Volume 14, Issue 1 , Pages 7-9, January 2008
Alemtuzumab-Induced Resolution of Refractory Cutaneous Chronic Graft-Versus-Host Disease
Article Outline
Abstract
A patient with extensive cutaneous chronic graft-versus-host disease (cGVHD) affecting 100% of the body surface, with painful ulcerations that involved 20% of it, was treated unsuccesfully during 9 months with steroids, cyclosporine-A (CSa), sirolimus, tacrolimus, mychophenolate mofetil (MMF), infliximab, and rituximab. Twenty-one months after the allograft the patient was started on alemtuzumab, 10 mg/day subcutaneously, for 6 consecutive days every 4 weeks. Seven months after starting the treatment, 100% of the ulcers had disappeared, as had the pain. To our knowledge, there are no reports of the use of alemtuzumab in the treatment of extensive, ulcerated, refractory cutaneous cGVHD. The data presented here suggest that this agent may be useful in some patients with refractory forms of cGVHD.
Key Words: GVHD, cutaneous, alemtuzumab, ulcers
Introduction
Chronic graft-versus-host disease (cGVHD) is a common complication following allogeneic hematopoietic cell transplantation (HCT); it is the leading cause of nonrelapse mortality (NRM) in transplant survivors and has a significant impact upon their functional status and quality of life. Despite significant advances in the field of HCT in recent years, there has been little change in the incidence, morbidity, and mortality of cGVHD [1]. The main clinical targets of GVHD are the skin, liver, gastrointestinal tract, and possibly the lungs. The standard initial therapy for GVHD includes the use of high-dose steroids, which result in an unsatisfactory complete response rate of about 40% and the need to develop more effective therapies [2]. Etanercept, mycophenolate mofetil (MMF), denileukin diftitox, pentostatin, rituximab, daclizumab, sirolimus (rapamycin), basiliximab, thalidomide, extracorporeal photopheresis, and other approaches have been tried, with variable results [2]. Skin is the most frequently affected organ in cGVHD and manifestations are highly variable 3, 4.
Alemtuzumab (Campath 1H) is an unconjugated, humanized IgG1 kappa monoclonal antibody which targets the CD52 antigen on T and B lymphocytes, as well as on monocytes, macrophages, eosinophils, and dendritic cells [5]. This antibody has been used in the conditioning regimens employed for allogeneic HCT to remove donor T cells so as to prevent GVHD, however, only a few patients have received this antibody for the treatment of established GVHD, and only anecdotal information is available in this setting 6, 7, 8, 9, 10. Alemtuzumab has also been used to treat autoimmune diseases [11].
We describe the case of a female patient with a severe, ulcerated refractory form of cutaneous cGVHD who had received, unsuccessfully, several treatments. She finally cleared the cutaneous ulcers and the pain with the use of subcutaneous alemtuzumab.
Case Report
A 19-year-old woman was diagnosed with M2 acute myelogenous leukemia (AML) in January 2003. Her blast cells expressed CD7, CD13, CD33, CD34, and CD45. After achieving a complete remission with conventional chemotherapy, a relapse ensued in October 2003. She was then induced to a second remission and afterwards, allografted from her HLA identical male sibling in December 2003, using a conventional conditioning regimen. Cytomegalovirus (CMV) serology (IgG) was positive both in the donor and the patient. Without having developed acute GVHD (aGVHD), extensive cutaneous GVHD ensued 1 year after the allograft, affecting 100% of the body surface. The skin lesions were initially lichenoid, but some progressed to overt painful ulcerations despite treatment. Treatment consisted of oral steroids (prednisone) for 7 months; cyclosporine-A (CSa) for 7 months; sirolimus, tacrolimus, and for 1 month each; one dose of infliximab and two doses of rituximab. All these drugs were administered unsuccessfully to the patient during a 9-month period, and no GVHD involvement of other organs ensued.
