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Originally published as JCO Early Release 10.1200/JCO.2007.13.6028 on February 11 2008 © 2008 American Society of Clinical Oncology. Prospective Oral Mucositis Audit: Oral Mucositis in Patients Receiving High-Dose Melphalan or BEAM Conditioning Chemotherapy—European Blood and Marrow Transplantation Mucositis Advisory Group
From the Department of Hematology, University Medical Centre St Radboud, Nijmegen; University Hospital Maastricht, Maastricht, the Netherlands; European Center of Pharmaceutical Medicine, University of Basel, Basel; Amgen (Europe) GmbH, Zug, Switzerland; Institute of Hematology and Medical Oncology "L. and A. Seragnoli", Bologna, Italy; Department of Internal Medicine II, University Medical Center Würzburg; Department of Hematology and Oncology, University of Leipzig, Leipzig, Germany; Department of Hematology, Universitaire Ziekenhuizen Leuven, Catholic University, Leuven, Belgium; Bone Marrow Transplantation Unit, Medical University of Vienna, Austria; Karolinska Institute, Inst of Odontology, Huddinge, Huddinge, Sweden; Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland; Nottingham City Hospital National Health Service Trust, Nottingham; Royal Marsden School of Cancer Nursing and Rehabilitation, London, United Kingdom; University Hospital Alej Svobody 80, Plzen, Czech Republic; and St James Hospital, Trinity College, Dublin, Ireland Corresponding author: Nicole Blijlevens, MD, Department of Hematology, University Medical Center St Radboud, PO Box 9101 6500 HB Nijmegen, the Netherlands; e-mail: n.blijlevens{at}hemat.umcn.nl
Purpose The Prospective Oral Mucositis Audit assessed the incidence, duration, and determinants of severe oral mucositis (OM; WHO oral toxicity scale grades 3 to 4) in patients with multiple myeloma (MM) or non-Hodgkin's lymphoma (NHL) receiving high-dose conditioning chemotherapy before autologous stem-cell transplantation. Patients and Methods Patients with MM (n = 109; mean age, 57 ± 8 years) or NHL (n = 88; mean age, 50 ± 13 years) were treated with high-dose melphalan (200 mg/m2) or carmustine 300 mg/m2, etoposide 800 mg/m2, cytarabine 800 to 1,600 mg/m2, and melphalan 140 mg/m2 chemotherapy, respectively, in 25 European centers. OM assessments were made daily until 30 days after transplantation or hospital discharge. High quality of OM assessment was ensured by an intensive training program. Results Severe OM occurred in 46% (95% CI, 36% to 56%) of patients with MM and 42% (95% CI, 32% to 53%) of patients with NHL, with a mean duration of 5.3 days (95% CI, 4.4 to 6.1 days) and 5.5 days (95% CI, 4.5 to 6.7 days), respectively. Time from start of conditioning to peak OM score was 12.1 ± 2.6 and 14.6 ± 2.4 days. Severe OM risk and/or duration was significantly associated with higher chemotherapy dose per kilogram of body weight and poor performance status, but in contrast with some previous reports, this was not related to age. Conclusion Severe OM is more common in the transplantation setting than previously reported, justifying effective preventative and therapeutic measures.
