Busulfan in the Treatment of Chronic Myelocytic Leukemia. The Effect of Long Term Intermittent Therapy

1. The observations made during the administration of 114 courses of busulfan to 30 patients over a period of seven years are recorded. The responses to initial courses of therapy corresponded with those reported previously. With repeated courses of therapy, subjective improvement, the decline in the number of leukocytes, decrease of anemia and the subsidence of physical signs of the disease were as satisfactory as during the first course but tended to appear later. Patients were ambulatory and most were symptomatically and objectively improved during and after repeated courses as compared to their status beforehand.

2. Remissions were longest when the leukocyte values were 10,000 per cu. mm., or less, at the time busulfan was discontinued. Among such patients, remissions of six months or longer were seen in 85 per cent after the initial course of busulfan but in only 19 per cent after fifth or later courses.

3. Evidence of partial resistance to busulfan was seen in some cases after multiple courses of treatment. Complete resistance occurred in 15 patients upon development of the acute, myeloblastic phase of chronic myelocytic leukemia. When busulfan failed, 6-mercaptopurine and colcemide were temporarily of value; x-ray was not of benefit. After the onset of the acute phase. the median survival was three months. This mode of termination is probably no more frequent (50 per cent of cases) since the advent of busulfan therapy than before.

4. If anemia was not relieved, or a large spleen was not reduced 50 per cent in size following a course of therapy, the prognosis was poor and the acute phase imminent.

5. Thrombocytopenia in early, untreated cases was not necessarily a bad sign, nor was the use of busulfan precluded because of it. However, when thrombocytopenia appeared in a previously treated patient, without other evidence indicating busulfan toxicity, or when it occurred in a patient with three or more years of known disease, it usually presaged the development of the terminal acute phase.

6. Side effects of busulfan were significant in only one patient; this man received 8 milligrams daily, double the usual dose, for eight months and developed glossitis, anhydrosis and alopecia totalis. The major hazard in the use of the drug was the occurrence of pancytopenia. This could be related to excessive dosage.

7. Morbidity was clearly decreased. Longevity (median 42 months) was greater than in Minot’s untreated cases (median 31 months) and at least as great as that achieved by treatment with radioactive phosphorus and x-ray (median 32-41 months). Repeated courses of busulfan are considered to offer an effective and practical palliative form of therapy for chronic myclocytic leukemia, up to the time of appearance of the terminal acute myeloblastic phase.