Palifermin is a recombinant keratinocyte growth factor with biologically similar activity to fibroblast growth factor-7 [4]. The mechanism of action of Palifermin appears to involve stimulation of epithelial proliferation, modulation of clonogenic cell death, and alteration of various cytokines [6, 27]. Previous studies have demonstrated the superiority of palifermin to placebo in reducing the severity and duration of OM, oral pain, and the need for parenteral nutrition in HSCT patients receiving chemotherapy with or without TBI [7, 14, 17, 30]. SCPR is an oral rinse with a high concentration of calcium and phosphorus ions. The exact mechanism of action of SCPR is not known. However, it readily diffuses into mucosal tissue and mucositis lesions. Calcium and phosphorus ions are thought to play a major role in intracellular signaling, inflammation, and mucosal repair [19]. SCPR has been shown to lower mean measures of oral toxicity, oral pain, and OM duration compared to controls in HSCT patients receiving TBI and/or chemotherapy-based conditioning [19, 23]. In this study, administration of palifermin resulted in a notable reduction in the prevalence of severe OM compared to SCPR. In addition, the benefit of palifermin appears to be consistent across various subgroups, suggesting that demographic variables, disease variables, and donor type have little influence on the outcome of therapy.
The heterogeneity of the conditioning regimens used in prior studies makes generalization of results difficult, particularly as it relates to comparison of the efficacy of palifermin and SCPR. In contrast, most patients in this study received FBT conditioning. A minority received TBI in combination with other conditioning chemotherapeutic agents at doses known to cause severe mucositis. Therefore, the results of this study can reasonably be applied to patients receiving FBT therapy. Notably, the prevalence of grade 3 and 4 mucositis among patients who received SCPR in this study (100%) is comparable to the previously reported incidence when placebo is used (98%) [30] , which suggests that SCPR is ineffective in preventing OM in this patient population. Interestingly, recently published studies showed that palifermin may have limited efficacy in chemotherapy-induced OM, particularly in high-dose melphalan-induced OM [5, 14]. Our study suggests the efficacy of palifermin in preventing severe OM in patients receiving chemoradiotherapy myeloablative conditioning.
The pathobiology of OM is remarkably complex. It was once thought to be secondary to direct mucosal injury inflicted by cytotoxic therapy [10, 28, 29, 32]. The beneficial effect of cryotherapy in preventing high-dose melphalan-induced OM supports this hypothesis. Cryotherapy results in vasoconstriction, which limits the exposure of the oral mucosa to melphalan and therefore decreases the severity of OM [1, 34]. Recently, a more complex five-phase model was developed to elucidate the pathogenesis of OM [26]. However, this model continues to view OM as a universal outcome regardless of the causative agent. The differential benefit of palifermin in TBI-induced OM but not in melphalan-induced OM suggests a fundamental difference in the pathobiology. Interestingly, the nrf2 pathway has been extensively implicated in radiotherapy-induced mucosal injury [16, 27]. Palifermin is thought to exert its OM prophylactic effect through this pathway, which may explain the superiority of palifermin over SCPR in TBI-induced mucosal injury [6, 27].
Despite advances in treatment and prevention of OM, prediction of who is at risk remains a difficult task. There is a significant gap in the literature on which host, donor, and disease variables alter this risk. In our exploratory multivariable analysis, none of the tested variables proved predictive of development of severe OM, except the type of prophylactic agent employed. A recent study has identified a common deletion polymorphism in the GSTM1 and GSTT1 genes, which results in a lack of glutathione-S-transferase activity and a two-fold increased risk of OM [16, 27]. If replicated, this may present an attractive method to predict the incidence of OM and its severe forms, which may allow clinicians to deploy more aggressive OM preventive measures to those at risk.
The efficacy of palifermin in preventing severe OM is faced with its high cost. According to the Center of Medicare and Medicaid, the cost of 50mcg of palifermin is $21.275. Therefore, the cost of palifermin for a 70kg patient is estimated to be $10,722.6 [8]. A 30 day supply of SCPR has a retail cost of $826.30 [15]. Compared to no prophylaxis, palifermin was associated with favorable economic outcome in a large cost-effectiveness study. After accounting for all costs incurred, palifermin was associated with a non-significant mean cost-saving of $3,595. Moreover, these findings were robust to all plausible values of costs with cost-saving that can reach $5,103 per patient [13]. Nonetheless, whether palifermin will continue to be cost saving and/or cost-effective if compared to SCPR remains uncertain.
Limitations
There are several limitations of this study. Most of our patients received lower dose TBI (400 cGy) than used in most other studies. Nonetheless, the prevalence of grade 3 or 4 OM incurred in our patients was 57%, which is comparable to the incidence of 63% reported with TBI dosing of 1200 cGy [26]. Moreover, the retrospective design of our study and hospital policy-driven selection of OM prophylactic therapy may be susceptible to bias. Prophylactic therapy was administered according to institutional protocols extant during the time under study and was not based on any specific patient, disease, or donor characteristics. Additionally, these results may not be applicable to subjects receiving chemotherapy-only conditioning (without radiotherapy). Finally, our study evaluated the prevalence and severity of OM but not oral pain, analgesic use, use of parenteral nutrition, systemic infection, length of hospital stays or physical and psychological well-being. Yet, these parameters are predominantly influenced by the development of OM, particularly severe grades, which makes our outcome measures reasonable surrogates of these parameters.
In conclusion, this study suggests that palifermin is potentially more effective than SCPR in reducing the severity of OM in HSCT patients receiving TBI-containing myeloablative conditioning therapy. Based on this study and others, palifermin could be considered for OM prophylaxis in HSCT patients receiving myeloablative TBI-containing conditioning. However, further studies are needed to determine the optimal OM prophylactic strategy in TBI-containing and non-TBI-containing conditioning regimens and explore the potential synergistic effect of combination therapy in preventing OM.