Leucomax

Use Following Induction Chemotherapy In Acute Myelogenous Leukemia

Leucomax 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 Leucomax 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 FrenchAmerican-British (FAB) system of classification.

Use In Mobilization And Following Transplantation Of Autologous Peripheral Blood Progenitor Cells

Leucomax 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 Leucomax following peripheral blood progenitor cell transplantation.

Use In Myeloid Reconstitution After Autologous Bone Marrow Transplantation

Leucomax is indicated for acceleration of myeloid recovery in patients with nonHodgkin'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, Leucomax 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 Leucomax 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

Leucomax is indicated for acceleration of myeloid recovery in patients undergoing allogeneic BMT from HLA-matched related donors. Leucomax 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

Leucomax is indicated in patients who have undergone allogeneic or autologous bone marrow transplantation (BMT) in whom engraftment is delayed or has failed. Leucomax 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 Leucomax can be detected by complete blood count (CBC) with differential performed twice per week.

Clinical Experience

Acute Myelogenous Leukemia

The safety and efficacy of Leucomax 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 Leucomax 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, Leucomax (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. Leucomax 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.

Leucomax 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 Leucomax 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; Leucomax 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

During the consolidation phase of treatment, Leucomax 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 Leucomax. During induction or consolidation, 27 of 52 patients receiving Leucomax and 35 of 47 patients receiving placebo had at least one grade 3, 4 or 5 infection (p=0.02). Twenty-five patients receiving Leucomax and 30 patients receiving placebo experienced severe and fatal infections during induction only. There were significantly fewer deaths from infectious causes in the Leucomax 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 Leucomax. The proportion of patients achieving complete remission (CR) was higher in the Leucomax 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 Leucomax 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 Leucomax and 268 days for those on placebo (p=0.17). The study was not sized to assess the impact of Leucomax 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 Leucomax 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 Leucomax. The cohorts differed by dose (125 or 250 mcg/m²/day), route (IV over 24 hours or SC) and use of Leucomax 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 Leucomax; 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 Leucomax (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 CFU-GM/kg for all Leucomax-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 Leucomax 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 Leucomax following PBPC transplantation with Leucomax-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

A second retrospective review of data from patients undergoing PBPC at another single transplant center was also conducted. Leucomax 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 Leucomax 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 Leucomax 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 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 Leucomax for promoting hematopoietic reconstitution following autologous BMT. A total of 128 patients (65 Leucomax, 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 Leucomax 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 Leucomax. 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 Leucomax 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)

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 Leucomax 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 Leucomax 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 Leucomax. The median duration of antibacterial administration in the post-transplantation period was four days shorter for the patients treated with Leucomax 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 Leucomax derived less benefit than NHL subjects. However, both the leukemic and NHL groups receiving Leucomax 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. Leucomax-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 Leucomax for promoting hematopoietic reconstitution following allogeneic BMT. A total of 109 patients (53 Leucomax, 56 placebo) were enrolled in the study. Twenty-three patients (11 Leucomax, 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-versushost 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 Leucomax 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)

Median time to myeloid engraftment (ANC ≥ 500 cells/mm³) in 53 patients receiving Leucomax 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 Leucomax 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 Leucomax group (4/53) compared to the placebo group (16/56) at p<0.05.

Leucomax-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 Leucomax 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 Leucomax 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 nonHodgkin'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 Leucomax 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 Leucomax after autologous failure was 474 days versus 161 days for the historical patients. Similarly, after allogeneic failure, the median survival was 97 days with Leucomax 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 Leucomax 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)

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.

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, Leucomax should be administered approximately four days after the completion of chemotherapy if the bone marrow is hypoplastic with <5% blasts. Leucomax should be continued until an ANC >1500 cells/mm³ for 3 consecutive days or a maximum of 42 days. Leucomax 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 Leucomax therapy. Leucomax 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 Leucomax 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 Leucomax until the post marrow infusion ANC is less than 500 cells/mm³. Leucomax 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. Leucomax 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 Leucomax therapy. Leucomax 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. Leucomax 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 Leucomax therapy. Leucomax treatment should be interrupted or the dose reduced by half if the ANC exceeds 20,000 cells/mm³.

