Abstract
Sarcoma or sarcomatoid malignancies are a set of mesenchymal-origin malignancies with vast heterogeneity in clinical and molecular characteristics. Anaplastic lymphoma kinase (ALK) is a tyrosine kinase oncoprotein expressed by several tumors, including sarcomas. Crizotinib is an effective ALK inhibitor. In this review paper, we summarized findings from the literature regarding the use of crizotinib for the treatment of sarcoma and sarcomatoid malignancies harboring ALK fusions with definitive partners (with the given gene(s) name) from the years 2010 to 2021.One hundred and four articles were retrieved and after exclusion, 28 studies containing 33 patients were finally selected. All 33 patients were treated with crizotinib. Among the 33 cases, 19 were adult patients, 11 were pediatric patients, and 3 cases did not have data on age and/or gender. Most cases had a primary abdominal lesion (16/30), followed by thoracic (10/30), trunk (3/30), retroperitoneal (1/30), and one case of right medial thigh (case 7). Stage IV disease was reported in 76.7% (23/30) of patients. The objective response rate and disease control rate was 86.7% (26/30) and 96.7% (29/30), respectively, which were assessed on average of 8 weeks after crizotinib initiation. Rapid improvement of symptoms was observed within one to two weeks in some cases including patients with extensive diseases or poor performance. There was no difference in crizotinib response between pediatrics and adult cases. Crizotinib is effective; however, surgery remains the mainstay of therapy, with newer evidence showing concurrent crizotinib with surgery conferring long-term overall survival. However, we should still be cognizant of the heterogeneous landscape of crizotinib efficacy and its associated fatal adverse events.
Highlights
Anaplastic lymphoma kinase (ALK), a single-chain transmembrane receptor tyrosine kinase, was first described as a fusion partner in the t [2;5] chromosomal translocation in anaplastic large cell lymphoma (ALCL) in 1994
It was gradually off-label in the treatment of inoperable sarcomas that are carried with ALK fusions since the first case of inflammatory myofibroblastic sarcoma (IMT) with the ALK rearrangement showed a favorable response to crizotinib [4]
A brief clinical routine for treating ALK-positive sarcomatous malignancies was presented in Figure 3 as a reference for clinical decision-making. Findings from this analysis indicated that crizotinib-based palliative treatment regimens improved outcomes in patients with ALK-positive sarcoma and sarcomatoid malignancies
Summary
Anaplastic lymphoma kinase (ALK), a single-chain transmembrane receptor tyrosine kinase, was first described as a fusion partner in the t [2;5] chromosomal translocation in anaplastic large cell lymphoma (ALCL) in 1994. The resulting fusion oncoproteins are chimeric self-associating polypeptides with a variety of N-terminal domains and a common, constitutively active C-terminal tyrosine kinase domain, in the vast majority of cases including all 563 cytoplasmic amino acids from ALK. Crizotinib is a kinase inhibitor approved by Food and Drug Administration (FDA) for the treatment of ALK or c-ros oncogene 1 receptor kinase (ROS1) -positive patients with metastatic non-small cell lung cancer (NSCLC). It was gradually off-label in the treatment of inoperable sarcomas that are carried with ALK fusions since the first case of inflammatory myofibroblastic sarcoma (IMT) with the ALK rearrangement showed a favorable response to crizotinib [4]. Several questions remain unanswered, including if singleagent crizotinib is optimal, or if a partner of ALK fusion kinase variants influences tumor response to crizotinib [5], and if next-generation ALK inhibitors are effective postcrizotinib resistance
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