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Predictors of Oral Mucositis in Patients Receiving Hematopoietic Cell Transplants for Chronic Myelogenous Leukemia

From the Cancer Prevention Research Program, Fred Hutchinson Cancer Research Center; Interdisciplinary Graduate Program in Nutritional Sciences, Departments of Epidemiology and Oral Medicine, School of Dentistry, University of Washington; Oral Medicine Service, Seattle Cancer Care Alliance, Seattle, WA

Address reprint requests to Cornelia Ulrich, PhD, Cancer Prevention Research Program, Fred Hutchinson Cancer Research Center, PO Box 19024, M4-B402, Seattle, WA 98109-1024; e-mail: nulrich{at}fhcrc.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: Oral mucositis is a nearly universal and often severe complication following hematopoietic cell transplantation (HCT). The objective of this study was to evaluate factors predicting oral mucositis severity among 133 patients undergoing allogeneic HCT for chronic myelogenous leukemia.

PATIENTS AND METHODS: All patients were transplanted between 1992 and 1999, were 18 years of age, received either cyclophosphamide/total-body irradiation (TBI) or busulfan/cyclophosphamide conditioning regimens, and received four doses of methotrexate for graft-versus-host disease prophylaxis post-transplant. Oral mucositis was measured by a trained examiner every 2 to 3 days using the Oral Mucositis Index (OMI). Multiple linear regression analysis was used to identify predictors of mean OMI during days 6 to 12, 1 to 18, and the maximum OMI score between days 1 to 18.

RESULTS: TBI containing conditioning regimens, body mass index 25, and methylenetetrahydrofolate reductase 677 TT genotype were found to be predictive of higher mean OMI scores (P < .05). Pretransplant multivitamin supplement use was associated with lower mean OMI scores compared to those who did not use supplements. Smoking status, race, pretransplant treatment with interferon-alfa or hydroxyurea, and patient/donor ABO compatibility were not associated with mean OMI scores.

CONCLUSION: Patients who are scheduled to receive conditioning regimens containing TBI, have a pretransplant body mass index 25, or carry the methylenetetrahydrofolate reductase 677 TT genotype should be considered at greater risk of developing oral mucositis following HCT. Future studies should investigate whether multivitamin supplementation before HCT could reduce mucositis severity.

	INTRODUCTION

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With improving rates of long-term, disease-free survival following hematopoietic cell transplantation (HCT), efforts to minimize the side effects of treatment are receiving greater attention. Oral mucositis can be a significant early post-transplant complication often requiring pain medication, limiting the patient's ability to speak and eat, and increasing the risk of infections and bleeding.^1-3 Severe cases may lead to airway obstruction and the need for intubation. In certain situations, oral mucositis may necessitate the withholding of planned doses of chemotherapeutic agents.¹ Sonis et al⁴ have shown that a 1-point increase in oral mucositis on the oral mucositis assessment scale (a 1 to 5 scale)⁵ is associated with a more than two-fold increased risk of significant infection, 2.7 additional days of total parenteral nutrition, 2.6 additional days in the hospital, more than $25,400 in additional hospital charges, and a 3.9-fold increase in 100-day mortality. Bellm et al² found that patients reported mouth sores to be the single most debilitating side effect of the HCT process.

Oral mucositis in the allogeneic HCT population is largely attributable to the conditioning regimens and methotrexate (MTX) administration. Typically, oral mucositis peaks between days 6 to 12 post-transplant, and begins to resolve by days 14 to 18.^6,7 The timing of recovery from oral mucositis is highly correlated with, but not directly related to, engraftment.⁸

The chemotherapeutic agent MTX is an antifolate drug used for graft-versus-host disease prophylaxis following HCT.^9,10 Toxic sequelae of MTX therapy are known to include oral and intestinal mucositis and myelosuppression.¹¹ We previously reported that the variant methylenetetrahydrofolate reductase (MTHFR) C677T allele is associated with increased MTX toxicity following HCT.¹²

Most of the previous reports of the risk factors for oral mucositis in the HCT population required combined analysis of patients with different diagnoses and treatment regimens in order to achieve sufficient statistical power.^13-18 This study evaluates the factors related to development of oral mucositis among a largely homogenous adult patient population receiving allogeneic HCT for chronic myelogenous leukemia.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
Study Design and Patient Population
Patients transplanted at the Fred Hutchinson Cancer Research Center (FHCRC; Seattle, WA) for chronic myelogenas leukemia between August 1992 and March 1999 who: 1) were in chronic phase at the time of transplant, 2) were 18 years of age at time of transplant, 3) received either cyclophosphamide (CY)/total-body irradiation (TBI) or busulfan (BU)/CY conditioning regimens as previously described,^19-21 and 4) received all four scheduled doses of methotrexate (15 mg/m² on day 1 and 10 mg/m² on days 3, 6, and 11) for graft-versus-host disease prophylaxis¹⁰ were eligible for inclusion in this retrospective study. Patients requiring leucovorin rescue after receiving methotrexate (n = 13) were excluded from the study as leucovorin rescue was considered to be a potential confounding factor. Additionally, patients who did not receive all four doses of methotrexate (n = 8) were also excluded from the study. The study was approved by the FHCRC institutional review board, and all patients provided informed consent for research studies, including those employing genetic testing.

Oral Mucositis Measurement
Oral mucositis was measured using the Oral Mucositis Index (OMI) which assesses clinically evident oral mucosal changes (atrophy, erythema, ulceration, pseudomembranous ulcerations, and edematous changes) and consists of 34 items, each scaled from 0 to 3 (normal to severe).²² Each HCT patient at the FHCRC is examined for oral mucositis every 2 to 3 days during the early post-transplant period by a trained examiner. Results are recorded on a standardized machine-readable form, from which the OMI is computed. The intercorrelation of OMI scores comparing assessments between days 10 to 12 and 13 to 16 post-transplant was found to be 0.73 (P < .01).²² Because this correlation reflects the cumulative error of both the OMI assessment and changes of patients' oral mucositis between these two time periods, it constitutes a lower limit of the reliability of the measurement itself. Thus, the reproducibility of the OMI assessment is very good.

Potential predictors for oral mucositis were chosen based on clinical experience and a review of the existing literature on oral mucositis.^12-18 Data collected for analysis included height, weight, body-surface area, body mass index (BMI), age, sex, race, previous treatment with interferon-alfa, hydroxyurea, busulfan or cytarabine (yes/no), smoking history, time between diagnosis and treatment, date of transplant, conditioning regimen (including total dose and source of radiation, if applicable), donor relationship (related versus unrelated), source of hematopoietic progenitor cells (bone marrow versus peripheral blood), patient/donor ABO compatibility, use of growth factors, use of ganciclovir, and incidence and date of onset of acute graft-versus-host disease (any organ site). Additionally, chart review was used to confirm that study subjects received all four scheduled doses of MTX.

A registered dietitian or dietetic technician collected information on pretransplant multivitamin supplement use (yes/no) during an initial nutrition assessment visit approximately 2 weeks before HCT. For the purposes of this study, a patient was considered to have used a multivitamin or folate supplement pretransplant if there was documentation of use in either the Nutrition Program records or the medical record.

Body Weight Assessment and Chemotherapy Dosing
Height (cm) and weight (kg) measurements were obtained for all patients within the 30 days before HCT. Tables developed by Hathaway and Foard (US Department of Agriculture, 1960)²³ were used to determine ideal body weight. Adjusted body weight was calculated for all patients more than 100% of ideal body weight, using the following formula: adjusted body weight = ideal body weight + 0.25 (actual weight -ideal body weight). BMI was calculated as actual body weight divided by height squared. Body-surface area was calculated using the formula:

Actual body weight, or adjusted body weight for patients more than 100% of ideal body weight, was used to calculate CY and BU dosing. All patients received a total of 120 mg CY/kg in two divided doses regardless of whether they received the BU/CY or CY/TBI conditioning regimens. BU was given either as a fixed dose of 4 mg/kg per day for 4 days, or targeted to achieve a steady-state plasma concentration of at least 900 ng/mL as previously described.²¹ Targeted BU dosing was implemented for the later portion of our study period,²¹ and 17 (28%) of the 61 patients conditioned with BU/CY in this study cohort received targeted BU dosing. All patients who received CY/TBI conditioning regimens received a total radiation dose of 12 Gy, with the exception of one patient who received 13.2 Gy. Cobalt was the source of radiation for all of these patients. MTX was given as 15 mg/m² on day 1 and 10 mg/m² on days 3, 6, and 11 post-transplant.

MTHFR Genotyping
Genotyping for the MTHFR C677T polymorphism was performed using the polymerase chain reaction/restriction fragment length polymorphism method described previously.¹² All genotyping was performed blinded to any disease status of the patient. Ten percent blinded duplicate samples yielded 100% genotyping concordance, and genotypes were in Hardy-Weinberg equilibrium.

Statistical Analysis
Oral mucositis following marrow transplantation is generally noted to peak between days 7 to 11 and resolve by days 18 to 21 days post-transplant.^6,7,22 Therefore, the outcomes identified for analyses were mean OMI days 6 to 12 (patients with at least two assessments during this period; n = 122), mean OMI days 1 to 18 (patients with at least four assessments during this period; n = 112), and maximum OMI (single highest recorded OMI score between days 1 to 18 for each patient who met the criteria for inclusion in the analysis of mean OMI days 6 to 12 and/or days 1 to 18; n = 133).

Pearson correlation coefficients, analysis of variance, and multiple linear regression analyses (which adjusts for other predictors) were used to identify predictors of each mucositis outcome. Since donor relationship (related versus unrelated) is used to determine the conditioning regimen, these variables are highly correlated. Conditioning regimen, rather than donor relationship, was used for regression analyses. All statistical analyses were performed using SPSS for Windows (Version 10.0.7, SPSS Inc, Chicago, IL).

	RESULTS

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Characteristics of the study population are given in Table 1. Median time from original diagnosis to transplant was 260 days (range, 49 to 5,346 days) for this study cohort. Eighty-eight study subjects (66%) were transplanted within the first year of diagnosis. No significant correlation between patient's age and time to transplant was observed for this cohort (r = 0.06; P = .47).

Approximately 65% (87 patients) showed a clinically relevant elevation of OMI scores (maximum OMI > 20) between days 1 and 18, and 27% (36 patients) experienced severe oral mucositis (maximum OMI > 35). Mean number of days post-transplant on which the maximum OMI score occurred was 9.7 ± 3.5 (range, 1 to 18 days). Pearson correlation coefficients between potential predictors (continuous variables) and OMI scores are reported in Table 2. Table 3 shows the analyses of variance in OMI scores by potential predictors of oral mucositis for categoric variables (univariate analysis without adjustment for other predictors).

Table 4 presents results from multiple regression analyses, which simultaneously adjusts for all predictors, as well as age and sex, in the model. In these multivariate analyses, conditioning regimens that included TBI, BMI 25, MTHFR 677 TT genotype, and pretransplant multivitamin supplementation were found to be statistically significant predictors of oral mucositis. Further, a trend was seen for mean and maximum OMI scores to increase with age, although the only statistically significant finding was for individuals over 50 years of age, who experienced mean OMI scores that were on average 6.3 points higher than individuals who were in the 18- to 30-year-old reference group between days 1 and 18 (P = .04). Models containing conditioning regimen, BMI, multivitamin supplementation pretransplant, MTHFR genotype, age, and sex were able to explain between 20% and 28% of the observed variance in mucositis scores.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
This is the first report evaluating the predictors of oral mucositis in a large, homogenous group of patients with identical diagnoses, who received one of two general conditioning regimens and identical graft-versus-host disease prophylaxis. Our findings suggest that patients who are scheduled to receive conditioning regimens containing TBI, have a pretransplant BMI 25, or carry the MTHFR 677 TT genotype should be considered at greater risk of developing oral mucositis following HCT, whereas use of multivitamins pretransplant may be protective.

Chemotherapeutic agents previously associated with oral mucositis include methotrexate,^1,14 fluorouracil,²⁴ etoposide,^7,17,25 melphalan,⁷ and cytarabine.^1,7 Dodd et al²⁶ reported that use of dental appliances, history of oral lesions, history of smoking, or differences in oral care were not associated with significant differences in severity or time to onset of mucositis among patients with breast cancer, colorectal cancer, non-Hodgkin's lymphoma, and lung cancer treated with doxorubicin, bleomycin, etoposide, fluorouracil, methotrexate, paclitaxel, or fludarabine.

TBI has also been associated with increased risk of developing mucositis in various oncology patient populations.^8,15,16,27 Our findings are consistent with those of Zerbe et al¹⁵ and Rapoport et al¹⁶ in that TBI was found to be associated with increased oral mucositis scores in the HCT population. However, as mentioned earlier, our center uses donor relationship to determine which conditioning regimen the patient receives, and thus the conditioning regimen is perfectly correlated with donor relationship in this study cohort. All patients receiving transplants from unrelated donors were given the CY/TBI conditioning regimen. Unrelated donor transplants have been shown to have increased risk of acute graft-versus-host disease.²⁸ Thus, it is possible that the association between CY/TBI conditioning and increased OMI scores reflects early acute graft-versus-host disease in addition to, or instead of, conditioning related oral mucosal toxicity. In fact, mean day of onset for acute graft-versus-host disease (any organ site) was day 15 (range, 6 to 63 days; n = 62) for those receiving CY/TBI, and day 24 (range, 11 to 63 days; n = 46) for those receiving BU/CY (P = .32). Incidence of acute graft-versus-host disease was not included in our model, as the model was intended to be a tool for use in predicting, before transplant, who would be at increased risk for mucositis.