Oral mucositis (OM), a frequent adverse effect of high-dose chemotherapy or radiotherapy followed by hematopoietic stem-cell transplantation (SCT) or bone marrow transplantation (BMT),1-3 results from damage to the epithelial cells lining the oral cavity. Clinical findings range from soreness and mild erythema to painful severe ulceration.4-6 Severe mucositis can impair everyday functioning,7,8 and patients describe OM as the most debilitating adverse effect of cancer treatment.9 Clinical consequences of OM include dehydration, malnutrition, and potentially life-threatening infection10 and possibly reduced long-term survival in patients with lymphoid malignancies undergoing autologous SCT.11 Opioid analgesia, total parenteral nutrition, and prolonged hospitalization increase health care resource costs.12,13 Palifermin (Kepivance; Amgen, Thousand Oaks, CA), a recombinant human keratinocyte growth factor, reduces the incidence and duration of severe OM in patients with hematologic malignancies undergoing autologous SCT after fractionated total-body irradiation plus high-dose chemotherapy.14 Making optimal use of emerging treatment options requires a better understanding of OM. The incidence, severity, and duration of OM vary with the conditioning regimen used,1 but the influence of age, sex, and nutritional status on OM risk is not clearly defined.15 Few studies have addressed conditioning-induced OM as a primary end point,1-3 and its incidence is possibly underestimated.16 Sonis et al16 found OM assessments to be of varying quality and incidence estimates to be variable, reflecting the variety of assessment scales used, lack of standardized assessment rules, and different levels of training. Appropriate training of staff making OM assessments is essential.17,18 The Prospective Oral Mucositis Audit (POMA) aimed to obtain accurate data regarding patterns of OM in European patients with multiple myeloma (MM) or non-Hodgkin's lymphoma (NHL) receiving high-dose conditioning chemotherapy before undergoing autologous SCT. Objectives were to estimate the incidence, severity, and duration of OM; to explore determinants of OM risk; to assess European clinical practice in the prevention and treatment of OM; and to assess health care resource use and patient burden. This report focuses on the first two objectives.
Design This observational audit was conducted in 25 centers across 13 European countries. Treatment was as per normal institutional clinical practice. Ethical approval was obtained according to country-specific requirements.
Patients aged OM assessment was conducted daily from day 1 of conditioning chemotherapy until 30 days after transplantation or hospital discharge (whichever occurred first), using the WHO oral toxicity scale,19 which summarizes OM-related symptoms, signs, and functional disturbances on a five-point global scale16,20: grade 1, soreness and erythema, no further symptoms; grade 2, ulcers present, but solid diet possible; grade 3, only liquids can be swallowed; grade 4, oral alimentation impossible. To achieve high, consistent quality of OM assessment, nurses and physicians underwent multimedia-assisted face-to-face training, which included using a uniform step-by-step algorithm for OM assessment (including evaluation of eight specified oral sites for erythema or ulceration) and case evaluation exercises.21 The primary end point was duration of severe OM (WHO grades 3 to 4). Additional end points included the incidence of severe OM and the incidence and duration of OM by WHO grade. Daily OM assessments also documented bleeding, tongue scalloping, and abnormal salivation. Symptom-specific 10-point scales were used to record pain, mucosal dryness, dysphagia, and taste alteration. Patients answered four questions regarding their symptoms (extent of mouth pain, mucosal dryness, difficulty in swallowing, decreased taste function) using a number from 0 to 10 that best described how they were feeling, with 0 indicating no symptoms present and 10 representing the worst possible symptoms. Data on baseline patient characteristics, type and dosage of conditioning chemotherapy, time to transplantation and engraftment, duration of hospitalization, and the incidence of fever and infection were collected. Medical resource use for OM prevention and treatment was recorded. This included mouthwashes, total parenteral nutrition, opioid analgesics, antibiotics, antifungals, and antivirals; the drugs to be included in these categories were not prospectively defined, and allocation to category was at the center's discretion.
Statistical Methods Data were summarized using descriptive statistics. Exploratory univariate testing and subsequent multivariate logistic and negative binomial regression, using generalized estimation equations–based robust SEs to allow for clustering by study center, were performed to assess protocol-defined predictors of severe OM incidence and duration known at baseline. These included age, sex, weight, height, body-surface area (BSA), Eastern Cooperative Oncology Group (ECOG) performance status, and type and doses of chemotherapy administered (high-dose melphalan v BEAM; doses per kilogram of body weight or per square meters of BSA). The ability of the incidence models to predict severe OM was evaluated by calculating the area under the receiver operating characteristic (ROC) curve. An area under the ROC curve of 1.00 would indicate perfect prediction, whereas a model predicting no better than chance would result in a value of 0.50. Statistical tests were two-sided at the 5% significance level. Two-sided 95% CIs are shown, except where otherwise stated. CI calculation for binary variables assumed a binomial distribution. CI calculation for duration end points (counts) was based on bias-corrected bootstrapping using 1,000 repetitions. Statistical analyses were performed using the STATA version 9 statistical package (STATA Corp, College Station, TX).
Patients A total of 214 patients were enrolled (197 patients were assessable). Seventeen patients were excluded from the analysis because of not having received conditioning chemotherapy (n = 6), minimal data recorded (n = 6), and OM assessments ended more than 10 days before the end of the audit period (n = 5). Mean enrollment per center ± standard deviation (SD) was 7.9 ± 4.8 patients (range, 1 to 18 patients). A total of 109 patients (55.3%) diagnosed with MM and 88 patients (44.7%) with NHL were treated with high-dose melphalan or BEAM, respectively. Two (2%) of the NHL patients were reclassified later as having Hodgkin's lymphoma, but were treated as planned with BEAM and were therefore included in the analysis. Although the WHO scale score at screening was 0 for all included patients, three patients were found to have WHO grade 1 to 2 OM on day 1 of chemotherapy. Mean age was higher and there were fewer women in the MM group. Other parameters were comparable between the two groups (Table 1).
Conditioning Treatment and OM Prophylaxis Actual conditioning chemotherapy doses administered are listed in Table 1. Mean time between the first day of chemotherapy administration and transplantation was 3.4 ± 1.2 days (median, 3 days; range, 2 to 7 days) for patients with MM and 7.6 ± 0.9 days (median, 7 days; range, 6 to 12 days) for patients with NHL. Patients received various types of OM prophylaxis, including mouthwashes (78% of patients), antibiotics (36%), antifungals (54%), and antivirals (44%).
Incidence and Duration of OM
Other, symptom-specific indicators of OM (bleeding, tongue scalloping, abnormal salivation, pain, mucosal dryness, dysphagia, and taste alteration) showed high positive correlations with the WHO scale-based results (data not shown). The imputation procedure for missing WHO scale values and missing values of the pain, mucosal dryness, dysphagia, and taste alteration scores had virtually no impact on these results (data not shown).
Timing of OM
Determinants of Severe OM Incidence Multivariate logistic regression modeling showed severe OM incidence to be positively associated with melphalan dose per kilogram of body weight (patients with MM; P < .001; Fig 3), carmustine dose per kilogram of body weight (patients with NHL; P < .001), and ECOG performance status (P = .013; Table 2). The model had a low pseudo-R squared value of 0.07 and an area under the ROC curve of 0.65, indicating a poor ability to predict severe OM occurrence in individual patients. Similar results were seen when assessing the impact of melphalan or etoposide (instead of carmustine) for the NHL group. Replacing drug doses per kilogram of body weight with drug doses per square meters of BSA also yielded similar results, but female sex emerged as an additional significant covariate in some models. It was noted that body weight per square meters of BSA was 9.4% lower in women than in men (38.0 kg/m2 v 40.4 kg/m2; t test-based P < .001) and that drug doses per kilogram of body weight were higher in persons with lower body weight and BMI (Fig 4). Type of disease (MM or NHL) and age were not statistically significant.
Determinants of Severe OM Duration Multivariate negative binomial regression showed that increased severe OM duration (in those who experienced severe OM only) was positively associated with higher dosage of conditioning chemotherapy per square meters of BSA and higher BSA (Table 2). Chemotherapy dosage per kilogram of body weight and weight were alternative covariates. Using either carmustine dose or melphalan dose in the patients with NHL yielded similar results. The ability to individually predict duration of severe OM remained generally low, and type of disease and age were not significant. A longer time to neutrophil engraftment was also linked with increased OM duration, but this covariate was not used in the baseline models (as values became known retrospectively). Although there were some statistically significant center and country differences, small numbers per center and per country did not allow distinction of artifacts from true differences in OM reporting.
