$Treatment of Refractory ALK Rearranged Anaplastic Large Cell Lymphoma With Alectinib$

Treatment of Refractory ALK Rearranged Anaplastic Large Cell Lymphoma With Alectinib

Discussion: ALK translocations, most commonly involving chromosome 2 translocations resulting in EML4-ALK fusion, occur in approximately 3% to 5% of lung adenocarcinomas. Therapies targeting the ALK tyrosine kinase have been well studied in patients with ALK-rearranged NSCLC. The first generation ALK-tyrosine kinase inhibitor, crizotinib, was approved for use in ALK-rearranged NSCLC in 2011 based on the PROFILE 1001 study and received full United States Food and Drug Administration approval after... Conclusion: In summary, to the authors' knowledge, this is the first published case of a patient with ALK-rearranged ALCL successfully treated with alectinib. Given the rapid progression and the significant neurologic toxicities related to the primary treatment with CHOEP, our patient had limited second-line treatment options. Within 2 months of therapy with alectinib, he experienced resolution of fever and had an impressive and sustained radiographic response on PET/CT imaging, which allowed him to... READ ARTICLE

Clinical Lymphoma Myeloma and Leukemia DOI:10.1016/j.clml.2019.03.001

Authors: Daniel R. Reed, Richard D. Hall, Ryan D. Gentzler, Leonid Volodin, Michael G. Douvas, Craig A. Portell

A Complex Renal Cyst in a Patient on Crizotinib: Case Report

Crizotinib is a first generation tyrosine kinase inhibitor for ALK gene positive nonsmall cell lung cancer (ALK + NSCLC). The FDA approved its use in 2011. 1 There has been a recent recognition of crizotinib-associated renal cysts (CARCs). READ ARTICLE

Urology DOI:10.1016/j.urology.2019.04.035

Authors: Christine W. Liaw, Michael Palese, Larry Di Fabrizio

Case StudyKirk SmithMay 9, 2019Renal, Cyst, Crizotinib

Indoor Radon in EGFR- and BRAF-Mutated and ALK-Rearranged Non–Small-Cell Lung Cancer Patients

Background: Radon gas is the leading cause of lung cancer in the nonsmoking population. The World Health Organization (WHO) recommends indoor concentrations of < 100 Bq/m³. Several molecular alterations have been described in non–small-cell lung cancer (NSCLC), mainly in nonsmokers, with no risk factors identified. We studied the role of indoor radon in NSCLC patients harboring specific driver alterations. Conclusion: The median indoor radon concentration was above the WHO recommendations, with no differences between EGFR, ALK, and BRAF patients. Concentrations above the WHO recommendations were most common with ALKr and BRAFm. These findings should be validated in larger studies. READ ARTICLE

Clinical Lung Cancer DOI:10.1016/j.cllc.2019.04.009

Authors: Laura Mezquita, Amparo Benito, Alberto Ruano-Raviña, Javier Zamora,Maria Eugenia Olmedo, Pablo Reguera, Ainhoa Madariaga, María Villamayor, Silvia Patricia Cortez, Luis Gorospe, Almudena Santón, Sagrario Mayoralas, Raúl Hernanz, Alberto Cabañero, Edouard Auclin, Alfredo Carrato, Pilar Garrido

Case StudyKirk SmithMay 3, 2019Driver oncogene, Radioactivity, Radon gas, NSCLC

Isolated 5′ Signals Are an Atypical Pattern To Be Considered as Positive for ALK Rearrangement: A Brief Report of Three Cases and Review of the Literature

Anaplastic lymphoma kinase (ALK) rearrangement is reported in 3% to 8% of patients with lung adenocarcinoma and can be detected by fluorescent in situ hybridization (FISH) or indirectly by immunohistochemistry. In FISH assay, isolated 5′ signal (loss of 3′ signal) is usually considered negative. We report three young nonsmoking patients with stage IV lung adenocarcinoma. Strong ALK expression in tumor cells detected by immunohistochemistry was observed in all cases, but FISH revealed an isolated 5′ signal pattern. Massive parallel “next-generation” sequencing was performed in two patients and confirmed ALK rearrangement. The three patients were treated and responded to crizotinib after 14, 10, and 31 months. READ ARTICLE

Translational Oncology DOI:10.1016/j.tranon.2019.02.015

Authors: Alice Guyard, Cécile Charpy, Nathalie Théou-Anton,Anne Cremades, Frédéric Grassin, Anaïs Bourgogne, Karen Leroy, Anaïs Pujals, Christiane Copie-Bergman, Christos Chouaid, Audrey Mansuet-Lupo

