- Email: [email protected]
Long-term extracorporeal photochemotherapy in a pediatric patient with refractory sclerodermatous chronic graft-versus-host disease
Transfusion and Apheresis Science 45 (2011) 187–190
Contents lists available at ScienceDirect
Transfusion and Apheresis Science journal homepage: www.elsevier.com/locate/transci
Long-term extracorporeal photochemotherapy in a pediatric patient with refractory sclerodermatous chronic graft-versus-host disease Emil Bisaccia a,b,⇑, Mark Palangio b, Joselyn Gonzalez b,c a
Columbia University College of Physicians and Surgeons, New York, NY, USA Section of Photopheresis, Morristown Memorial Hospital, Morristown, NJ, USA c Department of Internal Medicine, Morristown Memorial Hospital, Morristown, NJ, USA b
a r t i c l e
i n f o
Keywords: Chronic graft-versus-host disease Extracorporeal photochemotherapy Hematopoietic stem cell transplantation Pediatric Photopheresis Steroids
a b s t r a c t Sclerodermatous chronic graft-versus-host disease (cGVHD) following allogeneic hematopoietic stem cell transplantation (HSCT) in children is difficult to treat and life-threatening. Extracorporeal photochemotherapy (ECP; photopheresis), an immunomodulatory therapy that involves the infusion of autologous peripheral blood leukocytes after ex vivo exposure to the photoactive agent 8-methoxypsoralen and ultraviolet A radiation, is an effective treatment for steroid-refractory cGVHD. After undergoing allogeneic HSCT for pre-B-cell acute lymphoblastic leukemia, a 14-year-old boy developed extensive sclerodermatous cGVHD that was refractory to prednisone, tacrolimus, and sirolimus. ECP was administered over the course of 53 months, during which the skin softened substantially and immunosuppressive therapy was discontinued. This case suggests that long-term ECP is a viable option in children with sclerodermatous cGVHD. Ó 2011 Published by Elsevier Ltd.
1. Introduction Chronic graft-versus-host disease (cGVHD) is a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (HSCT) in children, occurring in 20–50% of recipients [1]. cGVHD can affect virtually any organ system, with manifestations ranging from acute inflammation to chronic fibrosis. First-line therapy usually consists of prednisone combined with cyclosporine, and refractory cases are treated with additional immunosuppressants, often administered for years. Given the partial effectiveness and high toxicity with these agents, alternative approaches are being investigated. Extracorporeal photochemotherapy (ECP; photopheresis), an immunomodulatory therapy that involves the infusion of autologous peripheral blood leukocytes
⇑ Corresponding author at: Morristown Memorial Hospital, 100 Madison Avenue, Morristown, NJ 07962-1956, USA. Tel.: +1 973 971 4192; fax: +1 973 290 7148. E-mail address: [email protected] (E. Bisaccia). 1473-0502/$ - see front matter Ó 2011 Published by Elsevier Ltd. doi:10.1016/j.transci.2011.07.005
after ex vivo exposure to the photoactive agent 8-methoxypsoralen (8-MOP) and ultraviolet A (UVA) radiation, is an effective treatment for steroid-refractory cGVHD [2]. We describe the case of a child with refractory sclerodermatous cGVHD who was treated with ECP for more than 4 years. 2. Case report An 11-year-old boy with pre-B-cell acute lymphoblastic leukemia was brought into remission with the Memorial Sloan-Kettering-New York-II protocol after failing on standard-risk, front-line Children’s Oncology Group protocol. Because he was at high risk for relapse with continued chemotherapy, the patient underwent unrelated-donor bone marrow transplantation. Prophylaxis for acute graft-versus-host disease (aGVHD) consisted of cyclosporine and a short course of methotrexate. Approximately 9 months after transplantation, he suffered an isolated marrow relapse and was enrolled in a Phase I/II study with clofarabine, which rendered him aplastic for 6–8 weeks. He then underwent unmodified peripheral blood stem cell
E. Bisaccia et al. / Transfusion and Apheresis Science 45 (2011) 187–190
transplantation from the same donor and received the same aGVHD prophylaxis regimen. The patient later developed grade III cutaneous aGVHD (without liver or gastrointestinal involvement), which was treated successfully with steroid therapy. Approximately 3 months after the second transplantation, he developed cutaneous cGVHD, which responded completely after 3 months of treatment with prednisone and cyclosporine. Over the next few months, the patient experienced steroid-related myopathy and osteonecrosis of the hips, knees, and ankles. At that time, he had difficulty with ambulation, particularly while attending school. Approximately 2 years after the second transplantation, the patient developed, over the course of only 1 month, significant flexion contractures of the shoulders, elbows, wrists, and fingers, relatively sparing his lower extremities. Consequently, the patient was treated with resumption of cyclosporine and a ‘‘pulse’’ of moderate-dose prednisone. Joint mobility did not improve, and he was placed back on prednisone 5 mg on alternating mornings and cyclosporine. After he presented with seizures, cyclosporine was discontinued, and tacrolimus 1 mg twice daily was begun. In order to keep the steroid dose low, sirolimus 1 mg daily was added. Despite this regimen, skin tightness developed over his abdomen and around his shoulder girdle, along with a persistent decreased range of motion of multiple joints, including the shoulders, elbows, wrists, knees, and ankles. Severely sclerodermatous skin was noted on the neck, chest, abdomen, back, arms, thighs, and ankles. Mild erythematous and scaly lesions appeared on both axillas. However, there was no evidence of sicca or pulmonary or hepatic involvement. Approximately 8 months after the onset of sclerodermatous cGVHD, at 14 years of age, the patient was referred for ECP, rather than intensifying immunosuppressive therapy. ECP was performed using the UVAR XTS system (Therakos, Inc., Exton, PA, USA) according to the manufacturer’s guidelines. With this automated system, a small portion of the patient’s blood is obtained through an antecubital venous line and separated into erythrocyte and buffy coat fractions. While the erythrocyte fraction is immediately returned to the patient, the buffy coat fraction is exposed to 8-MOP (UVADEX; Therakos, Inc., Exton, PA, USA) and long-wave UVA radiation. At the conclusion of each session, the ECP-processed buffy coat fraction is reinfused. Each treatment session lasts 3–4 h. In our patient, skin was evaluated at various points during ECP using the modified Rodnan skin thickness scoring method, whereby the skin was palpated and scored on the following scale: 0 for normal skin thickness and texture, 1 for thickened skin, 2 for thickened skin that cannot be moved, and 3 for thickened skin that cannot be pinched [3]. Scores were determined for 22 body areas, with a possible maximum total body score of 66. ECP was administered twice weekly (non-consecutive days) during month 1 and thrice weekly (on alternating days) beginning during month 2. At ECP baseline, the patient’s body weight was 83.6 lb (37.9 kg), Lansky performance score was 70%, and modified Rodnan skin thickness score was 45 out of 66. Baseline immunosuppressive therapy consisted of prednisone 20 mg twice daily,
tacrolimus 1 mg twice daily, and sirolimus 1 mg daily. Laboratory tests performed prior to initiating ECP revealed low red blood cell count, platelet count, and hemoglobin level, which were subsequently treated with erythropoietin and transfusions. Additional therapies administered during ECP included antimicrobial agents, an antiepileptic agent, a calcium channel blocker, antilipemic agents, an adrenergic bronchodilator, opioid and non-opioid analgesics, levothyroxine, growth hormone, testosterone, antacids, vitamin D and calcium supplementation, iron supplementation, potassium supplementation, a multivitamin, an appetite stimulant, and physical therapy. ECP was beneficial, as evidenced by sustained decreases in modified Rodnan skin thickness scores and discontinuation of immunosuppressive therapy (Fig. 1). After 2 months of ECP, the skin score decreased from 45 to 22. Additionally, the patient reported softer skin, hair growth on extremities, increased range of motion, and improved ability to walk. At this time, sirolimus therapy was discontinued. Prednisone therapy was tapered and later discontinued during month 11, and tacrolimus was discontinued during month 16. The ECP frequency was reduced to twice weekly during month 19 and to alternating once-to-twice weekly during month 21. Over the course of 53 months of ECP, the patient’s skin steadily improved. The final skin score was 6, and thickened areas of skin were noted only on the upper body, where the skin was easily moved and able to be pinched. Moreover, red blood cell count, platelet count, and hemoglobin level normalized. At last assessment, the patient continued to be treated with alternating once-totwice weekly ECP, while remaining off all immunosuppressive agents, having normal mobility, attending college, and maintaining part-time employment. Additional therapies included an antilipemic agent, levothyroxine, testosterone, and non-opioid analgesics. The patient was treated with >540 sessions of ECP, with minimal ECP-related side effects. ECP sessions had to be suspended on three separate occasions because of transient asymptomatic hypotension, transient tachycardia, and venous port clotting that was unresponsive to alteplase. During the course of ECP, the patient experienced multiple steroid-related complications, including bilateral hip osteonecrosis requiring joint replacement surgery, a
Maximum possible score = 66
60 50
Skin Score
188
Sirolimus D/C
40
Prednisone D/C
30
Tacrolimus D/C
20 10 0 0
10
20
30
40
50
60
Months of ECP Fig. 1. Modified Rodnan skin thickness scores and points of discontinuation (D/C) of immunosuppressants during extracorporeal photochemotherapy (ECP) in a pediatric patient with refractory sclerodermatous chronic graft-versus-host disease.
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wrist fracture, hyperglycemia, hypertension, and cataracts requiring surgery. 3. Discussion Since being approved by the United States Food and Drug Administration (FDA) in 1988 as a palliative therapy for cutaneous T-cell lymphoma (CTCL), a rare skin malignancy of clonal CD4+ T cells, ECP has been investigated in several immune-meditated disorders, including aGVHD, cGVHD, allograft rejection, and autoimmune disease [2]. Patients with cGVHD selected for ECP have been those with extensive disease not responding to conventional treatments or responding but with unacceptable side effects. In ECP studies with adults and children with steroid-resistant cGVHD, overall response rates of 60% and higher have been reported, particularly with cutaneous, hepatic, oral, and ocular manifestations, and a steroid-sparing effect was evident among responders [4,5]. Studies exclusively enrolling children have been limited to small cases series and retrospective analyses [5–9]. The skin is the most frequently affected organ in cGVHD, and extensive skin involvement is associated with reduced survival [1]. Skin features with cGVHD range from acute erythematous rash to chronic sclerosis. There are few reported cases of sclerodermatous cGVHD in children, and, in the pediatric population, this condition is particularly difficult to treat, debilitating, and life-threatening [10,11]. Characterized by fibrosis of the skin and subcutaneous tissues, sclerodermatous cGVHD can lead to joint contractures, severe wasting, and chest wall restriction [1]. Sclerodermatous cGVHD is frequently refractory to firstline and second-line therapy [12]. Complete or partial regression of skin retraction has been reported in some children with sclerodermatous cGVHD treated with ECP [6]. In our patient, softening of sclerotic skin occurred as early as 2 months into ECP and continued for more than 4 years. The degree of skin softening in our patient allowed significant improvement in mobility and quality of life. The optimal duration of ECP with pediatric cGVHD has not yet been determined. In previous studies, ECP duration ranged from 2 to 34 months [6,9]. In most children with severe cGVHD, prolonged (>1 year) use of ECP was required to achieve meaningful improvements [7]. Therefore, it is recommended that ECP not be discontinued in patients with slow but steady improvement [7]. In our patient, the duration of ECP was extended beyond 53 months to maintain skin improvement. This might be the longest use of ECP documented thus far in a pediatric patient with cGVHD. Immunosuppressants are associated with significant toxicities, and children may be particularly susceptible to these side effects [6]. Immunosuppressive therapy can be associated with opportunistic infections, secondary malignancy, and multiorgan injury. Potential side effects of steroids include infection, osteoporosis, aseptic bone necrosis, myopathy, cataract formation, hyperglycemia, and growth retardation in children [1,13]. In previous studies in children with cGVHD, ECP has permitted reduction or discontinuation of steroids and other immunosuppressants [5–8]. In our patient, ECP was recommended as an alternative to
189
intensifying immunosuppressive therapy and enabled discontinuation of these agents without disease rebound. ECP is well tolerated, with most side effects being mild and transient (e.g., headache, fever, and chills) [14]. Serious side effects occur infrequently and include hypotension, vasovagal syncope, venous access site infection, septicemia, anemia, and abnormal clotting. Side effects typically reported in children include abdominal pain, transient pyretic reactions, episodes of hypotension (usually mild and asymptomatic), and transient decreases in white blood cell counts, platelet counts, and hemoglobin levels [5–9]. A low toxicity profile and side effects that do not overlap with those of immunosuppressive agents make ECP especially applicable to treating children with cGVHD. Our patient experienced few side effects related to ECP. The UVAR XTS system is approved by the FDA for use in patients weighing > 40 kg, because patients with lower body weights may experience clinically significant hypovolemia due to fluid shifts during treatment [15,16]. The UVAR XTS system uses a discontinuous flow system where the centrifuge bowl is filled with blood during the collection phase without simultaneous fluid replacement [15]. The volume of blood required to fill the bowl mostly depends on the patient’s hematocrit [16]. If the patient’s hematocrit is low, the volume of blood is large. Because it is recommended that the extracorporeal blood volume not exceed 15% of the total blood volume, patients must have a hematocrit of P19% [17]. In the UVAR XTS system, extracorporeal blood volume can only be adjusted by choice of bowl (125 vs 225 mL) and by changing the number of collection cycles [16]. The smaller centrifuge bowl is used in pediatric patients [16]. Despite its drawbacks, the UVAR XTS system has been safely used in children weighing < 40 kg by infusing fluids to balance extracorporeal blood volume, administering transfusions to maintain hematocrit, or priming the device with packed red blood cells [15,16]. At ECP initiation, our patient was below the weight requirement (37.9 kg) but tolerated treatment without these modifications. A new ECP device called the CELLEX system (Therakos, Inc., Exton, PA, USA), which uses continuous cell separation and requires less extracorporeal blood volumes than the UVAR XTS system, may be appropriate for low weight patients [16,18]. The CELLEX system is currently available and is being investigated in patients with cGVHD having body weights as low as 25 kg [19]. The mechanism of action of ECP has not been fully elucidated, but clinical and laboratory findings suggest that ECP exerts immunomodulatory effects [2,20]. 8-MOP is biologically inert until exposed to UVA radiation, at which time it covalently binds to DNA pyrimidine bases and cross-links DNA strands, initiating leukocyte apoptosis [2]. In the context of disease states of unwanted immunity (e.g., cGVHD and allograft rejection), there is growing evidence to suggest that after the ECP procedure the infused apoptotic leukocytes are phagocytosed by immature antigen-presenting cells that subsequently take on tolerogenic functions and give rise to regulatory T cells, thereby mediating immune tolerance [20]. Unlike immunosuppressive agents, ECP does not appear to induce generalized immunosuppression since patients who underwent long-term ECP for CTCL and progressive systemic sclerosis did not
