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Tacrolimus Ointment in the Treatment
of Chronic Cutaneous Graft-vs-Host Disease
A Case Series of 18 Patients
Caroline J. Choi, MD; Paul Nghiem, MD, PhD Background: Tacrolimus (formerly FK 506) is an im-
amination, side-by-side comparisons of tacrolimus vs a munosuppressive drug that works by inhibiting calci- vehicle control, and temporal flares of the cutaneous neurin, a calcium-dependent protein phosphatase re- symptoms of the disease in the context of stopping tac- quired for immune function. Tacrolimus has been shown rolimus ointment therapy. Because of the progression of to be effective topically in atopic dermatitis and systemi- GVHD and in 2 cases, loss of drug efficacy, all patients cally in psoriasis and graft-vs-host disease (GVHD). How- eventually went on to receive more aggressive treat- ever, its efficacy in treating cutaneous GVHD when ap- ment, including increases in steroid dosage, psoralen– plied topically has not been reported.
UV-A therapy, and extracorporeal photopheresis.
Objective: To assess the therapeutic efficacy of 0.1%
Conclusions: This case series suggests that tacrolimus
tacrolimus ointment on chronic cutaneous GVHD in pa- ointment has efficacy in treating the erythema and pru- tients with symptoms refractory to systemic corticoste- ritus of steroid-refractory, chronic cutaneous GVHD in most patients. The rapid response of tacrolimus oint-ment may provide a useful therapeutic bridge to sys- Results: Tacrolimus ointment effectively treated pruri-
temic therapies that have slower onset, such as psoralen– tus and/or erythema in 13 (72%) of 18 patients with UV-A therapy or extracorporeal photopheresis.
chronic GVHD. Responding patients had a rapid effectwithin several hours to days. Effectiveness was mea-sured by means of patient report, results of physical ex- DESPITEadvancesinpro- oferythema,pruritus,andscaling.Chronic
out previous acute GVHD. Given the broad- ening indications for BMT and protocols al- mains a frequent complication of allogeneic fecting 50% of patients with long-term trans- come an increasingly frequent challenge.
plant survival,1 with a 20% to 40% mortal- involves damage to the host tissue by the cyclosporine.7 These drugs cause signifi- quent cytokine release, activation, and clonal From the Department ofDermatology, Brigham and expansion of the donor’s effector T cells and fail to control the progression of the dis- fects.4-6 Principal targets of GVHD include the skin, gastrointestinal tract, and liver. The stay of local treatment of cutaneous GVHD, but their use has been limited by adverse ous, causing significant morbidity and mor- effects, including skin atrophy, telangiec- tasia, and striae cutis distensae. There- billiform eruption to a more severe epider- mal necrolysis, occurring within 100 days explored to improve the survival and qual- commercial, proprietary, orfinancial interest in the ity of life of patients with GVHD. Psoralen– (REPRINTED) ARCH DERMATOL / VOL 137, SEP 2001 2001 American Medical Association. All rights reserved.
see the beneficial effects of PUVA therapy and ECP, andbecause of the more immediate need to palliate local symp- PATIENTS AND METHODS
toms of cutaneous GVHD, there has been much interestin developing other topical therapies. Tacrolimus (for-merly FK 506) is a superb candidate for the topical treat- All patients in this case series were seen in the cuta- ment of chronic GVHD because of its ability to pen- neous oncology clinic at Dana Farber Cancer Insti- etrate the skin, limited profile of adverse effects, and potent tute, Boston, Mass, with the clinical diagnosis of chronicGVHD after allogeneic BMT. All patients were using at least 1 systemic immunosuppressive drug, includ- Tacrolimus is an immunosuppressive antibiotic from ing corticosteroids, cyclosporine, and mycopheno- the macrolide family, shown to be 10 to 100 times more late mofetil, for control of GVHD. However, their cu- potent than cyclosporine in the inhibition of T-cell acti- taneous symptoms were refractory, and the patients vation.14-16 This agent works by inhibiting calcineurin, a were referred to our clinic for additional therapy for calcium-activated protein phosphatase, which is neces- their disease. The clinical diagnosis of GVHD was given sary for appropriate immune modulation.17 Tacrolimus has to these patients in contrast to other diagnoses of atopic, also been shown to inhibit histamine release from mast seborrheic, or contact dermatitis, given the develop- cells and basophils, which may also contribute to its an- ment of cutaneous symptoms shortly after BMT, an tipruritic effect.18,19 Tacrolimus was first used clinically to incomplete