We evaluated the incidence of ALCL, clinical characteristics, survival status, and outcome of crizotinib use in four relapsed/refractory ALK-positive patients.
Difficulties with classification of lymphomas are also encountered, such as the distinction of classical Hodgkin's lymphoma from anaplastic large-cell lymphoma that is negative for anaplastic lymphoma kinase.
In this study, we investigated the therapeutic combination of a CD30-targeting ADC (anti-CD30-lidamycin [LDM]) with a small-molecule inhibitor (crizotinib) of nucleophosmin-anaplastic lymphoma kinase NPM-ALK in CD30<sup>+</sup>/ALK<sup>+</sup> anaplastic large cell lymphoma (ALCL).
Our findings suggest that overexpression of c-FLIP protects ALK+ ALCL cells from death-receptor-induced apoptosis and may contribute to ALCL pathogenesis.
Systemic anaplastic large-cell lymphoma (ALCL) is a childhood T cell neoplasm defined by the presence or absence of translocations that lead to the ectopic expression of anaplastic lymphoma kinase (ALK), with nucleophosmin-ALK (NPM-ALK) fusions being the most common.
Anaplastic large cell lymphoma (ALCL) is a subtype of aggressive non-Hodgkin's lymphoma that is characterized by expression of CD30 and the NPM/ALK chimeric protein, which is generated by t(2;5)(p23;q35).
To unravel signaling pathways required for NPM-ALK-mediated transformation and tumor maintenance, we analyzed the transcriptomes of ALK positive ALCL cell lines through experimentally controlled approaches in which ALK signaling was abrogated by an inducible ALKshRNA or by ALK inhibitors.
The NPM/ALK fusion gene, formed by the t(2;5) translocation in anaplastic large-cell lymphoma, encodes a M(r) 75,000 hybrid protein that containsthe amino-terminal portion of the nucleolar phosphoprotein nucleophosmin(NPM) joined to the entire cytoplasmic portion of the receptor tyrosine kinase anaplastic lymphoma kinase (ALK).
Anaplastic lymphoma kinase (ALK) is frequently observed in systemic anaplastic large cell lymphoma (ALCL), mostly in childhood or adolescence, but only rarely in primary cutaneous cases.
Moreover, ALK expression was confined to the cytoplasm of the tumor cells in each case, supporting the hypothesis that the observed nuclear localization of NPM-ALK in classical ALCL is not the site of oncogenic activity of the ALK kinase.
Here, we identified CH5424802, a potent, selective, and orally available ALK inhibitor with a unique chemical scaffold, showing preferential antitumor activity against cancers with gene alterations of ALK, such as nonsmall cell lung cancer (NSCLC) cells expressing EML4-ALK fusion and anaplastic large-cell lymphoma (ALCL) cells expressing NPM-ALK fusion in vitro and in vivo.
Our study, which to our knowledge includes the largest series of childhood systemic ALK-positive ALCL so far, demonstrates the adverse prognostic value of SC and/or LH morphologic features.
Furthermore co-expression of NK and ALCL features supports the concept that a minority of null-ALCL may be derived from NK cells and expands the spectrum of phenotypes that can be seen in tumors produced by ALK fusion proteins.(Blood.2001;98:1209-1216)
LY293111 inhibited proliferation of both ALK(+) and ALK(-) ALCL cell in a dose-dependent fashion and induced complete G(1)-S cell cycle arrest, which was accompanied by upregulation of p27 and downregulation of cyclin E. Pretreatment with LY293111 for 4 h resulted in profound inhibition of serum-induced phosphorylation of extracellular-regulated kinases-1 and 2 and Akt and a concomitant increase in the phosphorylation of the stress-activated kinase c-jun N-terminal kinases (JNK).