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have an increased risk of infections or malignancies, responded normally to both novel and recall antigens, and were able to mount a primary vaccine response [13]. Furthermore, in the setting of allogeneic HSCT, ECP does not lead to increased relapse rates, as with immunosuppressive therapy, suggesting preservation of the graft-versus-leukemia effect [13]. Therefore, ECP seems to offer selective immune control. This case expands on the current knowledge of ECP with pediatric cGVHD by suggesting that long-term ECP in children with sclerodermatous cGVHD is feasible, beneficial, and well tolerated. Recent consensus guidelines on the second-line treatment of cGVHD recommend using ECP earlier in the disease course rather than as a last resort when all other therapies have failed and serious adverse events, such as aseptic bone necrosis, have occurred [21]. Further investigation of ECP in pediatric sclerodermatous cGVHD is warranted. Conflict of interest statement Emil Bisaccia has received research funds and consultancy fees from Therakos, Inc. References [1] Baird K, Cooke K, Schultz KR. Chronic graft-versus-host disease (GVHD) in children. Pediatr Clin North Am 2010;57:297–322. [2] Knobler R, Barr ML, Couriel DR, Ferrara JL, French LE, Jaksch P, et al. Extracorporeal photopheresis: past, present, and future. J Am Acad Dermatol 2009;61:652–65. [3] Clements PJ, Lachenbruch PA, Seibold JR, Zee B, Steen VD, Brennan P, et al. Skin thickness score in systemic sclerosis: an assessment of interobserver variability in 3 independent studies. J Rheumatol 1993;20:1892–6. [4] Couriel DR, Hosing C, Saliba R, Shpall EJ, Anderlini P, Rhodes B, et al. Extracorporeal photochemotherapy for the treatment of steroidresistant chronic GVHD. Blood 2006;107:3074–80. [5] Messina C, Locatelli F, Lanino E, Uderzo C, Zacchello G, Cesaro S, et al. Extracorporeal photochemotherapy for paediatric patients with graft-versus-host disease after haematopoietic stem cell transplantation. Br J Haematol 2003;122:118–27. [6] Kanold J, Paillard C, Halle P, D’Incan M, Bordigoni P, Deméocq F. Extracorporeal photochemotherapy for graft versus host disease in pediatric patients. Transfus Apher Sci 2003;28:71–80.
[7] Chan KW. Extracorporeal photopheresis in children with graftversus-host disease. J Clin Apher 2006;21:60–4. [8] Kanold J, Merlin E, Halle P, Paillard C, Marabelle A, Rapatel C, et al. Photopheresis in pediatric graft-versus-host disease after allogeneic marrow transplantation: clinical practice guidelines based on field experience and review of the literature. Transfusion 2007;47: 2276–89. [9] Berger M, Pessolano R, Albiani R, Asaftei S, Barat V, Carraro F, et al. Extracorporeal photopheresis for steroid resistant graft versus host disease in pediatric patients: a pilot single institution report. J Pediatr Hematol Oncol 2007;29:678–87. [10] Terasaki K, Kanekura T, Setoyama M, Kanzaki T. A pediatric case of sclerodermatous chronic graft-versus-host disease. Pediatr Dermatol 2003;20:327–31. [11] Tolland JP, Devereux C, Jones FC, Bingham EA. Sclerodermatous chronic graft-versus-host disease – A report of four pediatric cases. Pediatr Dermatol 2008;25:240–4. [12] Skert C, Patriarca F, Sperotto A, Cerno M, Filì C, Zaja F, et al. Sclerodermatous chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation: incidence, predictors and outcome. Haematologica 2006;91:258–61. [13] Marshall SR. Technology insight: ECP for the treatment of GvHD–can we offer selective immune control without generalized immunosuppression? Nat Clin Pract Oncol 2006;3:302–14. [14] Scarisbrick J. Extracorporeal photopheresis: what is it and when should it be used? Clin Exp Dermatol 2009;34:757–60. [15] Schneiderman J, Jacobsohn DA, Collins J, Thormann K, Kletzel M. The use of fluid boluses to safely perform extracorporeal photopheresis (ECP) in low-weight children: a novel procedure. J Clin Apher 2010;25:63–9. [16] Hillen U, Meyer S, Schadendorf D, Kremens B. Photopheresis in pediatric patients with low-body weight using the UVAR XTS system. J Dtsch Dermatol Ges 2010;8:32–7. [17] Klassen J. The role of photopheresis in the treatment of graft-versushost disease. Curr Oncol 2010;17:55–8. [18] Bisaccia E, Vonderheid EC, Geskin L. Safety of a new, single, integrated, closed photopheresis system in patients with cutaneous T-cell lymphoma. Br J Dermatol 2009;161:167–9. [19] National Heart, Lung, and Blood Institute (NHLBI). A Phase II/III randomized, multicenter trial comparing sirolimus plus prednisone, sirolimus/extracorporeal photopheresis plus prednisone, and sirolimus/calcineurin inhibitor plus prednisone for the treatment of chronic graft-versus-host disease (BMT CTN #0801). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2010-[cited 2011 January 2]. Available from: http:// clinicaltrials.gov/show/NCT01106833 NLM Identifier: NCT01106833. [20] Xia CQ, Campbell KA, Clare-Salzler MJ. Extracorporeal photopheresisinduced immune tolerance. a focus on modulation of antigenpresenting cells and induction of regulatory T cells by apoptotic cells. Curr Opin Organ Transplant 2009;14:338–43. [21] Wolff D, Schleuning M, von Harsdorf S, Bacher U, Gerbitz A, Stadler M, et al. Consensus conference on clinical practice in chronic GVHD: Second-line treatment of chronic graft-versus-host disease. Biol Blood Marrow Transplant 2010 May 25. [Epub ahead of print].
