Plasma microRNA-143 and microRNA-145 levels are elevated in patients with left ventricular dysfunction.

MicroRNA(miR)-143 and miR-145 are mainly expressed in vascular smooth muscle cells. However, the relationship between plasma miR-143 or miR-145 levels and the left ventricular (LV) function in patients with heart diseases remains unclear. Blood samples were taken from the antecubital vein in patients with heart diseases (n = 52), such as coronary artery disease, old myocardial infarction, cardiomyopathy, and valvular heart disease, and controls without heart diseases (n = 22). We measured plasma miR-143 and -145 levels by quantitative RT-PCR using TaqMan MicroRNA Assays and THUNDERBIRD Probe qPCR Mix. Plasma BNP levels were also measured. Echocardiography was performed to measure the LV ejection fraction (LVEF) and LV dilation. Plasma miR-143 and miR-145 levels were significantly higher in patients with heart diseases than in controls, respectively. Plasma miR-143 and miR-145 levels were significantly higher in patients with LVEF < 50% than in those with LVEF ≧ 50%, respectively. Plasma miR-143 and miR-145 levels were inversely correlated with LVEF, respectively. Plasma miR-143 and miR-145 levels were positively correlated with LV end-systolic dimension, respectively. Plasma miR-143 and -145 levels were positively correlated with plasma BNP levels, respectively. Plasma BNP levels were inversely correlated with LVEF. Plasma miR-143 and miR-145 levels are elevated in patients with LV dysfunction and may counteract LV dysfunction.

Concomitant use of interleukin-2 and tacrolimus suppresses follicular helper T cell proportion and exerts therapeutic effect against lupus nephritis in systemic lupus erythematosus-like chronic graft versus host disease.

Introduction: Defective interleukin-2 (IL-2) production contributes to immune system imbalance in patients with systemic erythematosus lupus (SLE). Recent clinical studies suggested that low-dose IL-2 treatment is beneficial for SLE and the therapeutic effect is associated with regulatory T cell (Treg) expansion. Pharmacological calcineurin inhibition induces a reduction in the number of Tregs because they require stimulation of T cell receptor signaling and IL-2 for optimal proliferation. However, the activation of T cell receptor signaling is partially dispensable for the expansion of Tregs, but not for that of conventional T cells if IL-2 is present. Aim: We examined whether addition of IL-2 restores the Treg proportion even with concurrent use of a calcineurin inhibitor and if the follicular helper T cell (Tfh) proportion is reduced in an SLE-like murine chronic graft versus host disease model. Methods: Using a parent-into-F1 model, we investigated the effect of IL-2 plus tacrolimus on Treg and Tfh proportions and the therapeutic effect. Results: Treatment with a combination of IL-2 and tacrolimus significantly delayed the initiation of proteinuria and decreased the urinary protein concentration, whereas tacrolimus or IL-2 monotherapy did not significantly attenuate proteinuria. Phosphorylation of signal transducer and activator of transcription 3, a positive regulator of Tfh differentiation, was reduced by combination treatment, whereas phosphorylation of signal transducer and activator of transcription 5, a negative regulator, was not reduced. Conclusion: Addition of calcineurin inhibitors as adjunct agents may be beneficial for IL-2-based treatment of lupus nephritis.

An Increase in Plasma MicroRNA-143 Levels in the Acute Phase Is Positively Correlated With Recovery of Cardiac Function in the Chronic Phase in Patients With Acute Myocardial Infarction.

