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Hemophagocytic lymphohistiocytosis (HLH) involves pathological histiocytes and phagocytosis of normal blood cells through activation of inflammatory cytokines. We report a case of Epstein-Barr virus-HLH in a 75-year-old woman who presented with fever, thrombocytopenia, and loss of consciousness. Epstein-Barr virus-HLH was diagnosed after we identified massive hemophagocytosis in bone marrow and Epstein-Barr virus DNA in cerebrospinal fluid. The HLH-2004 protocol was applied, and lactate dehydrogenase levels-which reflect HLH disease status-decreased. However, persistent loss of consciousness and multiple organ failure led to the patient' s death on day 18. Most cases of primary and secondary HLH involve pediatric patients; adult cases are rare. Few cases of central nervous system involvement in older adults have been reported. Therefore, accumulation of more data will help in developing better treatment strategies.

B7 homolog 1 (B7-H1)–expressing myeloma cells not only inhibit myeloma-specific cytotoxic T lymphocytes (CTL), but also confer a proliferative advantage: resistance to antimyeloma chemotherapy. However, it remains unknown whether B7-H1 expressed on myeloma cells induces cellular responses associated with aggressive myeloma behaviors. To address this question, we analyzed the proliferation and drug sensitivity of B7-H1–expressing myeloma cells transfected with B7-H1–specific short-hairpin RNA or treated with programmed cell death (PD)-1-Fc–coupled beads. Knockdown of B7-H1 expression in myeloma cells significantly inhibited cell proliferation and increased apoptosis induced by the chemotherapeutic alkylating agent melphalan, with downregulation of the expression of cell cycle–related genes (CCND3 and CDK6) and antiapoptotic genes (BCL2 and MCL1). B7-H1 molecules thus contributed to myeloma cell-cycle progression and suppression of drug-induced apoptosis. B7-H1–expressing myeloma cells had a higher affinity for PD-1 than for CD80. PD-1-Fc bead–treated myeloma cells also became resistant to apoptosis that was induced by melphalan and the proteasome inhibitor bortezomib. Apoptosis resistance was associated with the PI3K/AKT pathway. Both myeloma cell drug resistance and antiapoptotic responses occurred through the PI3K/AKT signaling pathway, initiated from “reverse” stimulation of B7-H1 by PD-1. Therefore, B7-H1 itself may function as an oncogenic protein in myeloma cells. The interaction between B7-H1 on myeloma cells and PD-1 molecules not only inhibits tumor-specific CTLs but also induces drug resistance in myeloma cells through the PI3K/AKT signaling pathway. These observations provide mechanistic insights into potential immunotherapeutic benefits of blocking the B7-H1–PD-1 pathway. Cancer Immunol Res; 4(9); 779–88. ©2016 AACR.

We previously showed that the interaction of programmed death-ligand 1 (PD-L1) on multiple myeloma (MM) cells with PD-1 not only inhibits tumor-specific cytotoxic T-lymphocyte activity via the PD-1 signaling pathway but also induces drug resistance via PD-L1–mediated reverse signals. We here examined the regulation of PD-L1 expression by immunomodulatory drugs (IMiDs) and antimyeloma effects of the anti–PD-L1 antibody durvalumab in combination with IMiDs. IMiDs induced PD-L1 expression on IMiD-insensitive MM cells and plasma cells from patients newly diagnosed with MM. Gene-expression profiling analysis demonstrated that not only PD-L1, but also a proliferation-inducing ligand (APRIL), was enhanced by IMiDs. PD-L1 induction by IMiDs was suppressed by using the APRIL inhibitor recombinant B-cell maturation antigen (BCMA)-Ig, the antibody against BCMA, or an MEK/ERK inhibitor in in vitro and in vivo assays. In addition, its induction was abrogated in cereblon (CRBN)-knockdown MM cells, whereas PD-L1 expression was increased and strongly induced by IMiDs in Ikaros-knockdown cells. These results demonstrated that PD-L1 upregulation by IMiDs on IMiD-insensitive MM cells was induced by (i) the BCMA–APRIL pathway via IMiD-mediated induction of APRIL and (ii) Ikaros degradation mediated by CRBN, which plays a role in inhibiting PD-L1 expression. Furthermore, T-cell inhibition induced by PD-L1–upregulated cells was effectively recovered after combination treatment with durvalumab and IMiDs. PD-L1 upregulation by IMiDs on MM cells might promote aggressive myeloma behaviors and immune escape in the bone marrow microenvironment.

