Leukine (sargramostim) - 6 indications

Scroll down for information on each indication:

• to shorten time to neutrophil recovery and to reduce the incidence of severe, life-threatening, or fatal infections following induction chemotherapy in adult patients 55 years and older with acute myeloid leukemia; approved 1991
• for the mobilization of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis and autologous transplantation in adult patients; date unavailable
• for the acceleration of myeloid reconstitution following autologous bone marrow or peripheral blood progenitor cell transplantation in adult and pediatric patients 2 years of age and older; date unavailable
• for the acceleration of myeloid reconstitution following allogeneic bone marrow transplantation in adult and pediatric patients 2 years of age and older; date unavailable
• for treatment of delayed neutrophil recovery or graft failure after autologous or allogeneic bone marrow transplantation in adult and pediatric patients 2 years of age and older; date unavailable
• 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]); approved March of 2018

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 for the following:

• to shorten time to neutrophil recovery and to reduce the incidence of severe, life-threatening, or fatal infections following induction chemotherapy in adult patients 55 years and older with acute myeloid leukemia
• for the mobilization of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis and autologous transplantation in adult patients
• for the acceleration of myeloid reconstitution following autologous bone marrow or peripheral blood progenitor cell transplantation in adult and pediatric patients 2 years of age and older
• for the acceleration of myeloid reconstitution following allogeneic bone marrow transplantation in adult and pediatric patients 2 years of age and older
• for treatment of delayed neutrophil recovery or graft failure after autologous or allogeneic bone marrow transplantation in adult and pediatric patients 2 years of age and older
• 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. Scroll down to see the recommended dosing/administration for each indication.

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.

Side Effects

Adverse effects associated with the use of Leukine in recipients of autologous BMT may include, but are not limited to, the following:

• fever
• nausea
• diarrhea
• vomiting
• mucous membrane disorder
• alopecia
• asthenia
• malaise
• anorexia
• rash
• gastrointestinal disorder
• edema

Adverse effects associated with the use of Leukine in recipients of allogeneic BMT may include, but are not limited to, the following: 

• diarrhea
• fever
• nausea
• rash
• vomiting
• stomatitis
• anorexia
• high glucose
• alopecia
• abdominal pain
• low albumin
• headache
• hypertension

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

• fever
• liver toxicity
• skin reactions
• infections
• metabolic laboratory abnormalities
• nausea
• diarrhea
• genitourinary abnormalities
• pulmonary toxicity
• vomiting
• neurotoxicity
• stomatitis
• alopecia
• weight loss

Adverse effects associated with the use of Leukine in patients with H-ARS may include, but are not limited to, the following:

• fever
• nausea
• diarrhea
• vomiting

Indication 1 - to shorten time to neutrophil recovery and to reduce the incidence of severe, life-threatening, or fatal infections following induction chemotherapy in adult patients 55 years and older with acute myeloid leukemia

approved 1991

Dosing/Administration

The recommended dose is 250 mcg/m2/day administered intravenously over a 4-hour period starting approximately on day 11 or four days following the completion of induction chemotherapy, if the day 10 bone marrow is hypoplastic with less than 5% blasts. If a second cycle of induction chemotherapy is necessary, administer Leukine approximately four days after the completion of chemotherapy if the bone marrow is hypoplastic with less than 5% blasts. Continue Leukine until an absolute neutrophil count (ANC) greater than 1500 cells/mm3 for 3 consecutive days or a maximum of 42 days. Do not administer Leukine within 24 hours preceding or following receipt of chemotherapy or radiotherapy.

