Phenotypic variation of an ALK-positive large-cell neuroendocrine lung carcinoma with carcinoid morphology during treatment with ALK inhibitors

2017 ◽  
Vol 72 (4) ◽  
pp. 707-710 ◽  
Author(s):  
Delphine Hoton ◽  
Yves Humblet ◽  
Louis Libbrecht
Keyword(s):  
Lung Carcinoma ◽  
Phenotypic Variation ◽  
Large Cell ◽  
Alk Inhibitors ◽  
Alk Positive

scholarly journals TRAF1-ALK fusion indicates poor prognosis to ALK tyrosine kinase inhibitors in relapsed/refractory ALK-positive anaplastic large-cell lymphoma patients

2020 ◽  
Author(s):  
Diwen Pang ◽  
Ling Huang ◽  
Xinmiao Jiang ◽  
Feili Chen ◽  
Hanguo Guo ◽  
...  
Keyword(s):  
Anaplastic Large Cell Lymphoma ◽  
Poor Prognosis ◽  
Cell Lymphoma ◽  
Bone Marrow Involvement ◽  
Large Cell ◽  
Fusion Partner ◽  
Alk Inhibitors ◽  
Anaplastic Lymphoma ◽  
Large Cell Lymphoma ◽  
Alk Positive

Abstract Background Relapsed/refractory (R/R) anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) respond to ALK inhibitors, but resistance bears a poor prognosis. No biomarkers predict a long duration of response to ALK inhibitors. The ALK gene was first identified as the fusion partner of the nucleophosmin (NPM1) gene in recurrent t(2;5)(p23;q35) found in an ALCL subset. However, several distinct ALK fusions that result in highly different characteristics have also been described in lymphomas. Methods We retrospectively reviewed 43 patients with pathologically confirmed ALK-positive ALCL at Guangdong Provincial People’s Hospital from February 2007 through February 2020, including seven R/R patients who received ALK inhibitors (six with crizotinib and one with alectinib). We performed next-generation sequencing (NGS) with paraffin-embedded tissue for these seven R/R patients and one patient with a peripheral blood sample. We evaluated clinical characteristics and survival status. Results The median age of all patients was 29 (range 15–66) years. Most patients were male with advanced stage and B symptoms. The 5-year progression-free survival (PFS) and overall survival (OS) rates were 60% and 70%, respectively with a median follow-up of 52.2 (range 2.4–168.6) months. Multivariate analyses revealed that only bone marrow involvement was an independent prognostic factor for PFS (P = 0.03) and OS (P = 0.03). Of the seven R/R patients, the median line number of therapies was four (range 3–7) and that of ALK inhibitor usage was three (range 2–5). The overall response rate was 100% (n = 7). The NGS identified four patients with the NPM1-ALK fusion and two with tumor necrosis factor receptor-associated factor 1 gene (TRAF1)-ALK fusion; the latter quickly developed resistance to chemotherapy and ALK inhibitors. Conclusions ALK inhibitors improved survival of patients with R/R ALK-positive ALCLs. TRAF1-ALK fusion may predict a poor clinical outcome to chemotherapy and ALK inhibitors. This ALK fusion may reflect a trend toward the aggressive behavior of lymphomas.

scholarly journals TRAF1-ALK Fusion Predicts Poor Prognosis for ALK Positive Anaplastic Large Cell Lymphoma Patients with Chemotherapy and ALK Inhibitor

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5224-5224
Author(s):  
Ling Huang ◽  
Xinmiao Jiang ◽  
Hanguo Guo ◽  
Liu Sichu ◽  
Xiaojuan Wei ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Poor Prognosis ◽  
Large Cell ◽  
Fusion Partner ◽  
Alk Inhibitors ◽  
Alk Inhibitor ◽  
Alk Positive ◽  
Exon 20