Preparation Of Leucomax

1. Liquid Leucomax is formulated as a sterile, preserved (1.1% benzyl alcohol), injectable solution (500 mcg/mL) in a vial. Lyophilized Leucomax 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 Leucomax 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 Leucomax (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 Leucomax 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 Leucomax and lyophilized Leucomax reconstituted with Bacteriostatic Water for Injection) should not be used in neonates (see WARNINGS).
4. During reconstitution of lyophilized Leucomax 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. Leucomax 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 Leucomax is below 10 mcg/mL, Albumin (Human) at a final concentration of 0.1% should be added to the saline prior to addition of Leucomax 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 Leucomax.
7. Store liquid Leucomax and reconstituted lyophilized Leucomax 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 Leucomax. Use only 0.9% Sodium Chloride Injection, USP to prepare IV infusion solutions.
9. Aseptic technique should be employed in the preparation of all Leucomax 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.

Leucomax is contraindicated:

1. in patients with excessive leukemic myeloid blasts in the bone marrow or peripheral blood (≥ 10%);
2. in patients with known hypersensitivity to GM-CSF, yeast-derived products or any component of the product
3. for concomitant use with chemotherapy and radiotherapy.

Due to the potential sensitivity of rapidly dividing hematopoietic progenitor cells, Leucomax should not be administered simultaneously with cytotoxic chemotherapy or radiotherapy or within 24 hours preceding or following chemotherapy or radiotherapy. In one controlled study, patients with small cell lung cancer received Leucomax and concurrent thoracic radiotherapy and chemotherapy or the identical radiotherapy and chemotherapy without Leucomax. The patients randomized to Leucomax had significantly higher incidence of adverse events, including higher mortality and a higher incidence of grade 3 and 4 infections and grade 3 and 4 thrombocytopenia.¹¹

REFERENCES

11. Bunn P, Crowley J, Kelly K, et al. Chemoradiotherapy with or without granulocytemacrophage colony-stimulating factor in the treatment of limited-stage small-cell lung cancer: a prospective phase III randomized study of the southwest oncology group. JCO 1995; 13(7):1632-1641.

WARNINGS

Pediatric Use

Benzyl alcohol is a constituent of liquid Leucomax and Bacteriostatic Water for Injection diluent. Benzyl alcohol has been reported to be associated with a fatal "Gasping Syndrome" in premature infants. Liquid solutions containing benzyl alcohol (including liquid Leucomax) or lyophilized Leucomax reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) should not be administered to neonates (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Fluid Retention

Edema, capillary leak syndrome, pleural and/or pericardial effusion have been reported in patients after Leucomax administration. In 156 patients enrolled in placebo-controlled studies using Leucomax at a dose of 250 mcg/m²/day by 2-hour IV infusion, the reported incidences of fluid retention (Leucomax 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 Leucomax, the incidence is estimated to be less than 1%. In patients with preexisting pleural and pericardial effusions, administration of Leucomax may aggravate fluid retention; however, fluid retention associated with or worsened by Leucomax has been reversible after interruption or dose reduction of Leucomax with or without diuretic therapy. Leucomax should be used with caution in patients with preexisting fluid retention, pulmonary infiltrates or congestive heart failure.

Respiratory Symptoms

Sequestration of granulocytes in the pulmonary circulation has been documented following Leucomax infusion¹² and dyspnea has been reported occasionally in patients treated with Leucomax. Special attention should be given to respiratory symptoms during or immediately following Leucomax infusion, especially in patients with preexisting lung disease. In patients displaying dyspnea during Leucomax administration, the rate of infusion should be reduced by half. If respiratory symptoms worsen despite infusion rate reduction, the infusion should be discontinued. Subsequent IV infusions may be administered following the standard dose schedule with careful monitoring. Leucomax should be administered with caution in patients with hypoxia.

Cardiovascular Symptoms

Occasional transient supraventricular arrhythmia has been reported in uncontrolled studies during Leucomax administration, particularly in patients with a previous history of cardiac arrhythmia. However, these arrhythmias have been reversible after discontinuation of Leucomax. Leucomax should be used with caution in patients with preexisting cardiac disease.

