Bone Marrow Transplantation (2003) 31, 1–10 & 2003 Nature Publishing Group All rights reserved 0268-3369/03 $25.00 www.nature.com/bmt Mini review Mucosal injury in patients undergoing hematopoietic progenitor cell transplantation: new approaches to prophylaxis and treatment

J Filicko1, HM Lazarus2 and N Flomenberg1

1Hematologic Malignancies, Blood & Marrow Transplant Program, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA, USA;and 2Department of Medicine, Comprehensive Cancer Center of the Uiversity Hospitals of Cleveland/ Case Western Reserve University, Cleveland, OH, USA

Summary: problems, including ileus and possibly addiction in the long term. Gastrointestinal toxicity has also been associated Hematopoietic progenitor cell transplantation is often with a delay in neutrophil recovery3 and a longer duration associated with severe mucosal toxicity. The need for of parenteral nutritional support. parenteral analgesics and parenteral nutrition are evi- Each preparative regimen used in HPCT is associated dence of the severity of the problem in individual patients. with its own specific side effects. Patients develop varying However, the increased riskfor systemic infection related levels of mucosal injury based on the choice of preparative to bacteremia associated with the breakdown of mucosal regimen; however, all myeloablative preparatory regimens barriers is a significant cause of morbidity and mortality are associated with some degree of mucosal toxicity.2 It is as well. There is a multitude of grading scales, telling that grade III–IV mucositis has become a very demonstrating the lackof consensus among clinicians in common side effect in the HPCT field to the extent that 90– this area. Multiple agents have been used prophylactically 100% of patients in some recent studies develop this and therapeutically to address mucositis. While efforts problem with the associated need for parenteral nutrition have been less successful in the past, the advent of newer and parenteral analgesia, and regimens may still be agents including amifostine, keratinocyte growth factor, considered ‘well tolerated’.4,5 Unfortunately, progress in transforming growth factor beta and interleukin-11 developing newer agents has been hampered by the lack of provides hope that this toxicity will be significantly good preclinical models. While there are murine and decreased in the near future. hamster models of mucosal toxicity and multiple animal Bone Marrow Transplantation (2003) 31, 1–10. models of allogeneic HPCT, none are truly valid models of doi:10.1038/sj.bmt.1703776 the mucosal toxicity usually associated with HPCT. Thus, Keywords: stem cell transplant; mucositis; amifostine; our understanding of the pathophysiology of the problem, keratinocyte growth factor; transforming growth factor beta and attempts at alleviating it have been hampered. There appear to be two major events leading to symptomatic mucositis in HPCT patients.6 The first is direct mucosal Hematopoietic progenitor cell transplantation (HPCT) is injury, which can be related to toxic injury from commonly associated with significant morbidity from , or radiation therapy or to local infections. injury to the gastrointestinal mucosa.1 Oral mucositis This is exacerbated by the cytopenias associated with usually occurs between 2 and 18 days following HPCT.2 HPCT. While clinical evidence of injury is usually not seen The high turnover rate of mucosal epithelial cells renders until 3–4 days after the onset of the preparative regimen, this tissue highly vulnerable to direct toxic injury from the actual damage starts at the time the first stomatoxic chemotherapy and radiation. Damaged mucosa leads to agent is given. Many different agents are known to cause significant morbidity and impaired quality of life related to injury and the most commonly by used in HPCT are listed oral mucositis and diarrhea. Additionally, derangements in in Table 1. These include chemotherapy and radiation used immune mechanisms, including secretion of toxic cytokines in the preparative regimens and that is and prolonged neutropenia contribute to the severity of commonly used for GVHD prophylaxis. Each agent tissue damage and duration of mucositis. While severe oral individually may predispose to mucosal injury. Combina- pain is often the most obvious and troublesome symptom tion therapy, while adding to the effectiveness of the to patients undergoing HPCT, gastrointestinal toxicity is preparative regimens also adds to the toxicity. also associated with more life-threatening morbidity and Following disruption of the basal cell layer of the mortality.3 Prolonged narcotic use may lead to significant mucosal epithelium, local cytokines are released 7 including interleukin-1 and tumor necrosis factor alpha (TNF-a), leading to futher damage. Following direct injury, a second Correspondence:Dr J Filicko, Hematologic Malignancies, Blood & 6 Marrow Transplant Program, Jefferson Medical College, Thomas phase has been described during which aerobic and Jefferson University, 125 South 9th Street, 801 Sheridan Building, anaerobic bacteria cause local infections and may lead to Philadelphia, PA 19107, USA systemic infection in up to 75% of HPCT patients. This Mucositis in the HPCT setting J Filicko et al 2 Table 1 Agents commonly used in HPCT associated with mucositis

Agent Common total dose (in combination therapy) 10–16 mg/kg 1.8–2.1 g/m2 60–600 mg/m2 100–150 mg/kg 800–3600 mg/m2 625–300 mg/m2 Ifosphamide 16–20 g/m2 80–140 mg/m2 180–200 mg/m2 (as a single agent) Mitoxantone 50–90 mg/m2 500–1200 mg/m2

Methotrexate (for GVHD prophylaxis) 15 mg/m2on day +1, followed by 10 mg/m2on days +3, +6 and +11.

Total body irradiation 9–15 Gy

phase is complicated by the development of neutropenia infections by a variety of organisms, as discussed above. and the use of systemic broad spectrum antibiotics (which Viral infections, particularly those in the herpes family, and may lead to the development of resistant organisms). An fungal superinfection may further complicate the picture increased risk of bacterial infections has been associated and lead to increased morbidity and mortality. with more severe mucositis in several studies.3,8 In a study of 202 patients, Rapoport et al 3 found that mucositis was significantly more severe in recipients of marrow grafts Mucosal toxicity grading scales compared with peripheral blood stem cell grafts, in recipients of unrelated donor or matched sibling graft Discussions about mucosal injury are hampered by a lack compared with autologous grafts or who carried a of consistency among investigators when describing toxi- diagnosis of acute leukemia or myelodysplasia. Similar city. Grading scales vary among institutions. The most results were obtained when the duration of parenteral commonly used is that of the World Health Organization12 nutrition support was used as the measure of gastrointest- (see Table 2), which is similar to that of the National inal toxicity, but prolonged neutropenia also contributed Cancer Institute and the cooperative oncology groups when this analysis was used. In this study, higher peak (ECOG, SWOG, CALGB).13,14 These scales are simple and mucositis scores and prolonged use of parenteral nutrition easily applied, but variability among graders is common. both correlated with the occurrence of bacteremias and Other grading systems, including the Oral Mucosal transplant-related mortality. While 60% of patients with Assessment Scale15 and the University of Nebraska Oral moderate to severe mucositis developed positive blood Assessment Scale16 are more detailed and may be more cultures, only 30% of patients with less severe mucositis reproducible. In the late 1980s,17,18 a grading system developed this complication. Alpha hemolytic streptococcal specific for patients undergoing bone marrow transplanta- infections in this setting are related to mucosal injury, tion was published. Commonly known as the ‘Bearman particularly oral mucositis, and can be problematic.9 Criteria,’ it provides a grading scale from 1 to 3 for all Neutropenic enterocolitis and associated enteric Gram- major organs, including the oral mucosa, which may be negative infections are likewise related to mucosal injury in affected following HPCT. While the Bearman criteria have the lower gastrointestinal tract, and represent a significant limitations, they have held up well in HPCT studies. More cause of morbidity and mortality in the post-transplant recently,15 a newer scoring system – the Oral Mucosal setting.10 The combination of infectious complications and Assessment Score – was developed and validated in a large- pain with the consequent need for antibiotics, other scale study. A panel of experts including nurses, dental supportive care for sepsis, parenteral narcotics, and hygienists, physicians and dentists agreed on a grading parenteral nutrition result in increased length of hospital scheme based on a consensus of mucositis indicators. stay and increased cost.1 Indicators were either primary (ulceration, pseudomem- In his recent report ‘Oral Health in America’,11 the US brane formation, erythema in specific sites within the Surgeon General commented on oral mucositis as a dose- mouth) or secondary (oral pain, swallowing and the ability limiting side effect of several anticancer agents, including 5- to eat as assessed by the patient). It has been validated in fluorouracil, methotrexate and . Radiation, several large-scale studies with high interobserver consis- including both radiation delivered for patients with head tency and scores that demonstrated good correlation with and neck malignancies and total body irradiation asso- symptoms. It is, however, more cumbersome and time ciated with HPCT, may be associated with systemic consuming for the clinician who scores the mucosal complications, particularly in patients with periodontal pathology. The University of Nebraska Oral Assessment disease. While ulceration of gingival epithelium may not be Score16 takes into consideration not only the appearance of directly observed, it represents a source for disseminated the oral mucosa and swallowing function, but also voice

Bone Marrow Transplantation Mucositis in the HPCT setting J Filicko et al 3 Table 2 Grading scales

Scale designation Primary scoring focus Criteria for peak toxicity World Health Organization Mucositis Scale Focuses on oral intake Grade IV toxicity based on requirement for parenteral nutrition NCI Common Toxicity Criteria for HPCT Focuses on ability to swallow Grade IV toxicity based on requirement for Studies prophylactic intubation or aspiration pneumonia Bearman Toxicity Criteria Focuses on need for narcotics Grade III toxicity based on requirement for prophylactic intubation or aspiration pneumonia University of Nebraska Oral Focuses on phonation, swallowing Grade III toxicity based on composite of eight Assessment Score and anatomic changes individual assessments Oral Mucositis Assessment Scale Focuses on anatomic changes Toxicity based on composite score of 18 different assessments (nine anatomic sites, each with two assessments)

Table 3 Oral factors

Agent Mechanism of action Summary Oral cryotherapy (ice chips) Decreases blood flow and exposure to chemotherapy Studies primarily with 5-FU rather than BMT; decreases local toxicity in the mouth, but not throughout the GI tract Chlorhexidine Antimicrobial Prophylaxis and treatment; not found to be effective Oral decontamination Antimicrobial k dysphagia, weight loss and oral yeast infections; no effect on systemic infections Glutamine Improved nitrogen balance and wound healing Oral glutamine – not effective. Parenteral glutamine (in parenteral nutrition) – mixed results Pentoxifylline k TNF-a Mixed results GM-CSF m keratinocyte growth, proliferation of endothelial Topical formulation – mixed results. Intravenous – cells and wound healing not effective Sucralfate Barrier k severe mucositis Keratinocyte growth factor m keratinocyte growth and epithelial hyperplasia k grade III/IV mucositis Iseganan Antimicrobial k severity of mucositis, oral pan and swallowing dysfunction Immunol oral rinse Antimicrobial, anti-inflammatory, downregulation k ulceration and duration of mucositis of PGE2 Interleukin-11 k TNF-a, IL-12 and IFN-g Trend towards k mucositis Amifostine free radical scavenger k mucositis Transforming growth factor-b k epithelial cell growth preclinical work is promising; ongoing studies Laser therapy m fibroblast transformation into myofibroblasts k severity of mucositis and diarrhea

quality, lips, saliva and teeth assessment. Other grading therapy. It has been recommended that all patients undergo systems include the Western Consortium for Cancer a pretransplant oral examination by a qualified dentist Nursing Research (WCCNR) Staging System and the Oral prior to embarking on this course.20 Assessment Guide (OAG).19 Unfortunately, the multitude of grading scales, although attempting to provide for uniformity, often provide confusion in interpreting the Oral cryotherapy toxicities associated with a particular therapy. Grade 0 is understood as ‘normal’ to all investigators. However, the Decreasing blood flow to oral mucosa should also serve to severity of grade 2 or 3 toxicity is quite variable from one decrease mucosa exposure to the drug. Therefore, it is scoring system to the next. As reflected in the multiplicity of assumed that oral cryotherapy will, through vasoconstric- grading schemes, no single system has emerged which is tion, decrease the toxicity of agents associated with consistently applied in clinical trials. mucosal damage. When used with agents with short half- Thus, the need for prevention or early intervention is lives, such as 5-fluoruracil (5-FU) and melphalan, this obvious. As noted above,11 the Surgeon General has made should be particularly efficacious. This has been studied oral health a priority. He has included patients receiving most consistently with 5-FU, but could be applied more chemotherapy and those undergoing HPCT. As investiga- broadly. Mahood et al 21 randomized 95 patients to receive tors learn more about the pathophysiology of mucosal a short course of cryotherapy during 5-FU and leucovorin damage in this setting, newer approaches and agents will be therapy. Patients who were randomized to receive therapy developed. These are described in further detail below and were asked to suck on ice chips for 30 min, starting 5 min in Table 3, and include both attempts at prophylaxis and prior to a 5-FU infusion. During a second cycle of 5-FU treatment. In addition, efforts must be made to understand and leucovorin, patients who had previously received no each individual patient’s risk prior to undergo high-dose therapy were asked to use cryotherapy, whereas those who

Bone Marrow Transplantation Mucositis in the HPCT setting J Filicko et al 4 had used the ice chips for the first cycle then received no of the pastilles in this patient group. Given the decrease in therapy. Mucosal toxicity, as graded by patients, and dysphagia and oral yeast infections described by Sy- duration of mucositis, was significantly decreased during monds,25 it is possible that patients at particularly high cycles when patients received cryotherapy. Subsequently, risk for theses complications, including HPCT recipients Cascinu et al22 performed a similar study in 84 patients with receiving radiation therapy or particularly stomatoxic similar results in terms of oral mucositis. Toxicity was the therapy, may benefit. Further studies in this patient group same in both studies and limited primarily to the ‘ice cream are warranted. headache’ sensation associated with the ice chips. However, Several different rinses have been used to prevent or treat while mucosal toxicity was significantly improved in terms mucosal injury. These are frequently favorite remedies of of pain control, other side effects of chemotherapy the treating clinician, rather than products which have including diarrhea, nausea and emesis did not differ. Roche undergone vigorous testing. Often they are remedies passed et al 23 examined cryotherapy for 30 min vs 60 min and found on from patient to patient. Recently, Dodd et al 27 looked at that there was no advantage in prolonging cryotherapy past three of the more commonly used regimens in a randomized the 30 min mark. Interesting observations from the three clinical trial. Adult patients undergoing ‘stomatoxic’ studies include a trend towards more mucositis in older therapy who developed mucositis were invited to partici- patients, but less in cigarette smokers. pate in the study. Patients undergoing induction therapy for acute leukemia, HPCT or patients with acquired immune deficiency syndrome were excluded. All patients Chlorhexidine received instruction regarding good oral hygiene as part of the PRO-SELF Mouth Aware Program and all patients Chlorhexidine is a broad-spectrum topical antimicrobial undertook 12 days of mouth rinses four times daily. that has been effective in preventing gingivitis and oral Patients were randomized to one of three rinses:chlorhex- infection. Mouth rinses with chlorhexidine have been used idine gluconate mouthwash (0.12%), ‘Magic Mouthwash’ in many transplant centers as part of ‘standard of care’ for (viscous lidocaine – 0.5%, 5 ml + diphenhydramine many years. However, in a randomized study of 100 hydrochloride – 0.0312%, 0.25 ml + aluminum hydroxide patients,24 chlorhexidine use resulted in a trend towards suspension 14.75 ml), or ‘salt and soda’ mouth wash (1 improved oral hygiene and oral candidiasis, but there was teaspoon of salt and 1 teaspoon of sodium bicarbonate per no distinct therapeutic advantage of chlorhexidine over pint of water). There was no benefit provided by any of the placebo in reducing mucositis, oral pain, or oral (re) three rinses beyond that provided by the use of a systematic infection with herpes simplex virus. oral hygiene program.

Oral decontamination Glutamine Other attempts have been made at oral decontamination Multiple studies have been performed to assess the effects both in patients undergoing HPCT and those undergoing of oral or intravenous glutamine on chemotherapy induced other therapies with a high incidence of mucositis. For mucositis. Glutamine is the most abundant amino acid in example, Symonds et al 25 studied 275 patients undergoing plasma and is reduced significantly in plasma and tissue radiation therapy for head and neck malignancies. Patients during sepsis or nutritional depletion. Its role in maintain- were randomized to receive an antibiotic pastille (poly- ing gastrointestinal integrity has been described pre- myxin E 2 mg, tobramycin 1.8 mg, and amphotericin B viously.28 Both animal models and human trials have 10 mg) or placebo four times a day from the start of demonstrated an increased glutamine requirement during radiation through the resolution of radiation induced certain catabolic states.29 While the intravenous formula- symptoms. There was a beneficial effect for patients tion has provided little benefit, oral glutamine has been receiving the antibiotic pastilles in terms of functional found to be effective in reducing bacteremia and mucositis consequences of mucosal injury, including dysphagia and associated with methotrexate administration.30 Studies of weight loss. There was also a striking decrease in the low-dose oral glutamine (2 g amino acid/m2 b.i.d) in number of oral yeast infections, but no difference in the patients receiving standard doses of -based oral carriage of Gram-negative rods. A similar study, by chemotherapy regimens have shown a decrease in both Okumo et al,26 also looked at the use of these pastilles in severity and duration of oral mucositis.31 There has been a comparison to chlorhexidine or placebo mouth rinses. mixed response to glutamine supplementation in HPCT Patients who were receiving radiation therapy that involved patients. While one study suggested decreased ulceration, at least one-third of the oral cavity were randomized to pain and oral bleeding in patients who received oral receive one of the three therapies four times daily. The arms glutamine,32 these findings did not reach statistical sig- of the study that included chlorhexidine and placebo mouth nificance. Other studies33,34 have not shown a consistent rinses were closed early when the chlorhexidine was found benefit. However, given the trends which have been noted, to be detrimental. The study continued with a randomiza- additional studies are ongoing, including combination tion between a placebo lozenge and the antibiotic lozenge. therapy with glutamine and other agents. There have been There were no difference in the mucositis scores or in the at least 20 randomized controlled clinical trials of incidence or duration of radiation therapy interruptions. glutamine in parenteral nutrition in adults or children. Patients may have found some relief in symptoms, but there Most indicate some benefit from supplemental glutamine. was no significant difference to warrant recommending use Adding supplemental glutamine to parenteral nutrition in

Bone Marrow Transplantation Mucositis in the HPCT setting J Filicko et al 5 recipients of HPCT has led to increased glutamine levels of GM-CSF to wounds results in improved wound and improved nitrogen balance without any adverse side healing.40–42 Results of trials with patients suffering from effects. It has been associated with improved number of mucositis following high-dose chemotherapy have been circulating lymphocytes and attenuation of extracellular mixed. Several trials have looked at the use of intravenous fluid. However, there have been mixed results in terms of GM-CSF in this setting. Nemunaitis et al43 reported on 109 effects on diarrhea and mucositis. Oral glutamine has patients who were randomized to receive either 250 mg/m2/ generally not been beneficial. However, in one study, day or placebo. He found that patients receiving GM-CSF Anderson et al35 did show improved survival on day 28 were less likely to develop Grade III/IV mucositis (8 vs post-HPCT and significantly less mouth pain and narcotic 29%; P ¼ 0.005); however, the overall incidence of muco- use in patients who received oral glutamine. In general, the sitis was no different from one group to another. In a study use of either oral or parenteral glutamine has not been comparing a dose of 125 mg/m2/day continuous intrave- shown to be detrimental. Patients receiving parenteral nous infusion with no growth factor, Gordon et al44 nutrition should have particular attention paid to gluta- reported a shorter duration of mucositis in patients mine supplementation and nitrogen balance. However, receiving GM-CSF (12.2 vs 20.3 days; P ¼ 0.02). However, ongoing studies are needed to further clarify the specific this was only observed in patients who received a role of glutamine therapy in recipients of HPCT. preparative regimen of thiotepa, etoposide and total body irradiation. There was no difference in the severity or Pentoxifylline duration of mucositis when patients received a preparative regimen of thiotepa, etoposide and cyclophosphamide. Several studies have examined the use of pentoxifylline for Conversely, both Legros et al45 and Atkinson et al46 the prevention of not only mucosal injury, but also other reported no reduction in the severity or duration of transplant-related toxicities. Pentoxifylline is a xanthine mucositis when patients received GM-CSF. derivative capable of downregulating TNF-a. In preclinical Other investigators have studied the use of topical GM- models,36 it decreased the production of radiation-induced CSF in gel formulations or mouthwashes. Studies using TNF-a and decreased endotoxin production. In an inter- GM-CSF prophylactically have not shown any benefit.47,48 esting study by Bianco et al,37 pentoxifylline was given to Therapeutic use of GM-CSF mouth washes, starting with patients undergoing HPCT in a dose escalation study first sign or symptom of mucositis, has shown both a (1200, 1600 and 2000 mg/day). A total of 26 patients reduced severity and a decreased duration of mucositis.49,50 underwent allogeneic HPCT and four underwent auto- logous HPCT. Out of 30 patients, 24 received preparative Sucralfate regimens that included total body irradiation and six received preparative regimens that included only che- In a double-blind randomized control of sucralfate for the motherapy. Patients who received pentoxifylline had less prevention of mucositis in patients undergoing HPCT,51 mucositis, less hepatic veno-occlusive disease, less renal severe mucositis was less frequent in patients who received insufficiency, required less parenteral nutrition and were sucralfate (29%) than in those who did not (47%; less likely to develop Xgrade II graft-versus-host disease P ¼ 0.07). Patients who received sucralfate were also less (GVHD). A larger prospective randomized study36 was likely to develop diarrhea (25 vs 53%; P ¼ 0.005). Although conducted in 140 patients who received 1600 mg of sucralfate has been used extensively for esophagitis related pentoxifylline daily (400 mg, four times per day) starting to gastroesophageal reflux disease and has been given in an with the first day of the preparative regimen and continuing attempt to ameliorate the toxicities of radiotherapy and through 100 days following HPCT. A total of 89 patients chemotherapy in patients undergoing standard dose received autologous grafts, while 51 received allogeneic therapy for head and neck cancers, it has not otherwise grafts. In all 62% received preparative regimens that been studied extensively in the HPCT setting. Additional included total body irradiation, while 38% received only studies are needed to investigate this agent, particularly chemotherapy. Patients who received an allogeneic graft with combination therapy. received methotrexate for GVHD prophylaxis on days 1, 3 and 6 following HPCT. While there were no adverse side Keratinocyte growth factors (KGF) effects attributable to the pentoxifylline, there was also no difference in mucositis, veno-occlusive disease, survival, KGF are members of the fibroblast growth factor family, hematologic toxicity, renal toxicity, or septicemia. Thus, which have been shown in preclinical models to protect while pentoxifylline offered some early promise, its use animals from chemotherapy and radiation induced gastro- cannot be advocated outside of a clinical trial setting. intestinal damage.52,53 In a study performed recently in normal monkeys,52 investigators administered repifermin (keratinocyte growth factor 2), either intravenously or GM-CSF subcutaneously daily. Epithelial hyperplasia was found in the buccal mucosa and dorsal tongue of all monkeys, and GM-CSF (sargramostim) has been used in an attempt to esophageal thickening was also noted. The frequency and reduce the severity and duration of mucositis. GM-CSF is degree of hyperplasia was dose-dependent, with monkeys known to stimulate migration and proliferation of en- receiving 200 mg/kg/day IV developing more hyperplasia dothelial cells and to promote keratinocyte growth.38,39 than those who received lower doses. While there were no Preclinical data have shown that topical application gastric changes seen, there was mucosal and goblet cell

Bone Marrow Transplantation Mucositis in the HPCT setting J Filicko et al 6 hyperplasia in the intestine. These changes were greatly throughout the world for treatment of gingivitis. Immunol reduced, or resolved following discontinuation of repifer- oral rinse is a formulation of triclosan in an oral rinse min. In vitro studies of more than a dozen cell lines54 have which has recently been studied in a multicenter, double- not shown any enhanced neoplastic transformation with blind randomized trial to prevent mucositis in patients repifermin. Similarly, subcutaneous injection of repifermin undergoing HPCT.60,61 Patients were randomized to receive in tumor-bearing nude mice did not promote tumor either Immunol or antibiotic containing vehicle rinses four growth.40 times daily from the start of the preparative regimen until In a phase I study conducted in patients with colorectal engraftment or healing of all ulcers. Patients who received cancer,55 patients received KGF by intravenous bolus on preparative regimens containing melphalan, etoposide, days 1–3 followed by 5-fluoruracil and leucovorin on days busulfan or TBI were more likely to develop severe 4–8. All cohorts who had received doses of at least 10 mg/ mucositis. However, in this group, erythema and/or kg/day had decreased grades II–IV mucositis. In a recent ulceration developed in 90.24% of patients in the control phase 2 study in the autologous HPCT setting,56 91 patients arm compared with only 68.89% in the treatment arm. were randomized to receive repifermin or placebo. Re- There was also a significant reduction in the duration of pifermin was administered intravenously for 14 days at mucositis (5.18 vs 7.88 days, P ¼ 0.011). doses ranging from 1 to 50 mg/kg. Preparative regimens were expected to provide at least a 50% incidence of grade Interleukin 11 III or IV mucositis. The Oral Mucosal Assessment Scale was used to grade mucositis. The overall incidence of grade Interleukin-11 (rhIL-11) has been used to treat thrombo- III or IV mucositis was only 38%. Minimal side effects, cytopenia in patients receiving chemotherapy. Several including hyperamylasemia, fever, and infection, occurred investigators62,63 have looked into the use of IL-11 in in similar numbers in patients receiving repifermin or preclinical models and found it to decrease the severity, placebo. frequency and duration of mucositis and to inhibit the KGF may also provide other benefits in the allogeneic release of proinflammatory mediators, leading to decreased HPCT setting. Delayed immune reconstitution following levels of tumor necrosis factor, interleukin 12 and inter- transplant and the associated infectious complications are a feron g. There are less data in humans at present. However, significant cause of morbidity and mortality. Preclinical given that IL-11 has been shown to block Th1 differentia- work has shown KGF to provide protection from thymic tion, by inhibition of IL-12, it was studied in a phase I epithelial cell injury, thereby allowing more rapid immune investigation in patients with psoriasis.64 Patients received recovery.57 Furthermore, in a murine GVHD model, KGF subcutaneous injections of IL-11 in a dose escalation study. was administered from day 3 through day 7 and Out of 12 patients, seven responded with decreased significantly reduced the mortality and severity of the keratinocyte production and decreased cutaneous inflam- GVHD. While GVHD was reduced, the graft-versus- mation. In a recently reported study,65 patients who leukemia effect was not compromised in mice receiving received a preparative regimen of busulfan, melphalan lethal doses of leukemia cells, as evidenced by a prolonged and thiotepa were randomized to receive rhIL-11 or leukemia-free survival.58 placebo daily for 15 days following autologous HPCT. While patients who received rhIL-11 did have other side effects, including infections, sepsis, and veno-occlusive Iseganan disease, there was a trend towards decreasing severity, incidence and duration of oral mucositis in this group. Iseganan is a novel Protegrin-derived antimicrobial peptide preparation (oral solution) which has been studied in patients undergoing high-dose therapy and HPCT. In a Amifostine recent randomized double-blind, placebo-controlled phase Amifostine is an organic thiophosphate prodrug that is 3 trial,59 patients received myeloablative chemotherapy that dephosphorylated in the tissues to its active metabolite was expected to cause at least grade II mucosal toxicity (WR-1065) by membrane-bound alkaline phosphatase. (National Cancer Institute – Common Toxicity Criteria). Differences in the alkaline phosphatase concentration of Patients were followed for the development of infections, normal vs malignant tissues result in greater activation in hospitalizations, and death. These events were more normal tissues,66 resulting in selective cytoprotection. By common in patients with peak stomatitis grades of III or acting as a potent scavenger of free radicals, amifostine has IV than in those with lesser grades of mucosal toxicity (47.4 been shown to protect against the toxicities of both vs 32.9%, P ¼ 0.0145). The Iseganan oral solution was chemotherapy,67–71 and radiotherapy 72–75 in normal cells, found to reduce stomatitis severity, oral pain and swallow- without diminishing the effects of therapy on malignant ing dysfunction. tissues.66 It was originally approved to ameliorate the renal toxicity associated with cis-platin-based chemotherapy Immunol oral rinse regimens. However, it has been shown in various settings to decrease mucosal toxicity associated with both radia- Triclosan is a compound which has demonstrated anti- tion- and chemotherapy-induced injury. Low doses of microbial, anti-inflammatory, analgesic, and anticytotoxic amifostine (200 mg/m2), when given within 30 min prior to properties through downregulation of PGE2 production radiotherapy, can decrease the mucositis which is proble- induced by TNF-a and IL1b in preclinical models. It is used matic in patients being treated for cancers of the head and

Bone Marrow Transplantation Mucositis in the HPCT setting J Filicko et al 7 Table 4 Recommendations for patients undergoing HPCT

Pretransplant oral evaluation by a qualified dentist Good routine oral health maintenance during the peritransplant period (eg PRO-SELF Mouth Aware Program) +/À ‘Salt & Soda’ mouth rinses (to maintain moist mucous membranes) Antifungal prophylaxis (eg nystatin, amphotericin) Antiviral prophylaxis (eg acyclovir, valacyclovir) Analgesics including parenteral narcotics (eg MSO4 by patient-controlled analgesia (PCA) pump) Maintenance of adequate platelet and neutrophil counts Participation in investigational studies of new agents

neck.76 Higher doses (740–910 mg/m2) will decrease toxicity not. Low-energy lasers are known to provide wound related to high dose chemotherapy.77–79 In an ongoing healing, presumably by increasing collagen production study77 using amifostine at a dose of 910 mg/m2, we have stimulating fibroblast transformation into myofibroblasts. been able to escalate the dose of in induction therapy for acute myelogenous leukemia to 23 mg/m2 daily for 3 days. In the HPCT setting,78 patients with various Summary hematologic and non hematologic malignancies have received a dose of 740 mg/m2 prior to treatment with HPCT is based on the concept that dose escalation can escalating doses of melphalan (200-300 mg/m2), with eradicate residual microscopic burdens of malignancy. dose-limiting side effects reached at the 300 mg/m2 dose. Regimen-related toxicity has been reduced by the accelera- Surprisingly, even at 280 and 300 mg/m2, mucosal toxicity tion of hematopoietic recovery and shorter durations of was no worse, and frequently less, than that seen with the neutropenia. In this setting, reducing the incidence and more commonly used 200 mg/m2. severity of other post-transplant toxicities is the next crucial step to making HPCT safer and/or allowing further dose escalation. The multiplicity of agents tested in the hopes Transforming growth factor beta that they might provide protection of the gastrointestinal Transforming Growth Factor Beta 3 (TGF-b3) is one of mucosa attests to the importance of this problem in the the family of growth factors, including TGF-b1, TGF-b2, transplant community. While no single agent has defini- and TGF-b3, which act by arresting or prolonging cell tively demonstrated benefit, a number of agents show cycling in G1, providing potent negative regulation of clinical promise and warrants further trials either as single epithelial and hematopoietic stem cell growth.80 In ham- agents or as combination therapy. Many centers are sters, both topical and submucosal injections of TGF-b3 attempting to adjust current strategies, including the use have been shown to decrease proliferation of oral mucosal of mycophenolate mofetil instead of methotrexate for cells. In hamsters treated with 5-fluorouracil, TGF-b3 GVHD prophylaxis, the use of decreased doses of total decreased the severity and duration of mucositis, leading to body irradiation and the use of nonmyeloablative trans- less weight loss and prolonged survival. Early studies in plant regimens. While there may be promise in such humans have also shown promising results. In a dose endeavors, each has its own risk, including that of graft escalation study,81 11 patients with breast cancer received rejection, relapse or GVHD. Thus, these endeavors are best chemotherapy, with or without stem cell rescue with TGF- suited to investigational studies. b3 mouthwashes four times daily for 4 days starting with Specific recommendations can be made for all patients the first day of chemotherapy. All dose levels (20, 50 and undergoing HPCT (Table 4). These include:pretransplant 100 mg/ml) were well tolerated. Further studies are needed oral evaluation by a qualified dentist, good routine oral to evaluate the efficacy. health maintenance during the peritransplant period, use of appropriate analgesics including parenteral narcotics as necessary, active participation in investigational studies Laser therapy of new agents, and maintenance of adequate platelet An interesting study, using laser therapy, was conducted in and neutrophil counts (as far as possible) to improve patients who received preparative regimens of total body healing. irradiation (2 Gy BID, days À3 through À1) combined with high-dose cyclophosphamide (60 mg/kg, days À5 and À4) or high-dose melphalan (140 mg/kg, day –4) prior to References autologous bone marrow transplant.82 On days À5 through À1, patients also received helium–neon laser (632.8 nm 1 Sonis ST, Oster G, Fuchs H et al. Oral mucositis and the wavelength, power 60 mW) applications to five sites on the clinical and economic outcomes of hematopoietic stem-cell J Clin Oncol oral mucosa, or sham treatments. Oral assessment was transplantation. 2001; 19:2201–2205. 2 Schubert MM, Peterson DE, Lloid ME. Oral complications. performed through day 20 following transplant. Oral In:Thomas KG, Forman Blume SJ (eds). Hematopoietic Stem mucositis including time of onset, peak severity and Cell Transplantation, 2nd edn. Blackwell Science:Malden, duration were reduced in patients who received laser MA, 1999. treatments, as were associated pain, narcotic use, and 3 Rapoport AP, Miller Watelet LF, Linder T et al. Analysis of xerostomia. However, the need for parenteral nutrition was factors that correlate with mucositis in recipients of autologous

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