Background: Relapsed/refractory anaplastic lymphoma kinase (ALK) positive anaplastic large cell lymphomas (ALCLs) respond to ALK inhibitors, but resistance, which bear a poor prognosis. No biomarkers were found to predict long duration of response to ALK inhibitors. The ALK gene was first identified as the fusion partner of the nucleophosmin (NPM1) gene in the recurrent t(2;5)(p23;q35) found in a subset of ALCL. However, several distinct ALK fusions which result in highly different characteristics have also been described in lymphomas. Methods: We retrospectively reviewed seven relapsed/refractory ALK positive ALCLs who received ALK inhibitors (six with Crizotinib and one with Alectinib) at Guangdong Provincial People's Hospital from June 2007 through March 2019. We did next generation sequencing (NGS) with paraffin-embedded tissue for two patients who quickly developed resistance. Results: Of the seven patients, four were male and three were female, with a median age of 18 years (range 15-51) old. The median line of therapies was four (range 3-7) and that of ALK inhibitor usage was three (range 2-5). The overall response rate was 7 of 7 (100%) and the median overall survival of 21.2 months (8.5-86 months). Three patients obtained complete response (CR) on Crizotinib and then received autologous stem cell transplantation, and are still CR. One patient obtained CR, but died of serious infection five months after allogeneic stem cell transplantation. One patient is in CR under continuous crizotinib administration. One patient received Crizotinib obtained CR, but three months later got progression disease, the NGS showed TNF receptor-associated factor 1 gene (TRAF1) exon 6-ALK exon 20 fusion junction. The last patient was CR on alectinib, but quickly developed resistance, with a progression free survival of 1 month, the NGS indicated TRAF1 exon 7-ALK exon 20 fusion. Conclusions: ALK inhibitors improved survival of relapsed/refractory ALK positive ALCLs. TRAF1-ALK fusion may predict poor clinical outcome to chemotherapy and ALK inhibitors. This ALK fusion may reflect a trend to aggressive behaviour in lymphomas. Disclosures Li: Guangdong Province Hospital: Employment.

Establishment and Characterization of a Patient-Derived Model of ALK-Positive Anaplastic Large Cell Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5121-5121
Author(s):  
Michael J Wick ◽  
Elena Helman ◽  
Teresa L Vaught ◽  
Monica Farley ◽  
Drew W Rasco ◽  
...  
Keyword(s):  
Research Funding ◽  
Clinical Course ◽  
Cell Lymphoma ◽  
Treatment Options ◽  
Large Cell ◽  
Alk Inhibitors ◽  
Pdx Model ◽  
Large Cell Lymphoma ◽  
Alk Positive

Abstract Background: Anaplastic large cell lymphoma (ALCL) is an uncommon, aggressive CD30-positive T-cell lymphoma exhibiting or lacking chromosomal translocation involving the Anaplastic Lymphoma Kinase (ALK) gene and expression of ALK protein. ALK positive ALCL (ALK+-ALCL) typically has an improved prognosis compared with ALK-negative; however, patients often respond favorably to standard chemotherapy and CD30-directed immunoconjugates only to progress and are left with few treatment options. To help identify additional treatment options, we collected tumor tissue and established, characterized and evaluated in vivo an ALK+-ALCL patient-derived xenograft (PDX) model from a thirty one year old Caucasian female with relapsed ALCL following initial therapy with a pediatric S-phase specific regimen. Methods: The ST2698 ALK+-ALCL model was established in CB17 SCID mice using tissue collected from a lymph node tumor biopsy. Clinical tissue, patient blood and the PDX model were subjected to WGS sequencing using an augmented and content-enhanced exome. The augmented exome is optimized to detect major cancer mutations by enhancing coverage over known sequencing gaps and GC-rich regions across >1300 cancer and 200 miRNA genes. We also performed whole-transcriptome sequencing on the PDX model. All data were analyzed using a cancer bioinformatics pipeline optimized for high accuracy detection of small variants and indels, somatic copy-number aberrations, gene expression and fusions. Drug sensitivity studies were performed evaluating sensitivity of the model to patient's current clinical treatment and relevant targeted therapies; study endpoints included tumor volume and time from treatment initiation with tumor growth inhibition, delay and regression reported at study completion. Results: Exome analysis identified several variants which were confirmed by transcriptome data. Efficacy studies confirmed model sensitivity to the patient's current clinical course (CHOP). In addition, ST2698 was found moderately sensitive to the IMiD lenalidomide (T/C=47%). However, treatment with the ALK-inhibitors crizotinib or ceritinib resulted in tumor regressions including durable complete responses in some mice. Conclusion: We have established and characterized a patient-derived ALK+-ALCL xenograft model using DNA and RNA-based analysis. In addition we evaluated the model in vivo and confirmed sensitivity to the patient's current clinical course and identified two ALK inhibitors as active, including reported complete tumor regressions. Disclosures Rasco: Celgene: Research Funding; Asana BioSciences, LLC: Research Funding. Tolcher:Asana BioSciences, LLC: Consultancy, Research Funding; AbbVie: Consultancy; ArQule: Consultancy; Bayer: Consultancy; BioMed Valley Discoveries: Research Funding; Janssen R&D: Consultancy.

Peripheral T-cell repertoire alterations are common and affect outcome in large cell neuroendocrine lung carcinoma

Pneumologie ◽  
2018 ◽  
Vol 72 (S 01) ◽  
pp. S53-S54
Author(s):  
P Christopoulos ◽  
M Schneider ◽  
F Bozorgmehr ◽  
W Engel-Riedel ◽  
C Kropf-Sanchen ◽  
...  
Keyword(s):  
T Cell ◽  
Lung Carcinoma ◽  
Large Cell ◽  
T Cell Repertoire ◽  
Cell Repertoire

scholarly journals Increased Tenascin C, Osteopontin and HSP90 Levels in Plasmatic Small Extracellular Vesicles of Pediatric ALK-Positive Anaplastic Large Cell Lymphoma: New Prognostic Biomarkers?

