Hairy Cell Leukemia: Description, Work-Up, and Treatment
Disease Description
Hairy cell leukemia (HCL) is a rare chronic B-cell malignancy characterized by pancytopenia, splenomegaly, and distinctive lymphoid cells with cytoplasmic projections ("hairy" appearance), marked by the pathognomonic BRAF V600E mutation present in >95% of classical cases. 1
Key Clinical Features:
- Monocytopenia is a hallmark finding that distinguishes classical HCL from the variant form 1
- Splenomegaly is present in most symptomatic patients 1
- "Dry tap" on bone marrow aspiration is characteristic due to marrow fibrosis 1
- Patients typically present with cytopenias and increased infection risk 1
Classical HCL vs HCL-Variant:
The variant form (HCL-V) differs critically: it lacks CD25 expression, has prominent nucleoli, presents with lymphocytosis rather than monocytopenia, lacks the BRAF V600E mutation, and responds poorly to purine analogues 1
Diagnostic Work-Up
Essential Diagnostic Tests:
The diagnostic work-up must include peripheral blood film morphology, flow cytometry on peripheral blood and bone marrow aspirate, and bone marrow trephine biopsy with immunohistochemistry. 1
1. Peripheral Blood Studies:
- Complete blood count with differential showing cytopenias and monocytopenia 1
- Peripheral blood smear demonstrating hairy cells with cytoplasmic projections 1
- Flow cytometry identifying the characteristic immunophenotype 1
2. Bone Marrow Evaluation:
- Trephine biopsy (not aspirate, due to frequent dry tap) showing the "fried egg" pattern with lymphoid cells surrounded by clear halos 1
- Immunohistochemistry panel: CD20+, CD11c+, CD25+, CD103+, annexin A1+, and tartrate-resistant acid phosphatase (TRAP)+ 1
3. Molecular Testing:
- BRAF V600E mutation testing should be performed in difficult or atypical cases to confirm classical HCL 1
- This mutation has high specificity and sensitivity for HCL and can be detected by immunohistochemistry 1
4. Staging Studies:
- Chest X-ray and abdominal ultrasound or CT to assess organomegaly 1
- Physical examination focusing on spleen size (measure distance below costal margin) 1
Common Pitfall:
Do not rely on bone marrow aspirate alone—the dry tap phenomenon necessitates trephine biopsy for definitive diagnosis 1
Treatment Approach
When to Treat vs Observe:
Treatment is NOT indicated in asymptomatic patients, who should be monitored with history, physical examination, and complete blood count every 3-6 months. 1, 2
Treatment should be initiated when patients have:
- Symptomatic disease with bulky or progressive splenomegaly 1, 2
- Cytopenias: hemoglobin <10 g/dL, platelets <100 × 10⁹/L, or neutrophils <1 × 10⁹/L 1
- Recurrent or severe infections 1, 2
- Systemic symptoms 1, 2
First-Line Treatment
Purine analogues—specifically cladribine (2-CdA) or pentostatin (deoxycoformycin, DCF)—are the standard first-line treatments for symptomatic HCL patients. 2
Cladribine (Preferred by Most Centers):
- Dosing options: 0.1 mg/kg/day continuous IV infusion for 7 days, OR 0.14 mg/kg/day as 2-hour IV infusion for 5 consecutive days, OR 0.14 mg/kg subcutaneously weekly for 5 weeks 2
- Subcutaneous administration is more convenient, doesn't require hospitalization, and has similar efficacy to IV 2
- Response rates: Complete remission in 85-91% of patients after a single course 2
- Durability: Induces durable, unmaintained responses in 87-100% of patients 2
Pentostatin (Alternative):
- Dosing: 4 mg/m² IV every 2 weeks until complete remission is achieved 2
- Induces high rates of long-lasting complete remissions similar to cladribine 2
- May require dose adjustment for renal impairment 2
Special Circumstances:
- Severe neutropenia (neutrophils <0.2 × 10⁹/L): Consider interferon-α temporarily to increase neutrophil count before starting purine analogue therapy 1
- Pregnancy: Interferon-α is the treatment of choice, as purine analogues are contraindicated 1
Response Assessment
Response should be evaluated 4-6 months after cladribine treatment and after 8-9 courses of pentostatin. 1
Response Criteria:
Complete Response (CR):
- No hairy cells in peripheral blood and bone marrow 1, 2
