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Leukine

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Leukine

CLINICAL PHARMACOLOGY

General

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 multi lineage factor and, in addition to dose-dependent effects on the myelo monocytic lineage, can promote the proliferation of megakaryocytic and erythroid progenitors.1 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.2

In vitro Studies of LEUKINE (sargramostim) in Human 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 LEUKINE (sargramostim) . In vitro exposure of human bone marrow cells to LEUKINE (sargramostim) 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.3 Chemotactic, anti-fungal and anti-parasitic4 activities of granulocytes and monocytes are increased by exposure to LEUKINE (sargramostim) in vitro. LEUKINE (sargramostim) increases the cytotoxicity of monocytes toward certain neoplastic cell lines3 and activates polymorpho nuclear neutrophils to inhibit the growth of tumor cells.

In vivoPrimate Studies of LEUKINE (sargramostim)

Pharmacology/toxicology studies of LEUKINE (sargramostim) were performed in cynomolgus monkeys. An acute toxicity study revealed an absence of treatment-related toxicity following a single IV bolus injection at a dose of 300 mcg/kg. Two subacute studies were performed using IV injection (maximum dose 200 mcg/kg/day x 14 days) and subcutaneous injection (SC) (maximum dose 200 mcg/kg/day x 28 days). No major visceral organ toxicity was documented. Notable histopathology findings included increased cellularity in hematologic organs and heart and lung tissues. A dose-dependent increase in leukocyte count, which consisted primarily of segmented neutrophils, occurred during the dosing period; increases in monocytes, basophils, eosinophils and lymphocytes were also noted. Leukocyte counts decreased to pretreatment values over a 1-2 week recovery period.

Pharmacokinetics

Pharmacokinetic profiles have been analyzed in controlled studies of 24 normal male volunteers. Liquid and lyophilized LEUKINE (sargramostim) , at the recommended dose of 250 mcg/m², have been determined to be bioequivalent based on the statistical evaluation of AUC.5

When LEUKINE (sargramostim) (either liquid or lyophilized) was administered IV over two hours to normal volunteers, the mean beta half-life was approximately 60 minutes. Peak concentrations of GM-CSF were observed in blood samples obtained during or immediately after completion of LEUKINE (sargramostim) infusion. For liquid LEUKINE (sargramostim) , the mean maximum concentration (Cmax) was 5.0 ng/mL, the mean clearance rate was approximately 420 mL/min/m² and the mean AUC (0-inf) was 640 ng/mL•min. Corresponding results for lyophilized LEUKINE (sargramostim) in the same subjects were mean Cmax of 5.4 ng/mL, mean clearance rate of 431 mL/min/m², and mean AUC (0-inf) of 677 ng/mL•min. GM-CSF was last detected in blood samples obtained at three or six hours.

When LEUKINE (sargramostim) (either liquid or lyophilized) was administered SC to normal volunteers, GM-CSF was detected in the serum at 15 minutes, the first sample point. The mean beta half-life was approximately 162 minutes. Peak levels occurred at one to three hours post injection, and LEUKINE (sargramostim) remained detectable for up to six hours after injection. The mean Cmax was 1.5 ng/mL. For liquid LEUKINE (sargramostim) , the mean clearance was 549 mL/min/m² and the mean AUC (0-inf) was 549 ng/mL•min. For lyophilized LEUKINE (sargramostim) , the mean clearance was 529 mL/min/m² and the mean AUC (0-inf) was 501 ng/mL•min.

Clinical Experience

Acute Myelogenous Leukemia

The safety and efficacy of LEUKINE (sargramostim) 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 (sargramostim) 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 (sargramostim) (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 (sargramostim) 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 (sargramostim) 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 (sargramostim) 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 (sargramostim) 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=52*
Median (25%, 75%)
Placebo
n=47
Median (25%, 75%)
p-value**
ANC > 500/m m³ a 13 (11, 16) 17 (13, 25) 0.0 09
ANC > 1000/m m³ b 14 (12, 18) 21 (13, 34) 0.0 03
PLT > 20,0 00/m m³ c 11 (7, 14) 12 (9, > 42) 0.10
RBCd 12 (9, 24) 14 ( 9 , 42) 0.53
* Patients with missing data censored.
a 2 patients on sargramostim and 4 patients on placebo had missing values.
b 2 patients on sargramostim and 3 patients on placebo had missing values.
c 4 patients on placebo had missing values.
d 3 patients on sargramostim and 4 patients on placebo had missing values.
** p=Generalized Wilcoxon

