Novel treatment of endobronchial inflammatory myofibroblastic tumor in a child

Isolated endobronchial inflammatory myofibroblatic tumors (IMT) are rare, accounting for about 1% of primary endobronchial tumors in children. The mainstay of treatment for this tumor has been surgical resection. Recently, the identification of anaplastic lymphoma kinase (ALK) gene mutations in half of the IMTs and promising results of treatment with ALK inhibitors in other ALK-positive tumors have opened the possibility of alternative approaches. We present a 4-year-old child with an ALK-positive endobronchial IMT, treated with endoscopic resection and neoadjuvant therapy with Crizotinib, without evidence of tumor recurrence 2 years after the initial resection. READ ARTICLE

Pediatric Pulmonology DOI:10.1097/CAD.0000000000001224

Authors: Jessica Reyes-Angel, Louis B. Rapkin, Jeffrey P. Simons and Hiren Muzumdar

Lorlatinib in a Child with ALK-Fusion–Positive High-Grade Glioma

A child near death with an ALK-fusion–positive high-grade glioma refractory to standard treatment had a dramatic response when treatment with lorlatinib was begun. The drug was stopped once the child had an apparent complete remission, but treatment with lorlatinib resumed when relapse occurred 6 months later. At this time, the child is attending preschool and has normal neurologic function. READ ARTICLE

New England Journal of Medicine DOI:10.1056/NEJMc2101264

Authors: Aditi Bagchi, Brent A Orr, Olivia Campagne, Sandeep Dhanda, Sreenath Nair, Quynh Tran, Anthony M Christensen, Amar Gajjar, Larissa V Furtado, Aksana Vasilyeva, Frederick Boop, Clinton Stewart and Giles W Robinson

Case Study, group3Kirk SmithAugust 19, 2021ALK, glioma, loraltinib, pediatric

$Activity of Crizotinib in Patients with ALK-Aberrant Relapsed/Refractory Neuroblastoma: A Children's Oncology Group Study (ADVL0912)$

Activity of Crizotinib in Patients with ALK-Aberrant Relapsed/Refractory Neuroblastoma: A Children's Oncology Group Study (ADVL0912)

Anaplastic lymphoma kinase (ALK) aberrations are a promising target for patients with neuroblastoma. We assessed the activity of first-generation ALK inhibitor crizotinib in patients with no known curative treatments and whose tumors harbored an activating ALK alteration. The objective response rate for patients with neuroblastoma was 15% [95% confidence interval (CI): 3.3%–34.3%]: two with partial responses and 1 with a complete response. All three patients had a somatic ALK Arg1275Gln mutation, the most common ALK hotspot mutation observed in neuroblastoma and the only mutation predicted to be sensitive to ALK inhibition with crizotinib. Two patients had prolonged stable disease (10 and 13 cycles, respectively); both harbored an ALK Arg1275Gln mutation. Three patients with ALK Phe1174Leu mutations progressed during cycle 1 of therapy, and one patient with an ALK Phe1174Val received three cycles before disease progression. The two patients with ALK amplification had no response. The ..... READ ARTICLE

Clinical Cancer Research DOI:10.1158/1078-0432.CCR-20-4224

Authors: Jennifer H. Foster, Stephan D. Voss, David C. Hall, Charles G. Minard, Frank M. Balis, Keith Wilner, Stacey L. Berg, Elizabeth Fox, Peter C. Adamson, Susan M. Blaney, Brenda J. Weigel and Yael P. Mossé

Case Study, group4Kirk SmithJuly 1, 2021ALK, neuroblastoma, pediatric, crizotinib

Exceptional response to the ALK and ROS1 inhibitor lorlatinib and subsequent mechanism of resistance in relapsed ALK F1174L-mutated neuroblastoma

In summary, we describe a patient with relapsed, refractory neuroblastoma harboring the ALK F1174L mutation resistant to the first-generation ALK inhibitor crizotinib combined with chemotherapy in whom lorlatinib induced a durable complete remission of 13 mo. However, as is often the case with targeted therapeutic approaches, resistance, potentially mediated by new genomic alterations including CDK4 and FGFR1 amplification and NRAS mutation, led to disease recurrence. Our case provides an example of clinical benefit made possible by the development of next-generation ALK inhibitors but also highlights the need for increased understanding of mechanisms of acquired resistance. We propose that molecular monitoring during therapy may guide rational combination multidrug approaches to overcome and prevent resistance. READ ARTICLE

Cold Spring Harbor: Molecular Case Studies DOI:10.1101/mcs.a006064

Authors: Tingting Liu, Matthew D., Merguerian, Steven P. Rowe, Christine A. Pratilas, Allen R. Chen and Brian H. Ladle