Contents lists available at ScienceDirect
Transfusion and Apheresis Science journal homepage: www.elsevier.com/locate/transci
Long-term extracorporeal photochemotherapy in a pediatric patient with refractory sclerodermatous chronic graft-versus-host disease Emil Bisaccia a,b,⇑, Mark Palangio b, Joselyn Gonzalez b,c a
Columbia University College of Physicians and Surgeons, New York, NY, USA Section of Photopheresis, Morristown Memorial Hospital, Morristown, NJ, USA c Department of Internal Medicine, Morristown Memorial Hospital, Morristown, NJ, USA b
a r t i c l e
i n f o
Keywords: Chronic graft-versus-host disease Extracorporeal photochemotherapy Hematopoietic stem cell transplantation Pediatric Photopheresis Steroids
a b s t r a c t Sclerodermatous chronic graft-versus-host disease (cGVHD) following allogeneic hematopoietic stem cell transplantation (HSCT) in children is difficult to treat and life-threatening. Extracorporeal photochemotherapy (ECP; photopheresis), an immunomodulatory therapy that involves the infusion of autologous peripheral blood leukocytes after ex vivo exposure to the photoactive agent 8-methoxypsoralen and ultraviolet A radiation, is an effective treatment for steroid-refractory cGVHD. After undergoing allogeneic HSCT for pre-B-cell acute lymphoblastic leukemia, a 14-year-old boy developed extensive sclerodermatous cGVHD that was refractory to prednisone, tacrolimus, and sirolimus. ECP was administered over the course of 53 months, during which the skin softened substantially and immunosuppressive therapy was discontinued. This case suggests that long-term ECP is a viable option in children with sclerodermatous cGVHD. Ó 2011 Published by Elsevier Ltd.
1. Introduction Chronic graft-versus-host disease (cGVHD) is a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (HSCT) in children, occurring in 20–50% of recipients [1]. cGVHD can affect virtually any organ system, with manifestations ranging from acute inflammation to chronic fibrosis. First-line therapy usually consists of prednisone combined with cyclosporine, and refractory cases are treated with additional immunosuppressants, often administered for years. Given the partial effectiveness and high toxicity with these agents, alternative approaches are being investigated. Extracorporeal photochemotherapy (ECP; photopheresis), an immunomodulatory therapy that involves the infusion of autologous peripheral blood leukocytes
⇑ Corresponding author at: Morristown Memorial Hospital, 100 Madison Avenue, Morristown, NJ 07962-1956, USA. Tel.: +1 973 971 4192; fax: +1 973 290 7148. E-mail address: [email protected] (E. Bisaccia). 1473-0502/$ - see front matter Ó 2011 Published by Elsevier Ltd. doi:10.1016/j.transci.2011.07.005
after ex vivo exposure to the photoactive agent 8-methoxypsoralen (8-MOP) and ultraviolet A (UVA) radiation, is an effective treatment for steroid-refractory cGVHD [2]. We describe the case of a child with refractory sclerodermatous cGVHD who was treated with ECP for more than 4 years. 2. Case report An 11-year-old boy with pre-B-cell acute lymphoblastic leukemia was brought into remission with the Memorial Sloan-Kettering-New York-II protocol after failing on standard-risk, front-line Children’s Oncology Group protocol. Because he was at high risk for relapse with continued chemotherapy, the patient underwent unrelated-donor bone marrow transplantation. Prophylaxis for acute graft-versus-host disease (aGVHD) consisted of cyclosporine and a short course of methotrexate. Approximately 9 months after transplantation, he suffered an isolated marrow relapse and was enrolled in a Phase I/II study with clofarabine, which rendered him aplastic for 6–8 weeks. He then underwent unmodified peripheral blood stem cell
E. Bisaccia et al. / Transfusion and Apheresis Science 45 (2011) 187–190
transplantation from the same donor and received the same aGVHD prophylaxis regimen. The patient later developed grade III cutaneous aGVHD (without liver or gastrointestinal involvement), which was treated successfully with steroid therapy. Approximately 3 months after the second transplantation, he developed cutaneous cGVHD, which responded completely after 3 months of treatment with prednisone and cyclosporine. Over the next few months, the patient experienced steroid-related myopathy and osteonecrosis of the hips, knees, and ankles. At that time, he had difficulty with ambulation, particularly while attending school. Approximately 2 years after the second transplantation, the patient developed, over the course of only 1 month, significant flexion contractures of the shoulders, elbows, wrists, and fingers, relatively sparing his lower extremities. Consequently, the patient was treated with resumption of cyclosporine and a ‘‘pulse’’ of moderate-dose prednisone. Joint mobility did not improve, and he was placed back on prednisone 5 mg on alternating mornings and cyclosporine. After he presented with