The POMA study is the first multicountry audit of OM occurrence in routine European practice and the first prospective study with OM as the main objective. We studied two uniform cohorts of patients each receiving the same regimens for conditioning. Consistent high-quality OM assessment was achieved by developing a specific training program in close collaboration with physicians, nurses, and dentists within the European Group for Blood and Marrow Transplantation framework.21 Quality controls showed a high level of internal consistency of reported WHO scale grades and ulceration and oral intake ability information.21 Patients received various types of OM prophylaxis, but their efficacy in preventing severe OM is yet to be demonstrated.22 Our data confirm that OM is a substantial clinical problem in patients with MM and NHL receiving high-dose melphalan or BEAM conditioning chemotherapy before undergoing autologous SCT and also yielded detailed information on patterns of OM occurrence. In both disease settings, more than 40% of patients experienced severe (WHO grades 3 to 4) OM episodes with a mean duration of 5 days, and more than 60% experienced ulcerative (WHO grades 2 to 4) OM. On average, the maximum OM grade was reached 13 days after the start of conditioning chemotherapy, consistent with earlier reports.2 Patients with MM, who typically received high-dose melphalan administered within a single day, reached the maximum OM grade earlier than did patients with NHL (receiving BEAM chemotherapy over 6 days). Other symptom-specific indicators of OM were highly correlated with the WHO scale-based results and showed similar temporal distributions. The WHO scale-based clinical assessments also corresponded closely with the patient-reported symptom scores, and patient self-administered questionnaires seem to allow a reliable assessment of OM. Stiff et al23 evaluated an OM questionnaire requiring patients to answer 10 questions evaluating mouth and throat soreness. Comparison of the patient and clinician assessments revealed high correlations between the average daily scores between mucositis grade and mouth and throat soreness measurements. We found higher severe OM incidence rates than previously reported. A recent analysis of clinical trial data found a 36% severe OM risk for patients with MM undergoing SCT.16 Moreau et al24 reported a 31% to 36% risk in patients receiving high-dose melphalan. For patients receiving BEAM regimens, mucositis rates ranged from 15% (severe mucositis only)25 to 27%,26 although there were some differences in dosages used. An incidence of 50% was seen when etoposide dosage was escalated to 1,600 mg/m2.27 The lower OM incidences are most likely explained by an element of under-reporting in trials of cancer treatments where OM was recorded as an adverse event of secondary interest.1 Methodologic issues such as nonuniform assessment and lack of stratification and clear definition of risk factors may partly explain the inconsistent data reported in the literature regarding risk factors for OM.15-17 The type of treatment regimen has been shown to be the main determinant of severe OM risk.1,16 We found high-dose melphalan and BEAM to have a similar potential in this respect. Disease effect independent of regimen type was not noted. In a study of 79 patients, most of whom underwent conditioning with busulfan and cyclophosphamide, with or without the addition of etoposide, Bolwell et al28 observed worse OM in patients with NHL, possibly because of the higher level of pretreatment in these patients. Additional risk factors for OM include prior radiation therapy above the diaphragm and progenitor cell-mobilizing regimens containing etoposide. A correlation of these factors with the conditioning chemotherapy doses administered to our patients (driven mostly by BSA) and distortion of the reported chemotherapy dosage effects seem unlikely. Although with different focus, both studies highlight the importance of chemotherapy choice and dosage in predicting the incidence and severity of OM. Systemic drug exposure, as a key driver of OM, can be impacted by individual patient factors such as renal function27 and polymorphisms in genes that regulate drug metabolism.29 Elevated serum creatinine was a predictor of severe mucositis in patients receiving melphalan, which is cleared by the kidneys.29 Polymorphisms in methylenetetrahydrofolate reductase, an enzyme critical for normal DNA synthesis and repair, are associated with an increased risk of OM in patients receiving methotrexate, but the relevance of this finding in patients receiving non–methotrexate-containing regimens is unclear.30 Doses of the BEAM components were not specified in the protocol and differed somewhat between centers. Actual drug dosage given varied for both BEAM and high-dose melphalan (Table 1), potentially reflecting various factors (such as dose-rounding/capping, dose reduction for reduced renal function, and so on) and was a key modifier of risk responsible for introducing differences within the regimens studied.
The use of higher drug doses per square meters of BSA and of higher drug doses per kilogram of body weight in patients with lower weight and BMI led to a higher severe OM risk in this group and to an apparent effect of body weight and BMI. Grazziutti et al29 reported that BSA-based dosing of high-dose melphalan resulted in wide variation in milligrams per kilogram doses. Raber-Durlacher31 found that among patients treated for solid tumors, those with low BMI were slightly more susceptible to OM. This might be linked to poor nutritional status, which may in turn influence immune responses, as well as cellular repair functions. Inflammation plays a key role in the pathophysiology of OM,5 and factors that influence the immune response, for example polymorphisms that influence production of cytokines involved in tissue injury, such as tumor necrosis factor Several studies found female sex to be a significant risk factor for OM.32-34 In our study, female sex became a near-significant predictor of severe OM when the modeling used drug doses per square meters of BSA instead of per kilogram of body weight. This may be partly explained by women receiving more chemotherapy per kilogram of body weight than men with BSA-based dosing (Fig 4). The influence of age on chemotherapy-induced severe OM risk is controversial, with older age reported to be a risk factor.32,35 We found that, consistent with earlier reports,1,34 severe OM incidence and duration were not substantially influenced by age. Chronologic age does not in itself accurately reflect the functional reserve of an individual,36 and it may be more appropriate to consider individual factors that can be altered by aging, such as renal function, ECOG and nutritional/general health status, and oral health and hygiene. Indeed, we found higher baseline ECOG performance status to be a risk factor for severe OM. Although our sample size of 200 patients allowed the main end points to be estimated with precision, a larger sample size would have increased our analytic possibilities. Between-center differences were noted for the OM incidence and duration results, and patient numbers per center were small. Use of generalized estimation equations–based SE estimates in multivariate regression analysis allowed partial correction for center effects. The POMA data add to knowledge about patterns and determinants of OM occurrence in the transplantation setting and have shown that severe OM is a more frequent problem than previously reported. Given the considerable patient burden and clinical and economic implications of severe OM, these findings justify using new effective preventative and therapeutic modalities. Further research, using larger data sets, is warranted to extend our findings.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: Pamela Bacon, Amgen GmbH (C) Consultant or Advisory Role: Nicole MA Blijlevens, Amgen (C); Matthias Schwenkglenks, Amgen (C); Johan Maertens, Amgen—Palifermin Trial (U); Rebecca Stone, Amgen (C); Barry Quinn, Amgen—Palifermin Trial (U) Stock Ownership: Pamela Bacon, Amgen Honoraria: Nicole MA Blijlevens, speaker's buro; Dietger Niederwieser, 2000 Euro for speaker's buro; Rebecca Stone, Amgen; Barry Quinn, EBMT Workshop Mucositis Research Funding: Nicole MA Blijlevens, Amgen; Matthias Schwenkglenks, Amgen via employment restitution Expert Testimony: None Other Remuneration: Hermann Einsele, travel grant
Conception and design: Nicole MA Blijlevens, Matthias Schwenkglenks, Pamela Bacon, Johan Maertens, Ann Roosaar, Tapani Ruutu, Harry Schouten, Rebecca Stone, Barry Quinn, Shaun McCann Administrative support: Pamela Bacon Provision of study materials or patients: Nicole MA Blijlevens, Alessandra D'Addio, Hermann Einsele, Johan Maertens, Dietger Niederwieser, Werner Rabitsch, Tapani Ruutu, Harry Schouten, Rebecca Stone, Vokurka Samuel, Shaun McCann Collection and assembly of data: Nicole MA Blijlevens, Hermann Einsele, Johan Maertens, Harry Schouten, Rebecca Stone, Barry Quinn Data analysis and interpretation: Nicole MA Blijlevens, Matthias Schwenkglenks, Pamela Bacon, Hermann Einsele, Johan Maertens, Tapani Ruutu, Barry Quinn Manuscript writing: Nicole MA Blijlevens, Matthias Schwenkglenks, Pamela Bacon, Dietger Niederwieser, Harry Schouten, Rebecca Stone, Barry Quinn, Shaun McCann Final approval of manuscript: Nicole MA Blijlevens, Matthias Schwenkglenks, Pamela Bacon, Alessandra D'Addio, Hermann Einsele, Johan Maertens, Dietger Niederwieser, Werner Rabitsch, Ann Roosaar, Tapani Ruutu, Harry Schouten, Rebecca Stone, Vokurka Samuel, Barry Quinn, Shaun McCann
