Leukine

LEUKINE is indicated 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 (AML).

LEUKINE is indicated in adult patients with cancer undergoing autologous hematopoietic stem cell transplantation for the mobilization of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis.

LEUKINE is indicated for the acceleration of myeloid reconstitution following autologous peripheral blood progenitor cell (PBPC) or bone marrow transplantation in adult and pediatric patients 2 years of age and older with non-Hodgkin's lymphoma (NHL), acute lymphoblastic leukemia (ALL) and Hodgkin's lymphoma (HL).

LEUKINE is indicated for the acceleration of myeloid reconstitution in adult and pediatric patients 2 years of age and older undergoing allogeneic bone marrow transplantation from HLA-matched related donors.

LEUKINE is indicated for the treatment of adult and pediatric patients 2 years and older who have undergone allogeneic or autologous bone marrow transplantation in whom neutrophil recovery is delayed or failed.

LEUKINE is 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]).

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 [see Warnings and Precautions (5.3)].

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 [see Clinical Studies (14)].

If WBC greater than 50,000 cells/mm³, reduce the LEUKINE dose by 50%. Consider other mobilization therapy if adequate numbers of progenitor cells are not collected.

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 [see Warnings and Precautions (5.3)].

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.

For patients with H-ARS, 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.

• Do not administer LEUKINE simultaneously with or within 24 hours preceding cytotoxic chemotherapy or radiotherapy or within 24 hours following chemotherapy [see Warnings and Precautions (5.3)].
• LEUKINE injection is formulated as a sterile solution preserved with 1.1% benzyl alcohol.
• LEUKINE for injection is a sterile, preservative-free lyophilized powder that requires reconstitution with 1 mL Sterile Water for Injection (without preservative), USP, to yield a clear, colorless single-dose solution or 1 mL Bacteriostatic Water for Injection, USP (with 0.9% benzyl alcohol as preservative) to yield a clear, colorless single-dose solution.

Use only LEUKINE for injection (lyophilized powder) reconstituted with Sterile Water for Injection without preservatives when administering LEUKINE to neonates or infants to avoid benzyl alcohol exposure [see Warnings and Precautions (5.9)].

Do NOT use an in-line membrane filter for intravenous infusion of LEUKINE.

• Store LEUKINE solution and reconstituted lyophilized LEUKINE solutions under refrigeration at 2°C–8°C (36°F–46°F); DO NOT FREEZE.
• In the absence of compatibility and stability information, do not add other medication to infusion solutions containing LEUKINE. Use only 0.9% Sodium Chloride Injection, USP to prepare intravenous infusion solutions.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. If particulate matter is present or the solution is discolored, the vial should not be used.

Serious hypersensitivity reactions, including anaphylactic reactions, have been reported with LEUKINE. Parenteral administration of LEUKINE should be attended by appropriate precautions in case an allergic or untoward reaction occurs. If any serious allergic or anaphylactic reaction occurs, immediately discontinue LEUKINE therapy and institute medical management. Discontinue LEUKINE permanently for patients with serious allergic reactions.

LEUKINE can cause infusion-related reactions. Infusion-related reactions may be characterized by respiratory distress, hypoxia, flushing, hypotension, syncope, and/or tachycardia following the first administration of LEUKINE in a particular cycle. These signs have resolved with symptomatic treatment and usually do not recur with subsequent doses in the same cycle of treatment.

Observe closely during infusion for symptoms, particularly in patients with pre-existing lung disease. If patients display dyspnea or other acute symptoms, reduce the rate of infusion by 50%. If symptoms persist or worsen despite rate reduction, discontinue the LEUKINE infusion. If patient experiences infusion-related reaction, subsequent intravenous infusions may be administered following the standard dose schedule with careful monitoring.

Due to the potential sensitivity of rapidly dividing hematopoietic progenitor cells, LEUKINE should not be administered simultaneously with or within 24 hours preceding cytotoxic chemotherapy or radiotherapy or within 24 hours following chemotherapy. In one controlled study, patients with small cell lung cancer received LEUKINE and concurrent thoracic radiotherapy and chemotherapy or the identical radiotherapy and chemotherapy without LEUKINE. The patients randomized to LEUKINE had significantly higher incidence of adverse reactions, including higher mortality and a higher incidence of grade 3 and 4 infections and grade 3 and 4 thrombocytopenia.

Edema, capillary leak syndrome, and pleural and/or pericardial effusion, have been reported in patients after LEUKINE administration. In 156 patients enrolled in placebo-controlled studies using LEUKINE at a dose of 250 mcg/m²/day by 2-hour IV infusion, the reported incidences of fluid retention (LEUKINE vs. placebo) were as follows: peripheral edema, 11% vs. 7%; pleural effusion, 1% vs. 0%; and pericardial effusion, 4% vs. 1%. Capillary leak syndrome was not observed in this limited number of studies; based on other uncontrolled studies and reports from users of marketed LEUKINE, the incidence is estimated to be less than 1%. In patients with preexisting pleural and pericardial effusions, administration of LEUKINE may aggravate fluid retention; however, fluid retention associated with or worsened by LEUKINE has been reversible after interruption or dose reduction of LEUKINE with or without diuretic therapy. LEUKINE should be used with caution in patients with preexisting fluid retention, pulmonary infiltrates, or congestive heart failure. Body weight and hydration status should be carefully monitored during LEUKINE administration.

