Treatment of several complications remains as important issues after stem cell transplantation. Potent immunosuppressive drugs or T-cell depletion of the graft can eliminate graft-versus-host disease (GVHD) but this strategy leads to an increased risk of tumor relapse as well as fatal viral infections. Mortality remains high when conventional treatment fails. Because the underlying mechanism of cellular immunity has been elucidated and an innovative cell isolation and culture system developed recently, alternative strategies have been developed; to enhance the engraftment, decrease relapse rate, and prevent/treat GVHD and viral infections. Ex vivo expanded mesenchymal stem cells or viral specific cytotoxic T cells have been shown to efficiently inhibit lethal GVHD or fatal viral infections, respectively. Preclinical data has provided encouraging evidence that regulatory T cells lessened the incidence of GVHD and facilitated engraftment. However, few reports with a limited number of patients are available on the safety and efficacy of these novel cell therapies. The optimal dose and frequency of cell administration should be evaluated in phase II clinical trials. High scientific and ethical standards are required according to Good Clinical Practice guidelines in the clinical trials. Furthermore, the manufacturing of clinical trial materials mandate current good manufacturing practices grade cell processing to assure the safety and quality of manipulated cell products. This review presents an overview of the current progress and remainine issues in the cell therapies.

View full abstract

Epstein-Barr virus (EBV) is a ubiquitous virus and is related to various diseases. Primary EBV infection is usually asymptomatic, and it sometimes progresses to infectious mononucleosis, which resolves spontaneously after the emergence of EBV-specific immunity. But, in some apparently immunocompetent hosts, chronic infections can develop. Chronic active EBV infection (CAEBV) is characterized by chronic or recurrent infectious mononucleosis-like symptoms, such as fever, extensive lymphadenopathy, hepatosplenomegaly, and pancytopenia. Patients with CAEBV have high viral loads in their peripheral blood and/or an unusual pattern of EBV-related antibodies. This disease is rare but severe with high morbidity and mortality. Recent advances in technology have increased our understanding of CAEBV pathophysiology, indicating that the clonal expansion of EBV-infected T or natural killer (NK) cells plays a central role in the pathogenesis of CAEBV. However, it remains unclear whether CAEBV is truly a monoclonal lymphoproliferative disorder. In this review, I summarize the clinical feature of CAEBV and discuss our current understanding of the pathogenicity of the disease.

View full abstract

It is difficult to distinguish bronchial asthma from bronchiolitis obliterans organizing pneumonia (BOOP), when dyspnea with wheeze is revealed after allogeneic stem cell transplantation. However, to clarify the cause of wheeze is important because treatment and prognosis are quite different between bronchial asthma and BOOP. We described here infantile acute lymphoblastic leukemia (ALL) for an 8-month-old female case that developed respiratory disorder with wheeze after unrelated cord blood transplantation (CBT). She got onset of infantile ALL, and underwent CBT from an HLA-one-locus-mismatched unrelated donor at the first complete remission. When dyspnea with wheeze appeared two months after CBT, she was treated with methylprednisolone pulse therapy as the possibility of lung graft-versus-host-disease (GVHD) could not be excluded. Blood examination revealed an increase of serum eosinophil cationic protein (ECP) levels (111 μg/l, compared to a normal range of less than 8.8 μg/l), which indicates that dyspnea with wheeze was a symptom of asthmatic BOOP. An effective treatment with steroid inhalation was applied. As a result, serum ECP level measurement was shown to be a useful diagnostic tool and indicator for clinical course in the case of lung complication with wheeze after CBT.

