Source: FDA, National Drug Code (US) Revision Year: 2024
Sargramostim (GM-CSF) 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.
The biological activity of GM-CSF is species-specific. Consequently, in vitro studies have been performed on human cells to characterize the pharmacological activity of GM-CSF. In vitro exposure of human bone marrow cells to GM-CSF at concentrations ranging from 1-100 ng/mL results in the proliferation of hematopoietic progenitors and in the formation of pure granulocyte, pure macrophage, and mixed granulocyte macrophage colonies. Chemotactic, anti-fungal, and anti-parasitic activities of granulocytes and monocytes are increased by exposure to GM-CSF in vitro. GM-CSF increases the cytotoxicity of monocytes toward certain neoplastic cell lines and activates polymorphonuclear neutrophils to inhibit the growth of tumor cells.
LEUKINE stimulates hematopoietic precursor cells and increases neutrophil, eosinophil, megakaryocyte, macrophage, and dendritic cell production. In AML adult patients undergoing induction chemotherapy [see Clinical Studies (14.1)], LEUKINE at daily doses of 250 mcg/m² significantly shortened the median duration of ANC <500/mm³ by 4 days and <1000/mm³ by 7 days following induction; 75% of patients receiving sargramostim achieved ANC greater than 500/mm³ by day 16 compared to day 25 for patients receiving placebo. Animal data and clinical data in humans suggest a correlation between sargramostim exposure and the duration of severe neutropenia as a predictor of efficacy. At doses of 250 mcg/m² (approximately 7 mcg/kg in a 70 kg human with a body surface area of 1.96), daily LEUKINE treatment reduced the duration of severe neutropenia.
Peak concentrations of sargramostim were observed in blood samples obtained during or immediately after completion of LEUKINE infusion.
Based on a population pharmacokinetics analysis of lyophilized LEUKINE data, the mean Cmax after a 7 mcg/kg SC dose (equivalent to a 250 mcg/m² dose in a 70 kg human with a body surface area of 1.96) was 3.03 ng/mL and mean AUC0-24 was 21.3 ng•h/mL (Table 4). There is no accumulation of GM-CSF after repeat SC dosing and steady state conditions are met after a single SC dose.
Table 4. Sargramostim serum Cmax and AUC Exposure (CV%) in Humans after Subcutaneous Administration:
| Data type | Sargramostim dose | Formulation | Number of healthy subjects | AUC (CV%) (ng·h/mL ) | Cmax (CV%) (ng/mL) |
|---|---|---|---|---|---|
| Observed | 6.5 mcg/kg | Lyophilized LEUKINE | 39 | 20.4 (28.7%) | 3.15 (35.2%) |
| Population PK model simulation | 7 mcg/kg | Lyophilized LEUKINE | 500 | 21.3 (32.6) | 3.03 (31.0) |
After SC administration GM-CSF was detected in the serum early (15 min) and reached maximum serum concentrations between 2.5 and 4 h. The absolute bioavailability with the SC route, when compared to the IV route, was 75%.
The observed volume of distribution after IV (Vz) administration was 96.8.
LEUKINE administered SC to healthy adult volunteers, GM-CSF had a terminal elimination half-life of 1.4 h. The observed total body clearance/subcutaneous bioavailability (CL/F) was 23 L/h. Specific metabolism studies were not conducted, because LEUKINE is a protein and is expected to degrade to small peptides and individual amino acids.
The pharmacokinetics of sargramostim are not available in adult patients acutely exposed to myelosuppressive doses of radiation. Pharmacokinetic data in irradiated and non-irradiated non-human primates and in healthy human adults were used to derive human doses for patients acutely exposed to myelosuppressive doses of radiation. Modeling and simulation of the healthy human adult pharmacokinetic data indicate that sargramostim Cmax and AUC exposures at a LEUKINE dose of 7 mcg/kg in patients acutely exposed to myelosuppressive doses of radiation are expected to exceed sargramostim Cmax (97.6% of patients) and AUC (100% of patients) exposures at a LEUKINE dose of 7 mcg/kg in non-human primates.
The pharmacokinetics of sargramostim was not available in pediatric patients acutely exposed to myelosuppressive doses of radiation. The pharmacokinetics of sargramostim in pediatric patients after being exposed to myelosuppressive doses of radiation were estimated by scaling the adult population pharmacokinetic model to the pediatric population. The model-predicted mean AUC0-24 values at 7, 10, and 12 mcg/kg doses of LEUKINE in pediatric patients weighing greater than 40 kg (~adolescents), 15 to 40 kg (~young children), and 0 to less than 15 kg (~newborns to toddlers), respectively, were similar to AUC values in adults after a 7 mcg/kg dose.
Carcinogenicity and genetic toxicology studies have not been conducted with LEUKINE.
LEUKINE had no effect on fertility of female rabbits up to a dose of 200 mcg/kg/day.
The toxicology studies with up to 6 weeks of exposure to LEUKINE in sexually mature female and male cynomolgus monkeys did not reveal findings in male or female reproductive organs that would suggest impairment of fertility up to a dose of 200 mcg/kg/day. At 200 mcg/kg, the AUC exposure of LEUKINE was 8.8 to 11.4 times (monkeys) and 2.0 to 25.3 times (rabbits) the exposure in humans at the recommended clinical dose of 250 mcg/m².
