Plasma Cell-Free RNA PD-L1 Expression and Clinical Outcomes With Immunotherapy

Author(s):  
S. Jayananda ◽  
M. Muzaffar ◽  
P. Namireddy ◽  
N. Sharma ◽  
P. Walker
2019 ◽  
Vol 37 (8_suppl) ◽  
pp. 103-103
Author(s):  
Nicolas Guibert ◽  
Greg Jones ◽  
John F. Beeler ◽  
Clive D. Morris ◽  
Vincent Plagnol ◽  
...  

103 Background: Tumor mutational burden is an emerging biomarker of response to immune checkpoint inhibitors (ICI), whose clinical adoption is challenging, especially in liquid biopsies. We hypothesized that targeting limited but relevant genetic alterations in plasma cell-free DNA with next generation sequencing (NGS) along with early monitoring may represent a non-invasive approach to predict response to ICI. Methods: Plasma samples from responders (PFS > 6 months) and non-responders (progressive disease at first evaluation) patients collected before nivolumab (second line) initiation and at 1 month were tested using tagged amplicon sequencing of hotspots and coding regions from 36 genes, blinded to clinical outcomes and tumor genotype. Molecular profile of ctDNA, and its early kinetics (1 month) were analyzed as potential early indicators of response. Results: 98 patients were analyzed, of which 86 (39 responders, 47 non-responders) were evaluable for response. Alterations in ctDNA were detectable in 67/86 baseline samples (78%). The detection of a targetable oncogenic driver (5 EGFR, 1 ALK) was associated with progressive disease on the first CT-scan The presence of a PTEN and/or STK11 mutations (b-PS(+)) was correlated with poor outcomes (median PFS 1.5 months vs. 8 months in b-PS(-)) patients, p = 0.0007), while the presence of transversion mutations in KRAS and/or TP53 (b-KP-Tv(+)) predicted good outcomes (median PFS 11 months vs. 2 months in b-KP-Tv(-) patients, p = 0.0088). Combining these results, patients with a low “immune score” (driver and/or b-PS(+) and/or b-KP-Tv(-)) derived poor outcomes (PFS 2 months), compared with patients with a high immune score (no driver, b-PS(-) and b-KP-Tv(+), PFS 14 months, p = 0.0001, HR 2.96). Studying early changes in 65 specimens, molecular response was correlated with clinical outcomes (14 months PFS in patients with early ctDNA decrease compared to 2 months in patients with increase, p < 0.0001; HR 2.7). Using cut-off of 30% and 50% of plasma response increased the ability of ctDNA to predict response (HR 4 and 4.17, respectively). Conclusions: Targeted sequencing of plasma ctDNA and its early variations can predict response to anti-PD-1. Clinical trial information: NCT02827344.


Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1086-1086
Author(s):  
Nelli Bejanyan ◽  
Aleksandr Lazaryan ◽  
Michael Clemente ◽  
Matthew Howard ◽  
Karl S. Theil ◽  
...  

