Tacrolimus Therapy for Management of Oral Chronic GVHD

ORIGINAL ARTICLE Combined topical dexamethasone/tacrolimus therapy for management of oral chronic GVHD

H Mawardi1, K Stevenson2, B Gokani3, R Soiffer4 and N Treister5

1Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, USA; 2Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA; 3Imperial College London, London, UK; 4Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA, USA and 5Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine and Division of Oral Medicine and Dentistry, Brigham and Women’s Hospital, Boston, MA, USA

Chronic GVHD (cGVHD) frequently affects the oral donor T-lymphocytes that initiate inflammation, apoptosis cavity. The purpose of this study was to estimate the and subsequent target tissue dysfunction.1,2 Multiple efficacy of combined topical dexamethasone (DEX) and organs may be affected, with the most common being the tacrolimus (TAC) solutions in the management of oral skin, gastrointestinal tract and liver.3 Despite prophylaxis cGVHD. The records of 14 patients with oral cGVHD regimens and available immunosuppressive and immuno- treated with combined topical DEX/TAC were reviewed modulatory therapies, cGVHD remains the leading cause retrospectively. Pre-to-post treatment changes in subjec- of non-relapse treatment-related mortality in those surviv- tive and objective measures were evaluated at a median ing beyond 2 years after allogeneic HCT.2,4–6 follow-up of 60 days. Serum TAC levels were examined. The oral cavity is involved in approximately 80% of Marginal objective improvement was detected at follow- patients with cGVHD, with variable mucosal findings that up. The median pre-to-post treatment differences were 0.5 include lichenoid changes, erythema, ulceration and super- (range, À1 to 1) for erythema score, and 0.5 (range, 0 to ficial mucoceles.5–8 Mouth pain, and in particular sensitiv- 2) for lichenoid score, (P ¼ 0.06, 0.07 and 0.02, respec- ity or intolerance to normally tolerated foods and drinks, is tively). Subjective improvement was noted in three of four a common complaint.1 In addition, the major and minor measures at the follow-up visit. The median differences in salivary glands are frequently affected, with symptoms of pain, sensitivity and dryness scores were 1 (range À1 to 6), xerostomia and dysphagia further contributing to limited 1 (range À3 to 5) and 2.5 (range, À5 to 5), respectively oral intake and impaired quality of life.9,10 (0–10 scale, Po0.05). Four patients (37%) showed Despite systemic therapy with corticosteroids and increased serum TAC levels; however, all remained within steroid-sparing immunomodulatory agents, effective man- therapeutic range. In conclusion, combined topical DEX/ agement of oral cGVHD often requires intensive localized TAC therapy appears to be effective in reducing topical treatment.11 Both topical corticosteroids and symptoms attributable to oral cGVHD. Our data has calcineurin inhibitors have shown evidence of efficacy in shown minimal evidence of systemic TAC absorption. the form of ointments, gels and rinses.12–14 Oral lesions Bone Marrow Transplantation (2010) 45, 1062–1067; refractory to topical immunosuppressive monotherapy may doi:10.1038/bmt.2009.301; published online 2 November 2009 require combined therapy; however, this therapeutic Keywords: topical; dexamethasone; tacrolimus; cGVHD; approach has not been previously reported. The primary oral objective of this retrospective review was to describe the clinical outcomes of combined dexamethasone (DEX) and tacrolimus topical rinses in the management of patients with symptomatic oral cGVHD. Introduction Materials and methods Chronic GVHD (cGVHD) is a common and serious complication following allogeneic hematopoietic cell trans- Patients plantation (HCT). cGVHD develops due to alloreactive A retrospective record review was conducted for patients who had undergone allogeneic HCT, and were referred to the Division of Oral Medicine and Dentistry, Brigham and Correspondence: Dr H Mawardi, Division of Oral Medicine and Women’s Hospital, Boston, MA, USA for the evaluation Dentistry, Brigham and Women’s Hospital, 75 Francis Street, Boston, and management of oral cGVHD from August 2005 to MA 02115, USA. E-mail: [email protected] March 2009. All patients who were referred for treatment Received 16 June 2009; revised 12 August 2009; accepted 18 August were either (1) off all immunosuppressive medication, 2009; published online 2 November 2009 but with persistent oral cGVHD, or (2) had oral disease Topical dexamethasone/tacrolimus therapy for oral cGVHD H Mawardi et al 1063 that was inadequately managed symptomatically despite Statistical analysis systemic therapies. We included all patients who had The first follow-up visit (FU1) was defined as 12–49 days clinically evident and symptomatic oral cGVHD that were from the initial visit and initiation of therapy, and the treated with combined topical DEX (0.5 mg/5 ml) and second follow-up visit (FU2) was defined as 49–86 days tacrolimus (0.5 mg/5 ml; TAC) solutions, and had at least following the initial visit. The change in subjective and one follow-up visit, 49–89 days after the initial treatment, objective component scores from baseline to FU1 and FU2 for a response assessment. None of the patients were using was calculated (difference ¼ baseline–FU1 or FU2; a any additional topical or localized therapies for manage- positive difference is indicative of improvement) and ment of their oral cGVHD. assessed using a Wilcoxon’s signed-rank exact test. Objective measures were also considered categorically as Response criteria the proportion of patients who improved (lower scores at Standardized subjective and objective data were prospectively FU1 or FU2 from baseline), remained stable, or worsened collected at the time of clinical evaluation by a single oral (higher scores at FU1 or FU2 from baseline) and were medicine specialist (NT). Subjective data included National assessed using a marginal homogeneity exact test (an Institutes of Health (NIH) staging (0–3; Table 1), pain (0–10), extension of McNemar’s test for multinomial ordered sensitivity (0–10) and dryness (0–10) scores. Objective data responses). P-values were considered significant at the included scoring for lichenoid changes, erythema, ulcerations o0.05 level. All statistical analyses were performed using and mucoceles using the NIH total score. Serial serum TAC SAS version 9.1 (SAS Institute, Cary, NC, USA) and measurements were obtained for patients who were also being StatXact version 8.0 (Cytel Inc., Cambridge, MA, USA). treated with concurrent systemic TAC. This study was approved by the Dana–Farber/Harvard Cancer Center’s Office for Human Research Subjects.

