Should the Initial Starting Dose of Imatinib for Treatment of Some Patients with Chronic Myelocytic Leukemia (CML) Be Lower Than 400 mg Daily?.

A 62-year-old female was referred to me, on January 23, 2004, because of leukocyosis. She was obese with the weight of 141.5 Kg. Her WBC was 37.6 x 10e9/L with neutrophillia. The findings on examination of her blood smear were strongly suggestive of CML. Her blood was sent for BCR-ABL detection and bone marrow aspirate was sent for cytogenetic studies. No therapy was given while awaiting the result of these tests. On March 12, 2004, Hgb was 144 G/L, platelet count 318 x 10e9/L, WBC 66.5 x10e9/L. WBC differential showed 57% neutrophils, 11% bands, 4% metamyelocytes, 8% myelocytes, 2% promyelocytes.... BCR-ABL fusion gene product had been detected in her peripheral blood; and cytogenetic studies had demonstrated Philadelphia (Ph) chromosome in all of the cells examined. The diagnosis of Ph + CML in chronic phase with low Sokal score was made. Despite her morbid obesity, she was started on standard recommended dose of imatinib 400 mg daily. After 6 weeks of therapy her WBC was 9.5 x 10e9/L with normal WBC differential and she was in complete hematological remission. When she was tested after 7 months of therapy, there was a three log decrease in BCR-ABL fusion gene. BCR-ABL fusion gene was undetectable in the next study that was done at 16 months of therapy. Since then, she has remained in complete molecular remission, with no detectable BCR-ABL fusion gene (last test 3 years after starting therapy), on imatinib 200 mg daily. The only repeat cytogenetic study of the bone marrow carried out 2 years after starting therapy showed normal karyotype and no Ph + chromosome.

Discussion: There is a marked difference in active transport of imatinib in and out of the cells and sensitivity of Ph + CML cells of different patients to imatinib. In the initial trials the dose of 400 mg daily was selected because, in most of the patients, irrespective of their weight, this dose was associated with adequate uptake of imatinib which could inhibit cellularr tyrosin kinase activity. Furthermore, in the majority of the cases, the side effects of this dose of imatinib were tolerable. However, this drug is very expensive and because it has to be taken for many years, it creates a major financial burden for the patient or for the health care system. The question then arises whether it is justified to give unnecessary higher doses of imatinib that are needed, to many patients in order to produce higher rate of remission in patients with CML. In the case cited above, considering her weight, she was given a dose of imatinib which would be the equivalent of 200 mg daily for average weight patients. Nevertheless, she responded promptly to such a relatively low dose of imatinib without experiencing any side effects attributed to imatinib. Carella and Lerma (Ann Hematol 2007: June 19, Epub ahead of print) recently reported the outcome of four CML patients who were imatinib-intolerant but who had undetectable residual disease. The imatinib dose in these patients was reduced to 200 mg daily. All four patients have remained in complete remission with undetectable residual disease from 4 to 37 months.

Conclusion: Until an in vitro test of imatinib sensitivity of Ph + cells becomes available, it seems reasonable that an average weight patient with CML in chronic phase and low Sokal score be started on imatinib 200 mg daily initially. Only if such patient fails to show a complete hematological response within three months, should the dose of imatinib be increased to 400 mg daily.