International Journal of Rheumatic Diseases 2015
CORRESPONDENCE
Allogeneic hematopoietic stem cell transplantation for refractory Behcet’s disease with myelodysplastic syndrome: a case report Dear Editor, Behcet’s disease (BD) is a chronic inflammatory disorder characterized by recurrent oral aphthae, genital ulcers, uveitis and skin lesions. Hematopoietic stem cell transplantation (HSCT) has been performed either for refractory BD or accompanying hematological conditions.1 Here we describe a case of gastrointestinal BD with trisomy 8-positive myelodysplastic symptoms (MDS) with successful myeloablative allogeneic stem cell transplantation (SCT) that resulted in complete remission of both BD and MDS. In 2009, a 52-year-old woman was admitted to our hospital with dizziness, general weakness and fever. Complete blood count (CBC) tests showed a decreased leukocyte count of 2.08 9 103/lL (30% neutrophils, 56% lymphocytes, 12% monocytes and 0.5% eosinophils), hemoglobin levels of 7.5 g/dL and a platelet count of 72 9 103/lL. Bone marrow (BM) examination showed trilineage dysplasia with less than 5% blasts, and a chromosomal analysis of BM aspirates showed trisomy 8. The patient was diagnosed with refractory cytopenia with multilineage dysplasia and the disease was classified as ‘intermediate-1’ according to the International Prognostic Scoring System. Azacitidine (intravenous bolus, 75 mg/m2 per day) was administered for 7 days in a 4-week cycle. Her symptoms and laboratory findings showed recovery after the 10th cycle of azacitidine therapy. In 2011, at the age of 54, the patient was re-admitted with recurrent abdominal pain, fever and frequent diarrhea for 25 days. Her abdominal pain was located in the right lower quadrants, without rebound tenderness, and she experienced intermittent cramping pain. Physical examination at admission revealed multiple ulcers in the oral and genital regions but no abnormal skin lesions. She reported that the mouth ulcers started gradually in the buccal cavity and on the tongue and that there had been periods of complete healing of approximately 1–2 weeks, followed by recurrences. An ophthalmologist’s examination revealed signs of uveitis by
slitlamp examination. The patient also had several symptoms compatible with BD based on the diagnostic criteria of the International Study Group for BD (ISGBD) in 1990,2 such as oral ulcers, genital ulcers and uveitis. The laboratory findings at re-admission were as follows: white blood cell count: 4.04 9 103/lL without blast cells; hemoglobin level, 8.9 g/dL; platelet count, 107 9 103/lL; and C-reactive protein level, 2.48 mg/ dL. Autoantibodies were negative, both complement and normal. A colonoscopy revealed diffuse mucosal edema with purulent discharge and multiple active ulcers in the ileocecal area. However, there were no ulcerative lesions at the rectum or other sites of the colon, the hallmark sign of ulcerative colitis. Histopathology of the ulcers indicated chronic ulcerative inflammation with lymphocyte infiltration, compatible with Behcet’s colitis. However, there were no granulomas, the hallmark of Crohn’s colitis. Initial treatment with corticosteroids alone did not relieve symptoms and although azathioprine was added to the treatment regimen, recurrent abdominal pain persisted. In response, sulfasalazine was administered but without improvement. Despite active management of Behcet’s colitis, abdominal pain persisted in a waxing and waning manner. In 2012, CBC showed further decreases in the leukocyte count (1.65 9 103/lL) and hemoglobin level (7.9 g/dL), and thrombocytopenia (125 9 103/lL) was detected. Bone marrow biopsy revealed a hypocellular marrow with dysplasia of the erythroid and megakaryocytic series. Hematologic supportive care was initiated with intermittent red cell transfusion at approximately 2-week intervals for 6 months. Since the diagnosis of MDS, we had been searching for unrelated donors from the public blood and marrow donation program. A fully matched human leukocyte antigen (HLA)-compatible unrelated donor was found in 2013. The patient underwent allogeneic peripheral blood SCT with a myeloablative regimen in January of 2013.
