240mg Q2W was also approved. Fixed dose regimens can lead to unnecessarily high doses for patients under 80 kg. Methods: We performed a cost analysis using weight data from 53 patients diagnosed with melanoma or metastatic renal cell carcinoma who were treated with nivolumab at our institution. With that information we generated a model which calculated the total cost if they were to receive the 240mg fixed dose regimen, versus a a cost-saving strategy as follows: all patients weighing up to 79.9Kg were to be dosed at 3mg/kg, while patients 80kg or more were to use the fixed 240mg dose. Since nivolumab is available in 100mg, 40mg and 240mg vials, there is dose wastage when using the 3mg/kg calculation, this was considered for the cost analysis. Results: The median weight of our patients was 73.6kg (range 56,0kg - 103,1kg). Analyzing individual patient data, 75% of them would receive a higher dose if treated with the fixed dose regimen, versus 3mg/kg dosing. Among them, the median comparative overdosage is 50,9mg (range 3.0mg - 87.0mg). Considering drug wastage, and a USD 12.96 per mg local price for nivolumab, treating our 53 patients with the proposed model for one year would result in USD 366.886 in cost savings, versus using the 240mg fixed dose regimen, equivalent to a 9.3% of the total treatment costs. Conclusions: Expanding access to immunotherapy is a challenge for health systems. We have shown a potential 9.3% cost savings using a rational dosing regimen for nivolumab, which could be very important in cost-constrained scenarios which many countries are facing. Considering the world average weight is 62.0kg, it is plausible than even greater cost savings could be realized in many other locations around the globe.
Hepatitis B reactivation with pembrolizumab, atezolizumab, and nivolumab: A pharmacovigilance study and literature review.
Authors: Muhsen Ibrahim , Burns Ethan , Umoru Godsfavour , Arain Abeer , Xu Jiaqiong , Abdelrahim Maen 
Published: May 2020

e15127 Background: Chronic Hepatitis B virus (HBV) impacts 257 million people worldwide. Chemo- and immunotherapies may predispose to HBV reactivation (HBVr), which can negatively impact oncologic outcomes. Programmed death (PD) and programmed death ligand (PDL)-1 inhibitors have been implicated in HBVr. The aim of this study is to report HBVr in patients who are treated with PD-1/PD L-1 inhibitors by utilizing the FDA Adverse Events Reporting System (FAERS) and literature review. Methods: This is a retrospective pharmacovigilance study using FAERS. We reviewed cases of HBVr reported in patients treated with pembrolizumab, atezolizumab, and nivolumab from 2016-2019. Signal disproportionality analysis was conducted using a reporting odds ratio (ROR). A systematic review using Ovid MEDLINE(R) was conducted for additional reports of HBVr and associated outcomes. Results: There were 15 cases of HBVr associated with the use of PD1/PDL1 inhibitors on FAERS (ROR 1.2, 95% CI [0.72-1.99]). Only pembrolizumab was shown to a have significant association with HBVr (ROR 2.93, 95% CI [1.57-5.46]) (Table). Moreover, 7 cases of HBVr were reported in the literature, 3 with pembrolizumab and 4 with nivolumab. Median time to diagnosis following initiation of immunotherapy was 12 (5-24) weeks and 8 (3-10.5) weeks for resolution of HBVr. Conclusions: Pembrolizumab was the only agent with a significant association of HBVr. Future institutional studies in both endemic and nonendemic areas are warranted to determine the true incidence and necessity of pretreatment screening for HBV in patients on PD-1/PDL-1 therapy. [Table: see text]
What happens at radiographic disease progression in patients with metastatic cancer receiving immune checkpoint inhibitors? A single institution analysis.
Authors: Lin Justin , Patel Vaibhav G. , Qin Qian , Wang Bo , Mellgard George , Gogerly-Moragoda Mahalya , Leiter Amanda , Gallagher Emily J. , Zhong Xiaobo , Oh William K. , Galsky Matt D. , Tsao Che-Kai 
Published: May 2020

e15157 Background: Immune checkpoint inhibitors (ICIs) are widely adopted for multiple indications across various malignancies. Despite the surge in their use, what occurs at radiographic progression (rPOD) remains poorly characterized. Herein, we describe patients at our institution that experienced rPOD on ICIs. Methods: We retrospectively reviewed charts of patients (pts) with solid tumors that received at least 2 doses of ICI at our institution from 12/01/2010 to 04/25/2017. Patients’ demographic data, medical history, ICI course, and outcomes were recorded. Characteristics at rPOD included change in tumor size by metastatic site, symptoms, and hospital utilization. Additionally, we characterized outcomes of pts who continued ICIs after rPOD. Fisher’s exact test was performed to identify potential clinical predictors of hospitalization at rPOD. Results: Of the 361 evaluable pts, 238 experienced rPOD. In this cohort, the most common primary sites of disease are: genitourinary (24%), thoracic (24%), skin (21%), and hepatobiliary (15%). At rPOD, 71 (30%) patients were hospitalized within 30 days, with infection (27%) and pain (18%) being the most common reasons. Median survival of pts with hospitalization was 2 months (mos; 95% CI: 0-4), compared to 10 months (95% CI: 8-12) for those not hospitalized (p<0.001). Forty-six (19%) pts continued ICI treatment after rPOD (median duration = 2.8 mos), with eleven (5%) pts continuing for at least 6 months (median duration = 8 mos). Conclusions: In our study of real-world cancer pts treated with ICI, a higher than expected proportion was hospitalized within 30 days after rPOD, and this population had a worse overall survival compared to those that were not. A subgroup of pt with rPOD did not experience clinical progression, and thus treatment was continued, although further benefit was limited to a small subset. Further studies are needed to better understand the underlying mechanism to identify those who benefits from treatment beyond rPOD. [Table: see text]
Investigating the impact of medical comorbidities in patients taking beta blockers and treated with immunotherapy for metastatic melanoma.
Authors: Hong Paul Pyunggang , Zhu Junjia , Drabick Joseph J. , Schell Todd D. 
Published: May 2020

