About the Condition

Description/definition:

Hairy cell leukemia (HCL) is an indolent mature B cell neoplasm originally named for hairy-appearing cytoplasmic projections in peripheral blood smear.

Accounts for 2% of all leukemias (about 1240 new cases per year in the US).

Pathophysiology:

HCL is caused by a malignant proliferation of mature B cells. Patients with HCL have a characteristic BRAF p.V600E gene mutation which leads to continued activation of the RAF-MEK-ERK pathway. This activation leads to continued cell proliferation and survival.

Over 90% of HCL has the BRAF V600E mutation, a driver mutation that leads to Ras independent activation of the RAF/MEK/ERK pathway, thereby promoting the survival and proliferation of HCL.

In addition to classical HCL, there are two distinct high-risk variants:

  • HCL variant (HCLv)
    • More lymphocytosis and less severe cytopenias compared with classic HCL, and poorer response to therapy.
    • Lacks CD25, CD123, and TRAP.
    • Has wild-type BRAF.
    • Considered by the World Health Organization to be a distinct entity under splenic B-cell lymphoma/leukemia.
    • Half of HCLv harbors MAP2K1 (MEK) mutations.
  • HCL with unmutated IGHV4-34
    • Can be associated with or without phenotypic markers of classic HCL (CD25, TRAP, and Anxa1).
    • Lacks the BRAF V600E mutation.
    • Half of IGHV4-34þ HCL harbors MAP2K1 (MEK) mutations.
    • Patients have an aggressive course and poor outcome with single-agent purine analog.

Clinical Presentation:

  • Median age of patients with classical HCL is 55–60 years.
  • 4–5-fold more common in men than women.
  • Patients may present with:
    • Fatigue
    • Weakness
    • Symptomatic splenomegaly
    • Opportunistic infections
    • Pancytopenia

Diagnosis:

Diagnosis is based on:

  • Peripheral smear
  • Bone marrow biopsy (with or without aspirate) with immunophenotyping by immunohistochemistry or flow cytometry

The diagnosis of HCL begins with a routine blood smear which may show the classic cytoplasmic projections characteristic of hairy cells. A bone marrow aspirate will often yield a “dry tap” secondary to HCL-associated bone marrow fibrosis. Flow cytometry shows characteristics of a mature B cell lymphoma with a unique immunophenotype including CD11c, CD25, and CD103. A next-generation sequencing panel will then reveal the classic BRAF p.V600E to further confirm the diagnosis of HCL.

Treatment:

Asymptomatic disease is managed using a watch and wait approach.

Standard indications for treatment include:

  • The presence of at least one cytopenia, neutrophils <1–1.5 x 109/L, hemoglobin <10–12 g/dL, or platelets <100
  • Malignant lymphocytosis >5–20
  • Symptomatic splenomegaly
  • Enlarging lymph nodes
  • Frequent infections

The first line treatment for patients with symptomatic hairy cell leukemia is monotherapy with a purine analog (e.g., Cladribine). Cladribine is given as a single cycle of either 5 or 7 days and induces complete remission in >90% of cases.  Cladribine works by inhibiting adenosine deaminase, leading to accumulation of adenosine, which are toxic to lymphocytes.

Although splenectomy was once a standard therapy for HCL, the indications for removing the spleen now are quite limited.

Prognosis:

Median overall survival (OS) was 4 years in 1976. Now much improved with introduction of purine analogues in the 1980s.

Clinical course may be complicated by:

  • Infection
  • Complications of bone marrow failure
  • Disease-related autoimmune complications, including vasculitis and autoimmune hemolytic anemia
  • Spontaneous splenic rupture

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