Renal And Hepatic Dysfunction

In some patients with preexisting renal or hepatic dysfunction enrolled in uncontrolled clinical trials, administration of Leucomax has induced elevation of serum creatinine or bilirubin and hepatic enzymes. Dose reduction or interruption of Leucomax administration has resulted in a decrease to pretreatment values. However, in controlled clinical trials the incidences of renal and hepatic dysfunction were comparable between Leucomax (250 mcg/m²/day by 2-hour IV infusion) and placebo-treated patients. Monitoring of renal and hepatic function in patients displaying renal or hepatic dysfunction prior to initiation of treatment is recommended at least every other week during Leucomax administration.

PRECAUTIONS

General

Parenteral administration of recombinant proteins should be attended by appropriate precautions in case an allergic or untoward reaction occurs. Serious allergic or anaphylactic reactions have been reported. If any serious allergic or anaphylactic reaction occurs, Leucomax therapy should immediately be discontinued and appropriate therapy initiated.

A syndrome characterized by respiratory distress, hypoxia, flushing, hypotension, syncope, and/or tachycardia has been reported following the first administration of Leucomax 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.

Stimulation of marrow precursors with Leucomax may result in a rapid rise in white blood cell (WBC) count. If the ANC exceeds 20,000 cells/mm³ or if the platelet count exceeds 500,000/mm³, Leucomax administration should be interrupted or the dose reduced by half. The decision to reduce the dose or interrupt treatment should be based on the clinical condition of the patient. Excessive blood counts have returned to normal or baseline levels within three to seven days following cessation of Leucomax therapy. Twice weekly monitoring of CBC with differential (including examination for the presence of blast cells) should be performed to preclude development of excessive counts.

Growth Factor Potential

Leucomax is a growth factor that primarily stimulates normal myeloid precursors. However, the possibility that Leucomax 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.

Should disease progression be detected during Leucomax treatment, Leucomax therapy should be discontinued.

Leucomax has been administered to patients with myelodysplastic syndromes (MDS) in uncontrolled studies without evidence of increased relapse rates.^{13, 14, 15} Controlled studies have not been performed in patients with MDS.

Use In Patients Receiving Purged Bone Marrow

Leucomax is effective in accelerating myeloid recovery in patients receiving bone marrow purged by anti-B lymphocyte monoclonal antibodies. Data obtained from uncontrolled studies suggest that if in vitro marrow purging with chemical agents causes a significant decrease in the number of responsive hematopoietic progenitors, the patient may not respond to Leucomax. When the bone marrow purging process preserves a sufficient number of progenitors (>1.2 x 10⁴/kg), a beneficial effect of Leucomax on myeloid engraftment has been reported.¹⁶

Use In Patients Previously Exposed To Intensive Chemotherapy/Radiotherapy

In patients who before autologous BMT, have received extensive radiotherapy to hematopoietic sites for the treatment of primary disease in the abdomen or chest, or have been exposed to multiple myelotoxic agents (alkylating agents, anthracycline antibiotics and antimetabolites), the effect of Leucomax on myeloid reconstitution may be limited.

Use In Patients With Malignancy Undergoing Leucomax-Mobilized PBPC Collection

When using Leucomax to mobilize PBPC, the limited in vitro data suggest that tumor cells may be released and reinfused into the patient in the leukapheresis product. The effect of reinfusion of tumor cells has not been well studied and the data are inconclusive.

Immunogenicity

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

Laboratory Monitoring

Leucomax can induce variable increases in WBC and/or platelet counts. In order to avoid potential complications of excessive leukocytosis (WBC >50,000 cells/mm³; ANC >20,000 cells/mm³), a CBC is recommended twice per week during Leucomax therapy. Monitoring of renal and hepatic function in patients displaying renal or hepatic dysfunction prior to initiation of treatment is recommended at least biweekly during Leucomax administration. Body weight and hydration status should be carefully monitored during Leucomax administration.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Animal studies have not been conducted with Leucomax to evaluate the carcinogenic potential or the effect on fertility.