Case StudyKirk SmithMay 1, 2019Isolated 5′ Signals, ALK Rearrangement

Expanding the Molecular Characterization of Thoracic Inflammatory Myofibroblastic Tumors beyond ALK Gene Rearrangements

Introduction: Half of inflammatory myofibroblastic tumors (IMTs) regardless of anatomic location harbor anaplastic lymphoma kinase gene (ALK) rearrangements and overexpress anaplastic lymphoma kinase protein. The wide application of next-generation sequencing and the clinical benefit to tyrosine kinase inhibitors have opened new opportunities for investigation of ALK-negative IMTs. Conclusions: By using a battery of complementary molecular techniques, we have shown that all the thoracic IMTs harbored a tyrosine kinase abnormality, with 30% involving a kinase gene other than ALK, including ROS1, NTRK3, and RET gene fusions. We have also described for the first time ALKATI-induced ALK oncogenic activation in IMTs. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2018.12.003

Authors: Jason C. Chang, Lei Zhang, Alexander E. Drilon, Ping Chi, Rita Alaggio, Laetitia Borsu, Ryma Benayed, William D. Travis, Marc Ladanyi, Cristina R. Antonescu

Case StudyKirk SmithMay 1, 2019Inflammatory myofibroblastic tumor (IMT), ALK, ROS1, NTRK3, Fusion, Kinase

Fusion of ALK to the melanophilin gene MLPH in pediatric Spitz nevi

Spitzoid neoplasms typically affect young individuals and include Spitz nevus, atypical Spitz tumor, and Spitzoid melanoma. Spitz tumors can exhibit gene fusions involving the receptor tyrosine kinases NTRK1, NTRK3, ALK, ROS1, RET, or MET, or the serine-threonine kinase BRAF. Because most studies have been based on adult cases, we studied ALK fusions in Spitz nevi occurring in pediatric patients. Twenty-seven cases were screened for ALK expression by immunohistochemistry, and 6 positive cases were identified. These cases were studied further using the TruSight RNA Fusion Panel, and in 4 cases, exon 20 of the ALK gene was found to be fused to exon 14 of the MLPH (melanophilin) gene, a gene fusion that has only been reported in a Spitz nevus in an adult. The remaining 2 cases showed no fusion of ALK with any gene. The cases with the MLPH-ALK fusion showed a similar histology to that described for Spitz nevi with ALK fusions, with spindle-shaped and epithelioid melanocytes in fusiform nes..... READ ARTICLE

Human Pathology DOI:10.1016/j.humpath.2019.03.002

Authors: Catherine T. Chung, Paula Marrano, David Swanson, Brendan C. Dickson, Paul Scott Thorner

Intra-cranial efficacy of brigatinib in an ALK-positive non-small cell lung cancer patient presenting leptomeningeal carcinomatosis

Objectives: Brigatinib is a second-generation ALK inhibitor which demonstrated activity over crizotinib-resistance, especially on brain metastasis by increased blood-brain penetration. However, its activity on lepto-meningeal disease is unknown and scarcely reported. Conclusion: Our case provides additional data on brigatinib’s intracranial activity, not only on brain metastasis but also on leptomeningeal disease, after experiencing resistance to both crizotinib and ceretinib, 1st and 2nd generation ALK inhibitors. READ ARTICLE

Lung Cancer
DOI:10.1016/j.lungcan.2019.04.013

Authors: Elisabeth Gaye, Margaux Geier, Paul Bore, Marine Guilloïque, Francois Lucia, Gilles Quéré, Sylvie Gouva, Gilles Robinet, Renaud Descourt

Refinement of diagnosis and supporting evidence for the use of immunotherapy through sequential biopsies in a case of EML4-ALK positive lung cancer

In this case report, we describe a tortuous, yet rare, treatment process of the patient. The first biopsy of the patient suggested inflammatory myofibroblastic tumor, ALK (D5F3) positive. Considering the benign progression of the disease, and no indication for surgical resection, oral prednisone was given first. However, the disease rapidly progressed, and a second biopsy revealed a pulmonary sarcomatoid cancer. Since the biopsy was ALK (D5F3) positive, the effect of crizotinib treatment was significant, though crizotinib resistance unfortunately only occurred after 4 months. The third biopsy pathology was performed and confirmed lung adenocarcinoma. After switching to pembrolizumab treatment, the lesions were significantly reduced after four courses of treatment. The current condition of patient persisted in partial response. READ ARTICLE