Diagnostics ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 253
Author(s):  
Federica Lovisa ◽  
Anna Garbin ◽  
Sara Crotti ◽  
Piero Di Battista ◽  
Ilaria Gallingani ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Enrichment Analysis ◽  
Heat Shock Protein 90 ◽  
Large Cell ◽  
Tenascin C ◽  
Anaplastic Lymphoma ◽  
Large Cell Lymphoma ◽  
Alk Positive

Over the past 15 years, several biological and pathological characteristics proved their significance in pediatric anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALCL) prognostic stratification. However, the identification of new non-invasive disease biomarkers, relying on the most important disease mechanisms, is still necessary. In recent years, plasmatic circulating small extracellular vesicles (S-EVs) gathered great importance both as stable biomarker carriers and active players in tumorigenesis. In the present work, we performed a comprehensive study on the proteomic composition of plasmatic S-EVs of pediatric ALCL patients compared to healthy donors (HDs). By using a mass spectrometry-based proteomics approach, we identified 50 proteins significantly overrepresented in S-EVs of ALCL patients. Gene Ontology enrichment analysis disclosed cellular components and molecular functions connected with S-EV origin and vesicular trafficking, whereas cell adhesion, glycosaminoglycan metabolic process, extracellular matrix organization, collagen fibril organization and acute phase response were the most enriched biological processes. Of importance, consistently with the presence of nucleophosmin (NPM)-ALK fusion protein in ALCL cells, a topological enrichment analysis based on Reactome- and Kyoto Encyclopedia of Genes and Genomes (KEGG)-derived networks highlighted a dramatic increase in proteins of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway in ALCL S-EVs, which included heat shock protein 90-kDa isoform alpha 1 (HSP90AA1), osteopontin (SPP1/OPN) and tenascin C (TNC). These results were validated by Western blotting analysis on a panel of ALCL and HD cases. Further research is warranted to better define the role of these S-EV proteins as diagnostic and, possibly, prognostic parameters at diagnosis and for ALCL disease monitoring.

scholarly journals Crizotinib Resistance Mediated by Autophagy Is Higher in the Stem-Like Cell Subset in ALK-Positive Anaplastic Large Cell Lymphoma, and This Effect Is MYC-Dependent

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 181
Author(s):  
Chuquan Shang ◽  
Bardes Hassan ◽  
Moinul Haque ◽  
Yuqi Song ◽  
Jing Li ◽  
...  
Keyword(s):  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Cell Subset ◽  
Large Cell ◽  
Autophagic Flux ◽  
Cytoprotective Effect ◽  
Direct Role ◽  
Large Cell Lymphoma ◽  
Alk Positive ◽  
First Time

Previously it was shown that autophagy contributes to crizotinib resistance in ALK-positive anaplastic large cell lymphoma (ALK + ALCL). We asked if autophagy is equally important in two distinct subsets of ALK + ALCL, namely Reporter Unresponsive (RU) and Reporter Responsive (RR), of which RR cells display stem-like properties. Autophagic flux was assessed with a fluorescence tagged LC3 reporter and immunoblots to detect endogenous LC3 alongside chloroquine, an autophagy inhibitor. The stem-like RR cells displayed significantly higher autophagic response upon crizotinib treatment. Their exaggerated autophagic response is cytoprotective against crizotinib, as inhibition of autophagy using chloroquine or shRNA against BECN1 or ATG7 led to a decrease in their viability. In contrast, autophagy inhibition in RU resulted in minimal changes. Since the differential protein expression of MYC is a regulator of the RU/RR dichotomy and is higher in RR cells, we asked if MYC regulates the autophagy-mediated cytoprotective effect. Inhibition of MYC in RR cells using shRNA significantly blunted crizotinib-induced autophagic response and effectively suppressed this cytoprotective effect. In conclusion, stem-like RR cells respond with rapid and intense autophagic flux which manifests with crizotinib resistance. For the first time, we have highlighted the direct role of MYC in regulating autophagy and its associated chemoresistance phenotype in ALK + ALCL stem-like cells.

Genomic profiling of pediatric ALK-positive anaplastic large cell lymphoma: A Children's Cancer and Leukaemia Group Study

2009 ◽  
Vol 48 (11) ◽  
pp. 1018-1026 ◽  
Author(s):  
Catrin Youssif ◽  
Jan Goldenbogen ◽  
Rifat Hamoudi ◽  
Joaquim Carreras ◽  
Maria Viskaduraki ◽  
...  
Keyword(s):  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Genomic Profiling ◽  
Large Cell Lymphoma ◽  
Alk Positive
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