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, placebocontrolled, 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 g/kg per day (cohort 1 only) or 60 g/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. (Blood. 2006;108:3216-3222)

Systematic review of cytokines and growth factors for the management of oral mucositis in cancer patients

“…None showed an impact on the occurrence of acute GVHD [28,35,37] or chronic GVHD [90]. The impact on mucositis was not consistent, with one study showing a decrease of oral mucositis only in patients conditioned with cyclophosphamide and TBI, but not in patients receiving a less mucotoxic regimen of busulfan and cyclophosphamide [35]. These findings are in line with a retrospective study on 251 patients published after the cut-off date for this review [91].…”

“…The question whether palifermin reduces GVHD has been addressed in a number of clinical trials of allogeneic HSCT following myeloablative conditioning using cyclophosphamide plus TBI or CT only. None showed an impact on the occurrence of acute GVHD [28,35,37] or chronic GVHD [90]. The impact on mucositis was not consistent, with one study showing a decrease of oral mucositis only in patients conditioned with cyclophosphamide and TBI, but not in patients receiving a less mucotoxic regimen of busulfan and cyclophosphamide [35].…”

“…Evidence on the efficacy of palifermin in autologous HSCT without TBI conditioning is conflicting [28][29][30][31][32][33][34], and these rather small studies did not allow a guideline. In addition, no guideline could be provided for the use of palifermin in the setting of allogeneic HSCT with or without TBI [28,[35][36][37]. No guideline could be provided for the use of palifermin in the setting of CT for solid and hematological tumors [38][39][40][41] due to insufficient evidence, although a single center RCT of 49 patients, using a single dose of palifermin (180 μg/kg) before each cycle of CT prevented mucositis in multicycle CT for sarcoma [41].…”

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

“…Palifermin was associated with reduced incidence and severity of mucositis (measured three times weekly), but only in patients conditioned with fractionated TBI-based regimens. 12 Levine et al 13 reported on the long-term outcomes of this cohort and found no difference between the palifermin and placebo groups in the incidence of chronic GVHD or relapse risk. As shown in some of the prior trials, 11,12 there was no positive impact of palifermin on either grade 2 --4 or grade 3 --4 acute GVHD incidence or severity.…”

“…10 However, another retrospective cohort study showed no effect of palifermin on GVHD in allo-SCT. 11 In a prospective, randomized trial, Blazar et al 12 investigated various dosing regimens of palifermin in allo-SCT and concluded there were no significant differences in acute GVHD incidence, acute GVHD severity, survival or day 100 relapse rates between the palifermin and placebo groups. Palifermin was associated with reduced incidence and severity of mucositis (measured three times weekly), but only in patients conditioned with fractionated TBI-based regimens.…”