Palifermin Injection (KepivanceTM)
By William T. Elliott, MD, FACP, and James Chan, PhD, PharmD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Asst. Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Both are Associate Editors of Internal Medicine Alert.
Amgen has received approval to market palifermin. The drug is approved to decrease the incidence and duration of severe oral mucositis in patients with hematologic malignancies undergoing chemotherapy, with or without radiation, followed by a bone marrow transplant. Palifermin is a protein produced by recombinant DNA technology that is a truncated copy of the keratinocyte growth factor which stimulates proliferation, differentiation, and migration of epithelial cells. Palifermin is marketed as KepivanceTM.
Indications
Palifermin is indicated to decrease the incidence and duration of severe oral mucositis in patients with hematologic malignancies receiving myelotoxic therapy requiring hematologic stem cell support.1
Dosage
The recommended dose is 60 mg/kg/day, given as an intravenous bolus for 3 consecutive days before and 3 consecutive days after myelotoxic therapy. The third dose should be given 24-48 hours before myelotoxic therapy. Administration within 24 hours may increase the severity and duration of oral mucositis.1
Potential Advantages
Palifermin has been shown to reduce the incidence of grade 3 and grade 4 oral mucositis, use of total parenteral nutrition, use of opioid analgesics, incidence of febrile neutropenia, and patient-reported soreness of the mouth and throat.1,2
Potential Disadvantages
Adverse events include rash, pruritus, erythema, mouth and tongue disorders and altered taste.1,2 Palifermin has shown evidence of stimulation of tumors in cell cultures (eg, epithelial tumor cell lines) and animal models of non-hematopoietic human tumors.1
Comments
Palifermin is a truncated version of the endogenous human keratinocyte growth factor (KGF) produced by recombinant DNA technology. Twenty-three amino acids in the N-terminal chain were deleted to improve stability but retain activity.1-3 The KGF receptor is present on epithelial cells including the tongue, the GI tract, salivary gland, lung, liver, pancreas, kidney, bladder, mammary gland, and skin. Efficacy was reported in one published study (n = 212).2 Patients enrolled in this study were scheduled to undergo autologous stem-cell transplantation after receiving fractionated total-body irradiation and high-dose etoposide and high-dose cyclophosphamide for non-Hodgkin’s lymphoma, Hodgkin’s disease, acute myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and multiple myeloma. All patients received filgrastim (G-CSF). Oral mucositis was assessed for 28 days after transplantation. WHO grade 3 was defined as inability to swallow solid food and grade 4 as no form of oral alimentation possible.
Palifermin reduced days of WHO grade 3/4 oral mucositis from a median of 9 days for placebo to 3 days. Incidence of mucostitis vs placebo was 63% vs 98. Grade 4 mucositits was 20% vs 62%. The use of opioid analgesics was reduced from a median of 535 mg of morphine equivalent per day to 212 mg, incidence of total parenteral nutrition was 31% vs 55% for placebo, and incidence of febrile neutropenia 75% vs 92%. There was also a lower score of patient-reported soreness of the mouth and throat. All the above were statistically significant at P < 0.001. Similar reduction in grade 3 and 4 mucositis was reported for a similar study that varied the schedule of palifermin who received the same dose and schedule. Adverse events were generally related to skin and epithelium. These tended to be mild to moderate in severity and occurred approximately 3 days after the last dose, lasting about 3 days.2 Transient elevations of serum amylase and lipase have also been observed.2 The wholesale cost for a 6 doses of palifermin is $8250.
Clinical Implications
Oral mucositis is a common adverse event resulting from radiation as well as chemotherapy. The incidence is estimated to be about 40% with standard chemotherapy and increases with subsequent cycles.4 For patients undergoing bone marrow transplantation who received high dose chemotherapy the incidence is about 76% up to 100%.5 Mucositis with neutropenia increases the risk of life-threatening infections and prolonged hospitalization.6 Palifermin is approved for severe oral mucositis in patient with hematologic cancers receiving myelotoxic chemotherapy and requiring hematopoietic stem cell support. Effective alternatives for these patients are limited.5 Low-level laser therapy is being studies with some encouraging evidence.5
References
1. Kepivance Product Information. Amgen Inc, December 2004.
2. Spielberger R, et al. N Engl J Med. 2004;351: 2590-2598.
3. Rubin JS, et al. Proc Natl Acad Sci. 1989;86:802-806.
4. Naidu MU, et al. Neoplasia. 2004;6(5):423-431.
5. Rubenstein EB, et al. Cancer. 2004;100(9):2026-2045.
6. Peterson DE, Cariello A. Semin Oncol. 2004; 31(3 Suppl 8):35-44.
Amgen has received approval to market palifermin. The drug is approved to decrease the incidence and duration of severe oral mucositis in patients with hematologic malignancies undergoing chemotherapy, with or without radiation, followed by a bone marrow transplant.
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