Akane Kunitomi

Successful Allogeneic Stem Cell Transplantation From an Unrelated Donor for Aggressive Epstein-Barr Virus—Associated Clonal T-Cell Proliferation With Hemophagocytosis

We present here a case of aggressive Epstein-Barr virus (EBV)-associated clonal T-cell proliferation with hemophagocytosis that was successfully treated by allogeneic stem cell transplantation using an unrelated donor. A 17-year-old woman was admitted into the hospital with a high fever and liver dysfunction. Laboratory data including bone marrow aspiration revealed hemophagocytic syndrome with proliferation of immature T-lymphoid cells. The clonal proliferation of EBV-infected T cells was confirmed by Southern blot analysis using a terminal-repeat probe from the EBV genome and also by demonstrating T cell—receptor β gene rearrangement. Intensive immunochemotherapy consisting of cyclosporin A, vincristine, etoposide, and high-dose methylprednisolone did not control the disease and relapse occurred repeatedly. Therefore, during remission after chemotherapy according to the CHOP-E regimen, the patient underwent allogeneic bone marrow transplantation (BMT) from an HLA-matched, unrelated donor. Donor selection was performed with help from the Japanese Association for Marrow Donor Program (JMDP). The patient has remained in good condition without recurrence of disease for 18 months after BMT. Allogeneic BMT is the treatment of choice for aggressive EBV-associated hemophagocytic lymphohistiocytosis even in the case where an HLA-matched sibling donor is not available, especially when the patient is refractory to intensive chemotherapy and/or there is a ready recurrence of disease after conventional therapy.

Bone Marrow Transplantation with a Reduced-Intensity Conditioning Regimen in a Patient with Wegener Granulomatosis and Therapy-Related Leukemia

We describe a patient with Wegener granulomatosis (WG) who underwent long-term cyclophosphamide treatment and thereafter developed acute myelogenous leukemia (AML). After the AML was induced into remission, the patient received an allogeneic stem cell transplant (allo-SCT) from his sibling after undergoing a reduced-intensity conditioning regimen. His clinical course shortly after allo-SCT was uneventful. No clinically apparent acute or chronic graft-versus-host disease developed. Repeated analysis of the peripheral blood lymphocytes after transplantation showed complete donor chimerism. The level of proteinase 3 antineutrophil cytoplasmic antibody (PR3-ANCA) remained undetectable until 4 months after transplantation, when it began to increase. When the level of PR3-ANCA peaked, the patient suddenly presented with fever and joint pain, which later spontaneously resolved in parallel with the declining titer of PR3-ANCA. He is now in remission for both AML and WG at 22 months after transplantation. The patient’s clinical course after allo-SCT may provide us with valuable information regarding the establishment of allo-SCT as a therapeutic option for WG.

OX40 Signaling Renders Adult T-Cell Leukemia Cells Resistant to Fas-Induced Apoptosis

We reported previously that OX40, a member of the tumor necrosis factor receptor family, is expressed constitutively on fresh leukemia/lymphoma cells isolated from patients with adult T-cell leukemia (ATL). In this study, we tested whether OX40 signaling affects the Fas-mediated apoptosis of fresh ATL cells isolated from 7 patients (3 acute type, 3 chronic type, and 1 smoldering type). In all these patients, the coculture of ATL cells with MMCE/OX40 ligand gp34, a stable human gp34 transfectant of a mouse epithelial cell line, resulted in a decrease in the percentage of apoptotic cells after treatment with anti-Fas monoclonal antibody, compared to coculture with MMCE/mock controls. Similar findings were obtained in OX40+_ human T-cell leukemia virus type I-transformed T-cell lines. To elucidate the molecular mechanism of this phenomenon, we used Kit225/OX40, a stable OX40 transfectant of an IL-2-dependent T-cell line, and its deletion mutant, Kit225/del-OX40, in which the intracytoplasmic domain of OX40 had been deleted. Coculture with MMCE/gp34 inhibited the apoptosis of Kit225/OX40, but Kit225/del-OX40 apoptosis was hardly affected.These results suggest that ATL cells may escape Fas-mediated destruction of the immune system through OX40 signaling.

