Leukine (Sargramostim) - Indications and Dosage

INDICATIONS AND USAGE

Use Following Induction Chemotherapy in Acute Myelogenous Leukemia

LEUKINE is indicated for use following induction chemotherapy in older adult patients with acute myelogenous leukemia (AML) to shorten time to neutrophil recovery and to reduce the incidence of severe and life-threatening infections and infections resulting in death. The safety and efficacy of LEUKINE have not been assessed in patients with AML under 55 years of age.

The term acute myelogenous leukemia, also referred to as acute non-lymphocytic leukemia (ANLL), encompasses a heterogeneous group of leukemias arising from various non-lymphoid cell lines which have been defined morphologically by the French-American-British (FAB) system of classification.

Use in Mobilization and Following Transplantation of Autologous Peripheral Blood Progentior Cells

LEUKINE is indicated for the mobilization of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis. Mobilization allows for the collection of increased numbers of progenitor cells capable of engraftment as compared with collection without mobilization. After myeloablative chemotherapy, the transplantation of an increased number of progenitor cells can lead to more rapid engraftment, which may result in a decreased need for supportive care. Myeloid reconstitution is further accelerated by administration of LEUKINE following peripheral blood progenitor cell transplantation.

Use in Myeloid Reconstitution After Autologous Bone Marrow Transplantation

LEUKINE is indicated for acceleration of myeloid recovery in patients with non-Hodgkin's lymphoma (NHL), acute lymphoblastic leukemia (ALL) and Hodgkin's disease undergoing autologous bone marrow transplantation (BMT). After autologous BMT in patients with NHL, ALL, or Hodgkin's disease, LEUKINE has been found to be safe and effective in accelerating myeloid engraftment, decreasing median duration of antibiotic administration, reducing the median duration of infectious episodes and shortening the median duration of hospitalization. Hematologic response to LEUKINE can be detected by complete blood count (CBC) with differential cell counts performed twice per week.

Use in Myeloid Reconstitution After Allogeneic Bone Marrow Transplantation

LEUKINE is indicated for acceleration of myeloid recovery in patients undergoing allogeneic BMT from HLA-matched related donors. LEUKINE has been found to be safe and effective in accelerating myeloid engraftment, reducing the incidence of bacteremia and other culture positive infections, and shortening the median duration of hospitalization.

Use in Bone Marrow Transplantation Failure or Engraftment Delay

LEUKINE is indicated in patients who have undergone allogeneic or autologous bone marrow transplantation (BMT) in whom engraftment is delayed or has failed. LEUKINE has been found to be safe and effective in prolonging survival of patients who are experiencing graft failure or engraftment delay, in the presence or absence of infection, following autologous or allogeneic BMT. Survival benefit may be relatively greater in those patients who demonstrate one or more of the following characteristics: autologous BMT failure or engraftment delay, no previous total body irradiation, malignancy other than leukemia or a multiple organ failure (MOF) score ≤ two (see CLINICAL EXPERIENCE). Hematologic response to LEUKINE can be detected by complete blood count (CBC) with differential performed twice per week.

CLINICAL EXPERIENCE

Acute Myelogenous Leukemia

The safety and efficacy of LEUKINE in patients with AML who are younger than 55 years of age have not been determined. Based on Phase II data suggesting the best therapeutic effects could be achieved in patients at highest risk for severe infections and mortality while neutropenic, the Phase III clinical trial was conducted in older patients. The safety and efficacy of LEUKINE in the treatment of AML were evaluated in a multi-center, randomized, double-blind placebo-controlled trial of 99 newly diagnosed adult patients, 55–70 years of age, receiving induction with or without consolidation.⁶ 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 IV over four hours each day, starting four days after the completion of chemotherapy. Study drug was continued until an ANC ≥1500/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/mm³ by 4 days and <1000/mm³ by 7 days following induction (see Table 1). 75% of patients receiving LEUKINE achieved ANC >500/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 versus 15 days) or two cycles (14 versus 23 days) of induction chemotherapy was administered. Median times to platelet (>20,000/mm³) and RBC transfusion independence were not significantly different between treatment groups.