© 2015 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
Correspondence
The pre-transplantation conditioning regimen comprised busulfan and cyclophosphamide, while an infusion of 1.67 9 106/kg CD34+ cells was introduced. Methotrexate and cyclosporine-A were used for graft-versus-host disease (GVHD) prophylaxis, and granulocyte colony-stimulating factor (G-CSF) was administered from day 3 to facilitate myeloid recovery. Neutrophil engraftment was documented on day 12 and complete chimerism was confirmed using short tandem repeat (STR). Colonoscopy performed on day 180 showed multiple ulcer scars but no active ulcers. The patient achieved complete remission of MDS, without chronic GVHD or abdominal symptoms. Recently, the coexistence of MDS with trisomy 8 with rare disorders of the immune system, such as BD, has been reported.3 BD-associated MDS shows notably cytogenetic abnormalities such as trisomy 8 in BM cells. Bone marrow failure is frequently reported in patients with BD, especially in Korea and Japan, and the proportion with trisomy 8 is markedly high (63.6–86.0%).4,5 Patients with BD-associated MDS are frequently treated with immunosuppressive therapies; however, a recent report has suggested that immunosuppressive agents alone cannot control BD-associated MDS and that the condition may become fatal because of infection or hemorrhage.6 Among eight patients who underwent HSCT for BD-associated MDS, similar to the case presented here, autologous-SCT was performed in six patients and allogeneic SCT was performed in two.1,7 These patients had active BD manifestations despite corticosteroid and/or immunosuppressive treatment, before undergoing HSCT. All of these patients achieved successful engraftment after HSCT; the symptoms and signs related to BD disappeared and no patient experienced a serious transplant-related complication. Major complications of allogeneic SCT are infections, GVHD, and hepatic, renal and pulmonary damage.8 Among 35 patients receiving allogeneic SCT for autoimmune disease, treatment-related mortality was 22% at 2 years.9 When considering allogeneic-SCT as a treatment option for BD, one must consider the possible risks and benefits; improved risk assessment and supportive care have reduced transplant-related mortality in allogeneic-SCT in recent years. Thus, considering past cases in combination with the case presented here, immediate allogeneic SCT may be a therapeutic option for treating BD-associated MDS. More patients and longer follow-up are necessary to
2
assess the efficacy of this modality for treating severe BD-associated high-grade MDS.
CONFLICT OF INTEREST The authors have no conflicts of interest to declare. Won-Seok LEE, Mi-Hee KANG, Joo-Hee HWANG, Yoo-Jeong OH and Wan-Hee YOO
Division of Rheumatology, Department of Internal Medicine, Chonbuk National University Medical School and Research Institute of Clinical Medicine, Chonbuk National University Hospital, Chonbuk National University, Jeonbuk, South Korea Correspondence: Wan-Hee Yoo, MD. Ph.D. email: [email protected]
REFERENCES 1 Soysal T, Saliho glu A, Esato glu SN et al. (2014) Bone marrow transplantation for Behcßet’s disease: a case report and systematic review of the literature. Rheumatology 53, 1136–41. 2 International Study Group for Behcet’s Disease (1990) Critera for diagnosis of Behcet’s disease. Lancet 335, 1078– 80. 3 Fujimura T, Yukawa N, Nakashima R et al. (2010) Periodic fever and erythema nodosum associated with MDS with trisomy 8: report of two cases and review of the literature. Mod Rheumatol 20, 413–9. 4 Ahn JK, Cha H-S, Koh E-M et al. (2008) Behcet’s disease associated with bone marrow failure in Korean patients: clinical characteristics and the association of intestinal ulceration and trisomy 8. Rheumatology 47, 1228–30. 5 Kawabata H, Sawaki T, Kawanami T et al. (2006) Myelodysplastic syndrome complicated with inflammatory intestinal ulcers: significance of trisomy 8. Intern Med 45, 1309–14. 6 Nonami A, Takenaka K, Sumida C et al. (2007) Successful treatment of myelodysplastic syndrome (MDS)-related intestinal Behcßet’s disease by up-front cord blood transplantation. Intern Med 46, 1753–6. 7 Kook MH, Yhim HY, Lee NR et al. (2014) Successful treatment of myelodysplastic syndrome and Behcet colitis after allogeneic hematopoietic stem cell transplantation. Korean J Intern Med 29, 123–5. 8 Gooley TA, Chien JW, Pergam SA et al. (2010) Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med 363, 2091–101. 9 Daikeler T, H€ ugle T, Farge D et al. (2009) Allogeneic hematopoietic SCT for patients with autoimmune diseases. Bone Marrow Transplant 44, 27–33.
