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Chronic leukemia usually manifests as abnormal leukocytosis with or without cytopenia in an otherwise asymptomatic person. Findings and management differ significantly between chronic lymphocytic leukemia (CLL) and chronic myelocytic leukemia (CML).
Chronic Lymphocytic Leukemia (CLL)
(Chronic Lymphatic Leukemia)
The most common type of leukemia in the Western world, CLL involves mature-appearing defective neoplastic lymphocytes (almost always B cells) with an abnormally long life span. The peripheral blood, bone marrow, spleen, and lymph nodes are infiltrated. Symptoms may be absent or may include lymphadenopathy, splenomegaly, hepatomegaly, and nonspecific symptoms attributable to anemia (fatigue, malaise) and immunosuppression (eg, fever). Diagnosis is by examination of peripheral blood smear and bone marrow aspirate. Treatment, delayed until symptoms develop, is aimed at lengthening life and decreasing symptoms and may involve chlorambucil or fludarabine, prednisone, and cyclophosphamide or doxorubicin or both. Monoclonal antibodies, such as alemtuzumab and rituximab, are increasingly being used. Palliative radiation therapy is reserved for patients whose lymphadenopathy or splenomegaly interferes with other organs.
Incidence of CLL increases with age; 75% of cases are diagnosed in patients > 60 yr. CLL is twice as common in men. Although the cause is unknown, some cases appear to have a hereditary component. CLL is rare in Japan and China and does not seem to increase among Japanese expatriates in the US, suggesting a genetic factor. CLL is more common among Jews of Eastern European descent.
Pathophysiology
In about 98% of cases, CD5+ B cells undergo malignant transformation, with lymphocytes initially accumulating in the bone marrow and then spreading to lymph nodes and other lymphoid tissues, eventually inducing splenomegaly and hepatomegaly. As CLL progresses, abnormal hematopoiesis results in anemia, neutropenia, thrombocytopenia, and decreased immunoglobulin production. Many patients develop hypogammaglobulinemia and impaired antibody response, perhaps related to increased T-suppressor cell activity. Patients have increased susceptibility to autoimmune disease characterized by immunohemolytic anemias (usually Coombs' test–positive) or thrombocytopenia and a modest increase in risk of developing other cancers.
In 2 to 3% of cases, the clonal expansion is T cell in type, and even this group has a subtype (eg, large granular lymphocytes with cytopenias).
In addition, other chronic leukemic patterns have been categorized under CLL:
Differentiation of these subtypes from typical CLL is usually made by using light microscopy and phenotyping.
Symptoms and Signs
Onset is usually insidious. CLL is often diagnosed incidentally during routine blood tests or through evaluation of asymptomatic lymphadenopathy. Symptomatic patients usually have nonspecific complaints of fatigue, anorexia, weight loss, dyspnea on exertion, or a sense of abdominal fullness (secondary to an enlarged spleen). Initial findings include generalized lymphadenopathy and minimal-to-moderate hepatomegaly and splenomegaly. With progressive disease, there may be pallor due to anemia. Skin infiltration, either maculopapular or diffuse, may be a feature of T-cell CLL. Hypogammaglobulinemia and granulocytopenia in late CLL may predispose to bacterial, viral, and fungal infection, especially pneumonia. Herpes zoster is common.
Diagnosis
CLL is confirmed by examining the peripheral smear and bone marrow; the hallmark is sustained, absolute peripheral lymphocytosis (> 5000/μL) and increased lymphocytes (> 30%) in the bone marrow. Differential diagnosis is simplified by immunophenotyping. Other findings at diagnosis may include hypogammaglobulinemia (< 15% of cases) and, rarely, elevated LDH. About 10% of patients present with moderate anemia (sometimes immunohemolytic), thrombocytopenia, or both. A monoclonal serum immunoglobulin spike of the same type may be found on the leukemic cell surface in 2 to 4% of cases.
Clinical staging is useful for prognosis and treatment. Two common approaches are Rai and Binet staging, primarily based on hematologic changes and extent of disease (see Table 3: Leukemias: Clinical Staging of Chronic Lymphocytic Leukemia ).
