Hematological neoplasms associated with ALK fusion genes

The anaplastic lymphoma kinase gene (ALK) is located at chromosome 2p23 and encodes a transmembrane receptor tyrosine kinase. As a result of chromosomal translocation/inversion, the 3′ sequence of ALK fuses to the 5′ sequence of a partner gene, producing an oncogenic chimeric protein that activates downstream signal transduction pathways. ALK fusion genes are found in diverse tumor types of different lineages, including hematological neoplasms. ALK-positive (ALK+) anaplastic large cell lymphoma (ALCL) is a distinct subtype of peripheral T-cell lymphoma that is characterized by the expression of CD30 and ALK by immunohistochemistry (IHC). Approximately 70 to 80% of ALK+ ALCL cases have t(2;5)(p23;q35)/NPM1::ALK associated with the nuclear/cytoplasmic ALK IHC staining pattern. In the remaining cases, ALK fuses to various partner genes and ALK staining pattens vary with these partners. ALK+ large B-cell lymphoma (LBCL), accounting for <1% of all diffuse large B-cell lymphoma cases, is characterized by an immunoblast/plasmablast-like cytomorphology. ALK+ LBCL cases with t(2;17)(p23;q23)/CLTC::ALK show the cytoplasmic granular pattern of ALK IHC. Acute myeloid leukemia (AML) harboring inv(2)(p23q13)/RANBP2::ALK defines a small subset of AML characterized by monocytic differentiation and monosomy 7. Extramedullary plasmacytoma/multiple myeloma with the ALK fusion gene shares cytomorphological and immunophenotypic features with ALK+ LBCL. ALK+ histiocytosis is an emerging rare histiocytic entity and most cases carry KIF5B::ALK. The antibody-drug conjugate, brentuximab vedotin, which targets cell-surface CD30, is approved for the treatment of ALK+ ALCL as a single agent or in combination with other cytotoxic agents in both the front-line and relapsed/refractory (R/R) settings. R/R ALK+ hematological neoplasms respond well to first- to third-generation ALK tyrosine kinase inhibitors and an optimal treatment strategy including these novel agents is being tested.