During the consolidation phase of treatment, LEUKINE (sargramostim) 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 (sargramostim) . During induction or consolidation, 27 of 52 patients receiving LEUKINE (sargramostim) 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 (sargramostim) and 30 patients receiving placebo experienced severe and fatal infections during induction only. There were significantly fewer deaths from infectious causes in the LEUKINE (sargramostim) 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 (sargramostim) . The proportion of patients achieving complete remission (CR) was higher in the LEUKINE (sargramostim) 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 (sargramostim) 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 (sargramostim) and 268 days for those on placebo (p=0.17). The study was not sized to assess the impact of LEUKINE (sargramostim) 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 (sargramostim) 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 (sargramostim) . The cohorts differed by dose (125 or 250 mcg/m²/day), route (IV over 24 hours or SC) and use of LEUKINE (sargramostim) 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 x 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 (sargramostim) ; 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 (sargramostim) (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 x 104 CFUGM/ kg for all LEUKINE (sargramostim) -mobilized patients, compared to 0.96 x 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 x 104/kg for patients mobilized with 250 mcg/m² doses of LEUKINE (sargramostim) administered SC vs. 1.63 x 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 (sargramostim) following PBPC transplantation with LEUKINE (sargramostim) -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 250 mcg/m² V I no 21 24
V I 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 (sargramostim) 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 (sargramostim) administration and continued until the targeted MNC count of 9 x 108/kg or CD34+ cell count of 1 x 106/kg was reached. There was no difference in CD34+ cell count in patients receiving LEUKINE (sargramostim) 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 non mobilized patients and to an autologous historical bone marrow transplant group showed no differences in median survival time.

Autologous Bone Marrow Transplantation7

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 (sargramostim) for promoting hematopoietic reconstitution following autologous BMT. A total of 128 patients (65 LEUKINE (sargramostim) , 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 (sargramostim) 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 (sargramostim) . 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 (sargramostim) 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/m m³ ANC ≥ 100 0/mm³ Duration of Hospitalization Duration of Infection Duration of Antibacterial Therapy
LEUKINE (n=54) 18*# 24*# 25* 1* 21*
Placebo (n=50) 24 32 31 4 25
* p < 0.05 Wilcoxon or CMH ridit chi-squared # p < 0.05 Log rank
Note: The single AML patient was not included.

Patients with Lymphoid Malignancy (Non-Hodgkin's Lymphoma and Acute Lymphoblastic Leukemia)

Myeloid engraftment (absolute neutrophil count [ANC] ≥ 500 cells/mm³) in 54 patients receiving LEUKINE (sargramostim) was observed 6 days earlier than in 50 patients treated with placebo (see Table 3). Accelerated myeloid engraftment was associated with significant clinical benefits. The median duration of hospitalization was six days shorter for the LEUKINE (sargramostim) 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 (sargramostim) . The median duration of antibacterial administration in the post-transplantation period was four days shorter for the patients treated with LEUKINE (sargramostim) than for placebo-treated patients. The study was unable to detect a significant difference between the treatment groups in rate of disease relapse 24 months post transplantation. As a group, leukemic subjects receiving LEUKINE (sargramostim) derived less benefit than NHL subjects. However, both the leukemic and NHL groups receiving LEUKINE (sargramostim) engrafted earlier than controls.

Patients with Hodgkin's Disease

If patients with Hodgkin's disease are analyzed separately, a trend toward earlier myeloid engraftment is noted. LEUKINE (sargramostim) treated patients engrafted earlier (by five days) than the placebo treated patients (p=0.189, Wilcoxon) but the number of patients was small (n=22).

Allogeneic Bone Marrow Transplantation

A multi-center, randomized, placebo-controlled, and double-blinded study was conducted to evaluate the safety and efficacy of LEUKINE (sargramostim) for promoting hematopoietic reconstitution following allogeneic BMT. A total of 109 patients (53 LEUKINE (sargramostim) , 56 placebo) were enrolled in the study. Twenty-three patients (11 LEUKINE (sargramostim) , 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 graft-versus-host disease (GVHD) prophylaxis was cyclosporine A and a corticosteroid. Accelerated myeloid engraftment was associated with significant laboratory and clinical benefits. Compared to placebo, administration of LEUKINE (sargramostim) significantly improved the following: time to neutrophil engraftment, duration of hospitalization, number of patients with bacteremia and overall incidence of infection (see Table 4).