We thank Roisin Cinnéide and Kim Champion for serving as Data Manager and Study Coordinator, respectively, and Julia Balfour of Amgen (Europe) GmbH for assisting with the writing of the manuscript. We also thank the investigators, staff, and patients from the following centers for their participation: Klinik für Innere Medizin I, Medizinische Universität Wien, Vienna, Austria (Dr W. Rabitsch); Department of Hematology, Cliniques Universitaires St. Luc Brussels, Belgium (Dr A. Ferrant); Department of Hematology, University Hospital Gasthuisberg, Leuven, Belgium (Dr J. Maertens); Department of Hematology/Oncology, Charles University Hospital, Pilsen, Czech Republic (Dr Samuel Vorkurka); Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland (Dr T. Ruutu); Department de Hematologie, Hotel Dieu, Nantes, France (Dr J-L Harousseau); Medizinische Klinik und Poliklinik V, University of Heidelberg, Heidelberg, Germany (Dr M. Villalobos); Division of Hematology and Oncology, University of Leipzig, Leipzig, Germany (Dr Eggers); Department of Hematology/Oncology, University of Münster, Muenster, Germany (Dr J. Kienast); Medizinische und Poliklinik II, Würzburg, Germany (Dr H. Einsele); Department of Hematology, St James Hospital Trinity College, Dublin, Ireland (Dr S. McCann); Divisione di Ematologia, Ospedale Bergamo, Bergamo, Italy (Dr C. Mico); Institute of Hematology and Medical Oncology L & A Seràgnoli, Bologna University, S. Orsola-Malpighi Hospital, Bologna, Italy (Dr. A. Isidori/Dr. A. Curti); Division of Hematology, Cardarelli Hospital, Naples, Italy (Dr G. Mele); Dip. Biotecnologie Cellulari ed Ematologia, Univ.‘La Sapienza‘, Rome, Italy (Dr G. Meloni); Department Internal Medical Hematology/Oncology, University Hospital Maastricht, Maastricht, Netherlands (Dr. B. Span); St Radboud University Medical Center, Nijmegen, Netherlands (Dr N. Blijlevens); Clinical Hematology Division, Hospital Santa Creu i Sant Pau, Barcelona, Spain (Dr D. Valcarcel); Institute of Hematology and Oncology, Hospital Clinic, Barcelona, Spain (Dr C. Martinez); Servicio de Hematología, Hospital Clínico, Salamanca, Spain (Dr S. Perez); Huddinge Hematology Centre, Karolinska University Hospital, Huddinge, Sweden (Dr P. Ljungman); Hematology, University Hospital, Basel, Switzerland (Dr A. Theocharides); Department of Hematology, Belfast City Hospital, Belfast, United Kingdom (Dr M. Drake); Nottingham City Hospital, Nottingham, United Kingdom (Dr N. Russell); Leukemia Myeloma Units, Royal Marsden Hospital, Sutton, United Kingdom (Dr G. Morgan).
published online ahead of print at www.jco.org on February 11, 2008. Supported by Amgen (Europe) GmbH, Zug, Switzerland. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Moreau P, Facon T, Attal M, et al: Comparison of 200 mg/m(2) melphalan and 8 Gy total body irradiation plus 140 mg/m(2) melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: Final analysis of the Intergroupe Francophone du Myelome 9502 randomized trial. Blood 99:731-735, 2002 25. Josting A, Sieniawski M, Glossmann JP, et al: High-dose sequential chemotherapy followed by autologous stem cell transplantation in relapsed and refractory aggressive non-Hodgkin's lymphoma: Results of a multicenter phase II study. Ann Oncol 16:1359-1365, 2005 26. Argiris A, Seropian S, Cooper DL: High-dose BEAM chemotherapy with autologous peripheral blood progenitor-cell transplantation for unselected patients with primary refractory or relapsed Hodgkin's disease. Ann Oncol 11:665-672, 2000 27. 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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
18 years with a diagnosis of MM or NHL and receiving, respectively, high-dose melphalan (200 mg/m2) or carmustine 300 mg/m2, etoposide 800 mg/m2, cytarabine 800 to 1,600 mg/m2, and melphalan 140 mg/m2 (BEAM) as conditioning chemotherapy, followed by autologous SCT, were eligible. Exclusion criteria were previous SCT or BMT, palifermin administration, and presence of oral abnormalities at baseline corresponding to a WHO scale grade 
and interleukin-1, may influence OM risk.
