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 is the most common genetic abnormality. 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 66-2). 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 Leukemia Supportive 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. Monthly IV immunoglobulin (IVIg) significantly reduces risk of serious infection but is expensive and usually reserved for pts who have had a serious infection. Alkylating agents are also active against the tumor. Ibrutinib, an inhibitor of Bruton's tyrosine kinase, is highly active in CLL and some use it as primary therapy. 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. |
See Chaps. 134 and 135e in HPIM-19 for discussion of the rarer entities.
Section 6. Hematology and Oncology