Abstract Abstract 1086 Poster Board I-108 T-cell large granular lymphocyte (LGL) leukemia is a rare clonal lymphoproliferative disorder derived from cytotoxic T-lymphocytes (CTL) associated mostly with lineage-restricted cytopenias. While the clinical course is often indolent, some patients exhibit severe morbidities due to transfusion dependence, infections or thrombocytopenia. Intuitively, the level of the aberrant CTL clone as expressed by high LGL count or TCR Vβ clonal expansion by flow cytometry, the severity of neutropenia, pancytopenia, or the association with clonal myeloid disorders such as myelodysplastic syndromes (MDS) should herald a worse clinical outcome. Moreover, expression of CD56 has been established as an adverse marker for morbidity and mortality in number of hematological malignancies. In addition, rare cases of aggressive T-cell LGL leukemia were reported to display a CD3+/CD56+ immunophenotype. Based on the availability of a large, well characterized cohort of patients with T-cell LGL leukemia (n=86), we studied features associated with a poor clinical outcome and perceived need for aggressive therapy, including histomorphologic parameters, immunophenotype (CD56 expression). Both clinical response and overall survival (OS) were analyzed by means of categorical and survival statistical methods. The median patient age was 64 years (range, 15–80), and 55% were males. Rheumatoid arthritis was present in 14% of patients, 47% of patients had splenomegaly and 43% of those underwent splenectomy. Concomitant hematologic malignancies (5 cases of plasma cell dyscrasia, 8 with B-cell malignancies, and 3 with MDS/sAML) were found in 18% of patients, whereas solid cancers accounted for 15%. Neutropenia, anemia, and thrombocytopenia were seen in 63%, 50%, and 24%, respectively. Overall clinical response to a variety of therapies given was observed in 60% of patients. CD56 expression on the LGL clone was found in 15 patients (21%). Cases expressing CD56 were enriched among females (p=.005). CD56-positive cases were less likely to have neutropenia (p=.03) or thrombocytopenia (p=.03). In contrast to aggressive NK-cell lymphoma, the CD56 phenotype in T-cell LGL leukemia did not negatively impact OS (p=.85). However, increasing number of cytopenias (p=.006) were associated with poor survival. A dose-response pattern of association with OS was detected for pancytopenia (hazard ratio [HR]=9.9, p=.002) vs. bicytopenia (HR=4, p=.06) vs. single/none (reference) cytopenia. Similar results were obtained from logistic regression of factors associated with clinical response to therapeutic intervention. Neutropenia (p=.004) and thrombocytopenia (p=.02), but not anemia were associated with poorer clinical responses. All 5 patients with plasma cell dyscrasia had a complete response to the therapies targeting LGL (p=.01). Similarly, patients who underwent splenectomy tended to have a more favorable clinical response (p=.045). Multiple lineage cytopenias adversely affect both clinical outcomes and OS of T-cell LGL leukemia. In contrast to other diseases (T-cell acute lymphoblastic leukemia, AML, and multiple myeloma) a CD56+ immunophenotype was not associated with poor outcome in our cohort. Thus, as opposed to other studies, we would not suggest aggressive systemic chemotherapy in management of patients with T-cell LGL leukemia based purely on CD56 expression. Disclosures No relevant conflicts of interest to declare.


2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 159-159
Author(s):  
Edmond Michael Kwan ◽  
Chao Dai ◽  
Heidi Fettke ◽  
Christine Hauser ◽  
Patricia Bukczynska ◽  
...  

159 Background: Tumour tissue from metastatic castration-resistant prostate cancer (mCRPC) harbors frequent copy number variations (CNVs) in the phosphatidylinositol-3-kinase (PI3K)/Akt-signaling pathway. However, identifying CNVs in plasma cell-free DNA (cfDNA) has proven challenging. With emerging data supporting Akt inhibition in PTEN-deficient mCRPC, cfDNA assays for robustly identifying PI3K/Akt pathway aberrations including CNVs are urgently required. Methods: In this multi-institutional prospective biomarker study, we used the Predicine cfDNA assay, optimised for CNV detection, to perform targeted sequencing in 231 mCRPC patients in two independent cohorts (Australian, n = 78; US, n = 153). Kaplan-Meier survival estimates and multivariable Cox regression analysis were used to assess associations between genomic aberrations and progression-free survival (PFS) and overall survival (OS). Results: PTEN loss and PIK3CA gain were detected in 37% (85/231) and 17% (39/231) of patients, respectively. Poorer outcomes were observed in patients with PI3K/Akt pathway aberrations, including those with dual PTEN loss and PIK3CA gain (HR 2.3, 95% CI 1.2-4.4). Similarly, cumulative CNV burden in the PI3K/Akt and AR pathways (0 vs 1 vs ≥2 CNVs in Australian cohort: median OS 33.5 vs 17.2 vs 9.7 months, p< 0.001; 0 vs 1 vs ≥2 CNVs in US cohort: median OS 35.5 vs 14.3 vs 9.2 months, p< 0.001) was associated with significantly worse clinical outcomes. Notably, 21% (31/146) of PTEN-neutral patients harbored other alterations in the PI3K/Akt pathway. Conclusions: Our cfDNA assay readily detected PI3K/Akt pathway CNVs, with the prevalence of PTEN loss comparable to prior tissue sequencing studies. CNVs in the PI3K/Akt pathway were associated with deleterious clinical outcomes, especially when concurrent with AR gain. Additional PI3K/Akt pathway aberrations were found in approximately one-fifth of PTEN-neutral mCRPC. Collectively, our data demonstrate the potential utility of profiling cfDNA to facilitate and optimize patient selection for treatment with Akt inhibitors in mCRPC. [Table: see text]