Supraventricular arrhythmia has been reported in uncontrolled studies during LEUKINE administration, particularly in patients with a previous history of cardiac arrhythmia. These arrhythmias have been reversible after discontinuation of LEUKINE. Use LEUKINE with caution in patients with preexisting cardiac disease.

White blood cell counts of ≥ 50,000/mm³ were observed in patients receiving LEUKINE. Monitor complete blood counts (CBC) with differential twice per week. Base the decision whether to reduce the dose or interrupt treatment on the clinical condition of the patient [see Dosage and Administration (2.1, 2.4, 2.5, 2.6)]. Following cessation of LEUKINE therapy, excessive blood counts have returned to normal or baseline levels within 3 to 7 days.

LEUKINE is a growth factor that primarily stimulates normal myeloid precursors. However, the possibility that LEUKINE can act as a growth factor for any tumor type, particularly myeloid malignancies, cannot be excluded. Because of the possibility of tumor growth potentiation, precaution should be exercised when using this drug in any malignancy with myeloid characteristics.

Discontinue LEUKINE therapy if disease progression is detected during LEUKINE treatment.

Treatment with LEUKINE may induce neutralizing anti-drug antibodies. The incidence of anti-sargramostim neutralizing antibodies may be related to duration of exposure to LEUKINE. In a study of patients with normal neutrophil count and a solid tumor in complete response (an unapproved use) treated with LEUKINE for up to 12 months, 82.9% of 41 evaluable patients developed anti-sargramostim neutralizing antibodies and the myelostimulatory effect of LEUKINE was not sustained by day 155 as assessed by WBC count. Use LEUKINE for the shortest duration required [see Adverse Reactions (6.2)].

Serious and fatal adverse reactions including "gasping syndrome" can occur in neonates and low birth weight infants treated with benzyl alcohol-preserved drugs, including LEUKINE injection (solution) or LEUKINE for injection (lyophilized powder) reconstituted with Bacteriostatic Water. The "gasping syndrome" is characterized by central nervous system depression, metabolic acidosis and gasping respirations.

Avoid administration of solutions containing benzyl alcohol (including LEUKINE injection [solution] or LEUKINE for injection [lyophilized powder] reconstituted with Bacteriostatic Water for Injection, USP [0.9% benzyl alcohol]) to neonates and low birth weight infants. Instead, administer lyophilized LEUKINE reconstituted with Sterile Water for Injection, USP [see Dosage and Administration (2.7)].

If LEUKINE injection (solution) or LEUKINE for injection (lyophilized powder) reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) must be used in neonates and low birth weight infants, consider the combined daily metabolic load of benzyl alcohol from all sources including LEUKINE (LEUKINE injection and LEUKINE for injection reconstituted with Bacteriostatic Water contain 11 mg and 9 mg of benzyl alcohol per mL, respectively). The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known [see Use in Specific Populations (8.4) and Dosage and Administration (2.7)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

As with all therapeutic proteins, there is the potential for immunogenicity with LEUKINE. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, duration of treatment, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to sargramostim in the studies described below with the incidence of antibodies in other studies or other products may be misleading.

In 214 patients with a variety of underlying diseases, neutralizing anti-sargramostim antibodies were detected in 5 patients (2.3%) after receiving LEUKINE by continuous IV infusion (3 patients) or SC injection (2 patients) for 28 to 84 days in multiple courses (as assessed by GM-CSF dependent human cell-line proliferation assay). All 5 patients had impaired hematopoiesis before the administration of LEUKINE, and consequently the effect of the development of anti-sargramostim antibodies on normal hematopoiesis could not be assessed.

Antibody studies of 75 patients with Crohn's disease (a disease for which LEUKINE is not indicated), with normal hematopoiesis and no other immunosuppressive drugs, receiving LEUKINE daily for 8 weeks by SC injection, showed 1 patient (1.3%) with detectable neutralizing anti-sargramostim antibodies (as assessed by GM-CSF dependent human cell-line proliferation assay).

In an experimental use trial where LEUKINE was given for an extended period, 53 patients with melanoma in complete remission (a disease for which LEUKINE is not indicated) received adjuvant therapy with LEUKINE 125 mcg/m² once daily (maximum dose 250 mcg) from day 1 to 14 every 28 days for 1 year. Serum samples from patients assessed at day 0, 2 weeks, 1 month, and 5 and/or 12 months were tested retrospectively for the presence of anti-sargramostim antibodies. Of 43 evaluable patients (having at least 3 timepoint samples post treatment), 42 (97.7%) developed anti-sargramostim binding antibody as assessed by ELISA and confirmed using an immunoprecipitation assay. Of these 42 patients, 41 had sufficient sample and were further tested: 34 patients (82.9%) developed anti-sargramostim neutralizing antibodies (as determined by a cell based luciferase reporter gene neutralizing antibody assay); 17 (50%) of these patients did not have a sustained pharmacodynamic effect of LEUKINE by day 155 as assessed by WBC counts. This study provided limited assessment of the impact of antibody formation on the safety and efficacy of LEUKINE.