BACKGROUND: MicroRNA (miR)-143 and miR-145 are non-coding RNAs present in smooth muscle cells and the heart. However, their behavior and physiological role in patients with acute myocardial infarction (AMI) have not been clarified.Methods and Results: Plasma miR-143 and miR-145 concentrations were measured on Day 0 (on admission) and on Day 7 in AMI patients who could be followed up for 6 months (n=25). The control group consisted of subjects without significant coronary stenosis (n=20). Blood samples were collected from the antecubital vein, and plasma miR-143 and miR-145 concentrations were measured by quantitative reverse transcription-polymerase chain reaction. In AMI patients (n=25), left ventricular ejection fraction (LVEF) was measured by echocardiography in the acute and chronic (6 months) phases. On Day 7, plasma miR-143 and miR-145 concentrations were significantly higher in AMI patients than in the control group and on Day 0 in AMI patients. Plasma miR-143 and miR-145 concentrations increased significantly from Day 0 to Day 7. The increase in plasma miR-143 concentrations (∆miR-143) in the acute phase was positively correlated with the increase in LVEF in the chronic phase. Among many factors, only ∆miR-143 was favorably correlated with left ventricle (LV) functional recovery in the chronic phase. CONCLUSIONS: An increase in plasma miR-143 concentrations in the acute phase may be a biomarker predicting recovery of LV function in the chronic phase in AMI patients.

Mutational analysis of DNMT3A improves the prognostic stratification of patients with acute myeloid leukemia.

Nucleophosmin1 (NPM1) mutations are the most frequently detected gene mutations in acute myeloid leukemia (AML) and are considered a favorable prognostic factor. We retrospectively analyzed the prognosis of 605 Japanese patients with de novo AML, including 174 patients with NPM1-mutated AML. Although patients with NPM1-mutated AML showed a high remission rate, this was not a favorable prognostic factor for overall survival (OS); this is contrary to generally accepted guidelines. Comprehensive gene mutation analysis showed that mutations in codon R882 of DNA methyltransferase 3A (DNMT3AR882 mutations) were a strong predicative factor indicating poor prognosis in all AML (p < 0.0001) and NPM1-mutated AML cases (p = 0.0020). Furthermore, multivariate analysis of all AML cases showed that DNMT3AR882 mutations and the co-occurrence of internal tandem duplication in FMS-like tyrosine kinase 3 (FLT3-ITD), NPM1 mutations, and DNMT3AR882 mutations (triple mutations) were independent factors predicting a poor prognosis related to OS, with NPM1 mutations being an independent factor for a favorable prognosis (hazard ratios: DNMT3AR882 mutations, 1.946; triple mutations, 1.992, NPM1 mutations, 0.548). Considering the effects of DNMT3AR882 mutations and triple mutations on prognosis and according to the classification of NPM1-mutated AML into three risk groups based on DNMT3AR882 /FLT3-ITD genotypes, we achieved the improved stratification of prognosis (p < 0.0001). We showed that DNMT3AR882 mutations are an independent factor for poor prognosis; moreover, when confounding factors that include DNMT3AR882 mutations were excluded, NPM1 mutations were a favorable prognostic factor. This revealed that ethnological prognostic discrepancies in NPM1 mutations might be corrected through prognostic stratification based on the DNMT3A status.

Incidence and predictors of recurrent sick leave in survivors who returned to work after allogeneic hematopoietic cell transplantation.

BACKGROUND: Although rather favorable probabilities of return to work have been reported after allogeneic hematopoietic cell transplantation (allo-HCT), survivors often have difficulty continuing to work because of their immunocompromised status and diverse late effects after allo-HCT. We evaluated the incidence of and risk factors for recurrent sick leave in allo-HCT survivors after they initially returned to work. METHODS: We targeted allo-HCT survivors who were employed at diagnosis, aged 20-64 at survey, and survived for ≥ 2 years without relapse. Of the 1904 survivors who were informed of the study, 1148 returned the questionnaire (60%), and 1048 eligible participants were included in the overall analysis. In the present study that considered recurrent sick leave after return to work, we targeted 896 participants who returned to work at least once after allo-HCT. Participants stated if they had recurrent sick leave after returning to work and its reasons, as well as associated patient-, HCT/HCT center-, and work-related factors and clinical events after allo-HCT. A logistic regression analysis was conducted to explore correlated factors for recurrent sick leave. RESULTS: In survivors who returned to work, 30% required recurrent sick leave. The most frequent causes of recurrent leave were physical issues (72%), and analysis of free descriptions demonstrated that these were mainly associated with graft-versus-host disease, infection, or readmission. Other reasons included work-related issues such as gap between physical and working conditions. Multivariate analysis showed that cord blood transplantation, longer employment duration, and counseling from healthcare professionals were associated with a lower risk of recurrent leave. Readmission, immunosuppressant use, and symptoms involving the respiratory system, gut, and joints and muscles were associated with a higher risk. CONCLUSIONS: Our results drawn from a large cohort study should help healthcare professionals identify and assist at-risk patients. Multi-professional teams that provide continuous support and effective communication with the workplace are necessary to improve long-term outcomes after allo-HCT. IMPLICATIONS FOR CANCER SURVIVORS: In order to continue working after the initial return to work, it is important to receive counseling from healthcare professionals and obtain reasonable accommodation from workplace.

Early administration of lenalidomide after allogeneic hematopoietic stem cell transplantation suppresses graft-versus-host disease by inhibiting T-cell migration to the gastrointestinal tract.

INTRODUCTION: Allogeneic hematopoietic stem cell transplantation (aHSCT) is a curative treatment for hematopoietic malignancies. Graft-versus-host disease (GVHD) is a major complication of aHSCT. After transplantation, the balance of immune conditions, such as proinflammatory cytokine level and T-cell subset count, influences GVHD magnitude. Lenalidomide (LEN) is an immunomodulatory drug used for treating several hematological malignancies such as multiple myeloma, adult T-cell lymphoma/leukemia, and follicular lymphoma. However, the impact of LEN on immune responses after aHSCT has not been elucidated. METHODS: We analyzed the lymphocyte composition in naïve mice treated with LEN. Subsequently, we treated host mice with LEN, soon after aHSCT, and analyzed GVHD severity as well as the composition and characteristics of lymphocytes associated with GVHD. RESULTS: Using a mouse model, we demonstrated the beneficial effects of LEN for treating acute GVHD. Although natural killer cells were slightly increased by LEN, it did not significantly change T-cell proliferation and the balance of the T-cell subset in naïve mice. LEN did not modulate the suppressive function of regulatory T cells (Tregs). Unexpectedly, LEN prevented severe GVHD in a mouse acute GVHD model. Donor-derived lymphocytes were more numerous in host mice treated with LEN than in host mice treated with vehicle. Lymphocyte infiltration of the gastrointestinal tract in host mice treated with LEN was less severe compared to that in host mice treated with vehicle. The percentage of LPAM-1 (α4 ß7 -integrin)-expressing Foxp3- CD4+ T cells was significantly lower in host mice treated with LEN than in host mice treated with vehicle, whereas that of LPAM-1-expressing Tregs was comparable. CONCLUSIONS: LEN may be useful as a prophylactic agent for acute GVHD-induced mortality through the inhibition of lymphocyte migration to the gastrointestinal tract. Our data show the effect of LEN on immune responses early after aHSCT and suggest that cereblon, a molecular target of LEN, may be a therapeutic target for preventing acute GVHD-induced mortality.

Real-world efficacy of letermovir prophylaxis for cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation: A single-center retrospective analysis.

