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Recently, the ratio of C-reactive protein to albumin (CAR) is used as an inflammatory marker that has been demonstrated to be a simple and reliable prognostic factor in solid tumors and hematological malignancy. However, no studies of the CAR have been performed in patients with adult T-cell leukemia-lymphoma (ATL). We retrospectively analyzed the clinical features and outcomes in 68 newly diagnosed acute- and lymphoma-type ATL [(acute-(n=42) or lymphoma-type (n=26)] patients in Miyazaki Prefecture from 2013 to 2017. Furthermore, we investigated correlations between pretreatment CAR levels and clinical features. The median age was 67 years (range, 44 - 87). Patients were initially treated by either palliative therapy (n=14) or chemotherapy [n=54; CHOP therapy (n=37)/ VCAP-AMP-VECP therapy (n=17)], and showed median survival durations of 0.5 months and 7.4 months, respectively. The factors affecting OS by multivariate analysis were age, BUN, and CAR. Importantly, we revealed that the high CAR group (optimal cut-off point; 0.553) was a significant indicator of worse OS by multivariate analysis (p< 0.001, HR; 5.46). The median survival of patients with a CAR< 0.553 was 8.37 months, while patients with a CAR>0.553 had a median survival of 3.94 months. The different clinical features between high CAR and low CAR groups were hypoproteinemia and the implementation of chemotherapy. Furthermore, in the chemotherapy group, but not the palliative therapy group, CAR was a significant prognostic marker. Our study indicated that CAR may be a new simple and significant independent prognostic marker in acute- and lymphoma-type ATL patients.

The relapse of acute lymphoblastic leukemia (ALL) usually involves the bone marrow, with the central nervous system being the most frequent extramedullary site. The relapse of ALL in the female genital organs, particularly the uterus, is markedly rare. We report such a patient who developed relapse in the bone marrow and uterus. The uterine lesion, which presented as abnormal uterine bleeding, consisted of a mass on MRI and proliferation of ALL cells on histology. MRI revealed a heterogeneous high-intensity mass (T2-WI/D-WI) with a diameter of 6.8 cm, a notable decrease in the apparent diffusion coefficient (ADC), and mild enhancement by contrast enhancement study. Histological findings of the uterine cervix demonstrated the infiltration of ALL. The patient achieved remission by allogeneic haplo-identical hematopoietic stem-cell transplantation, but died of complications of the transplantation. This case suggested that attention should be paid to the uterus as a site of extramedullary relapse. In addition, abnormal uterine bleeding, which is a common sign of hormonal imbalance and hormone replacement therapy after chemotherapy, may be an initial sign of extramedullary recurrence. To confirm uterine relapse as an intractable disease, the accumulation of more cases is required.

As opportunistic infections among human T-lymphotrophic virus type 1 (HTLV-1) carriers and patients with adult T-cell leukemia/lymphoma (ATL) pose a serious problem, it is necessary to clarify their clinical characteristics and outcomes in these patients. We retrospectively analyzed the clinical features and outcomes of opportunistic infections in 127 HTLV-1 carriers and 153 ATL patients between 2006 and 2016. The cumulative incidence rates of opportunistic infections among HTLV-1 carriers and ATL patients were 1.5% (2/127) and 6.5% (10/153), respectively. The etiology of opportunistic infections was as follows: fungal infections (3 cases), pneumocystis pneumonia, and cytomegalovirus (CMV) infections. Even after aggressive treatment, the prognosis of opportunistic infections was poor (50% of overall survival at 28 days). Regarding prognostic factors affecting the OS of opportunistic infections, higher SOFA scores (especially the respiratory subscore) and higher LDH values were identified by univariate analysis. Moreover, 3 out of 6 patients achieved spontaneous remission of ATL as the short-term outcome after the development of opportunistic infection. However, 5 out of 6 surviving patients exhibited ATL progression or relapse after a median of 194 days (133-226) after contracting an opportunistic infection as the long-term outcome of ATL. In conclusion, opportunistic infections should be carefully followed among HTLV-1 carriers and ATL patients because of their aggressive clinical course and poor outcomes. Furthermore, early diagnosis and subsequent prompt treatment are necessary in clinical practice.

