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Leukine (sargramostim)

The following drug information is obtained from various newswires, published medical journal articles, and medical conference presentations.

Approval Status:

Approved March 2018

Specific Treatments:

hematopoietic syndrome of acute radiation syndrome

Therapeutic Areas

General Information

Leukine (sargramostim) is a man-made form of granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF is a type of protein known as a growth factor is produced by the body to help increase the number of white blood cells - made in your bone marrow - which are responsible for fighting infections and initiating an immune response.

Leukine is specifically indicated to increase survival in adult and pediatric patients from birth to 17 years of age acutely exposed to myelosuppressive doses of radiation (Hematopoietic Syndrome of Acute Radiation Syndrome [H-ARS]). 

Leukine is supplied as an injection, for subcutaneous or intravenous administration. The recommended dose of Leukine is a subcutaneous injection administered once daily as follows:

• 7 mcg/kg in adult and pediatric patients weighing greater than 40 kg

• 10 mcg/kg in pediatric patients weighing 15 kg to 40 kg

• 12 mcg/kg in pediatric patients weighing less than 15 kg

Administer Leukine as soon as possible after suspected or confirmed exposure to radiation doses greater than 2 gray (Gy). Estimate a patient’s absorbed radiation dose (i.e., level of radiation exposure) based on information from public health authorities, biodosimetry if available, or clinical findings such as time to onset of vomiting or lymphocyte depletion kinetics.

Obtain a baseline CBC with differential and then serial CBCs approximately every third day until the ANC remains greater than 1,000/mm3 for three consecutive CBCs. Do not delay administration of Leukine if a CBC is not readily available. Continue administration of Leukine until the ANC remains greater than 1,000/mm3 for three consecutive CBCs or exceeds 10,000/mm3 after a radiation-induced nadir.

Clinical Results

FDA Approval

Efficacy studies of Leukine could not be conducted in humans with acute radiation syndrome for ethical and feasibility reasons. The use of Leukine in the H-ARS indication was based on efficacy studies conducted in animals and data supporting Leukine’s effect on severe neutropenia in patients undergoing autologous or allogeneic BMT following myelosuppressive chemotherapy with or without total body irradiation, and in patients with acute myelogenous leukemia following myelosuppressive chemotherapy.

The recommended dose of Leukine for adults exposed to myelosuppressive doses of radiation is 7 mcg/kg as a single daily SC injection. The 7 mcg/kg dosing regimen is based on population modeling and simulation analyses. The sargramostim exposure associated with the 7 mcg/kg adult dose is expected to be higher than sargramostim exposure in the nonclinical efficacy study and therefore are expected to provide sufficient pharmacodynamic activity to treat humans exposed to myelosuppressive doses of radiation. The safety of Leukine at a dose of 250 mcg/m2/day (approximately 7 mcg/kg) has been assessed on the basis of clinical experience in myeloid reconstitution in patients after autologous or allogeneic BMT, and in patients with AML.

The efficacy of Leukine was studied in a randomized, blinded, placebo-controlled study in a nonhuman primate model of radiation injury. Rhesus macaques (50% male) were randomized to a control (n = 36) or treated (n = 36) group. Animals were exposed to total body irradiation at a dose that would be lethal in 50% to 60% of animals (655 cGy) by day 60 post irradiation (lethal dose [LD]50-60/60). Starting 48 ± 1 hour after irradiation, animals received daily SC injections of placebo (sterile water for injection, USP) or Leukine (7 mcg/kg/day). Blinded treatment was stopped when one of the following criteria was met: ANC ≥1,000 cells/mm3 for 3 consecutive days or if the ANC ≥10,000 cells/mm3. Animals received minimal supportive care that included a prophylactic antibiotic, antiemetic, analgesics and parenteral fluids. No whole blood, blood products or individualized antibiotics were provided. Leukine significantly (p=0.0018) increased survival at day 60 in irradiated nonhuman primates: 78% survival (28/36) in the Leukine group compared to 42% survival (15/36) in the control group. In the same study, an exploratory cohort of 36 rhesus macaques randomized to control (n=18) or treated (n=18) was exposed to total body irradiation at a dose that would be lethal in 70-80% of animals (713 cGY) by day 60 post irradiation. Leukine increased survival at day 60 in irradiated nonhuman primates: 61% survival (11/18) in the Leukine group compared to 17% survival (3/18) in the control group.

Side Effects

Adverse effects associated with the use of Leukine in this population may include, but are not limited to, the following:

fever

nausea

diarrhea

vomiting 

Mechanism of Action

Leukine (sargramostim) belongs to a group of growth factors termed colony stimulating factors which support survival, clonal expansion, and differentiation of hematopoietic progenitor cells. GM-CSF induces partially committed progenitor cells to divide and differentiate in the granulocyte-macrophage pathways which include neutrophils, monocytes/macrophages and myeloid-derived dendritic cells. GM-CSF is also capable of activating mature granulocytes and macrophages. GM-CSF is a multilineage factor and, in addition to dose-dependent effects on the myelomonocytic lineage, can promote the proliferation of megakaryocytic and erythroid progenitors. However, other factors are required to induce complete maturation in these two lineages. The various cellular responses (i.e., division, maturation, activation) are induced through GM-CSF binding to specific receptors expressed on the cell surface of target cells.

Additional Information

For additional information regarding Leukine or hematopoietic syndrome of acute radiation syndrome, please visit www.leukine.com/patient-index

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