The Significance of Imatinib Mesylate (Gleevec®)-Induced Cytopenias in Patients with Chronic-Phase CML
Abstract & Commentary
Synopsis: In a series of chronic-phase CML patients who had previously been treated with interferon and who subsequently received imatinib mesylate, the appearance of myelosuppression (Grade > 3 neutropenia or thrombocytopenia) was associated with significantly less frequent major or complete cytogenetic responses.
Source: Sneed TB, et al. Cancer. 2004;100:116-121.
Imatinib mesylate (Gleevec®) is a potent and selective tyrosine kinase inhibitor against Bcr/Abl, the protein product of the Philadelphia chromosome.1 The drug, administered orally, has rapidly become firstline therapy for patients with chronic myelogenous leukemia (CML). One major advantage of Gleevec, in addition to its remarkable effectiveness, is that it is relatively nontoxic. Non-myeloid toxicities are usually mild and infrequently require dose reductions or delays. However, myelotoxicity occurs more commonly. In the current series, 45% of chronic-phase CML patients who were treated with imatinib at 400 mg/d after they had failed treatment with interferon developed grade ³ 3 myelosuppression requiring either dose modification or delay. The prognostic importance of the myelosuppression is the subject of this report.
Sneed and colleagues analyzed 143 consecutive patients seen at M.D. Anderson Cancer Center in 1999 and 2000. These patients had all received prior interferon a and were part of a multi-institutional study examining the efficacy of imatinib in this population. During the therapy, neutropenia ³ Grade 3 (according to National Cancer Institute Common Toxicity Criteria) occurred in 64 patients (45%), and thrombocytopenia > Grade 3 occurred in 31 patients (22%). Any myelosuppression ³ Grade 3 was associated with a lower rate of major (P = .04) or complete (P = .01) cytogenetic responses. This was more pronounced with myelosuppression that lasted more than 2 weeks. The major cytogenetic response rate was 58% with Grade ³ 3 myelosuppression compared with a rate of 75% without Grade ³ 3 myelosuppression (P = .03); the complete cytogenetic response rates were 36% and 63%, respectively (P = .001).
In multivariate analysis, pretreatment platelet count, imatinib dose reductions, and duration of imatinib-induced myelosuppression were associated significantly with response.
Comment by William B. Ershler, MD
One logical explanation for the less favorable outcomes observed in those who experienced myelosuppression is the corresponding reduced dose of imatinib delivered. As is the case with other hematologic and non-hematologic tumors, delivery of the planned dose on time is an apparent favorable prognostic factor.2,3 Yet, it is conceivable that myelosuppression in response to imatinib is a selective feature of a marrow that has more extensive disease or is indicative of a biological feature of more advanced disease. Under any circumstance, the finding is of importance because it is now apparent that those chronic-phase patients who experience myelosuppression with conventional dose imatinib have a reduced rate of achieving optimal response (complete cytogenetic remission). Use of colony-stimulating factor in an effort to maximize exposure to imatinib is one potential solution, but this approach will require careful clinical investigation before it should be adopted as a standard of care.
It is notable that the relatively high rate of myelosuppression observed in this series of previously treated (with interferon) patients may exceed what is currently observed, as imatinib has moved up to first-line therapy in many practices. It will be interesting to examine current series for the prevalence of myelosuppression in those exposed to imatinib as first-line treatment.
Dr. Ershler is from Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC.
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