- Normalization of organomegaly and peripheral blood counts 1, 2
- Hemoglobin >12 g/dL, platelets >100 × 10⁹/L, absolute neutrophil count >1,500 × 10⁶/L 2
- Bone marrow biopsy is required to confirm CR 1, 2
Partial Response (PR):
- Normalization of peripheral counts 1
- At least 50% reduction in organomegaly and bone marrow hairy cells 1
- <5% circulating hairy cells 1
Relapse Definition:
- Any deterioration in blood counts with detection of hairy cells in peripheral blood/bone marrow and/or increasing splenomegaly 1
Critical Point:
Patients achieving CR have significantly longer disease-free survival than those with PR (5-year PFS 71% vs 39%), making bone marrow biopsy confirmation essential. 1
Treatment of Relapsed/Refractory Disease
Relapsed Disease (After 12-18 Months):
Relapsed patients can be successfully retreated with the same purine analogue (cladribine or pentostatin) if relapse occurs after 12-18 months. 1
- The alternative purine analogue can be used for early relapse within 2 years 1
- CR rates decrease with each course, but CR duration remains similar after first-, second-, or third-line therapy 1
Enhanced Strategies for Relapsed Disease:
Combination therapy with rituximab plus a purine analogue produces better outcomes than purine analogue alone in relapsed patients. 1
- Rituximab dosing: 375 mg/m² for 4-8 weekly IV infusions 1
- Rituximab alone is inferior to purine analogues and should not be used as monotherapy 1
- Concurrent therapy induces higher response rates but also higher toxicity than sequential administration 1
Multiply Relapsed/Refractory Options:
For patients previously treated with cladribine:
- Fludarabine 40 mg/m² PO for 5 consecutive days + rituximab 375 mg/m² IV on day 1, every 28 days for 4 cycles achieves 5-year PFS of 89% and OS of 83% 1
For multiply relapsed/refractory HCL:
- Bendamustine 70-90 mg/m² combined with rituximab is a therapeutic option after failure of standard therapies 1
Novel Targeted Therapies (Emerging Evidence):
BRAF inhibitors (vemurafenib or dabrafenib) show remarkable activity in multiply relapsed/refractory HCL patients with rapid clinical improvement. 3, 4
- Vemurafenib combined with rituximab is emerging as a short, safe, chemotherapy-free regimen inducing deep complete remissions 4
- These agents target the pathognomonic BRAF V600E mutation present in classical HCL 3, 5, 4
- Optimal dosing and duration remain under investigation 1
Other investigational agents:
- Moxetumomab pasudotox (anti-CD22 immunotoxin): 86% overall response rate, 46% CR in phase I trials 1
- Ibrutinib (BTK inhibitor): Phase II studies ongoing 1
Role of Splenectomy
Splenectomy may be indicated in patients with resistant massive symptomatic splenomegaly (>10 cm below costal margin) with low-level bone marrow infiltration. 1, 6
Specific Indications:
- Response rates of 60-100% documented 1, 6
- Progressive HCL during pregnancy 1
- Patients refractory to both purine analogues and interferon-α 1
Critical Management Points:
- Splenectomized patients respond better and faster to subsequent chemotherapy 1, 6
- Systemic therapy should NOT be performed earlier than 6 months after splenectomy to achieve full benefits 1, 6
- Vaccination against Haemophilus influenzae and pneumococcus is mandatory before splenectomy 1, 6
Allogeneic Stem Cell Transplantation
Allogeneic stem cell transplantation has a potential role in younger, heavily pretreated HCL patients who have exhausted other options 1
Key Clinical Pitfalls to Avoid
- Do not delay treatment in symptomatic patients with cytopenias—this increases infection risk 2
- Do not skip bone marrow biopsy for response assessment—CR confirmation is essential for prognostication 1, 2
- Do not use rituximab monotherapy in relapsed disease—it is inferior to purine analogues 1
- Do not start systemic therapy within 6 months of splenectomy—wait for full surgical benefit 1, 6
- Do not forget pre-splenectomy vaccinations—this prevents life-threatening post-splenectomy infections 1, 6
- Do not overlook renal function when considering pentostatin—dose adjustment may be necessary 2