2012 ◽  
Vol 136 (3) ◽  
pp. 268-276 ◽  
Author(s):  
Richard Attanoos

Context.—A diverse and complex variety of lymphoproliferative diseases may involve the serosa, with widely differing clinical outcomes encompassing a spectrum of benign and malignant conditions. Objective.—To review lymphoproliferative disease involving the serosa and to provide a practical approach to the evaluation of lymphoid and plasma cell infiltrates in the serosa, together with a review of various tumors and tumorlike conditions that may mimic lymphoproliferative disease. Data Sources.—Analysis of published literature. Conclusions.—All forms of hematologic malignancy may involve the various serosal sites, although this is usually observed as secondary involvement in persons with known lymph nodal, marrow-based, or extranodal disease. Primary pericardial, pleural, and peritoneal lymphomas are rare; many nonneoplastic conditions may mimic lymphoma and a variety of nonhematolymphoid tumors may simulate hematologic malignancies. An understanding of the role of ancillary tests, together with an appreciation of their limitations, will prevent misdiagnosis.


2017 ◽  
Vol 24 (1) ◽  
pp. 181-188 ◽  
Author(s):  
Lino Möhrmann ◽  
Helen J. Huang ◽  
David S. Hong ◽  
Apostolia M. Tsimberidou ◽  
Siqing Fu ◽  
...  

2021 ◽  
pp. 622-637
Author(s):  
Edmond M. Kwan ◽  
Chao Dai ◽  
Heidi Fettke ◽  
Christine Hauser ◽  
Maria M. Docanto ◽  
...  

PURPOSE Tumor tissue from metastatic castration-resistant prostate cancer (mCRPC) harbors frequent copy number variations (CNVs) in the PTEN-PI3K-AKT pathway. However, identifying CNVs in plasma cell–free DNA (cfDNA) has proven to be challenging. With emerging data supporting Akt inhibition in PTEN-deficient mCRPC, we profiled PTEN-PI3K-AKT pathway aberrations in patients with mCRPC using a novel cfDNA assay optimized for CNV detection. METHODS A next-generation sequencing–based cfDNA assay was used to profile 231 patients with mCRPC from two independent cohorts (Australian, n = 78; United States, n = 153). PTEN-PI3K-AKT pathway genomic aberrations were correlated with clinical outcomes, including progression-free survival and overall survival (OS). RESULTS PTEN loss and PIK3CA gain were detected in 37% (85 of 231) and 17% (39 of 231) of patients, respectively. Poorer outcomes were observed in patients with PTEN-PI3K-AKT pathway aberrations, including those with dual PTEN loss and PIK3CA gain (hazard ratio 2.3, 95% CI 1.2 to 4.4). Cumulative CNV burden in the PTEN-PI3K-AKT and androgen receptor (AR) pathways was associated with significantly worse clinical outcomes (0 v 1 v ≥ 2 CNVs in Australian cohort: median OS 33.5 v 17.2 v 9.7 months, P < .001; 0 v 1 v ≥ 2 CNVs in US cohort: median OS 35.5 v 14.3 v 9.2 months, P < .001). Notably, 21% (31 of 146) of PTEN-neutral patients harbored alternative PTEN-PI3K-AKT pathway aberrations. CONCLUSION PTEN-PI3K-AKT pathway CNVs were readily detected using our cfDNA assay, with the prevalence of PTEN loss comparable with tissue-based studies. Additional PTEN-PI3K-AKT pathway aberrations were found in one fifth of PTEN-neutral cases. Concurrent CNVs in the PTEN-PI3K-AKT and AR pathways portended poor survival, and identifying this high-risk patient subset for dual AR/Akt inhibition may optimize precision treatment with Akt inhibitors in mCRPC.


2012 ◽  
Vol 21 (4) ◽  
pp. 127-135 ◽  
Author(s):  
Cathy Binger ◽  
Jennifer Kent-Walsh

Abstract Clinicians and researchers long have recognized that teaching communication partners how to provide AAC supports is essential to AAC success. One way to improve clinical outcomes is to select appropriate skills to teach communication partners. Although this sometimes seems like it should be a straightforward component of any intervention program, deciding which skills to teach partners can present multiple challenges. In this article, we will troubleshoot common issues and discuss how to select skills systematically, resulting in the desired effects for both communication partners and clients.


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