Pregnancy (Category C)

Animal reproduction studies have not been conducted with Leucomax. It is not known whether Leucomax can cause fetal harm when administered to a pregnant woman or can affect reproductive capability. Leucomax should be given to a pregnant woman only if clearly needed.

Nursing Mothers

It is not known whether Leucomax is excreted in human milk. Because many drugs are excreted in human milk, Leucomax should be administered to a nursing woman only if clearly needed.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established; however, available safety data indicate that Leucomax does not exhibit any greater toxicity in pediatric patients than in adults. A total of 124 pediatric subjects between the ages of 4 months and 18 years have been treated with Leucomax in clinical trials at doses ranging from 60-1,000 mcg/m²/day intravenously and 4-1,500 mcg/m²/day subcutaneously. In 53 pediatric patients enrolled in controlled studies at a dose of 250 mcg/m²/day by 2-hour IV infusion, the type and frequency of adverse events were comparable to those reported for the adult population. Liquid solutions containing benzyl alcohol (including liquid Leucomax) or lyophilized Leucomax reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) should not be administered to neonates (see WARNINGS).

Geriatric Use

In the clinical trials, experience in older patients (age ≥65 years), was limited to the acute myelogenous leukemia (AML) study. Of the 52 patients treated with Leucomax in this randomized study, 22 patients were age 65-70 years and 30 patients were age 55-64 years. The number of placebo patients in each age group were 13 and 33 patients respectively. This was not an adequate database from which determination of differences in efficacy endpoints or safety assessments could be reliably made and this clinical study was not designed to evaluate difference between these two age groups. Analyses of general trends in safety and efficacy were undertaken and demonstrate similar patterns for older (65-70 yrs) vs younger patients (55-64 yrs). Greater sensitivity of some older individuals cannot be ruled out.

REFERENCES

12. Herrmann F, Schulz G, Lindemann A, et al. Yeast-expressed granulocytemacrophage colony-stimulating factor in cancer patients: A phase Ib clinical study. In Behring Institute Research Communications, Colony Stimulating Factors-CSF. International Symposium, Garmisch-Partenkirchen, West Germany. 1988; 83:107-118.

13. Estey EH, Dixon D, Kantarjian H, et al. Treatment of poor-prognosis, newly diagnosed acute myeloid leukemia with Ara-C and recombinant human granulocytemacrophage colony-stimulating factor. Blood 1990; 75(9):1766-1769.

14. Vadhan-Raj S, Keating M, LeMaistre A, et al. Effects of recombinant human granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndromes. NEJM 1987; 317:1545-1552.

15. Buchner T, Hiddemann W, Koenigsmann M, et al. Recombinant human granulocytemacrophage colony stimulating factor after chemotherapy in patients with acute myeloid leukemia at higher age or after relapse. Blood 1991; 78(5):1190-1197.

16. Blazar BR, Kersey JH, McGlave PB, et al. In vivo administration of recombinant human granulocyte/macrophage colony-stimulating factor in acute lymphoblastic leukemia patients receiving purged autografts. Blood 1989; 73(3):849-857.

Autologous And Allogeneic Bone Marrow Transplantation

Leucomax is generally well tolerated. In three placebo-controlled studies enrolling a total of 156 patients after autologous BMT or peripheral blood progenitor cell transplantation, events reported in at least 10% of patients who received IV Leucomax or placebo were as reported in Table 6.

Table 6: Percent of AuBMT Patients Reporting Events

No significant differences were observed between Leucomax and placebo-treated patients in the type or frequency of laboratory abnormalities, including renal and hepatic parameters. In some patients with preexisting renal or hepatic dysfunction enrolled in uncontrolled clinical trials, administration of Leucomax has induced elevation of serum creatinine or bilirubin and hepatic enzymes (see WARNINGS). In addition, there was no significant difference in relapse rate and 24 month survival between the Leucomax and placebo-treated patients.

In the placebo-controlled trial of 109 patients after allogeneic BMT, events reported in at least 10% of patients who received IV Leucomax or placebo were as reported in Table 7.

