Statins can suppress DC-mediated Th2 responses through the repression of OX40-ligand and CCL17 expression.

DCs and epithelial cell-derived thymic stromal lymphopoietin (TSLP) have pivotal roles in allergic inflammation. TSLP stimulates myeloid DCs to express OX40-ligand (OX40L) and CCL17, which trigger and maintain Th2 cell responses. We have previously shown that statins, which are HMG-CoA reductase inhibitors, have the ability to suppress type I IFN production by plasmacytoid DCs. Here, we extended our previous work to examine the immunomodulatory effect of statins on allergic responses, particularly the TSLP-dependent Th2 pathway induced by myeloid DCs. We found that treatment of TSLP-stimulated DCs with either pitavastatin or simvastatin suppressed both the DC-mediated inflammatory Th2 cell differentiation and CRTH2+ CD4+ memory Th2 cell expansion and also repressed the expressions of OX40L and CCL17 by DCs. These inhibitory effects of statins were mimicked by treatment with either a geranylgeranyl-transferase inhibitor or Rho-kinase inhibitor and were counteracted by the addition of mevalonate, suggesting that statins induce geranylgeranylated Rho inactivation through a mevalonate-dependent pathway. We also found that statins inhibited the expressions of phosphorylated STA6 and NF-κB-p50 in TSLP-stimulated DCs. This study identified a specific ability of statins to control DC-mediated Th2 responses, suggesting their therapeutic potential for treating allergic diseases.

Clinical efficacy of mogamulizumab for relapsed/refractory aggressive adult T-cell leukemia/lymphoma: A retrospective analysis.

OBJECTIVES: Although phase 2 studies have confirmed the efficacy of mogamulizumab for adult T-cell leukemia/lymphoma (ATL), real-world data on its benefits are limited. We assessed the benefits of mogamulizumab for relapsed/refractory ATL in clinical practice. METHODS: We retrospectively analyzed patients with acute- and lymphoma-type ATL. Among 57 patients diagnosed with ATL between January 2008 and August 2018, 42 who received salvage therapy were eligible, including 24 who received mogamulizumab. RESULTS: The overall response rate to mogamulizumab was 54.2%. Median survival time (MST) and 1-year overall survival (OS) rate from mogamulizumab initiation were 7.7 months and 42.0%, respectively. Patients with acute-type ATL showed longer MST (15.1 months) and higher 1-year OS (63.6%). MST without skin rash was 5.0 months, and 1-year OS was 34.3%; however, MST with skin rash was not reached and 1-year OS was 66.7%. Among patients who received the salvage therapy, longer MST and higher 1-year OS were observed with mogamulizumab than without mogamulizumab (P = .078; 9.2 vs. 3.9 months; 47.9% vs. 17.6%, respectively). Mogamulizumab administration improved prognosis in patients with acute-type ATL and skin rash. CONCLUSIONS: In clinical practice, mogamulizumab improved OS in patients with relapsed/refractory ATL, especially those with acute-type ATL and skin rash.

[Successful treatment with brentuximab vedotin maintenance therapy after autologous stem cell transplantation in high-risk Hodgkin lymphoma].

A 56-year-old woman was diagnosed with classical Hodgkin lymphoma in December 2012. She achieved complete remission (CR) with six cycles of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD). In March 2015, she experienced a relapse marked by high fever, respiratory discomfort, and pain in the left thigh owing to tumor involvement of the femur. She was treated with one cycle of brentuximab vedotin (BV), followed by irradiation of the left femoral lesion. She achieved partial remission (PR) but developed recurrence after the third cycle of BV. She achieved PR again with two cycles of standard bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) regimen; therefore, autologous stem cell transplantation (ASCT) was performed. Because the dosing interval used for BV therapy was longer than that in the recommended schedule, we could not definitively attribute her recurrence to BV resistance. Moreover, she maintained a good performance status after recurrence during subsequent cycles of BV therapy. Because of attaining PR after ASCT, she subsequently received a total of 12 BV cycles for consolidation. She achieved CR 3 months after ASCT and has remained in CR until 29 months. For patients who show relapse after initial BV therapy, retreatment with BV should be carefully considered. Patients who show relapse after achieving at least PR with initial BV therapy are potential candidates for post-ASCT BV maintenance therapy to reduce their tumor burden.

Realistic Lenalidomide Dose Adjustment Strategy for Transplant-Ineligible Elderly Patients with Relapsed/Refractory Multiple Myeloma: Japanese Real-World Experience.