OncoTargets and Therapy DOI:10.2147/OTT.S203192

Authors: Peng Song, Jingcheng Zhang, and Li Zhang

Case StudyKirk SmithApril 17, 2019Sequential biopsies, EML4-ALK, immunotherapy, lung adenocarcinoma

Anaplastic Lymphoma Kinase (ALK)-positive Tumors: Clinical, Radiographic and Molecular Profiles, and Uncommon Sites of Metastases in Patients With Lung Adenocarcinoma

Introduction: Anaplastic lymphoma kinase (ALK) gene rearrangements are observed in about 4% to 8% non-small cell lung cancer (NSCLC). ALK+ tumors have been associated with increased pleural and pericardial disease. Our primary objective was to determine the uncommon sites of metastasis of ALK+ NSCLC. Secondary objectives included study of coexisting mutations and factors impacting survival of ALK+ NSCLC. Conclusion: In NSCLC, ALK rearrangements may not be mutually exclusive mutations and can present with unique radiographic patterns. Patients with uncommon sites of metastasis may have worse outcomes. READ ARTICLE

American Journal of Clinical Oncology
DOI:COC.0000000000000508

Authors: Rohan Gupta, Idoroenyi Amanam, Syed Rahmanuddin, Isa Mambetsariev, Yingyu Wang, Charity Huang, Karen Reckamp, Lalit Vora, Ravi Salgia

Genomic alterations and survival in young patients aged under 40 years with completely resected non-small cell lung cancer

Background: Young patients are rarely diagnosed with non-small cell lung cancer (NSCLC), and little is known about its predisposing genomic alterations and survival. Conclusions: Younger patients with NSCLC had a higher frequency of gene fusions than older patients and had a trend of worse OS. READ ARTICLE

Annals of Translational Medicine DOI:10.21037/atm.2019.03.39

Authors: Shifeng Yang, Zhengbo Song, Guoping Cheng

$Squamous Cell Transformation of Primary Lung Adenocarcinoma in a Patient With EML4-ALK Fusion Variant 5 Refractory to ALK Inhibitors$

Squamous Cell Transformation of Primary Lung Adenocarcinoma in a Patient With EML4-ALK Fusion Variant 5 Refractory to ALK Inhibitors

Background: Originally discovered in lymphomas,1 the ALK fusion oncogene with gain-of-function cytoplasmic tyrosine kinase activity has since been identified as an oncogenic driver in 3% to 10% of patients with non–small cell lung cancer (NSCLC).2,3 FDA approval of crizotinib, a small molecule ALK tyrosine kinase inhibitor (TKI), only 3 years after the discovery of the ALK fusion oncogene represents one of the most rapid bench-to-bedside translational advances in the history of targeted cancer therapy.4 Among the many fusion partners that have been reported, EML4 is the most common gene partner of ALK through a paracentric inversion of chromosome 2 inv(2) (p21;p23). We previously reported that in a cohort of 200 NSCLC specimens, the EML4-ALK–positive transcripts included 109 variant 1 (V1; 54.5%), 20 V2 (10.0%), 68 V3 (34.0%), and 3 V5a (1.5%) variants.5 Most (n=188; 94.0%) EML4-ALK–positive NSCLC tumors had adenocarcinoma histology... Conclusions: To our knowledge, this is the first..... READ ARTICLE

Journal of National Comprehensive Cancer Network DOI:10.6004/jnccn.2019.7291

Authors: Jay Gong, Jeffrey P. Gregg, Weijie Ma, Ken Yoneda, Elizabeth H. Moore, Megan E. Daly, Yanhong Zhang, Melissa J. Williams, Tianhong Li

SRBD1-ALK, a Novel ALK Fusion Gene Identified in an Adenocarcinoma Patient by Next-Generation Sequencing

... Here, we report a case of adenocarcinoma harboring a novel S1 RNA binding domain 1 (SRBD1)–ALK fusion gene identified accidentally during routine molecular profiling by next-generation sequencing... Without any other oncogenic mutation detected, we speculate that the novel SRBD1-ALK fusion served as a driver mutation of the patient’s disease. And ALK TKIs might be effective in the treatment of tumors with this new fusion gene. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2018.11.027

