Search

Aims The CONtrolling NUTritional status (CONUT) score represents the nutritional status of patients with heart failure (HF). Although high CONUT scores on admission are associated with increased risks of cardiovascular (CV) events in patients with HF, the impact of CONUT changes during hospitalization on their long‐term prognosis is unclear. This study aimed to investigate the impact of CONUT score changes on the clinical outcomes of patients with HF after discharge. Methods and results This observational study included 1705 patients hospitalized with HF who were discharged alive. The patients were categorized depending on their CONUT scores at admission and discharge into persistently high, high at admission and normal at discharge, normal at admission and high at discharge, and persistently normal CONUT groups. The primary endpoint was a composite of CV death and readmission for HF after discharge. The primary endpoint occurred in 652 patients (38%) during the median 525 day follow‐up period. Patients with persistently high CONUT scores had the highest composite endpoint rate (log‐rank trend test: P

Minimal residual disease (MRD) is a surrogate marker for survival in multiple myeloma (MM), while the lymphocyte-to-monocyte ratio (LMR) is a prognostic factor associated with the patients' immunological status. We retrospectively evaluated the clinical impact of MRD negativity and LMR. MRD was analyzed by multicolor flowcytometry (threshold, 1 × 10-5). Fifty-eight patients (median age 70 years) who achieved complete response were included in this study. Twenty-two patients received autologous stem cell transplantation, 14 received daratumumab-based chemotherapy, and 22 received another treatment. Forty-one (70.7%) patients achieved MRD negativity. Over the median follow-up time of 15.1 months, PFS in MRD-negative patients was significantly longer than in MRD-positive patients (P = 0.020). In addition, a high LMR at MRD assessment was associated with MRD negativity (P = 0.019) and long PFS (P = 0.009). Finally, neither MRD negativity nor high LMR at MRD assessment was associated with significantly shorter PFS compared with MRD positivity or low LMR (P = 0.002). In conclusion, high LMR was associated with MRD negativity and can be used as a predictor of long PFS. Change of treatment strategy might be essential for patients with MRD positivity and high LMR at MRD assessment due to their short PFS.

New drugs for multiple myeloma (MM) have dramatically improved patients’ overall survival (OS). Autologous stem cell transplantation (ASCT) remains the mainstay for transplant‐eligible MM patients. To investigate whether the post‐ASCT prognosis of MM patients has been improved by new drugs, we undertook a retrospective observational analysis using the Transplant Registry Unified Management Program database in Japan. We analyzed 7323 patients (4135 men and 3188 women; median age, 59 years; range 16‐77 years) who underwent upfront ASCT between January 2007 and December 2018. We categorized them by when they underwent ASCT according to the drugs’ introduction in Japan: group 1 (2007‐2010), group 2 (2011‐2016), and group 3 (2017‐2018). We compared the groups’ post‐ASCT OS. The 2‐year OS rates (95% confidence interval [CI]) of groups 1, 2, and 3 were 85.8% (84.1%‐87.4%), 89.1% (88.0%‐90.1%), and 92.3% (90.0%‐94.2%) (P, The overall survival of patients with multiple myeloma (MM) after autologous stem cell transplantation has improved over time along with the introduction of new drugs for the treatment of MM.

Simple Summary Improving the immunological environment and eradicating minimal residual disease (MRD) are the two main treatment goals for long-term survival in patients with multiple myeloma (MM). An improved immunological environment may be useful for maintaining MRD negativity. Whether the ongoing treatment should be continued or changed if the MRD status remains positive is controversial. In this case, genetic, immunophenotypic, and clinical analysis of residual myeloma cells may be necessary to select the effective treatment for the residual myeloma cells. The purpose of this review is to discuss the MM treatment strategy to “cure MM” based on currently available therapies and expected immunotherapies via improvement of the immunological environment and maintenance of MRD negativity. Abstract Improving the immunological environment and eradicating minimal residual disease (MRD) are the two main treatment goals for long-term survival in patients with multiple myeloma (MM). Immunomodulatory drugs (IMiDs), monoclonal antibody drugs (MoAbs), and autologous grafts for autologous stem cell transplantation (ASCT) can improve the immunological microenvironment. ASCT, MoAbs, and proteasome inhibitors (PIs) may be important for the achievement of MRD negativity. An improved immunological environment may be useful for maintaining MRD negativity, although the specific treatment for persistent MRD negativity is unknown. However, whether the ongoing treatment should be continued or changed if the MRD status remains positive is controversial. In this case, genetic, immunophenotypic, and clinical analysis of residual myeloma cells may be necessary to select the effective treatment for the residual myeloma cells. The purpose of this review is to discuss the MM treatment strategy to “cure MM” based on currently available therapies, including IMiDs, PIs, MoAbs, and ASCT, and expected immunotherapies, such as chimeric antigen receptor T cell (CAR-T) therapy, via improvement of the immunological environment and maintenance of MRD negativity.

The combination of bortezomib, lenalidomide, and dexamethasone (VRD) is used as induction treatment in multiple myeloma; however, the optimum schedule for this regimen remains controversial. In this retrospective study, we compared the efficacy and tolerability of twice-weekly VRD (twVRD) and modified VRD-lite in transplant-eligible myeloma patients. Fifty-five patients (median age 61 years) were included; 22 received twVRD (bortezomib [1.3 mg/m2 on days 1, 4, 8, and 11] and lenalidomide [25 mg/body on days 1–14] over 21-day cycles) and 33 received modified VRD-lite (bortezomib [1.3 mg/m2 on days 1, 8, 15, and 22) and lenalidomide [15 mg/body on days 2–7, 9–14, 16–21] over 28-day cycles). Overall response, very good partial response, and complete response rates after VRD were 96.4%, 45.5%, and 20.0%, respectively (median follow-up period, 17.7 months). The 1-year progression-free survival (PFS) and overall survival rates were 95.8% and 98.2%, respectively. The response rate and PFS were similar between the groups, regardless of cytogenetic risk and age. The incidence of peripheral neuropathy ≥ grade 2 and thrombocytopenia ≥ grade 3 was higher in the twVRD group (27.2% vs. 0.0%, P = 0.003 and 27.2% vs. 0.0%, P = 0.003). In conclusion, modified VRD-lite had similar efficacy with, but better tolerability than, twVRD in transplant-eligible patients.

Maintenance ± consolidation or continuous therapy is considered a standard of care for both transplant–eligible and –ineligible patients with multiple myeloma (MM). However, long-term benefits of such therapy have not yet been clarified in the context of clinical practice. To clarify the efficacy of maintenance/continuous approach, we retrospectively analyzed the cohort data of newly diagnosed MM patients by propensity-score matching based on age, gender, revised International Staging System (R-ISS) stage, and implementation of transplantation to reduce the bias due to confounding variables. Among 720 patients, 161 were identified for each of the maintenance and no maintenance groups. Maintenance/continuous therapy employed immunomodulatory drugs (n = 83), proteasome inhibitors (n = 48), combination of both (n = 29), or dexamethasone alone (n = 1). Progression-free survival (PFS) was significantly prolonged in the maintenance group compared with the no maintenance group (median 37.7 and 21.9 months, p = 0.0002, respectively). Prolongation of PFS was observed in both transplanted and non-transplanted patients (p = 0.017 and p = 0.0008, respectively), with standard risk (p