e15162 Background: Combined administration of β-adrenergic antagonist with IL-2, anti-PD-1, and/or anti-CTLA-4 immunotherapy was associated with a better overall survival in metastatic melanoma patients. This result was also reinforced by the significant reduction in tumor growth in a murine melanoma model when a β2-selective antagonist was combined with anti-PD1/IL-2 immunotherapy. Here we sought to elucidate the impact of the various comorbidities behind the indications of β-blockers, and how they might have influenced the patients’ immunotherapy treatment response. Methods: A single-institution retrospective chart review was performed to examine the medical comorbidities with indications for β-blockers in the melanoma patients who received IL-2, αPD-1 and/or αCTLA-4 immunotherapy between January 2000 and March 2015. Two groups were identified: one that took a selective β-1 blocker (N = 41), and another that took a nonselective pan β-blocker (N = 17). The primary analysis compared the distribution of different comorbidity types between two groups, using the Fisher’s exact test. A secondary analysis examined the association of overall survival and the β-blocker groups by further controlling for comorbid conditions, using the multivariate Cox Proportional-Hazard regression model. Results: Seven different comorbidities with indications for β-blocker usage were identified. Of those comorbidities, only the presence of ischemic heart disease was marginally different between the two groups (β-1 group 19.5% vs. pan-β group 47.1%, p-value = 0.0697). There was no difference for overall survival between each of the comorbidity conditions. When performing the multivariate Cox Proportional-Hazard regression model, β-blocker usage still remained statistically significant for the overall survival (HR 0.27, CI 0.0966-0.768, p = 0.0139), even after controlling for the comorbid conditions. Conclusions: Immunotherapy with pan β-adrenergic blockade was associated with a significantly improved overall survival rate for metastatic melanoma. Furthermore, having a comorbid condition that indicated for the prescription of β-blockers was not a factor in establishing this survival rate.
Management of immune-related adverse events: A single-center retrospective analysis in a real-world scenario.
Authors: Iacono Donatella , Vitale Maria Grazia , Cortiula Francesco , Macerelli Marianna , Cinausero Marika , Minisini Alessandro Marco , Valent Francesca , Tullio Annarita , Palmero Lorenza , Targato Giada , Zara Diego , Fasola Gianpiero 
Published: May 2020

e15163 Background: Immune checkpoint inhibitors (ICI), anti CTLA-4 and anti PD-1/PD-L1 agents, have demonstrated an improvement in survival outcome in several malignancies. Therapy with ICI is characterized by immune-related adverse events (irAEs) as a result of exuberant immune system activation. Despite good tolerance for ICI, the potentially severe and life-threatening irAEs underscore the importance of investigating optimal management strategies. Methods: A retrospective series of 130 consecutive patients (pts) treated with ICI from Jan 2012 to Dec 2017 was analyzed. Adverse events with a potential immunological etiology were defined as irAEs and graded according to CTCAE v.4.0. The aim of the study was to evaluate irAEs management in an academic hospital center. Results: Pts with a diagnosis of NSCLC n = 64 (49%), melanoma n = 55 (42%), kidney n = 9 (7%) and others n = 2 (2%) were investigated. Baseline ECOG PS was ≤ 1 in 96% of the pts. ICI represented first line treatment for 27% pts, second line for 57% and third or further line for the remaining 16%. 18% were treated with ipilimumab and 82% with anti PD-1/PD-L1 agents (nivolumab 60%, pembrolizumab 21%, atezolizumab 1%). Overall, 50 (38% of pts) developed an irAE.42% of irAEs were grade 1, 38% grade 2, 14% grade 3 and 6% grade 4. The most frequent irAEs were endocrinopathies in 17 pts (34%), followed by cutaneous toxicity in 9 pts (18%) and colitis and diarrhea in 7 pts (14%). A total of 373 unscheduled accesses were observed, 89 (24%) of them were due to irAEs: 78 were unplanned consultations in the oncology department and 11 in the emergency department. irAEs led to hospitalization in 14 pts for 118 days, cumulatively. Grade ≥ 2 colitis was the most frequent irAE associated with hospitalization, it occurred in 4 pts (29%). Colitis and diarrhea required the longest hospitalization (range 4-31 days). 48% (24 pts) required immunosuppressive treatment. Systemic steroids were the most common immunosuppressive agents used. Only one patient received infliximab as second line immunosuppressive treatment after steroid failure. Totally, irAEs required 67 specialist consultancies and additional diagnostic examinations. 15 pts required ICI discontinuation because of irAEs. Conclusions: In our center prevalence and severity of irAEs were similar to literature data. Considered the complexity of irAEs management, multidisciplinary approach and a trained hospital network plays a key role for a more efficient diagnostic and treatment work-up in pts who received ICI therapy and experienced irAEs.