Application of topical therapies All patients were instructed to rinse with both solutions at Results the same time, using a total of 5.0 ml (2.5 ml DEX, 2.5 ml TAC), for 5 min before expectorating. Based on severity of Twenty-three patients were identified who had been symptoms, patients were allowed to rinse up to four times a referred to the Division of Oral Medicine and Dentistry, day, with most rinsing 2–3 times a day (data not shown). Brigham and Women’s Hospital, Boston, MA, USA for the Patients were instructed not to eat or drink for at least evaluation and management of oral cGVHD and had been 15 min after applications. Tacrolimus solution was com- treated with combined topical DEX and TAC solutions. pounded according to the following formulary for 100 ml: Fourteen cases fulfilled the eligibility criteria and were tacrolimus powder 0.01 g, flavor 4.0 ml, Oral plus 50 ml, included for analysis (Table 2). All patients were evaluated Oral sweet to 100 ml (America’s Compounding Center, during the FU2 period, and 11 (79%) were also evaluated Newton, MA, USA). DEX solution (Roxane Laboratories during FU1. Serial TAC serum levels were available for 11 Inc., Columbus, OH, USA), was obtained through patients’ (79%) patients. At baseline, five patients (36%) were local pharmacies. already being treated with single-agent topical DEX (3/5) or TAC (2/5) therapy with inadequate response. Concur- Evaluation of serum tacrolimus levels rent systemic immunomodulatory therapies are summar- Serum TAC levels were evaluated in eleven patients who ized in Table 3. were already being treated with systemic TAC therapy and The median improvement in the NIH total score was 0.5 had at least one measurement before and after the at FU2 (range À2to6,P ¼ 0.06), and unchanged at FU1 administration of topical therapy (day 0). Per standard (range À2to5,P ¼ 0.41; Figure 1). Both erythema and institutional monitoring, serial trough TAC serum mea- lichenoid feature scores demonstrated a statistically sig- surements were collected routinely beginning with the nificant improvement at FU2 (Table 4). For erythema, 50% initiation of systemic therapy. Systemic absorption second- improved, 43% remained stable and only 7% worsened ary to topical therapy could not be evaluated because (Po0.05). Lichenoid changes similarly showed 50% serum levels were not collected according to a uniform improving and 50% unchanged (Po0.05). Overall the schedule and the frequency of topical dosing (including the majority of objective scores remained stable at FU1 and day of serum collection) was not standardized. improved at FU2 (Figure 1 and Table 4). Patient-reported subjective outcomes are plotted in Figure 2. There were Table 1 NIH oral cGVHD staging statistically significant improvements in median pain (1.0, range À3to5,Po0.05) and sensitivity (1.0, range À1to6, Stage 0 Stage 1 Stage 2 Stage 3 Po0.05) scores at FU2, but not FU1. There was a No Mild symptoms Moderate symptoms Severe symptoms statistically significant improvement in the median dryness symptoms with disease signs with disease signs with disease signs score at FU1 (2.0, range À3to4,Po0.05) and FU2 (2.5, but not limiting with partial on examination range À5to5,Po0.05). oral intake limitation of with major Serum TAC levels were evaluated in 11 patients significantly oral intake limitation of (Figure 3). All patients included in this part of the study oral intake had at least one TAC serum level read before and after the Abbreviations: cGVHD ¼ chronic GVHD; NIH ¼ National Institutes of start of topical treatment within a specified time frame (À50 Health. to þ 90 days). Over all data points, the median serum level