Simple Summary Multiple myeloma is an uncurable hematological malignancy, although the prognosis of myeloma patients is getting better using proteasome inhibitors (PIs), immune modulatory drugs (IMiDs), monoclonal antibodies (MoAbs), and cytotoxic agents. Drug resistance makes myeloma difficult to treat and it can be subdivided into two broad categories: de novo and acquired. De novo drug resistance is associated with the bone marrow microenvironment including bone marrow stromal cells, the vascular niche and endosteal niche. Acquired drug resistance is related to clonal evolution and non-genetic diversity. The initial treatment plays the most important role considering de novo and acquired drug resistance and should contain PIs, IMIDs, MoAbs, and autologous stem cell transplantation because these treatments improve the bone marrow microenvironment and might prevent clonal evolution via sustained deep response including minimal residual disease negativity. Abstract Multiple myeloma is an uncurable hematological malignancy because of obtained drug resistance. Microenvironment and clonal evolution induce myeloma cells to develop de novo and acquired drug resistance, respectively. Cell adhesion-mediated drug resistance, which is induced by the interaction between myeloma and bone marrow stromal cells, and soluble factor-mediated drug resistance, which is induced by cytokines and growth factors, are two types of de novo drug resistance. The microenvironment, including conditions such as hypoxia, vascular and endosteal niches, contributes toward de novo drug resistance. Clonal evolution was associated with acquired drug resistance and classified as branching, linear, and neutral evolutions. The branching evolution is dependent on the microenvironment and escape of immunological surveillance while the linear and neutral evolution is independent of the microenvironment and associated with aggressive recurrence and poor prognosis. Proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), monoclonal antibody agents (MoAbs), and autologous stem cell transplantation (ASCT) have improved prognosis of myeloma via improvement of the microenvironment. The initial treatment plays the most important role considering de novo and acquired drug resistance and should contain PIs, IMIDs, MoAb and ASCT. This review summarizes the role of anti-myeloma agents for microenvironment and clonal evolution and treatment strategies to overcome drug resistance.

This is the rare case report that bilateral vagus nerve paralysis was emerged as the initial symptom of acute myelogenous leukemia (AML). An 83-year-old man admitted to our hospital because of dysphagia. His dysphagia progressed two months prior to admission. Although physical examination revealed no abnormality, videoendoscopy and videofluorography examination clearly revealed bilateral vagus nerve palsy. Brain MRI showed hypointense signals at the bilateral clivus on T1 weighted images, suggesting tumor infiltration to bilateral petroclivus. He was diagnosed as AML by blood samples and bone marrow biopsy. After initiation of the treatment including radiation therapy, dysphagia shows mild improvement. Although bilateral cranial nerve palsy due to malignant tumor involving at the clivus is very uncommon, we should pay attention to the symptom.

Background: Novel agents capable of inducing deeper responses dramatically improve the prognosis of patients with multiple myeloma (MM). Innovative technologies such as multiparameter flow cytometry (MFC) and next-generation sequencing (NGS) are utilized to assess minimal residual disease (MRD) for further stratification of patients who achieve a complete response (CR). EuroFlow-next-generation flow (EuroFlow-NGF) is one of the gold standard MFC methods. Recently, both NGF and NGS have been used in many clinical trials to assess MRD levels associated with progression-free survival (PFS) and overall survival (OS). The present study prospectively assessed MRD levels by both NGF and NGS to elucidate the prognostic impact of both methods and clarify their characteristics in MM patients in an autologous stem cell transplantation (ASCT) setting. Methods: We prospectively assessed the response in Japanese patients with newly diagnosed MM who underwent ASCT and lenalidomide-based maintenance therapy at multiple Japanese medical centers between September 2016 and July 2021. The diagnosis of MM and patients' responses to therapy were assessed using the IMWG criteria. Only patients with CR or stringent CR on days 100-365 post-ASCT were included, and bone marrow (BM) samples were obtained to assess MRD. Four milliliters of BM was divided equally. Cells derived from 2 mL BM were analyzed by the NGF method (Flores-Montero et al., Leukemia 2017) at Kanazawa University, and DNA extracted from the remaining 2 mL BM cells was processed by Adaptive Biotechnologies' standardized NGS-MRD assay (Seattle, WA) (Ching et al., BMC Cancer 2020) to assess MRD levels. MRD levels in BM were also monitored at 1-year (± 20 days) and 2-year (± 20 days) post-ASCT. The prognostic value of MRD levels in BM was assessed, and their correlation between NGF and NGS was compared at a cut-off value of 1×10 -5. Sustained MRD negativity was defined as the maintenance of MRD negativity in the BM for more than 6 months. BM cells were analyzed for high-risk cytogenetics (del(17p), t(4;14), and t(14;16)) by FISH. Results: A total of 60 patients (male = 29, female = 31) underwent bortezomib-based induction therapy, ASCT conditioned with high-dose melphalan, and lenalidomide-based maintenance. The median age was 62 years at the ASCT (range 36-71; ISS 1 [n = 13], 2 [n = 24], and 3 [n = 23]). Thirty-three percent of patients showed high-risk chromosomal abnormalities (del17p (n=11), t(4;14) (n=10), t(14;16) (n=2)), 3 patients had double hit diseases, and five patients had extramedullary diseases. With a median follow-up of 3 years, the 3-year progression-free survival (PFS) and 3-year overall survival (OS) rates were 69.2% and 94.2%, respectively. In total, 148 samples were analyzed using NGF and 138 were analyzed using NGS. The rates of MRD negativity at least once using NGF and NGS were 80% and 61%, respectively. The patients who achieved at least one MRD negativity exhibited significantly better 3-year PFS (82.9% by NGF; 84.8% by NGS) than those who did not (P < 0.0001, 0% by NGF; P = 0.005, 49.1% by NGS). Patients who sustained MRD negativity for more than 6 months also showed significantly better 3-year PFS (96.7% by NGF; 92.3% by NGS) compared with those without sustained MRD negativity (Figure; P < 0.0001, 37.1% by NGF; P < 0.01, 50.9% by NGS). The MRD levels between the NGF and NGS methods were significantly correlated with each other (r = 0.9295, P < 0.0001). Among the 17 patients who developed PD after ASCT, seven cases showed discrepancies in the MRD results and two cases in which one case was MRD-positive and the other was MRD-negative by both methods progressed with extramedullary diseases. Five of the seven cases were MRD-positive by NGS and MRD-negative by NGF. Conclusions: In this prospective comparison study of MRD assessment in BM cells using EuroFlow-NGF and NGS approaches, MRD levels highly correlated with each other, and MRD negativity and sustained MRD negativity were significantly associated with prolonged PFS. Multiple MRD assessments by NGF or NGS are essential for predicting durable remission and prolonged clinical outcomes. Figure 1 Figure 1. Disclosures Takamatsu: Bristol-Myers Squibb: Honoraria, Research Funding; Adaptive Biotechnologies, Eisai: Honoraria; SRL: Consultancy; Janssen: Consultancy, Honoraria, Research Funding. Yoshihara: Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Novartis: Honoraria. Matsumoto: Sanofi: Honoraria; Janssen: Honoraria; Ono: Honoraria; Bristol-Myers Squibb: Honoraria. Yamashita: Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; celgene: Honoraria; Takeda: Honoraria. Fuchida: Takeda Pharmaceutical Co., Ltd.: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Sanofi: Honoraria; Bristol-Myers Squibb Co., Ltd.: Honoraria; Celgene Co., Ltd.: Honoraria. Hiragori: BML: Current Employment. Suzuki: Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; ONO: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; Abie: Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Nakao: Symbio: Consultancy; Kyowa Kirin: Honoraria; Novartis Pharma: Honoraria; Alexion Pharma: Research Funding. Durie: Amgen: Other: fees from non-CME/CE services ; Amgen, Celgene/Bristol-Myers Squibb, Janssen, and Takeda: Consultancy.

