Recommendations for Optimal Myeloid Growth Factors Use

June 2011, Vol 2, No 3 -

Hollywood, FL—The evidence for the use of myeloid growth factors in patients at high risk for febrile neutropenia (FN) is solid, Jeffrey Crawford, MD, of Duke Cancer Institute, Durham, NC, told attendees at the 2011 National Comprehensive Cancer Network (NCCN) annual meeting.

Myeloid growth factors are the primary means of preventing chemotherapy-induced neutropenia. This often leads to FN, which can be fatal in 10% of patients, according to a database of more than 40,000 individuals. Some clinicians have recently expressed concern, however, that myeloid growth factor use is associated with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).

As chairman of the NCCN’s Myeloid Growth Factors Panel, Dr Crawford reassured attendees that the benefits substantially outweigh any risks associated with the granulocyte colony-stimulating factors (G-CSFs) filgrastim (Neupogen) and pegfilgrastim (Neulasta).

The newer agent, pegfilgrastim, has a unique neutrophil-regulated clearance and, because of high sustained serum levels, is longer lasting, but its clinical efficacy appears to be similar to that of filgrastim’s.

The clinical outcomes for the single dose of pegfilgrastim and the daily dose of filgrastim were comparable in a 2007 meta-analysis, but the impact of pegfilgrastim on overall survival and disease-free survival has been apparent in all major prognostic subgroups studied to date, Dr Crawford said.

Sargramostim (Leukine) is another myeloid growth factor option; however, because of its greater toxicity, it has a category 2B recommendation in the NCCN guidelines.

The only major change to the 2011 clinical guidelines in this regard is the inclusion of a discussion of MDS/AML risk associated with the use of G-CSF.

Timing of Growth Factor Use
In a 2008 study conducted by Dr Crawford’s group, FN developed during the first 3 cycles in 11% of patients. Because most FN events occur during the first cycle of chemotherapy, G-CSF prophylaxis should be initiated soon after the first chemotherapy and continued in subsequent treatments in any patient with a ≥20% risk for developing FN.

“Our window for starting [G-CSF] prophylaxis is not big. We should start 24 to 72 hours after chemotherapy is completed,” he said. When administration is delayed, the duration of grade 4 neutropenia may be longer, and the risk of FN greater, Dr Crawford added. “The data suggest that what we do in the very first cycle of treatment makes a big difference.”

Some clinicians also try to lower FN risk by reducing the dose of chemotherapy, but this approach is not advisable, because it diminishes the survival benefit obtained from fulldose chemotherapy.

Prophylactic antibiotics can add to the protective benefit of G-CSF in selected settings, but they should not be used instead of them. To avoid the risk of antibiotic resistance,“The routine application of prophylactic antibiotics should be limited to high-risk inpatients with hematologic malignancies and stem-cell transplantation,” he said.

Despite MDS/AML Risk, Mortality Greatly Reduced
The risk for MDS/AML with G-CSF prophylaxis was elevated by a recent meta-analysis (Lyman GH, et al. J Clin Oncol. 2010;28:2914-2924), regardless of tumor type or treatment regimen; however, all-cause mortality was significantly lower among patients who received G-CSF therapy.

“There was an increase in MDS and leukemia, but the all-cause mortality analysis showed a significant reduction in risk. Leukemia risk was 0.005%, but the survival benefit was 5%. This amounts to an almost 10-fold difference in probabilities,” he said. “There clearly is an overall net benefit of G-CSF.”

Who Should Receive Prophylaxis?
Primary G-CSF prophylaxis should be determined by the chemotherapy regimen, according to the NCCN guidelines, along with patient risk factors (Lyman GH, et al. Cancer. 2011;117: 1917-1927) and treatment intent (curative vs palliative). Clinicians should then determine whether the patient’s risk is high (>20%), intermediate (10%- 20%), or low (<10%).

High-risk patients, whose risk is elevated 5-fold over low-risk patients, should receive a G-CSF, regardless of treatment intent; low-risk patients should not receive them; and intermediate-risk patients should be considered for treatment based on risk factors, Dr Crawford said.

In addition to the type of chemotherapy, other risk factors include type of malignancy, age, previous treatment, preexisting conditions, performance status, and other factors.