Masaharu Nohgawa

Intravascular hemolytic anemia in a patient with antibodies related to meropenem.

A 76-year-old woman treated with meropenem developed intravascular hemolytic attacks. A direct antiglobulin test was positive for C3d and IgG, and drug-dependent antibody testing indicated that the antibodies were indeed drug-dependent and reacted with drug-treated RBCs and RBCs in the presence of the drug. To our knowledge, this is the first reported case in which the causative antibodies related to meropenem were identified. This case highlights the importance of maintaining a high level of suspicion for drug-induced immune hemolytic anemia in patients with explained hemolysis as well as conducting specialized serologic testing.

EB virus reactivation triggers thrombotic thrombocytopenic purpura in a healthy adult

Thrombotic thrombocytopenic purpura (TTP) is rare but life-threatening disease, characterized typically by microangiopathic hemolytic anemia (MAHA), profound peripheral thrombocytopenia and severe deficiency in the von Willebrand factor-cleaving prortease ADAMTS13. It has been reported that acquired immune TTP is closely associated with human immunodeficiency virus infection and influenza infection or vaccination. However, it has not been reported to be associated with Epstein Barr Virus infection or reactivation. We herein report a first case of acquired TTP associated with EBV reactivation in an otherwise healthy adult.

Successful Treatment of Catastrophic Antiphospholipid Antibody Syndrome Associated with MALT Lymphoma by Autologous Hematopoietic Stem Cell Transplantation

A 37-year-old woman with extranodal marginal-zone lymphoma was admitted with a fever, hemiplegia, and severe dyspnea after chemotherapy. Catastrophic antiphospholipid antibody syndrome (CAPS) was suspected based on the histopathological confirmation of small-pulmonary vessel occlusion, evidence of the involvement of three organs, and elevated lupus anticoagulant assay results in a short time span. The patient responded to the initial treatment. One month later, the CAPS and lymphoma relapsed, and the patient underwent autologous hematopoietic stem cell transplantation. Complete remission of the lymphoma has been successfully maintained, and the condition of the patient has remained stable for two years with no further evidence of thrombosis.

Successful treatment with azacitidine for the simultaneous occurrence of multiple myeloma and acute myeloid leukemia with concomitant del(5q) and the JAK2 V617F mutation

Dear Editor, A 73-year-old female with 5q-syndrome and the co-existent JAK2V617 mutation following 92-month treatment with lenalidomide exhibited evidence of disease progression, with leukopenia (WBC 2.2 × 10/l), anemia (hemoglobin 68 g/l), and 30% blasts in her bone marrow (Fig. 1a). Strong nuclear p53 and CD34 immunostaining was detected in 30 and 10% of hematopoietic cells, respectively (Fig. 1b), and CD138 immunostaining was noted in 10% of plasma cells (Fig. 1c). A FISH analysis revealed 5q31 in 86% of nuclei andmolecular analyses were positive for the JAK2 V617F mutation (60%). Her serum interleukin (IL)-6 level was 37 pg/ml (normal range, lower than 4 pg/ml). The medullary plasma cell count was <10%. Serum IgG paraprotein and β2-microglobulin (β2MG) levels increased to 65 g/l (normal range, 7–16 g/l) and 7.8 mg/l (normal range <2 mg/l), respectively. The serum-free light chain ratio was 6.5 (normal range, 0.26–1.25). However, she had no evidence ofmyeloma-defining events or amyloidosis. A diagnosis of the simultaneous occurrence of acute myeloid leukemia (AML) and smoldering multiple myeloma (MM) was made, and 5-azacytidine (75 mg/m, days 1–7 in a 28-day cycle) was initiated. After 2 cycles of this treatment, she had normal peripheral blood counts and no evidence of circulating blasts. Serum IgG paraprotein, β2-microglobulin (β2-MG) and IL-6 levels decreased to 18 g/l, 2.6 mg/l, and 2.3 pg/ml, respectively. A repeat marrow examination showed slightly hypercellular marrow, with a significant decrease in myeloblasts to 1% blasts and 5% of plasma cells (Fig. 1d). Strong nuclear p53 and CD34 immunostaining decreased in hematopoietic cells (Fig. 1e), and CD138 immunostaining was detected in a few plasma cells (Fig. 1f). Karyotypic analyses showed 46, XX, del(5q)(q13q31) (11/20 cells), 46, XX, del(5q) (q13q31), t(17;21)(q25;q11.2)(9/20 cells). A FISH analysis revealed 5q31 in 20% of nuclei and molecular analyses were positive for the JAK2 V617F mutation (8%). The azacitidine treatment has been continued, and the patient maintained hematological CR without the progression of MM in the subsequent 12 months. Concomitant occurrence of myelodysplastic syndrome (MDS)/myeloproliferative neoplasms (MPN), and MM is a rare event, and the reason of this association remains unclear. The management of these patients involves the treatment of MDS/MPN and the monitoring of MM for transformation to an overt plasma-cell malignancy. However, in patients who develop MM, management is focused on treating myeloma. Agents such as melphalan, thalidomide, lenalidomide, pomalidomide, and bortezomib exhibit clear activity in such patients and need to be considered in the treatment strategy. Azacitidine functions though the proteosomic destruction of DNA methyltransferase and resultant chromatin decondensation, and is not only active in higher-risk disease; similar response rates have been reported in IPSS low/int-1 patients including those with a del(5q) abnormality. The frequencies of TP53 mutations in MDS and MM were 7–19 and 8–15%, respectively, and TP53 mutant clones may drive disease progression [1–4]. In MDS, p53 nuclear expression has been correlated with hemizygous TP53 mutations, and strong p53 immunostaining in >1% of bone marrow progenitor cells has also been correlated with a higher risk of AML and resistance to lenalidomide therapy [1, 2, 5]. In MM, the presence of TP53 mutations indicates a dismal * Satoko Oka okas@jasmine.ocn.ne.jp

Multiple myeloma presenting as cutaneous leukocytoclastic vasculitis and eosinophilia disclosing a T helper type 1/T helper type 2 imbalance: a case report

BackgroundMultiple myeloma is a very heterogeneous disease comprising a number of genetic entities that differ from each other in their evolution, mode of presentation, response to therapy, and prognosis. Due to its more chronic nature and cumulative toxicities that patients develop from multiple lines of treatments, a number of symptoms are associated with multiple myeloma. However, the mechanisms responsible for the relationship between these symptoms and multiple myeloma currently remain unclear.Case presentationAn 85-year-old Japanese woman exhibited the rare presentation of multiple myeloma (immunoglobulin kappa chain type) with leukocytoclastic vasculitis and eosinophilia. The serum level of interferon-γ was decreased; however, serum levels of interleukin-4, interleukin-5, interleukin-6, interleukin-10, and tumor growth factor-β levels were elevated. She received a bortezomib, lenalidomide, and dexamethasone regimen. After one course of the treatment, the cutaneous manifestation rapidly improved and laboratory tests showed decrease of eosinophil cell count. Serum concentrations of immunoglobulin G decreased and plasma cells in bone marrow decreased. The serum level of interferon-γ was elevated and serum levels of interleukin-4, interleukin-5, interleukin-6, interleukin-10, and tumor growth factor-β decreased.ConclusionsIt is the first case of leukocytoclastic vasculitis and eosinophilia in multiple myeloma that was associated with a T helper type 1/T helper type 2 imbalance and T regulatory cells, and was successfully treated with bortezomib, lenalidomide, and dexamethasone. The present case reinforces the value of early evaluations for paraneoplastic symptoms in order to reach a diagnosis and allow for the prompt initiation of appropriate treatments and achieve successful therapeutic management.

Successful retreatment with lenalidomide for relapsed and refractory multiple myeloma previously treated with bortezomib, lenalidomide and pomalidomide

Optimal strategies for treating patients with very advanced relapsed and refractory multiple myeloma (RRMM) have not been clarified.

Successful Treatment of Syndrome of Inappropriate Antidiuretic Hormone Secretion Associated with Neuro-Sweet Disease in Myelodysplastic Syndrome

Sweet disease may occur in several organs, and central nervous system involvement, known as Neuro-Sweet disease (NSD), is rare. The clinical features of NSD include recurrent encephalomeningitis accompanied by fever and erythematous plaques; systemic corticosteroid therapy is highly effective. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is an important electrolyte abnormality because it can be life-threatening. We describe the first case of SIADH and NSD associated with low-risk myelodysplastic syndrome that was successfully treated with corticosteroids and cyclosporine. The patient has remained stable for 1 year without any recurrence.

Successful treatment of refractory TAFRO syndrome with elevated vascular endothelial growth factor using thyroxine supplements

Although the clinical significance of hypothyroidism in TAFRO syndrome is unknown, vascular endothelial growth factor (VEGF) levels decreased with improvements in the condition of our refractory TAFRO cases after thyroxine supplement therapy. Our results indicate that elevated VEGF levels are a potential factor in the pathogenesis and anasarca of TAFRO syndrome with hypothyroidism.