Our finding of a correlation between higher BMI and higher OMI scores is most likely a result of the fact that patients with higher BMIs receive larger absolute doses of chemotherapy. Overweight has been defined as a BMI of 25 to 29.9, and 30 is considered obese.^29-31 The ratio of adipose to lean body weight is often increased in individuals with greater than normal body weight, especially those with BMI 30, which may affect drug distribution and pharmacokinetics.³² Although increased absolute dose and alterations in drug clearance are the most likely explanations for the observation of higher OMI scores among overweight individuals, we cannot exclude the possibility that other factors related to obesity may increase risk of oral mucositis or delay the repair of damaged tissue. The only previous report to evaluate BMI as a potential risk factor for oral mucositis found a nonsignificant increase in risk for individuals with a low BMI (which they defined as < 20 for males and < 19 for females) among 150 patients being treated with chemotherapy for several different types of solid tumors.²⁵

We previously reported that the variant MTHFR C677T allele was associated with increased MTX toxicity following HCT.¹² Folate is a carrier of single carbon groups, and is essential for purine and pyrimidine synthesis as well as the provision of methyl groups for DNA, RNA, and protein methylation.^33-35 Individuals with the MTHFR C677T TT genotype have been shown to have 30% in vitro MTHFR enzyme activity as compared with the wildtype,³⁶ resulting in imbalances in intracellular folate pools among individuals with the MTHFR 677 TT genotype³⁷ and the possibility of a decrease in one-carbon groups available for nucleotide synthesis and DNA repair during recovery from mucosal damage.¹² Toxic sequelae of MTX therapy are known to include oral and intestinal mucositis and myelosuppression.¹¹ Our findings are consistent with reports of greater toxicity among individuals with the MTHFR 677 TT genotype who have received MTX for breast cancer,³⁸ ovarian cancer,³⁹ and acute leukemia.⁴⁰ It has been suggested that in situations where there is abundant intracellular folate, the folate molecule may be able to hold the variant MTHFR protein in the appropriate and fully functional three-dimensional structure.^41,42 This study found that even after adjustment for use of multivitamin supplements (which typically provide 100% US recommended daily allowance for folate), MTHFR 677 TT genotype is a significant predictor of higher OMI scores.

Although we found that multivitamin use was associated with a significant decrease in mean and maximum OMI scores, this finding should be considered exploratory. No specific information on duration of supplement use or actual composition of the individual supplement was available. Previous reports have suggested that oral supplementation of antioxidants such as vitamin E⁴³ and beta-carotene⁴⁴ may modify the severity of oral mucositis, and supplemental folate may also contribute to the findings of a protective effect of multivitamin supplement use. Multivitamin supplement users may have other unidentified health habits that contribute to lower risk of oral mucositis, which may be a source of confounding that is unaccounted for in our current analysis. A randomized trial would be needed to further explore whether multivitamin supplementation before HCT is truly a protective factor.

Because of the retrospective nature of this study, data analysis was limited to patients with available OMI scores, and thus may represent a subgroup of patients with a greater degree of oral mucositis and increased requirements for oral medicine interventions. Also, oral examinations were not performed on a daily basis, and thus may not fully reflect the true course of OMI scores for all patients.

Complicating the comparisons between this analysis and the existing literature is a lack of a single authoritative scale for measuring, describing, and reporting oral mucositis across patient populations.^1,5 Approaches to measurement vary from simple 4 to 5 point scales such as the National Cancer Institute Common Toxicity Criteria version 3.0 and the WHO Handbook for Reporting Results of Cancer Treatment⁴⁵ to scales that include a functional component such as the Eiler's Oral Assessment Guide (also known as the University of Nebraska Oral Assessment Score).⁴⁶ Since these scales tend to have mixed variables (subjective, objective, and performance), their ability to measure distinct mucosal changes can be compromised. This study used the OMI, which only assesses clinically evident oral mucosal changes that are felt to relate directly to mucosal toxicity. Thus, our study utilizes a detailed, objective, and sensitive research tool for the assessment of oral mucositis, with demonstrated internal consistency and inter-rater reliability.²²

Our findings suggest that patients scheduled to receive CY/TBI conditioning regimens, those at a BMI 25 before HCT, and those with the MTHFR 677 TT genotype are at higher risk of developing oral mucositis. Multivitamin supplementation was found to significantly lower risk and severity of oral mucositis, although further studies are needed to verify the relevance of this finding as a potential strategy for oral mucositis prevention.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
The authors indicated no potential conflicts of interest.

	Acknowledgment

 
We thank the investigators and staff members who were involved in various aspects of this study, including Gary Schoch, who provided data from the master patient database, and the MTX/MTHFR study team.

	NOTES

 
Supported by National Cancer Institute training grants T32 CA80416 and R25 CA94880 (K.R.).

An abstract based on this research was presented at the American Association for Cancer Research Annual Meeting, Washington, DC, July 11-14, 2003.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
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Submitted May 21, 2003; accepted July 3, 2003.

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