Authors: Xue Hou, Huamin Xu, Likun Chen

Case StudyKirk SmithApril 1, 2019SRBD1-ALK, ALK Fusion, Adenocarcinoma, Next-Generation Sequencing

Ceritinib-related interstitial lung disease improving after treatment cessation without recurrence under either crizotinib or brigatinib: a case report

Anaplastic lymphoma kinase inhibitors (ALKi) like ceritinib are considered standard for front-line treatment of non-small cell lung cancers (NSCLC) harboring a translocation of the anaplastic lymphoma kinase (ALK) gene. We report herein a case of interstitial lung disease (ILD) that developed following a 7-month ceritinib treatment without recurrence under either crizotinib or brigatinib, two others ALKi. READ ARTICLE

Annuals of Translational Medicine DOI:10.21037/atm.2019.01.24

Authors: Laura Bender, Guillaume Meyer, Elisabeth Quoix and Bertrand Mennecier

Lorlatinib Salvages CNS Relapse in an ALK-Positive Non–Small-Cell Lung Cancer Patient Previously Treated With Crizotinib and High-Dose Brigatinib

To our knowledge, this is the first detailed case of an anaplastic lymphoma kinase (ALK)-positive patient with central nervous system (CNS) disease who experienced clinical benefit with lorlatinib after disease progression during treatment with high-dose brigatinib.
The efficacy of lorlatinib might reflect activity against an interval change in the biology of ALK-positive CNS disease occurring after initial brigatinib benefit that was not able to be suppressed by brigatinib. READ ARTICLE

Clinical Lung Cancer DOI:10.1016/j.cllc.2018.11.010

Authors: Mandy R. Sakamoto, Justin M. Honce, Deborah L. Lindquist, D. Ross Camidge

Case StudyKirk SmithMarch 1, 2019ALK, Brigatinib, CNS, Lorlatinib

Identification and Development of a Lung Adenocarcinoma PDX Model With STRN-ALK Fusion

Gene fusions involving the anaplastic lymphoma kinase gene (ALK) often leads to oncogenic activation of the ALK kinase resulting in tumor development in lung and other solid tumors. Accurate identification of the fusion gene in patients with lung cancer has profoundly impacted patients’ clinical performance and long-term survival. READ ARTICLE

Clinical Lung Cancer DOI:10.1016/j.cllc.2018.11.002

Authors: Hongzheng Ren, Xiaonan Hou, Patrick W. Eiken, Jin Zhang, Karlyn E. Pierson, Asha A. Nair, Jaime I. Davila, Helena Kovarikova, Jin Sung Jang, Sarah H. Johnson, Julian R. Molina, Randolph S. Marks, Ping Yang, Joanne E. Yi, Aaron S. Mansfield, Jin Jen

Discovery and Characterization of Recurrent, Targetable ALK Fusions in Leiomyosarcoma

A subset of leiomyosarcomas harbor previously unrecognized oncogenic ALK fusions that are highly responsive to ALK inhibitors and thus these data emphasize the importance of detailed genomic investigations of leiomyosarcoma tumors. Overall, these findings suggest that some soft-tissue sarcomas may harbor previously unknown kinase gene translocations, and their discovery may propel new therapeutic strategies in this treatment-refractory cancer. READ ARTICLE

Molecular Cancer Research DOI:10.1158/1541-7786.MCR-18-1075

Authors: Lara E. Davis, Kevin D. Nusser, Joanna Przybyl, Janét Pittsenbarger, Nicolle E. Hofmann, Sushama Varma, Sujay Vennam, Maria Debiec-Rychter, Matt van de Rijn and Monika A. Davare

Case StudyKirk SmithMarch 1, 2019leiomyosarcoma, ALK rearrangements, KANK2-ALK, ACTG2-ALK, Lorlatinib

Gastric CLTC-ALK fusion-positive inflammatory myofibroblastic tumor showing an endoscopic superficial depressed-type appearance

We present a 76-year-old Japanese male who had a history of removal of a gastric gastrointestinal stromal tumor (GIST) 6 years ago. Although asymptomatic and having no evidence of recurrence, follow-up endoscopy revealed a small, white depressed lesion of approximately 1 cm with converging mucosal folds in the greater curvature of the fundus, which was suspicious of depressed-type early gastric cancer (GC) by conventional endoscopy. However, no evidence of GC except a “white globe appearance”-like area was identified by magnifying endoscopy with blue laser imaging. The biopsy specimens showed a proliferation of anaplastic lymphoma kinase (ALK)-positive spindle cells in the gastric mucosa, and ALK-rearrangement was detected by fluorescent in situ hybridization. Furthermore, clathrin heavy chain (CLTC)-ALK fusion was seen by genetic analysis, thus the lesion was preoperatively diagnosed as gastric inflammatory myofibroblastic tumor (IMT). For the curative intent, a laparoscopic endoscopi..... READ ARTICLE

