Chronic Lymphocytic Leukemia (CLL)
(Chronic Lymphatic Leukemia)
The most common type of leukemia in the Western world, chronic lymphocytic leukemia (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, rituximab, and obinutuzumab, are increasingly being used. Palliative radiation therapy is reserved for patients whose lymphadenopathy or splenomegaly interferes with other organs.
(See also Overview of Leukemia.)
The incidence of chronic lymphocytic leukemia 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 the incidence does not seem to be increased among Japanese expatriates in the US, suggesting the importance of genetic factors. CLL is more common among Jews of Eastern European descent.
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.
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 lactate dehydrogenase. 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: Clinical Staging of Chronic Lymphocytic Leukemia*).
Clinical Staging of Chronic Lymphocytic Leukemia*
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.
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
Because neutropenia and agammaglobulinemia limit bacterial killing, antibiotic therapy should be bactericidal. Therapeutic infusions of gamma-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 may be instituted when symptoms begin. Symptoms that prompt treatment include
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.
Ibrutinib is a novel, oral inhibitor of Bruton tyrosine kinase. Bruton tyrosine kinase is an enzyme essential for activation of several downstream B-cell mediated pathways that enhance survival of CLL cells. Ibrutinib appears to be highly active in CLL and has induced durable remissions in some patients with relapsed or refractory CLL. Its role as a single agent or as part of combination chemotherapy is evolving.
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.
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.
Obinutuzumab is a newer monoclonal antibody that targets the same CLL cell surface protein as rituximab. The combination of obinutuzumab and chlorambucil was recently found to be superior to rituximab in prolonging progression-free survival and achieving a complete response to treatment.
Obinutuzumab plus chlorambucil has now been approved as frontline therapy for elderly patients or frail patients with comorbidities (1). In the specific instance of CLL with a deletion of 17p, the Bruton tyrosine kinase inhibitor ibrutinib has shown excellent activity. Single-agent ibrutinib is an approved frontline treatment for such patients. This is distinct from the group of CLL patients with deletion 11q abnormalities, who seem to benefit most from initial alkylator therapy. In patients with relapsed or refractory disease, new options include idelalisib (a phosphoinositide 3-kinase inhibitor) plus rituximab and monotherapy with ibrutinib.
In general, monoclonal antibodies are well tolerated, although they may cause allergic reactions and significant immunosuppression. This favorable toxicity profile allows these agents to be combined with conventional chemotherapy, often with excellent clinical efficacy.
1. 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.