[Atypical hemolytic uremic syndrome in an elderly patient successfully treated with eculizumab].

Herein, we present an elderly onset case of aHUS successfully treated with eculizumab. An 80-year-old woman with severe anemia, thrombocytopenia, and acute renal dysfunction was admitted to our hospital. A laboratory test revealed steep elevation in the LDH level, and the peripheral blood smear showed erythrocyte fragmentations. Accordingly, we diagnosed thrombotic microangiopathy, and treatment with plasma exchange was immediately initiated. In addition, she required hemodialysis because of rapid impairment of the renal function. After excluding Shiga toxin-producing Escherichia coli infection and malignancy and confirming her ADMTS13 activity above 10%, we diagnosed aHUS, according to the Japanese diagnostic criteria for aHUS. Next, we initiated treatment with eculizumab. Her hematological findings improved 23 days after the starting of eculizumab. In addition, her renal function gradually recovered, and hemodialysis was discontinued. The genetic test for several complement regulatory genes tested negative. The onset of aHUS is reported in children or young adults and is rarely reported in elderly. However, our case suggests the importance of precisely diagnosing aHUS and initiating early administration of eculizumab for improving the outcome even in elderly patients.

18F-FDG-PET/CT is effective in distinguishing myelofibrosis due to bone marrow infiltration of diffuse large B-cell lymphoma from triple-negative primary myelofibrosis.

Although myelofibrosis is mainly associated with myeloproliferative neoplasms (MPN), especially primary myelofibrosis (PMF), a variety of hematological malignancies, including acute myeloid leukemia, multiple myeloma and malignant lymphoma, also cause myelofibrosis with markedly varying degrees of severity. Thus, it is extremely important to accurately diagnose the underlying diseases that cause fibrosis in bone marrow. Analyses of JAK2, MPL and calreticulin gene mutations are useful for distinguishing MPN from other diseases, since 90% of MPN patients have a mutation in one of these genes. However, 10% of PMF patients do not have mutations in any of these genes, and these patients have a disease known as triple negative PMF. It is sometimes difficult to accurately distinguish triple negative PMF from secondary myelofibrosis caused by other diseases. Herein, we present a case of diffuse large B cell lymphoma (DLBCL) with bone marrow involvement, mimicking triple negative primary myelofibrosis. 18F-FDG-PET was useful for correctly diagnosing DLBCL.

[Adult T cell leukemia-lymphoma with allo-HSCT after treatment for pulmonary involvement with Mogamulizumab].

Adult T cell lymphoma-leukemia (ATL) is a highly aggressive disease and allogeneic hematopoietic transplantation (allo-HSCT) is the only therapeutic option for achieving a cure. However, some ATL patients cannot undergo HSCT. One of the important reasons for restricting HSCT in ATL is the high incidence of pulmonary complications associated with ATL including opportunistic infections, infiltration of ATL cells, and HTLV-1 associated bronchopneumonopathy. Herein, we report an ATL case with pulmonary infiltration of ATL cells successfully treated with allo-HSCT after improvement of pulmonary function with administration of the anti-CCR4 antibody mogamulizumab. To our knowledge, this is the first ATL case showing improvement of pulmonary invasion of ATL cells after treatment with mogamulizumab. In addition, this case suggests that mogamulizumab treatment might be useful as a bridge to allo-HSCT in ATL patients.

[Successful treatment with rituximab and romiplostim for thrombocytopenia associated with Waldenström's macroglobulinemia initially presenting as Evans syndrome].