INTRODUCTION: Cytomegalovirus (CMV) infection is a common complication following allogeneic hematopoietic stem cell transplantation (aHSCT) and is associated with increased mortality. Letermovir (LET) is a novel antiviral drug used to prevent CMV infection. METHODS: We analyzed 111 consecutive patients who underwent aHSCT, retrospectively, to evaluate the efficacy of LET prophylaxis for clinically significant CMV infection (csCMVi) in real-world situations. In addition, we analyzed the influence of LET on transplant outcomes. Thirty-eight patients who were administered LET prophylactically were compared with 73 patients without LET prophylaxis after aHSCT. RESULTS: On day 180, the cumulative incidence of csCMVi in patients who received LET prophylaxis was significantly lower than that in patients without LET prophylaxis (29.7% vs. 56.2%, P < 0.001). Among the patients who developed csCMVi, the interval from aHSCT to the initiation of preemptive therapy was significantly longer in patients who received LET prophylaxis than in those who did not (129.5 days vs. 42 days, P < 0.001). The six-month overall survival was 86.1% in patients who received LET prophylaxis and 66.8% in the non-LET group (P = 0.035). CONCLUSION: LET prophylaxis was highly effective in preventing csCMVi and could potentially improve transplant outcomes, particularly when initiated early after transplantations.

Real-world treatment patterns and clinical outcomes in patients with AML in Japan who were ineligible for first-line intensive chemotherapy.

Acute myeloid leukemia (AML) predominantly affects elderly adults, and its prognosis worsens with age. Treatment options for patients in Japan ineligible for intensive chemotherapy include cytarabine/aclarubicin ± granulocyte colony-stimulating factor (CA ± G), azacitidine (AZA), low-dose cytarabine (LDAC), targeted therapy, and best supportive care (BSC). The country's aging population and the evolving treatment landscape are contributing to a need to understand treatment pathways and associated outcomes. This retrospective chart review evaluated outcomes in patients across Japan with primary/secondary AML who were ineligible for intensive chemotherapy and began first-line treatment or BSC between 01/01/2015 and 12/31/2018. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS) and healthcare resource utilization (HRU). Of 199 patients (58% > 75 years), 121 received systemic therapy (38 CA ± G, 37 AZA, 7 LDAC, 39 other) and 78 received BSC. Median OS was 5.4, 9.2, 2.2, 3.8, and 2.2 months for CA ± G, AZA, LDAC, other systemic therapy, and BSC, respectively; median PFS was 3.4, 7.7, 1.6, 2.3, and 2.1 months, respectively. HRU rates were uniformly high, with > 80% patients hospitalized in each cohort. The poor clinical outcomes and high HRU among Japanese AML patients who are ineligible for intensive chemotherapy highlight an unmet need for novel therapies.

NPM1-mutation-based measurable residual disease assessment after completion of two courses of post-remission therapy is a valuable clinical predictor of the prognosis of acute myeloid leukemia.

Recent studies have reported that measurable residual disease (MRD) analysis using NPM1 mutations helps determine whether allogeneic hematopoietic stem cell transplantation (allo-HSCT) is indicated in acute myeloid leukemia (AML) patients. However, the optimal timing and cutoff value for measuring MRD using genomic DNA remain undetermined. This study aimed to investigate the optimal timing and cutoff value to ascertain the value of NPM1 mutation in MRD assessment. NPM1-mutated MRD was quantified by real-time polymerase chain reaction of bone marrow samples from 56 patients with NPM1-positive AML who achieved hematological remission. The area under the receiver-operating characteristic curve was greatest when MRD was assessed after two courses of post-remission therapy with a cutoff value of 0.010% (specificity, 68.4%; sensitivity, 87.0%). Patients whose MRD was below the cutoff value throughout the course of treatment had significantly better overall survival and relapse-free survival rates. Of the 33 patients who did not undergo transplantation during the first remission, all of the 11 who were never MRD-negative at any point experienced a relapse. Evaluating MRD with a cutoff value of 0.010% after two courses of post-remission therapy helps predict prognosis and determine the indication for allo-HSCT.

Prognostic impact of CEBPA bZIP domain mutation in acute myeloid leukemia.