Case Study, group4Kirk SmithJuly 1, 2021neuroblastoma, pediatric, ALK, lorlatinib, crizotinib combination

Pediatric Mesothelioma With ALK Fusions: A Molecular and Pathologic Study of 5 Cases

Pediatric mesotheliomas are rare and their pathogenesis remains undefined. In this study, we report 5 cases of malignant mesothelioma in children, characterized by fusions involving the anaplastic lymphoma kinase (ALK) gene. Four cases occurred in females involving the abdominal cavity and were characterized by a pure epithelioid morphology. The fifth arose in the tunica vaginalis of a 15-year-old male and displayed a biphasic epithelioid-sarcomatoid phenotype. All cases demonstrated the classic morphologic and immunohistochemical features of malignant mesothelioma, including tubulopapillary architecture and cuboidal epithelioid cells with eosinophilic cytoplasm and uniform nuclei with vesicular chromatin. Immunohistochemically, all cases showed labeling for ALK, cytokeratins, WT1, and calretinin, while lacking expression of adenocarcinoma immunomarkers. Four cases demonstrated weak-moderate labeling for PAX8 protein, which resulted in diagnostic challenges with primary peritoneal sero..... READ ARTICLE

The American Journal of Surgical Pathology DOI:10.1097/PAS.0000000000001656

Authors: Argani, Pedram, Lian, Derrick W.Q., Agaimy, Abbas, Metzler, Markus, Wobker, Sara E. Matoso, Andres, Epstein, Jonathan I., Sung, Yun-Shao; Zhang, Lei and Antonescu, Cristina R

Case StudyKirk SmithMay 1, 2021mesothelioma, ALK, translocation, pediatric

EP101-26 Non-Small Cellular Pulmon Cancer ALK Positive in Pediatrics

This case report is from a 14-year-old adolescent patient treated in our institution with an ALK inhibitor. ALK disease is 3% to 5% of all non-cell lung cancers small adenocarcinoma type, more frequent in young people, women, nonsmokers, and with advanced disease.Male patient 14 years with respiratory symptoms productive cough. Tomography computed tomography: injury to the middle lobe and right lower lobe, biopsy: Adenocarcinoma poorly differentiated, immunohistochemistry: positive for cytokeratin 7, napsin-a, MUC-1, CK1E1 / AE3 positive and transcription factor -1 (TTF-1) and cytokeratin 20 negative, EGFR-KRAS wild type, ALK (EML-4 with clone D5F3) positive. Treatment was started with Crizotinib 250mg every 12 hours, obtaining partial response and with PFS of 36 months, gastrointestinal toxicity, hematological I grade.We report the experience of a case with excellent tolerability to an inhibitor of ALK, and its clinical benefit, (partial response and stable disease). Patients under 18..... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.1985

Authors: L. Ramirez, A. Guerrero Villota, J. Herrera Parga. M. Velasco, J. Lòpez

Case StudyKirk SmithOctober 1, 2019ALK, pediatric, gastrointestinal, toxicity, tolerability, Colombia

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

The biology and management of systemic anaplastic large cell lymphoma

Systemic anaplastic large cell lymphoma (ALCL) is an aggressive CD30+ non-Hodgkin lymphoma. Anaplastic lymphoma kinase–positive (ALK+) ALCL is associated with the NPM-ALK t(2;5) translocation, which is highly correlated with the identification of the ALK protein by immunohistochemistry. ALK+ ALCL typically occurs in younger patients and has a more favorable prognosis with 5-year survival rates of 70% to 90% in comparison with 40% to 60% for ALK-negative (ALK−) ALCL. Studies support young age as a strong component of the favorable prognosis of ALK+ ALCL. Until recently, no recurrent translocations were identified in ALK− ALCL. However, emerging data now highlight that ALK− ALCL is genetically and clinically heterogeneous with a subset having either a DUSP22 translocation and a survival rate similar to ALK+ ALCL or a less common P63 translocation, the latter associated with an aggressive course. Anthracycline-based regimens such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) remain the standard first-line treatment choice for systemic ALCL, but in many patients with ALK− ALCL, it is ineffective, and thus it is often followed by consolidative autologous stem cell transplantation. However, selection of appropriate patients for intensified therapy remains challenging, particularly in light of genetic and clinical heterogeneity in addition to the emergence of new, effective therapies. The antibody drug conjugate brentuximab vedotin is associated with a high response rate (86%) and durable remissions in relapsed/refractory ALCL and is under investigation in the first-line setting. In the future, combining clinical and genetic biomarkers may aid in risk stratification and help guide initial patient management. READ ARTICLE

Blood DOI: 10.1182/blood-2014-10-567461

Authors: Greg Hapgood, Kerry J. Savage