Phase 1/2 randomized, placebo-control trial of palifermin to prevent graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT)

Abstract

Palifermin, a recombinant human keratinocyte growth factor, was tested for potential benefits on acute graft-versus-host disease (GVHD) and hematopoietic recovery in allogeneic hematopoietic stem cell transplantation (HSCT) recipients. This randomized, double-blind, placebo-controlled, dose-escalation study assessed the safety and tolerability of palifermin (n = 69) as compared with placebo (n = 31) in patients conditioned with cyclophosphamide and fractionated total-body irradiation (Cy/TBI) or busulfan and cyclophosphamide (Bu/Cy) and given methotrexate along with a calcineurin inhibitor (cyclosporine A, tacrolimus) for GVHD prophylaxis. All patients received 3 doses before conditioning and either 3 (cohort 1), 6 (cohort 2), or 9 (cohort 3) doses after HSCT. Palifermin doses were 40 mug/kg per day (cohort 1 only) or 60 mug/kg per day (all cohorts). Six patients (placebo = 2, palifermin = 4) experienced a total of 11 dose-limiting toxicities (most often skin, respiratory, or oral mucositis). The most common adverse events included edema, infection, skin pain, or rash. Times to neutrophil and platelet engraftment were similar. No significant differences in acute GVHD incidence or severity, survival, or day 100 relapse rates were observed between groups. Palifermin was associated with reduced incidence and mean severity of mucositis in patients conditioned with Cy/TBI but not Bu/Cy. We conclude that palifermin was generally safe in allogeneic HSCTs but had no significant effect on engraftment, acute GVHD, or survival in this trial.

Figure 1.

Study schema. (a) Cy 60 mg/kg per day, TBI total dose 13.2 Gy, fractionated as 165 cGy twice daily for 4 days; (b) busulfan 1 mg/kg per dose given 4 times daily, Cy 60 mg/kg per day; (c) GVHD prophylaxis: cyclosporine A (in the Cy/TBI group) or cyclosporine A or tacrolimus (in the Bu/Cy group) starting day –3 in combination with methotrexate 15 mg/m², IV bolus on day +1 and methotrexate 10 mg/m², IV bolus on days 3, 6, and 11; (d) filgrastim 5 μg/kg per day from 24 hours after transplantation until neutrophil recovery (absolute neutrophil count [ANC], 1 × 10⁹/L for 3 consecutive days, or 10 × 10⁹/L for 1 day, whichever occurred first). K₄₀ indicates palifermin 40 μg/kg per day; K₆₀, palifermin 60 μg/kg per day; P, placebo; Cy, cyclophosphamide; Bu, busulfan; RT, radiotherapy.

Figure 2.

Cumulative incidence of aGVHD grades 2 to 4 and 3 to 4 for placebo and palifermin therapy.

Figure 3.

Cumulative survival according to the Kaplan-Meier method for placebo and palifermin.