Serious allergic and anaphylactoid reactions have been reported with LEUKINE, but the rate of occurrence of antibodies in such patients has not been assessed.

The following adverse reactions have been identified during postapproval use of LEUKINE in clinical trials and/or postmarketing surveillance. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Infusion related reactions including dyspnea, hypoxia, flushing, hypotension, syncope and/or tachycardia [see Warnings and Precautions (5.1)]
• Serious allergic reactions/hypersensitivity, including anaphylaxis, skin rash, urticaria, generalized erythema, and flushing [see Warnings and Precautions (5.2)]
• Effusions and capillary leak syndrome [see Warnings and Precautions (5.3)]
• Supraventricular arrhythmias [see Warnings and Precautions (5.4)]
• Leukocytosis including eosinophilia [see Warnings and Precautions (5.6)]
• Thromboembolic events
• Pain, including chest, abdominal, back, and joint pain
• Injection site reactions

Avoid the concomitant use of LEUKINE and products that induce myeloproliferation (such as lithium and corticosteroids). Such products may increase the myeloproliferative effects of LEUKINE. Monitor patients receiving both LEUKINE and products that induce myeloproliferation frequently for clinical and laboratory signs of excess myeloproliferative effects.

The safety and effectiveness of LEUKINE have been established in pediatric patients 2 years of age and older for autologous peripheral blood progenitor cells and bone marrow transplantation, allogeneic bone marrow transplantation, and treatment of delayed neutrophil recovery or graft failure. Use of LEUKINE for these indications in this age group is based on adequate and well-controlled studies of LEUKINE in adults, in addition to clinical data in 12, 23, and 37 pediatric patients, respectively [See Clinical Studies (14.3, 14.4 and 14.5)]. The pediatric adverse reactions were consistent with those reported in the adult population.

The safety and effectiveness of LEUKINE for pediatric patients less than 2 years of age for autologous peripheral blood progenitor cells and bone marrow transplantation, allogeneic bone marrow transplantation, and treatment of delayed neutrophil recovery or graft failure have not been established.

The use of LEUKINE to increase survival in pediatric patients acutely exposed to myelosuppressive doses of radiation (H-ARS) is based on efficacy studies conducted in animals and clinical data supporting the use of LEUKINE in patients undergoing autologous or allogeneic BMT following myelosuppressive chemotherapy with or without total body irradiation. Efficacy studies of LEUKINE could not be conducted in humans with acute radiation syndrome for ethical and feasibility reasons. Modeling and simulation was used to derive dosing regimens that are predicted to provide pediatric patients with exposure comparable to the observed exposure in adults receiving 7 mcg/kg [see Clinical Pharmacology (12.3)]. The dose for pediatric patients is based on weight [see Dosage and Administration (2.2)].

Safety and effectiveness in pediatric patients have not been established in:

• Acute Myeloid Leukemia: Neutrophil Recovery Following Induction Chemotherapy
• Autologous Peripheral Blood Progenitor Cell Mobilization and Collection

Avoid administration of solutions containing benzyl alcohol [including LEUKINE injection (solution) or LEUKINE for injection (lyophilized powder) reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol)] to neonates and low birth weight infants. Instead, administer lyophilized LEUKINE reconstituted with Sterile Water for Injection, USP [see Dosage and Administration (2.7)].

Serious adverse reactions including fatal reactions and the "gasping syndrome" occurred in premature infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.38 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol.

If LEUKINE injection (solution) or LEUKINE for injection (lyophilized powder) reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) must be used in neonates and low birth weight infants, consider the combined daily metabolic load of benzyl alcohol from all sources including LEUKINE (LEUKINE injection [solution] and LEUKINE for injection [lyophilized powder] reconstituted with Bacteriostatic Water for Injection, USP [0.9% benzyl alcohol] contain 11 mg and 9 mg of benzyl alcohol per mL, respectively). The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known [see Dosage and Administration (2.7)].

Clinical studies of LEUKINE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

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.

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.

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.

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.

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).

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 3/4) 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.

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.

How Supplied

LEUKINE (sargramostim) for injection is a sterile, preservative-free, white lyophilized powder supplied in a carton containing five 250 mcg single-dose vials. (NDC 0024-5843-05).

LEUKINE (sargramostim) injection is a sterile, clear, colorless solution preserved with 1.1% benzyl alcohol supplied in a carton containing one 500 mcg/mL multiple-dose vial (NDC 0024-5844-01) and a carton containing five 500 mcg/mL multiple-dose vials (NDC 0024-5844-05).

Storage and Handling

Store LEUKINE vials refrigerated at 2°C–8°C (36°F–46°F) in the original carton to protect from light. Do not freeze or shake. Do not use beyond the expiration date printed on the vial.