response to high-dose systemic immuno-suppression, and the absence of a history of external prevent graft rejection in organ transplantation. It has also skin irritants. Patients were excluded from this series been shown to be efficacious in pyoderma gangrenosum, if they were concurrently using topical corticoste- Behc¸et’s disease, and Crohn’s disease, and large multi- roids or systemic tacrolimus. The risks and benefits center studies have reported topical administration to be of tacrolimus ointment were discussed with each pa- effective in atopic dermatitis20,21 and oral administration to be effective in psoriasis.22 Because tacrolimus does not The mean age of the patients (10 men and 8 affect collagen synthesis,23 there is no risk for skin atro- women) was 42.8 years (range, 28-59 years). The 18 phy, and with topical application, serum levels of the drug patients had the following primary diseases: chronic remain low or undetectable,24 thus avoiding the risk for myelogenous leukemia (4 patients), non-Hodgkin nephrotoxic effects found with oral tacrolimus. The ma- lymphoma (4 patients), acute lymphocytic leuke-mia (3 patients), acute myelogenous leukemia (4 pa- jor reported adverse effect of tacrolimus ointment has been tients), myelodysplastic syndrome (1 patient), chronic a transient burning sensation, making it a safe alternative lymphocytic leukemia (1 patient), and multiple my- to topical steroids. We hypothesized that given its im- eloma (1 patient). Patients had undergone the fol- munomodulatory activity and its efficacy in treating other lowing types of BMT: matched sibling (6 patients), inflammatory cutaneous diseases, tacrolimus ointment matched unrelated donor (3 patients), T-cell deple- would have therapeutic efficacy in treating patients with tion and matched sibling (5 patients), and T-cell deple- tion and matched unrelated donor (4 patients).
Because it was not yet available in an ointment form, topical tacrolimus therapy was prepared extem- poraneously as a 0.1% ointment as described byAoyama et al.25 Tacrolimus powder was com- A summary of our results is presented in the Table. Eigh-
pounded with 8% beeswax, 3% cholesterol, and 3% teen patients were treated with tacrolimus ointment for stearyl alcohol, and patients were instructed to apply their refractory chronic cutaneous GVHD. Thirteen pa- the ointment 2 to 3 times daily to affected areas. Se- tients (72%) responded to the treatment. A response was rum tacrolimus levels were measured to monitor sys- defined as effective relief of erythema and/or pruritus. Scal- temic absorption in 2 patients who applied tacroli- ing, pain, and “tightness” were also relieved by tacroli- mus ointment over their entire body and had a mus ointment, as reported by patients. Only 1 patient ex- response. The clinical course of patients was fol- perienced a negative effect, which was described as an lowed in the weeks and months after the initiation of uncomfortable sensation, as he felt that the extempora- tacrolimus ointment therapy. Efficacy of the therapywere evaluated by means of subjective patient report neously compounded ointment was “clogging the pores” and results of physician examination. Evidence of ef- ficacy was also inferred when possible from more ob- Of 6 patients who performed side-by-side compari- jective measures, including side-by-side compari- sons of tacrolimus ointment vs vehicle control, 4 (67%) sons of tacrolimus ointment on one side of the body had a positive effect of the tacrolimus compared with the with a petroleum vehicle control ointment on the other, control. In addition, 3 patients experienced flares of cu- as well as temporal flares of the disease after stopping taneous symptoms when stopping application of the tac- therapy. Treatment with tacrolimus ointment was dis- rolimus ointment for days, with rapid resolution on re- continued if it appeared that there was no benefit or application of the tacrolimus. Responding patients found if the patient experienced adverse effects.
that tacrolimus ointment was effective within hours todays. Of the 13 patients with a response, 6 (46%) used itfor 3 to 4 weeks; 4 (31%), 2 to 4 months; and 3 (23%), for a variety of T-cell–mediated skin diseases since more than 1 year. Two patients who responded to the the1980s,8,9 and recent case series have suggested that tacrolimus ointment lost efficacy of the therapy in 10 to these therapies are also effective for the treatment of 15 weeks. Of the 5 patients who did not respond to chronic GVHD.10-13 However, because it takes months to tacrolimus ointment, none continued therapy beyond 1 (REPRINTED) ARCH DERMATOL / VOL 137, SEP 2001 2001 American Medical Association. All rights reserved.