Bone Marrow Transplantation Topical dexamethasone/tacrolimus therapy for oral cGVHD H Mawardi et al 1064 was 4.4 ng/ml (range 1.0–16.3 ng/ml; therapeutic range trending upwards before the administration of topical 5–20 ng/ml). Four patients (37%) had increased TAC serum therapy, and throughout FU2 none exceeded the upper peak levels that correlated temporally to the administration therapeutic range limit. Case 13 had a systemic TAC dose of topical therapy (cases 6, 8, 13 and 14). Of these four adjustment during the serum level peak, from 0.5 to 1.0 mg. patients, cases 8 and 14 had levels that were already

Table 2 Patient characteristics Discussion N (%) ChronicGVHDisamajorimpediment for the broader use N 14 of HCT and remains the leading cause of non-relapse Age, median (range) 54 (20, 66) treatment-related mortality.2 Oral involvement in cGVHD is Sex common and can have a tremendous impact on oral intake, Female 4 (29) nutrition and overall quality of life. Several localized ancillary Male 10 (71) treatment regimens have been reported in the literature Type of transplant including rinsing with corticosteroid- or calcineurin inhibitor- 11,15 Myeloablative (standard) 8 (57) containing solutions, steroid injections and phototherapy. Non-myeloablative (mini) 6 (43) Topical corticosteroids and tacrolimus have been reported as effective monotherapy.12–14,16 As cGVHD is routinely HLA matching managed systemically with multiple medications with com- Matched—Related 4 (29) Matched—Unrelated 10 (71) plementary mechanisms of action, it is possible that cases of oral cGVHD that are refractory to monotherapy may benefit Time to cGVHD in months, median (range)a 7 (1, 20) from a combined topical approach. It was from this premise that we began treating our refractory patients with combined Disease AA 1 (7) topical DEX/TAC therapy. AML 5 (36) Combined DEX/TAC topical therapy resulted in im- CLL 2 (14) provement of objective and subjective outcomes in the MM 1 (7) majority of patients measured during this study period. NHL 3 (21) Although most were on concurrent systemic therapy, most PTCL 2 (14) regimens were stable or tapered during the study period, Sites of cGVHDa strongly suggesting a direct topical effect of the combined Oral 14 (100) rinses. As the NIH instruments were only recently Skin 10 (71) introduced, there have been few publications with which Eyes 5 (36) 16 GI 3 (21) to compare these results. The overall magnitude of Liver 2 (14) responses was greater at FU2 compared with FU1, Lung 3 (21) suggesting that duration of therapy is likely an important Joints 1 (7) factor in clinical efficacy. Concurrent systemic immunomodulatory therapies were in large part stable during the Abbreviations: AA=aplastic anemia; AML=acute myeloid leukemia; evaluation period, further supporting the efficacy of CLL=chronic lymphocytic leukemia; MM=multiple myeloma; NHL=non-Hodgkin lymphoma; PTCL=peripheral T-cell lymphoma. combined topical therapy. As data were evaluated retro- aMultiple sites are possible. spectively, and a standard dosing frequency was not

Table 3 Number, type and stability of cGVHD-speciﬁc medications

Case Baseline # meds Change FU1 no. Change FU2 no. All meds Dose Modiﬁcation PRD at each of meds of meds visit (mg)