Table 1

Hematological Recovery (in Days): Induction
Dataset	sargramostim n=52Patients with missing data censored. Median (25%, 75%)	Placebo n=47 Median (25%,75%)	p-valuep=Generalized Wilcoxon
ANC>500/mm3 2 patients on sargramostim and 4 patients on placebo had missing values.	13 (11, 16)	17 (13, 25)	0.009
ANC>1000/mm3 2 patients on sargramostim and 3 patients on placebo had missing values.	14 (12, 18)	21 (13, 34)	0.003
PLT>20,000/mm3 4 patients on placebo had missing values.	11 (7, 14)	12 (9, >42)	0.10
RBC3 patients on sargramostim and 4 patients on placebo had missing values.	12 (9, 24)	14 (9, 42)	0.53

During the consolidation phase of treatment, LEUKINE did not shorten the median time to recovery of ANC to 500/mm³ (13 days) or 1000/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 versus 11, p=0.02). The majority of deaths in the placebo group were associated with fungal infections with pneumonia as the primary infection.

Disease outcomes were not adversely affected by the use of LEUKINE. The proportion of patients achieving complete remission (CR) was higher in the LEUKINE group (69% as compared to 55% for the placebo group), but the difference was not significant (p=0.21). There was no significant difference in relapse rates; 12 of 36 patients who received LEUKINE and five of 26 patients who received placebo relapsed within 180 days of documented CR (p=0.26). The overall median survival was 378 days for patients receiving LEUKINE and 268 days for those on placebo (p=0.17). The study was not sized to assess the impact of LEUKINE treatment on response or survival.

Mobilization and Engraftment of PBPC

A retrospective review was conducted of data from 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/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 phereses (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 five, another cytokine was substituted for LEUKINE; these subjects were all successfully leukapheresed and transplanted. The most marked mobilization and post-transplant 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 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).

After transplantation, mobilized subjects had shorter times to myeloid engraftment and fewer days between transplantation and the last platelet transfusion compared to non-mobilized subjects. Neutrophil recovery (ANC >500/mm³) was more rapid in patients administered LEUKINE following PBPC transplantation with LEUKINE-mobilized cells (see Table 2). 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 2

ANC and Platelet Recovery after PBPC Transplant
	Route for Mobilization	Post-transplant LEUKINE	ENGRAFTMENT (median value in days)
			ANC>500/mm3	Last platelet transfusion
No Mobilization	—	no	29	28
LEUKINE	IV	no	21	24
250 mcg/m2	IV	yes	12	19
	SC	yes	12	17

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 the phereses. Phereses were 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 median time to ANC>500/mm³ was 12 days and to platelet recovery (>25,000/mm³) was 23 days.

Survival studies comparing mobilized study patients to the nonmobilized patients and to an autologous historical bone marrow transplant group showed no differences in median survival time.

Autologous Bone Marrow Transplantation

Following a dose-ranging Phase I/II trial in patients undergoing autologous BMT for lymphoid malignancies,^{8, 9} three single center, randomized, placebo-controlled and double-blinded studies were conducted to evaluate the safety and efficacy of LEUKINE for promoting hematopoietic reconstitution following autologous BMT. A total of 128 patients (65 LEUKINE, 63 placebo) were enrolled in these three studies. The majority of the patients had lymphoid malignancy (87 NHL, 17 ALL), 23 patients had Hodgkin's disease, and one patient had acute myeloblastic leukemia (AML). In 72 patients with NHL or ALL, the bone marrow harvest was purged prior to storage with one of several monoclonal antibodies. 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 (n=44 and 47) significantly improved the following hematologic and clinical endpoints: time to neutrophil engraftment, duration of hospitalization and infection experience or antibacterial usage. In the third study (n=37) 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's disease who had also received extensive radiation and chemotherapy prior to harvest of autologous bone marrow. A subgroup analysis of the data from all three studies revealed that the median time to engraftment for patients with Hodgkin's disease, regardless of treatment, was six days longer when compared to patients with NHL and ALL, but that the overall beneficial LEUKINE treatment effect was the same. In the following combined analysis of the three studies, these two subgroups (NHL and ALL vs. Hodgkin's disease) are presented separately.