Table 7: Percent of Allogeneic BMT Patients Reporting Events

There were no significant differences in the incidence or severity of GVHD, relapse rates and survival between the Leucomax and placebo-treated patients. Adverse events observed for the patients treated with Leucomax in the historically-controlled BMT failure study were similar to those reported in the placebo-controlled studies. In addition, headache (26%), pericardial effusion (25%), arthralgia (21%) and myalgia (18%) were also reported in patients treated with Leucomax in the graft failure study.

In uncontrolled Phase I/II studies with Leucomax in 215 patients, the most frequent adverse events were fever, asthenia, headache, bone pain, chills and myalgia. These systemic events were generally mild or moderate and were usually prevented or reversed by the administration of analgesics and antipyretics such as acetaminophen. In these uncontrolled trials, other infrequent events reported were dyspnea, peripheral edema, and rash.

Reports of events occurring with marketed Leucomax include arrhythmia, fainting, eosinophilia, dizziness, hypotension, injection site reactions, pain (including abdominal, back, chest, and joint pain), tachycardia, thrombosis, and transient liver function abnormalities.

In patients with preexisting edema, capillary leak syndrome, pleural and/or pericardial effusion, administration of Leucomax may aggravate fluid retention (see WARNINGS). Body weight and hydration status should be carefully monitored during Leucomax administration.

Adverse events observed in pediatric patients in controlled studies were comparable to those observed in adult patients.

Acute Myelogenous Leukemia

Adverse events reported in at least 10% of patients who received Leucomax or placebo were as reported in Table 8.

Table 8: Percent of AML Patients Reporting Events

Nearly all patients reported leukopenia, thrombocytopenia and anemia. The frequency and type of adverse events observed following induction were similar between Leucomax and placebo groups. The only significant difference in the rates of these adverse events was an increase in skin associated events in the Leucomax group (p=0.002). No significant differences were observed in laboratory results, renal or hepatic toxicity. No significant differences were observed between the Leucomax and placebo-treated patients for adverse events following consolidation. There was no significant difference in response rate or relapse rate.

In a historically-controlled study of 86 patients with acute myelogenous leukemia (AML), the Leucomax treated group exhibited an increased incidence of weight gain (p=0.007), low serum proteins and prolonged prothrombin time (p=0.02) when compared to the control group. Two Leucomax treated patients had progressive increase in circulating monocytes and promonocytes and blasts in the marrow which reversed when Leucomax was discontinued. The historical control group exhibited an increased incidence of cardiac events (p=0.018), liver function abnormalities (p=0.008), and neurocortical hemorrhagic events (p=0.025).¹⁵

Immunogenicity

As with all therapeutic proteins, there is the potential for immunogenicity with Leucomax. 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 Leucomax by continuous IV infusion (3 patients) or subcutaneous 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 Leucomax 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, with normal hematopoiesis and no other immunosuppressive drugs, receiving Leucomax daily for 8 weeks by subcutaneous 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 Leucomax was given for an extended period, 53 patients with melanoma in complete remission (an unapproved use) received adjuvant therapy with Leucomax 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 antisargramostim 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 antisargramostim 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 Leucomax by day 155 as assessed by white blood cell counts This study provided limited assessment of the impact of antibody formation on the safety and efficacy of Leucomax.

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

The maximum amount of Leucomax that can be safely administered in single or multiple doses has not been determined. Doses up to 100 mcg/kg/day (4,000 mcg/m²/day or 16 times the recommended dose) were administered to four patients in a Phase I uncontrolled clinical study by continuous IV infusion for 7 to 18 days. Increases in WBC up to 200,000 cells/mm³ were observed. Adverse events reported were dyspnea, malaise, nausea, fever, rash, sinus tachycardia, headache and chills. All these events were reversible after discontinuation of Leucomax.

In case of overdosage, Leucomax therapy should be discontinued and the patient carefully monitored for WBC increase and respiratory symptoms.

To report SUSPECTED ADVERSE REACTIONS, contact Genzyme Corporation at 1-8884RX-Leucomax or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch