Hematopoietic stem cell transplantation (HSCT) with high-dose chemo-radiotherapy is frequently used in the treatment of patients with hematologic malignancies. During the conditioning regimen for HSCT (which includes total body irradiation or high dose chemotherapy), and immediately after the transplant, patients may present a variety of symptoms Lauritano et al., 2014. Oral mucositis (OM) as one of symptoms of HSCT, is a common and important adverse effect Filicko et al., 2003Jilani et al., 2014Radtke and Kolesar, 2005 and OM creates in approximately 70–80 % of patients receiving radiation-based conditioning regimens Epstein et al., 2012. The European Group for Blood and Marrow Transplantation (EBMT) Registry reported that there were annually around 23500 transplants including 38% of allogeneic SCT (allo-SCT) and 62% of autologous SCT (auto-SCT) Hołowiecki, 2008. Allo-SCT is a form of immunotherapy and as one of HSCT types has increased survival of patients with relapsed leukemia and high-risk leukemia in remission that graft versus host disease (GVHD) was one of the most important complaints involving vital organs and infections Kolb, 2017. Auto-SCT that is another HSCT type has become a well-established treatment for a variety of cancers Vitale et al., 2014. Severe mucositis may create pain requiring opioid analgesics, a higher risk of infection, total parenteral nutrition, increased hospital charges, and decreased quality of life in the patients Horsley et al., 2007. The incidence of severe OM in patients receiving high-dose myeloablative therapy with HSCT is 70-80% Woo et al., 1993. This incidence in pediatric patients is higher than adults Sonis and Clark, 1991. Palifermin as a recombinant human keratinocyte growth factor was approved in the European Union in October 2005 for prophylactic purpose to prevent severe OM in patients receiving high-dose therapy and auto-HSCT Jilani et al., 2014Czyzewski et al., 2014Kobbe et al., 2010. In patients with hematologic cancer, a palifermin dosage of 60 µg/kg/day (total six doses, three doses before the preparative regimen and three doses after the stem-cell infusion), significantly decreases the incidence and duration of severe OM that this setting has been confirmed by the Food and Drug Administration (FDA) Spielberger et al., 2004Stiff et al., 2006. The aim of this meta-analysis study was to evaluate the efficacy of palifermin on the incidence and severity of OM and acute GVHD after HSCT in hematologic malignancy patients in case-control or matched-control studies.

The search in the databases resulted in 117 studies that out of these studies, 32 studies were eligible for assessment. Out of 32 studies, 22 studies were excluded after searching and reading of full-text that the reasons for excluding have been written in Figure 1 . Therefore, 10 studies were included in meta-analysis study. One study was commentary study that had complete information for meta-analysis.

This meta-analysis study assessed OM and aGVHD after HSCT in the patients undergoing palifermin therapy compared with the control group. The results showed that palifermin had an effect on reducing the incidence of OM, but not aGVHD. The OM is the most disabling factor in patients with HSCT Stiff et al., 2006. A case-control study Nguyen et al., 2015 reported that palifermin associated with a decrease in the severity of OM and duration of overall OM in patients receiving an allo-HSCT with fractionated total body irradiation (TBI) based conditioning. Also, the administration of palifermin during auto-HSCT in children results in a lower incidence of OM Czyzewski et al., 2014, but a case-control in children evaluated that palifermin could not be recommended as a cure for OM (of any grade) due to the variability in the two groups Kobbe et al., 2010. A randomized-controlled trial by Lucchese et al., 2016 showed a significant reduction in pediatric patients with acute lymphocytic leukemia in the incidence of OM grade 3 and 4 in the palifermin group compared with the control group. There was also a decrease in the degree of severity of OM in the palifermin group. Horsley et al., 2007 concluded a significant reduction in the incidence of severe OM in the standard care group compared to the palifermin group (13 versus 48%) and also a higher incidence of severe OM in the standard care group compared to the palifermin group. A placebo-controlled, double-blind, phase ΙΙΙ trial by Spielberger et al., 2004 reported palifermin reduced the duration and severity of OM after intensive chemotherapy and radiotherapy for hematologic malignancies. It has been confirmed that 60 μg/kg/day for 6 doses of palifermin, can effectively reduce the incidence, severity, and duration of OM and its consequences in TBI- and non-TBI based auto- and allografts without negative influence on transplantation Radtke et al., 2005Spielberger et al., 2004Nasilowska-Adamska et al., 2007Horsley et al., 2007Langner et al., 2008Blazar et al., 2006. A case-control study by Vitale et al. (2014) reported that palifermin prescription did not culminate in a statistically significant decrease in the incidence and grade of OM or the supportive care required following myeloablative auto-HSCT.