Treatment of Patients With Chronic GVHD*
Effect of Tacrolimus
Duration of
Duration of GVHD
Patient No./
Side-by-Side
Tacrolimus
Sites With
Flare Before
Sex/Age, y
Erythema
Pruritus
Comparison†
Chronic GVHD
Most Benefit
Tacrolimus Therapy
*GVHD indicates graft-vs-host disease; plus sign, improved; 2 plus signs, markedly improved; minus sign, no improvement; NA, not applicable; NP, not performed; ALL, acute lymphocytic leukemia; AML, acute myelogenous leukemia; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; MDS,myelodysplastic syndrome; MM, multiple myeloma; NHL, non-Hodgkin lymphoma; URD, unrelated donor; sib, sibling; PUVA, psoralen−UV-A; and ECP,extracorporeal photopheresis.
†Indicates comparison with petroleum vehicle control ointment.
‡Decadron (Merck & Co, Inc, Whitehouse Station, NJ).
month, and 1 patient described his use of the ointment as “sparing.” Serum tacrolimus levels were measured inthe 2 patients who were using tacrolimus ointment mostintensively and who had responded to an entire-body ap- A 59-year-old Egyptian American man (patient 5) plication of the ointment. During the initial period of received a diagnosis of acute myelogenous leukemia, heavy application, serum tacrolimus levels were unde- evolving in the setting of a previous myelodysplastic tectable for one of these patients and 1.7 ng/mL for the other (well below the systemic therapeutic range indi- The patient was treated with induction therapy for cated for the prevention of graft rejection, 5-15 ng/mL).
acute myelogenous leukemia, from which he achieved a In no patient was tacrolimus ointment alone suffi- complete response. He then underwent a T-cell deple- cient to control cutaneous GVHD in an ongoing man- tion allogeneic BMT from a matched sibling donor. At 1.5 ner. Four (22%) of 18 patients had long-term improve- months after BMT, a dry, scaly rash without erythema de- ment of their cutaneous GVHD with adjustment of their veloped bilaterally on his arms, consistent with mild, cu- oral immunosuppressive therapy, 12 patients (67%) taneous, acute GVHD. He started prednisone therapy at a started or are waiting to receive PUVA therapy or ECP, dosage of 20 mg/d. However, during the next few months, and 5 patients (28%) died secondary to progression of the patient had flaring and generalization of cutaneous their primary cancer, GVHD, and/or infection.
GVHD and symptoms of gastrointestinal tract involve- (REPRINTED) ARCH DERMATOL / VOL 137, SEP 2001 2001 American Medical Association. All rights reserved.
Transplant
Medications
A, Scaling and erythroderma of chronic cutaneous graft-vs-host disease on the face of a 59-year-old man (patient 5). B, Resolution of these cutaneous symptoms after 3 weeks of treatment with 0.1% tacrolimus ointment twice follow-up visit, the risks and benefits of topical tacroli-mus therapy were discussed with the patient.
The patient was instructed to apply 0.1% tacrolimus ointment twice daily to all affected areas with cutaneousGVHD. After 3 weeks of using tacrolimus ointment, the ment of the disease when tapering the prednisone dos- patient returned to the clinic and reported that his itch and age. His nausea and diarrhea responded to an increased redness were much improved, even in the context of ta- prednisone dosage of 60 mg/d and initiation of cyclospor- pering the prednisone dosage recently from 40 to 25 mg/d.
ine therapy at a dosage of 100 mg twice daily (BID). How- Although he had started a BID regimen, he quickly con- ever, cutaneous GVHD continued to be refractory to this verted to an every-night regimen for convenience. On physi- cal examination, there was marked improvement in the The patient was referred to the cutaneous oncology amount of erythema and scaling diffusely, most notably on clinic at Dana Farber Cancer Institute 7 months after BMT his face (Figure B), and he had no excoriations. However, for further management of chronic cutaneous GVHD. On the erythema was slightly worse on the upper arms, and results of physical examination, he had an impressive de- there was still a small amount of blanching discoloration gree of generalized erythroderma, with fine scale across on his thighs and knees. The patient was encouraged to the entire head, trunk, and extremities (Figure A). There
continue applying the tacrolimus ointment BID to the af- was marked hyperkeratosis on the weight-bearing sur- fected areas. Three months after initiation of the tacroli- faces of his feet and minimal excoriations on his body. A mus therapy, the efficacy of this treatment diminished, and regimen of a nightly colloidal oatmeal bath, followed by in a side-by-side comparison conducted at this time, the 12% ammonium lactate cream BID and mometasone fu- benefit of tacrolimus therapy was no longer greater than roate ointment, had not been helpful. Therefore, at his next that of the control vehicle. His cutaneous GVHD appeared (REPRINTED) ARCH DERMATOL / VOL 137, SEP 2001 2001 American Medical Association. All rights reserved.