Humanized anti-interleukin 6 receptor antibody induced long-term remission in a patient with life-threatening refractory autoimmune hemolytic anemia

Refractory autoimmune hemolytic anemia (AIHA) is associated with considerable rates of mortality. Interleukin 6 (IL-6) has been reported to play a role in the pathogenesis of AIHA. This report describes a patient with AIHA who was successfully treated with a humanized anti-human IL-6 receptor (IL-6R) monoclonal antibody (MoAb). He had experienced life-threatening AIHA and had received conventional therapy with corticosteroids, azathioprine, cyclophosphamide, cyclosporin A, melphalan, plasma exchange, and irradiation to his spleen. However, the patient’s symptoms and laboratory data did not show a sufficient improvement. Because his serum IL-6 level was elevated, we attempted to block IL-6 signaling by using a humanized anti-IL-6R MoAb, MRA.With 8 mg/kg of MRA administration every 2 weeks, the serum hemoglobin level gradually increased and normalized within 4 months. After 2 years of MRA treatment, the disease activity was well controlled without adverse reactions. Anti-IL-6R MoAb can be a novel and effective therapeutic agent for AIHA.

CD8+ T-cell lymphoproliferative disorder associated with Epstein-Barr virus in a patient with rheumatoid arthritis during methotrexate therapy

A 75-year-old woman with rheumatoid arthritis (RA) who was receiving methotrexate (MTX) therapy developed Epstein–Barr virus (EBV)-associated CD8+ T-cell lymphoproliferative disorder (LPD) and meningoencephalitis. She was successfully treated with acyclovir and corticosteroids plus MTX cessation. T-cell LPD is relatively rare in RA patients receiving MTX. To our knowledge, this is the first report of CD8+ T-cell LPD with EBV genome occurring during MTX therapy for RA. EBV infection should be carefully monitored to assess severe EBV-associated complications.

Hairy Cell Leukemia with Systemic Lymphadenopathy: Detection of BRAF Mutations in Both Lymph Node and Peripheral Blood Specimens

A 47-year-old woman with pancytopenia, excessive systemic lymphadenopathy and splenomegaly was referred to our hospital. The peripheral blood (PB) smear findings indicated neutropenia with lymphoid cells exhibiting hairy projections, while the histological findings of the cervical lymph node (LN) suggested hairy cell leukemia (HCL). In addition, the BRAF V600E mutation was detected, and the immunoglobulin gene rearrangement patterns were identical in both the cervical LN and PB specimens. Based on these findings, we diagnosed the patient with systemic lymphadenopathy due to HCL. This is the first report of a BRAF mutation detected in both the PB and LN at the onset of HCL.

EBV-positive Reactive Hyperplasia Progressed into EBV-positive Diffuse Large B-cell Lymphoma of the Elderly over a 6-year Period

A 70-year-old woman with lymphadenopathy was admitted to hospital in 2008. Lymph node biopsy showed reactive lymphoid hyperplasia (RH) with monoclonal proliferation of Epstein-Barr virus (EBV). Her lymphadenopathy regressed without treatment. In 2014, the patient presented with nasal obstruction because of a left nasal mass. She was diagnosed with EBV-positive diffuse large B-cell lymphoma (DLBCL) of the elderly based on the examination of a biopsy specimen of the mass. The IgH rearrangement in the specimens from the 2008 and the 2014 revealed that they were genetically identical. This is the first report of RH progressing to DLBCL, and suggests that EBV-positive B-cells in RH lymph nodes predict the evolution to DLBCL.

Successful treatment using tacrolimus ointment for cutaneous graft-versus-host disease

