Management Of Myelosuppression

Overall, imatinib is well tolerated. Probably the most common adverse event with imatinib is myelosuppres-sion. Grade 3 or higher neutropenia (i.e., neutrophils <1 X 109/L) occurs in up to 35-45% of patients, and thrombocytopenia in 20-25%.26'28'32'51'52 Severe anemia is less common, occurring in 5-10% of the patients. All of these are more common in patients who have failed prior therapies (e.g., IFN-a), and are dose-related, occurring more frequently among patients treated with higher doses. Patients who develop grade 3 or higher neutropenia or thrombocy-topenia may have a lower probability of achieving a cytogenetic response. The adverse prognosis is particularly noticeable among patients whose myelosup-pression lasts longer than 2 weeks.5153 This has been attributed to a decreased dose intensity, as the current recommendation is to interrupt therapy in patients who develop this degree of myelosuppres-sion and reduce the doses for those who take more than 2 weeks to recover.54 To try to overcome these events, hematopoietic growth factors have been used. Most patients who develop neutropenia respond rapidly to the use of filgrastim (G-CSF)55-57, allowing for more continued therapy with imatinib and improved response in many instances. A similar effect has been reported with oprelvekin (inter-leukin-11) for patients with thrombocytopenia.58 Patients with anemia do not carry an inferior prog-nosis.59 This is probably due to the fact that most patients have only grade 1 or 2 anemia, and it is not currently recommended to interrupt therapy for anemia grade 3 or higher. There have been reports about the effective use of erythropoietin59,60 and darbepo-etin61 for these patients. Although these short series suggest that the use of these growth factors is safe in these settings, their use is not currently standard or approved and should be considered with caution. In addition, most patients who develop myelosuppres-sion will not need hematopoietic growth support. This adverse event is more frequently seen during the first few months of therapy. Treatment interruption is frequently all that is needed for recovery, and most patients will not even require dose reductions. Myelosuppression after the first 3 months of therapy is less common and it is in this setting that it may represent a more significant management problem, particularly when prolonged or recurrent.

Management of adverse events associated with imatinib therapy

Myelosuppression Monitor CBC weekly for 2-3 months, then every 4-6 weeks Hold therapy for grade >3 neutropenia or thrombocytopenia:

- Platelets <50 X 109/L Do not hold for anemia

Monitor CBC at least weekly after holding

Restart when ANC >1 X 109/L, platelets >50 X 109/L

- If recovery occurs within 2 weeks, restart at the same dose

- If recovery takes longer than 2 weeks, decrease the dose (not less than 300 mg/d)

Consider use of growth factors (G-CSF, IL-11, EPO) for patients with recurrent myelosuppression

Nonhematologic toxicity Manage grade <2 toxicity early. Some suggestions include Adverse event Management

Nausea Antiemetics (Compazine,

Diarrhea Zofran, etc)

Skin rash Antiadiarrhea (Imodium,

Peripheral edema Lomotil, etc)

Periorbital edema Topical and/or systemic

Muscle cramps steroids, antihistamines

Bone aches Diuretics

Liver dysfunction Preparation H

Tonic water, quinine, calcium supplements Nonsteroidal anti-inflammatory agents Monitor frequently Hold therapy for grade >3 toxicity or persistent grade 2 toxicity not responding to optimal management Restart therapy at a lower dose when toxicity resolves to grade <1

CBC, complete blood count; ANC, absolute neutrophil count.

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