to be stable with a diffuse, mild erythema and scaling in future blinded, randomized, placebo-controlled studies addition to tenderness on the soles of his feet. Because of are warranted to investigate the effectiveness of therapy this loss of efficacy, tacrolimus ointment therapy was dis- with tacrolimus ointment for cutaneous GVHD.
continued. During the next 3 months, the patient’s healthdeteriorated with a wasting syndrome and worsening of cu- Accepted for publication May 2, 2001. taneous GVHD. He was treated with anti–interleukin 2 re- This work was supported in part by the American Acad- ceptor antibody daclizumab (Zenapax) and became se- emy of Dermatology (Schaumburg, Ill) Young Investigator verely immunocompromised. He eventually experienced mental status changes, at which point he was found to have We would like to thank Stephanie Lee, MD, for her help- a JC virus infection. The patient died of sepsis 3 months after discontinuation of topical tacrolimus therapy.
Corresponding author: Paul Nghiem, MD, PhD, Har- vard University, Department of Chemistry and Chemical Bi-ology, 12 Oxford St, Cambridge, MA 02138 (e-mail: The results of this case series suggest that tacrolimus oint-ment, when applied 2 to 3 times daily, is effective in re- ducing erythema and pruritus in most patients with sys-temic steroid-refractory chronic cutaneous GVHD. This 1. Atkinson K. Chronic graft-versus-host disease. Bone Marrow Transplant. 1990; case series describes patient reports, physician observa- 2. Wingard JR, Piantadosi S, Vogelsang GB, et al. Predictors of death from chronic tions, side-by-side comparisons, and temporal flares to graft-versus-host disease after bone marrow transplantation. Blood. 1989;74: evaluate the benefit of tacrolimus therapy. Because of the 3. Billingham RE. The biology of graft-versus-host reaction. In: The Harvey Lec- observational nature of this case series, no histological tures. Orlando, Fla: Academic Press Inc; 1966;62:21-78.
evaluation was performed before or after tacrolimus treat- 4. Ferrara JLM, Deeg HG. Graft-versus-host disease. N Engl J Med. 1991;324:667- ment. However, such evaluation should be considered in 5. Ferrara JLM. The cytokine modulation of acute graft-versus-host-disease. Bone Marrow Transplant. 1998;21(suppl 3):13-15.
The 2 subtherapeutic serum tacrolimus levels from pa- 6. Antin JH, Ferrara JLM. Cytokine dysregulation and acute graft-versus-host dis- tients who were responsive to the ointment confirmed that 7. Sullivan KM, Witherspoon RP, Storb R, et al. Alternating-day cyclosporine and their response was local and that they were not prone to prednisone for treatment of high-risk chronic graft-versus-host disease. Blood.
the systemic adverse effects of tacrolimus. Because of its 8. Powell FC, Spiegel GT, Muller SA. Treatment of parapsoriasis and mycosis fun- limited profile of adverse effects, tacrolimus ointment could goides. Mayo Clin Proc. 1984;59:538-546.
be a useful steroid-sparing therapy for areas of thinner skin, 9. Edelson R, Berger C, Gasparro F, et al. Treatment of cutaneous T-cell lymphoma by extracoporeal photochemotherapy. N Engl J Med. 1987;316:297-303.
such as the face and genitals. Consistent with previous stud- 10. Wiesmann A, Weller A, Lischka G, Klingebiel T, Kanz L, Einsele H. Treatment of ies of tacrolimus ointment for other inflammatory skin dis- acute graft-versus-host disease with PUVA (psoralen and ultraviolet irradia- eases, this case series showed that patients experienced an tion): results of a pilot study. Bone Marrow Transplant. 1999;23:151-155.
