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Response to crizotinib in a squamous cell lung carcinoma patient harbouring echinoderm microtubule-associated protein-like 4-anaplastic lymphoma translocation: A case report.

ABSTRACT: Squamous cell lung cancer (SCC) presenting with anaplastic lymphoma kinase (ALK) translocation is rare. We present a case of ALK gene translocation-SCC in which a remarkable tumor response to crizotinib was achieved after the failure of prior chemoradiotherapy. Considering this remarkable response, we conclude that ALK testing in female non-smokers or in any patient unresponsive to the initial regimen of chemotherapy, is recommended for SCC patients.

SUBMITTER: Wang W

PROVIDER: S-EPMC4846625 | biostudies-other | 2016 Apr

REPOSITORIES: biostudies-other

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Successful oral desensitization with crizotinib after crizotinib-induced hepatitis in an anaplastic lymphoma kinase-rearranged non-small-cell lung cancer patient: A case report.

Project description:Crizotinib is one of the molecularly-targeted agents targeted against anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC). Although its effects appear to be promising, crizotinib may cause adverse effects in patients with ALK-rearranged NSCLC. Hepatic laboratory abnormalities are frequently observed with crizotinib and treatment discontinuation is occasionally required. We herein report the case of a 51-year-old woman diagnosed with relapsed ALK-rearranged NSCLC, who received crizotinib as second-line systemic chemotherapy. After 17 days of crizotinib therapy, the patient developed grade >3 hepatotoxicity. Treatment discontinuation improved the laboratory abnormalities and fifth-line oral desensitization with crizotinib achieved successful response without hepatotoxicity. Therefore, oral desensitization with crizotinib may be a viable option following crizotinib-induced hepatitis.

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Systemic therapy for echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase non-small cell lung cancer brain metastases.

Project description: Not available

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Crizotinib in Combination with Everolimus Synergistically Inhibits Proliferation of Anaplastic Lymphoma Kinase?Positive Anaplastic Large Cell Lymphoma.

Project description:Anaplastic large cell lymphoma (ALCL) is a rare aggresive non-Hodgkin lymphoma, of which over 50% of cases have an aberrant nucleophosmin (NPM)?anaplastic lymphoma kinase (ALK) fusion protein. Both mechanistic target of rapamycin (mTOR) inhibitor everolimus and ALK inhibitor crizotinib have shown promising antitumor activity in ALK-positive cancer cell lines. However, their combined effect has not yet been investigated.We evaluated the anti-proliferative effects of everolimus and/or crizotinib in ALK-positive ALCL cell lines, Karpas 299 and SU-DHL-1, and lung adenocarcinoma cell line, NCI-H2228.We found that individually, both everolimus and crizotinib potently inhibited cell growth in a dose-dependent manner in both Karpas 299 and SU-DHL-1 cells. A combination of these agents synergistically inhibited proliferation in the two cell lines. Crizotinib down-regulated aberrant AKT and ERK phosphorylation induced by everolimus. Combination treatment also significantly increased G0/G1 cell-cycle arrest, DNA damage, and apoptosis compared with everolimus or crizotinib alone in ALK-positive ALCL cells. In the Karpas 299 xenograft model, the combination treatment exerted a stronger antitumor effect than monotherapies, without significant change in body weight. The synergistic effect of everolimus and crizotinib was also reproduced in the ALK-positive lung adenocarcinoma cell line NCI-H2228. The combination treatment abrogated phosphoinositide 3-kinase/AKT and mTOR signaling pathways with little effect on the Ras/ERK pathway in NCI-H2228 cells.Crizotinib combinedwith everolimus synergistically inhibits proliferation of ALK-positive ALCL cells. Our results suggest that this novel combination is worthy of further clinical development in patients with ALK-positive ALCL.

| S-EPMC5912135 | biostudies-literature

Echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase-targeted therapy for advanced non-small cell lung cancer: molecular and clinical aspects.

Project description:The identification of oncogenic genomic alterations is expected to facilitate the development of new molecularly targeted therapies for cancer. EML4 (echinoderm microtubule-associated protein-like 4)-ALK (anaplastic lymphoma kinase) was recently identified as a transforming fusion gene in non-small cell lung cancer (NSCLC). A small-molecule tyrosine kinase inhibitor of ALK, crizotinib, shows pronounced clinical activity in the treatment of patients with NSCLC positive for EML4-ALK, and it has rapidly entered into daily clinical practice. This review focuses on the biology and clinical features of, as well as diagnostic testing for, EML4-ALK-positive NSCLC. Current data on the efficacy and toxicity of crizotinib are also examined, and future directions for the treatment of NSCLC positive for ALK rearrangement are addressed.

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A novel patient-derived tumorgraft model with TRAF1-ALK anaplastic large-cell lymphoma translocation.

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IL10RA modulates crizotinib sensitivity in NPM1-ALK+ anaplastic large cell lymphoma.

