FDA Approves New Indication for Neupogen: Chronic Neutropenia

February 1, 1995

NEW YORK--Neupogen, Amgen's recombinant granulocyte colony-stimulating factor (G-CSF, filgrastim) has received FDA approval for use in treating severe chronic neutropenia.

NEW YORK--Neupogen, Amgen's recombinant granulocyte colony-stimulatingfactor (G-CSF, filgrastim) has received FDA approval for use intreating severe chronic neutropenia.

In 1991, the agent was approved for use in cancer patients onvarious chemotherapy regimens, and in 1994 it was licensed foruse in bone marrow transplants. In both settings, the growth factorreduces the duration of neutropenia and neutropenia-related clinicalconditions.

Severe chronic neutropenia is said to affect some 1,000 to 2,000children and adults in the United States. Many children with congenitalforms of the condition die before adolescence. Until now, severechronic neutropenia could only be managed episodically with regularor continuous antibiotic therapy and frequent hospitalizations,leading to debilitation and drug resistance.

In the phase III randomized multicenter trial of G-CSF in chronicneutropenia, in which 120 patients in the United States took part,90% of patients achieved normal neutrophil levels with daily subcutaneousinjections. Overall, there was a 60% reduction in infections anda 59% reduction in antibiotic use.

In addition to medical outcomes, the trial also examined qualityof life issues as measured by patient's self-perceptions, andon that score as well, G-CSF was of significant benefit. Virtuallyall of the patients reported feeling better.

"Our findings show that nearly all people with severe chronicneutropenia can benefit substantially from this new therapy,"said David Dale, MD, professor of medicine, University of WashingtonMedical Center, Seattle. "I think one of the remarkable thingsfor me was that it worked with the very first patient," hesaid at an Amgen press conference introducing the new indication.

Dr. Dale was lead investigator of the trials in which MemorialSloan-Kettering Cancer Center, University of Michigan, St. JudeChildren's Research Hospital, and Duke University Medical Centeralso took part.

Increased neutrophil counts alone do not tell the whole story,Dr. Dale said. In fact, clinical benefits were seen even amongthe minority of patients who did not show much of an increasein their blood cell counts.

"Counting the cells may be the easy thing to do, but theremay be more to the picture," he said, pointing out that theprecise number of neutrophils required to prevent infection isnot known, and the lower limit of normal is a conservative number."Even a few more cells will often make someone feel betterand prevent entry of bacterial toxins into the body," Dr.Dale said.

G-CSF may also affect the production of other cytokines and mayhave other anti-inflammatory effects contributing to clinicalimprovements in patients, he said.

Treatment Well Tolerated

The daily subcutaneous doses of G-CSF were generally well tolerated,and compliance was high in the phase III trial. Adverse reactionsincluded mild to moderate bone and muscle pain, and an enlargedspleen.

"Basically these patients, like other patients who receiveG-CSF, have some bone pain, often early in treatment, as the hematopoietictissues expand. It tends to be relatively mild, and we have learnedin this trial that the pain tends to melt away as blood cell expansionreaches a plateau stage, at least in most patients," he said.Similarly, a modest enlargement of the spleen also plateaus andhas no associated negative consequences.

Probably the most important toxicity issue is the possible adverseeffects in terms of cell formation in patients receiving long-termstimulation of the bone marrow, Dr. Dale said.

To date, throughout the entire series of G-CSF trials for chronicneutropenia in which 325 patients were treated overall, less than3% have developed myelodysplasia or myeloid leukemia. Acute myeloidleukemia or abnormal cytogenetics have been reported to occurin the natural history of severe chronic neutropenia, even withoutcytokine therapy, Dr. Dale pointed out.

Because the natural history of severe chronic neutropenia is notwell understood, Amgen is sponsoring an international registryto collect information on the health and treatment of patientswith the condition, and will provide G-CSF to the patients. Thecompany is also organizing a support group for patients.