Lenalidomide is an immunomodulatory drug that is administered commonly in patients with relapsed or refractory multiple myeloma (RRMM). Eosinophils have immunological functions, for instance, in allergic diseases and asthma. The purpose of this study was to investigate the clinical significance of elevated eosinophil levels in patients with RRMM treated with lenalidomide. A total of 59 patients were included. Elevated eosinophil level was defined as an increase in the eosinophil count of ≥250/µL from the eosinophil count on day 1 during the first cycle. The percentage of patients with elevated eosinophil levels was 22.0%. The overall response ratio in the elevated eosinophil group and nonelevated eosinophil group was 84.6% and 63.0% (P = .189), respectively. The median time to next treatment (TTNT) in the elevated eosinophil group was significantly longer than that in the nonelevated group (40.3 months vs 8.4 months; P = .017). Additionally, TTNT in the elevated eosinophil group with partial response (PR) or better was significantly longer than that in the nonelevated eosinophil group with PR or better (40.3 months vs 11.9 months; P = .021). We concluded that elevated eosinophil levels were frequently observed and might predict a longer TTNT in patients with RRMM treated with lenalidomide., Elevated eosinophils predicted significantly long time to next treatment in relapsed or refractory multiple myeloma patients treated with lenalidomide. Elevated eosinophils might show an immunological effect of lenalidomide. We considered that NKG2D and IL‐2 were associated with elevated eosinophils according to the literature review.

Background This study aimed to examine the impact of baseline eicosapentaenoic acid ( EPA ) to arachidonic acid ( AA ) ratio on clinical outcomes of patients with acute coronary syndrome. Methods and Results In the HIJ‐PROPER (Heart Institute of Japan Proper Level of Lipid Lowering With Pitavastatin and Ezetimibe in Acute Coronary Syndrome) study, 1734 patients with acute coronary syndrome and dyslipidemia were randomly assigned to pitavastatin+ezetimibe therapy or pitavastatin monotherapy. We divided the patients into 2 groups based on EPA / AA ratio on admission (cutoff 0.34 μg/mL as median of baseline EPA / AA ratio) and examined their clinical outcomes. The primary end point comprised all‐cause death, nonfatal myocardial infarction, nonfatal stroke, unstable angina pectoris, or ischemia‐driven revascularization. Percentage reduction of low‐density lipoprotein cholesterol and triglyceride from baseline to follow‐up was similar regardless of baseline EPA / AA ratio. Despite the mean low‐density lipoprotein cholesterol level during follow‐up being similar between the low‐ and high‐ EPA / AA groups, the mean triglyceride levels during follow‐up were significantly higher in the low‐ than in the high‐ EPA / AA group. After 3 years of follow‐up, the cumulative incidence of the primary end point in patients with low EPA / AA was 27.2% in the pitavastatin+ezetimibe group compared with 36.6% in the pitavastatin‐monotherapy group (hazard ratio 0.69; 95% CI , 0.52‐0.93; P =0.015). However, there was no effect of pitavastatin+ezetimibe therapy on the primary end point in patients with high EPA / AA (hazard ratio 0.92; 95% CI , 0.70‐1.20; P =0.52). Conclusions Among acute coronary syndrome patients who have dyslipidemia and low EPA / AA ratio, adding ezetimibe to statin decreases the risk of cardiovascular events compared with statin monotherapy. Clinical Trial Registration URL : http://www.umin.ac.jp/ctr . Unique identifier: UMIN 000002742

A 66-year-old man with a swollen right inguinal lymph node (LN) had pain on the lower side of the back. Computed tomography revealed bone disease in the back and swollen right inguinal LNs. Laboratory studies showed anemia and serum immunoglobulin G-lambda (IgG-λ) type monoclonal protein. The bone marrow contained 39.6% plasma cells. He was diagnosed with IgG-λ type multiple myeloma (MM). However, the pathological findings of the right inguinal LN were mixed cellular classical Hodgkin lymphoma (HL). The administration of melphalan, prednisone, and bortezomib (MPB) was started for MM; however, swelling in the right inguinal LN increased. After three cycles of MPB, the administration of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) was started for HL. However, HL was refractory to ABVD. Pancytopenia subsequently progressed and rapid swelling occurred in his LNs. He died 7 months after diagnosis. Multiple myeloma was diagnosed, based on the typical symptoms, although the pathological findings of the LN indicated a diagnosis of HL. We analyzed the molecular relationship between MM and HL cells using a direct sequencing method. The sequencing results demonstrated that the variable-diversity-joining (VDJ) region of the IgH gene was identified with 94.4% of IGLV3-32*01 in the bone marrow sample at diagnosis. Furthermore, clonotypic IgH sequence was identified in CD30-positive cells from the LN. These results suggested that the clonal HL cells were derived from the same source as the clonal MM cells and demonstrated that MM and HL in this patient may have originated from the same B cell progenitor.

The clinical features and prognostic significance of myeloma cells containing granules remain unclear. The purpose of this retrospective study was to investigate the clinical significance of granule‐containing myeloma cells in patients with newly diagnosed multiple myeloma (NDMM). We retrospectively analyzed the records of 122 patients diagnosed with NDMM between January 2007 and December 2013. Granule‐containing myeloma cells were defined as myeloma cells that exhibited three or more granules in their cytoplasm by May‐Giemsa staining. The patients were classified into two groups, the granule‐containing myeloma (GM) and nongranule‐containing myeloma (non‐GM) groups, depending on the proportion of myeloma cells that contained granules (cut‐off value: 10%). There were 25 (20.5%) patients in the GM group. Patients in the GM group displayed significantly higher CD56 and CD49e expression than those in the non‐GM group (t‐test, P = 0.027 and 0.042). None of the patient characteristics differed significantly between the two groups. There was no significant difference in the chemotherapy profiles of the two groups, and the overall response rates of the two groups were similar. During the median follow‐up period of 33.9 months, the overall survival (OS) in the GM group was similar to that in the non‐GM group; 4‐year OS of the GM and non‐GM groups were 78.5% and 51.9%, respectively (P = 0.126). We concluded that cases of NDMM involving granule‐containing myeloma cells are not infrequent. Moreover, CD56 and CD49e expression was significantly higher in the presence of myeloma cell populations, and the presence of granules did not affect survival.

Supplemental Digital Content is available in the text., Bromodomain and extraterminal protein (BET) inhibitors suppress the expression of c-MYC. U266, a human myeloma cell line, expresses the MYCL gene, but not the c-MYC gene. Our aim was to analyse the antimyeloma activity of BET inhibitors on U266 cells. Two BET inhibitors, I-BET151 and JQ1, were tested. U266 cell proliferation decreased to 61.5 and 54.0% of the control after incubation with 500 nmol/l I-BET151 for 72 and 96 h and to 53.5 and 56.4% of control after incubation with 500 nmol/l JQ1 for 72 and 96 h by MTS tetrazolium, respectively. BET inhibitors induced cell cycle arrest at the G1 phase in U266 cells, but did not induce apoptosis by flow cytometry. According to Gene Set Enrichment Analysis, MYC-related genes were significantly downregulated in U266 cells treated with I-BET151 similar to KMS11 cells that expressed c-MYC. The MYCL1 was expressed in U266 cells, whereas c-MYC and MYCN were not by quantitative real-time reverse-transcription-PCR. Incubation with I-BET151 induced downregulation of MYCL1 in U266 cells. BET inhibitors decreased the cell proliferation in U266 cells with overexpression of MYCL less than those without overexpression of MYCL. BET inhibitors induce G1 arrest without apoptosis and interfere with the proliferation of U266 myeloma cells, which express MYCL, but not c-MYC. BET inhibitors might be active in cancers that express MYCL, but not c-MYC.

Myeloma cast nephropathy is a major complication of multiple myeloma. Recent evidence has demonstrated that the earlier induction of bortezomib-based chemotherapy with plasma exchange (PE) provides better results for kidney function and patient survival. Due to its non-selectivity, PE with albumin replacement carries the risk of fibrinogen loss, leading to bleeding. We herein report a case of successful treatment of myeloma cast nephropathy using bortezomib-based chemotherapy and selective PE. A 61-year-old woman who had a 20-year history of type II diabetes mellitus was admitted to our hospital for the evaluation of hypercalcemia, severe kidney dysfunction, and anemia. Subsequent bone marrow evaluation and renal biopsy revealed that she had multiple myeloma (IgG-κ) and myeloma cast nephropathy. Ten days after admission, bortezomib-based chemotherapy with selective PE achieved rapid and thorough free light-chain (FLC) reduction; within a month, her kidney function had been recovered (creatinine level, 1.2 mg/dl). Her serum fibrinogen level was not reduced, and no bleeding complication occurred. Five months later, autologous hematopoietic stem-cell transplantation was performed successfully, and the patient’s kidney function was stable (creatinine level, 1.1 mg/dl) thereafter. This case report demonstrates the importance of early induction therapy with bortezomib-based chemotherapy and PE in a patient with myeloma cast nephropathy, which is especially applicable in patients aged

Cancer-related fatigue (CRF) is one of the adverse events in multiple myeloma (MM) patients treated with cytotoxic agents, proteasome inhibitors (PIs), and immunomodulatory drugs (IMiDs) such as bortezomib, lenalidomide, and thalidomide. The aims of our study were to prospectively analyze the clinical significance of CRF, and to evaluate the cumulative incidence of CRF and the survival rates of 16 MM patients who were treated with PIs and IMiDs. Reactivation of salivary human herpes virus (HHV)-6 and HHV-7 was analyzed using real-time quantitative polymerase chain reaction (qPCR). CRF was evaluated using a visual analog scale (VAS). Eleven newly diagnosed multiple myeloma (NDMM) and five relapsed or refractory MM patients were enrolled in this study. The cumulative incidence of CRF was 54.9%. The treatment types were not associated with the CRF incidence. The cumulative incidence of reactivation of HHV-6 and HHV-7 was 73.1% and 45.6%, respectively. However, the reactivation of HHV-6 and HHV-7 was not related to CRF. The overall survival (OS) and progression-free survival (PFS) in NDMM patients with CRF was significantly shorter than in those without CRF. In conclusion, CRF was one of the major symptoms in MM patients, and predicted shorter OS and PFS in NDMM patients.

Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (LPDs) sometimes occur following Anti-thymocyte globulin (ATG) administration for allogenic stem cell transplantation but are rare in aplastic anemia (AA) patients. A 55-year-old woman with AA following ATG developed refractory fever and was diagnosed with EBV-LPD. She was successfully treated with weekly rituximab monotherapy; however, she developed EBV encephalitis. She was admitted to the intensive care unit and finally recovered from unconsciousness. EBV-LPD should be considered after ATG for AA when symptoms appear. Because EBV-LPD following ATG for AA can rapidly progress, weekly monitoring of EBV-DNA and early intervention may be necessary.

Introduction: Survival outcome of patients with multiple myeloma (MM) is heterogeneous because of different disease- and patient-related prognostic factors as well as in treatment-related factors. A survival benefit of continuous and maintenance (C/M) therapies after induction therapy in both transplant-eligible and -ineligible patients has been demonstrated in clinical trials. However, its usefulness is still to be clarified in the patients treated in routine clinical practice. Here, we report survival outcome of patients who received C/M therapy after induction therapy by analyzing the data of a multicenter retrospective study of the Japanese Society of Myeloma. Methods: Compiled clinical data of the patients diagnosed with MM and treated between 2013 and 2016 were analyzed retrospectively. Treatment decision whether or not to implement autologous stem cell transplantation (ASCT) was made at the discretion of a physician-in-charge. Treatment response was assessed by the investigators according to the International Myeloma Working Group uniform response criteria. Treatment decision to implement maintenance therapy after ASCT or to continue frontline treatment in non-transplanted patients was made based on the response to frontline treatment by the physician-in-charge. Patients were bifurcated using the propensity score methods in terms of age, gender, R-ISS stage, and commencement of ASCT to those who received C/M therapy and others without. Results: A total of 771 patients were enrolled. Among them, 216 patients received frontline C/M therapy, while the remaining 555 patients did not. In 720 patients who have achieved at least stable disease after induction therapy with or without ASCT, 161 patients of C/M group and another 161 patients of non-C/M group were matched according to the baseline covariates. Patient demographics and disease characteristics were well balanced between the matched set of patients (C/M vs non-C/M) in terms of median age (years, 65 vs 65), gender (male, 52% vs 53%), and R-ISS (stage I, 19% vs 20%; stage II, 70% vs 69%; and stage III, 11% vs 11%), respectively. ASCT were performed in 54% vs 54% in either group. C/M regimens included lenalidomide (n=73), bortezomib (n=35), ixazomib (n=9), elotuzumab (n=6), thalidomide (n=5), carfilzomib (n=2), combination of proteasome inhibitors and IMiDs (n=28), and others (n=3). Median PFS was significantly prolonged in the C/M group compared with the non-C/M group (37.7 vs 21.6 months, p=0.00017, Figure A). Median PFS in each of the two groups of the transplanted and non-transplanted patients were 40.5 vs 29.5 months (p=0.0063) and 24.6 vs 11.2 months (p=0.0013), respectively. For patients who have attained a CR after the frontline therapy, there was no significant difference in median PFS between the C/M and non-C/M groups (not reached vs 37.5 months, p=0.39). However, there was a significant prolongation of median PFS in the C/M group among those who did not achieve a CR (33.0 vs 19.2 months, p=0.006). Median OS was not reached in either groups, but it appeared to be longer in the C/M group than in the non-C/M group (p=0.061, Figure B). Although median OS of both groups were similar in the transplanted patients (p=0.56), there was a significant prolongation in the non-transplanted patients (58.1 months vs not reached, p=0.024). For those who have attained a CR, there was no significant difference in median OS between the C/M and non-C/M groups (p=0.29), but for those who did not achieve a CR, there was a significant prolongation of median OS in the C/M group (58.1 months vs not reached, p=0.048). A significant beneficial impact of C/M therapy on PFS and OS was observed in the R-ISS stage II and III patients but not in the stage I patients. In multivariate analysis, R-ISS stage, CR response after frontline therapy, ASCT, and C/M therapy were significant prognostic factors for PFS, whereas R-ISS and C/M therapy were associated with prolonged OS. Conclusions: C/M therapy had a beneficial impact on PFS and OS especially in patients with non-transplanted, non-CR response, and R-ISS stage II and III cohorts, but exerted less impact on standard-risk patients in our current clinical practice. Thus, C/M therapy is a key strategy for high-risk patients, but clarification of patients other than risk status who benefit from C/M therapy might be needed to further improve the prognosis of high-risk patients with MM. Disclosures Handa: Ono: Research Funding. Sunami:MSD: Research Funding; GSK: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Alexion-pharma: Research Funding; Janssen: Research Funding; Takeda: Honoraria, Research Funding; Sanofi: Research Funding; Daiichi Sankyo: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Suzuki:Ono: Research Funding; BMS: Honoraria, Research Funding; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Iida:Takeda: Honoraria, Research Funding; Sanofi: Research Funding; Gilead: Research Funding; Celgene: Honoraria, Research Funding; Daichi Sankyo: Honoraria, Research Funding; Kyowa Kirin: Research Funding; Abbvie: Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; MSD: Research Funding; Chugai: Research Funding; Janssen: Honoraria, Research Funding; Astellas: Research Funding; Teijin Pharma: Research Funding. Nishimura:Chugai-Roche Pharmaceuticals Co.,Ltd.: Consultancy; Celgene K.K.: Honoraria. Shimizu:Amgen: Consultancy; Fujimoto: Consultancy; Daiichi: Consultancy; Medical Biological Laboratory: Consultancy; Takeda: Speakers Bureau.