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Table 3
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| Clinical Staging of Chronic Lymphocytic Leukemia |
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Classification and Stage
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Description
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Rai
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Absolute lymphocytosis of > 10,000/μL in blood and ≥ 30% lymphocytes in bone marrow
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Stage 0 plus enlarged lymph nodes
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Stage 0 plus hepatomegaly or splenomegaly
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Stage 0 plus anemia with Hb < 11 g/dL
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Stage 0 plus thrombocytopenia with platelet counts < 100,000/μL
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Binet
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Absolute lymphocytosis of > 10,000/μL in blood and ≥ 30% lymphocytes in bone marrow
Hb ≥ 10 g/dL
Platelets ≥ 100,000/μL
≤ 2 involved sites*
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As for stage A, but 3–5 involved sites
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As for stage A or B, but Hb < 10 g/dL or platelets < 100,000/μL
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*Sites considered: Cervical, axillary, and inguinal lymph nodes; liver; and spleen.
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Prognosis
The median survival of patients with B-cell CLL or its complications is about 7 to 10 yr. Patients in Rai stage 0 to II at diagnosis may survive for 5 to 20 yr without treatment. Patients in Rai stage III or IV are more likely to die within 3 to 4 yr of diagnosis. Progression to bone marrow failure is usually associated with short survival. Patients with CLL are more likely to develop a secondary cancer, especially skin cancer.
Treatment
Although CLL is progressive, some patients may be asymptomatic for years; therapy is not indicated until progression or symptoms occur. Cure usually is not possible, so treatment attempts to ameliorate symptoms and prolong life. Supportive care includes transfusion of packed RBCs or erythropoietin injections for anemia; platelet transfusions for bleeding associated with thrombocytopenia; and antimicrobials for bacterial, fungal, or viral infections. Because neutropenia and agammaglobulinemia limit bacterial killing, antibiotic therapy should be bactericidal. Therapeutic infusions of γ-globulin should be considered in patients with hypogammaglobulinemia and repeated or refractory infections or for prophylaxis when ≥ 2 severe infections occur within 6 mo.
Specific therapy includes
These modalities may alleviate symptoms and prolong survival. Overtreatment is more dangerous than undertreatment.
Chemotherapy:
Chemotherapy may be instituted when symptoms begin. Symptoms that prompt treatment include constitutional symptoms (fever, night sweats, extreme fatigue, weight loss); significant hepatomegaly, splenomegaly, or lymphadenopathy; lymphocytosis > 100,000/μL; and infections accompanied by anemia, neutropenia, or thrombocytopenia. Alkylating drugs, especially chlorambucil, alone or with corticosteroids, have long been the usual therapy for B-cell CLL. However, fludarabine is more effective. Combination chemotherapy with fludarabine, cyclophosphamide, and rituximab more often induces complete remissions. It also lengthens remission duration and prolongs survival. Interferon alfa, deoxycoformycin, and 2-chlorodeoxyadenosine are highly effective for hairy cell leukemia. Patients with prolymphocytic leukemia and lymphoma leukemia usually require multidrug chemotherapy and often respond only partially.
Corticosteroids:
Immunohemolytic anemia and thrombocytopenia are indications for corticosteroids. Prednisone 1 mg/kg po once/day may occasionally result in striking, rapid improvement in patients with advanced CLL, although response is often brief. The metabolic complications and increasing rate and severity of infections warrant caution in its prolonged use. Prednisone used with fludarabine increases the risk of Pneumocystis jirovecii and Listeria infections.
Monoclonal antibody therapy:
Rituximab is the first monoclonal antibody used in the successful treatment of lymphoid cancers. In previously untreated patients, the response rate is 75%, with 20% of patients achieving complete remission. Alemtuzumab has a 33% response rate in previously treated patients refractory to fludarabine and a 75 to 80% response rate in previously untreated patients. More problems with immunosuppression occur with alemtuzumab than with rituximab. Rituximab has been combined with fludarabine and with fludarabine and cyclophosphamide; these combinations have markedly improved the complete remission rate in both previously treated and untreated patients. Alemtuzumab is now being combined with rituximab and with chemotherapy to treat minimal residual disease and has effectively cleared bone marrow infiltration. Reactivation of cytomegalovirus and other opportunistic infections has occurred with alemtuzumab. Reactivation of hepatitis B infection may occur with rituximab.
