Pharmacology - Treating Cancer (Armitage)

Two major areas are considered in this discussion of pharmacologic strategies for high-dose therapy (HDT). The first is the rational basis for the selection of the chemotherapeutic agents to be used in myeloablative regimens for the treatment of cancer and other diseases. The second is the use of pharmacokinetic measurements and dose adjustment to ensure adequate antitumor and myeloablative effect while avoiding drug exposures that produce intolerable toxicity.

INITIAL HIGH-DOSE REGIMENS

The initial type of marrow transplant developed was allogeneic bone marrow transplantation (ALBMT). The two purposes of the preparative chemotherapeutic regimen for ALBMT are to sufficiently eradicate the endogenous marrow to allow complete engraftment of the allogenic marrow being infused and to eradicate the tumor either completely or to a sufficient degree to allow the complete eradication of persisting tumor by an immune response to the residual tumor. That the immune response can fulfill such a role is indicated by the better long-term tumor-free survival in patients undergoing ALBMT as opposed to autologous bone marrow transplantation using the same preparative regimens for lymphomas and leukemias. This experience has also established the paradigm of the combination of chemotherapy followed by immunotherapy for tumor eradication. Recently, the concept of “transplant-lite” has been introduced by Khouri et al. This concept utilizes relatively nontoxic regimens, such as fludarabine phosphate (Fludara) and a modest dose of cyclophosphamide, or fludarabine, cisplatin (Platinol), and cytarabine (Cytosar-U) to produce sufficient immunosuppression for engraftment of an allogeneic stem cell infusion from HLA-identical siblings.
The first agent used for BMT for malignancy was total-body irradiation (TBI) alone . While TBI eradicated the endogenous marrow, it was insufficient to eradicate the leukemias being treated. High-dose cyclophosphamide was also initially used as a single agent but did not consistently eradicate the endogenous marrow or the leukemia in patients. The combinations of high-dose cyclophosphamide plus TBI or high-dose cyclophosphamide plus the alkylating agent busulfan (Myleran) soon became the two most common regimens for ALBMT for leukemias, as well as for lymphomas. Cyclophosphamide and busulfan have also been used successfully for HDT and autotransplant for leukemias, lymphomas, and solid tumors.