Mutations of CCAAT/enhancer-binding protein alpha (CEBPAmu) are found in 10% to 15% of de novo acute myeloid leukemia (AML) cases. Double-mutated CEBPA (CEBPAdm) is associated with a favorable prognosis; however, single-mutated CEBPA (CEBPAsm) does not seem to improve prognosis. We investigated CEBPAmu for prognosis in 1028 patients with AML, registered in the Multi-center Collaborative Program for Gene Sequencing of Japanese AML. It was found that CEBPAmu in the basic leucine zipper domain (bZIP) was strongly associated with a favorable prognosis, but CEBPAmu out of the bZIP domain was not. The presence of CEBPAmu in bZIP was a strong indicator of a higher chance of achieving complete remission (P < .001), better overall survival (OS; P < .001) and a lower risk of relapse (P < .001). The prognostic significance of CEBPAmu in bZIP was also observed in the subgroup with CEBPAsm (all patients: OS, P = .008; the cumulative incidence of relapse, P = .063; patients aged ≤70 years and with intermediate-risk karyotype: OS, P = .008; cumulative incidence of relapse, P = .026). Multivariate analysis of 744 patients aged ≤70 years showed that CEBPAmu in bZIP was the most potent predictor of OS (hazard ratio, 0.3287; P < .001). CEBPAdm was validated as a cofounding factor, which was overlapping with CEBPAmu in bZIP. In summary, these findings indicate that CEBPAmu in bZIP is a potent marker for AML prognosis. It holds potential in the refinement of treatment stratification and the development of targeted therapeutic approaches in CEBPA-mutated AML.

Elevation of Early Plasma Biomarkers in Patients with Clinical Risk Factors Predicts Increased Nonrelapse Mortality after Allogeneic Hematopoietic Stem Cell Transplantation.

Early prediction of nonrelapse mortality (NRM) in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) based on the results of laboratory tests is challenging. Thus, there is a need to evaluate biomarkers for prediction of NRM, a major problem that offsets the advantages of allo-HSCT. We tested the validity and efficacy of 2 plasma biomarkers, ST2 and Reg3α, based on the Mount Sinai Acute GVHD International Consortium (MAGIC) algorithm, for early prediction of NRM in Japanese patients who underwent allo-HSCT. We conducted a multicenter retrospective study to analyze the clinical data of 112 patients with hematopoietic malignancies who underwent allo-HSCT. Patient blood samples on day 7 after allo-HSCT were obtained from 6 hospitals. The plasma concentrations of ST2 and Reg3α were used to calculate a 6-month NRM risk score. Based on the scores determined in this study, we identified 64 low-risk patients and 48 high-risk patients for the 6-month NRM. The cumulative incidence of 6-month NRM was 29.2% in the high-risk group and 10.9% in the low-risk group (P < .05). The cumulative incidence of relapse mortality was similar in the high-risk and low-risk patients. The biomarker score was predictive in patients with an unrelated donor, an HLA-mismatched donor, high/very high Disease Risk Index, and Hematopoietic Cell Transplantation Comorbidity Index ≥1. Multivariate analysis identified high biomarker probability as a significant predictor of NRM. The MAGIC algorithm based on blood samples obtained at 7 days after allo-HSCT can identify individuals at high risk for NRM among patients with clinical risk factors for NRM in a Japanese cohort.

Multiple Myeloma with Central Nervous System Relapse Early after Autologous Stem Cell Transplantation: A Case Report and Literature Review.

Few reports have so far described central nervous system (CNS) involvement in multiple myeloma (MM), which shows a poor prognosis owing to its resistance to several treatments. We herein describe a 45-year-old woman who had MM (diagnosed with IgA-κ type) with CNS relapse early after undergoing autologous hematopoietic stem cell transplantation. Because no standard treatment for CNS lesions of MM has been established, we conducted a literature review on the cerebrospinal fluid (CSF) transferability of drugs for MM, since it was considered to be a useful tool for CNS involvement. Immunomodulatory-drugs including pomalidomide exhibit a good CSF transfer ability, and, therefore, may be beneficial against the CNS involvement of MM.

Analysis of HLA haplotype and clinical factors during hematopoietic stem cell transplantation.