Table 4: Allogeneic BMT: Analysis of Data from Placebo-Controlled Clinical Trial

Median Values (days or number of patients)
  ANC ≥ 500/mm³ ANC ≥ 1000/mm³ Number of Patients with Infections Number of Patients with Bacteremia Days of Hospitalization
LEUKINE
( n =53)
13 * 14* 30* 9** 25*
Placebo
( n =56)
17 19 42 19 26
* p < 0.05 generalized Wilcoxon test ** p < 0.05 simple chi-square test

Median time to myeloid engraftment (ANC ≥ 500 cells/mm³) in 53 patients receiving LEUKINE (sargramostim) was 4 four days less than in 56 patients treated with placebo (see Table 4). The number of patients with bacteremia and infection was significantly lower in the LEUKINE (sargramostim) 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 (sargramostim) group (4/53) compared to the placebo group (16/56) at p < 0.05. LEUKINE (sargramostim) -treated patients also had a shorter median duration of post-transplant IV antibiotic infusions, and shorter median number of days to last platelet and RBC transfusions compared to placebo patients, but none of these differences reached statistical significance.

Bone Marrow Transplantation Failure or Engraftment Delay

A historically-controlled study was conducted in patients experiencing graft failure following allogeneic or autologous BMT to determine whether LEUKINE (sargramostim) improved survival after BMT failure.

Three categories of patients were eligible for this study:

  1. patients displaying a delay in engraftment (ANC ≤ 100 cells/mm³ by day 28 post-transplantation);
  2. patients displaying a delay in engraftment (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 engraftment (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 patients from 35 institutions were treated with LEUKINE (sargramostim) 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 non-Hodgkin's lymphoma, 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.

One hundred day survival was improved in favor of the patients treated with LEUKINE (sargramostim) after 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 (sargramostim) 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 (sargramostim) treatment and 35 days for the historical controls. Improvement in survival was better in patients with fewer impaired organs.

The MOF score is a simple clinical and laboratory assessment of seven major organ systems: cardiovascular, respiratory, gastrointestinal, hematologic, renal, hepatic and neurologic.10 Assessment of the MOF score is recommended as an additional method of determining the need to initiate treatment with LEUKINE (sargramostim) in patients with graft failure or delay in engraftment following autologous or allogeneic BMT (see Table 5).

Table 5: 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)

Factors that Contribute to Survival

The probability of survival was relatively greater for patients with any one of the following characteristics: autologous BMT failure or delay in engraftment, exclusion of total body irradiation from the preparative regimen, a non-leukemic malignancy or MOF score ≤ two (zero, one or two dysfunctional organ systems). Leukemic subjects derived less benefit than other subjects.

REFERENCES

1. Metcalf D. The molecular biology and functions of the granulocyte- macrophage colony-stimulating factors. Blood 1986; 67(2):257-267.

2. Park LS, Friend D, Gillis S, Urdal DL. Characterization of the cell surface receptor for human granulocyte/macrophage colony stimulating factor. J Exp Med 1986; 164:251-262.

3. Grabstein KH, Urdal DL, Tushinski RJ, et al. Induction of macrophage tumoricidal activity by granulocyte-macrophage colony-stimulating factors. Science 1986; 232:506-508.

4. Reed SG, Nathan CF, Pihl DL, et al. Recombinant granulocyte/ macrophage colony-stimulating factor activates macrophages to inhibit Trypanosoma cruzi and release hydrogen peroxide. J Exp Med 1987; 166:1734-1746.

5. Data on file Bayer HealthCare Pharmaceuticals.

6. Rowe JM, Andersen JW, Mazza JJ, et al. A randomized placebo controlled phase III study of granulocyte-macrophage colony stimulating factor in adult patients ( > 55 to 70 years of age) with acute myelogenous leukemia: a study of the Eastern Cooperative Oncology Group (E1490). Blood 1995; 86(2):457-462.

7. Nemunaitis J, Rabinowe SN, Singer JW, et al. Recombinant human granulocyte-macrophage colony-stimulating factor after autologous bone marrow transplantation for lymphoid malignancy: Pooled results of a randomized, double-blind, placebo controlled trial. NEJM 1991; 324(25):1773-1778.

8. Nemunaitis J, Singer JW, Buckner CD, et al. Use of recombinant human granulocyte-macrophage colony stimulating factor in autologous bone marrow transplantation for lymphoid malignancies. Blood 1988; 72(2):834-836.

9. Nemunaitis J, Singer JW, Buckner CD, et al. Long-term follow-up of patients who received recombinant human granulocyte- macrophage colony stimulating factor after autologous bone marrow transplantation for lymphoid malignancy. BMT 1991; 7:49-52.

10. Goris RJA, Boekhorst TPA, Nuytinck JKS, et al. Multiple organ failure: Generalized auto-destructive inflammation? Arch Surg 1985; 120:1109-1115.

Last reviewed on RxList: 8/12/2008
This monograph has been modified to include the generic and brand name in many instances.

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