GMHC Treatment Issues, No. 43; Volume 4 Number 3 -- May 22, 1990
Roy Gulick, M. D.

In the 1960s, scientists discovered that certain secretions are necessary for normal cell maturation and growth. CSFs are natural proteins which control the development and function of human blood cells. These proteins stimulate "stem" cells to develop into various types of mature cells (red and white blood cells and platelets). With the development of DNA gene technology in the 1980s, it became possible to produce large quantities of highly purified synthetic CSFs.

Individual CSFs work at different stages in blood cell maturation. Some, such as Interleukin-1 (meaning "between white blood cells") and Interleukin-3, act very early in the process, directing immature cells to develop into red blood cells (RBCs), white blood cells (WBCs), or platelets. Other CSFs work at later stages of maturation and promote development of more specific cell types.

For example, GM-CSF (granulocyte-macrophage colony- stimulating factor) stimulated the development of both granulocytes and macrophages (types of WBCs), while G (granulocyte)-CSF and M (macrophage)-CSF promote the specific development of only granulocytes or macrophages, respectively. Erythropoeitin (EPO) stimulates production of RBCs.

GM-CSF for HIV-Related Neutropenia

In 1987, Dr. Jerome Groopman and colleagues at the New England Deaconess Hospital and UCLA reported a phase 1 study of GM-CSF in 16 patients with AIDS who had low WBC counts. Their average WBC count was 2225 cells per cubic ml before therapy, with normal being 5000-12,000. Patients received an initial treatment followed by a two-day observation period. Then patients began 14 days of continuous intravenous GM-CSF at one of five doses. Results showed a temporary rise in WBCs after the initial treatment which quickly returned to original counts. However, with continuous infusion, there was a rapid rise in WBCs which varied with different doses. After seven days all patients had at least doubled their WBC counts, with some achieving substantially higher counts. Unfortunately, counts fell quickly to original levels when GM-CSF was stopped, implying the need for continued treatment for a sustained effect. Of note, the type of WBC most affected was the neutrophil. The number of T4 cells was not changed with treatment. The main side effects were muscle aches, facial flushing, temporary rash and low-grade fever. Most patients tolerated the drug well, but several patients with opportunistic infections (MAI and CMV) had higher fevers. Further studies showed that neutrophils produced with GM-CSF had completely normal function. In two patients with pre-existing neutrophil function defects, GM-CSF corrected those defects.

In a subsequent study GM-CSF was administered in a more convenient way, by subcutaneous ("under the skin") injection. Researchers followed 12 patients with AIDS who had an average WBC count of 2500. Patients self-injected one of six doses, one to three times a day until their counts were above 5000. GM-CSF again promoted a dose-dependent increase in WBCs. Even patients given the lowest dose developed normal WBC counts on therapy. Again, the most common WBC produced was the mature neutrophil, with essentially no change in T4 numbers. After 7-10 days of treatment, WBC counts typically stabilized at 5-6000. Side effects were mild and well tolerated, consisting of redness at the injection site, low grade fever, muscle aches, fatigue, rash, headache, nausea, and dizziness.

GM-CSF to Counter Drug Toxicities

Researchers next focused their efforts on assessing the use of GM-CSF in treating low WBC counts caused by AZT, ganciclovir (DHPG) or chemotherapy for lymphoma and KS. Current studies are being sponsored by the AIDS Clinical Trials Group (ACTG) and by the manufacturer of GM-CSF, Schering-Plough, Inc. Preliminary results have generally shown a positive effect of GM-CSF in raising low WBC counts caused by these other drugs.

Separate studies from New England Deaconess Hospital, Memorial Sloan-Kettering, and the Rochester ACTG confirmed the efficacy of GM-CSF in restoring WBC counts reduced by AZT in a small number of patients with only mild toxicities. The Sloan- Kettering study in particular noted that the increase in WBC counts allowed several patients to restart AZT. AZT-related neutropenia is becoming less common since the recommended effective dose has been halved from 1200 mg/day to 600 mg/day.