Background The phase 3 ICARIA study demonstrated that isatuximab (Isa) plus pomalidomide and dexamethasone (Pd) significantly improved progression free survival (PFS) compared with Pd in patients (pts) with relapsed/refractory multiple myeloma (RRMM) (HR = 0.596, 95%CI 0.44-0.81, P = 0.001). We evaluated the efficacy/safety of Isa-Pd in the East Asian pts (13 Japanese, 9 Korean and 14 Taiwanese pts) of ICARIA. Methods RRMM pts who had received ≥2 prior lines of therapies, including lenalidomide (len) and at least a proteasome inhibitor (PI), and were refractory to their last therapy were enrolled. Pts were randomized into either Isa-Pd arm who received Isa 10 mg/kg IV weekly for the first 4 weeks (wks) followed by biweekly or Pd arm, and all pts received Pom (4mg PO days 1-21) and dex (40mg [20mg if older than 75 yrs] PO or IV weekly) in 28 day cycle until disease progression or unacceptable toxicity. Results Data from 36 East Asian pts (21 Isa-Pd, 15 Pd) including Japanese pts (9 Isa-Pd, 4 Pd) were analyzed. Patient’s characteristics were similar in the East Asian subgroup and the entire population of ICARIA study (n = 307). Of these pts, median age: 65 (range, 41-85) yrs; median prior lines of therapy: 3 (range, 2-7); 91.7% and 69.4% were refractory to len and PI, respectively; and 13.9% had high-risk cytogenetics. After median follow-up of 11.6 months, median PFS was not reached yet in Isa-Pd arm and was 7.9 months in Pd arm (HR 0.517 [95% CI 0.19-1.39]). ORR (≥PR) was 71.4% in Isa-Pd arm 60% in Pd arm. The VGPR rate or better was 61.9% and 13.3% in Isa-Pd and Pd arm, respectively. Median time to first response was 32 days and 59 days for Isa-Pd and Pd arm, respectively. Grade ≥3 AEs were observed in 90.5% and 73.3% pts in Isa-Pd and Pd arm, respectively and which caused 9.5% pts in the Isa-Pd arm and 0 % in Pd arm to discontinue their treatment. Infusion associated reactions were reported in 57.1% pts receiving Isa-Pd but none of them were grade 3-4. Conclusions This subgroup analysis of ICARIA demonstrates that the efficacy and safety of Isa-Pd in East Asian population, including Japanese pts, are comparable with the entire population of ICARIA. Isa-Pd is a novel treatment option for East Asian pts with RRMM. Clinical trial identification Clinical trial information: NCT02990338. Legal entity responsible for the study Sanofi. Funding Sanofi. Disclosure K. Sunami: Speaker Bureau / Expert testimony: Sanofi; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: GlaxoSmithKline; Speaker Bureau / Expert testimony: Janssen Pharmaceutical. M. Matsumoto: Speaker Bureau / Expert testimony: Celgene Co., LTD; Speaker Bureau / Expert testimony: Janssen Pharmaceutical Co., LTD; Speaker Bureau / Expert testimony: Bristol-Myers Squibb K.K.; Speaker Bureau / Expert testimony: Ono Pharmaceutical Co., LTD. C. Shimazaki: Speaker Bureau / Expert testimony: Ono Pharmaceutical Co. Ltd.; Speaker Bureau / Expert testimony: Celgen Co. Ltd.; Speaker Bureau / Expert testimony: Fujimoto Pharmaceutical Co. Ltd. F. Campana: Full / Part-time employment: Sanofi. K. Tada: Full / Part-time employment: Sanofi. S. Iida: Speaker Bureau / Expert testimony: Ono; Speaker Bureau / Expert testimony: Janssen; Speaker Bureau / Expert testimony: Celgene; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: Takeda; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: Daiichi-Sankyo; Speaker Bureau / Expert testimony: Chugai; Speaker Bureau / Expert testimony: Kyowa Hakko Kirin; Speaker Bureau / Expert testimony: Sanofi; Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: Daiichi Sankyo; Speaker Bureau / Expert testimony: Gilead; Speaker Bureau / Expert testimony: AbbVie. K. Suzuki: Speaker Bureau / Expert testimony: Janssen; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: Celgene; Speaker Bureau / Expert testimony: Ono; Speaker Bureau / Expert testimony: Fujimoto; Speaker Bureau / Expert testimony: Takeda; Speaker Bureau / Expert testimony: Sumitomo Dainippon ; Speaker Bureau / Expert testimony: BMS; Speaker Bureau / Expert testimony: Sanofi. All other authors have declared no conflicts of interest.

Objective: Prognostic predictors for newly diagnosed malignant lymphoma are well known. However, they have not been compared for patients with recurrent or refractory malignant lymphoma. Methods: We retrospectively analyzed biological prognostic predictors for patients with recurrent or refractory aggressive lymphoma, such as serum levels of C-reactive protein, lactate dehydrogenase, hemoglobin, b2-microglobulin and soluble interleukin-2 receptor before salvage therapy. The primary endpoint was overall survival after salvage treatment. First, univariate and multivariate analyses were performed for each of the parameters, using the logrank test and Cox regression analysis, respectively. Secondly, we classified the patients into three risk groups on the basis of significant poor predictors. Results: Sixty-three patients, including 41 patients with diffuse large B-cell lymphoma, were included in this study. Overall survival was significantly worse in patients with elevated C-reactive protein level (hazard ratio 3.757; P ¼ 0.017), elevated lactate dehydrogenase level (hazard ratio 3.948; P ¼ 0.010) and anemia (hazard ratio 3.925; P ¼ 0.016) by multivariate analysis. We classified patients into two groups based on these three biological parameters. The median overall survival of the high- and low-risk patients was 5.8 and 60.1 months, respectively (log-rank test; P , 0.001). The overall response rate was significantly higher among the low-risk patients than among the high-risk patients (71.4 versus 28.6%, P ¼ 0.005). Those results were similar among all aggressive lymphoma and diffuse large B-cell lymphoma. Conclusions: Elevated C-reactive protein level, elevated lactate dehydrogenase level and anemia before salvage treatment predicted poorer outcomes among patients with recurrent or refractory aggressive lymphoma.

