Case report

Treatment of overlap cutaneous graft-versus-host disease with combination therapy of extracorporeal photopheresis and alemtuzumab Choon Chiat Oh1, MBBS, MRCP (UK), Haur Yueh Lee1, MBBS, MRCP (UK), Mei Fung Michelle Chan2, MBBS, FRCPath (UK), and Sathish Kumar Gopalakrishnan3, MBBS, MRCP, FRCPath, CCST Hematology

1 Department of Dermatology, Singapore General Hospital, Singapore, Singapore, 2 Department of Pathology, Singapore General Hospital, Singapore, Singapore, and 3Department of Hematology, Singapore General Hospital, Singapore, Singapore

Correspondence Choon Chiat Oh, MBBS, MRCP (UK) Department of Dermatology Singapore General Hospital Outram Road Singapore 169608 Singapore E-mail: [email protected] Conflicts of interest: None.

Although graft-versus-host disease (GVHD) has been traditionally classified into acute and chronic forms based on an arbitrary cut-off of 100 days from date of onset, it is now recognized that the onset and presentation of disease may be modified by evolutions in transplant strategies and immunomodulatory treatments.1 The National Institutes of Health (NIH) consensus development project was conceived to standardize diagnostic criteria for clinical trials in chronic GVHD. Acute GVHD was divided into classic acute GVHD, in which symptoms appear within 100 days without any other features of chronic GVHD, and persistent, recurrent, or late-onset acute GVHD, in which symptoms appear after 100 days without features of chronic GVHD. Chronic GVHD includes classic chronic GVHD, which shows features supportive of chronic GVHD without those of acute GVHD regardless of time of presentation, and overlap syndrome, which includes features of both acute and chronic GVHD.2 ª 2014 The International Society of Dermatology

Case report A 36-year-old Indian woman underwent related non-myeloablative, allogenic, peripheral blood stem cell transplant for hematological anaplastic large cell lymphoma. The donor was the recipient’s sister and was fully matched for human leukocyte antigen (HLA). The conditioning regimen consisted of fludarabine and low-dose total body irradiation in a non-myeloablative transplantation protocol. The transplant phase was uneventful, and the patient made a hematological recovery on day 10 post-transplant. On day 16, she presented with generalized erythema with fever. The differential diagnosis considered acute GVHD and an exanthematous drug eruption secondary to the administration of antibiotics. However, despite the switching of antibiotics, the patient’s exanthema persisted, which favored the former diagnosis. A skin biopsy showed scattered apoptotic keratinocytes, exocytosis of lymphocytes, and mild spongiosis (Fig. 1). The patient was treaInternational Journal of Dermatology 2016, 55, 335–338

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Treatment of overlap GVHD with ECP and alemtuzumab

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Figure 1 Histopathology of a skin biopsy in a 36-year-old woman with graft-versus-host disease shows scattered apoptotic keratinocytes, exocytosis of lymphocytes and mild spongiosis. (Hematoxylin and eosin stain; original magnification 2009)

ted with emollients, topical corticosteroids, and oral prednisolone 1 mg/kg with improvement. On day 23, she developed a scaly erythematous eruption affecting 40– 50% of body surface area. This progressed to generalized exfoliative dermatitis with scattered erosions despite ongoing treatment with prednisolone, tacrolimus, and mycophenolate. Concurrently, new areas of confetti depigmentation developed over her limbs and trunk (Fig. 2a–c). A second biopsy showed features of acanthosis, necrotic keratinocytes, and satellitosis (Fig. 3). Based on the sequential and overlapping presentations of exanthema and generalized exfoliative dermatitis with areas of confetti depigmentation, a diagnosis of overlap GVHD was made. A trial of alemtuzumab (20 mg for 3 d) and extracorporeal photopheresis (ECP) (twice weekly for 5 weeks) was initiated. Within 10 sessions of ECP, the resolution of the erythema and scaling was apparent. On day 113, the patient demonstrated the total repigmentation of the previously depigmented lesions (Fig. 4a–c).

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Discussion Typical features of acute GVHD include erythema of the palms, soles, and ears, perifollicular erythema, and generalized exanthema, which may progress to bullae formation or necrolysis. The features of chronic GVHD are protean and include lichen planus-like, lichen sclerosuslike, morphea-like, eosinophilic fasciitis-like lesions, hypo-/hyperpigmentation, keratosis pilaris-like eruption, alopecia, and mucosal changes such as white reticulated plaques, as well as nail changes. Although recommendations for histological criteria for the diagnosis and grading of acute and chronic GVHD International Journal of Dermatology 2016, 55, 335–338

(c) Figure 2 Extensive scaling, scattered erosions and confetti depigmentation are apparent on the (a) abdomen, (b) thighs and (c) legs in a 36-year-old woman with graft-versus-host disease

have been proposed,3 making a diagnosis and ruling out differentials based solely on the histological specimen is challenging. Features such as keratinocyte apoptosis, ª 2014 The International Society of Dermatology

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Treatment of overlap GVHD with ECP and alemtuzumab

Case report

(a)

