Hairy Cell Leukemia: 2026 Update on Diagnosis, Risk-Stratification, and Treatment

Hairy cell leukemia (HCL) and HCL-like disorders, including HCL variant (HCL-V) and splenic diffuse red pulp lymphoma (SDRPL), are a very heterogeneous group of mature lymphoid B-cell disorders characterized by the identification of hairy cells, a specific immunophenotypic and genetic profile, a different clinical course and the need for appropriate treatment.

Diagnosis of HCL is based on morphological evidence of hairy cells, characteristic flow cytometric immunophenotype (CD11c, CD103, CD123, CD25) bone marrow trephine biopsy which makes it possible to specify the degree of tumoral bone marrow infiltration and presence of the Annexin A1 marker in immunohistochemistry, and presence of the BRAF^V600E mutation.

Progression of patients with HCL is based on a large splenomegaly, leukocytosis, a high number of hairy cells in the peripheral blood and the unmutated ImmunoGlobulin HeaVy (IGHV) chain variable region gene mutational status. VH4-34 positive HCL cases are associated with a poor prognosis, as well as the rare cases of HCL with TP53 mutations and HCL-V.

Patients should be treated only if HCL is symptomatic. Chemotherapy with purine analogs (PNAs) are indicated in first-line HCL patients. The use of chemo-immunotherapy combining cladribine (CDA) and rituximab (R) represents an increasingly used therapeutic approach. Management of relapsed/refractory disease is based on the use of BRAF inhibitors (BRAFi) plus R, MEK inhibitors (MEKi), Bruton Tyrosine Kinase inhibitors (BTKi) and/or Bcl-2 inhibitors (Bcl-2i). The optimal sequence of the different treatments remains to be determined.