Project description:Anaplastic large cell lymphoma (ALCL) is a T-cell malignancy predominantly driven by a hyperactive anaplastic lymphoma kinase (ALK) fusion protein. ALK inhibitors, such as crizotinib, provide alternatives to standard chemotherapy with reduced toxicity and side effects. Children with lymphomas driven by nucleophosmin 1 (NPM1)-ALK fusion proteins achieved an objective response rate to ALK inhibition therapy of 54% to 90% in clinical trials; however, a subset of patients progressed within the first 3 months of treatment. The mechanism for the development of ALK inhibitor resistance is unknown. Through genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) activation and knockout screens in ALCL cell lines, combined with RNA sequencing data derived from ALK inhibitor-relapsed patient tumors, we show that resistance to ALK inhibition by crizotinib in ALCL can be driven by aberrant upregulation of interleukin 10 receptor subunit alpha (IL10RA). Elevated IL10RA expression rewires the STAT3 signaling pathway, bypassing otherwise critical phosphorylation by NPM1-ALK. IL-10RA expression does not correlate with response to standard chemotherapy in pediatric patients, suggesting that a combination of crizotinib and chemotherapy could prevent ALK inhibitor resistance-specific relapse.

| S-EPMC7530646 | biostudies-literature

Anaplastic lymphoma kinase-positive anaplastic large-cell lymphoma with primary bone involvement: a case report.

Project description:BackgroundLymphomas originating in bone but not involving visceral or regional lymph nodes are diagnosed as primary bone lymphoma (PBL). Few case reports of anaplastic large-cell lymphoma (ALCL) originating in bone have been reported. The purpose of this report is to describe the difficulty in diagnosing and complete treatment process of this rare type of bone lymphoma.Case descriptionWe describe a case of anaplastic lymphoma kinase positive (ALK+) ALCL patient with primary multiple bone lesions. The patient was initially in the local hospital due to lumbosacral pain and was diagnosed with multiple myeloma. However, after receiving two cycles of bortezomib, lenalidomide and dexamethasone (VRD) chemotherapy, the patient's pain increased. After discussion with the patient and his family, the patient finally agreed to accept the biopsy of the T10 and L2 vertebral bodies and diagnosed as ALK+ ALCL stage IV with primary bone involvement. After receiving multiple cycles of chemotherapy, local bone radiotherapy and denosumab treatment, the patient's bone pain and osteolytic lesions were improved. Regular follow-up shows that the patient's bone pain has been controlled and he is generally in good condition.ConclusionsALK+ ALCL originating primarily in the bone may be easily misdiagnosed and hence require appropriate evaluation in the upfront setting. In consideration of the lack of relevant experience due to the rarity of the disease, choosing a suitable treatment regimen requires comprehensive consideration. In the next clinical work, we must observe relevant cases to summarize the treatment experience better.

| S-EPMC10789887 | biostudies-literature

Lymphomatous Meningitis From Anaplastic Lymphoma Kinase+ Anaplastic Large T-Cell Lymphoma Treated With Lorlatinib: A Case Report.

Project description: Not available

| S-EPMC8865515 | biostudies-literature

A patient with anaplastic lymphoma kinase-positive non-small cell lung cancer with development of leptomeningeal carcinomatosis while on targeted treatment with crizotinib.

Project description:Leptomeningeal carcinomatosis (LM) is an infrequent yet morbid and often fatal complication of non-small cell lung cancer (NSCLC). Management of LM is multimodal, often involving systemic chemotherapy, radiotherapy, and a variety of symptom management maneuvers to address elevated intracranial pressure, pain, and mood changes that can accompany the disease. It is increasingly recognized that tumors with actionable mutations in NSCLC, including epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) translocations, respond well to systemic therapy with tyrosine kinase inhibitors yet often progress in the central nervous system. More information is needed regarding the natural history and optimal management of LM in specific molecular subtypes of NSCLC. This case report summarizes the management of a patient with ALK-positive NSCLC who developed LM while on targeted treatment with crizotinib within the context of current NCCN Clinical Practice Guidelines in Oncology and recently published studies.

| S-EPMC6329611 | biostudies-literature

Targeting autophagy enhances the anti-tumoral action of crizotinib in ALK-positive anaplastic large cell lymphoma.

Project description:Anaplastic Lymphoma Kinase-positive Anaplastic Large Cell Lymphomas (ALK+ ALCL) occur predominantly in children and young adults. Their treatment, based on aggressive chemotherapy, is not optimal since ALCL patients can still expect a 30% 2-year relapse rate. Tumor relapses are very aggressive and their underlying mechanisms are unknown. Crizotinib is the most advanced ALK tyrosine kinase inhibitor and is already used in clinics to treat ALK-associated cancers. However, crizotinib escape mechanisms have emerged, thus preventing its use in frontline ALCL therapy. The process of autophagy has been proposed as the next target for elimination of the resistance to tyrosine kinase inhibitors. In this study, we investigated whether autophagy is activated in ALCL cells submitted to ALK inactivation (using crizotinib or ALK-targeting siRNA). Classical autophagy read-outs such as autophagosome visualization/quantification by electron microscopy and LC3-B marker turn-over assays were used to demonstrate autophagy induction and flux activation upon ALK inactivation. This was demonstrated to have a cytoprotective role on cell viability and clonogenic assays following combined ALK and autophagy inhibition. Altogether, our results suggest that co-treatment with crizotinib and chloroquine (two drugs already used in clinics) could be beneficial for ALK-positive ALCL patients.

| S-EPMC4745787 | biostudies-literature

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