Chronic myelogenous leukemia (CML) arises from a chromosomally abnormal hematopoietic stem cell in which a balanced translocation between the long arms of chromosomes 9 and 22, t(9:22), is observed in 90–95% of cases. This translocation results in constitutive expression of the Bcr-Abl fusion oncoprotein with a molecular weight of 210 kDa. The clinical symptoms and course are related to the white blood cell count and its rate of increase. Most patients with white cell counts greater than 50,000/μL should be treated. The goals of treatment are to reduce the granulocytes to normal levels, to raise the hemoglobin concentration to normal, and to relieve disease-related symptoms. The tyrosine kinase inhibitor imatinib is considered as standard first-line therapy in previously untreated patients with chronic phase CML. Nearly all patients treated with imatinib exhibit a complete hematologic response, and up to 40–50% of patients show a complete cytogenetic response. As described previously, this drug is generally well tolerated and is associated with relatively minor adverse effects. Initially, dasatinib and nilotinib were approved for patients who were intolerant or resistant to imatinib; each shows clinical activity, and both are now also indicated as first-line treatment of chronic phase CML. In addition to these tyrosine kinase inhibitors, other treatment options include IFN-α, busulfan, other oral alkylating agents, and hydroxyurea.
Patients with early-stage chronic lymphocytic leukemia (CLL) have a relatively good prognosis, and therapy has not changed the course of the disease. However, in the setting of high-risk disease or in the presence of disease-related symptoms, treatment is indicated.
Chlorambucil and cyclophosphamide are the two most widely used alkylating agents for this disease. Chlorambucil is frequently combined with prednisone, although there is no clear evidence that the combination yields better response rates or survival compared with chlorambucil alone. In most cases, cyclophosphamide is combined with vincristine and prednisone (COP), or it can also be given with these same drugs along with doxorubicin (CHOP). Bendamustine is the newest alkylating agent to be approved for use in this disease, either as monotherapy or in combination with prednisone. The purine nucleoside analog fludarabine also is effective in treating CLL. This agent can be given alone, in combination with cyclophosphamide and with mitoxantrone and dexamethasone, or combined with rituximab. Monoclonal antibody targeted therapies are being widely used in CLL, especially in relapsed or refractory disease. Rituximab is an anti-CD20 antibody that has documented clinical activity in this setting. This chimeric antibody appears to enhance the antitumor effects of cytotoxic chemotherapy and is also effective in settings in which resistance to chemotherapy has developed. Ofatumumab is a fully human IgG1 antibody that binds to a different CD20 epitope than rituximab. Of note, it maintains activity in rituximab-resistant tumors, and it is presently approved for CLL that is refractory to fludarabine and alemtuzumab therapy.
The treatment of Hodgkin’s lymphoma has undergone dramatic evolution over the last 40 years. This lymphoma is now widely recognized as a B-cell neoplasm in which the malignant Reed-Sternberg cells have rearranged VH genes. In addition, the Epstein-Barr virus genome has been identified in up to 80% of tumor specimens.