Radiation therapy:
Local irradiation for palliation may be given to areas of lymphadenopathy or for liver and spleen involvement that does not respond to chemotherapy. Total body irradiation in small doses is occasionally successful in temporarily ameliorating symptoms.
Key Points
Chronic Myelocytic Leukemia (CML)
(Chronic Granulocytic Leukemia; Chronic Myelogenous Leukemia; Chronic Myeloid Leukemia)
CML occurs when a pluripotent stem cell undergoes malignant transformation and clonal myeloproliferation, leading to a striking overproduction of immature granulocytes. Initially asymptomatic, CML progression is insidious, with a nonspecific “benign” stage (malaise, anorexia, weight loss) eventually giving way to accelerated or blast phases with more ominous signs, such as splenomegaly, pallor, easy bruising and bleeding, fever, lymphadenopathy, and skin changes. Peripheral blood smear, bone marrow aspirate, and demonstration of Philadelphia chromosome are diagnostic. Treatment is with imatinib, which significantly improves response and prolongs survival. The curative potential of imatinib is undefined. Myelosuppressive drugs (eg, hydroxyurea), stem cell transplantation, and interferon alfa are also used.
CML accounts for about 15% of all adult leukemias. CML can strike at any age, although it is uncommon before age 10, and the median age at diagnosis is 45 to 55. CML may occur in either sex.
Pathophysiology
Most cases of CML appear to be induced by a translocation known as the Philadelphia (Ph) chromosome, which is demonstrable in 95% of patients. It is a reciprocal translocation t(9;22) in which a piece of chromosome 9 containing the oncogene c-abl is translocated to chromosome 22 and fused to the gene BCR. The fusion gene BCR-ABL is important in the pathogenesis and expression of CML and results in the production of a specific tyrosine kinase. CML ensues when an abnormal pluripotent hematopoietic progenitor cell initiates excessive production of granulocytes, primarily in the bone marrow but also in extramedullary sites (eg, spleen, liver). Although granulocyte production predominates, the neoplastic clone includes RBCs, megakaryocytes, monocytes, and even some T and B cells. Normal stem cells are retained and can emerge after drug suppression of the CML clone.
CML has 3 phases:
The blast phase leads to fulminant complications resembling those of acute leukemia, including sepsis and bleeding. Some patients progress directly from the chronic to the blast phase.
Symptoms and Signs
Patients are often asymptomatic early on, with insidious onset of nonspecific symptoms (eg, fatigue, weakness, anorexia, weight loss, fever, night sweats, a sense of abdominal fullness), which may prompt evaluation. Initially, pallor, bleeding, easy bruising, and lymphadenopathy are unusual, but moderate or occasionally extreme splenomegaly is common (60 to 70% of cases). With disease progression, splenomegaly may increase, and pallor and bleeding occur. Fever, marked lymphadenopathy, and maculopapular skin involvement are ominous developments.
Diagnosis
CML is most frequently diagnosed by a CBC obtained incidentally or during evaluation of splenomegaly. Granulocyte count is elevated, usually < 50,000/μL in asymptomatic patients and 200,000/μL to 1,000,000/μL in symptomatic patients. Platelet count is normal or moderately increased. Hb level is usually > 10 g/dL.
Peripheral smear may help differentiate CML from leukocytosis of other etiology. In CML, peripheral smear frequently shows immature granulocytes as well as absolute eosinophilia and basophilia, although in patients with WBC counts < 50,000/μL, immature granulocytes may not be seen. Leukocytosis in patients with myelofibrosis is usually associated with nucleated RBCs, teardrop-shaped RBCs, anemia, and thrombocytopenia. Leukemoid reactions resulting from cancer or infection are not often associated with absolute eosinophilia and basophilia.