Schering-Plough reported its experience with GM-CSF in a small number of patients with neutropenia caused by ganciclovir treatment for CMV retinitis. In all patients, WBC counts were increased, allowing effective doses of ganciclovir to be used for longer periods of time. All patients had normalization of WBC counts and none developed progressive retinitis or resistance to ganciclovir during the course of therapy. Up to 42% of patients receiving ganciclovir for CMV retinitis may become neutropenic, and additional trials are underway (more details below).

Studies in San Francisco, Miami, and Italy have provided data on the use of GM-CSF in a few patients receiving various chemotherapy regimens for KS or lymphoma. Preliminary results show a sustained or increased WBC count on chemotherapy in each case. Results in similar studies of HIV-infected patients receiving cancer chemotherapy have also shown the effectiveness of GM-CSF therapy in sustaining or restoring WBCs.

Does GM-CSF Promote HIV Production?

A potential concern about GM-CSF in HIV disease is the drug's ability to stimulate macrophages, a type of WBC which may also be infected with HIV. This stimulation theoretically may increase HIV reproduction. To explore this possibility, studies have been conducted with certain HIV strains exposed to GM-CSF. Initially, these results were conflicting. At New England Deaconess Hospital, researchers found GM-CSF suppressed HIV replication, while other investigators at the NIH, using a different, but related, cell type observed increased replication. Subsequent test tube studies seem to confirm an increase in HIV expression from infected cells treated with GM-CSF. One study, at the National Cancer Institute (NCI), however, also showed an increase in the antiviral effect of AZT on cells exposed to GM- CSF, with effective viral inhibition at doses 10-100 times less than normal.

Attempts to measure this potential side effect in patients using GM-CSF have been more limited. A rise in p24 antigen levels in six patients on subcutaneous GM-CSF plus AZT at New England Deaconess Hospital and Sloan-Kettering, p24 antigen levels were measured, and patients' blood cells were cultured for HIV. Neither of these two groups found evidence of HIV stimulation. A small study from San Francisco measured p24 antigen levels in serum and spinal fluid in a few patients on chemotherapy for lymphoma. Some of these patients were receiving GM-CSF, but researchers could find no consistent effect. Researchers also followed the neurologic function of patients in the Sloan-Kettering AZT/GM-SCF study. There is a theoretical concern that HIV-infected macrophages exposed to GM-CSF might cause increased HIV expression in the central nervous system. Over the course of the study, no evidence of change in any patient's neurologic function was seen. Based on these laboratory and clinical findings, the potential remains for GM- CSF to stimulate HIV production from infected macrophages. The clinical significance of such stimulation with or without antiviral drugs is still controversial. If possible, concomitant use of an antiviral such as AZT or ddI seems prudent. Most ACTG studies using GM-CSF mandate that participants take an antiviral. However, some studies of GM-CSF plus ganciclovir (e.g. ACTG 073) do not address this issue. At a conference of community-based clinical researchers in Maryland, Dr. Anthony Fauci, director of National Institute of Allergy and Infectious Diseases, stated that patients taking GM-CSF without an antiviral should be closely monitored for any evidence of HIV stimulation.

Current Studies of GM-CSF

Currently, GM-CSF is available through clinical trials at several New York City institutions. ACTG protocol #073 is a phase II (efficacy) randomized, placebo-controlled trial of GM- CSF in patients on ganciclovir for CMV retinitis with low WBC counts and is being conducted at Memorial Sloan-Kettering (contact: Jill Solan, RN 212-639-7161). Schering-Plough is sponsoring similar trials at NYU (contact: Kathleen Farrell, 212-340-6485) and Cabrini Medical Center (contact: Alfred Giosa, RN 212-995-6872). ACTG protocol #090 is a phase I (dose determination/toxicity assessment) study of the use GM-CSF, alpha interferon, and AZT in patients with Kaposi's sarcoma, also being conducted at Memorial Sloan-Kettering (contact: Denise Bundow, 212-639-8633). Off-study, GM-CSF is available on a case-by-case, limited "compassionate use" basis from Schering-Plough (201-298- 4000, Professional Services Department). Patients who qualify must have low WBC counts due to underlying disease or drug therapy. Schering-Plough representatives will speak about individual cases with the patient's physician. Further study of GM-CSF and other colony-stimulating factors will hopefully define their optimal use in patients with HIV disease and bone marrow damage.

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