(See also Overview of Leukemia.)
Chronic lymphocytic leukemia is the most common type of leukemia in the Western world. The American Cancer Society estimates that in the United States in 2020 there will be about 21,040 new cases of CLL and about 4060 deaths; most cases and almost all deaths will be in adults. The average age of a patient with CLL is 70 years; CLL is extremely rare in children. The average lifetime risk of CLL in both sexes is about 0.57% (1 in 175 Americans).
Although the cause of CLL is unknown, some cases appear to have a hereditary component. CLL is rare in Japan and China, and the incidence does not seem to be increased among Japanese expatriates in the United States, suggesting the importance of genetic factors. CLL is more common among Jews of Eastern European descent.
In chronic lymphocytic leukemia, CD5+ B cells undergo malignant transformation. The B cells become continuously activated by acquisition of mutations that lead to monoclonal B-cell lymphocytosis (MBL). Further accumulation of genetic abnormalities and subsequent oncogenic transformation of monoclonal B cells leads to CLL. Lymphocytes initially accumulate in the bone marrow and then spread to lymph nodes and other lymphoid tissues, eventually inducing splenomegaly, hepatomegaly, and systemic symptoms such as fatigue, fever, night sweats, early satiety, and unintentional weight loss.
As CLL progresses, abnormal hematopoiesis results in anemia, neutropenia, thrombocytopenia, and decreased immunoglobulin production. Hypogammaglobulinemia can develop in up to two thirds of patients, increasing risk for infectious complications. Patients have increased susceptibility to autoimmune hemolytic anemias (with a positive direct antiglobulin test) and autoimmune thrombocytopenia.
CLL can evolve into B-cell prolymphocytic leukemia and can transform to a higher grade non-Hodgkin lymphoma. About 2 to 10% of CLL cases develop into diffuse large B-cell lymphoma (called Richter's transformation).
Patients are often asymptomatic early on, with insidious onset of nonspecific symptoms (eg, fatigue, weakness, anorexia, weight loss, fever, and/or night sweats) that may prompt evaluation. More than 50% of patients have lymphadenopathy. Lymphadenopathy can be localized (with cervical and supraclavicular nodes being the most commonly involved) or generalized. Splenomegaly and hepatomegaly are less common than lymphadenopathy. Skin involvement (leukemia cutis) is rare.
The diagnosis of chronic lymphocytic leukemia is first suspected when an absolute peripheral lymphocytosis of > 5000/mcL (> 5 × 109/L)) is found. Peripheral blood flow cytometry can confirm clonality in circulating B cells. The circulating lymphocytes should express CD5, CD19, CD20, CD23, and kappa or lambda light chains. Patients with an absolute lymphocyte count < 5000/mcL (< 5 × 109/L) but evidence of clonality are diagnosed with monoclonal B cell lymphocytosis (MBL). About 1 to 2% of monoclonal B-cell lymphocytosis cases progress to CLL per year (1). Bone marrow aspirate and biopsy are not required for the diagnosis of CLL. However, if done, the marrow often demonstrates > 30% lymphocytes.
Other findings at diagnosis can include hypogammaglobulinemia (< 15% of cases), elevated lactate dehydrogenase (LDH), elevated uric acid, elevated hepatic enzymes, and rarely, hypercalcemia. Cytogenetic and molecular studies done from peripheral blood at the time of diagnosis help in determining prognosis.
Classification uses the Rai or Binet staging systems. Neither system effectively predicts early disease progression. Routine imaging is not recommended for initial staging (see table Clinical Staging of CLL).
Clinical Staging of Chronic Lymphocytic Leukemia*
The natural history of chronic lymphocytic leukemia is highly variable. Survival ranges from about 2 to > 20 years, with a median of about 10 years. Patients presenting as Rai stage 0 to II may survive for 5 to 20 years without treatment.
Other prognostic features of CLL include
Lymphocyte doubling time is the number of months it takes the absolute lymphocyte count to double. Untreated patients with a lymphocyte doubling time < 12 months have a more aggressive clinical course.
Specific high-risk cytogenetic abnormalities include del(17p) and del(11q). Other adverse prognostic features include an unmutated immunoglobulin heavy chain variable gene, presence of CD38 on flow cytometry, and expression of ZAP-70.
Chronic lymphocytic leukemia is considered incurable with the current standard of care; treatment is aimed at symptom amelioration. Thus, treatment is withheld until patients have one of the following:
Symptoms that prompt treatment in patients with CLL include
Disease-directed treatment options include
Supportive care includes
Because neutropenia and hypogammaglobulinemia limit bacterial killing, antibiotic therapy should be bactericidal. Gamma-globulin infusions should be considered for treatment in patients with hypogammaglobulinemia and refractory infections or for prophylaxis when ≥ 2 severe infections occur within 6 months.
Chemoimmunotherapy aims to
There is no standard chemoimmunotherapy regimen. Selection of initial therapy depends on patient characteristics, disease-specific features such as presence of del(17p), and the overarching goals of therapy.
Purine analogs (eg, fludarabine) as well as alkylating agents (eg, bendamustine, chlorambucil, cyclophosphamide) have been used in combination with the anti-CD20 monoclonal antibody, rituximab. Untreated patients who can tolerate chemotherapy are often offered the combination of fludarabine, cyclophosphamide, and rituximab. Alternatively, elderly untreated patients are often offered bendamustine and rituximab because this regimen is easier to tolerate (1).
CLL with del(17p) is often refractory to chemoimmunotherapy, but ibrutinib has been shown to improve outcome. Ibrutinib is a novel, oral inhibitor of Bruton tyrosine kinase (Btk), an enzyme essential for activation of several pathways that enhance CLL cell survival. Studies comparing ibrutinib monotherapy with ibrutinib plus chemoimmunotherapy are ongoing.
In older patients with comorbid conditions, the anti-CD20 monoclonal antibody obinutuzumab is added to chlorambucil. Obinutuzumab targets the same CLL cell surface protein as rituxumab. Obinutuzumab plus chlorambucil was recently found to be superior to rituximab plus chlorambucil in prolonging progression-free survival and achieving a complete response (2).
Relapsed or refractory CLL should be confirmed histologically before restarting treatment. Transformation to large cell lymphoma (Richter's transformation) should be excluded specifically. Asymptomatic patients with recurrent CLL are monitored closely for symptoms that warrant treatment. Factors that influence choice of treatment at relapse include
Ibrutinib (a Btk inhibitor) can improve response rate and progression-free survival in relapsed or refractory CLL. Ibrutinib is continued until toxicity develops or disease progresses. Other effective targeted therapies for relapsed CLL included idelalisib (an oral inhibitor of phosphoinositide 3'-kinase [PI3K] delta) and venetoclax (an oral inhibitor of Bcl-2). Venetoclax can be used for patients with del(17p) who have received at least one prior therapy.
Monotherapy with an anti-CD20 monoclonal antibody (rituximab, ofatumumab, obinutuzumab) may transiently palliate symptoms.
Allogeneic stem cell transplantation should be considered for patients who are fit.
1. Eichhorst B, Fink AM, Bahlo J et al: First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): An international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol 17:928–942, 2016.
2. Goede V, Fischer K, Busch R, et al: Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. New Engl J Med 370:1101–1111, 2014.
Chronic lymphocytic leukemia (CLL) is an indolent lymphoproliferative malignancy involving mature lymphocytes which predominantly affects older individuals.
CLL is the most common type of leukemia in the Western world.
Natural history is highly variable.
Treatment is generally not curative and is not initiated until symptoms develop.
Chemoimmunotherapy decreases symptoms and prolongs survival.
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