Overview

Rare chronic B-cell leukemia with characteristic hairy projections on microscopy. BRAF V600E mutation in >95% of classical HCL. Indolent but causes profound pancytopenia when symptomatic. Cladribine (2-CdA) or pentostatin achieve complete remission in >80% with single course. Median remission duration 10+ years. Vemurafenib or dabrafenib + trametinib for BRAF-mutated relapsed disease. Moxetumomab pasudotox (CD22-directed immunotoxin) for multiply relapsed.

Clinical Management: Treatment individualized based on stage, histology, molecular profile, and patient factors. Multidisciplinary tumor board review recommended. Refer to NCCN guidelines and FDA package inserts for complete dosing and administration.

Epidemiology & Impact

Hairy cell leukemia is a rare chronic B-cell malignancy accounting for approximately 2% of all leukemias, with roughly 1,000 new cases annually in the United States. It has a striking male predominance (4:1) and median age of 55 years. Despite its rarity, HCL is one of the first cancers where single-agent chemotherapy achieved durable complete remissions. Patients typically present with pancytopenia, splenomegaly, and increased infection susceptibility. The variant form (HCLv) is a distinct entity lacking the classic BRAF V600E mutation.

Molecular Biology & Biomarkers

The molecular hallmark is the BRAF V600E mutation, present in virtually 100% of classic HCL cases. This discovery in 2011 was diagnostically definitive and therapeutically actionable. BRAF V600E activates MAPK/ERK signaling and is used as a diagnostic criterion to distinguish classic HCL from HCL variant and other mimics. HCLv lacks BRAF V600E and instead harbors MAP2K1 (MEK1) mutations in approximately 40% of cases.

Evolving Treatment Landscape

Purine analogs (cladribine, pentostatin) remain frontline, achieving complete remission in 80-90% with single-agent therapy. Many patients remain in remission for decades. Vemurafenib, a BRAF inhibitor, achieves response rates exceeding 95% in relapsed HCL. Combination approaches using vemurafenib with rituximab show impressive MRD-negative complete remission rates.

Approved Hairy Cell Leukemia Therapies

Note: Note: Lumoxiti (moxetumomab pasudotox) was FDA-approved in 2018 for R/R HCL but was voluntarily withdrawn from the market by AstraZeneca in 2023.

Leustatin
cladribine
FDA Approved 1993 Frontline
Approved Indications (US/FDA)
Treatment of active hairy cell leukemia as defined by clinically significant anemia, neutropenia, thrombocytopenia, or disease-related symptoms.
Dosing Schedule
0.09 mg/kg/day by continuous IV infusion for 7 consecutive days as a single course
Drug Class
Purine Analog (Antimetabolite)
Manufacturer
Janssen
Approval Year
1993
Key Publication
Piro et al. Blood 1990 ↗
Nipent
pentostatin
FDA Approved 1991 Frontline / R/R
Approved Indications (US/FDA)
Treatment of adult patients with hairy cell leukemia, including alpha-interferon-refractory disease.
Dosing Schedule
4 mg/m² IV every other week
Drug Class
Purine Analog (Adenosine Deaminase Inhibitor)
Manufacturer
Pfizer
Approval Year
1991
Key Publication
Grever et al. JCO 1995 ↗