Insufficient Granulocyte Recovery After Pegfilgrastim

Another issue with which clinicians grapple is the patient who returns on d 21 (or d 15) for her next course of chemotherapy but whose granulocyte count has still not recovered despite receiving pegfilgrastim on d 2 after her previous treatment. Although the usual practice has been to delay treatment a few days to a week, this may not be an optimal solution, depending on the severity of the patient's underlying illness, i.e., is this a potentially curative treatment in an adjuvant or neoadjuvant setting or is the patient experiencing rapid disease progression and is she in need of rapid tumor regression to prevent rapid clinical decline. The same logistic and financial issues cited earlier also apply.

Data may help clinicians and patients. The first is, again, the study by Johnson et al. (33) that looked at optimal dosing of pegfilgrastim. As with all drugs, there is a dose-response curve. The highest dose tested in the original weight-based studies was 300 mg/kg. This produced a higher granulocyte response than lower doses. This dose was not chosen for subsequent development, however, because it was clearly superior to filgrastim administered at the 5 mg/kg dose, and the objective was to develop pegfilgrastim for use in the same clinical situations with which clinicians had experience and filgrastim was known to be effective. For patients whose bone marrow reserve has been depleted by prior chemotherapy or radiation therapy, however, higher doses may be needed.

This dosing is analogous to our current practice with erythropoietin and dar-bopoeitin alfa. If patients fail to achieve either a normal hemoglobin concentration or a 2-g increase after four-weekly erythropoietin injections or two-fortnightly darbopoeitin alfa injections, the dose is escalated. In clinical practice, when patients who have received filgrastim on d 2 return and d 21 granulocyte counts are <1 x 109/L, we usually increase the granulocyte count by one or two injections of filgrastim 5 mg/kg. For patients on Medicare, however, this may be a problem, as some regional Medicare carriers will not pay for treatment with two similar growth factors.

A second piece of data to help clinicians and patients comes from the dose-dense CALGB 9741 trial (50). To allow retreatment at 14-d intervals and with the assurance that patients randomized to the dose-dense cohort were to receive filgrastim on d 2, the lower limit for retreatment was relaxed to 1 x 109/L. In this short treatment regimen using only eight courses of therapy, cumulative myelosuppression did not occur and hematologic profiles remained normal after completion of treatment.

Thus, from a practical standpoint, it is clear that "standard, one-size-fits all" doses may sometimes be inadequate for patients with inadequate bone marrow reserve. Additional granulocyte growth factor support, either with a higher dose of pegfilgrastim or with additional filgrastim, may be needed. The weight-based studies with pegfilgrastim herein reported were reviewed by the FDA and provide justification for this approach in specific situations. Because of the uncertainty of reimbursement, especially with certain regional Medicare carriers and payors, this approach should not be undertaken without prior discussion with the patient.

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