Tumor-lysis syndrome (TLS) describes a group of metabolic disturbances caused by the massive and abrupt release of cellular components into the blood after the rapid lysis of malignant cells. TLS is a potentially life-threatening complication in rapidly proliferating, bulky tumor, or highly chemo-radiosensitive cancers. In contrast, TLS is the rare complication among patients with multiple myeloma (MM). TLS seems to occur more frequently in MM patients receiving bortezomib (BOR) and carfilzomib (CFZ) than in those receiving other cytotoxic agents. We retrospectively investigated the frequency, risk factors, and clinical outcome among the relapsed or refractory MM (RRMM) patients treated with proteasome inhibitors (PI), such as BOR, CFZ, and ixazomib (IXA), in our institute. Between November 2005 and December 2017, seventy-two RRMM myeloma patients treated with BOR, CFZ, or IXA, in our institute. The number of patients treated PI was defined as below. Relapse or refractory disease and response criteria were defined according to the International Myeloma Working Group criteria. Patients with monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and primary plasma cell leukemia were excluded. We evaluated TLS by the Cario-Bishop grading classification. After starting of PI, the following parameters were recorded and evaluated for prognosis: serum hemoglobin concentration (Hb), serum level of lactate dehydrogenase (LDH), creatinine (Cr), uric acid (UA). The cutoff levels of LDH, Cr, and UA were the upper normal limit. Anemia was defined by the CRAB criteria. Hepatosplenomegaly and plasmacytoma were evaluated using computed tomography. We analyze these two groups in terms of patient characteristics, laboratory findings, response, and survival. Fisher's exact tests were used to compare differences between the two groups. We analyzed prognostic factors for survival in significant poor predictors of laboratory parameters and well-established prognostic factors by Cox regression analysis. Overall survival (OS) and time to next treatment (TTNT) were analyzed by the Kaplan-Meier method. Median age of the patients was 71 years (range, 41-86) at the time of PI treatment. Median number of prior treatments was 2 (range, 1-8). The number of patients treated 53 of BOR, 10 of IXA, 4 of BOR + CFZ, 3 of CFZ + IXA, 1 of BOR + IXA, and 1of BOR + CFZ + IXA, respectively. TLS occurred in 13 patients (18.1%); such as 8 of BOR (13.3%), 4 of CFZ (40.0%), and 1 of IXA (6.7%). TLS occurred more frequently in the patients treated with twice weekly CFZ plus dexamethasone (CFZ 56mg/m2) than twice weekly CFZ, lenalidomide, plus dexamethasone (CFZ 27mg/m2); 50% and 25%, respectively. Median day of TLS after PI was 8 (range, 4-21). Median day of TLS in BOR, CFZ, and IXA were 7.5, 5.5, and 13 days, respectively. Two patients received rasbricase after TLS occurred. There was no patient who underwent hemodialysis for TLS. The mortality related with TLS was none. The significant factors associated TLS were anemia, high LDH level, prior treatments of 2 or more and hepatosplenomegaly according to univariate analysis. In multivariate analysis, high LDH level (Odds ratio; 12.9, P=0.027) and hepatosplenomegaly (Odds ratio; 13.4, P=0.035) was related with TLS significantly. There was no significant difference between overall response rate in the TLS group and non-TLS group (46.4% vs 64.8%, P=0.117). In median follow-up was 12.9 months, the median TTNT of the TLS group was significantly shorter than that of the non-TLS group (1.9 vs 7.0 months, P = 0.009, Figure 1a). The median OS of the TLS group was significantly shorter than that of the non-TLS group as well (5.8 vs 46.4 months, P = 0.017, Figure 1b). Our analysis revealed that 18.1% of RRMM patients treated with PI developed TLS although TLS was manageable by prophylaxis.gh LDH level and hepatosplenomegaly were identified with significant risk factors for TLS. TLS was not associated with good response of treatment. The TTNT and OS in the TLS group was significantly shorter than those in the non-TLS group. We considered that TLS might be related with progressive disease without activity of treatment in RRMM patients treated with PI. Among the RRMM patients with high LDH level, TLS is one of common adverse events in first cycle of PI but tolerable. Disclosures No relevant conflicts of interest to declare.

Background: We recently reported that the International Prognostic Scoring System for Waldenström macroglobulinemia (ISSWM), which is widely used to predict the prognosis of WM patients, might not be applicable to Japanese patients, and evidence of pleural effusion might be a novel adverse prognostic factor for symptomatic WM in the rituximab era. Further studies with a large number of patients are deemed to be conducted. Methods: We retrospectively analyzed the clinical data of 498 patients with WM diagnosed between January 2001 and December 2015 from 44 institutes involved with the Japanese Society of Myeloma. The overall survival (OS) was analyzed using Kaplan-Meier methods and compared using log-rank test. Several clinical characteristics at the diagnosis were assessed by Cox regression for univariate and multivariate analyses of the OS. Results: We included 420 cases diagnosed with symptomatic (n=314) and asymptomatic WM (n=106) in accordance with the classification of the Second International Workshop on WM. The median age at the diagnosis was 69 (range, 32-91) years, with 75.5% male, and 16.0% had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 2-4. Oral alkylating agents, purine analogs, cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) or CHOP-like regimens ± rituximab, rituximab monotherapy, or dexamethasone, rituximab and cyclophosphamide (DRC) were mainly administered as initial treatment. Rituximab-containing therapy was administered in 76.8% of all patients. The median follow-up was 45 months. The 5-year OS rate for all patients was 77.9%, while the rates for those with symptomatic and asymptomatic WM were 72.9% and 92.2%, respectively. Significant differences in the survival were seen between risk groups of ISSWM in symptomatic WM patients (5-year OS: high, 55.4%; intermediate, 81.2%; low, 90.2%; p65 years, platelet count ≤10×104/µL, serum β2-microglobulin (β2-MG) >3 mg/L, ECOG PS 2-4, abnormal karyotype, pleural involvement, WBC 1.5 mg/dL, CRP >2.0 mg/dL and sIL-2R >4000 U/mL were significant adverse prognostic factors for the OS. A multivariate analysis revealed that a platelet count ≤10×104/µL (hazard ratio [HR] 5.942; 95% confidence interval [CI] 2.265-14.761), serum β2-MG >3 mg/L (HR 2.748; 95% CI 1.091-7.655), ECOG PS 2-4 (HR 2.899; 95% CI 1.219-6.290), and pleural involvement (HR 11.066; 95% CI 3.672-29.829) were adverse independent risk factors for symptomatic WM. We constructed a prognostic model by combining these prognostic variables as follows: patients with good risk (n=219), no adverse factors or only serum β2-MG >3 mg/L or ECOG PS 2-4; patients with poor risk (n=81), ≥1 adverse factors with a platelet count ≤10×104/µL, pleural involvement, or both serum β2-MG >3 mg/L and ECOG PS 2-4. The 5-year OS rates were 82.3% for good risk and 44.4% for poor risk, and this prognostic model significantly stratified symptomatic WM patients separately by the survival (p Conclusion: Although ISSWM may be useful for survival risk stratification in Japanese patients, we found that intermediate- and high-risk patients seemed to have a better prognosis than those in Western studies in the rituximab era (Dimopoulos MA, et al. Haematologica. 2008; 93: 1420-22). Thrombocytopenia and pleural involvement were found to be strong adverse prognostic factors in symptomatic WM, and our new prognostic index including them was easy to use in daily clinical practice and superior to ISSWM for detecting high-risk patients. Further studies are warranted to validate our prognostic index, especially in the era of novel agents. Disclosures Yamamoto: Bristol-Myers Squibb: Honoraria. Hagiwara:Celgene: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Sunami:Celgene: Honoraria, Research Funding; Sanofi: Research Funding; Janssen: Research Funding; Daiichi-Sankyo: Research Funding; Ono: Honoraria, Research Funding; Bristol-Myers Squibb K.K.: Honoraria, Research Funding; AbbVie: Research Funding; Takeda: Research Funding; MSD: Research Funding; GlaxoSmithKline: Research Funding; Novartis: Research Funding. Kurokawa:Teijin Pharma: Research Funding; Eizai: Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Chugai Pharmaceutical: Research Funding; Sumitomo Dainippon Pharma: Research Funding; Pfizer: Research Funding; Takeda Pharmaceutical: Research Funding; MSD: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Nippon Sinyaku: Honoraria, Research Funding; Astellas Pharma: Research Funding; Otsuka Pharmaceutical: Research Funding. Takamatsu:Janssen: Honoraria; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Ono: Research Funding. Ito:Bristol-Myers Squibb, Celgene: Honoraria. Tamura:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria; Takeda Pharmaceutical: Honoraria.