International Journal of Rheumatic Diseases 2015
CORRESPONDENCE
Allogeneic hematopoietic stem cell transplantation for refractory Behcet’s disease with myelodysplastic syndrome: a case report Dear Editor, Behcet’s disease (BD) is a chronic inflammatory disorder characterized by recurrent oral aphthae, genital ulcers, uveitis and skin lesions. Hematopoietic stem cell transplantation (HSCT) has been performed either for refractory BD or accompanying hematological conditions.1 Here we describe a case of gastrointestinal BD with trisomy 8-positive myelodysplastic symptoms (MDS) with successful myeloablative allogeneic stem cell transplantation (SCT) that resulted in complete remission of both BD and MDS. In 2009, a 52-year-old woman was admitted to our hospital with dizziness, general weakness and fever. Complete blood count (CBC) tests showed a decreased leukocyte count of 2.08 9 103/lL (30% neutrophils, 56% lymphocytes, 12% monocytes and 0.5% eosinophils), hemoglobin levels of 7.5 g/dL and a platelet count of 72 9 103/lL. Bone marrow (BM) examination showed trilineage dysplasia with less than 5% blasts, and a chromosomal analysis of BM aspirates showed trisomy 8. The patient was diagnosed with refractory cytopenia with multilineage dysplasia and the disease was classified as ‘intermediate-1’ according to the International Prognostic Scoring System. Azacitidine (intravenous bolus, 75 mg/m2 per day) was administered for 7 days in a 4-week cycle. Her symptoms and laboratory findings showed recovery after the 10th cycle of azacitidine therapy. In 2011, at the age of 54, the patient was re-admitted with recurrent abdominal pain, fever and frequent diarrhea for 25 days. Her abdominal pain was located in the right lower quadrants, without rebound tenderness, and she experienced intermittent cramping pain. Physical examination at admission revealed multiple ulcers in the oral and genital regions but no abnormal skin lesions. She reported that the mouth ulcers started gradually in the buccal cavity and on the tongue and that there had been periods of complete healing of approximately 1–2 weeks, followed by recurrences. An ophthalmologist’s examination revealed signs of uveitis by
slitlamp examination. The patient also had several symptoms compatible with BD based on the diagnostic criteria of the International Study Group for BD (ISGBD) in 1990,2 such as oral ulcers, genital ulcers and uveitis. The laboratory findings at re-admission were as follows: white blood cell count: 4.04 9 103/lL without blast cells; hemoglobin level, 8.9 g/dL; platelet count, 107 9 103/lL; and C-reactive protein level, 2.48 mg/ dL. Autoantibodies were negative, both complement and normal. A colonoscopy revealed diffuse mucosal edema with purulent discharge and multiple active ulcers in the ileocecal area. However, there were no ulcerative lesions at the rectum or other sites of the colon, the hallmark sign of ulcerative colitis. Histopathology of the ulcers indicated chronic ulcerative inflammation with lymphocyte infiltration, compatible with Behcet’s colitis. However, there were no granulomas, the hallmark of Crohn’s colitis. Initial treatment with corticosteroids alone did not relieve symptoms and although azathioprine was added to the treatment regimen, recurrent abdominal pain persisted. In response, sulfasalazine was administered but without improvement. Despite active management of Behcet’s colitis, abdominal pain persisted in a waxing and waning manner. In 2012, CBC showed further decreases in the leukocyte count (1.65 9 103/lL) and hemoglobin level (7.9 g/dL), and thrombocytopenia (125 9 103/lL) was detected. Bone marrow biopsy revealed a hypocellular marrow with dysplasia of the erythroid and megakaryocytic series. Hematologic supportive care was initiated with intermittent red cell transfusion at approximately 2-week intervals for 6 months. Since the diagnosis of MDS, we had been searching for unrelated donors from the public blood and marrow donation program. A fully matched human leukocyte antigen (HLA)-compatible unrelated donor was found in 2013. The patient underwent allogeneic peripheral blood SCT with a myeloablative regimen in January of 2013.
