Most of these entities have a natural history measured in years. (Prolymphocytic leukemia is very rare and can be very aggressive.) Chronic lymphocytic leukemia (CLL) is the most common entity in this group (∼21,000 cases/year in the United States) and the most common leukemia in the Western world.
Usually presents as asymptomatic lymphocytosis in pts >60 years. The malignant cell is a CD5+ B cell that looks like a normal small lymphocyte. Trisomy 12 and deletions of 13q, 11q, and 17p are the most common genetic abnormalities. Prognosis is related to stage; stage is determined mainly by the degree to which the tumor cells crowd out normal hematopoietic elements from the marrow (Table 67-2 Staging of B-Cell CLL and Relation to Survival). Cells may infiltrate nodes and spleen as well as marrow. Nodal involvement may be related to the expression of an adhesion molecule that allows the cells to remain in the node rather than recirculate. Pts often have hypogammaglobulinemia. Up to 20% have autoimmune antibodies that may produce autoimmune hemolytic anemia, thrombocytopenia, or red cell aplasia. Death is from infection, marrow failure, or intercurrent illnesses. In 5%, the disease evolves to aggressive lymphoma (Richter's syndrome) that is refractory to treatment.
Subsets of CLL may exist based on whether the immunoglobulin expressed by the tumor cell contains mutations (more indolent course, good prognosis) or retains the germ-line sequence (more aggressive course, poor response to therapy). Methods to distinguish the two subsets clinically are not well defined; CD38+ tumors may have poorer prognosis. The expression of ZAP-70, an intracellular tyrosine kinase normally present in T cells and aberrantly expressed in about 45% of CLL cases, may be a better way to define prognostic subsets. ZAP-70-positive cases usually need treatment within about 3-4 years from diagnosis; ZAP-70-negative cases usually don't require treatment for 8-11 years.
| TREATMENT | ||
Chronic Lymphocytic LeukemiaSupportive care is generally given until anemia or thrombocytopenia develops. At that time, tests are indicated to assess the cause of the anemia or thrombocytopenia. Decreased RBC and/or platelet counts related to peripheral destruction may be treated with splenectomy or glucocorticoids without cytotoxic therapy in many cases. If marrow replacement is the mechanism, therapy is indicated. Fludarabine, 25 (mg/m2 )/d IV × 5 days every 4 weeks, induces responses in about 75% of pts, complete responses in half. Rituximab (375-500 mg/m2 day 1), fludarabine (25 mg/m2 days 2-4 on cycle 1 and 1-3 in subsequent cycles), plus cyclophosphamide (250 mg/m2 with fludarabine) induce complete responses in nearly 70% of pts but the regimen is associated with significant myelotoxicity. Glucocorticoids increase the risk of infection without adding a substantial antitumor benefit. Ibrutinib, an inhibitor of Bruton's tyrosine kinase, is highly active in CLL and many use it as primary therapy. Alkylating agents such as bendamustine and chlorambucil are also active against the tumor. Venetoclax (an inhibitor of bcl-2) is also an effective agent. Monthly IV immunoglobulin (IVIg) significantly reduces risk of serious infection but is expensive and usually reserved for pts who have had a serious infection. Therapeutic intent is palliative in most pts. Young pts may be candidates for high-dose therapy and autologous or allogeneic hematopoietic cell transplantation; long-term disease-free survival has been noted. Minitransplant, in which the preparative regimen is immunosuppressive but not myeloablative, may be less toxic and as active or more active in disease treatment than high-dose therapy. Monoclonal antibodies alemtuzumab (anti-CD52) and rituximab, obinutuzumab, and ofatumumab (all anti-CD20s) also are active as single agents or combined with chlorambucil. Chimeric antigen receptor T cells directed at CD19 or CD22 are also used. The bcl-2 inhibitor venetoclax in combination with ibrutinib has a high level of activity. |