The ulcers evolved until they comprised approximately 20% of the body surface area (BSA) according to Greinix et al [12]. At this point, a skin biopsy from the patient's right thigh showed a thinned atrophic epidermis with loss of rete ridges and some dyskeratotic cells, vacuolar alteration of the interface with detachment of the epidermis, and a superficial perivascular lymphocytic inflammatory infiltrate with plasma cells and some eosinophils with a hint of lichenoid pattern, as well as pigment incontinence. Some thickening of collagen bundles were seen in deeper reticular dermis. No appendages were found (Figure 1). After a 1-month washout period of all the drugs, and 21 months after the allograft, with an extensive, painful, severe ulcerative variant of cutaneous cGVHD (Figure 2), the patient, with a Karnofsky score of 40% and after giving her written informed consent, was started on alemtuzumab, 10 mg/day subcutaneously, for 6 consecutive days every 4 weeks. No other immunosuppressive drugs were delivered. Cotrimoxasole was given prophylactically and CMV antigen was assesed every 2 weeks. Three weeks after starting alemtuzumab, the cutaneous lesions began to scar. Twenty percent of the skin surface was ulcerated at the beginning of the treatment and 0% of the skin surface was ulcerated 7 months later (Figure 2); lichenoid plaques with xerosis, skin thickening, and limited motion became apparent. In addition, the pain disappeared completely when the ulcers healed. At this point, alemtuzumab was switched to 10 mg/week subcutaneously. CMV antigenemia has remained persistently negative, and the complete blood cell counts were normal. The patient is currently a full chimera. She is now able to walk by herself, with a Karnofsky score of 80%. She received a total of 460 mg of alemtuzumab.
Figure 1
Skin biopsy obtained before treatment with alemtuzumab. Thinned and detached epidermis is apparent, with a hint of lichenoid arrangement of the lymphocytic infiltrate in the upper dermis.
Figure 2
A, Skin changes in the right lower limb of the patient prior to the treatment with alemtuzumab; extensive ulceration is obvious. B, The same region 6 months after the treatment.
Discussion
cGVHD complicates allogeneic SCT in 6% to 80% of cases, according to variables such as recipient age, donor age, donor type, stem cell source, graft manipulation, and the use of donor lymphocyte infusions [1]. Skin is the most frequently affected organ, and severe sclerotic features characterized by thickened tight and fragile skin are often associated with poor wound healing, inadequate lymphatic drainage, and skin ulcers from minor trauma [12]. In cutaneous cGVHD, the combination of corticosteroids and cyclosporine is used, whereas other immunosuppressants may be added depending on whether lichenoid or sclerodermatous lesions are present [13]. High response rates to phototherapy have been found in lichenoid disease, whereas sclerodermatous disease responds better to etretinate or extracorporeal photochemotherapy. Localized cutaneous cGVHD may be treated with topical corticosteroids alone, but experience with the treatment of extensive, ulcerated, refractory cutaneous cGVHD is limited.
Intravenous administration of alemtuzumab has been approved in the United States and in Europe for the treatment of patients with B cell chronic lymphocytic leukemia. Recent reports suggest that alemtuzumab can also be delivered subcutaneously achieving blood levels equivalent to those when given intravenously 14, 15. As the incidence of the infusion-related events reported using the i.v. route is as high as 90% [16], we administered the drug subcutaneously to minimize adverse events [17]; we also used this study to test the 10 mg/day dose. There are few reports about the usefulness of alemtuzumab in the treatment of GVHD 7, 8, 9, 10, 16, but most of these reports have been made regarding individuals with the aGVHD.
To our knowledge, there are no reports of the use of alemtuzumab in the treatment of extensive cutaneous GVHD; additional studies are needed to support this observation.
Acknowledgments
The alemtuzumab was provided by Bayer-Schering México.
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PII: S1083-8791(07)00488-0
doi:10.1016/j.bbmt.2007.09.013
© 2008 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Volume 14, Issue 1 , Pages 7-9, January 2008
