ingle doses in mice are 123mg/kg. In rats, a single intraperitoneal dose of 12.5mg/kg of chlorambucil produces typical nitrogen-mustard effects; these include atrophy of the intestinal mucous membrane and lymphoid tissues, severe lymphopenia becoming maximal in 4days, anemia, and thrombocytopenia. After this dose, the animals begin to recover within 3days and appear normal in about a week, although the bone marrow may not become completely normal for about 3weeks. An intraperitoneal dose of 18.5mg/kg kills about 50% of the rats with development of convulsions. As much as 50mg/kg has been given orally to rats as a single dose, with recovery. Such a dose causes bradycardia, excessive salivation, hematuria, convulsions, and respiratory dysfunction.
DOSAGE AND ADMINISTRATION
The usual oral dosage is 0.1 to 0.2mg/kg body weight daily for 3 to 6weeks as required. This usually amounts to 4 to 10mg per day for the average patient. The entire daily dose may be given at one time. These dosages are for initiation of therapy or for short courses of treatment. The dosage must be carefully adjusted according to the response of the patient and must be reduced as soon as there is an abrupt fall in the white blood cell count. Patients with Hodgkin’s disease usually require 0.2mg/kg daily, whereas patients with other lymphomas or chronic lymphocytic leukemia usually require only 0.1mg/kg daily. When lymphocytic infiltration of the bone marrow is present, or when the bone marrow is hypoplastic, the daily dose should not exceed 0.1mg/kg (about 6mg for the average patient).
Alternate schedules for the treatment of chronic lymphocytic leukemia employing intermittent, biweekly, or once-monthly pulse doses of chlorambucil have been reported. Intermittent schedules of chlorambucil begin with an initial single dose of 0.4mg/kg. Doses are generally increased by 0.1mg/kg until control of lymphocytosis or toxicity is observed. Subsequent doses are modified to produce mild hematologic toxicity. It is felt that the response rate of chronic lymphocytic leukemia to the biweekly or once-monthly schedule of chlorambucil administration is similar or better to that previously reported with daily administration and that hematologic toxicity was less than or equal to that encountered in studies using daily chlorambucil.
Radiation and cytotoxic drugs render the bone marrow more vulnerable to damage, and chlorambucil should be used with particular caution within 4weeks of a full course of radiation therapy or chemotherapy. However, small doses of palliative radiation over isolated foci remote from the bone marrow will not usually depress the neutrophil and platelet count. In these cases chlorambucil may be given in the customary dosage.
It is presently felt that short courses of treatment are safer than continuous maintenance therapy, although both methods have been effective. It must be recognized that continuous therapy may give the appearance of “maintenance” in patients who are actually in remission and have no immediate need for further drug. If maintenance dosage is used, it should not exceed 0.1mg/kg daily and may well be as low as 0.03mg/kg daily. A typical maintenance dose is 2mg to 4mg daily, or less, depending on the status of the blood counts. It may, therefore, be desirable to withdraw the drug after maximal control has been achieved, since intermittent therapy reinstituted at time of relapse may be as effective as continuous treatment.
Procedures for prope