Human Pathology DOI:10.1016/j.ehpc.2018.12.005

Authors: Mai Nakanishi, Jiro Watari, Toshihiko Tomita, Yasutaka Nakanishi, Yoshitane Tsukamoto, Shohei Matsuo, Takashi Uchihashi, Junichi Miyazaki, Hironori Tanaka, Shoudou Kojima, Nobukazu Kuroda,Ikuo Matsuda, Hiroto Miwa, Hisashi Shinohara, Seiichi Hirota

Case StudyKirk SmithMarch 1, 2019Stomach, Superficial depressed-type, IMT, CLTC-ALK fusion

Case Report: Temporal Heterogeneity of ALK Activating Mutations in Sequential ALK TKI–Treated Non–Small-Cell Lung Cancer Revealed Using NGS-Based Liquid Biopsy

Mutation profiling using liquid biopsy has become a promising approach for monitoring tumor genomic evolution when tissue biopsy is not available. READ ARTICLE

Clinical Lung Cancer DOI:10.1016/j.cllc.2019.02.014

Authors: MeijuanDing, Lili Deng, Ruoying Yu, Dan Lu, Yun Bai, Xue Wu, Yang W. Shao, Yu Yang

Next-generation Sequencing for ALK and ROS1 Rearrangement Detection in Patients With Non–small-cell Lung Cancer: Implications of FISH-positive Patterns

Background: Detection of ALK and ROS1 gene rearrangements in non–small-cell lung cancer is required for directing patient care. Although fluorescence in situ hybridization (FISH) and immunohistochemistry have been established as gold standard methods, next-generation sequencing (NGS) platforms are called to be at least equally successful. Comparison of these methods for translation into daily use is currently under investigation. Conclusion: Our data support that the identification of 3' isolated signal FISH pattern in ALK and ROS1 cases might suggest a false-positive result. NGS seems a reliable technique to assess ALK and ROS1 rearrangements, offering the advantage over immunohistochemistry of detecting other molecular alterations with potential therapeutic implications. READ ARTICLE

Clinical Lung Cancer DOI:10.1016/j.cllc.2019.02.008

Authors: Sergi Clavé, Natalia Rodon, Lara Pijuan, Olga Díaz, Marta Lorenzo, Pedro Rocha, Álvaro Taus, Remei Blanco, Joaquim Bosch-Barrera, Noemí Reguart, Noelia de la Torre, Glòria Oliveras, Blanca Espinet, Beatriz Bellosillo, Xavier Puig, Edurne Arriola, Marta Salido

Discordance between FISH, IHC, and NGS Analysis of ALK Status in Advanced Non–Small Cell Lung Cancer (NSCLC): a Brief Report of 7 Cases

BACKGROUND: Anaplastic lymphoma kinase (ALK) rearrangement represents a landmark in the targeted therapy of non–small cell lung cancer (NSCLC). Immunohistochemistry (IHC) is a sensitive and specific method to detect ALK protein expression, possibly an alternative to fluorescence in situ hybridization (FISH). In this study, the concordance of FISH and IHC to determine ALK status was evaluated, particularly focusing on discordant cases. In our discordant cases, a coexistent complex pattern (deleted, split, and amplified/polysomic) of ALK gene was observed by FISH analysis. These complex rearranged cases were not detectable by IHC, and it could be speculated that more complex biological mechanisms could modulate protein expression. These data highlight the role of IHC and underscore the complexity of the genetic pattern of ALK. It could be crucial to consider these findings in order to best select patients for anti-ALK treatment in daily clinical practice. READ ARTICLE

Translational Oncology
DOI:10.1016/j.tranon.2018.11.006

Authors: Anna Scattone, Annamaria Catino, Laura Schirosi, Lucia Caldarola, Stefania Tommasi, Rosanna Lacalamita, Elisabetta Sara Montagna, Domenico Galetta, Gabriella Serio, Francesco Alfredo Zito, Anita Mangia

Case StudyKirk SmithFebruary 1, 2019FISH, IHC, NGS, ALK Status, Advanced Non–Small Cell Lung Cancer (NSCLC)