seizures, cyclosporine was discontinued, and tacrolimus 1 mg twice daily was begun. In order to keep the steroid dose low, sirolimus 1 mg daily was added. Despite this regimen, skin tightness developed over his abdomen and around his shoulder girdle, along with a persistent decreased range of motion of multiple joints, including the shoulders, elbows, wrists, knees, and ankles. Severely sclerodermatous skin was noted on the neck, chest, abdomen, back, arms, thighs, and ankles. Mild erythematous and scaly lesions appeared on both axillas. However, there was no evidence of sicca or pulmonary or hepatic involvement. Approximately 8 months after the onset of sclerodermatous cGVHD, at 14 years of age, the patient was referred for ECP, rather than intensifying immunosuppressive therapy. ECP was performed using the UVAR XTS system (Therakos, Inc., Exton, PA, USA) according to the manufacturer’s guidelines. With this automated system, a small portion of the patient’s blood is obtained through an antecubital venous line and separated into erythrocyte and buffy coat fractions. While the erythrocyte fraction is immediately returned to the patient, the buffy coat fraction is exposed to 8-MOP (UVADEX; Therakos, Inc., Exton, PA, USA) and long-wave UVA radiation. At the conclusion of each session, the ECP-processed buffy coat fraction is reinfused. Each treatment session lasts 3–4 h. In our patient, skin was evaluated at various points during ECP using the modified Rodnan skin thickness scoring method, whereby the skin was palpated and scored on the following scale: 0 for normal skin thickness and texture, 1 for thickened skin, 2 for thickened skin that cannot be moved, and 3 for thickened skin that cannot be pinched [3]. Scores were determined for 22 body areas, with a possible maximum total body score of 66. ECP was administered twice weekly (non-consecutive days) during month 1 and thrice weekly (on alternating days) beginning during month 2. At ECP baseline, the patient’s body weight was 83.6 lb (37.9 kg), Lansky performance score was 70%, and modified Rodnan skin thickness score was 45 out of 66. Baseline immunosuppressive therapy consisted of prednisone 20 mg twice daily,
tacrolimus 1 mg twice daily, and sirolimus 1 mg daily. Laboratory tests performed prior to initiating ECP revealed low red blood cell count, platelet count, and hemoglobin level, which were subsequently treated with erythropoietin and transfusions. Additional therapies administered during ECP included antimicrobial agents, an antiepileptic agent, a calcium channel blocker, antilipemic agents, an adrenergic bronchodilator, opioid and non-opioid analgesics, levothyroxine, growth hormone, testosterone, antacids, vitamin D and calcium supplementation, iron supplementation, potassium supplementation, a multivitamin, an appetite stimulant, and physical therapy. ECP was beneficial, as evidenced by sustained decreases in modified Rodnan skin thickness scores and discontinuation of immunosuppressive therapy (Fig. 1). After 2 months of ECP, the skin score decreased from 45 to 22. Additionally, the patient reported softer skin, hair growth on extremities, increased range of motion, and improved ability to walk. At this time, sirolimus therapy was discontinued. Prednisone therapy was tapered and later discontinued during month 11, and tacrolimus was discontinued during month 16. The ECP frequency was reduced to twice weekly during month 19 and to alternating once-to-twice weekly during month 21. Over the course of 53 months of ECP, the patient’s skin steadily improved. The final skin score was 6, and thickened areas of skin were noted only on the upper body, where the skin was easily moved and able to be pinched. Moreover, red blood cell count, platelet count, and hemoglobin level normalized. At last assessment, the patient continued to be treated with alternating once-totwice weekly ECP, while remaining off all immunosuppressive agents, having normal mobility, attending college, and maintaining part-time employment. Additional therapies included an antilipemic agent, levothyroxine, testosterone, and non-opioid analgesics. The patient was treated with >540 sessions of ECP, with minimal ECP-related side effects. ECP sessions had to be suspended on three separate occasions because of transient asymptomatic hypotension, transient tachycardia, and venous port clotting that was unresponsive to alteplase. During the course of ECP, the patient experienced multiple steroid-related complications, including bilateral hip osteonecrosis requiring joint replacement surgery, a
Maximum possible score = 66
60 50
Skin Score
188
Sirolimus D/C
40
Prednisone D/C
30
Tacrolimus D/C
20 10 0 0
10
20
30
40
50
60
Months of ECP Fig. 1. Modified Rodnan skin thickness scores and points of discontinuation (D/C) of immunosuppressants during extracorporeal photochemotherapy (ECP) in a pediatric patient with refractory sclerodermatous chronic graft-versus-host disease.
