Understanding Hairy-Cell Leukemia: A Comprehensive Patient Guide

Table of Contents

• Introduction: What is Hairy-Cell Leukemia?
• Who Gets HCL? Epidemiology and Clinical Features
• Symptoms and Presentation
• Pathological Features and Diagnosis
• Genetic Basis: The BRAF V600E Mutation
• Treatment Approaches
• First-Line Therapy Options
• Clinical Implications for Patients
• Limitations and Considerations
• Patient Recommendations
• Source Information

Introduction: What is Hairy-Cell Leukemia?

Hairy-cell leukemia (HCL) is a unique type of blood cancer that was first identified as a distinct disease in 1958. The name comes from the characteristic "hairy" appearance of the cancerous cells when viewed under a microscope, caused by thin projections from their surface. For many years, doctors debated where these cells came from, but we now know they originate from mature B cells - a type of white blood cell that normally helps fight infections.

The treatment of HCL has evolved significantly over time. In the 1980s, interferon alfa was introduced as the first effective treatment. This was followed by purine analogues in the late 1980s, which remain standard care today. The most important breakthrough came in 2011 when researchers discovered that approximately 95% of HCL cases are caused by a specific genetic mutation called BRAF V600E. This discovery has led to new diagnostic tests and targeted therapies that specifically address this genetic abnormality.

Who Gets HCL? Epidemiology and Clinical Features

HCL is considered a rare cancer, accounting for only 1.4% of all lymphomas. The incidence rate is approximately 0.28 to 0.30 cases per 100,000 people per year in Europe and the United States. Interestingly, the disease occurs less frequently in Asia, Africa, and Arab countries. Because treatments don't completely eradicate the disease and patients often experience relapses, the actual prevalence (total number of people living with HCL) is higher than the incidence rate - about 3.12 cases per 100,000 people in Europe, equating to roughly 15,000 cases in 2008.

The disease shows clear demographic patterns:

• Median age at diagnosis: 55-60 years
• Gender distribution: Strong male predominance with a 4:1 male-to-female ratio
• Age limitation: Does not occur in children
• Treatment response: Women under 60 may have longer time to second-line treatment after purine analogue therapy compared to men of the same age

Thanks to modern treatments, the life expectancy of patients with HCL is now almost identical to that of the general population.

Symptoms and Presentation

Patients with HCL typically present with various blood cell deficiencies (cytopenias) and usually have a low percentage of leukemic cells in their blood. However, about 10-15% of patients present with high white blood cell counts and more circulating HCL cells. Almost all cases show monocytopenia (low monocyte count).

The most common physical finding is splenomegaly (enlarged spleen), which occurs in 80-85% of patients. The spleen can become extremely enlarged, causing discomfort in the left upper abdomen and sometimes even splenic infarction (tissue death due to blocked blood flow). Constitutional symptoms like night sweats and weight loss are rare.

When symptoms do occur, they're usually related to blood cell deficiencies:

• Fatigue (from anemia)
• Bleeding or bruising (from low platelets)
• Infections (from low neutrophils and monocytes)

Approximately 20-30% of patients may experience opportunistic infections during their disease course due to disease-related neutropenia and monocytopenia, combined with T-cell depletion caused by purine analogue treatments. About 20% of cases are discovered incidentally during testing for cytopenias or splenomegaly found on routine examination.

Pathological Features and Diagnosis

HCL primarily involves the bone marrow, spleen, and peripheral blood. The cancerous cells are mature B cells of small-to-intermediate size with ample cytoplasm and oval or cleaved nuclei. Their most distinctive feature is the thin, circumferential surface projections that give them their "hairy" appearance under the microscope.

Bone marrow biopsies typically show a "fried-egg" pattern due to the large amount of cytoplasm between cell nuclei. The bone marrow often shows increased reticulin fibers, which frequently causes a "dry tap" - difficulty obtaining marrow during aspiration. The proliferation rate of these cells is very low.

HCL cells express all normal B-cell markers (CD19, CD20, CD22, PAX5, CD79a) but also show an abnormal immunophenotypic profile with positivity for:

• CD103
• CD11c
• CD25
• CD123
• DBA44
• FMC7
• CD200
• T-bet

The two most sensitive and specific markers for HCL are annexin A1 and the BRAF V600E mutant protein, both detectable through specialized staining of bone marrow samples. Testing for these markers is crucial because it helps distinguish true HCL from similar-looking diseases that require different treatment approaches.

Genetic Basis: The BRAF V600E Mutation

The groundbreaking discovery in HCL research was identifying that at least 95% of cases are driven by the BRAF V600E mutation. This genetic alteration is stable over time, remaining present even when the disease relapses decades after initial diagnosis.

The BRAF gene normally produces a protein that helps regulate cell growth and survival. The V600E mutation changes a single building block in this protein, causing it to be constantly active. This leads to continuous signaling through the RAF-MEK-ERK pathway, which promotes cancer cell survival and creates the characteristic features of HCL cells, including their hairy appearance.

In most cases, HCL cells have one normal BRAF gene and one mutated gene. However, about 20% of cases lose the normal gene through a deletion on chromosome 7. Rare cases without the BRAF V600E mutation may have other BRAF mutations or specific chromosomal translocations.