The leukocyte alkaline phosphatase score is usually low in CML and increased in leukemoid reactions. Bone marrow examination should be done to evaluate the karyotype as well as cellularity and extent of myelofibrosis.
Diagnosis is confirmed by finding the Ph chromosome in samples examined with cytogenetic or molecular studies, although it is absent in 5% of patients.
During the accelerated phase of disease, anemia and thrombocytopenia usually develop. Basophils may increase, and granulocyte maturation may be defective. The proportion of immature cells and the leukocyte alkaline phosphatase score may increase. In the bone marrow, myelofibrosis may develop and sideroblasts may be seen on microscopy. Evolution of the neoplastic clone may be associated with development of new abnormal karyotypes, often an extra chromosome 8 or isochromosome 17.
Further evolution may lead to a blast phase with myeloblasts (60% of patients), lymphoblasts (30%), and megakaryoblasts (10%). In 80% of these patients, additional chromosomal abnormalities occur.
Prognosis
With imatinib, survival is > 90% at 5 yr after diagnosis for chronic phase CML. Before imatinib was used, with treatment, 5 to 10% of patients died within 2 yr of diagnosis; 10 to 15% died each year thereafter. Median survival was 4 to 7 yr. Most (90%) deaths followed a blast phase or an accelerated phase of the disease. Median survival after blast crisis was about 3 to 6 mo or longer if remission was achieved.
Ph chromosome–negative CML and chronic myelomonocytic leukemia have a worse prognosis than Ph chromosome–positive CML. Their clinical behaviors resemble a myelodysplastic syndrome (see Leukemias: Myelodysplastic Syndrome).
Treatment
Except when stem cell transplantation is successful, treatment is not known to be curative. However, when tyrosine kinase inhibitors are used, survival is prolonged and maximum overall survival has not been reached. Some patients may be able to discontinue tryrosine kinase inhibitors and remain in remission. The durability of these remissions is as yet not known.
Imatinib and several newer drugs (dasatinib, nilotinib) inhibit the specific tyrosine kinase that results from the BCR-ABL gene product. Tyrosine kinase inhibitors are dramatically effective in achieving complete clinical and cytogenetic remissions of Ph chromosome–positive CML and are clearly superior to other regimens (eg, interferon with or without cytarabine). Imatinib also is superior to other treatments in the accelerated and blast phases. In the blast phase, combinations of chemotherapy with imatinib have a higher response rate than does therapy with either approach alone. Treatment tolerance is excellent. The high level of durable complete remissions associated with imatinib therapy has led to the prospect of cure of the disease.
Older chemotherapy regimens are reserved for BCR-ABL–negative patients, patients who relapse after receiving imatinib, and patients in the blast phase. The main agents are busulfan, hydroxyurea, and interferon. Hydroxyurea is easiest to manage and has the fewest adverse effects. The starting dosage is generally 500 to 1000 mg po bid. Blood counts should be done every 1 to 2 wk and the dosage adjusted accordingly. Busulfan often causes unexpected general myelosuppression, and interferon causes a flu-like syndrome that frequently is unacceptable to patients. The main benefit of these therapies is reduction in distressing splenomegaly and adenopathy and control of the tumor burden to reduce the incidence of tumor lysis and gout. None of these therapies prolongs median survival > 1 yr compared with untreated patients; thus, reduction in symptoms is the major goal, and therapy is not continued when patients have significant toxic symptoms.
Allogeneic stem cell transplantation can be useful for patients refractory to therapy.
Although splenic radiation is rarely used, it may be helpful in refractory cases of CML or in patients with terminal disease and marked splenomegaly. Total dosage usually ranges from 6 to 10 Gy delivered in fractions of 0.25 to 2 Gy/day. Treatment should begin with very low doses and with careful evaluation of the WBC count. Response is usually disappointing.
Splenectomy may alleviate abdominal discomfort, lessen thrombocytopenia, and relieve transfusion requirements when splenomegaly cannot be controlled with chemotherapy or irradiation. Splenectomy does not play a significant role during the chronic phase of CML.
Key Points
Last full review/revision July 2012 by Michael E. Rytting
Content last modified November 2012
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