Busulfan Alone as Cytoreduction Before Autografting for Chronic Myelogenous Leukemia

To the Editor:

A number of prospective randomized studies have recently been designed to address the question of whether autografting prolongs survival for patients with chronic myelogenous leukemia (CML) in chronic phase,1,2 but there is no general agreement as to the optimal approach to cytoreduction before transfusion of autologous stem cells. We believe that the use of high-dose busulfan alone, as used in patients subjected to second allograft procedures,3 may be a good compromise between maximal cytoreduction and minimal regimen-related toxicity.

A heterogeneous group of 37 patients with CML in different phases of CML were autografted at the Hammersmith Hospital in London over a 5-year period by using busulfan alone as cytoreduction (Table1). The regimen consisted of 4 mg/kg/d busulfan orally for 4 consecutive days (total, 16 mg/kg). A loading dose of 1,000 mg oral phenytoin was administered 1 day before the start of chemotherapy and phenytoin was continued at a dose of 300 mg/d for 7 days to prevent epileptic seizures. Neither busulfan nor phenytoin levels were monitored. Autologous cells were infused 48 hours after the last dose of busulfan. All patients had some degree of stomatitis, but no other major toxicities4 were encountered (Table 2). Specifically, no patient had busulfan-related pulmonary toxicity, hepatic veno-occlusive disease, or epileptic seizures, and no patient experienced persisting alopecia.

We did not formally compare the use of busulfan alone with that of other more intensive cytoreduction regimens. However, the complete/major cytogenetic response rate at 3 months postautograft was 20% (6 patients) and the median survival postautograft was 3.4 years (95% confidence interval [CI]: 1.7 to 5.9) (Table 1). Thus, we can be reasonably confident that the use of this cytoreduction regimen produced results at least as good as those achieved with the combinations of busulfan plus cyclophosphamide or cyclophosphamide plus total body irradiation.

The principal reason why busulfan alone might be preferable to more intensive regimens is simply the fact that it may achieve the same level of cytoreduction with less toxicity. Conversely, the fact that the cells used for the autograft usually contain at least some Ph⁺ progenitor cells such that relapse must originate at least partly from the autografted material5 might mean that the attempt at complete marrow ablation with maximal chemotherapy or chemoradiotherapy was not justified. Moreover, busulfan alone is relatively easy to administer and administration will become even more straightforward when the intravenous preparations now being developed become available for routine use.

We conclude that if one chooses to autograft a patient with CML, then busulfan alone is a reasonable cytoreduction regimen associated with minimal toxicity which should still permit the possibility of a subsequent allograft or second autograft procedure.