Tsirigotis et al. (2008) observed a significant decrease in the incidence and severity of OM in patients treated with keratinocyte growth factor. Palifermin might decrease the incidence, severity, and duration of OM in high-dose methotrexate (HD-MTX)-based treatment Schmidt et al., 2008. This meta-analysis of case-control/matched-control studies showed that palifermin reduced significantly the incidence and severity of OM after HSCT in hematologic malignancy patients.

The safety and efficacy profiles of palifermin were assessed by a case-control study on OM and aGVHD in allo-HSCT. There was no significant difference in the incidence of mild or severe aGVHD grades on day 100 after allo-HSCT Langner et al., 2008 that so Nasilowska-Adamska et al. in a non-randomized and matched-control study Nasilowska-Adamska et al. 2011, confirmed prescription of palifermin doesn’t seem to change the incidence and severity of aGVHD, whereas three other studies indicated that the prescription of palifermin decreases the incidence and severity of aGVHD in allo-HSCT Blazar et al., 2006Krijanovski et al., 1999Panoskaltsis-Mortari et al., 1998. The results of a case-control study suggested that the use of palifermin reduces OM and probably aGVHD after HSCT Nasilowska-Adamska et al., 2007. The severity of regimen-induced OM is dependent on the conditioning regimen and not the source of hematopoietic stem cells; thus, the ability of palifermin to reduce the incidence of severe OM in patients with allo-HSCT is not expected to be different than in patients with auto-HSCT Hensley et al., 2008. Sonis et al. (2004) reported that several factors may affect the incidence of mucositis during HSCT. The most important factors are the diagnosis, type of transplant and type of conditioning regimen. This meta-analysis of case-control studies confirmed that the incidence of OM is the same in auto- and allo-HSCT groups and therefore, type of transplant can’t be an important factor in the severity and incidence of OM. Spielberger et al. (2004) stated that in patients with various hematologic cancers, the incidence of severe mucositis was 98% following conditioning with TBI in combination with high-dose etoposide and cyclophosphamide. In contrast, high-dose melphalan was associated with severe mucositis in 20–45% of patients with multiple myeloma Grazziutti et al., 2006Blijlevens et al., 2008. The rate of severe mucositis increased to 80% when the conditioning regimen was augmented with idarubicin and cyclophosphamide Fenk et al., 2005. Two studies Nguyen et al., 2015Cutler et al., 2005 found the patients who received MTX as part of their GVHD prophylaxis regimen were more to develop severe OM (p<0.05). This meta-analysis showed that palifermin was not effective on the incidence and severity of aGVHD after HSCT in hematologic cancer patients in case-control studies that due to paucity of studies about the efficacy of palifermin on aGVHD, this result can not be precise. Palifermin could also reduce infections, a complication that after high-dose chemotherapy and auto-HSCT may affect 60-90% of all cases and that is the cause of deaths in 2-3% of all treated patients Gil et al., 2007Kolbe et al., 1997Mossad et al., 1996. The results of this meta-analysis showed that palifermin was effective on fever (p = 0.01) and not infection (p>0.05). In case-control/matched-control studies, one study confirmed the result of the meta-analysis about fever, but three studies Czyzewski et al., 2014Nasilowska-Adamska et al., 2007Vitale et al., 2014 were disagree with the result. The use of antibiotics given empirically to HSCT recipients can decrease fever thereby lowering the risk of adverse events and the induction of microbial resistance Herbers et al., 2014. Therefore, antibiotics and topical palliative drugs can help the patients to overcome infections and other unwanted events Dazzi et al., 2003Stiff et al., 2001.

In conclusion, although this meta-analysis (the strength: lack of heterogeneity in more analyses) showed that palifermin was associated with reductions in the incidence and severity of OM and also was effective and safe on OM after allo-or auto-HSCT, but did not seem to affect on the incidence and severity of aGVHD, it had several limitations including the numbers of patients in some studies were relatively small; there were variable types of chemotherapy during HSCT in the studies; the age range, the type of HSCT and malignancy were different in the studies. Therefore, due to the above-mentioned limitations and the contradictions of the combined results, studies of large-scale and well-designed with better exposure evaluations are guaranteed to support the findings of our study and create a higher level of evidence.

aGVHD: Acute GVHD

CI: Confidence intervals

FDA: Food and Drug Administration

HD-MTX: High-dose methotrexate

HSCT: Hematopoietic Stem Cell Transplantation

OM: Oral mucositis

OR: Odds ratio

TBI: Total body irradiation

WHO: World Health Organization

Conceptualization: MP MS HRM

Data curation: MR MS

Formal analysis: MR MS

Funding acquisition: MP HRM

Investigation: MP MS

Methodology: MR MS

Project administration: MP HRM

Resources: MR MS

Software: MS

Supervision: MP MR HRM

Validation: MP MR HRM

Visualization: MR MS

Writing – original draft: MS HRM

Writing – review & editing: MR MP MS HRM