## 1 Introduction  
Allogeneic hematopoietic stem cell transplantation (aHSCT) is the standard of care for several congenital and acquired disorders of the hematopoietic system. Patients undergoing aHSCT can develop various complications related to transplantation itself (e.g., the conditioning regimen, delayed regeneration of hematopoiesis), a hindered immune response, or treatment toxicity. The gastrointestinal (GI) tract is one of the systems most affected by HSCT complications, especially the oral cavity. Advancements in infection control protocols, pain management modalities and reducing the intensity of conditioning regimens pre-aHST have minimized these complications. However, oral mucositis (OM) has remained the most persistent debilitating and challenging complication of HST [1,2]. OM in patients undergoing aHST has a high incidence and a wide range of effects in 75% to 99% of cases. This wide variation is probably due to the presence of different pre-transplant condition regimens, the presence of patients-related risk factors, the lack of standardized scoring criteria, and the presence of many complications to cancer therapy that may result in underreporting OM [3, 4, 5]. OM is acute inflammation and ulcerative lesions of the oral mucosa, and it is usually caused by cancer therapy [2,6]. The pathophysiology of OM is a complex biological process that can be described in five phases: the initiation, upregulation and/or activation, damage amplification phase, mucosal ulceration, and the healing phase. Proinflammatory cytokines and pathways, reactive oxygen species, and the metabolic byproducts of oral bacteria have been associated with the pathogenesis and aggravation of OM [3,4,7,8]. OM manifests as erythema and/or ulcerations conjugated with pain and difficulty eating, drinking, and talking. Severe OM may have critical clinical sequences, such as hindering normal nutrition, which leads to the need for parenteral nutrition, an increase in the incidence of secondary infections, an increase in systemic analgesic intake, interruption of cancer therapy, and prolongation of hospital stay. These consequences may have a negative impact on the patients' quality of life and cancer prognosis [4,6,9]. Therefore, several interventions and agents have been studied and proposed for the prevention or treatment of OM [10, 11, 12, 13, 14]. Several organizations, such as the American Society of Clinical Oncology (ASCO), the Multinational Association of Supportive Care in Cancer (MASCC), and the National Comprehensive Care Network (NCCN) have evaluated these interventions by carrying out systematic reviews to prepare an evidence-based guideline [15, 16, 17, 18]. Photo-biomodulation (PBM) is one of these evaluated interventions. PBM is the application of light at low power to utilize the effect of light energy on living cells for therapeutic purposes. The absorbed light energy triggers several pathways that eventually result in anti-inflammatory, analgesic, and biomodulatory effects [19, 20, 21]. Many studies have demonstrated the beneficial effect of PBM on the management of OM [22, 23, 24]. In 2014, the MASCC and the International Society of Oral Oncology (ISOO) published an updated clinical practice outline, recommending PBM as a method of preventing OM in patients undergoing HST, with or without total body irradiation (TBI), with a level of evidence II [15]. In addition, recent systematic reviews have demonstrated the effectiveness of prophylactic PBM in reducing the severity and duration of OM [25, 26, 27, 28, 29]. However, heterogeneity in the basic parameters and schedules for PBM application has been observed among previous studies [24, 25, 26, 27, 28]. It is difficult to define an optimal PBM protocol if the precise role and contribution of each parameter of PBM and the complexity of the light-tissue interactions are not fully understood [25].