Lenalidomide is an immunomodulatory drug administered orally in the treatment of multiple myeloma. Some elderly patients require a reduced lenalidomide dose because of comorbidities and/or adverse events. This study investigated the actual dose of lenalidomide in elderly patients, finding that most received reduced (5-10 mg) doses. The most common reasons for dose reduction were renal dysfunction (54% of patients), fatigue (grade ≥3; 20%), hematologic disorder (grade ≥3; 14%), and rash (grade ≥3; 9%). Their median time to progression was 11.8 months and their median overall survival was 39.2 months. The overall response rate was 73%, including 17% with a complete response, 19% with a very good partial response, and 37% with a partial response. These results showed that, contrary to western countries, most patients were treated with a reduced dose of lenalidomide in Japan. However, it is suggested that continued treatment with a tolerable dose may yield favorable outcomes.

Rapid improvement of hyperammonemic encephalopathy by bortezomib treatment in IgD-type multiple myeloma.

A 74-year-old man visited our hospital with complaints of anorexia, weight loss, and impaired activities of daily living. He presented mild consciousness disturbance at the first visit, but specific causes were identified. The IgD level was>2,000 mg/dl and bone marrow biopsy was performed after aspiration failed due to excessive density. He was diagnosed with IgD/λ multiple myeloma (MM). He lapsed into a coma with an extremely high ammonia level of 484 µg/dl on day 8 after admission. His diagnosis was established as hyperammonemic encephalopathy (HE). He was treated with dexamethasone (Dex) pulse therapy and continuous hemodiafiltration. Minor improvement of hyperammonemia was achieved. Combination therapy with bortezomib and Dex was commenced. His ammonia level rapidly decreased and his mental state improved. HE accompanied by MM is rare and further studies are needed to clarify outcomes in response to treatment using the novel agent Bor. Although HE is potentially fatal, we found Bor to be rapidly effective against HE.

[Primary Central Nervous System Post-Transplant Lymphoproliferative Disorder in a Patient with Acute Lymphocytic Leukemia].

A 27-year-old woman with acute lymphocytic leukemia, who underwent allogeneic hematopoietic stem cell transplantation, complained of nausea and blurred vision 288 days after the transplantation. Intracranial tumors were identified on brain MRI. She received whole brain radiation after open biopsy, but she died. The tumors had characteristics of diffuse large B cell lymphoma, and she was finally diagnosed with primary central nervous system post-transplant lymphoproliferative disorder. This disease is rare and has a poor outcome. Therefore, accumulation of cases and establishment of treatments for this condition are urgently needed.

[The basic research on the high-sensitive troponin I assay, and the application to evaluation of chronic heart failure].

The mortality among patients with heart diseases increases steadily in an aging society like Japan. Among those, the patients with chronic heart failure (CHF) are thought to be increasing rapidly although the official report is missing. It is well-known that BNP or NT-proBNP is useful for a clinical diagnosis of CHF, but a role of the cardiac troponin (cTn) attracts attention as a novel biomarker of their prognosis. However, because the level of cTn in patients with CHF is far lower than that in cases of acute coronary syndrome (ACS), development of the high-sensitive method with precision is desired. In the present study, a new sensitive assay system with an analyzer, ARCHITECT STAT (cTnI hs-ARCH) was basically studied and found more sensitive than other conventional 2 sensitive methods. The performance of cTnI hs-ARCH was evaluated in patients with CHF by comparing it to findings with other 2 methods. When CHF patients are allocated into categories of NYHA classification according to their subjective symptoms, cTnI hs-ARCH was superior to other methods in discriminating subgroups. In addition, multivariable analysis disclosed that cTnI hs-ARCH is influenced by the level of renal function at the minimum among the 3 methods. Therefore, cTnI hs-ARCH may be a useful method for evaluation of prognosis in patients with CHF who often have impaired renal function.

Immunomodulatory drugs suppress Th1-inducing ability of dendritic cells but enhance Th2-mediated allergic responses.