Supplementary Materials and methods; Supplementary Table S1: Cell characteristics and phenotypes of MM cell lines; Supplementary Table S2: Characteristics of patients with newly diagnosed MM in Figure 1H; Supplementary Table S3: Primer and shRNA sequence; Supplementary Table S4: Four hundred four genes differentially expressed in MM cell lines treated with or without POM; Supplementary Figure S1: Antitumor effect of LEN and POM on MM cell lines; Supplementary Figure S2: Relationship of POM sensitivity with CRBN expression; Supplementary Figure S3: DNA copy numbers of PD-L1 in MM cell lines; Supplementary Figure S4: The level of cell-surface expression of PD-L2; Supplementary Figure S5: Cell-surface expression of BCMA and TACI on MM cell lines treated with IMiDs; Supplementary Figure S6: Enrichment plots for the gene sets of the MAPK/ERK pathway; Supplementary Figure S7: In vivo analysis using a murine xenograft model of human myeloma MM.1S cells inoculated into the flanks of NOG mice; Supplementary Figure S8: PD-L1 mRNA expression in CRBN-knockout and Ikaros- and Aiolos-knockdown cells after 3-day cultivation with LEN or POM; Supplementary Figure S9: Ikaros binding sites in the promoter of the PD-L1 gene; Supplementary Figure S10: Cell proliferation and T-cell activation of CD8+ T cells on day 4 when co-cultivation of T cells with untreated or LEN-pretreated U266 cells was treated with durvalumab and LEN; Supplementary Figure S11: APRIL protein and mRNA expression in CRBN-knockout and Ikaros- and Aiolos-knockdown MOSTI-1 cells after 3-day cultivation with LEN or POM.

Table S1. Primer sequences Table S2. Patient characteristics in cell - surface SLAMF3 and CD138 expression analysis. Table S3. One hundred and sixty-eight gene sets that were significantly upregulated in SLAMF3-KMS34 cells compared with Î"SLAMF3 cells (NOM P-value

Supplementary Table S1 Primer Sequence. Supplementary Figure S1. (A) Surface antigen expression and (B) Cell morphology of MOSTI-1 cells, and (C) drug sensitivity to melphalan and bortezomib of MOSTI-1, U266, and RPMI8226 cells. Supplementary Figure S2. Expression of cell cycle-related and antiapoptotic genes in B7-H1.KMS28-PE (B7-H1) and mock.KMS28-PE (mock) cells. Supplementary Figure S3. No effect of cell aggregation on drug sensitivity in MOSTI-1.

The MEAM regimen consisting of ranimustine (MCNU), etoposide (ETP), cytarabine (Ara-C), and melphalan (MEL) is widely used before auto-peripheral blood stem cell transplantation (auto-PBSCT) for malignant lymphoma in Japan. The MEAM regimen generally consists of 200-400 mg/mThe high-dose Ara-C MEAM protocol consisted of MCNU 300 mg/mAll patients got engraftment and there were no cases of treatment-related mortality. In all cases, the 3-year overall survival (OS) and progression-free survival (PFS) after transplantation were 80.6% and 65.7%, respectively. Twenty-one cases of diffuse large B-cell lymphoma recurrence, for which there is proven usefulness of auto-PBSCT, showed good results after transplantation, with the 3-year OS and PFS after transplantation being 100% and 74.3%, respectively.The safety and efficacy of high-dose Ara-C MEAM therapy were demonstrated, but the expected therapeutic effect on central nervous system lesions could not be fully evaluated owing to the small number of cases.

Histiocytic sarcoma is a relatively new disease category and the gastrointestinal origin is sporadic. We report a case of a 74-year-old woman who underwent chemotherapy and proximal gastrectomy for extremely rare, advanced gastric histiocytic sarcoma. The resected specimen was subjected to numerous immunostainings to meet the diagnostic criteria of histiocytic sarcoma and was positive for the histiocyte markers' cluster of differentiation 68 and lysozyme. The markers of Langerhans cells, follicular dendritic cells, and myelocyte were all negative. Six reports of surgical resection of histiocytic sarcoma originating in the stomach exist, including our case. We reviewed the clinical course and the histological and immunohistochemical diagnostic features of surgically resected gastric histiocytic sarcoma.