Because there are limited clinical reports on the impact of human T-lymphotropic virus type 1 (HTLV-1) on organ transplantation, its effects on the development of adult T-cell leukemia-lymphoma (ATL), post-transplantation lymphoproliferative disorder (PTLD) and HTLV-1-associated myelopathy (HAM) or atypical HAM after organ transplantation remain unclear.We retrospectively analyzed the impact of HTLV-1 in 54 allogeneic hematopoietic stem cell transplantation (allo-HSCT) cases and 31 renal transplantation cases between January 2006 and December 2016.Among the 54 allo-HSCT cases, nine recipients with ATL tested positive for HTLV-1, and one was found to be an HTLV-1 carrier. All donors tested negative for HTLV-1. Only one HTLV-1 carrier did not present with ATL or HAM development after allo-HSCT. Among nine ATL cases after allo-HSCT, four eventually relapsed due to proliferation of recipient-derived ATL cells. However, in one ATL case, atypical HAM developed rapidly at 5 months after allo-HSCT.Among the 31 renal transplantation cases, all donors tested negative for HTLV-1, and only recipients tested positive. Only one HTLV-1 carrier recipient did not present with ATL or HAM development after renal transplantation. However, one HTLV-1-negative recipient developed PTLD in the brain 10 years after renal transplantation.In clinical practice, careful follow-up of HTLV-1 infected recipients after organ transplantation is important because atypical HAM can develop in ATL patients after allo-HSCT. Furthermore, to clarify the risk of ATL or HAM development in HTLV-1 infected recipients, we prospectively followed up our cohort.

Although a humanized CCR4 antibody (mogamulizumab) was reported to be effective for refractory adult T-cell leukemia-lymphoma (ATL), several reports regarding the use of mogamulizumab before allo-hematopoietic stem cell transplantation (HSCT) strongly indicated a high incidence of severe acute graft-versus-host-disease (GVHD) and treatment-related mortality (TRM). We retrospectively analyzed nine aggressive-type ATL patients who underwent allo-HSCT at a single institution in Miyazaki from 2006.1.1 to 2015.7.31. Among nine ATL patients, three had used mogamulizumab before treatment with allo-HSCT because of the poor control of refractory ATL. All three patients were treated with four to eight cycles of mogamulizumab. The interval from last administration of mogamulizumab to allo-HSCT was two to five months. All three patients with prior mogamulizumab treatment developed mild-moderate acute GVHD (grade 2) 28, 34, or 40 days after allo-HSCT. Acute GVHD was controlled by prednisolone treatment. Two patients in complete remission before allo-HSCT exhibited relatively prolonged survival (survival rate, 66%). Moreover, one patient developed human T-cell leukemia virus type 1-associated myelopathy-mimicking myelitis at five months after allo-HSCT. In contrast, two of six ATL patients without a history of mogamulizumab use survived (survival rate 33%). Thus, in cases of mogamulizumab use before treatment with allo-HSCT for refractory ATL, an appropriately long interval from the last administration of mogamulizumab to allo-HSCT may be one of factors to reduce TRM by acute GVHD, and to subsequently enhance graft-versus-tumor effects in ATL cases. Furthermore, caution is needed when administering mogamulizumab before allo-HSCT for severe GVHD and TRM.