Immunomodulatory drugs (IMiDs), lenalidomide and pomalidomide, are widely used treatments for multiple myeloma; however, they occasionally lead to episodes of itchy skin and rashes. Here, we analyzed the effects of IMiDs on human myeloid dendritic cells (mDCs) as major regulators of Th1 or Th2 responses and the role they play in allergy. We found that lenalidomide and pomalidomide used at clinical concentrations did not affect the survival or CD86 and OX40-ligand expression of blood mDCs in response to lipopolysaccharide (LPS) and thymic stromal lymphopoietin (TSLP) stimulation. Both lenalidomide and pomalidomide dose-dependently inhibited interleukin-12 (IL-12) and TNF production and STAT4 expression, and enhanced IL-10 production in response to LPS. When stimulated with TSLP, both IMiDs significantly enhanced CCL17 production and STAT6 and IRF4 expression and promoted memory Th2-cell responses. In 46 myeloma patients, serum CCL17 levels at the onset of lenalidomide-associated rash were significantly higher than those without rashes during lenalidomide treatment and those before treatment. Furthermore, serum CCL17 levels in patients who achieved a very good partial response (VGPR) were significantly higher compared with a less than VGPR during lenalidomide treatment. The median time to next treatment was significantly longer in lenalidomide-treated patients with rashes than those without. Collectively, IMiDs suppressed the Th1-inducing capacity of DCs, instead promoting a Th2 response. Thus, the lenalidomide-associated rashes might be a result of an allergic response driven by Th2-axis activation. Our findings suggest clinical efficacy and rashes as a side effect of IMiDs are inextricably linked through immunostimulation.

Evaluation of azacitidine in patients with transplant-ineligible myelodysplastic syndromes and acute myeloid leukemia with myelodysplasia-related changes in a Japanese clinical setting.

Patients with high-risk myelodysplastic syndromes (MDS) treated with azacitidine (AZA) have exhibited improved overall survival. However, information on AZA in real-world settings is limited. The present study retrospectively analyzed 85 patients with MDS treated with AZA. Complete response was achieved in 24% of cases and hematologic improvement in 29%. Severe adverse events (grade ≥3) included neutropenia and infection. Multivariate analysis identified higher revised international prognostic scoring system (IPSS-R) and male sex as significant factors affecting survival. However, the present study did not identify any significant associations between patient characteristics and response to AZA. In conclusion, AZA could produce a hematologic response in ~53% of patients with MDS. Furthermore, IPSS-R may reflect MDS prognosis. Further studies are required to establish the criteria for identifying patients likely to obtain maximum benefit from AZA treatment.

Mycophenolic acid, the active form of mycophenolate mofetil, interferes with IRF7 nuclear translocation and type I IFN production by plasmacytoid dendritic cells.

BACKGROUND: Both humoral and cellular immune mechanisms are involved in the onset and progression of autoimmune responses in systemic lupus erythematosus (SLE). Plasmacytoid dendritic cells (pDCs) play a central role in the pathogenesis of SLE via the dysregulation of type I interferon (IFN) production; these cells act together with activated myeloid DCs (mDCs) to amplify the vicious pathogenic spiral of autoimmune disorders. Therefore, control of aberrant DC activation in SLE may provide an alternative treatment strategy against this disease. Mycophenolate mofetil (MMF), which has been used to treat lupus nephritis, specifically blocks the proliferation of B and T lymphocytes via inhibition of inosine-5-monophosphate dehydrogenase. Here, we focus on the effects of MMF in targeting DC functions, especially the IFN response of pDCs. METHODS: We isolated human blood pDCs and mDCs by flow cytometry and examined the effect of mycophenolic acid (MPA), which is a metabolic product of MMF, on the toll-like receptor (TLR) ligand response of DC subsets. Additionally, we cultured pDCs with serum from SLE patients in the presence or absence of MPA and then examined the inhibitory function of MPA on SLE serum-induced IFN-α production. RESULTS: We found that treatment with 1-10 µM of MPA (covering the clinical trough plasma concentration range) dose-dependently downregulated the expression of CD80 and CD86 on mDCs (but not pDCs) without inducing apoptosis, in response to R848 or CpG-ODN, respectively. Notably, in pDCs, MPA significantly suppressed IFN-α production with IRF7 nuclear translocation and repressed the AKT activity. In addition, MPA inhibited IL-12 production with STAT4 expression in mDCs. We further identified that MPA had an inhibitory effect on SLE serum-induced IFN-α production by pDCs. CONCLUSIONS: Our data suggest that MPA can interrupt the vicious pathogenic spiral of autoimmune disorders by regulating the function of DC subsets. This work unveiled a novel mechanism for the therapeutic ability of MMF against SLE.

Myodesopsia is a symptom of central nervous system blast crisis in chronic myeloid leukemia.

A 49-year-old woman diagnosed with chronic myeloid leukemia in the chronic phase was started on dasatinib treatment, after which she complained of myodesopsia. Nineteen months after diagnosis, the patient again complained of myodesopsia and developed bilateral optic neuritis. Cerebrospinal fluid analysis revealed an increase in blasts, although peripheral blood and bone marrow examination confirmed that the patient remained in a molecular response to tyrosine kinase inhibitor (TKI) therapy. The patient was diagnosed with an isolated central nervous system blast crisis, a rare occurrence with second-generation TKI therapy, and the initial presentation of myodesopsia represented a symptom of this condition.