View full abstract

A 6-year-old boy was diagnosed with aplastic anemia. His initial bone marrow showed a normal karyotype and trilineage hypoplasia. He was enrolled in AA-97 protocol including immunosuppressive therapy consisting of antithymocyte globulin, cyclosporin and granulocyte colony-stimulating factor, which resulted in hematological remission. Eighteen months later, his bone marrow showed t (3;3) (q21;q26) clones in 3 of the 20 cells. His peripheral blood and bone marrow morphology did not show any abnormalities at that time, but he soon developed neutropenia, anemia and thrombocytosis. His marrow karyotype in 3 months revealed t (3;3) (q21;q26) clones with a monosomy of chromosome 7 in 20 of the 30 cells. The percentage of myeloblast and megakaryocyte in the marrow was 6.5% and 3.5%, respectively, leading to the diagnosis of myelodysplastic syndrome. Dysmegakaryopoiesis including micromegakaryocyteswas also recognized. He developed acute myeloid leukemia (FAB M6) over 3 months. He received a bone marrow transplant from an unrelated donor, and now almost a year has passed since off-therapy in complete remission. AML or MDS associated with 3q21q26 chromosome abnormalities, the so-called 3q21q26 syndrome, has been reported since the mid-1970s. To our knowledge, this is the first case that developed 3q21q26 syndrome after immunosuppressive therapy conducted for aplastic anemia.

View full abstract

We describe a 2-year-old boy with CNS AML recurring five months after completion of JACLS AML 99. He took BMT in CR2 from HLA 1 locus mismatched from his mother and was seriously complicated with bloody diarrhea (MAX : 5, 000 ml/m²/day). We diagnosed his complication as thrombotic microangiopathy (TMA) based on findings of a large intestine biopsy, emergence of crushed red blood cells and high t-PAI-1 complex. So we changed his injection from tacrolimus (FK506) to m-PSL, supplemented with AT, and started continuous MAP and PC blood transfusion. In effect, the bloody stool decreased slowly and no further MAP blood transfusion was necessary after 2 months. During this period he was complicated with skin GVHD and sepsis with methicillin-resistant staphylococcus epidermidis (MRSE) repeatedly, so he needed infusion of teicoplanin (TEIC) for a long time. After that we discontinued the infusion of TEIC because his fever subsided and he had a negative blood culture, but one week later he was complicated with acute respiratory distress syndrome (ARDS) from sepsis and died suddenly. In this case severe intestinal TMA improved with early diagnosis of TMA, discontinuation of FK506 and the device of supportive therapy. This case suggests the possibility of improvement of severe intestinal TMA.

View full abstract

We reported a 15-year-old boy who developed fatal visceral dissemination of varicella-zoster virus (VZV) after his 2nd allogeneic stem cell transplantation for Phl positive acute myeloid leukemia (AML). At 12 years of age, he was given a diagnosis of Phi positive AML. On day 511 of the second stem cell transplantation, he was admitted for severe right epigastralgia. He had been treated with cyclosporin and prednisolone for chronic graft versus host disease. Laboratory findings, radiographic and ultrasonographic studies were performed but non-diagnostic. He was treated with various analgesics, but severe abdominal pain did not disappear. On the fifth day of his admission, vesicular skin eruptions appeared on his face and trunk. Then antiviral therapy with acyclovir (ACV) was started. However, he died of multiple organ failure on the following day. VZV was detected in the liver tissue obtained from the autopsy by using polymerase chain reaction (PCR). Visceral VZV infection should be considered in the case of patients who underwent hematopoietic stem cell transplantation developing severe acute abdominal pain. Early ACV administration and detection of VZV using PCR on blood or biopsy sample is recommended.

View full abstract

Castleman's disease is a rare B cell lymphoproliferative disorder characterized by excessive interleukin 6 (IL-6) production. We report the case of a 6-year-old girl with Castleman's disease in a retroperitoneal cavity presenting with severe hypochromic and microcytic anemia. Initial laboratory findings revealed a low level of Hb (6.0 g/dl) with low MCV (51.6 fl) and MCHC and high levels of CRP and IL-6 in the serum. An abdominal ultrasound and computed tomography scan showed a solid tumor in her peritoneal area. She was diagnosed with Castleman's disease according to the pathological finding. Her general condition and laboratory abnormalities promptly improved after the complete resection of the tumor. Castleman's disease should be included as a differential diagnosis with severe microcytic anemia and fever.

View full abstract