Leukine in Allogeneic Bone Marrow Transplantation (AlloBMT)
Leukine®(sargramostim) is indicated for acceleration of myeloid recovery in patients undergoing allogeneic BMT from HLA-matched related donors. Leukine has been found to be safe and effective in accelerating myeloid engraftment, reducing the incidence of bacteremia and other culture positive infections, and shortening the median duration of hospitalization.
Multi-center, randomized, placebo-controlled, and double-blinded study was conducted to evaluate the safety and efficacy of Leukine for promoting hematopoietic reconstitution following allogeneic BMT. A total of 109 patients (53 LEUKINE, 56 placebo) were enrolled in the study. Twenty-three patients (11 LEUKINE, 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. Adverse events occurring in >10% of Allogeneic BMT patients receiving Leukine in controlled clinical trials and reported in a higher frequency than placebo 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).
Neutrophil recovery occurred significantly earlier in the Leukine group1,6
Hematopoietic Cell Recovery
- Leukine patients reached an ANC of ≥500/mm3 4 days earlier than patients in the placebo group: 13 days versus 17 days, respectively (P <.05)
- Leukine patients reached an ANC of ≥1000 /mm3 5 days earlier than patients in the placebo group: 14 days versus 19 days, respectively (P<.05)*
Summary of Infection
Nemunaitis J, et al. Bone Marrow Transplant. 1995.
Leukine decreased the incidence of bacteremias by 50%1
- 9 patients in the Leukine group developed bacteremia versus 19 in the placebo group (P =.043)
Leukine decreased duration of hospitalization1
- 25 days of hospitalization in the Leukine group versus 26 days in the placebo group (P =.02)
- Leukine should be used with caution and monitored in patients with preexisting fluid retention, pulmonary infiltrates, or CHF; respiratory symptoms or disease; cardiac symptoms or disease; and renal or hepatic dysfunction.
| 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. | |||||
References:
- 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.