Background Peripheral blood stem cell (PBSC) collection places a burden on the patient and ideally should be completed in a single procedure. Consequently, a convenient predictive factor is needed for clinical use. Methods This retrospective study included 72 patients who underwent autologous PBSC collection. A median volume of 3.9×106 CD34-positive cells/kg (range: 0.3-47.4×106 cells/kg) was collected on the first day. We defined failure as an inability to collect 2.0×106 cells/kg on the first day. Patients were classified into failure (n = 25, 34.7%) and success groups (n = 47, 65.3%), and their clinical backgrounds were analyzed. Results The success group included a significantly larger number of cases in which a differential white blood cell count of the peripheral blood on the day of PBSC collection detected promyelocytes (n = 34, 72.3% vs. failure group: n = 11, 44.0%; P＝0.008). Sixty-two patients underwent autologous PBSC transplantation with a median of 5.6×106 transplanted cells/μL (range: 1.60-47.4×106 cells/μL). Among transplanted patients, no significant differences were observed between the success and failure groups in terms of the intervals until neutrophil, platelet, and red blood cell engraftment. Conclusion The presence of promyelocytes in peripheral blood may be a useful indicator of the optimal timing for single-step PBSC collection.

BACKGROUND Because the cause of liver dysfunction after allogeneic hematopoietic stem cell transplantation (HSCT) is difficult to identify in the early stages, treatment may be delayed. Therefore, early factors associated with unfavorable outcomes of liver dysfunction must be identified. The objective of this study was to identify unfavorable prognostic factors for liver dysfunction during the early period after transplantation. METHODS We defined liver dysfunction as elevated liver or biliary enzyme levels (corresponding to Grade 2 in the Common Terminology Criteria for Adverse Events version 4.0) within 30 days of transplantation and retrospectively investigated data from 82 patients who had undergone allogeneic HSCT at our center. RESULTS Elevated liver or biliary enzyme levels were observed in almost half of the patients studied (n=40, 48.7%). Elevated total bilirubin (T-Bil) level was the most frequently observed unfavorable prognostic factor and had the greatest effect on overall survival (OS), progression-free survival (PFS), and non-relapse mortality (NRM) (probability of unfavorable outcome in patients without and with elevated T-Bil level: OS, 58.9% vs. 15.4%, p < 0.001; PFS, 46.4% vs. 15.4%, p < 0.001; NRM, 10.7% vs. 53.8%, p < 0.001). Moreover, the probability of an unfavorable outcome increased in relation to the degree of T-Bil elevation and absence of improvement over time in T-Bil level. CONCLUSION Elevated T-Bil level was an important marker of outcomes for liver dysfunction after allogeneic HSCT.

In patients with hematologic malignancies, acute kidney injury (AKI) is the most common kidney complication requiring nephrologist consultation. Although the causes of AKI are multifactorial, primary tumor infiltration is rare in patients with acute myeloblastic leukemia (AML). This makes it challenging to determine the cause of AKI and the optimal chemotherapy regimen for AML. We describe two cases of AML (French-American-British classification: M2, M4) in patients with AKI requiring hemodialysis. We successfully identified the cause of AKI as primary leukemic infiltration and started induction chemotherapy in the setting of hemodialysis. This treatment significantly improved renal function and resulted in AML remission. In this report, we describe several clinical characteristics of AKI due to primary tumor infiltration. In addition, we emphasize the importance of onconephrology, a new subspecialty concerned with the complex relationship between the kidneys and cancer.

Cyclophosphamide (CY)-induced cardiotoxicity involves rare lethal complications. We previously reported the cardiac events of 811 allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients; 12 out of 811 recipients (1.5%) developed fatal heart failure. The mortality rate was also very high (91.6%, 11/12). CY dose (200 mg/kg or more) was reported as the independent risk factor. The main disease in patients treated with 200 mg/kg or more of CY was severe aplastic anemia (AA). Therefore, we reduced the dose of CY during conditioning for AA (from 200 to 100 mg/kg), and then we analyzed the clinical features of 294 patients who received a total dose of at least 100 mg/kg of CY. We also compared the clinical features between the current study and our previous study. The proportion of patients treated with at least 200 mg/kg of CY was reduced from 4.2% to 0%. However, CY-induced heart failure occurred in four of the 294 patients (1.4%), which was similar to the finding reported in our previous study (1.5%). Two of these four patients received a post-transplant CY (PTCy) regimen (CY 100 mg/kg). All four patients were treated in the cardiac intensive care unit (C-ICU), and two patients survived. In summary, even the CY dose of 120 mg/kg or less would cause cardiotoxicity. We should also carefully monitor patients treated with PTCy, considering the possibility of CY-induced cardiotoxicity. Early diagnosis and ICU management have contributed to improved outcomes.

