Granulocyte-macrophage colony-stimulating factor

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a biochemical messenger that triggers a step toward the creation of leukocytes or platelets from the original pluripotent stem cells. GM-CSF actually operates on committed stem cells that have differentiated into pools of cell progenitors, as a result of the action of various interleukins on the pluripotent stem cells. It is not the same agent as granulocyte colony-stimulating factor (G-CSF), the synthetic version of which is filagastrim.

GM-CSF is a natural molecule, but, for clinical use, is produced through genetic engineering. When the protein is expressed in yeast cells, sargramostim (U.S. trade name: Leukine™). When made by Escherichia coli, the compound is called molgramostim (U.S. trade name: Macrogen™). The exact FDA approval status of Macrogen is being checked.

Indications

While the function is a natural one, the clinical use of synthetic GM-CSF requires a careful balancing of benefits and risks, and, at the present level of understanding, definitely a matter for specialists. One version was temporarily withdrawn from the market, although was reintroduced after reformulation; the problem appeared to be not with the active molecule itself but with the ingredients in the entire preparation.

The best-established indication, described for is for restoring blood cell formation in adults undergoing autologous or allogeneic bone marrow transplantation (BMT), typically after bone marrow purging, outside the body, of abnormal marrow cells. It is also used to activete progenitor cell development so that leukocytes can be collected by leukapheresis, and to after autologous peripheral blood progenitor cell (PBPC) transplantation.

It is also used after delay or failure of recovery from BMT, and as prophylaxis against infection in adults, 55 years or more years of age, following induction chemotherapy age or older with acute myeloid (AML).

Experimentally, synthetic GM-CSF has been used for myelodysplastic syndrome (MDS) and aplastic anemia. It has been used, on a case-by-case basis, to reduce neutrophil deficiency (i.e., neutropenia) in patients with a variety of neutropenias, including neutropenia associated with human immunodeficiency virus.

Safety

One study of 490 patients, in ten centers, showed that sargramostim GM-CSF had fewer adverse events than with filagastrim G-CSF. The researchers stated there had been only two safety studies directly comparing the safety of the two; they found methodological problems with the placebo-controlled safety studies. This randomized controlled trial used a refinement of the usual cross-over study: crossover was by center, not within the volunteer population at each center. In other words, if a center had been using filgrastrim, its experimental-arm patients were put on sargramostim, and vice versa. Fever of unknown origin (FUO) was 1% with GM-CSF vs. 7% with G-CSF, $p<0.001$. Also reduced were fatigue, diarrhea, injection site reactions, other dermatologic disorders, and edema (all $p<0.05$).

Efficacy

In a prospective, randomized, placebo-controlled phase III study in 109 patients with leukemias (AML, CML), lymphoid disorders, (ALL, NHL), Hodgkin’s disease, multiple myeloma, myelodysplastic disease, or aplastic anemia who were given allogeneic BMT from human lymphocyte antigen (HLA)-matched, related donors. Patients who received sargramostim had faster restoration of an acceptable neutrophil count and a shorter duration of hospitalization versus patients who received placebo.