A 74-year-old man with multiple myeloma was refractory to melphalan/prednisolone (MP), high-dose dexamethasone and VAD chemotherapy. He had the following poor prognostic factors: 1) multiple extramedullary plasmacytomas, 2) massive myelomatous effusion, 3) increasing immature myeloma cells with plasmablastic morphology, and 4) predominance of MPC1-CD49e-CD45+ phenotype immature myeloma cells. Combination therapy with thalidomide and dexamethasone resulted in a rapid response and a partial remission despite his multiple poor prognostic factors. The present case suggests that combination therapy with thalidomide and dexamethasone is still an alternative treatment regimen for resistant extramedullary plasmacytoma with a plasmablastic morphology.

A once-daily modified release formulation of oral tacrolimus (Tac QD) has been developed in response to the problem of nonadherence. However, there have been no data available about the efficacy of Tac QD conversion from intravenous Tac (Tac i.v.) in allogeneic hematopoietic stem cell transplantation (allo-SCT). We analyzed the pharmacokinetics (PK) of Tac QD in allo-SCT recipients. A total of 10 patients with hematological malignancies who received allo-SCT from unrelated donors were enrolled. Patients received Tac i.v. at 0.03 mg/kg a day before transplantation. Administration of Tac i.v. was converted to Tac QD at a 1:4 ratio when the patients had recovered from regimen-related gastrointestinal toxicity and could tolerate oral medication. After conversion, six out of 10 patients (60 %) showed a sustained decrease in Tac exposure and required dose adjustment. The conversion from Tac i.v. to Tac QD should be performed under close medical supervision. Area under the curve (AUC) and the trough of Tac QD showed a correlation, and the trough should be maintained above 7.5 ng/ml to provide an adequate AUC. Although four patients received bone marrow from an HLA DRB1 1 antigen-mismatched unrelated donor, no patients developed grade III-IV acute graft-versus-host disease (GVHD). The modification of Tac QD to maintain a whole-blood trough concentration above 7.5 ng/ml may be as effective as Tac BID.

Objective: Tumor-lysis syndrome is a rare complication in patients with multiple myeloma. However, bortezomib treatment for myeloma is often associated with tumor-lysis syndrome. Methods: We developed an index called the rapid anemia progression index, which represents the duration and progression of anemia, to evaluate risk factors for tumor-lysis syndrome. We retrospectively reviewed 35 relapsed or refractory myeloma patients treated with bortezomibcontaining treatment in our institution. We analyzed various parameters, including albumin, lactase dehydrogenase, b2-microglobulin and creatinine, similar to the rapid anemia progression index, and evaluated the risk factors for tumor-lysis syndrome associated with bortezomib by the Cairo–Bishop definition. Results: Clinical tumor-lysis syndrome occurred in six patients (17.1%). Tumor-lysis syndrome occurred during the first course of bortezomib-containing treatment among all the patients. The result of the area under the receiver operating characteristic curve for the rapid anemia progression index was 0.759 (P ¼ 0.049). The rapid anemia progression index was more accurate than the index of lactate dehydrogenase, b2-microglobulin, albumin and creatinine according to the receiver operating characteristic curve. For a cut-off point of 21.12 for the rapid anemia progression index, the sensitivity and specificity were 66.7 and 82.8%, respectively. Conclusions: The rapid anemia progression index is related to clinical tumor-lysis syndrome associated with bortezomib treatment for multiple myeloma patients with a cut-off point of 21.12 g/dl/month.

Introduction Reactivation of HHV-6 and HHV-7 (HHV-6/7) are associated with encephalopathy, skin rush, institutional pneumonia, and cytopenia in patients with hematological malignancies. Our colleges in the department of virology reported that reactivation of saliva HHV-6/7 was measurable in healthy person and non-immunosuppressive patients although reactivation of serum HHV-6/7 was not detected. Hence determination of HHV-6/7 from salvia sample must be more sensitive than from serum sample. Clinical significance of reactivation of HHV-6/7 has not been well-analyzed in multiple myeloma (MM) patients treated with novel agents. Patients and Methods We prospectively analyzed saliva sample from MM patients treated with bortezomib (BOR), lenalidomide (LEN) or thalidomide from May 2013 to January 2016. Saliva sample was harvested on day 1 of each cycles. DNA copy numbers of HHV-6/7 in saliva samples were also measured using real-time PCR. We analyzed factors associated with reactivation of HHV-6/7 in univariate analysis by Fisher's exact test. We evaluated the correlation between HHV-6/7 ratio and M-protein ratio, which was calculated using DNA copy number of HHV-6/7 and M-protein level at each time points, by Pearson's product moment correlation coefficient. The cutoff value of reactivation of HHV-6 and HHV-7 were defined as 1 x103 and 1 x105 copy/mL. High and low corticosteroid (CS) groups were defined depending on daily estimated dose of predonisolone; the cutoff value was 100mg/body. Results One hundred and ninety-one saliva samples were collected from 20 patients. Median age was 69 years. Patients with newly diagnosed and relapsed or refractory MM were 14 and 6. Seventeen patients were treated with bortezomib (BOR) and 7 patients were treated with lenalidomide (LEN). All patients received either dexamethasone or predonisolone. The cumulative incidence of reactivation of HHV-6 and HHV-7 were 78.2% and 65.5%. High CS was related with reactivation of HHV-6 and HHV-7. LEN was related with only reactivation of HHV-7 while BOR did not induce reactivation of HHV-6/7. There was significant reverse correlation between HHV-7 ratio and M-protein ratio (r=-0.34, P Conclusion The cumulative incidence of reactivation of HHV-6/7 from salvia samples was relatively common in the MM patients treated with novel agents. High CS may induce reactivation of HHV-6/7. There was significant reverse correlation between HHV-7, but not HHV-6, ratio and M-protein ratio. DNA copy number of HHV-7 decreased before M protein elevated in patients who relapsed. The reason about the relationship between DNA copy number of HHV-7 and M-protein was not clear. We considered that reactivation of saliva HHV-7 might be associated with cytokines, and will evaluate the relationship between reactivation of saliva HHV-7 and cytokines in future. Disclosures Usui: Janssen Pharmaceutiical Co.Ltd: Consultancy; Celgene Co.Ltd: Consultancy, Honoraria, Research Funding.

Background —Little is known regarding intravascular ultrasound (IVUS) criteria to determine the functional severity of coronary stenosis. Recently, fractional flow reserve (FFR) has emerged as a lesion-specific index of the functional severity of a coronary stenosis that is independent of systemic hemodynamic variability. The present study was undertaken to determine the IVUS parameters for the physiological severity of coronary stenosis. Methods and Results —Fifty-one lesions in 42 patients were evaluated by means of quantitative coronary angiogram, IVUS, and intracoronary pressure measurements. The FFR was calculated as the ratio of the distal coronary pressure divided by the proximal coronary pressure under hyperemia. We considered a value of the FFR r 2 =0.62, P r 2 =0.60, P 2 (sensitivity, 83.0%; specificity, 92.3%) and area stenosis >0.6 (sensitivity, 92.0%; specificity, 88.5%). The combination of both criteria (MLA 2 and area stenosis Conclusions —Anatomic parameters obtained by IVUS showed a significant correlation to the FFR values. The present study demonstrated that the combination of the MLA and area stenosis measured by IVUS can be an anatomic predictor for the physiological impact of coronary epicardial stenosis.