Evaluation of eltrombopag in patients with aplastic anemia in real-world experience.

BACKGROUND: Although eltrombopag has recently been approved for treating AA, the effects of its clinical use remain unknown. METHODS: We retrospectively analyzed 11 patients with AA, who had been treated with eltrombopag from August 2017 to May 2018. RESULTS: Overall response rate was 55%. There was tri-lineage recovery in four patients and platelet recovery in two. The reactive time was within 8 weeks after treatment initiation. Stage at the initial assessment, the neutrophil-to-lymphocyte ratio and platelet counts were significantly different between the responders and non-responders. CONCLUSION: Eltrombopag is a promising agent for treating patients with any degree of AA.

Neutrophil-to-lymphocyte ratio (NLR) fails to predict outcome of diffuse large B cell lymphoma.

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) has been recognized as a poor prognostic indicator in various solid tumors. METHODS: We retrospectively analyzed 530 patients with de novo DLBCL who were diagnosed from April 2002 to November 2017. RESULTS: The median age of patients was 69 (range, 20-95) years, and 59% were male. The optimal cutoff for NLR was 5.2. NLR (5.2) was not associated with overall and progression free survival. CONCLUSION: Our study failed to reveal the predictive value of NLR and demonstrated that the NCCN-IPI might be the most powerful predictor in DLBCL.

Trend of salvage treatment in diffuse large B cell lymphoma in the outpatient chemotherapy era.

Patients with diffuse large B cell lymphoma (DLBCL) who have failed to achieve complete remission with first-line therapy can subsequently receive salvage therapy. However, there is no definite consensus on the use of salvage therapy, and little information on the optimal treatment regimen. The present study retrospectively analyzed data from 131 patients diagnosed with DLBCL between April 2002 and November 2017 who relapsed and received salvage therapy. Primary treatment included R-CHOP or R-CHOP-like regimens. The most common salvage regimen was R-DeVIC (42%), followed by R-ESHAP (23%), other aggressive regimens (12%) and palliative therapy (23%). The median overall survival (OS) was 45.7 months for R-DeVIC, 41.8 months for palliative therapy, 29.4 months for R-ESHAP, and 28.5 months for aggressive regimens (P=0.937). A total of 25 patients underwent autologous stem cell transplantation (ASCT), and the OS was 75.6 months for these patients compared with 33.5 months (range, 25.6-45.6 months) for patients who did not undergo ASCT (P=0.033). Following the establishment of an outpatient chemotherapy unit in 2014, R-DeVIC use became more common, increasing from 37% prior to 2014 to 46% after 2014, whereas R-ESHAP use decreased (31 to 17%). The present study did not identify the optimal salvage regimen for patients with DLBCL. However, salvage ASCT improved the outcome, and regimens administered via peripheral veins were demonstrated to be more common in outpatient chemotherapy settings.

Effects of recombinant thrombomodulin on long-term prognosis after allogeneic hematopoietic stem cell transplantation.

We investigated the effects of early recombinant thrombomodulin (rTM) treatment on long-term prognosis after hematopoietic stem cell transplantation (HSCT). Subjects included 300 patients who underwent allogeneic HSCT (131 in the rTM(+) group and 169 in the rTM(-) group). The control group received heparin or no anti-coagulation therapy. When we examined patients with confirmed complications (day 1-100), the frequencies of acute graft-versus-host disease (aGVHD) and thrombotic microangiopathy (TMA) were significantly lower in the rTM(+) group, while the frequencies of veno-occlusive disease did not show such differences. rTM administration was associated with significant differences in the cumulative incidence of aGVHD (any grade and II-IV grades) and TMA. The cumulative overall survival probability was significantly higher in the rTM(+) group (42.3% versus 26.2%, p = .037). Therefore, some causes of a poor prognosis included aGVHD and TMA. The present findings suggest that rTM plays a preventive role in transplant-related complications, such as aGVHD and TMA, after allogeneic HSCT.

A variant of acute promyelocytic leukemia with t(4;17)(q12;q21) showed two different clinical symptoms.

A 63-year-old man was diagnosed with a rare variant of acute promyelocytic leukemia (APL) with t(4;17)(q12; q21) that showed atypical morphological features and two different clinical symptoms. He was started on standard induction chemotherapy for acute myeloid leukemia, which decreased myeloblast numbers; however, APL-like blasts remained. He then received a salvage therapy that added all-trans retinoic acid (ATRA). After ATRA commenced, APL-like blasts disappeared and cytogenetic analysis became normal. However, myeloblasts subsequently increased, and he became resistant. In summary, this patient exhibited two different clinical courses of acute myeloid leukemia and APL.

