Classic Hairy Cell Leukemia and Related Disorders: An Updated Review of Molecular Features and Personalized Therapies

Classic Hairy Cell Leukemia (cHCL) and related conditions are rare, indolent B-cell malignancies characterized by distinctive morphological, immunophenotypic, and molecular features. Over the past decade, major advances in understanding the pathophysiology and molecular underpinnings have reshaped diagnostic and therapeutic approaches. This review synthesizes current knowledge on the cellular origins and signaling pathways that drive cHCL and Hairy Cell Variant (HCL-v)/splenic B-cell lymphoma/leukemia (SBLPN) and other molecular aberrations in disease pathogenesis. We discuss evolving diagnostic modalities, including flow cytometry, immunohistochemistry, and next-generation sequencing, that enhance diagnostic precision and disease monitoring. Additionally, we examine established and emerging therapeutic strategies—from purine nucleoside analogs (PNA) to targeted inhibitors and immunotherapies—that have significantly improved patient outcomes while highlighting challenges such as relapse and treatment resistance. By integrating insights from molecular biology and clinical practice, this review aims to provide a comprehensive understanding of cHCL and related disorders.