The purpose of the present study was to evaluate the feasibility and efficacy of stenting following suboptimal percutaneous transluminal coronary angioplasty (PTCA) in angiographically small coronary arteries. The clinical and angiographic outcome of unplanned stenting in 33 patients with coronary arteries

The purpose of this study was to investigate prognostic factors for overall survival (OS) among patients with previously untreated diffuse large B-cell lymphoma (DLBCL) treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP). We evaluated four biological parameters, including thymidine kinase (TK) activity. This study included 183 patients. The median level of TK was 14.0 IU/L, which we chose as the cut-off. After a median follow-up time of 50.0 months, the OS rate at 4 years in the high and low TK arm were 46.7% and 66.7%, respectively (p = 0.001). By multivariate analysis, OS was significantly inferior in the high TK arm (hazard ratio 2.705; p = 0.045). The complete response (CR) rate in the high TK arm was significantly worse than in the low TK arm. OS was significantly better in patients who had achieved CR than in those with partial response or less. In conclusion, high TK activity was a strong predictor for short OS and poor response among patients with previously untreated DLBCL treated with R-CHOP.

The prognosis of patients with peripheral T-cell lymphoma (PTCL) treated with cyclophosphamide, adriamycin, vincristine and prednisone (CHOP) is poor, but their laboratory prognostic parameters had not previously been evaluated. We retrospectively reviewed 55 patients with newly diagnosed PTCL treated with CHOP from August 1999 to May 2009 at our institution. We analyzed six laboratory parameters, including thymidine kinase (TK) activity, to evaluate overall survival, which was the primary end-point. In multivariate analysis, the overall survival was significantly worse in patients with high TK activity (hazard ratio 34.8, 95% confidence interval [CI] 1.03–1176.23). The overall response rate among patients with high TK activity was 21.4%, significantly poorer compared with other parameters (p = 0.001). High TK activity predicts poor overall survival among patients with newly diagnosed PTCL treated with CHOP. Response to CHOP treatment is significantly decreased in patients with PTCL with high TK a...

e256 Our results demonstrate different immune and hormonal abnormalities in MM patient’s. We have focused attention on differences in male and female patients. Immune response in women tend to be more vigorous .CD3+,CD4+,CD19+ and NK-cells are lower in female patients than in males. In men decreased FSH, LH and significantly decreased T/E2 ratio with increased E2 and cortisol concentrations were found. Female patients with multiple myeloma demonstrated normal values of FSH, LH ,but a diminished E level and T/E2 ratio, with significantly elevated cortisol level. Conclusion: a significant cellular imuune dysfunction and hormonal imbalances were found in multiple myeloma patients. Which will improve the approaches of MM patients according to gender and facilitate the introduction and optimization of novel immunotherapeutic and hormonal agents.

Objective evaluation of the functional significance of individual stenosis in patients with multiple lesions is crucial when performing percutaneous coronary intervention (PCI). Here we propose a novel lesion-specific parameter, the epicardial resistance index (ERI), which is derived from intracoronary pressure measurements, and validate its clinical usefulness. The ERI is defined as the ratio of the resistance of an epicardial coronary stenosis to that of downstream myocardium. After obtaining intracoronary pressure data by pull-back of a 0.014″ pressure wire, the ERI was calculated as the trans-lesional pressure gradient divided by (Pd–Pv) at maximum hyperemia, where Pd = the mean distal coronary pressure in the absence of any stenosis and Pv = the central venous pressure. Using 170 measurements obtained from 75 patients, the correlation of ERI with parameters obtained from quantitative coronary angiography (QCA) and intravascular ultrasound (IVUS) was studied. ERI showed a significant correlation with the QCA-derived percent diameter stenosis (r = 0.67, P < 0.001), and with the IVUS-derived minimum luminal area (r = 0.68, P < 0.001). In 55 patients who underwent PCI with bare metal stents, a postprocedural target lesion ERI value greater than 0.16 strongly predicted the need for subsequent revascularization within six months (81% sensitivity and 80% specificity). The ERI is a useful pressure-derived hemodynamic parameter that correlates with anatomical parameters. In addition, the postprocedural resistance of the target lesion indicated by the ERI is a reliable predictor of the late outcome of PCI.

Background: Oral tacrolimus (Tac) was first developed as a twice-daily formulation (Tac BID) and has been widely used in solid organ and allogeneic hematopoietic stem cell transplantation (allo-SCT). Lifelong immunosuppression is required to preserve graft function after solid organ transplantation, and medical nonadherence of transplant recipients has been identified as a major cause of allograft failure. It has been well documented that frequent drug dosing affects patients' adherence. In response to this potential nonadherence problem, a once-daily modified release formulation of oral tacrolimus (Tac QD) has been developed. Results of randomized prospective phase III studies have indicated that Tac QD is well tolerated with similar efficacy and safety profiles as those of Tac BID in recipients after organ transplantation. Although Tac BID has been widely used in allo-SCT recipients, there are no available data on the use of Tac QD in this population. In this study, we compared retrospectively the efficacy of Tac QD versus Tac BID administration. The objective of this study was to investigate whether Tac QD is as effective as Tac BID in the setting of allo-SCT from unrelated donors. Methods: The study cohort included 77 consecutive patients who received allogeneic bone marrow transplantation from unrelated donors for treatment of hematologic malignancies between 2000 and 2014: AML (n=35), ALL (n=15), CML (n=8), MDS (n=12), NHL (n=5), and MPN (n=2). Patients received Tac iv from day -1 with short-term methotrexate (MTX) on days 1, 3, 6, and 11; Tac iv was converted to either Tac QD (n=37) or Tac BID (n=40) when the patients were engrafted and could tolerate oral medication. Doses were modified to maintain a whole-blood trough concentration of 8-12 ng/ml. Tac BID was administrated until Oct 2008, and Tac QD was used from Nov 2008. Kaplan-Meier estimates were used for overall survival (OS), and cumulative incidence estimates were used for acute GVHD, chronic GVHD, and non-relapse mortality (NRM). Results: Median age was 53 years (range: 23-66) for Tac QD cohorts and 39 years (range: 17-56) for Tac BID cohorts. Tac QD patients were older (P Conclusions: Although Tac QD cohorts included older patients than Tac BID cohorts, there was no difference in the risk of acute GVHD or chronic GVHD between Tac QD cohorts and BID cohorts. As Tac QD possibly contributes to reducing physical and mental stress for patients who need to take several different medications, our findings may indicate that the use of Tac QD for GVHD prophylaxis is beneficial for patients undergoing allo-SCT from unrelated donors. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Background: The use of imatinib in combination with chemotherapy has increased a complete remission (CR) rate and allows to receive allogeneic hematopoietic cell transplantation (HCT) for the patients with Philadelphia chromosome positive acute lymphoblastic leukemia (Ph + ALL). HCT is the standard of care for the eligible patients with Ph + ALL in first CR. We hypothesized that an intensified pre-transplant conditioning regimen might improve the outcome. The aim of this study was to assess the efficacy and safety of intensified conditioning regimen for the Ph + ALL patients who received imatinib-containing chemotherapy before HCT. Methods: We retrospectively analyzed the data of 12 patients with Ph + ALL in the first CR who underwent HCT in our hospital between 2003 and 2012. An intensified conditioning regimen consisted of total body irradiation (TBI) 10 Gy administered in 5 fractions, ETP 60mg/kg, and CY 120mg/kg. Results: The median time from achievement of CR to HCT was 4.1 months (range, 1.4-7.4 months). The median age at the time of HCT was 40 years (range, 30-52 years). Donors were related bone marrow or peripheral blood (n = 4), unrelated bone marrow (n = 5) or umbilical cord blood (n = 3). With a median follow-up of 4.3 years (range, 1.1-10.1 years), the probability of overall survival, relapse, and non-relapse mortality at 4 years were 91%, 18%, and 0%, respectively. All of the 7 patients who achieved molecular remission at the time of HCT remained alive in CR, whereas 2 of 5 patients who did not achieve molecular remission had relapse after HCT. Conclusions: Our results suggest that TBI and CY plus ETP might be a feasible and effective conditioning regimen for the Ph + ALL patients in the imatinib era, especially if the patients obtained molecular remission before HCT.