Table 3

Autologous BMT: Combined Analysis from Placebo-Controlled Clinical Trials of Responses in Patients with NHL and ALL Median Values (days)
	ANC ≥500/mm3	ANC ≥1000/mm3	Duration of Hospitalization	Duration of Infection	Duration of Antibacterial Therapy
Note: The single AML patient was not included.
LEUKINE (n=54)	18 1 2	24	25	1	21
Placebo (n=50)	24	32	31	4	25

DOSAGE AND ADMINISTRATION

Neutrophil Recovery Following Chemotherapy in Acute Myelogenous Leukemia

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 <5% blasts. If a second cycle of induction chemotherapy is necessary, LEUKINE should be administered approximately four days after the completion of chemotherapy if the bone marrow is hypoplastic with <5% blasts. LEUKINE should be continued until an ANC >1500 cells/mm³ for 3 consecutive days or a maximum of 42 days. LEUKINE should be discontinued immediately if leukemic regrowth occurs. If a severe adverse reaction occurs, the dose can be reduced by 50% or temporarily discontinued until the reaction abates.

In order to avoid potential complications of excessive leukocytosis (WBC > 50,000 cells/mm³ or ANC > 20,000 cells/mm³) a CBC with differential is recommended twice per week during LEUKINE therapy. LEUKINE treatment should be interrupted or the dose reduced by half if the ANC exceeds 20,000 cells/mm³.

Mobilization of Peripheral Blood Progenitor Cells

The recommended dose is 250 mcg/m²/day administered IV over 24 hours or SC once daily. Dosing should 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 by day 5 and performed daily until protocol specified targets were achieved (see CLINICAL EXPERIENCE, Mobilization and Engraftment of PBPC). If WBC > 50,000 cells/mm³, the LEUKINE dose should be reduced by 50%. If adequate numbers of progenitor cells are not collected, other mobilization therapy should be considered.

Post Peripheral Blood Progenitor Cell Transplantation

The recommended dose is 250 mcg/m²/day administered IV over 24 hours or SC once daily beginning immediately following infusion of progenitor cells and continuing until an ANC>1500 cells/mm³ for three consecutive days is attained.

Myeloid Reconstitution After Autologous or Allogeneic Bone Marrow Transplantation

The recommended dose is 250 mcg/m²/day administered IV 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. Patients should not receive LEUKINE until the post marrow infusion ANC is less than 500 cells/mm³. LEUKINE should be continued until an ANC >1500 cells/mm³ for three consecutive days is attained. If a severe adverse reaction occurs, the dose can be reduced by 50% or temporarily discontinued until the reaction abates. LEUKINE should be discontinued immediately if blast cells appear or disease progression occurs.

In order to avoid potential complications of excessive leukocytosis (WBC > 50,000 cells/mm³, ANC > 20,000 cells/mm³) a CBC with differential is recommended twice per week during LEUKINE therapy. LEUKINE treatment should be interrupted or the dose reduced by 50% if the ANC exceeds 20,000 cells/mm³.

Bone Marrow Transplantation Failure or Engraftment Delay

The recommended dose is 250 mcg/m²/day for 14 days as a 2-hour IV infusion. The dose can be repeated after 7 days off therapy if engraftment has not occurred. If engraftment 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. If a severe adverse reaction occurs, the dose can be reduced by 50% or temporarily discontinued until the reaction abates. LEUKINE should be discontinued immediately if blast cells appear or disease progression occurs.

In order to avoid potential complications of excessive leukocytosis (WBC > 50,000 cells/mm³, ANC > 20,000 cells/mm³) a CBC with differential is recommended twice per week during LEUKINE therapy. LEUKINE treatment should be interrupted or the dose reduced by half if the ANC exceeds 20,000 cells/mm³.