After the first administration, a dose of 200 mcg/kg/day corresponds to an AUC of approximately 11.4 (monkeys) and 25.3 (rabbits) times the exposures observed in patients treated with the clinical LEUKINE dose of 250 mcg/m²; however, due to the production of anti-LEUKINE antibodies with repeat administration, the AUC decreased to 8.8 (monkeys) and 2.0 (rabbits) times the clinical exposure by the end of the dosing periods.
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 4 days and <1000 cells/mm³ by 7 days following induction (see Table 5). Of patients receiving LEUKINE, 75% achieved 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. Median times to platelet (>20,000 cells/mm³) and RBC transfusion independence were not significantly different between treatment groups.
Table 5. Hematological Recovery (in Days) in Patients with AML: Induction:
| Dataset | LEUKINE n=52a Median (25%, 75%) | Placebo n=47 Median (25%, 75%) | p-valueb |
|---|---|---|---|
| ANC >500/mm³c | 13 (11, 16) | 17 (13, 25) | 0.009 |
| ANC >1000/mm³d | 14 (12, 18) | 21 (13, 34) | 0.003 |
| PLT >20,000/mm³e | 11 (7, 14) | 12 (9, >42) | 0.10 |
| RBCf | 12 (9, 24) | 14 (9, 42) | 0.53 |
a Patients with missing data censored
b p = Generalized Wilcoxon
c 2 patients on LEUKINE and 4 patients on placebo had missing values
d 2 patients on LEUKINE and 3 patients on placebo had missing values
e 4 patients on placebo had missing values
f 3 patients on LEUKINE and 4 patients on placebo had missing values
During the consolidation phase of treatment, LEUKINE did not shorten the median time to recovery of ANC to 500 cells/mm³ (13 days) or 1000 cells/mm³ (14.5 days) compared to placebo. There were no significant differences in time to platelet and RBC transfusion independence.
The incidence of severe infections and deaths associated with infections was significantly reduced in patients who received LEUKINE. During induction or consolidation, 27 of 52 patients receiving LEUKINE and 35 of 47 patients receiving placebo had at least one grade 3, 4 or 5 infection (p=0.02). Twenty-five patients receiving LEUKINE and 30 patients receiving placebo experienced severe and fatal infections during induction only. There were significantly fewer deaths from infectious causes in the LEUKINE arm (3 vs. 11, p=0.02). The majority of deaths in the placebo group were associated with fungal infections with pneumonia as the primary infection.
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).
A second retrospective review of data from patients undergoing PBPC at another single transplant center was also conducted. LEUKINE was given SC at 250 mcg/m²/day once a day (n=10) or twice a day (n=21) until completion of apheresis. Apheresis was begun on day 5 of LEUKINE administration and continued until the targeted MNC count of 9 × 108/kg or CD34+ cell count of 1 × 106/kg was reached. There was no difference in CD34+ cell count in patients receiving LEUKINE once or twice a day.
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 (see Table 6). 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.
Table 6. ANC and Platelet Recovery after PBPC Transplantation:
| LEUKINE Route for Mobilization | Post transplant LEUKINE | Median Day ANC >500 cells/mm³ | Median Day of Last platelet transfusion | |
|---|---|---|---|---|
| No Mobilization | — | No | 29 | 28 |
| LEUKINE 250 mcg/m² | IV | No | 21 | 24 |
| IV | Yes | 12 | 19 | |
| SC | Yes | 12 | 17 |
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 (65 LEUKINE, 63 placebo) were enrolled in these three studies. The median age was 38 years (range 3-62 years), and 12 patients were younger than 18 years of age. The majority of the patients had lymphoid malignancy (87 NHL, 17 ALL), 23 patients had Hodgkin lymphoma, and one patient had AML. In 72 patients with NHL or ALL, the bone marrow harvest was purged with one of several monoclonal antibodies prior to storage. No chemical agent was used for in vitro treatment of the bone marrow. Preparative regimens in the three studies included cyclophosphamide (total dose 120-150 mg/kg) and total body irradiation (total dose 1,200-1,575 rads). Other regimens used in patients with Hodgkin's disease and NHL without radiotherapy consisted of three or more of the following in combination (expressed as total dose): cytosine arabinoside (400 mg/m²) and carmustine (300 mg/m²), cyclophosphamide (140-150 mg/kg), hydroxyurea (4.5 grams/m²), and etoposide (375-450 mg/m²).
Compared to placebo, administration of LEUKINE in two studies (study 301: 44 patients, 23 patients treated with LEUKINE, and study 303: 47 patients, 24 treated with LEUKINE) 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. This latter study differed from the other two in having enrolled a large number of patients with Hodgkin lymphoma who had also received extensive radiation and chemotherapy prior to harvest of autologous bone marrow. In the following combined analysis of the three studies, these two subgroups (NHL and ALL vs. Hodgkin lymphoma) are presented separately.