Clinical Trial Results

The efficacy of Leukine in the treatment of AML was evaluated in a multicenter, randomized, double-blind placebo-controlled trial (study 305) of 99 newly-diagnosed adult patients, 55-70 years of age, receiving induction with or without consolidation. A combination of standard doses of daunorubicin (days 1-3) and ara-C (days 1-7) was administered during induction and high dose ara-C was administered days 1-6 as a single course of consolidation, if given. Bone marrow evaluation was performed on day 10 following induction chemotherapy. If hypoplasia with <5% blasts was not achieved, patients immediately received a second cycle of induction chemotherapy. If the bone marrow was hypoplastic with <5% blasts on day 10 or four days following the second cycle of induction chemotherapy, Leukine (250 mcg/m2/day) or placebo was given intravenously over four hours each day, starting four days after the completion of chemotherapy. Study drug was continued until an ANC ≥1500 cells/mm3 for three consecutive days was attained or a maximum of 42 days. Leukine or placebo was also administered after the single course of consolidation chemotherapy if delivered (ara-C 3-6 weeks after induction following neutrophil recovery). Study drug was discontinued immediately if leukemic regrowth occurred. Leukine significantly shortened the median duration of ANC 500 cells/mm3 by day 16, compared to day 25 for patients receiving placebo. The proportion of patients receiving one cycle (70%) or two cycles (30%) of induction was similar in both treatment groups. Leukine significantly shortened the median times to neutrophil recovery whether one cycle (12 vs. 15 days) or two cycles (14 vs. 23 days) of induction chemotherapy was administered.

Indication 2 - for the mobilization of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis and autologous transplantation in adult patients

Approval date unavailable

Dosing/Administration

The recommended dose is 250 mcg/m2/day administered intravenously over 24 hours or subcutaneously once daily. Continue at the same dose through the period of PBPC collection. The optimal schedule for PBPC collection has not been established. In clinical studies, collection of PBPC was usually begun after 5 days of Leukine and performed daily until protocol specified targets were achieved. If WBC greater than 50,000 cells/mm3, reduce the dose by 50%. Consider other mobilization therapy if adequate numbers of progenitor cells are not collected.

Clinical Trial Results

A retrospective review was conducted of data from adult patients with cancer undergoing collection of peripheral blood progenitor cells (PBPC) at a single transplant center. Mobilization of PBPC and myeloid reconstitution post transplant were compared between four groups of patients (n=196) receiving Leukine for mobilization and a historical control group who did not receive any mobilization treatment [progenitor cells collected by leukapheresis without mobilization (n=100)]. Sequential cohorts received Leukine. The cohorts differed by dose (125 or 250 mcg/m2/day), route (IV over 24 hours or SC) and use of Leukine post transplant. Leukaphereses were initiated for all mobilization groups after the WBC reached 10,000 cells/mm3. Leukaphereses continued until both a minimum number of mononucleated cells (MNC) were collected (6.5 or 8.0 × 108/kg body weight) and a minimum number of aphereses (5-8) were performed. Both minimum requirements varied by treatment cohort and planned conditioning regimen. If subjects failed to reach a WBC of 10,000 cells/mm3 by day 5, another cytokine was substituted for Leukine. Marked mobilization effects were seen in patients administered the higher dose of Leukine (250 mcg/m2) either IV (n=63) or SC (n=41). PBPCs from patients treated at the 250 mcg/m2/day dose had a significantly higher number of granulocyte-macrophage colony-forming units (CFU-GM) than those collected without mobilization. The mean value after thawing was 11.41 × 104 CFU-GM/kg for all Leukine-mobilized patients, compared to 0.96 × 104/kg for the non-mobilized group. A similar difference was observed in the mean number of erythrocyte burst-forming units (BFU-E) collected (23.96 × 104/kg for patients mobilized with 250 mcg/m2 doses of LEUKINE administered SC vs. 1.63 × 104/kg for non-mobilized patients).

Indication 3 - for the acceleration of myeloid reconstitution following autologous bone marrow or peripheral blood progenitor cell transplantation in adult and pediatric patients 2 years of age and older

Approval date unavailable

Dosing/Administration

The recommended dose is 250 mcg/m2 /day administered intravenously over 24 hours or subcutaneous injection once

Clinical Trial Results

The efficacy of Leukine to accelerate myeloid reconstitution following autologous PBPC was established in the retrospective review above. After transplantation, mobilized subjects had shorter times to neutrophil recovery and fewer days between transplantation and the last platelet transfusion compared to non-mobilized subjects. Neutrophil recovery (ANC >500 cells/mm3) was more rapid in patients administered Leukine following PBPC transplantation with Leukine-mobilized cells. Mobilized patients also had fewer days to the last platelet transfusion and last RBC transfusion, and a shorter duration of hospitalization than did non-mobilized subjects.