Non-severe form of severe fever with thrombocytopenia syndrome (SFTS)

Dear Editor, A 78-year-old Japanese womanwas referred to our hospital due to neutropenia and thrombocytopenia. She had experienced a high fever (39–40 °C) for 1 week before admission. She had received antibiotic orally or intravenously for 1 week at other clinic, without effect. Because of the patient’s neutropenia and thrombocytopenia, she was transferred to our hospital with the suspicion of sepsis. She had a > 10-year history of hypertension and had taken antihypertensive drugs. She was admitted to our hematological department for further investigation. The physical exam upon admission showed blood pressure 102/65 mmHg, heart rate 77/min, body temperature 36.6 °C, respiratory rate 24/min, and SpO2 95% at room air with clear consciousness. There were no apparent tick-bite site and any lymphadenopathy. Blood tests showed severe leukocytopenia and thrombocytopenia: red blood cell (RBC) count 4.42 × 10/L, hemoglobin 13.9 g/dL, white blood cell (WBC) count 0.8 × 10/L (reference range [r.r.] 40–70), and platelet count 42 × 10/L (r.r. 15–40). Atypical lymphocytes (11% among WBCs) and defect of granules in granulocytes were observed in her peripheral blood smear. Other laboratory tests revealed elevated aspartate aminotransferase 133 U/L (r.r. 5–40), alanine aminotransferases 48 U/L (r.r. 5–35), lactate dehydrogenase 384 IU/L (r.r. 106–211), total bilirubin level 0.5 mg/dL, serum creatinine 0.63 mg/dL, c-reactive protein 0.01 mg/dL, and mild elevated ferritin level 240.8 ng/mL (r.r. 10–60). As she showed bicytopenia, a bone marrow aspiration was performed to rule out possible hematological malignancies. Bone marrow examination revealed an increase of atypical lymphocytes (approx. 40% of total nucleated cell count (6000/μL)) but there was no evidence of hematological malignancy or hemophagocytosis. From these results, virus infection was suspected; however, hepatitis type B virus, hepatitis C type virus, human immunodeficiency virus, human T cell leukemia virus type 1, and herpes simple virus were all negative. The blood testing for cytomegalovirus and Epstein-Barr virus showed a prior infection pattern. The patient’s fever continued after admission. Other than fever, she was doing well. We performed blood culture tests and treated her with NSAIDs without using antibiotics. Her family members told us that she was living in a house with wild mice, and that she frequently worked outside on farmland. From this medical history, we suspected that she had possible zoonosis. As severe thrombocytopenia and leukocytopenia without anemia were detected, the diagnosis of severe fever with thrombocytopenia syndrome (SFTS) was suspected, and we had performed a polymerase chain reaction analysis for SFTS virus using peripheral blood. Her fever was sustained for one more day, after which she was de-fevered. The test for SFTS virus revealed a positive result, confirming the diagnosis of * Yutaka Shimazu yshimazu@kankyo.ne.jp

Relationship between Autoimmune Diseases and Imbalances in Helper/Suppressor T-cell Populations after Rituximab-containing Chemotherapyfor Non-Hodgkin Lymphoma

Immunologic abnormalities including autoimmune hemolytic anemia (AIHA) and immune thrombocytopenic purpura (ITP) have been described in patients with non-Hodgkin lymphoma. In some cases, anti-red cell or platelet antibodies are produced by lymphoma cells. However, cases of the occurrence of autoimmune diseases without recurrence of lymphomas have been also reported. The relationship between autoimmune diseases with post-bone marrow transplantation and Hodgkin disease may be attributed to immune dysfunctions, particularly those involving T cells. This autoimmune phenomenon may be related to imbalances in helper/suppressor T-cell populations. Imbalances in helper and suppressor T-cell populations have been reported after R-CHOP chemotherapy, and the recovery of serum IgG and CD4+ counts was observed more than 2 years after R-CHOP therapy in patients with B-cell lymphoma. In this report, we present a case of an 87-year-old man who was treated with rituximab-containing chemotherapy and maintained complete remission. However, the immunophenotyping of peripheral blood and bone mallow mononuclear cells revealed a reversed CD4/CD8 ratio. Two years later, he developed ITP. He was treated with intravenous immunoglobulin and eltrobopag, and thrombocytopenia improved. Five years later, he developed pneumonia and sudden Coombs-positive hemolytic anemia caused by autoantibodies against D antigen and thrombocytopenia without the recurrence of lymphoma. He was treated with prednisolone and a pulse dose of methylprednisolone; however, his response to therapy was poor and he subsequently died. We herein report a case who have been showed reversed imbalances in the helper/suppressor T cell populations over 2 years after R-CHOP therapy, developed AIHA and ITP without recurrence of lymphoma. The long-term monitoring of T-cell counts after rituximab containing chemotherapies is important, and careful attention to infection signs.