Palifermin for the reduction of acute GVHD: a randomized, double-blind, placebo-controlled trial

Abstract

This prospective, randomized, double-blind, placebo-controlled study evaluated the efficacy of palifermin to reduce the incidence of severe (grade 3 --4) acute GVHD after myeloablation and allo-SCT. Adults who received allo-SCT for hematologic malignancies received placebo or palifermin 60 mg/kg daily on three consecutive days before conditioning and a single dose of 180 mg/kg after conditioning, but often 1 or 2 days before allo-SCT. Subjects received MTX (plus CYA or tacrolimus) on days 1, 3, 6 and 11. Acute GVHD was evaluated once weekly and oral mucositis was evaluated daily. Subjects were randomly assigned to placebo (n ¼ 78) or palifermin (n ¼ 77). Conditioning included TBI in approximately half of the subjects (48% placebo, 51% palifermin). The primary efficacy end point, subject incidence of grade 3 --4 acute GVHD, was similar between treatment groups (17% placebo, 16% palifermin). Grade 3 --4 oral mucositis (73% placebo, 81% palifermin) and other secondary efficacy end points were similar between treatment groups. The most commonly reported treatment-related adverse events were skin/s.c. events such as rash, pruritus, and erythema. This exploratory study of acute GVHD after myeloablation and allo-SCT did not provide evidence of a treatment effect with this dosing regimen of palifermin. Keywords: hematopoietic cell transplantation; GVHD; palifermin; MTX INTRODUCTION Allo-SCT is the treatment of choice for a variety of hematological malignancies. 1 Although the use of reduced intensity conditioning regimens has increased, myeloablative regimens continue to be a standard of care for young patients. About 35 --50% of allo-SCT recipients develop grade 2 --4 acute GVHD, with a higher incidence after unrelated donor transplants and mismatched donor transplants compared with HLA-identical sibling donor transplants. 2 Oral mucositis with ulceration (World Health Organization (WHO) grade 2 --4) occurs in approximately 75% of patients receiving myeloablative regimens. 3 Prophylaxis with a MTX-and calcineurin inhibitor-based regimen is effective in reducing GVHD, 4 but worsens mucositis in many patients. 5 Keratinocyte growth factor appears to modulate the endogenous response to epithelial injury. In animal studies, recombinant human Keratinocyte growth factor (palifermin) reduced GVHD and inhibited rejection of allo-SCT. 6 --8 Palifermin was shown to decrease the incidence and duration of severe oral mucositis in patients who received TBI-based conditioning therapy and autologous SCT. 9 The approved dose of palifermin for reduction of severe oral mucositis is 60 mg/kg daily by i.v. bolus injections for 3 days before and 3 days after an myeloablative regimen and SCT.Prior studies evaluated the efficacy and safety of palifermin to reduce GVHD either with this dose, or with a collapsed 180 mg/kg dose 1 day before the start of the myeloablative regimen and 60 mg/kg daily for at least 3 days after the end of the myeloablative regimen. 10 --13 Because MTX is dosed 1, 3, 6 and 11 days after allo-SCT and the interaction ...

Preclinical models of acute and chronic graft-versus-host disease: how predictive are they for a successful clinical translation?

“…64 The drug palifermin did not reduce aGVHD in patients, but it did reduce the need for parenteral nutrition after TBI. 65,66 The concept of enhancing epithelial regeneration via stimulation of intestinal stem cells, eg, via R-spondin-1 67 is still actively investigated and may have the advantage of sparing GVL effects as donor T cells are not blocked.…”

CD34+ selection and the severity of oropharyngeal mucositis in total body irradiation-based allogeneic stem cell transplantation

“…However, its efficacy in non-TBI based myeloablative conditioning is controversial. [1,9,22] Palifermin does not offer a survival benefit and does not impact the incidence of acute or chronic GVHD. Another major drawback with the use of Palifermin is the cost associated with its use.…”

Clinical applications of palifermin: amelioration of oral mucositis and other potential indications

“…More recently, Jagasia et al conducted a randomized, doubleblind, placebo-controlled study to explore the potential of palifermin to reduce the incidence of severe acute GVHD in patients undergoing allo-HSCT for haematological malignancies from either a related donor or an HLA-matched, unrelated donor [69]. Patients received placebo or palifermin 60 mcg/kg on three consecutive days before the conditioning regimen (six different options, including ones with CT alone and others that combined CT with TBI) and a single dose of 180 mcg/kg after conditioning, but often 1-2 days before allo-HSCT.…”