Although clinical trials of first- and second-generation tyrosine kinase inhibitors (TKIs) have been shown to improve the prognosis of chronic myeloid leukemia (CML), there is still uncertainty about the clinical features, treatment outcomes, adverse effects, and other possible problems of their use in the clinical setting. We retrospectively analyzed 51 CML patients treated with TKIs at a single institution between 2002 and 2014. The patients (median age: 53.8 years) were classified as having chronic (n = 48), accelerated (n = 2), or blastic phase (n = 1) CML. Our treatments included both 1st generation TKIs (60.8%) and 2nd generation TKIs (39.2%). We found that the overall response rates of complete cytogenetic response (CCyR), major molecular response (MMR), and MR4 (molecular response 4) were 90.2%, 78.4%, and 64.7%, respectively. Second line 2nd generation TKIs had response rates equivalent to those of 1st line 1st generation TKIs. Moreover, 1st line 2nd generation TKIs tended to achieve an early response rate. Overall survival (OS) at 5 years was 93.2%. Sudden blastic crisis (BC) occurred in 2 CML patients receiving TKI with CCyR status. Hematopoietic stem cell transplantation was performed for BC (n = 1) and sudden BC (n = 2). Side effects of all grades (1-3) and grade 3 alone were 64.7% and 11.8%, respectively. Dose reduction, replacement with another TKI, or low dose TKI treatment may be useful methods to control side effects. Further reasons of TKI discontinuation were economic problems (n = 3) and pregnancy (n = 1). Consequently, our treatment strategy for CML demonstrated good response rate and OS. Currently, treatment discontinuation due to intolerance, resistance, economic problems, pregnancy, and sudden BC remains a concern in clinical practice.

Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is a serious disorder in which monoclonal growth of T cells infected with EBV and macrophage activation cause pancytopenia, high fever and acute liver failure. Patients with chemotherapy- or immunosuppression-resistant EBV-HLH require allogeneic hematopoietic stem cell transplantation (allo-HSCT), but patients who have no sibling donors may not have time to wait for an unrelated donor. In pediatric patients, there are some reports on allogeneic cord blood transplantation (allo-CBT) for the treatment of EBV-HLH; however, in adult patients, reports of allo-CBT for EBV-HLH are quite limited. The present case of a 20-year-old woman with chemotherapy-resistant EBV-HLH and systemic lupus erythematosus (SLE) who underwent allo-CBT following reduced-intensity conditioning (RIC-CBT). She achieved and maintained a complete donor type and the EBV-DNA load, and the titers of anti-double stranded DNA and antinuclear antibodies became negative. It is therefore considered that RIC-CBT is an effective treatment option for adult onset HLH. However, because the effectiveness of allo-HSCT for SLE remains unclear and transplant-related mortality is high, it is recommended that allo-HSCT for SLE is restricted to patients concomitant with oncohematological disease as with our present case.

Although graft failure (GF) is a fatal and life-threatening complication of umbilical cord blood transplantation (CBT), the standard treatment has not been established. We describe the case of a 28-year-old man diagnosed with acute myelogenous leukemia with myelodysplasia-related changes harboring a normal karyotype. This patient underwent 2 courses of idarubicin and cytosine arabinose therapy, and 3 courses of high-dose cytosine arabinose therapy. Subsequently, he underwent high-dose chemotherapy (total body irradiation and cyclophosphamide) followed by first CBT. Primary GF occurred after post-immunological reaction and hemophagocytic lymphohistiocytosis, and was diagnosed on day 27 after the first CBT. Therefore, the patient underwent secondary CBT for GF treated with a modified one-day conditioning regimen consisting of fludarabine (30 mg/m(2), 3 days), cyclophosphamide (2 g/m(2)), and total body irradiation (2 Gy), and graft-versus-host disease prophylaxis consisting of mycophenolate and tacrolimus. Consequently, the patient achieved neutrophil engraftment on day 17 after the second CBT. During the clinical course of the second CBT, the main complications were sepsis, BK virus-associated cystitis, and acute graft-versus-host disease (skin, grade 2, stage 3). After these treatments, the patient was disease-free for 39 months. Our case suggests that these treatments may be feasible, safe, and effective for the treatment of patients with GF. This case study may be helpful to physicians who directly care for GF patients, and may provide a future direction for a more efficient treatment modality.

Immunodeficiency-associated lymphoproliferative disorders (LPD) represent a rare life-threatening clinical entity characterized by heterogeneous histological findings that range from polymorphic to monomorphic proliferated abnormal lymphocytes. Currently, there is no standard treatment for LPD. To elucidate the clinical features and treatment outcomes of immunodeficiency-associated LPD patients with rheumatoid arthritis (RA), we retrospectively evaluated 9 cases observed over a 5-year period. The diagnoses of these patients included 5 diffuse large B-cell lymphomas, 3 LPD, and 1 mucosa-associated lymphoid tissue lymphoma. At initial diagnosis, 6 patients had advanced-stage RA, and half of these underwent total knee arthroplasty. All patients with RA received methotrexate (MTX) and low-dose prednisolone. Biologics were administered to 4 of 9 patients. After the development of immunodeficiency-associated LPD, MTX discontinuation resulted in 5 complete remissions (CR), 1 partial remission, and 3 cases of stable disease. Relapse was observed in 3 of 5 CR patients in the MTX-withdrawal remission group. Subsequently, conventional chemotherapy, rituximab, and radiation were administered to 4, 3, and 1 patient, respectively. These treatments induced a second CR. In the chemotherapy group, 1 patient developed acute myocardial infarction and another experienced ileus and pulmonary abscess. In the rituximab group, no severe complications were observed. Consequently, all patients remained disease-free during the median 23-month follow-up period. Our results indicate that, depending on the RA disease stage, performance status, and extent of treatment response, less intensive treatments than those commonly indicated for non-Hodgkin lymphoma, involving MTX discontinuation and subsequent therapy containing rituximab, might be an efficient therapeutic strategy for immunodeficiency-associated LPD.

Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disorder (EBV-PTLD) is a complication of hematopoietic stem cell transplantation (HSCT). Standard initial treatment of patients with EBV-PTLD includes administration of rituximab or dose reduction of a calcineurin inhibitor. We report successful chemotherapeutic treatment of rituximab-resistant EBV-PTLD after HSCT in a patient with severe aplastic anemia (AA). A 38-year-old woman with antithymocyte globulin (ATG)-resistant severe AA received bone marrow transplantation from an unrelated donor (human leukocyte antigen-DR single-locus mismatch). The conditioning regimen included fludarabine, cyclophosphamide, ATG, and total body irradiation, and prophylaxis for graft-versus-host disease consisted of short methotrexate and tacrolimus. Neutrophil engraftment occurred on day 21. Left cervical lymph node swelling was observed after day 45, and analysis of a biopsy specimen revealed EBV-PTLD and a high blood EBV load (56,000 copies). The patient was treated with rituximab 4 times per week, but the lymphadenopathy continued and the blood EBV load increased to 96,000 copies. Half-dose treatment with rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone (R-CHOP) was initiated on day 71. After 32 days of treatment with R-CHOP, the patient's neutrophil level was restored to > 0.5 × 10(9)/L and both the lymphadenopathy and the blood EBV load (< 100 copies) were rapidly reduced. Although chemotherapy is not preferred soon after HSCT, it may be an effective strategy for treating patients with rituximab-resistant EBV-PTLD.

Crystal-storing histiocytosis is a rare clinical entity characterized by an increase in the number of abnormal histiocytes accompanied by accumulation of crystallized immunoglobulins. We describe the case of an 80-year-old man who presented with crystal-storing histiocytosis of the lung 13 years after receiving a diagnosis of gastric non-Hodgkin lymphoma (NHL ; clinical stage, Lugano IA). After wedge resection of the left upper lobe, the histological findings showed crystal-storing histiocytosis with CD68(+), some small to medium lymphoid cells with CD79a(+) with κ(+(weekly)) and λ(-), and some plasma cells with CD138(+), and rearrangement of the immunoglobulin heavy chain. Based on the nonrecurrent gastric NHL, small B-cell population, and failure to detect the same clone by polymerase chain reaction analysis, our case was classified as pulmonary localized crystal-storing histiocytosis without underlying lymphoproliferative or plasma cell disorder. The findings of minor B-cell populations harboring a heavy chain rearrangement with slight light-chain restriction (κ > λ) may be related to the pathogenesis of crystallogenesis and crystal-storing histiocytosis. Moreover, surgical treatment may be an effective therapeutic option for solitary crystal-storing histiocytosis.

Portal vein thrombosis is a rare, aggressive and life-threatening complication of liver cirrhosis (LC). Eltrombopag is effective for the treatment of chronic hepatitis with thrombocytopenia, and portal vein thrombosis at this time has rarely been reported. We describe the case of a 78-year-old woman who suffered from LC due to hepatitis C viral infection. The patient developed immune thrombocytopenic purpura (ITP) that was diagnosed on the basis of nasal bleeding, progressive severe thrombocytopenia, elevation of platelet-associated IgG (PAIgG), no response to the transfusion of platelets and no abnormal findings on bone marrow biopsy. Although we first administered prednisolone (0.5 mg/kg/day), there was no recovery of platelet function and the nasal bleeding persisted. Subsequently, we administered eltrombopag for refractory ITP at a dose of 12.5 mg/day, and the thrombocytopenia gradually improved. Fifty-four days after the start of eltrombopag therapy, she developed portal vein thrombosis. Eltrombopag was stopped immediately, and antithrombin III was administered for prophylaxis against further portal vein thrombosis. Despite these treatments, there were subsequent deep vein and pulmonary artery thromboses. We then administered heparin for recanalization of the thrombi. One month after the initiation of heparin, there was recanalization as well as improvements of the portal vein, deep vein and pulmonary artery thromboses. There was no further thrombosis progression after switching from heparin to warfarin therapy. Our case suggests that eltrombopag may increase the risk of portal vein thrombosis ; therefore, this drug must be used carefully in the treatment of ITP in patients with LC due to hepatitis C viral infection.

Immunodeficiency-associated lymphoproliferative disorders (LPD) in rheumatoid arthritis are a rare, aggressive, and life-threatening clinical entity. We describe a 60-year-old man who had rheumatoid arthritis that was treated with methotrexate. Eight months after the treatment, the case was diagnosed as Epstein-Barr virus-negative LPD (diffuse large B-cell lymphoma) with abdominal bulky mass and clinical stage IVB at high risk in the international prognostic index. Immediate withdrawal of methotrexate led the patient to achieve complete remission, and 8 subsequent courses of rituximab treatment for the prevention of relapse kept the patient disease-free for 29 months. Our case suggests that these treatments may be an effective, safe, and feasible strategy for immunodeficiency-associated LPD in rheumatoid arthritis.

Disseminated intravascular coagulation (DIC) is a clinical entity with high mortality and is characterized by multiple organ failure caused by activation of systemic intravascular coagulation. Although a standard treatment for DIC has not been established owing to the absence of randomized controlled trials, recent reports have indicated that recombinant human soluble thrombomodulin (rTM) is effective against DIC. To elucidate the clinical characteristics and outcomes of DIC, we retrospectively analyzed 35 DIC patients treated with rTM at our institution over a 2-year period (infectious disease: 21 cases; hematological disease: 14 cases). Diagnosis of DIC was based on the diagnostic criteria for DIC of the Japanese Ministry of Health and Welfare. In addition to the treatment of underlying diseases, we administered rTM for 6 consecutive days. Twenty-one (60.0%) of the DIC patients attained resolution of DIC at 7 days after administration (infectious disease: 61.9%; hematological disease: 57.1%). Furthermore, 7 of the remaining 14 DIC patients (who did not attain resolution at 7 days) attained resolution at an average of 12.1 days. Consequently, 28 (80.0%) of the 35 patients were alive with resolution of DIC after a 28-day observation period (infectious disease: 76.2%; hematological disease: 85.7%). Among them, for 7 (70%) of the 10 DIC patients with severe life-threatening bleeding symptoms without hemorrhagic shock, treatment with heparin was contraindicated; these patients were successfully treated with rTM without the progression of hemorrhage. In the majority of DIC patients, rTM administration may be an effective, safe, and feasible therapeutic modality producing a good outcome.