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wrist fracture, hyperglycemia, hypertension, and cataracts requiring surgery. 3. Discussion Since being approved by the United States Food and Drug Administration (FDA) in 1988 as a palliative therapy for cutaneous T-cell lymphoma (CTCL), a rare skin malignancy of clonal CD4+ T cells, ECP has been investigated in several immune-meditated disorders, including aGVHD, cGVHD, allograft rejection, and autoimmune disease [2]. Patients with cGVHD selected for ECP have been those with extensive disease not responding to conventional treatments or responding but with unacceptable side effects. In ECP studies with adults and children with steroid-resistant cGVHD, overall response rates of 60% and higher have been reported, particularly with cutaneous, hepatic, oral, and ocular manifestations, and a steroid-sparing effect was evident among responders [4,5]. Studies exclusively enrolling children have been limited to small cases series and retrospective analyses [5–9]. The skin is the most frequently affected organ in cGVHD, and extensive skin involvement is associated with reduced survival [1]. Skin features with cGVHD range from acute erythematous rash to chronic sclerosis. There are few reported cases of sclerodermatous cGVHD in children, and, in the pediatric population, this condition is particularly difficult to treat, debilitating, and life-threatening [10,11]. Characterized by fibrosis of the skin and subcutaneous tissues, sclerodermatous cGVHD can lead to joint contractures, severe wasting, and chest wall restriction [1]. Sclerodermatous cGVHD is frequently refractory to firstline and second-line therapy [12]. Complete or partial regression of skin retraction has been reported in some children with sclerodermatous cGVHD treated with ECP [6]. In our patient, softening of sclerotic skin occurred as early as 2 months into ECP and continued for more than 4 years. The degree of skin softening in our patient allowed significant improvement in mobility and quality of life. The optimal duration of ECP with pediatric cGVHD has not yet been determined. In previous studies, ECP duration ranged from 2 to 34 months [6,9]. In most children with severe cGVHD, prolonged (>1 year) use of ECP was required to achieve meaningful improvements [7]. Therefore, it is recommended that ECP not be discontinued in patients with slow but steady improvement [7]. In our patient, the duration of ECP was extended beyond 53 months to maintain skin improvement. This might be the longest use of ECP documented thus far in a pediatric patient with cGVHD. Immunosuppressants are associated with significant toxicities, and children may be particularly susceptible to these side effects [6]. Immunosuppressive therapy can be associated with opportunistic infections, secondary malignancy, and multiorgan injury. Potential side effects of steroids include infection, osteoporosis, aseptic bone necrosis, myopathy, cataract formation, hyperglycemia, and growth retardation in children [1,13]. In previous studies in children with cGVHD, ECP has permitted reduction or discontinuation of steroids and other immunosuppressants [5–8]. In our patient, ECP was recommended as an alternative to
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intensifying immunosuppressive therapy and enabled discontinuation of these agents without disease rebound. ECP is well tolerated, with most side effects being mild and transient (e.g., headache, fever, and chills) [14]. Serious side effects occur infrequently and include hypotension, vasovagal syncope, venous access site infection, septicemia, anemia, and abnormal clotting. Side effects typically reported in children include abdominal pain, transient pyretic reactions, episodes of hypotension (usually mild and asymptomatic), and transient decreases in white blood cell counts, platelet counts, and hemoglobin levels [5–9]. A low toxicity profile and side effects that do not overlap with those of immunosuppressive agents make ECP especially applicable to treating children with cGVHD. Our patient experienced few side effects related to ECP. The UVAR XTS system is approved by the FDA for use in patients weighing > 40 kg, because patients with lower body weights may experience clinically significant hypovolemia due to fluid shifts during treatment [15,16]. The UVAR XTS system uses a discontinuous flow system where the centrifuge bowl is filled with blood during the collection phase without simultaneous fluid replacement [15]. The volume of blood required to fill the bowl mostly depends on the patient’s hematocrit [16]. If the patient’s hematocrit is low, the volume of blood is large. Because it is recommended that the extracorporeal blood volume not exceed 15% of the total blood volume, patients must have a hematocrit of P19% [17]. In the UVAR XTS system, extracorporeal blood volume can only be adjusted by choice of bowl (125 vs 225 mL) and by changing the number of collection cycles [16]. The smaller centrifuge bowl is used in pediatric patients [16]. Despite its drawbacks, the UVAR XTS system has been safely used in children weighing < 40 kg by infusing fluids to balance extracorporeal blood volume, administering transfusions to maintain hematocrit, or priming the device with packed red blood cells [15,16]. At ECP initiation, our patient was below the weight requirement (37.9 kg) but tolerated treatment without these modifications. A new ECP device called the CELLEX system (Therakos, Inc., Exton, PA, USA), which uses continuous cell separation and requires less extracorporeal blood volumes than the UVAR XTS system, may be appropriate for low weight patients [16,18]. The CELLEX system is currently available and is being investigated in patients with cGVHD having body weights as low as 25 kg [19]. The mechanism of action of ECP has not been fully elucidated, but clinical and laboratory findings suggest that ECP exerts immunomodulatory effects [2,20]. 8-MOP is biologically inert until exposed to UVA radiation, at which time it covalently binds to DNA pyrimidine bases and cross-links DNA strands, initiating leukocyte apoptosis [2]. In the context of disease states of unwanted immunity (e.g., cGVHD and allograft rejection), there is growing evidence to suggest that after the ECP procedure the infused apoptotic leukocytes are phagocytosed by immature antigen-presenting cells that subsequently take on tolerogenic functions and give rise to regulatory T cells, thereby mediating immune tolerance [20]. Unlike immunosuppressive agents, ECP does not appear to induce generalized immunosuppression since patients who underwent long-term ECP for CTCL and progressive systemic sclerosis did not