BACKGROUND: The human leukocyte antigen (HLA) haplotype of the recipient in hematopoietic stem cell transplantation (HSCT) is a key factor in its success or failure. We analyzed the relationship between HLA haplotype frequency and associated clinical factors in HSCT patients. METHODS: Patients who underwent allogeneic HSCT between 2000 and 2019 at our institution were enrolled in this study. The HSCT composition was 77 bone marrow transplantations (BMT), 38 peripheral blood stem cell transplantations (PBSCT), and 36 cord blood transplantations (CBT). Patients were classified into three groups according to their donor HLA haplotype frequency in the Japan Population: group A, top 1-10 haplotypes; group B, top 11-100 haplotypes; and group C, haplotype 101-. We then compared various items including clinical biomarkers with the HLA haplotype frequency. RESULTS: A significant negative correlation was identified between older persons and length of survival. There are also significant correlations between survival and levels of immunoglobulin G, D-dimer, and C-reactive protein, as well as the platelet-large cell ratio before transplantation. A total of 96, 30, and 25 patients were classified into groups A, B, and C, respectively. The HSCT match rate was significantly higher in group A patients than in those of groups B and C. In contrast, the death rate, D-dimer level, and length of time for engraftment were significantly higher in group B and C patients than in those of group A. CONCLUSION: An assessment of transplant-related complications is important in improving the performance of HSCT. The present data suggest that a special therapeutic strategy is necessary for HSCT using low-frequency HLA haplotypes.

Refractory Chronic Lymphocytic Leukemia with Central Nervous System Involvement: A Case Report with Literature Review.

There have been few reports on central nervous system (CNS) involvement in chronic lymphocytic leukemia (CLL). This is an extremely rare disease with poor prognosis, owing to resistance to various treatments. We describe a 33-year-old man with intractable CLL with CNS involvement. He was diagnosed with CLL, with diplopia as the first manifestation. Magnetic resonance imaging revealed a contrast-enhancing tumor in the right temporal lobe, which was diagnosed as CNS involvement in CLL on brain biopsy. High-dose methotrexate therapy was ineffective for this lesion, which was also resistant to subsequent whole-brain irradiation, treatment with fludarabine-cyclophosphamide-rituximab chemoimmunotherapy, and ibrutinib administration. Because no standard protocol exists for CLL with CNS involvement, it is important to accumulate case data to verify the choice of new drugs for administration at an early stage. Therefore, we also conducted a literature review of 50 case reports of CNS lesions in the last 10 years to consider the pathophysiology, diagnosis, and treatment of CNS involvement in CLL. The possibility of new therapeutic agents, eg, ibrutinib and venetoclax, or a combination of these agents and methotrexate, can be envisioned as a treatment strategy for CLL with CNS involvement.

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.

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.

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.

Comparison of starting doses of anagrelide as a first-line therapy in patients with cytoreductive therapy-naïve essential thrombocythemia: difference between starting at 0.5 and 1.0 mg/day.

Anagrelide is widely used for cytoreductive therapy in patients with essential thrombocythemia who are at high risk for thrombosis. The recommended starting dose in the package insert of anagrelide varies by country. A high starting dose leads to an early onset of action, but causes a higher incidence of adverse events. This relationship indicates that both the onset of action and side effects of anagrelide are dose dependent. We retrospectively compared the efficacy and safety of anagrelide as a first-line drug between patients with essential thrombocythemia who started at 0.5 or 1.0 mg/day. Incidence of total adverse events and anagrelide-related palpitation, discontinuation rates, and the median daily dose of anagrelide were lower in the 0.5 mg/day group than in the 1.0 mg/day group; however, comparable platelet-lowering effects were achieved in both groups. These data suggest that a low starting dose of anagrelide followed by dose escalation may result in fewer adverse events and lower discontinuation rates, while providing desirable platelet-lowering effects. Initiating anagrelide at a lower dose may be a useful approach in actual clinical practice.

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.

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.