Preparation of LEUKINE

1. Liquid LEUKINE is formulated as a sterile, preserved (1.1% benzyl alcohol), injectable solution (500 mcg/mL) in a vial. Lyophilized LEUKINE is a sterile, white, preservative-free powder (250 mcg) that requires reconstitution with 1 mL Sterile Water for Injection, USP, or 1 mL Bacteriostatic Water for Injection, USP.
2. Liquid LEUKINE may be stored for up to 20 days at 2–8°C once the vial has been entered. Discard any remaining solution after 20 days.
3. Lyophilized LEUKINE (250 mcg) should be reconstituted aseptically with 1.0 mL of diluent (see below). The contents of vials reconstituted with different diluents should not be mixed together.
   Sterile Water for Injection, USP (without preservative): Lyophilized LEUKINE vials contain no antibacterial preservative, and therefore solutions prepared with Sterile Water for Injection, USP should be administered as soon as possible, and within 6 hours following reconstitution and/or dilution for IV infusion. The vial should not be re-entered or reused. Do not save any unused portion for administration more than 6 hours following reconstitution. Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol): Reconstituted solutions prepared with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) may be stored for up to 20 days at 2–8°C prior to use. Discard reconstituted solution after 20 days. Previously reconstituted solutions mixed with freshly reconstituted solutions must be administered within 6 hours following mixing. Preparations containing benzyl alcohol (including liquid LEUKINE and lyophilized LEUKINE reconstituted with Bacteriostatic Water for Injection) should not be used in neonates (see WARNINGS).
4. During reconstitution of lyophilized LEUKINE the diluent should be directed at the side of the vial and the contents gently swirled to avoid foaming during dissolution. Avoid excessive or vigorous agitation; do not shake.
5. LEUKINE should be used for SC injection without further dilution. Dilution for IV infusion should be performed in 0.9% Sodium Chloride Injection, USP. If the final concentration of LEUKINE is below 10 mcg/mL, Albumin (Human) at a final concentration of 0.1% should be added to the saline prior to addition of LEUKINE to prevent adsorption to the components of the drug delivery system. To obtain a final concentration of 0.1% Albumin (Human), add 1 mg Albumin (Human) per 1 mL 0.9% Sodium Chloride Injection, USP (e.g., use 1 mL 5% Albumin [Human] in 50 mL 0.9% Sodium Chloride Injection, USP).
6. An in-line membrane filter should NOT be used for intravenous infusion of LEUKINE.
7. Store liquid LEUKINE and reconstituted lyophilized LEUKINE solutions under refrigeration at 2–8°C (36–46°F); DO NOT FREEZE.
8. In the absence of compatibility and stability information, no other medication should be added to infusion solutions containing LEUKINE. Use only 0.9% Sodium Chloride Injection, USP to prepare IV infusion solutions.
9. Aseptic technique should be employed in the preparation of all LEUKINE solutions. To assure correct concentration following reconstitution, care should be exercised to eliminate any air bubbles from the needle hub of the syringe used to prepare the diluent. 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.

HOW SUPPLIED

Liquid LEUKINE is available in vials containing 500 mcg/mL (2.8 × 10⁶ IU/mL) sargramostim. Lyophilized LEUKINE is available in vials containing 250 mcg (1.4 × 10⁶ IU/vial) sargramostim.

Each dosage form is supplied as follows:

Lyophilized LEUKINE

Carton of five vials of lyophilized LEUKINE 250 mcg                     (NDC 0024-5843-05)

Liquid LEUKINE

Carton of one multiple-use vial; each vial contains 1 mL of preserved 500 mcg/mL liquid LEUKINE (NDC 0024-5844-01)
Carton of five multiple-use vials; each vial contains 1 mL of preserved 500 mcg/mL liquid LEUKINE (NDC 0024-5844-05)

STORAGE

LEUKINE should be refrigerated at 2–8°C (36–46°F). Do not freeze or shake. Do not use beyond the expiration date printed on the vial.