Hairy cell leukemia

Definition

Hairy cell leukemia is a chronic B-cell lymphoproliferative process with the predominant involvement of the bone marrow and spleen. It is clinically manifested by hepatosplenomegaly, lymphadenopathy, lymphocytosis with “hairy” lymphocytes, and pancytopenia. The diagnosis is established considering the blood tests, immunophenotyping of lymphocytes, ultrasound/CT of abdominal cavity organs, and bone marrow puncture. Specific treatment includes the use of IFN-α, purine antagonists, BRAF-inhibitor, monoclonal antibodies, and others. Sometimes, splenectomy is effective.

General information

Hairy cell leukemia (HCL) is a hematologic oncologic disease characterized by a deficiency of all blood cell elements, the presence of “villous” lymphocytes, and enlargement of the spleen, visceral and parietal lymph nodes. In the adultpopulation, HCL accounts for up to 2% of all leukemias or 8% of other chronic lympholeukemias. The incidence of new cases of hemoblastosis is 1:150,000 per year. The average age of manifestation is 50-55 years, although an earlier disease debut is not excluded. Men develop hairy cell leukemia 2-4 times more often than women.

Causes

The etiology of hairy cell leukemia continues to be studied. To date, it is reliably known that more than 95% of cases of HCL are associated with a substitution of the amino acid valine for glutamine in the 600th codon of the BRAF gene. This mutation is also dominant in melanoma and can occur in other malignant tumors: colorectal cancer, non-small cell lung cancer, and papillary thyroid cancer.

The exact factors that trigger lymphoid cell proliferation have not been elucidated. Probable determinants are thought to be:

• a family history of leukemia;
• contact with carcinogens: radiation, chemicals (including radiation therapy, chemotherapy);
• ethnicity (hairy cell leukemia is more often diagnosed among Ashkenazi Jews).

Classification

Based on clinical manifestations in oncological hematology, two forms of hairy cell leukemia are distinguished:

• classical (indolent) – occurs in 80-90% of patients and is characterized by splenomegaly and pancytopenia.
• variant (leukemic, prolymphocytic) accounts for 10-20% of clinical observations; it is characterized by the absence of leukopenia, aggressive course, and poor prognosis.

There is no generally accepted division of HCL into stages. In practice, initially detected cases are staged according to the phases of the course: initial and advanced. According to the response to standard therapy, partial/complete remission, resistant course, and early/late relapse are distinguished.

Symptoms of hairy cell leukemia

Classic HCL develops subtly over many years. In 20% of cases, the disease is detected incidentally during examination, but aggressive, rapidly progressive variants of hairy cell leukemia occur. The most characteristic clinical markers are splenomegaly (72-86%), cytopenia, and the presence of “hairy” lymphocytes in the blood (95%). Other symptoms (hepatomegaly, lymphadenopathy) are less pathognomonic.

Spleen enlargement can range from slight to gigantic, causing left subcostal pain. Variants of hemoblastosis without splenomegaly are less common. Approximately 20% of patients are found to have concomitant hepatomegaly. From 10% to 25% of cases of hairy cell leukemia are accompanied by enlargement of abdominal, less often – intrathoracic, peripheral lymph nodes.

In the blood, there is a decrease in all cellular forms: leukopenia (monocytopenia, neutropenia, agranulocytosis), anemia, and thrombocytopenia. The consequences of pancytopenia are fatigue, dyspnea, dizziness, and hemorrhagic syndrome. The number of villous lymphocytes can vary (from 2% to 90%).

Sometimes, skeletal bones are affected: spine, sacrum, pelvic bones, accompanied by pain syndrome. The course of hairy cell leukemia is often associated with autoimmune diseases (scleroderma, dermatomyositis, nodular periarteritis) and blood diseases (mastocytosis, paraproteinemia). Extremely rarely (1%), HCL is combined with chronic lympholeukemia.