A 60-year-old woman was admitted to our hospital with anemia and thrombocytopenia. Serum testing showed platelet-associated IgG elevation and she was positive on the direct and indirect Coombs tests. Together with bone marrow examination, these findings indicated a diagnosis of Evans syndrome. At diagnosis, she also had an IgM-κ type of monoclonal gammopathy of unknown significance. Initially, we administered steroids and her hemolytic anemia showed improvement. In contrast, only transient recovery of platelet counts was observed and her platelet counts rapidly decreased after steroid dose reduction. Thus, we treated her with a TPO-agonist, romiplostim. During the clinical course, she showed gradual serum IgM elevation. We thus performed another bone marrow biopsy and diagnosed her as having Waldenström's macroglobulinemia (WM). We started treatment with rituximab for WM. Together with the serum IgM reduction, she showed marked improvement of thrombocytopenia. This is a very rare case of WM initially presenting as autoimmune hemolytic anemia and immunethrombocytopenia associated with IgG class auto-antibody. Our experience suggests the usefulness of rituximab and romiplostim for the treatment of immunethrombocytopenia associated with WM.

[Development of cytomegalovirus antigenemia in 3 patients with B cell lymphoma treated with bendamustine monotherapy].

Bendamustine is one of the new key drugs for patients with indolent lymphoma. Bendamustine, together with rituximab, significantly improves the treatment outcomes of these patients. In addition, previous clinical studies have shown the complication rate of severe infection in bendamustine-containing regimens to be relatively low as compared to those of conventional chemotherapeutic regimens such as CHOP. However, some clinical case reports have raised the possibility that bendamustine may abrogate the immune responses of patients and trigger opportunistic infections including cytomegalovirus reactivation. Herein, we report three indolent lymphoma cases becoming positive on cytomegalovirus antigenemia assay during bendamustine monotherapy. All events occurred after more than three courses of treatment with bendamustine. One patient showed decreased CD4 positive T lymphocytes before the development of cytomegalovirus antigenemia. All three patients were successfully treated with valganciclovir. Although the precise risk is unknown, it should be noted that bendamustine can potentially cause reactivation of/infection with cytomegalovirus and physicians should pay attention to the possibility of this infection during treatment with bendamustine-containing regimens.

Abrupt evolution of Philadelphia chromosome-positive acute myeloid leukemia in myelodysplastic syndrome.

Myelodysplastic syndrome (MDS) is a clonal disorder arising from an alteration in multipotent stem cells, which lose the ability of normal proliferation and differentiation. Disease progression occurs in approximately 30% MDS cases. Specific chromosomal alterations seem responsible for each step in the evolution of acute myeloid leukemia (AML). Multiple genetic aberrations occur during the clonal evolution of MDS; however, few studies report the presence of the Philadelphia (Ph) chromosome. We report a rare case of Ph-positive AML, which evolved during the course of low-risk MDS. The patient, a 76-year-old man with mild leukocytopenia, was diagnosed with MDS, refractory neutropenia (RN). After 1.5 yr, his peripheral blood and bone marrow were suddenly occupied by immature basophils and myeloblasts, indicating the onset of AML. A bone marrow smear showed multilineage dysplasia, consistent with MDS evolution. Chromosomal analysis showed an additional t(9;22)(q34;q11) translocation. Because progression occurred concurrently with emergence of the Ph chromosome, we diagnosed this case as Ph-positive AML with basophilia arising from the clonal evolution of MDS. The patient was initially treated with nilotinib. A hematological response was soon achieved with disappearance of the Ph chromosome in the bone marrow. Emergence of Ph-positive AML in the course of low-risk MDS has rarely been reported. We report this case as a rare clinical course of MDS.

[Non-traumatic splenic rupture during the chemotherapy and successful management by emergency splenectomy in a patient with blastic plasmacytoid dendritic cell neoplasm].

Spontaneous rupture of the spleen is a rare but important complication in hematological malignancies. Without splenectomy, the mortality rate of these patients is nearly 100%. We present a blastic plasmacytoid dendritic cell neoplasm case with this complication. Nine days after initiation of chemotherapy, the patient had increased epigastric pain and a drop in hemoglobin. CT scan showed an enlarged spleen surrounded by hemorrhage. Spontaneous rupture of the spleen was diagnosed. Although the patient had severe bone marrow suppression due to chemotherapy, emergency splenectomy was performed and the patient recovered.

