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
- 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|
|Mucous membrane disorder||75||78||Peripheral edema||11||7|
|Digestive System||Hemic and Lymphatic System|
|GI disorder||37||47||Urinary tract disorder||14||13|
|GI hemorrhage||27||33||Kidney function abnormal||8||10|
|Liver damage||13||14||CNS disorder||11||16|
|Skin and Appendages|
|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|
|Back pain||9||18||Increased alk. phosphatase||8||14|
|Digestive System||Respiratory System|
|Anorexia||51||57||Hemic and Lymphatic System|
|Skin and Appendages||Hematuria||9||21|
|Bone pain||21||5||Laboratory Abnormalities*|
|Special Senses||Low albumin|
|Eye hemorrhage||11||0||High BUN||23||17|
|Cardiovascular System||Low calcium||2||17|
|*Grade 3 and 4 laboratory abnormalities only. Denominators may vary due to missing laboratory measurements.|
- LEUKINE® (sargramostim) [package insert]. Genzyme Corporation 2009.
- 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.
- 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.
- 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.
- 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.
- 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.
- Data on file. Genzyme Corporation.