Important Safety Considerations

Leukine® (sargramostim) is indicated for the following uses: (i) following induction chemotherapy in older adult patients with acute myelogenous leukemia (AML) to shorten time to neutrophil recovery; (ii) for mobilization and following transplantation of autologous peripheral blood progenitor cells; (iii) for myeloid reconstitution after autologous or allogeneic bone marrow transplantation (BMT); (iv) for use in bone marrow transplantation failure or engraftment delay.
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Leukine in Engraftment Delay or Failure

Based on the safety and efficacy demonstrated in the following trial, Leukine® (sargramostim) was approved for autologous and allogeneic bone marrow transplantation failure and engraftment delay. Leukine is the only colony-stimulating factor with this indication.

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. Hematologic response to Leukine can be detected by complete blood count (CBC) with differential performed twice per week.

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

Three categories of patients were eligible for this study:

  • Patients displaying a delay in engraftment (ANC ≤ 100 cells/mm3 by day 28 post-transplantation).
  • Patients displaying a delay in engraftment (ANC ≤ 100 cells/mm3 by day 21 post-transplantation) and who had evidence of an active infection; and
  • 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 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 after graft failure following either autologous or allogeneic BMT. (P <.05)
  • Median survival improved greater than two-fold in the Leukine group (P <.05)
  • Serious allergic or anaphylactic reactions have been reported with Leukine. If any serious allergic or anaphylactic reactions occur, Leukine therapy should be immediately discontinued and appropriate therapy initiated.

The detailed results are provided below.

Median survival in patients receiving Leukine improved greater than two-fold1,7:

Survival Following Engraftment Failure or Delay

 Leukine in Engraftment Delay or Failure

Leukine in Engraftment Delay or Failure

  • AuBMT — Leukine patients had a median survival of 474 days compared with a median survival of only 161 days in the historical control group (P <.05)
  • AlloBMT — Leukine patients had a median survival of 97 days compared with a median survival of only 35 days in the historical control group (P <.05)
  • Improvement in survival was better in patients with fewer impaired organs
  • Edema, capillary leak syndrome, pleural and/or pericardial effusion, supraventricular tachycardia, sequestration of granulocytes in the pulmonary circulation, and dyspnea have been reported in patients after Leukine administration. Leukine has induced the elevation of serum creatinine or billirubin and hepatic enzymes in some patients. Monitoring of renal and hepatic function in patients with preexisting renal or hepatic dysfunction is recommended at least every other week during Leukine administration.

The most marked mobilization and post-transplant effects were seen in patients administered the higher dose of Leukine1:

  • Mobilized patients had fewer days to the last platelet transfusion and last RBC transfusion, and a shorter duration of hospitalization, than did non-mobilized patients
  • Liquid solutions containing benzyl alcohol (including liquid Leukine) or lyophilized Leukine reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) should not be administered to neonates
Percent of AuBMT Patients Reporting Events
Events by Body System LEUKINE (n=79) Placebo (n=77) Events by Body System LEUKINE (n=79) Placebo (n=77)
Body, General     Metabolic, Nutritional Disorder    
Fever 95 96 Edema 34 35
Mucous membrane disorder 75 78 Peripheral edema 11 7
Asthenia 66 51 Respiratory System    
Malaise 57 51 Dyspnea 28 31
Sepsis 11 14 Lung disorder 20 23
Digestive System     Hemic and Lymphatic System    
Nausea 90 96 Blood dyscrasia 25 27
Diarrhea 89 82 Cardiovascular System    
Vomiting 85 90 Hemorrhage 23 30
Anorexia 54 58 Urogenital System    
GI disorder 37 47 Urinary tract disorder 14 13
GI hemorrhage 27 33 Kidney function abnormal 8 10
Stomatitis 24 29 Nervous System    
Liver damage 13 14 CNS disorder 11 16
Skin and Appendages          
Alopecia 73 74      
Rash 44 38      

 