Neutrophil recovery (ANC ≥500 cells/mm³) in 54 patients with NHL or ALL receiving LEUKINE on Studies 301, 302 and 303 was observed on day 18, and on day 24 in 50 patients treated with placebo (see Table 7). The median duration of hospitalization was six days shorter for the LEUKINE group than for the placebo group. Median duration of infectious episodes (defined as fever and neutropenia; or two positive cultures of the same organism; or fever >38°C and one positive blood culture; or clinical evidence of infection) was three days less in the group treated with LEUKINE. The median duration of antibacterial administration in the post transplantation period was four days shorter for the patients treated with LEUKINE than for placebo-treated patients.
Table 7. Autologous BMT: Combined Analysis from Placebo-Controlled Clinical Trials of Responses in Patients with NHL and ALL Median Values (days):
| ANC ≥500 cells/mm³ | ANC ≥1000 cells/mm³ | Duration of Hospitalization | Duration of Infection | Duration of Antibacterial Therapy | |
|---|---|---|---|---|---|
| LEUKINE n=54 | 18a,b | 24a,b | 25a | 1a | 21a |
| Placebo n=50 | 24 | 32 | 31 | 4 | 25 |
a p<0.05 Wilcoxon or Cochran-Mantel-Haenszel RIDIT chi-squared
b p<0.05 Log rank
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. The median age was 34.7 years (range 2.2-65.1 years). Twenty-three patients (11 LEUKINE, 12 placebo) were 18 years old or younger. Sixty-seven patients had myeloid malignancies (33 AML, 34 CML), 17 had lymphoid malignancies (12 ALL, 5 NHL), three patients had Hodgkin's disease, six had multiple myeloma, nine had myelodysplastic disease, and seven patients had aplastic anemia. In 22 patients at one of the seven study sites, bone marrow harvests were depleted of T cells. Preparative regimens included cyclophosphamide, busulfan, cytosine arabinoside, etoposide, methotrexate, corticosteroids, and asparaginase. Some patients also received total body, splenic, or testicular irradiation. Primary GVHD prophylaxis was cyclosporine and a corticosteroid.
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 (see Table 8).
Table 8. Allogeneic BMT: Analysis of Data from Placebo-Controlled Clinical Trial Median Values (days or number of patients):
| ANC ≥500 cells/mm³ | ANC ≥1000 cells/mm³ | Number of Patients with Infections | Number of Patients with Bacteremia | Days of Hospitalization | |
|---|---|---|---|---|---|
| LEUKINE n=53 | 13a | 14a | 30a | 9b | 25a |
| Placebo n=56 | 17 | 19 | 42 | 19 | 26 |
a p<0.05 generalized Wilcoxon test
b p<0.05 simple chi-square test
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 (see Table 8). 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). There were a number of secondary laboratory and clinical endpoints. Of these, only the incidence of severe (grade ¾) mucositis was significantly improved in the LEUKINE group (4/53) compared to the placebo group (16/56) at p<0.05. LEUKINE-treated patients also had a shorter median duration of post transplant IV antibiotic infusions, and a shorter median number of days to last platelet and RBC transfusions compared to placebo patients, but none of these differences reached statistical significance.
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:
1. patients displaying a delay in neutrophil recovery (ANC ≤100 cells/mm³ by day 28 post transplantation);
2. patients displaying a delay in neutrophil recovery (ANC ≤100 cells/mm³ by day 21 post transplantation) and who had evidence of an active infection; and
3. 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 sixty-three patients had lymphoid or myeloid leukemia, 24 patients had NHL, 19 patients had Hodgkin's disease and 37 patients had other diseases, such as aplastic anemia, myelodysplasia or non-hematologic malignancy. The majority of patients (223 out of 243) had received prior chemotherapy with or without radiotherapy and/or immunotherapy prior to preparation for transplantation. The median age of enrolled patients was 27 years (range 1-66 years). Thirty-seven patients were younger than 18 years of age.
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. The Multiple Organ Failure (MOF) score is a clinical and laboratory assessment of seven major organ systems: cardiovascular, respiratory, gastrointestinal, hematologic, renal, hepatic, and neurologic. Median survival by MOF category is presented in Table 9.
Table 9. Median Survival by Multiple Organ Failure (MOF) Category Median Survival (days):
| MOF ≤2 Organs | MOF >2 Organs | MOF (Composite of both groups) | |
|---|---|---|---|
| Autologous BMT | |||
| LEUKINE | 474 (n=58) | 78.5 (n=10) | 474 (n=68) |
| Historical | 165 (n=14) | 39 (n=3) | 161 (n=17) |
| Allogeneic BMT | |||
| LEUKINE | 174 (n=50) | 27 (n=22) | 97 (n=72) |
| Historical | 52.5 (n=60) | 15.5 (n=26) | 35 (n=86) |
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 [see Dosage and Administration (2.1 to 2.6)].
The recommended dose of LEUKINE for adults exposed to myelosuppressive doses of radiation is 7 mcg/kg as a single daily SC injection [see Dosage and Administration (2.6)]. 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 [see Clinical Pharmacology (12.3)]. 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 [see Adverse Reactions (6.1)].
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.
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