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have an increased risk of infections or malignancies, responded normally to both novel and recall antigens, and were able to mount a primary vaccine response [13]. Furthermore, in the setting of allogeneic HSCT, ECP does not lead to increased relapse rates, as with immunosuppressive therapy, suggesting preservation of the graft-versus-leukemia effect [13]. Therefore, ECP seems to offer selective immune control. This case expands on the current knowledge of ECP with pediatric cGVHD by suggesting that long-term ECP in children with sclerodermatous cGVHD is feasible, beneficial, and well tolerated. Recent consensus guidelines on the second-line treatment of cGVHD recommend using ECP earlier in the disease course rather than as a last resort when all other therapies have failed and serious adverse events, such as aseptic bone necrosis, have occurred [21]. Further investigation of ECP in pediatric sclerodermatous cGVHD is warranted. Conflict of interest statement Emil Bisaccia has received research funds and consultancy fees from Therakos, Inc. References [1] Baird K, Cooke K, Schultz KR. Chronic graft-versus-host disease (GVHD) in children. Pediatr Clin North Am 2010;57:297–322. [2] Knobler R, Barr ML, Couriel DR, Ferrara JL, French LE, Jaksch P, et al. Extracorporeal photopheresis: past, present, and future. J Am Acad Dermatol 2009;61:652–65. [3] Clements PJ, Lachenbruch PA, Seibold JR, Zee B, Steen VD, Brennan P, et al. Skin thickness score in systemic sclerosis: an assessment of interobserver variability in 3 independent studies. J Rheumatol 1993;20:1892–6. [4] Couriel DR, Hosing C, Saliba R, Shpall EJ, Anderlini P, Rhodes B, et al. Extracorporeal photochemotherapy for the treatment of steroidresistant chronic GVHD. Blood 2006;107:3074–80. [5] Messina C, Locatelli F, Lanino E, Uderzo C, Zacchello G, Cesaro S, et al. Extracorporeal photochemotherapy for paediatric patients with graft-versus-host disease after haematopoietic stem cell transplantation. Br J Haematol 2003;122:118–27. [6] Kanold J, Paillard C, Halle P, D’Incan M, Bordigoni P, Deméocq F. Extracorporeal photochemotherapy for graft versus host disease in pediatric patients. Transfus Apher Sci 2003;28:71–80.
[7] Chan KW. Extracorporeal photopheresis in children with graftversus-host disease. J Clin Apher 2006;21:60–4. [8] Kanold J, Merlin E, Halle P, Paillard C, Marabelle A, Rapatel C, et al. Photopheresis in pediatric graft-versus-host disease after allogeneic marrow transplantation: clinical practice guidelines based on field experience and review of the literature. Transfusion 2007;47: 2276–89. [9] Berger M, Pessolano R, Albiani R, Asaftei S, Barat V, Carraro F, et al. Extracorporeal photopheresis for steroid resistant graft versus host disease in pediatric patients: a pilot single institution report. J Pediatr Hematol Oncol 2007;29:678–87. [10] Terasaki K, Kanekura T, Setoyama M, Kanzaki T. A pediatric case of sclerodermatous chronic graft-versus-host disease. Pediatr Dermatol 2003;20:327–31. [11] Tolland JP, Devereux C, Jones FC, Bingham EA. Sclerodermatous chronic graft-versus-host disease – A report of four pediatric cases. Pediatr Dermatol 2008;25:240–4. [12] Skert C, Patriarca F, Sperotto A, Cerno M, Filì C, Zaja F, et al. Sclerodermatous chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation: incidence, predictors and outcome. Haematologica 2006;91:258–61. [13] Marshall SR. Technology insight: ECP for the treatment of GvHD–can we offer selective immune control without generalized immunosuppression? Nat Clin Pract Oncol 2006;3:302–14. [14] Scarisbrick J. Extracorporeal photopheresis: what is it and when should it be used? Clin Exp Dermatol 2009;34:757–60. [15] Schneiderman J, Jacobsohn DA, Collins J, Thormann K, Kletzel M. The use of fluid boluses to safely perform extracorporeal photopheresis (ECP) in low-weight children: a novel procedure. J Clin Apher 2010;25:63–9. [16] Hillen U, Meyer S, Schadendorf D, Kremens B. Photopheresis in pediatric patients with low-body weight using the UVAR XTS system. J Dtsch Dermatol Ges 2010;8:32–7. [17] Klassen J. The role of photopheresis in the treatment of graft-versushost disease. Curr Oncol 2010;17:55–8. [18] Bisaccia E, Vonderheid EC, Geskin L. Safety of a new, single, integrated, closed photopheresis system in patients with cutaneous T-cell lymphoma. Br J Dermatol 2009;161:167–9. [19] National Heart, Lung, and Blood Institute (NHLBI). A Phase II/III randomized, multicenter trial comparing sirolimus plus prednisone, sirolimus/extracorporeal photopheresis plus prednisone, and sirolimus/calcineurin inhibitor plus prednisone for the treatment of chronic graft-versus-host disease (BMT CTN #0801). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2010-[cited 2011 January 2]. Available from: http:// clinicaltrials.gov/show/NCT01106833 NLM Identifier: NCT01106833. [20] Xia CQ, Campbell KA, Clare-Salzler MJ. Extracorporeal photopheresisinduced immune tolerance. a focus on modulation of antigenpresenting cells and induction of regulatory T cells by apoptotic cells. Curr Opin Organ Transplant 2009;14:338–43. [21] Wolff D, Schleuning M, von Harsdorf S, Bacher U, Gerbitz A, Stadler M, et al. Consensus conference on clinical practice in chronic GVHD: Second-line treatment of chronic graft-versus-host disease. Biol Blood Marrow Transplant 2010 May 25. [Epub ahead of print].