Transplantation of Peripheral Blood Progenitor Cells
Percent of Allogeneic BMT Reporting Events
Events by Body System LEUKINE (n=53) Placebo (n=56) Events by Body System LEUKINE (n=53) Placebo (n=56)
Body, General     Metabolic, Nutritional Disorder    
Fever 77 80 Bilirubinemia 30 27
Abdominal pain 38 23 Hyperglycemia 25 23
Headache 36 36 Peripheral edema 15 21
Chills 25 21 Increased creatinine 15 14
Pain 17 36 Hypomagnesemia 15 9
Asthemia 17 20 Increased SGPT 13 16
Chest pain 15 9 Edema 13 11
Back pain 9 18 Increased alk. phosphatase 8 14
Digestive System     Respiratory System    
Diarrhea 81 66 Pharyngitis 23 13
Nausea 70 60 Epistaxis 17 16
Vomiting 70 57 Dyspnea 15 14
Stomatitis 62 63 Rhinitis 11 14
Anorexia 51 57 Hemic and Lymphatic System    
Dyspensia 17 20 Thrombocytopenia 19 34
Hematamesis 13 7 Leukopenia 17 29
Dysphagia 11 7 Petechia 6 11
GI hemorrhage 11 5 Agranulocytosis 6 11
Constipation 8 11 Urogenital System    
Skin and Appendages     Hematuria 9 21
Rash 70 73 Nervous System    
Alopecia 45 45 Paresthesia 11 13
Pruritis 23 13 Insomnia 6 11
Musculo-skeletal System     Anxiety 11 2
Bone pain 21 5 Laboratory Abnormalities*    
Arthralgia 11 4 High glucose 41 49
Special Senses     Low albumin    
Eye hemorrhage 11 0 High BUN 23 17
Cardiovascular System     Low calcium 2 17
Hypertension 34 32 High cholesterol 17 8
Tachycardia 11 9      
*Grade 3 and 4 laboratory abnormalities only. Denominators may vary due to missing laboratory measurements.
Autologous Bone Marrow Transplantation
References:
  1. LEUKINE® (sargramostim) [package insert]. Genzyme Corporation 2009.
  2. Rowe JM, Rubin A, Mazza JJ, et al. Incidence of infections in adult patients (> 55 years) with acute myeloid leukemia treated with yeast-derived GM-CSF (sargramostim): results of a double-blind prospective study by the Eastern Cooperative Oncology Group. In: Hiddemann W, et al, eds. Acute Leukemias V: Experimental Approaches and Management of Refractory Diseases. Berlin, Germany: Springer-Verlag; 1996:178-184.
  3. Rowe JM. Treatment of acute myeloid leukemia with cytokines: effect on duration of neutropenia and response to infections. Clin Infect Dis. 1998;26:1290-1294.
  4. Rowe JM, Anderson 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;86:457-462.
  5. Nemunaitis J, Rabinowe S, Singer JW, et al. Recombinant granulocyte-macrophage colony-stimulating factor after autologous bone marrow transplantation for lymphoid cancer. N Engl J Med. 1991;324:1773-1778.
  6. Nemunaitis J, Rosenfeld CS, Ash R, et al. Phase III randomized, double-blind placebo-controlled trial of rhGM-CSF following allogeneic bone marrow transplantation.Bone Marrow Transplant. 1995;15:949-954.
  7. Data on file. Genzyme Corporation.

Leukine Resources

Indication

Leukine® (sargramostim) is indicated for the following uses: (i) following induction chemotherapy in older adult patients with acute myelogenous leukemia (AML) to shorten time to neutrophil recovery; (ii) for mobilization and following transplantation of autologous peripheral blood progenitor cells; (iii) for myeloid reconstitution after autologous or allogeneic bone marrow transplantation (BMT); (iv) for use in bone marrow transplantation failure or engraftment delay.

Important Safety Information for Leukine® (sargramostim)

  • Leukine is contraindicated in patients with excessive leukemic myeloid blasts in bone marrow or peripheral blood (≥10%); in patients with known hypersensitivity to GM-CSF, yeast-derived products, orany component of Leukine; and for concomitant use with chemotherapy and radiotherapy.
  • Serious allergic or anaphylactic reactions have been reported with Leukine. If any serious allergic or anaphylactic reactions occur, Leukine therapy should be immediately discontinued and appropriate therapy initiated.
  • Liquid solutions containing benzyl alcohol (including liquid Leukine) or lyophilized Leukine reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) should not be administered to neonates.
  • Leukine should be used with caution and monitored in patients with preexisting fluid retention, pulmonary infiltrates, or congestive heart failure, respiratory symptoms or disease; cardiac symptoms or disease; and renal or hepatic dysfunction.
  • Edema, capillary leak syndrome, pleural and/or pericardial effusion, sequestration of granulocytes in the pulmonary circulation, and dyspnea have been reported in patients after Leukine administration. Occasional transient supraventricular arrhythmia has been reported during Leukine administration. Leukine has induced the elevation of serum creatinine or bilirubin and hepatic enzymes in some patients. Monitoring of renal and hepatic function in patients with preexisting renal or hepatic dysfunction is recommended at least every other week during Leukine administration.
  • Adverse events occurring in >10% of patients receiving Leukine in controlled clinical trials and reported in a higher frequency than placebo were: in AML patients – (fever, skin reactions, metabolic disturbances, nausea, vomiting, weight-loss, edema, anorexia); in Autologous BMT patients – (asthenia, malaise, diarrhea, rash, peripheral edema, urinary tract disorder); and in Allogeneic BMT patients – (abdominal pain, chills, chest pain, diarrhea, nausea, vomiting, hematemesis, dysphagia, GI hemorrhage, pruritus, bone pain, arthralgia, eye hemorrhage, hypertension, tachycardia, bilirubinemia, hyperglycemia, increased creatinine, hypomagnesemia, edema, pharyngitis, epistaxis, dyspnea, insomnia, anxiety, high BUN, and high cholesterol).
  • If ANC > 20,000 cells/mm3 or if platelet counts > 500,000/mm3, Leukine administration should be interrupted or the dose reduced by half. Twice weekly monitoring of CBC with differential should be performed.
  • Leukine therapy should be discontinued if disease progression is detected during treatment.
  • Drugs that can increase WBCs, such as lithium and corticosteroids, should be used with caution while receiving Leukine. Interactions between Leukine and other drugs have not been fully evaluated.

Please see full Prescribing Information.