Neutropenia can occur by several mechanisms including massive use of neutrophils in the periphery (e.g., in the sepsis syndrome), redistribution of cells including accumulation in the spleen (e.g., rheumatoid arthritis and malaria), and impaired production by the bone marrow. In patients with acute myelogenous leukemia (AML), neutropenia occurs from the expansion of abnormal clone progenitor cells that lack the capacity for full myeloid development. In other hematologic malignancies, neutropenia can occur as a consequence of the disease. In most malignancies, however, neutropenia is attributable to the effects of chemotherapy that reduce myeloid cell proliferation in the bone marrow. With all myelotoxic chemotherapy, the risk of neutropenia depends on the dosing regimen and resiliency of the patient's hematopoietic system.
Our understanding of the risk of chemotherapy-induced neutropenia is based on the mechanism of action of the specific drugs and drug combinations, in vivo and in vitro studies of drug effects on hematopoietic cells, and results from clinical investigations. Of note, most of these agents cause a similar pattern of reduction in blood cell counts. Neutropenia is the most frequent dose-limiting toxicity. The usual duration of severe neutropenia after administration of a single agents or a combination of agents is approx 3-7 d, beginning approx 3-5 d after chemotherapy administration. Recovery of the bone marrow and return of blood neutrophil counts to normal often takes 3 or more wk. Exceptions include single doses of the alkylating agents that can cause myelosuppres-sion lasting only 2-3 d (i.e., cyclophosphamide) and myelosuppression lasting several weeks or more (i.e., busulfan and BCNU [carmustine]).
Chemotherapy-induced cellular and molecular changes resulting in myeloid cell toxicity are not well understood. Currently, most malignancies are treated with combination chemotherapy, administering treatments to maximize anticancer effects and minimize toxicity. The practice of administrating chemotherapy at 3- to 4-wk intervals was derived empirically from the time normally required for myeloid recovery after administration of most chemotherapy drugs.
Understanding the myelotoxicities of combination chemotherapy regimens requires careful clinical observation and serial blood cell counts over the course of several chemotherapy cycles, usually in the setting of a randomized, controlled trial; however, methods for measuring toxicity, such as timing of blood count samples, reporting of chemotherapy doses and dose intensity, assessing temperature and patient clinical status, and recording administration of antibiotics and other therapies, are not standardized. Many randomized treatment trials, such as those for non-Hodgkin's lymphoma (NHL) and metastatic breast cancer, have not reported on myelotoxicity (3). In trials reporting toxicity, wide variation is seen in the reported occurrence of neutropenia or granulocytopenia. Toxicities are also reported by grade (i.e., grades 1-4) in some studies and by absolute blood counts in others. In breast cancer trials of the combination of cyclophosphamide, methotrexate, and fluorouracil (CMF), the risk of grade 3 or 4 neutropenia varied from 1 to 78% (3). This wide range was undoubtedly owing to the timing of blood counts rather than the patients' responses to therapy. In patients with breast cancer, the mean risk of developing severe neutropenia with administration of a standard CMF regimen is probably 25%.
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