CHRONIC LYMPHOCYTIC LEUKEMIAS (CLL)
Chronic lymphocytic leukemias are generally associated with an increase in the number of circulating lymphocytes. This disorder is often associated with various degrees of lymphadenopathy, and is very similar to small cell lymphoma. The distinction between CLL and lymphoma is based on the degree of lymphadenopathy (when severe the diagnosis is lymphoma). There are various types of CLL depending on the type of cells involved to include: B cell, natural killer (NK) cell, and hairy-cell leukemia (HCL). T-cell CLL has been reclassified under the World Health Organization classification to T-cell prolymphocytic leukemia. At present, the etiology of CLL is unknown.
B-CELL CLL
This is a very common form of leukemia. Clinical symptoms may include malaise, fatigue, weight loss, night sweats, lymphadenopathy, splenomegaly and hepatomegaly. Hypogammaglobulinemia results from suppression of normal B cell function and this results in an increased susceptibility to infections from encapsulated bacteria. Often, patients are asymptomatic and the diagnosis is suspected secondary to abnormalities noted on a routine complete blood count (CBC). CBC abnormalities associated with CLL include lymphocytosis (which may be quite severe and generally involves mature cells), anemia, thrombocytopenia or pancytopenia. Autoimmune phenomenon to include idiopathic thrombocytopenia or Coomb’s positive hemolytic anemia are other common occurrences.
The abnormal B cell immunophenotype noted on flow cytometry with immunophenotyping is often CD5+, CD19+, dim or absent CD23+, bright CD20+, and FMC7- with possible weak expression of CD22, CD79b, and surface immunoglobulin (sIg) with variability between individual cases. Bone marrow examination may also prove diagnostic; however, the less invasive flow cytometry study with immunophenotyping is all that is required in most cases. Prognosis is based on staging and on the presence of symptoms (lymphadenopathy, hepatosplenomegaly, anemia, and thrombocytopenia). Other adverse prognostic factors include lymphocyte doubling time (LDT) of less than 12 months, atypical lymphocyte morphology, elevated serum beta-2 microglobulin levels, elevated soluble CD23 levels, elevated thymidine kinase levels, the presence of mutated-type IgVH genes, and deletions or mutations of the p53 gene. On cytogenetic analysis or interphase fluorescence in situ hybirdization (FISH) chromosomal abnormalities include 13q-, 11q-, trisomy 12, or 17p-. The presence of 17p- and 11q- were associated with a worse prognosis.
Asymptomatic patients with early disease and a good prognosis (early stage disease, LDT > 12 months, CD38 negative, normal beta-2 microglobulin, and no organomegaly, lymphadenopathy or associated cytopenias) require only close follow-up without therapy. Indications to initiate therapy include the presence of B symptoms (fever, sweats, or weight loss), progressive lymphadenopathy, progression of hepatomegaly/splenomegaly, obstructive adenopathy, worsening thrombocytopenia/anemia, rapid lymphocyte doubling times (<12 months), or immune hemolysis/thrombocytopenia not responsive to steroids. Extreme lymphocytosis is not an indication for therapy as it is rarely associated with hyperviscosity. Consultation with an oncologist is necessary as there are various treatment options available. The goal of therapy is to induce a complete remission and available options include chlorambucil, fludarabine, cladribine, rituximab, autologous stem cell transplantation, and combination regimens. Conditions and complications associated with CLL and its treatment include autoimmune hemolytic anemia, immune-mediated thrombocytopenia, pure red cell aplasia, infections, and secondary malignancies (Kaposi sarcoma, malignant melanoma, and cancers of the larynx, lung, brain, stomach and bladder). CLL may transform into Richter syndrome (rapidly progressive adenopathy, extanodal disease, monoclonal gammopathy, and an elevated LDH) or prolymphocytic leukemia.
T-CELL CLL/ T-CELL PROLYMPHOCYTIC LEUKEMIA
This disease formerly known as T-cell CLL and now reclassified as T-cell prolymphocytic leukemia is common in Japan but rare in Western countries. There are two subsets of prolymphocytic leukemia to include CD4 type and CD8 type. The CD4 type is associated with HTLV-1 infection. Skin involvement is common in CD4 type disease. These skin lesions are prone to infections which often result in death. There is also a propensity for hypergammaglobulinemia with CD4 type disease; however, despite the elevated levels of gammaglobulin (mostly IgA), these patients suffer from an increased frequency of infections. Treatment for CD4 type disease is aimed at decreasing the cell count and treating infections and skin involvement. Beta irradiation, topical steroids or alkylating agents and ultraviolet phototherapy may be used in the treatment for skin lesions. Systemic chemotherapeutic agent options include: chlorambucil (with or without steroids), cyclophosphamide (with or without steroids), methotrexate, bleomycin and adriamycin.
CD8 type disease is often associated without or with only a mild lymphocytosis. The malignant cells often resemble the atypical lymphocytes associated with infectious mononucleosis. Often there is associated granulocytopenia, aplastic anemia or pancytopenia. Many require no treatment other than supportive care for associated anemia or infections. Others with more severe disease may respond to chlorambucil or cyclophosphamide with or without prednisone.
HAIRY-CELL LEUKEMIA
So named secondary to the abnormal morphology of affected lymphocytes which display long filamentous cytoplasmic projections especially in wet mounts observed by phase microscopy. These neoplastic B cells with hairlike cytoplasmic projections infiltrate the bone marrow, liver. spleen, and lymph nodes. There is often an associated pancytopenia and physical examination may reveal splenomegaly. Peripheral smear review may reveal the presence of the “hairy cell”, and the tartrate-resistant acid phosphatase (TRAP) stain of the peripheral smear may be used to confirm its presence. Bone marrow aspirate is usually dry, but TRAP staining of the bone marrow biopsy will reveal the “hairy cells”. As with other chronic lymphoid leukemias, therapy should be initiated depending on the patient’s symptoms, and hairy cell leukemia often responds well to treatment with interferon or pentostatin. Symptomatic splenomegaly may be treated with splenectomy or splenic irradiation.