1 2 +PRD 3 — 3 PRD/TAC/SIR — 0, 40, 40 2 1 +SIAL 2 — 2 PRD/SIAL — 20, 20, 20 3 3 — 3 — 3 PRD/TAC/SIAL — 20, 20, 20 4 2 +SIAL 3 — 3 PRD/TAC/SIAL — 40, 40, 40 5 2 — 2 — 2 PRD/TAC PRDk 30, 20, 15 6 1 +TAC 2 — 2 PRD/TAC — 5, 5, 5 7 2 N/A — — 2 TAC/SIAL — — 8 0 +TAC/SIAL 2 +MMF 3 TAC/MMF/SIAL — — 9 2 N/A — +SIAL 3 PRD/SIR/SIAL PRDk 30, 20, 20 10 2 +MMF 3 — 3 TAC/SIR/MMF TACk — 11 2 N/A — — 2 PRD/TAC — 20, 20, 20 12 2 +SIAL 3 — 3 PRD/SIR/SIAL PRDk/SIRk 20, 20, 15 13 2 — 2 — 2 PRD/TAC PRDk/TACm 15, 10, 5 14 2 — 2 — 2 PRD/TAC PRDk 30, 30, 25

Abbreviations: cGVHD=chronic GVHD; MMF=mycophenolate mofetil; PRD=prednisone; SIAL=Sialogogue therapy; SIR=sirolimus; TAC=tacrolimus. Three patients did not have response evaluations at FU1 indicated by ‘N/A’.

Bone Marrow Transplantation Topical dexamethasone/tacrolimus therapy for oral cGVHD H Mawardi et al 1065 8 8 P=0.41 P=0.25 P=0.69 P>0.99 P>0.99 P=0.06 P=0.07 P=0.02 P=0.92 P=0.22 6 6

4 4

2 2

0 0

−2 −2

−4 −4 Difference pre minus FU2 Difference pre minus FU1 −6 −6 TotalEM L U TotalEM L U Figure 1 Differences in NIH objective scores—Calculated from the baseline visit to each follow-up visit (FU1, FU2). A positive difference indicates an improvement from the initial assessment. The horizontal black bars indicate the median difference for each assessment. Total ¼ NIH Total Score (triangles); E ¼ Erythema, L ¼ Lichenoid, M ¼ Mucoceles, U ¼ Ulceration (circles)

Table 4 NIH scoring change after the start of combined therapy was seen only in the oncology clinic. Follow-up visits were not scheduled according to a protocol, therefore it is N Percentage Percentage Percentage P-value improved no change worsened feasible that responders who experienced significant improvement in symptoms with the start of combined DEX/ Baseline to FU1 TAC therapy might have been less likely to return for Erythema 11 27 72 0 0.13 follow-up and therefore not meet the criteria for inclusion Lichenoid 11 36 45 18 0.34 Ulceration 11 11 77 11 0.50 in this study. In contrast, patients with no or minimal Mucoceles 11 36 45 18 0.50 response might have been more likely to return and be included in a higher proportion in this study, potentially Baseline to FU2 marginalizing the magnitude of the reported treatment Erythema 14 50 43 7 0.035 Lichenoid 14 50 50 0 0.008 effect. Another significant limitation is the lack of data on Ulceration 14 36 57 7 0.11 compliance with respect to both the frequency and duration Mucoceles 14 29 43 29 0.58 of rinses. Prescription instructions were reviewed in detail, and at follow-up every patient was specifically asked how Abbreviations: FU1=the first follow-up visit; FU2=the second follow-up they were using the topical medications (frequency and visit; NIH=National Institutes of Health. duration); as the requirement and motivation for treatment was driven by patient symptoms, we have no reason to believe that these answers were not accurate, as has been discussed by others.18 There have been several reports of the use of topical TAC followed, the role of intensity of therapy could not be for the management of oral cGVHD.13,14,19 All previous determined. Sialogogue therapy was included under mon- reports of intraoral topical tacrolimus applications have itored systemic therapy as this may have had a role in described the use of the commercially available ointment improving the dryness scores. (Protopic, Astellas Pharmaceuticals, North Deerfield, IL, Subjective response to combined therapy was more USA), which is not designed for application to wet mucosal pronounced compared with objective criteria. Subjective surfaces and can be very difficult to use. As oral cGVHD is measures are intended to reflect the impact of oral cGVHD often extensive, rinses, such as DEX, are often preferred, on quality of life, which is typically what drives targeted easy to use by patients and are considered a mainstay of therapy to the oral cavity.17 Our data failed to show therapy.20 Although the compounding of TAC in an significant objective response except for lichenoid scores. aqueous solution has been reported for oral dosing in One possible explanation for the non-significant change in pediatric patients, this is the first report on the use of objective scores is the retrospective design of this study and topical TAC in a compounded rinse.21 selective bias. Duration of therapy also appeared to be an Although many studies have established the safety profile important factor as greater improvement was noted at FU2 of topical tacrolimus in managing multiple conditions,22–25 compared with FU1. there have been recent reports raising the concern about the There are a number of limitations to the findings of this development of clinically significant tacrolimus serum levels study. The patients included were likely to have more with topical use.14,26–28 Although the extent of TAC severe/refractory oral cGVHD compared with all patients absorption through oral mucosa remains unclear, there is from our center that developed oral cGVHD during the evidence for increased absorption through diseased study period. Although such organ (oral cavity) specific skin.14,26–30 The mechanism behind higher absorption may data is not routinely collected outside of the oral medicine be explained by impairment of the mucosal barrier in severe clinic, it is highly unlikely that there were additional oral cGVHD cases. Two cases associated with intraoral patients treated with combined DEX/TAC therapy that topical TAC use have been reported. In one case, the TAC

