The effect of budesonide mouthwash on oral chronic graft versus host disease

American Journal of Hematology 82:349–356 (2007) The Effect of Budesonide Mouthwash on Oral Chronic Ismail Sari,1* Fevzi Altuntas,1 I˙smail Kocyigit,2 Yildiray Sisman,3 Bulent Eser,1 Aydin Unal,2 Turgay Fen,4 Ayten Ferahbas,5 Ahmet Ozturk,6 Ali Unal,1 and Mustafa Cetin1 1 Department of Hematology, Faculty of Medicine, M.K. Dedeman Oncology Hospital, Erciyes University, Cappadoccia Transplant Center, Kayseri, Turkey 2 Department of Internal Medicine, Faculty of Medicine, Erciyes University, Kayseri, Turkey 3 Department of Oral Diagnosis and Radiology, Dental Faculty, Erciyes University, Kayseri, Turkey4 Department of Hematology, Ankara Oncology Research and Education Hospital, Ankara, Turkey 5 Department of Dermatology, Faculty of Medicine, Erciyes University, Kayseri, Turkey 6 Department of Biostatistics, Faculty of Medicine, Erciyes University, Kayseri, Turkey Oral chronic graft versus host disease (cGVHD) is common and a major cause of morbidityand loss of quality of life in long term survivors. Cyclosporine with prednisone remains thefirst line therapy for oral manifestations of cGVHD. However, even with routine administra-tion of systemic agents, many patients with oral manifestations of cGVHD do not have reso-lution of their disease and may benefit from incorporation of local therapy. Budesonide is ahighly potent steroid which has minimal systemic side effects and being used for oralcGVHD. We designed a retrospective study to compare treatment results of patients withoral cGVHD who received topical budesonide in addition to systemic therapy that consistsof combined prednisone and cyclosporine (Group A, n = 12), with the treatment results ofpatients who were administered the same systemic therapy alone (Group B, n = 11) to deter-mine whether budesonide mouthwash had any advantage on response rates. Three mg topi-cal budesonide/10 ml saline was used 3–4 times a day for up to 6 months in group A. Diag-nosis, clinical staging, and treatment response scoring for cGVHD were performed accord-ing to National Institutes of Health (NIH) consensus criteria. At the baseline examination,there were no statistically significant differences in terms of median oral cGVHD examina-tion scores between two groups. After treatment, there was statistically significant decreasein median oral cGVHD examination scores compared to baseline (P < 0.001 and 0.021), andsignificant differences were found between two groups (P < 0.032). Overall response ratewas 83% and 36% for group A and B, respectively (P = 0.036). However, no statistically sig-nificant differences were found between median pain scores of two groups before and aftertreatment (P = 0.740 and P = 0.091). No major systemic side effects and oral candidiasiswere observed in two groups of patients. We concluded that topical budesonide might beadded to systemic therapy to obtain better response rates in patients with oral cGHVD. Am.
J. Hematol. 82:349–356, 2007.
Key words: budesonide; oral chronic graft versus host disease; stem cell transplantation *Correspondence to: Ismail Sari, M.D., Erciyes University, Chronic graft-versus-host disease (cGVHD) is a Faculty of Medicine, M.K. Dedeman Oncology Hospital, lethal and common long-term complication of Department of Hematology, Cappadoccia Transplant Center, allogeneic hematopoietic stem cell transplantation 38039, Kayseri/Turkey. E-mail: (HSCT). The syndrome has many features resem-bling autoimmune and other immunologic disorders Received for publication 26 January 2006; Accepted 28 August 2006 such as scleroderma, Sjo¨gren syndrome, primary bil- Published online 15 November 2006 in Wiley InterScience (www.
iary cirrhosis, wasting syndrome, bronchiolitis oblit- erans, immune cytopenias, and chronic immunodefi- ciency. Although the pathophysiology of cGVHD is not understood completely, it is believed to be pri- marily mediated by T cells recognizing tissue anti-gens of the recipient [1].
Between January 1999 and February 2006, 23 pa- Staging of cGVHD has been limited by the dearth tients with hematologic malignancies who underwent of high-quality studies. The original designation of allogeneic peripheral blood stem cell transplantation ‘‘limited’’ and ‘‘extensive’’ cGVHD was established from HLA-matched sibling donors and had chronic based on a small retrospective study [2] that has lim- graft versus host disease (cGVHD) including oral ited utility. Efforts to enhance prognostic accuracy manifestations were treated with either oral budeso- have resulted in improvements in grading, but those nide rinse in addition to combined prednisone plus systems have not adopted wide acceptance [3,4].
cyclosporine or the same systemic therapy alone Recently, the National Institutes of Health (NIH) (Group A; n ¼ 12), (Group B; n ¼ 11). Different have proposed a new consensus statement to im- conditioning regimens were used in the patients: prove the accuracy of diagnosis, staging, and treat- BuCy2 [16 mg/kg oral busulphan plus 120 mg/kg cyclophosphamide], IV Bu+Cy2 [12.8 mg/kg intra- Oral GVHD can occur in 25–70% of patients, de- venous (IV) busulphan plus 120 mg/kg cyclophos- spite GVHD prophylaxis consisting of immunosup- phamide], IV Bu-Flu [6.4 mg/kg intravenous busul-phan plus 125 mg/m2 fludarabine], po Bu-Flu [8 pressives such as, methotrexate, cyclosporine, and mg/kg intravenous busulphan plus 125 mg/m2 corticosteroids [5,6]. The oral findings of cGVHD fludarabine], and Flu-Cy [125 mg/m2 fludarabine include white plaques which resemble oral lichen plus 120 mg/kg cyclophosphamide]. Cyclosporine planus, mucosal atrophy, erythema, and ulcers [7].
and short-term methotrexate were used for GVHD Involvement of the salivary glands may cause dry- ness of the oral mucosa and oral pain may be thefirst presenting symptom [8]. First-line therapy is mostly systemic in nature, consisting of cyclosporinand steroids. The most common salvage treatments This study was a cohort analysis examining oral for cGVHD are thalidomide, tacrolimus, mycophe- cGVHD outcomes and comparing treatment results nolate mofetil, T cell depletion by Campath-1, and of two groups. Two cohorts of patients were eval- uated prospectively after allogeneic hematopoietic Oral manifestations of cGVHD can significantly stem cell transplantation (HSCT) in terms of oral affect the life quality of patients through discomfort GVHD as a part of routine examination, but the and impairment of the oral intake leading to malnu- associated outcomes were assessed retrospectively.
trition and increased morbidity [10]. It is often re- Before the analysis, the data of our transplant cen- fractory to conventional treatment and therefore ter regarding the diagnosis, staging, and treatment complementary topical treatment is required. Several response scoring of cGVHD were adapted according agents are currently used for local treatments such to new criteria recommended by NIH consensus [17,18]. Oral cGVHD was assessed twice weekly by agents, thalidomide, retinoids, and phototherapy for a specialist from the Oral Diagnosis and Radiology Department of the Dental Faculty of Erciyes Uni- Budesonide is a highly potent steroid, indicated versity as a part of routine clinical care.
for the treatment of asthma and gastrointestinaldisorders because of a very low bioavailability when absorbed through mucosal surfaces that mini- cGVHD was defined as at least one diagnostic or mizes systemic side effects [15,16]. Current knowl- distinctive manifestation of cGVHD confirmed by edge regarding the effect of topical budesonide pertinent biopsy. Infections and other causes related treatment in oral cGVHD is not sufficient. There- with differential diagnosis of cGVHD have been fore, we designed a retrospective study according excluded by routine diagnostic methods such as to NIH consensus criteria comparing the treatment results of patients with oral cGVHD who received Oral cGVHD was defined as presence of one of topical budesonide plus systemic therapy consisting the diagnostic or distinctive features of oral cGVHD of prednisone and cyclosporine with the treatment such as lichen planus-like changes, hyperkeratotic results of patients who were administered the same plaques, mucoceles, mucosal atrophy, pseudomem- systemic therapy alone to determine whether bude- branes, or ulcers. Infectious pathogens such as yeast sonide mouthwash had any advantage on response or herpes virus have been excluded by the cultures and the serological tests that were performed during American Journal of Hematology DOI 10.1002/ajh TABLE I. Scoring System for Oral CGVHD Recommended by NIH Consensus [18] routine oral examination. All biopsies were taken Budesonide mouthwash. Oral budesonide rinse from extraoral sites of the patients for the diagnosis was given to the patients in group A during systemic therapy to provide better local control of oralcGVHD. The 3-mg coated capsule form of the med- ication was selected for administration. Patients Each organ or sites were scored according to a were instructed to crush the budesonide capsule, dis- four point scale (0–3), with 0 representing no in- solve it in 10 ml of water, and rinse for 15 min three volvement and 3 reflecting severe impairment.
or four times daily, then expectorate the solution.
During the treatment, oral candidiasis was assessed clinically and cultures were taken accordingly.
For oral cGVHD, the definitions of the baseline clinical scores were as follows: Score 0, no symp- toms; Score 1, mild symptoms with disease signs but not limiting oral intake significantly; Score 2, mod- using the newly proposed modification of the Schu- erate symptoms with disease signs with partial limi- bert Oral Mucositis Rating Scale that scores oral tation of oral intake; Score 3, severe symptoms with surfaces from 0 to 15, with higher scores indicating disease signs with major limitation of oral intake.
more severe involvement. Four cGVHD manifesta- tions were assessed for all areas (lips, labial mucosa,tongue, and soft palate) in the mouth: (1) mucosal The terms ‘‘mild,’’ ‘‘moderate,’’ and ‘‘severe’’ were erythema (0–3) grading based on the color intensity; used for the global scoring of cGVHD at the initial (2) lichen-type hyperkeratosis (percent of oral sur- diagnosis. Mild cGVHD was defined as involvement face area); (3) ulcerations (percent of oral surface of only one or two organs or sites with no clinically area); and (4) presence of mucoceles (total number).
significant functional impairment (maximum score Severity of mucosal changes was determined relative of 1 in all affected organs or sites). Involvement of to entire mouth as ‘‘none,’’ ‘‘mild,’’ ‘‘moderate,’’ and at least one organ or site with clinically significant ‘‘severe.’’ Oral cGVHD scoring system was summa- but no major disability (maximum score of 2 in any affected organ or site) or involvement of three ormore organs or sites with no clinically significantfunctional impairment (maximum score of 1 in all affected organs or sites) were considered as moder- Complete response (CR) was defined as resolution ate cGVHD. Finally, severe cGVHD was described of all manifestations related to oral cGVHD in the as major disability caused by cGVHD (score of 3 in mouth. Partial response (PR) was defined as at least 50% improvement in the oral mucositis scale. Stabledisease (SD) was defined as no change in cGVHD.
Finally, progression of oral cGVHD was defined as Systemic therapy. Combination of prednisone (2 mg/ the absolute increase of at least 25% in the scale.
kg/day, po or IV) and cyclosporine (6 mg/kg/day,po or 3 mg/kg/day, IV) were administered for initial therapy to all patients in group A and B havingmoderate or severe cGVHD. The doses were adjusted The severity of pain was evaluated by using a according to the treatment responses of cGVHD visual analog scale (VAS) from 0 (no pain) to 10 (the most severe pain). This method of measuring pain American Journal of Hematology DOI 10.1002/ajh TABLE II. General Characteristics of the Patients in Group A and B performed by the Mann and Whitney U-test. Com-parisons of treatment response rates between two groups were accomplished by the x2 test. The Fisher’s exact test was used instead of the x2 test when any of the cells in a cross-tabulation contained sidered to indicate statistical significance.
General characteristics of total 23 patients in group A (12 patients) and group B (11 patients) were given in Table II. The median age of the patients were 29 (range, 23–57 years) and 36 (range, 23–52 years) for group A and B, respectively. In group A, 6 patients had acute myelogenous leuke- Clinical oral cGVHD score at baseline (number) mia (AML), 3 had acute lymphoblastic leukemia (ALL), 2 had chronic myeloid leukemia (CML), and 1 had Hodgkin’s disease (HD). In group B, 3 patients had AML, 1 had ALL, 1 had MDS, 4 had Extraoral cGVHD involvement sites (number) CML, 1 had NHL, and 1 had myelofibrosis (MF). In group A, the conditioning regimens consisted of IV Bu+Cy2 in eight cases, BuCy2 in three cases, and IV Bu-Flu in the remaining one case. In group B, Clinical global cGVHD score at baseline (number) the conditioning regimens consisted of IV Bu+Cy2 in eight cases, IV Bu-Flu in two cases, Bu-Flu in one case, and Flu-Cy in the remaining three cases.
Severe oral cGVHD was present in 4 and 3 patients for group A and B, respectively. Most frequent extraoral site with cGVHD involvement was skin for the patients of both groups (10 of 12 in group A HSCT, hematopoietic stem cell transplantation; cGVHD, chronic graft and 11 of 11 in group B). Other extraoral sites with versus host disease; AML, acute myeloid leukemia; ALL, acute lympho- cGVHD involvement were eyes, gastrointestinal blastic leukemia; MDS, myelodisplastic syndrome; CML, chronic mye- tract, and liver. No pulmonary involvement was loid leukemia; NHL, non-Hodgkin lymphoma; HD, Hodgkin’s disease;MF, myelofibrosis; IV Bu+Cy2, IV busulphan plus cyclophosphamide; observed in the patients. Global CGVHD scores BuCy2, po busulphan plus cyclophosphamide; IV Bu-Flu, IV busulphan was severe in 10 patients in group A and in 7 plus fludarabine; Bu-Flu, po busulphan plus fludarabine; Flu-Cy, fludara- patients in group B. The median time elapsed from the HSCT up to the enrollment in this study was8.5 months (range, 6–32 months) and 7 months(range, 4–24 months) for the patients in group A was chosen because it is simple, specific, and reliable for comparing patients’ changes within themselves.
Median follow-up period of the patients in group A receiving systemic therapy plus budesonide rinsewas 108 days (range, 84–280 days). Budesonide mouthwash was initiated at a median of 68.5 days The statistical evaluations were conducted by a (range, 46–90 days) to obtain higher response rates computer program (SPSS version 13.0, SPSS, Chi- in this group. Median duration of budesonide treat- cago, IL). For both groups the median values of the ment was 50 days (range 20–190 days). In group B, oral CGVHD examination scores and pain scores median follow-up period of the patients receiving were calculated. The Wilcoxon signed ranks test was systemic therapy alone was 120 days (range, 100– used to compare the data before and after treatment 210). General characteristics of the patients were for each group. Comparisons between treatment not significantly different in two groups (P > 0.05) groups at baseline and posttreatment period were American Journal of Hematology DOI 10.1002/ajh TABLE III. Oral cGVHD Examination Scores and Treatment Responses Before and After Treatment for the Patients in Group A After systemic therapy with budesonide mouthwash PR, partial remission; CR, complete remission; SD, stabil disease; Prog, progression.
TABLE IV. Oral cGVHD Examination Scores and Treatment Responses Before and After Treatment for the Patients in Group B PR, partial remission; CR, complete remission; SD, stable disease; Prog, progression.
1 progression was observed in this group (Table IV).
Overall response rate was 83% and 36% for group Erythema and ulcers were major manifestations A and B, respectively (P ¼ 0.036) (Table VI).
for both groups (Tables III and IV). Before treat- ment, median oral cGVHD examination scores were9 (range, 4–11) and 8 (range, 4–12) for group A and Before treatment, median pain scores were 5.5 B, respectively. At the baseline examination, there (range, 3–9) and 5 (range, 3–9) for the patients in were no statistically significant differences in terms group A and B, respectively. After treatment, there of median examination scores between two groups.
was statistically significant decrease in median pain After treatment, there was statistically significant scores compared to before treatment (P < 0.001 and decrease in median examination scores compared 0.006). However, no statistically significant differen- to baseline (P < 0.001 and 0.021), and significant ces were found between two groups before and after differences were found between two groups (P < treatment (P ¼ 0.740 and P ¼ 0.091) (Table VII).
In group A, 3 patients achieved CR and 7 PR at a median of 110 days (range, 92–125 days) and Major systemic side effects and oral candidiasis 100 days (range, 84–180 days), respectively. Two were not observed in two group of patients treated patients had SD, and no progression was observed with budesonide mouthwash plus systemic therapy (Table III). In group B, 1 patient achieved CR and or systemic therapy alone. One patient causing 3 patients achieved PR at a median of 117.5 days termination of the budesonide treatment in early (range, 100–148 days). Six patients had SD, and period complained about a local oral burning sensa- American Journal of Hematology DOI 10.1002/ajh TABLE V. Median Oral cGVHD Examination Scores of the Patients TABLE VII. Median Pain Scores of the Patients in Group A and B in Group A and B at Baseline and Post-treatment Period P*-value, significance of differences within (Wilcoxon signed ranks test) P*-value, significance of differences within (Wilcoxon signed ranks test) the groups. Pg-value, significance of differences between (Mann and the groups. Pg-value, significance of differences between (Mann and TABLE VI. The Comparison of Treatment Response Rates ofGroup A and B presented as a separate outcome measure. Othersystemic treatments such as sirolimus, mycopheno- late mofetil (MMF), extracorporeal photopheresis, hydroxychloroquine, clofazimine, thalidomide, pen- tostatin, and methotrexate have been used for cGHVD [25–32]. The response rates with these drugswidely vary from one study to another (24–67%). Inthe present study, combined cyclosporine-A andprednisone were used for systemic therapy, and the tion in group A. During the topical treatment, oral overall response rate in oral cavity disease was 36% herpes-simplex virus infection was seen in one in the patients being administered systemic therapy patient who was treated with direct appropriate Even with routine administration of systemic agents, many patients with oral manifestations of cGVHD do not have resolution of their disease and Oral cGVHD is common and a major cause of may benefit from incorporation of local therapy.
morbidity and loss of quality of life in long term Topical treatments offer a means to intensify ther- survivors [10,19]. In a randomized trial of PBSC apy to one area of the body while sparing the host versus BMSC transplants, oral mucosal changes further systemic immunosuppression. Despite this were the most common manifestation of cGVHD in advantage, few controlled trials have examined the BMSC recipients and the second most common in efficacy of topical treatments for oral mucosal PBSC transplants. Overall incidence was around GVHD. Wolff et al. [33] compared topical dexa- 85% [20]. Furthermore, in many patients severity of methasone rinse (0.1 mg/cc) to ultraviolet light therapy oral manifestations of cGHVD does not correlate after psoralen administration (PUVA). There were 16 patients in the dexamethasone arm with 9 re- Systemic immunosuppressive therapy is indicated sponding completely and 2 partially. In the same for severe cGHVD. Because most patients with oral study, complete response was achieved in 4 out of 7 cGVHD have a severe form of the disease, systemic patients and partial in 2 in PUVA arm. Epstein therapy is generally administered. The great disad- et al. [11] investigated the effect of cyclosporine rinse vantage of systemic immunosupression is significant on a group of 11 patients with oral cGVHD who side-effects such as diabetes mellitus, renal insuffi- previously failed in the therapies with topical dexa- ciency, osteoporosis, and increased frequency of op- methasone and topical cyclosporine 100 mg/ml as a rinse. The objective clinical response rate was 45% Cyclosporine with prednisone remains the first after 1 month of treatment. Another small trial of line therapy for severe and moderate cGVHD [21].
cyclosporine in adhesive base applied 4 times a day However, little is known about the effects of systemi- in 4 cGVHD patients by the same authors reported cally administered cyclosporine and prednisone on 75% objective response rate [34]. In a small open- the oral component of cGVHD. There are several label study, topical azathioprine rinse and gel have studies evaluating the effect of cyclosporine and been evaluated in the patients who had resistant oral prednisone in patients with cGVHD [22–24]. How- cGVHD. The mean response to topical azathioprine ever, survival was the primary outcome measure in was 60%, with mean duration of the treatment these studies and the effect on oral cGHVD was not of 16.7 weeks [35]. Recently, Eckardt et al. have American Journal of Hematology DOI 10.1002/ajh reported good responses by topical tacrolimus in 10 3. Lee S, Cook EF, Soiffer R, Antin JH. Development and vali- patients with steroid refractory oral GVHD [36].
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