THE LEUKEMIAS
THE LEUKEMIAS
Leukemia is a condition in which the bone marrow is replaced by a malignant clone of lymphocytic or granulocytic cells (Fig. 54-4). The course of the disease may be chronic or explosive; if left untreated, all leukemias are fatal.
Chronic Leukemias
Chronic myelogenous leukemia (CML) is often classified as a myeloproliferative disease as well as a leukemia, since it shares the major feature of the myeloproliferative diseases: uncontrolled expansion of all marrow elements. All marrow cell lines in CML express a marker chromosome, the Philadelphia chromosome, pointing to a mutation in a pluripotent stem cell as the initiating event. The Philadelphia chromosome represents a reciprocal translocation of part of the long arm of chromosome 22 to chromosome 9. The biological mechanism behind this rearrangement is not clear, but recent work suggests an association of the Philadelphia chromosome with activation of cellular oncogenes. Cellular oncogenes are Human DNA sequences that are homologous to DNA of viruses that cause cancer in other species. Further work is needed to define the meaning of this association.
Although CML is usually a disease of adults, it sometimes affects children as well. The average age at onset is between 40 and 50 years. The disorder is not familial, and most patients have no history of excess exposure to carcinogenic chemicals or increased radioactivity.
Nonetheless, the incidence of CML did increase markedly seven years after the atomic bomb explosion in Japan in 1945.
The typical patient with CML presents with few symptoms, and the disease may be discovered on routine blood count. Leukocytosis with early myeloid precursors in the peripheral blood and splenomegaly are almost always present at the time of diagnosis. Thrombocytosis is also common. Table 54-4 outlines the differential diagnosis between CML, MMM, and a leukemoid reaction.-Initially, affected patients are managed easily with periodic oral chemotherapy (alkylat. ing agents or hydroxyurea) to normalize the blood count and reduce splenomegaly. This chronic phase of CML lasts three to five years. Subsequently, the course of the disease accelerates. The white count and spleen size become more difficult to control. Anemia and, eventually, thrombocytopenia develop, and fever and increasing weakness may appear.
Eventually, white cell maturation ceases, so that the peripheral blood contains increasing numbers of promyelocytes and myeloblasts. This is termed the “blast phase,” and it heralds death within three to six months.
The events that transform CML from the chronic to the blast phase are not understood. Hyperdip-loidy or other chromosome abnormalities in addition to the Philadelphia chromosome often develop. In approximately 20 per cent of blast crises, the blast cells bear markers of lymphoid cell origin such as the enzyme terminal deoxynucleo-tidyl transferase (Tdt). This finding is important in therapeutic management, since drugs that are effective in lymphoid malignancies (e.g., vincristine and prednisone) may be useful in a lymphoid type (Tdt-positive) of blast crisis. Overall, however, the treatment of blast crisis is unsatisfactory, and any remissions are short.
New strategies are needed if patients with CML are to be cured. Bone marrow transplantation represents a potentially promising approach. Patients under 40 with an identical twin or HLA-identical sibling should be considered for bone marrow transplantation during the chronic phase, with the goal of producing long-term disease-free survival.
Chronic lymphocytic leukemia (CLL) was described by Dr. William Dameshek as an “accumulative disease of immunologically incompetent lymphocytes,” a concise definition that describes the majority of patients. CLL is a disease of older persons, and fewer than 10 per cent of cases are patients under 50 years old. Men develop CLL twice as often as women and, as in all forms of leukemia, the disorder is more common in whites than blacks.
The diagnosis of CLL is based on an absolute and sustained lymphocytosis in the peripheral blood of no less than 15,000 cells/(jil. The bone marrow is hypercellular, and more than 40 per cent of the cells are lymphocytes. The lymphocytes in the peripheral blood and marrow are of the small, well-differentiated type. Slowly enlarging lymph nodes and gradual enlargement of the liver and spleen due to the accumulation of neoplastic lymphocytes may occur early or late in the course of the disease. The immunological incompetence of the expanding lymphocyte population expresses itself in hypogammaglobulinemia with predisposition to infections and in the emergence of such autoimmune phenomena as the production of antibodies against host red blood cells, causing Coombs’ positive hemolytic anemia. Table 54-6 outlines the immune disorders in CLL.
Lymphocytes in chronic lymphocytic leukemia usually consist of a clonal proliferation of B lymphocytes (Fig. 54-5). The malignant cells all display immunoglobulin molecules on their plasma membranes bearing the same idiotype and the same single light chain type. The most common surface immunoglobulins represented are IgM and IgD. The finding of two heavy chain classes does not preclude the concept of monoclonality, as the IgD and IgM have the same idiotype specificity and presumably reflegt an early, frozen stage of differentiation of normal B lymphocytes. CLL lymphocytes also express the la antigen, the receptor for C3, and the receptor for the Fc portion of immunoglobulin.
About 1 per cent of patients with CLL demonstrate predominantly T lymphocytes in their peripheral blood. These lymphocytes form rosettes with sheep red blood cells and do not bear surface immunoglobulin. The T cell form of CLL appears to carry a poorer prognosis than the B cell type. Skin involvement is seen frequently in these patients, and standard forms of therapy for CLL are less effective.