Bone Marrow Transplantation Topical dexamethasone/tacrolimus therapy for oral cGVHD H Mawardi et al 1066 8 8 P=0.63 P=0.17 P=0.50 P=0.04 P=0.45 P=0.03 P=0.006 P=0.02 6 6

4 4

2 2

0 0

−2 −2

−4 −4 Difference pre minus FU1 Difference pre minus FU2 −6 −6 Staging Pain Sens Dryness Staging Pain Sens Dryness Figure 2 Differences in subjective scores (0–10 scale) calculated from the baseline visit to each follow-up visit (FU1, FU2). A positive difference indicates an improvement from the initial assessment. The horizontal black bars indicate the median difference for each assessment. Sens ¼ Sensitivity

20 |−−−−Pre−Topical Tac−−−−| |−−−−−−−−−FU1−−−−−−−−| |−−−−−−−−−FU2−−−−−−−−|

Case 1 Case 4 15 Case 5 Case 6 Case 7 Case 8 Case 10 Case 11 10 Case 12 Case 13 Case 14

Serum Level (ng/mL)

−50 −40 −30 −20 −10 0 10 20 30 40 50 60 70 80 90 Days from Topical Tacrolimus Administration Figure 3 Tacrolimus serum levels before and following administration of topical tacrolimus. Day 0 signiﬁes the initiation of combined topical therapy. Horizontal dashed lines show the therapeutic range of tacrolimus (5–20 ng/ml).

plasma level increased from 11.6 ng/ml to 45.6 ng/ml (stable sidered as more reliable measures of cGVHD disease activity level due to systemic therapy) 2 days after starting topical compared with objective criteria. Our findings, largely support ointment therapy.28 In the second case, increased TAC the combined topical therapy with DEX/TAC as a protocol plasma level was measured in a 6-year-old patient (8.6 ng/ for refractory oral cGVHD, and may be considered as first- ml) after erroneous over-dosage with topical TAC oint- line therapy in more severe cases. Investigations with other ment.14 Corrocher et al.31 reported undetectable serum topical agents, alone and in combination, in the context of TAC level (o1.5 ng/ml) in 11 patients treated with 0.1% larger well-designed clinical trials and quality of life studies are ointment for desquamative gingivitis after 4 weeks of still needed. We are currently investigating the efficacy of DEX treatment. Our data demonstrated minimal evidence of and TAC prospectively as a single-agent topical therapy for systemic TAC absorption; however, larger prospective new onset oral cGVHD (NCT00686855; www.clinicaltrials. studies are needed. gov). Prospective randomized studies are necessary to estab- Combined topical DEX/TAC therapy appears to be lish evidence-based management and monitoring guidelines effective in reducing the symptoms of oral cGVHD. Patient- for this significant and often long-term oral complication reported outcomes, in particular sensitivity, might be con- following allogeneic HCT.

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