While BRAF V600E is the primary driver, additional genetic alterations sometimes occur in:

• KLF2 transcription factor
• CDKN1B/p27 cell-cycle inhibitor
• KMT2C/MLL3 histone methyltransferase

These additional changes may work together with the BRAF mutation to drive the cancer, but targeting just the BRAF mutation alone can reverse many of the characteristic features of HCL cells.

Treatment Approaches

Treatment decisions for HCL depend on several factors, including the severity of symptoms and blood cell counts. For the 10-20% of patients who present without clinically significant cytopenias (hemoglobin ≥10 g/dL, neutrophils ≥1000/μL, platelets ≥100,000/μL) and without symptomatic organ enlargement or recurrent infections, a "watch and wait" approach is often recommended.

For patients requiring treatment, purine analogues (cladribine or pentostatin) are highly effective standard therapies. These drugs achieve complete remission in approximately 80-90% of patients. Complete remission is defined as:

• Near-normal blood counts (hemoglobin ≥11 g/dL, neutrophils ≥1500/μL, platelets ≥100,000/μL)
• No palpable splenomegaly
• No visible hairy cells in bone marrow or blood smears

Even with complete remission, minimal residual disease (MRD) may still be detectable through specialized testing. The duration of response is typically longer after complete remission (median relapse-free survival >10 years) compared to partial remission.

First-Line Therapy Options

The anti-CD20 monoclonal antibody rituximab is also active against HCL, often producing responses though mostly partial remissions. Studies combining rituximab with purine analogues as first-line treatment have shown promising results:

When used in combination approaches:

• Complete remission occurs in virtually all patients
• The proportion of patients without detectable minimal residual disease is significantly higher
• This is expected to lead to longer-lasting responses

However, one study of cladribine plus sequential rituximab showed that at a median follow-up of 16 years, overall survival was excellent regardless of whether patients achieved minimal residual disease-negative status. This suggests that while eliminating detectable disease is beneficial, patients can still do well long-term even with some residual disease.

Novel chemotherapy-free strategies using BRAF inhibitors (vemurafenib or dabrafenib) are increasingly used for patients with relapsed or refractory HCL and those with active infections. These targeted therapies are also being explored as front-line alternatives to chemotherapy.

Clinical Implications for Patients

The discovery of the BRAF V600E mutation has profoundly changed how we manage HCL. For patients, this means:

1. More accurate diagnosis: Testing for BRAF V600E or annexin A1 helps distinguish true HCL from similar diseases that require different treatment approaches

2. Targeted treatment options: BRAF inhibitors provide a chemotherapy-free alternative for appropriate patients

3. Monitoring: The mutation can be tracked in blood samples, allowing for less invasive monitoring

4. Improved outcomes: With current treatments, life expectancy for HCL patients is nearly identical to the general population

The stability of the BRAF V600E mutation over time means that targeted therapies remain effective even when the disease relapses after many years.

Limitations and Considerations

While treatment advances have been remarkable, several important limitations remain:

1. No cure: Current treatments don't eradicate the disease completely, and relapses are common

2. Treatment side effects: Purine analogues can cause significant side effects including:

• Rash
• Neutropenia (low neutrophil count)
• Fever
• Infections
• Long-lasting T-cell lymphopenia (especially CD4+ T cells)

3. Infection risk: Approximately 20-30% of patients may experience opportunistic infections during their disease course due to both the disease itself and treatment effects

4. Diagnostic challenges: A small number of cases with very low bone marrow cellularity may be misdiagnosed as aplastic anemia unless appropriate immunohistochemical staining is performed

5. Rare variants: The 5% of cases without BRAF V600E mutation may have different clinical behaviors and treatment responses

Patient Recommendations

If you or a loved one has been diagnosed with hairy-cell leukemia, here are important recommendations:

1. Seek specialized care: HCL is rare, so treatment at a center with experience managing this specific disease is important
2. Ensure proper testing: Ask your doctor about BRAF V600E and annexin A1 testing to confirm the diagnosis
3. Discuss all options: Treatment decisions should be personalized based on your specific situation, including:
   • Your blood counts and symptoms
   • Your age and overall health
   • Potential treatment side effects
   • Your preferences and quality-of-life considerations
4. Monitor for infections: Be vigilant about signs of infection and seek prompt medical attention if they occur
5. Consider clinical trials: New targeted therapies and combinations are being studied that may offer additional options
6. Maintain follow-up: Regular monitoring is essential even after successful treatment, as relapses can occur years later

Remember that with current treatments, most patients with HCL can expect to have a normal life expectancy and good quality of life.

Source Information

Original Article Title: Hairy-Cell Leukemia
Authors: Brunangelo Falini, M.D., and Enrico Tiacci, M.D.
Publication: The New England Journal of Medicine, October 10, 2024
DOI: 10.1056/NEJMra2406376

This patient-friendly article is based on peer-reviewed research from The New England Journal of Medicine. It provides comprehensive information about hairy-cell leukemia but should not replace personalized medical advice from your healthcare team.