Blastic Epstein-Barr virus associated post-transplant lymphoproliferative disorder after allogeneic stem cell transplantation for severe aplastic anemia.

Post-transplant lymphoproliferative disorder (PTLD) is a well-recognized complication of organ transplantation. Progress has recently been made in the pathological classification of PTLD. However, the clinical course has not been clarified because of the rarity of this disease. We experienced a case of PTLD with a fulminant clinical course. The patient had been under longterm immunosuppressive treatment for aplastic anemia. He received related allogeneic hematopoietic stem cell transplantation. Soon after transplantation, he developed PTLD. According to the guidelines, we reduced immunosuppression. However, the disease course was so fulminant that there was no time for the patient to respond, and he died of multi-organ failure. There may be various clinical types of PTLD, which may include some fulminant cases. In such a case, it is not sufficient to reduce immunosuppression. The patient should be carefully observed and an appropriate individual treatment should be chosen.

Secondary pure red cell aplasia in multiple myeloma treated with lenalidomide.

Pure red cell aplasia (PRCA) is a rare disorder characterized by marked erythroid hypoplasia with maturation arrest in the bone marrow. Secondary acquired PRCA may be associated with hematologic disorders. A few case reports have described PRCA associated with multiple myeloma (MM). However, the clinical course and mechanism of PRCA associated with MM remain unknown. We herein report two cases of PRCA associated with MM in patients undergoing treatment with lenalidomide.

Combined Use of Ninjin'yoeito Improves Subjective Fatigue Caused by Lenalidomide in Patients With Multiple Myeloma: A Retrospective Study.

Lenalidomide is an immunomodulating derivative of thalidomide, which shows anti-tumor activity against myeloma cells with immunomodulation including augmentation of T-cell and natural killer cell function. Continuous treatment with this agent shows better survival benefit in patients with multiple myeloma and combined lenalidomide with dexamethasone (LEN-DEX) is a standard treatment regimen. However, fatigue is a frequent symptom resulting from lenalidomide administration. This side-effect therefore reduces quality of life for elderly patients and, furthermore, is a reason for treatment discontinuation. Unfortunately, appropriate preventive countermeasures against lenalidomide-related fatigue have not been established. Ninjin'yoeito is a traditional Chinese medicine made from the extracts of 12 herbal plants, which positively affects immunity and inflammation. It is used to treat fatigue, decreased appetite, anemia, and general malaise associated with malignant tumors and chemotherapy. We have previously reported that ninjin'yoeito significantly improved patients' subjective fatigue symptoms treated with melphalan-prednisone for multiple myeloma. In the present study, we assessed the benefits of ninjin'yoeito as a supplementary treatment for patients with myeloma, and its effect on lenalidomide treatment regime compliance. We retrospectively analyzed 36 cases of newly diagnosed or relapsed/refractory multiple myeloma. The study included patients receiving LEN-DEX with onset of general fatigue after lenalidomide administration (13 and 23 patients with or without ninjin'yoeito, respectively). Frequency of subjective fatigue was significantly decreased in patients administered ninjin'yoeito, compared to those treated with LEN-DEX alone (92.3 and 47.8 % of patients with and without ninjin'yoeito, respectively; p = 0.008). In addition, combined use of ninjin'yoeito and LEN-DEX showed a trend toward reduced rates of treatment discontinuation (7.7 % and 34.8 % of patients with and without ninjin'yoeito, respectively; p = 0.076). Our results suggest that ninjin'yoeito is an effective method for treating subjective fatigue caused by lenalidomide and may have the potential to extend lenalidomide treatment duration.

Clinical significance of dasatinib-induced pleural effusion in patients with de novo chronic myeloid leukemia.

Dasatinib is currently approved for clinical use as a first-line treatment agent for newly diagnosed chronic myeloid leukemia (CML). However, only a few clinical trials have been performed to evaluate dasatinibinduced PE following first-line therapy. We investigated the incidence and clinical features of dasatinib-induced PE following first-line therapy in Japanese CML patients of real world clinical practice settings. Among 22 patients, the median age of PE-positive patients was higher than that of PE-negative patients. Major molecular response was achieved in 75% of PE-positive patients and 50% of PE-negative patients. Most patients developed PE more than 1 year after treatment. Appearance of PE is associated with better clinical response during dasatinib treatment, however it is developed at any time. Elderly and high-risk patients tend to develop PE. The clinical features of dasatinib-induced PE following first-line therapy might be late onset and might not immediately follow the increasing of large granular lymphocyte.