The efficacy of Leukine on time to myeloid reconstitution following autologous BMT was established by three single-center, randomized, placebo-controlled and double-blinded studies (studies 301, 302, and 303) in adult and pediatric patients undergoing autologous BMT for lymphoid malignancies. A total of 128 patients were enrolled in these three studies. Compared to placebo, administration of Leukine in two studies significantly improved the following hematologic and clinical endpoints: time to neutrophil recovery, duration of hospitalization and infection experience or antibacterial usage. In the third study (study 302: 37 patients who underwent autologous BMT, 18 treated with Leukine) there was a positive trend toward earlier myeloid engraftment in favor of Leukine.

Indication 4 - for the acceleration of myeloid reconstitution following allogeneic bone marrow transplantation in adult and pediatric patients 2 years of age and older

Approval date unavailable

Dosing/Administration

The recommended dose is 250 mcg/m2/day administered intravenously over a 2-hour period beginning two to four hours after bone marrow infusion, and not less than 24 hours after the last dose of chemotherapy or radiotherapy. Do not administer Leukine until the post marrow infusion ANC is less than 500 cells/mm3. Continue Leukine until an ANC greater than 1500 cells/mm3 for three consecutive days is attained. Do not administer Leukine within 24 hours preceding or following receipt of chemotherapy or radiotherapy.

Clinical Trial Results

A multicenter, randomized, placebo-controlled, and double-blinded study (study 9002) was conducted to evaluate the safety and efficacy of Leukine for promoting hematopoietic reconstitution following allogeneic BMT. A total of 109 adult and pediatric patients (53 Leukine, 56 placebo) were enrolled in the study. Accelerated myeloid engraftment was associated with significant laboratory and clinical benefits. Compared to placebo, administration of Leukine significantly improved the following: time to neutrophil engraftment, duration of hospitalization, number of patients with bacteremia, and overall incidence of infection. Median time to myeloid recovery (ANC ≥500 cells/mm3) in 53 patients receiving Leukine was 4 four days less than in 56 patients treated with placebo. The numbers of patients with bacteremia and infection were significantly lower in the Leukine group compared to the placebo group (9/53 versus 19/56 and 30/53 versus 42/56, respectively).

Indication 5 - for treatment of delayed neutrophil recovery or graft failure after autologous or allogeneic bone marrow transplantation in adult and pediatric patients 2 years of age and older

Approval date unavailable

Dosing/Administration

The recommended dose is 250 mcg/m2/day for 14 days as a 2-hour intravenous infusion. The dose can be repeated after 7 days off therapy if neutrophil recovery has not occurred. If neutrophil recovery still has not occurred, a third course of 500 mcg/m2/day for 14 days may be tried after another 7 days off therapy. If there is still no improvement, it is unlikely that further dose escalation will be beneficial.

Clinical Trial Results

A historically-controlled study (study 501) was conducted in patients experiencing graft failure following allogeneic or autologous BMT to determine whether Leukine improved survival after BMT failure. Three categories of patients were eligible for this study:

• patients displaying a delay in neutrophil recovery (ANC ≤100 cells/mm3 by day 28 post transplantation);
• patients displaying a delay in neutrophil recovery (ANC ≤100 cells/mm3 by day 21 post transplantation) and who had evidence of an active infection
• patients who lost their marrow graft after a transient neutrophil recovery (manifested by an average of ANC ≥500 cells/mm3 for at least one week followed by loss of engraftment with ANC <500 cells/mm3 for at least one week beyond day 21 post transplantation).

A total of 140 eligible adult and pediatric patients from 35 institutions were treated with Leukine and evaluated in comparison to 103 historical control patients from a single institution. One hundred-day survival was improved in favor of the patients treated with Leukine for graft failure following either autologous or allogeneic BMT. In addition, the median survival was improved by greater than two-fold. The median survival of patients treated with Leukine after autologous failure was 474 days versus 161 days for the historical patients. Similarly, after allogeneic failure, the median survival was 97 days with Leukine treatment and 35 days for the historical controls. Improvement in survival was better in patients with fewer impaired organs.

Indication 6 - patients acutely exposed to myelosuppressive doses of radiation (Hematopoietic Syndrome of Acute Radiation Syndrome [H-ARS])

approved March of 2018

Dosing/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 Trial Results

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.