Combined Coagulopathy Can Induce Both Hemorrhagic and Thrombotic Complications in Multiple Myeloma.

Coagulation abnormalities are a rare but critical complication associated with plasma cell diseases. We herein present a case of multiple myeloma (MM) with complicated coagulopathy. Initially, the patient showed severe bleeding tendency due to concomitant acquired hemophilia A and acquired von Willebrand syndrome. Interestingly, the patient also exhibited hyperactivation of factor IX. During treatment for MM, the bleeding complications were ameliorated; however, the patient had central retinal vein occlusion. All of the coagulation abnormalities were completely resolved after the complete remission of MM. This case suggests that MM patients may have concomitant risks for both bleeding and thromboembolic complications.

Tumor Lysis Syndrome after the Administration of Ruxolitinib in a Patient with Post-polycythemia Vera Myelofibrosis.

The development of tumor lysis syndrome (TLS) in association with treatment for myeloproliferative neoplasms (MPNs) is relatively rare. We herein present the case of a post-polycythemia vera (PV) myelofibrosis patient with massive splenomegaly who developed laboratory TLS after treatment with ruxolitinib, a potent JAK1/JAK2 inhibitor. She also exhibited a rapid reduction of spleen volume. Our present case suggests the potential risk of TLS development after ruxolitinib treatment, particularly in patients with massive splenomegaly.

Negative regulation of the LKB1/AMPK pathway by ERK in human acute myeloid leukemia cells.

Adenosine monophosphate-activated protein kinase (AMPK) is a sensor for cellular energy status. When the cellular energy level is decreased, AMPK is activated and functions to suppress energy-consuming processes, including protein synthesis. Recently, AMPK has received attention as an attractive molecular target for cancer therapy. Several studies have revealed that the activation of AMPK by chemical stimulators, such as metformin, induces apoptosis in a variety of hematologic malignant cells. From another perspective, these results suggest that the function of AMPK is impaired in hematologic tumor cells. However, the precise mechanisms by which this impairment occurs are not well understood. In melanoma cells, oncogenic BRAF constitutively activates the extracellular signal-regulated kinase (ERK) pathway and phosphorylates liver kinase B1, an upstream activator of 5' adenosine monophosphate-activated protein kinase (AMPK), resulting in the inactivation of liver kinase B1 and AMPK. In this study, we analyzed whether ERK is involved in the suppression of AMPK activity using established and primary human leukemia cells. We found an inverse correlation between the intensity of ERK activity and the degree of AMPK activation after stimulation with either glucose deprivation or metformin. We also found that the inhibition of ERK activity by U0126 restored AMPK activation after metformin treatment. Furthermore, a combined treatment with metformin and U0126 enhanced the antileukemic activity of metformin. Importantly, metformin induced ERK activation by suppressing the protein levels of dual specificity phosphatase 6, a negative regulator of ERK. This crosstalk between AMPK and ERK could diminish the antileukemic activity of metformin. Taken together, our present observations suggest a novel therapeutic strategy for improving the efficacy of metformin in treating leukemia.

Impact of high-dose chemotherapy and autologous transplantation as first-line therapy on the survival of high-risk diffuse large B cell lymphoma patients: a single-center study in Japan.

High-dose chemotherapy (HDT), together with autologous stem cell transplantation (ASCT), plays an important role in the treatment of diffuse large B cell lymphoma (DLBCL), especially as second-line therapy. However, its significance in up-front settings remains to be elucidated. In our institute, patients with DLBCL in both the high-intermediate and high international prognostic index (IPI) groups initially underwent CHOP/R-CHOP treatment followed by HDT/ASCT at upfront settings between 2002 and 2011. We retrospectively analyzed 25 patients who were all treated with upfront HDT/ASCT. We excluded one patient who failed to undergo transplantation because of primary refractory disease from the analysis. The median follow-up was 77 months (range 17-110 months). Five-year overall survival (OS) and progression-free survival (PFS) were 91.7 and 79.2 %, respectively, which were higher than the equivalents in previous studies. The OS and PFS in the high-risk group were lower than those in the high-intermediate group. Treatment-related mortalities or fatal complication were not observed. Our results confirm that HDT/ASCT for high-risk aggressive lymphoma is a feasible and promising therapy, but patients with high IPI continued to have poor prognoses; improvements in treatment strategy are clearly needed. Since HDT/ASCT is an aggressive treatment option associated with long-term complications, we need to identify patient groups that will gain the maximum benefit from HDT/ASCT in the upfront setting.

Anaplastic large cell lymphoma with paraneoplastic neutrophilia: an association between IL-17 elevation and aggressive disease progression.

We report a case of anaplastic large cell lymphoma (ALCL) with involvement of bone marrow, exhibiting extreme leukocytosis leading to death due to multi-organ failure within 1 week after admission. The patient had a history of rheumatoid arthritis, and had severe pneumonia at admission. To elucidate the basis for the observed extreme neutrophilia, we analysed the levels of several cytokines in serum samples taken from the patient at diagnosis. The patient exhibited an extreme increase in interleukin-17 (IL-17), one of the major regulatory cytokines for inflammation and neutrophil migration. Interestingly, a recent study revealed that anaplastic lymphoma kinase (ALK)-positive ALCL cells produce IL-17. IL-17 also contributes to treatment resistance in multiple types of cancer. Given these previous findings, our case may suggest a possible link between overproduction of IL-17 and an aggressive ALCL phenotype. Further studies will be required to determine whether serum IL-17 levels serve as a useful prognostic marker for ALCL.

Ratio of peripheral blood absolute lymphocyte count to absolute monocyte count at diagnosis is associated with progression-free survival in follicular lymphoma.

The prognosis of follicular lymphoma (FL) is significantly associated with host immunity and tumor microenvironment. Lymphopenia has been identified as a negative prognostic factor for FL. The association between monocytosis and progression-free survival (PFS) in FL remains controversial. It is unknown whether the ratio of peripheral blood absolute lymphocyte count to absolute monocyte count (ALC/AMC) at diagnosis is associated with FL prognosis. We studied 99 consecutive patients with FL who were treated with rituximab-containing chemotherapy at Kitano Hospital or Kyoto University Hospital between 2000 and 2012. We analyzed individual variables associated with the ALC/AMC ratio before treatment, as well as known prognostic factors of FL, and found that an ALC/AMC ratio of 4.7 was the best cut-off value for PFS. Kaplan-Meier analysis showed that a decreased ALC/AMC ratio was associated with inferior PFS (P = 0.022). Multivariate analysis showed that a decreased ALC/AMC ratio was a significant poor prognostic factor independent of other variables (hazard ratio, 2.714; 95 % confidence interval, 1.060-6.948; P = 0.037). The ALC/AMC ratio before treatment may be a significant prognostic factor predicting PFS of FL.

Immune reconstitution inflammatory syndrome mimics a relapse of AIDS-related Burkitt lymphoma.

Immune reconstitution inflammatory syndrome (IRIS) is associated with clinical manifestations that can overlap with the patients with acquired immunodeficiency disease (AIDS)-related non-Hodgkin's lymphoma. We herein report a case of AIDS-related Burkitt lymphoma which was successfully treated with dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine, and prednisone (EPOCH). However, the patient developed a lymphoma-like clinical presentation shortly after the conclusion of chemotherapy. The patient's symptoms were identical to the initial symptoms characteristic of lymphoma; however, the laboratory data revealed no evidence of a relapse of Burkitt lymphoma. A bone marrow examination showed T-cell clonality, even though there were no signs of any progression of the lymphoma. The patient was diagnosed with IRIS, and the clinical manifestations rapidly improved following treatment.