Figure 3 A second biopsy shows acanthosis, necrotic keratinocytes and satellitosis. The inflammatory cells comprise lymphocytes and macrophages with occasional eosinophils. (H&E stain; 2009)

atypia, basal vacuolar change, and dermal lymphocytes are nonspecific and may be found in other diagnoses, such as drug exanthems, viral infections, and toxic effects of chemotherapy.4,5 Similarly, the presence of tissue eosinophilia, often associated with hypersensitivity reactions, can only poorly discriminate drug-induced reactions from acute GVHD.6 The diagnosis of acute GVHD is thus a clinical diagnosis supported by other relevant investigations and histological findings.5,7 In chronic GVHD, histological findings may overlap with those of acute GVHD; however, the presence of lichenoid changes or collagenous deposition, sclerosis, or fascial thickening is diagnostic of lichen planus-like and sclerotic/morphei/fasciitis-like chronic GVHD. In cases of eczematoid or atopic dermatitis-like GVHD, features of parakeratosis, spongiosis, and acanthosis coexist with keratinocyte apoptosis and basal vacuolar degeneration.8,9 The histological findings in overlap GVHD have not been well documented; however, the coexistence of both acute changes and lichenoid features is considered predictive of the evolution of acute GVHD to chronic GVHD.10 Eczematous variants of chronic GVHD have been increasingly recognized.8,9 Alemtuzumab is a humanized monocolonal antibody against CD52, which is expressed on the surface of B and T lymphocytes. It has been used for the prevention of acute GVHD and for the treatment for steroid-refractory acute GVHD. Alemtuzumab has been used in the treatment of acute GVHD with overall response rates of 60–80% and complete response rates of 20–30%.11–14 Infective complications such as cytomegalovirus infection are common among patients treated with alemtuzumab.12 Extracorporeal photopheresis has been utilized as a treatment for acute GVHD, and complete remission rates of 40–60% have been reported, although improvements ª 2014 The International Society of Dermatology

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(c) Figure 4 Treatment with extracorporeal photopheresis and alemtuzumab results in the repigmentation and healing of erosions on the (a) abdomen, (b) thighs and (c) legs

in skin and liver GVHD are more significant, and a lesser response is shown in other sites.15–18 The strategy has also shown promising response rates of up to 60% in the International Journal of Dermatology 2016, 55, 335–338

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treatment of chronic GVHD, but, more importantly, it facilitates a steroid-sparing protocol.18 Two recent papers have highlighted prognostic markers in chronic GVHD.19,20 Evidence-based treatment protocols for non-sclerotic manifestations such as the lichen planus-like, eczematous, dyspigmentary, hair, nail, and mucosal forms remain limited. These non-sclerotic forms are often seen by dermatologists, who must therefore be able to make the diagnosis, assess disease activity, and engage multiple specialties in devising effective therapeutics.

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response to psoralen UV-A therapy. Arch Dermatol 2007; 143: 1157–1162. Bridge AT, Nelson RP Jr, Schwartz JE, et al. Histological evaluation of acute mucocutaneous graft-versus-host disease in non-myeloablative hematologic stem cell transplants with an observation predicting an increased risk of progression to chronic graft-versus-host disease. Am J Dermatopathol 2007; 29: 1–6. Carella AM, Beltrami G, Scalzulli PR, et al. Alemtuzumab can successfully treat steroid-refractory acute graft-versus-host disease (aGVHD). Bone Marrow Transplant 2004; 33: 131–132. G omez-Almaguer D, Ruiz-Arg€ uelles GJ, del Carmen Tarˇn-Arzaga L, et al. Alemtuzumab for the treatment of steroid-refractory acute graft-versus-host disease. Biol Blood Marrow Transplant 2008; 14: 10–15. Kanda J, Lopez RD, Rizzieri DA. Alemtuzumab for the prevention and treatment of graft-versus-host disease. Int J Hematol 2011; 93: 586–593. Martˇnez C, Solano C, Ferr a C, et al. Alemtuzumab as treatment of steroid-refractory acute graft-versus-host disease: results of a phase II Study. Biol Blood Marrow Transplant 2009; 15: 639–642. Couriel DR, Hosing C, Saliba R, et al. Extracorporeal photochemotherapy for the treatment of steroid-resistant chronic GVHD. Blood 2006; 107: 3074–3080. Greinix HT, Knobler RM, Worel N, et al. The effect of intensified extracorporeal photochemotherapy on longterm survival in patients with severe acute graft-versus-host disease. Haematologica 2006; 91: 405–408. Perfetti P, Carlier P, Strada P, et al. Extracorporeal photopheresis for the treatment of steroid refractory acute GVHD. Bone Marrow Transplant 2008; 42: 609– 617. Scarisbrick JJ, Taylor P, Holtick U. UK consensus statement on the use of extracorporeal photopheresis for treatment of cutaneous T cell lymphoma and chronic graft-versus-host disease. Br J Dermatol 2008; 159: 659– 678. Sally A, Madan J, Barry S, et al. Global and organspecific chronic graft-versus-host disease severity according to the 2005 NIH Consensus Criteria. Blood 2011; 118: 4242–4249. Jacobsohn DA, Kurland BF, Pidala J, et al. Correlation between NIH composite skin score, patient-reported skin score, and outcome: results from the Chronic GVHD Consortium. Blood 2012; 120: 2545–2552.

ª 2014 The International Society of Dermatology

Treatment of overlap cutaneous graft-versus-host disease with combination therapy of extracorporeal photopheresis and alemtuzumab.

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