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Chapter: Basic & Clinical Pharmacology : Cancer Chemotherapy

The Leukemias

Acute lymphoblastic leukemia (ALL) is the main form of leukemia in childhood, and it is the most common form of cancer in chil-dren.

THE LEUKEMIAS

ACUTE LEUKEMIA

Childhood Leukemia

Acute lymphoblastic leukemia (ALL) is the main form of leukemia in childhood, and it is the most common form of cancer in chil-dren. Children with this disease have a relatively good prognosis.A subset of patients with neoplastic lymphocytes expressing surface antigenic features of T lymphocytes has a poor prognosis . A cytoplasmic enzyme expressed by normal thymo-cytes, terminal deoxycytidyl transferase (terminal transferase), is also expressed in many cases of ALL. T-cell ALL also expresses high levels of the enzyme adenosine deaminase (ADA). This led to inter-est in the use of the ADA inhibitor pentostatin (deoxycoformycin) for treatment of such T-cell cases. Until 1948, the median length of survival in ALL was 3 months. With the advent of methotrexate, the length of survival was greatly increased. Subsequently, cortico-steroids, 6-mercaptopurine, cyclophosphamide, vincristine, dauno-rubicin, and asparaginase have all been found to be active against this disease. A combination of vincristine and prednisone plus other agents is currently used to induce remission. Over 90% of children enter complete remission with this therapy with only minimal toxicity. However, circulating leukemic cells often migrate to sanctuary sites located in the brain and testes. The value of pro-phylactic intrathecal methotrexate therapy for prevention of central nervous system leukemia (a major mechanism of relapse) has been clearly demonstrated. Intrathecal therapy with methotrexate should therefore be considered as a standard component of the induction regimen for children with ALL.

Adult Leukemia

Acute myelogenous leukemia (AML) is the most common leuke-mia in adults. The single most active agent for AML is cytarabine; however, it is best used in combination with an anthracycline, which leads to complete remissions in about 70% of patients. While there are several anthracyclines that can be effectively com-bined with cytarabine, idarubicin is preferred.Patients often require intensive supportive care during the period of induction chemotherapy. Such care includes platelet transfusions to prevent bleeding, the granulocyte colony-stimulat-ing factor filgrastim to shorten periods of neutropenia, and anti-biotics to combat infections. Younger patients (eg, age < 55) who are in complete remission and have an HLA-matched donor are candidates for allogeneic bone marrow transplantation. The trans-plant procedure is preceded by high-dose chemotherapy and total body irradiation followed by immunosuppression. This approach may cure up to 35–40% of eligible patients. Patients over age 60 respond less well to chemotherapy, primarily because their toler-ance for aggressive therapy and resistance to infection are lower.Once remission of AML is achieved, consolidation chemotherapy is required to maintain a durable remission and to induce cure.

CHRONIC MYELOGENOUS LEUKEMIA

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 constitu-tive 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 over 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, but both are now also indicated as first-line treat-ment of chronic phase CML. In addition to these tyrosine kinase inhibitors, other treatment options include interferon-α, busulfan, other oral alkylating agents, and hydroxyurea.

CHRONIC LYMPHOCYTIC LEUKEMIA

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 com-bined 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 pred-nisone. The purine nucleoside analog fludarabine is also effective in treating CLL. This agent can be given alone, in combination with cyclophosphamide and with mitoxantrone and dexamethasone, or combined with the anti-CD20 antibody 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. Alemtuzumab is a humanized monoclonal antibody directed against the CD52 antigen and is approved for use in CLL that is refractory to alkylat-ing agent or fludarabine therapy. Response rates up to 30–35% are observed, with disease stabilization in another 30% of patients.


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