Diagnosis

Hairy cell leukemia is diagnosed using clinical, instrumental, and laboratory data. Patients need to consult a hematologist. On examination for HCL, it is indicated by an increase in the borders of the liver and spleen, sometimes – palpable lymph nodes. The anemic syndrome is indirectly indicated by complaints of weakness, shortness of breath on exertion, and dizziness. Hyperthermia, bleeding, and frequent infections are possible. The main methods of confirmatory diagnostics include:

1. Clinical blood count. A comprehensive blood count with a leukocytic formula reveals agranulocytosis, monocytopenia, thrombocytopenia, and decreased hemoglobin. Against this background, there is absolute lymphocytosis with the presence of “hairy” cells—this appearance gives them uneven, ragged contours of the cytoplasm.
2. Bone marrow biopsy. Puncture in hairy cell leukemia can be obtained with difficulty due to the pronounced fibrosis of the bone marrow (dry puncture). In the sample of the material, suppression of hematopoietic sprouts, the phenomenon of “bee honeycomb” (areas of rarefaction), is observed. Pileated lymphocytes and infiltration of the bone marrow with leukemic cells are also detected.
3. Immunophenotyping of lymphocytes. It is performed by flow cytometry in a blood or bone marrow sample to identify specific immune markers. 
4. Genetic diagnosis. It aims to find a mutation of the BRAF gene in the lymphoid cells of blood or bone marrow punctate. The analysis is performed by PCR or immunohistochemistry. This gene defect is found in more than 90% of cases of hairy cell leukemia.
5. Other tests. A specific diagnostic criterion of APC is the detection of tartrate-resistant acid phosphatase (TRAP) in the cytoplasm of pathologic cells. Immunochemical studies reveal the secretion of poly- or monoclonal immunoglobulins (more often IgG3) in blood serum and Bence-Jones protein in urine.
6. Ultrasound and CT scan. Abdominal ultrasound evaluates the echo structure and size of the spleen. CT of the abdominal cavity and CT of the chest organs are indicated to visualize the state of visceral lymph nodes. CT of the spine and bones is performed to exclude bone tissue lesions.

Differential diagnosis

During the diagnosis of hairy cell leukemia, other hematological, tumor, and other diseases with splenomegaly, pancytopenia, and lymphocytosis are excluded:

• aplastic anemia;
• myelofibrosis;
• myelodysplastic syndrome;
• spleen lymphoma;
• T-cell lymphoma;
• Gaucher’s disease.

Treatment of hairy cell leukemia

In the initial asymptomatic phase, observation is carried out, and treatment is prescribed in the advanced stage of HCL. Indications for the start of therapy are increasing pancytopenia, marked splenomegaly, and infectious complications. The use of cytostatic drugs and corticosteroids has no effect. For the treatment of hairy cell leukemia is used:

• Interferon preparations. It is recommended as a starting therapy for patients with newly diagnosed HCL. Treatment efficacy with interferon alfa is 70-80%, but complete remission is usually not achieved.
• Purine antagonists are the main drugs used to treat HCL. Cytostatics in this group have shown efficacy both in newly diagnosed patients with hairy cell leukemia and in those who have already received other treatments. In 80% of cases, relapses are absent within 5 years after the course of treatment.
• Other drugs. If hairy cell leukemia is refractory to treatment, a BRAF-kinase inhibitor may be administered (if the BRAF gene mutation is proven). Alkylating drugs can also be included in the therapy regimen as monotherapy or in combination with monoclonal antibodies.
• Concomitant therapy. If systemic infectious complications develop, antimicrobials are prescribed. A short-term course of erythropoietin is recommended for patients with severe anemia.
• Splenectomy. Removal of the spleen quickly normalizes the blood picture. However, in several patients, remission is short-lived, which requires further drug therapy. As the first stage of treatment, surgery is indicated mainly in case of recurrent bleeding and infections.

All these treatment options are available in more than 680 hospitals worldwide (https://doctor.global/results/diseases/hairy-cell-leukemia). For example, Splenectomy can be performed in these countries at following approximate prices:

Turkey $6.3 in 12 clinics

China $14.7 K in 4 clinics

Germany $20.1 K in 30 clinics

Israel $20.2 K in 10 clinics

United States $51.1 K in 11 clinics.

Prognosis and prevention

Hairy cell leukemia tends to be recurrent. Within a 5-year follow-up period, relapses occur in 35% of patients and within ten years – in 50%. Without treatment, the life expectancy of HCL patients is less than five years. Methods of primary prevention of hairy cell leukemia have not been developed. After completion of course therapy, all patients should be observed by an oncologist-hematologist who controls blood tests twice a year and performs spleen ultrasounds annually. Timely antiretroviral treatment can achieve partial or complete remission and increase life expectancy.