Graft-versus-host disease (GVHD) is a well-known complication of allogeneic stem cell transplantation (allo-SCT). GVHD occurs when transplanted donor T cells react to foreign host cells, causing damage to a wide variety of host tissues. GVHD damage that is multi-organic is treated mainly with systemic cyclosporine, steroids, and other immunosuppressive agents. GVHD that manifests as only limited skin involvement can be treated topically, avoiding the severe side effects of the various systemic treatment options [1]. Although topical steroid therapy is the mainstay local treatment for cutaneous GVHD, its use is limited by adverse effects, including skin atrophy, telangiectasia, and striae cutis distensae, and therefore alternative approaches are being explored. Recently, topical tacrolimus has been used successfully in the treatment of chronic cutaneous GVHD [2, 3]. Here we report a case of severe acute cutaneous GVHD that was treated with tacrolimus ointment. A 50-year-old Japanese man was diagnosed with acute monocytic leukemia, or according to the French–American–British classification, acute myeloid leukemia (AML) M5b, with chromosomal abnormality of trisomy 8. The patient was treated with induction therapy for AML and achieved a partial remission. He then underwent an allogeneic bone marrow transplantation (BMT) from an HLA-matched unrelated donor. The conditioning regimen prior to BMT consisted of cyclophosphamide 60 mg/kg for 2 days and 8 Gy of total body irradiation. A combination of tacrolimus and short-term methotrexate was prescribed as prophylaxis for GVHD. At 11 days after BMT, the bone marrow engrafted and the patient presented with a high grade fever, elevated liver enzymes, and skin rash with erythema developed bilaterally on his arms and body. A skin biopsy revealed acute GVHD. Prednisone therapy was started at a dosage of 1 mg/kg, 70 mg/day. The symptoms of acute GVHD disappeared by day ?26. At day ?35, however, the patient had flaring and generalization of cutaneous GVHD without gastrointestinal or hepatic involvement of the disease. Prednisone at 60 mg/day and tacrolimus therapy were continued, and he received topical steroid therapy. Because the cutaneous GVHD remained, an evaluation of the effect of tacrolimus ointment on the affected area in comparison with steroid ointment only was discussed with the patient and, after obtaining written informed consult, he was instructed to apply 0.1% tacrolimus ointment once daily to the affected area on the left side, and only steroid ointment to the affected area on the right side. After 2 weeks of using tacrolimus ointment, his skin itch and redness on the left side were greatly reduced. Physical examination revealed a marked reduction in the amount of erythema, most notably on his thigh (Fig. 1). Skin biopsies were performed at day ?55 for the pathologic evaluation of the efficacy of tacrolimus ointment for cutaneous GVHD. The histologic and immunofluorescent findings from the right side, which was treated with control steroid ointment only, showed lymphocyte infiltration of the epithelium lesions with CD 8-positive T cells. In contrast, the findings from the left side, treated with tacrolimus ointment, showed no signs of GVHD (Fig. 2). Because the benefit of tacrolimus therapy was greater than that of the control steroid ointment, tacrolimus ointment was prescribed for both sides of his body. After 2 weeks, the skin redness was greatly reduced bilaterally. A. Kunitomi (&) H. Iida Y. Kamiya M. Hayashi H. Sao Department of Hematology, Meitetsu Hospital, 2-26-11 Sakoh, Nishi-ku, Nagoya 451-8511, Japan e-mail: akunitom@mx5.suisui-w.ne.jp

Myeloid blast crisis in chronic myeloid leukemia with a unique deletion near the BCR/ABL breakpoint

We describe a case of a 44-year-old man with chronic myeloid leukemia in blastic crisis phase based on peripheral blood smear findings, and the detection of BCR/ABL transcript signals by fluorescence in situ hybridization analysis. Our attempts to quantify the amount of the major BCR/ABL fusion gene revealed that some primers were unable to detect the gene, whereas other primers could detect the gene. We detected a unique deletion on the BCR area by cloning the sequence, which has not been reported previously. Our case suggests that direct sequencing is important when quantitative PCR yields ambiguous results.

Uneventful splenectomy and cholecystectomy in a patient treated with anti-interleukin-6 receptor antibody therapy

IntroductionInterleukin-6 (IL-6) is a multifunctional cytokine that regulates various aspects of the immune responses, acute phase reactions, and hematopoiesis. In rodent models, IL-6 has been suggested to be one of the essential mediators for optimal acute phase responses to infection and tissue damage. However, in humans, the roles of IL-6 in acute phase responses after surgery remain poorly understood.Case reportWe present the first case report of successful splenectomy and cholecystectomy in a severe autoimmune-associated hemolytic anemia patient during treatment with a humanized anti-IL-6 receptor antibody.DiscussionThis unique case suggests that IL-6 is not an essential cytokine to safely perform surgical intervention and to prevent postoperative complications and that surgical intervention may not be contraindicated but can be selected as a therapeutic modality in patients treated with anti-IL-6 receptor antibody therapy.