© 2015 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
Correspondence
The pre-transplantation conditioning regimen comprised busulfan and cyclophosphamide, while an infusion of 1.67 9 106/kg CD34+ cells was introduced. Methotrexate and cyclosporine-A were used for graft-versus-host disease (GVHD) prophylaxis, and granulocyte colony-stimulating factor (G-CSF) was administered from day 3 to facilitate myeloid recovery. Neutrophil engraftment was documented on day 12 and complete chimerism was confirmed using short tandem repeat (STR). Colonoscopy performed on day 180 showed multiple ulcer scars but no active ulcers. The patient achieved complete remission of MDS, without chronic GVHD or abdominal symptoms. Recently, the coexistence of MDS with trisomy 8 with rare disorders of the immune system, such as BD, has been reported.3 BD-associated MDS shows notably cytogenetic abnormalities such as trisomy 8 in BM cells. Bone marrow failure is frequently reported in patients with BD, especially in Korea and Japan, and the proportion with trisomy 8 is markedly high (63.6–86.0%).4,5 Patients with BD-associated MDS are frequently treated with immunosuppressive therapies; however, a recent report has suggested that immunosuppressive agents alone cannot control BD-associated MDS and that the condition may become fatal because of infection or hemorrhage.6 Among eight patients who underwent HSCT for BD-associated MDS, similar to the case presented here, autologous-SCT was performed in six patients and allogeneic SCT was performed in two.1,7 These patients had active BD manifestations despite corticosteroid and/or immunosuppressive treatment, before undergoing HSCT. All of these patients achieved successful engraftment after HSCT; the symptoms and signs related to BD disappeared and no patient experienced a serious transplant-related complication. Major complications of allogeneic SCT are infections, GVHD, and hepatic, renal and pulmonary damage.8 Among 35 patients receiving allogeneic SCT for autoimmune disease, treatment-related mortality was 22% at 2 years.9 When considering allogeneic-SCT as a treatment option for BD, one must consider the possible risks and benefits; improved risk assessment and supportive care have reduced transplant-related mortality in allogeneic-SCT in recent years. Thus, considering past cases in combination with the case presented here, immediate allogeneic SCT may be a therapeutic option for treating BD-associated MDS. More patients and longer follow-up are necessary to
2
assess the efficacy of this modality for treating severe BD-associated high-grade MDS.
CONFLICT OF INTEREST The authors have no conflicts of interest to declare. Won-Seok LEE, Mi-Hee KANG, Joo-Hee HWANG, Yoo-Jeong OH and Wan-Hee YOO
Division of Rheumatology, Department of Internal Medicine, Chonbuk National University Medical School and Research Institute of Clinical Medicine, Chonbuk National University Hospital, Chonbuk National University, Jeonbuk, South Korea Correspondence: Wan-Hee Yoo, MD. Ph.D. email: [email protected]
REFERENCES 1 Soysal T, Saliho glu A, Esato glu SN et al. (2014) Bone marrow transplantation for Behcßet’s disease: a case report and systematic review of the literature. Rheumatology 53, 1136–41. 2 International Study Group for Behcet’s Disease (1990) Critera for diagnosis of Behcet’s disease. Lancet 335, 1078– 80. 3 Fujimura T, Yukawa N, Nakashima R et al. (2010) Periodic fever and erythema nodosum associated with MDS with trisomy 8: report of two cases and review of the literature. Mod Rheumatol 20, 413–9. 4 Ahn JK, Cha H-S, Koh E-M et al. (2008) Behcet’s disease associated with bone marrow failure in Korean patients: clinical characteristics and the association of intestinal ulceration and trisomy 8. Rheumatology 47, 1228–30. 5 Kawabata H, Sawaki T, Kawanami T et al. (2006) Myelodysplastic syndrome complicated with inflammatory intestinal ulcers: significance of trisomy 8. Intern Med 45, 1309–14. 6 Nonami A, Takenaka K, Sumida C et al. (2007) Successful treatment of myelodysplastic syndrome (MDS)-related intestinal Behcßet’s disease by up-front cord blood transplantation. Intern Med 46, 1753–6. 7 Kook MH, Yhim HY, Lee NR et al. (2014) Successful treatment of myelodysplastic syndrome and Behcet colitis after allogeneic hematopoietic stem cell transplantation. Korean J Intern Med 29, 123–5. 8 Gooley TA, Chien JW, Pergam SA et al. (2010) Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med 363, 2091–101. 9 Daikeler T, H€ ugle T, Farge D et al. (2009) Allogeneic hematopoietic SCT for patients with autoimmune diseases. Bone Marrow Transplant 44, 27–33.
International Journal of Rheumatic Diseases 2015