11. Owsianowski M, Gollnick H, Siegert W, et al. Successful treatment of chronic effect of tacrolimus, defined as palliation of erythema and graft-versus-host-disease with extracorporeal photopheresis. Bone Marrow pruritus, within hours to days. Although most patients used the topical therapy for about 1 month, 3 patients used it 12. Rossetti F, Zulian F, Dall’Amico R, et al. Extracorporeal photo-chemotherapy as single therapy for extensive, cutaneous, chronic graft-versus-host disease. Trans- for more than 1 year and found that they continued to have a positive therapeutic response to the drug. Two patients 13. Greineix HT, Volc-Platzer B, Knobler RM. Extracorporeal photochemotherapy in the treatment of severe graft-versus-host-disease. Leuk Lymphoma. 2000;36: experienced a loss of response to the drug within 3 to 4 months of treatment. It is unclear whether this was due to 14. Sawada S, Suzuki G, Kawase Y, Takaku F. Novel immunosuppressive agent, FK506: drug tachyphylaxis or to disease progression beyond the in vitro effects on cloned T-cell activation. J Immunol. 1987;139:1797-1803.
15. Kina T, Hatanaka H, Hashimoto M, et al. FK506, a novel immunosuppressant iso- therapeutic efficacy of topical tacrolimus therapy.
lated from a Streptomyces, I. J Antibiot (Tokyo). 1987;40:1249-1255.
As demonstrated by our case report, the natural pro- 16. Kina T, Hatanaka H, Miyata S, et al. FK506, a novel immunosuppressant isolated gression of chronic GVHD can be difficult to control, and from a Streptomyces, II. J Antibiot (Tokyo). 1987;40:1256-1265.
17. Schreiber SL, Crabtree GR. The mechanism of action of cyclosporine A and FK506.
despite temporal palliation of cutaneous symptoms with topical tacrolimus, the underlying systemic disease needs 18. de Paulis A, Stellato C, Cirillo R, Ciccarelli A, Oriente A, Marone G. Anti- inflammatory effect of FK-506 on human skin mast cells. J Invest Dermatol. 1992; to be treated aggressively with an increase in steroid dos- age, PUVA therapy, or ECP. Although it appears unlikely 19. Eberlein-Konig B, Ruzicka T, Michel G, Przybilla B. Modulation of histamine re- to be suitable as a monotherapy for chronic GVHD, tacro- lease in vitro by FK506 and interleukin-3 is determined by sequence of incuba-tion. Arch Dermatol Res. 1997;289:606-608.
limus ointment may be a safe alternative to topical corti- 20. Ruzicka T, Bieber T, Schopf E, et al. A short-term trial of tacrolimus ointment for costeroids as a therapeutic bridge to therapies such as PUVA atopic dermatitis. N Engl J Med. 1997;337:816-821.
therapy or ECP, which may take months to show efficacy.
21. Reitamo S, Wollenberg A, Schopf E, et al. Safety and efficacy of 1 year of tacro- limus ointment monotherapy in adults with atopic dermatitis. Arch Dermatol. 2000; Because of the natural waxing and waning nature of the cutaneous symptoms of chronic GVHD, further 22. The European FK506 Multicentre Psoriasis Study Group. Systemic tacrolimus (FK506) is effective for the treatment of psoriasis in a double-blind, placebo- studies need to be implemented to more definitively cor- controlled study. Arch Dermatol. 1996;132:419-423.
relate topical tacrolimus therapy with alleviation of these 23. Reitamo S, Rissanen J, Remitz A, et al. Tacrolimus ointment does not affect col- symptoms. Future studies will also need to clarify the ef- lagen synthesis. J Invest Dermatol. 1998;111:396-398.
24. Kawashima M, Nakagawa H, Ohtsuki M, Tamaki K, Ishibashi Y. Tacrolimus con- ficacy of a longer duration of treatment with tacrolimus, centrations in blood during topical treatment of atopic dermatitis. Lancet. 1996; its use as an adjunctive treatment to systemic immuno- suppressive drugs, and its efficacy in acute GVHD. Given 25. Aoyama H, Tabata N, Tanaka M, Uesugi Y, Tagami H. Successful treatment of resistant facial lesions of atopic dermatitis with 0.1% FK506 ointment. Br J Der- the encouraging results of this preliminary case series, (REPRINTED) ARCH DERMATOL / VOL 137, SEP 2001 2001 American Medical Association. All rights reserved.

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