Summary Background BCR-ABL1 tyrosine kinase inhibitors (TKIs) are commonly initiated in older patients with chronic myeloid leukaemia in the chronic phase at standard doses. However, because of their safety profile in this population, appropriate therapy has not been established. We aimed to investigate whether a lower than standard dose of dasatinib was an appropriate therapy for older patients with chronic myeloid leukaemia in the chronic phase. Methods DAsatinib, Very Low-dose, for Elderly CML-CP patients (DAVLEC) was a multicentre, single-arm, phase 2 trial done in 25 Japanese hospitals. We enrolled patients older than 70 years with newly diagnosed chronic myeloid leukaemia in the chronic phase, ECOG performance status 0–2, and no previous treatment for CML other than hydroxyurea within 4 weeks. Second-generation TKI dasatinib was given orally at a starting dose of 20% of the standard dose (20 mg/day). If the treatment was assessed as optimal response at 3 months, 6 months, and 9 months and adverse events were grade 2 or better (according to the NCI Common Toxicity Criteria v 4.0), the same dose was continued. If response was suboptimal and adverse events were grade 2 or better, the dose was increased by 20 mg/day. Once a dose reduction had been made because of a grade 3 or worse adverse event, there were no further dose increases. Treatment was discontinued if assessed as failure (disease progression to the accelerated phase or acute phase). The primary endpoint was the achievement of major molecular response at 12 months, assessed using a per-protocol analysis. This trial is registered at with the UMIN clinical trial registry, UMIN000024548, and has completed its planned observation period. Findings Between Nov 1, 2016, and Oct 30, 2019, 52 patients received first-line dasatinib therapy at 20 mg/day. The median age at diagnosis was 77·5 years (73·5–83·0). 35 (67%) patients were male and 17 (33%) were female. 31 (60%) of 52 patients reached major molecular response at 12 months (one-sided 95% CI 48–71), with a median follow-up of 366 days (IQR 353–372). Grade 3–4 adverse events were reported in 12 (23%) patients. Neutropenia was the most frequent grade 3–4 adverse event, occurring in three (6%) patients. No treatment-related deaths were observed. Interpretation Low-dose dasatinib at 20mg/day is worthy of consideration as a starting dose for older patients with newly diagnosed chronic myeloid leukaemia in the chronic phase. However, this dose needs to be further studied in a larger cohort and with a more ethnically diverse population. Funding Bristol-Myers Squibb.

We report the results of a multicenter observational study using the New TARGET system, in which the effectiveness and safety of tyrosine kinase inhibitors (TKIs) were evaluated in newly diagnosed chronic-phase chronic myeloid leukemia (CML) patients. A total of 506 patients were enrolled between April 2010 and March 2013. Median age was 56 (range 18–92) years; 35% of patients were females. As the first-line therapy, 139 (27.9%), 169 (33.9%) and 144 (28.9%) patients were treated with imatinib, nilotinib, and dasatinib, respectively. Five-year progression-free survival (PFS) and overall survival (OS) were 93.8% and 94.5%, respectively. The OS curve was significantly superior for patients treated with second-generation TKIs than imatinib (P = 0.0068), and an early molecular response (EMR) at 3 months (BCR-ABL1

Key Points CEBPA mutation in the bZIP domain is associated with favorable prognosis in de novo AML, even if it was detected as CEBPAsm., Visual Abstract, 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.

Background Epstein–Barr virus (EBV) is associated with the pathogenesis of a variety of malignancies, most notably lymphomas. Especially in the background of immunodeficiency, such as primary immunodeficiency disorder (PID) and post-transplant lymphoproliferative disorder (PTLD), the role of EBV might be crucial. PIDs are rare heterogeneous diseases affecting the development and/or the function of the innate and adaptive immune system. Malignancy is the second-highest cause of death after infection, and lymphoma accounts for about half of malignancies. The most frequently reported lymphoma type is diffuse large B-cell lymphoma (DLBCL) and the incidence of T-cell lymphoma is rare. PTLDs are also rare serious lymphoid and/or plasmacytic proliferative disorders that occur after undergoing solid organ or hematopoietic stem cell transplantation (HSCT). In the context of HSCT, most reported PTLDs have occurred in patients who received allogenic HSCT, but only a few cases have been reported in autologous HSCT (AutoHSCT) recipients. Case presentation A 53-year-old female patient initially presented with enlargement of the left cervical lymph nodes and was diagnosed with EBV-positive DLBCL. She was treated with R-CHOP, R-ACES, and AutoHSCT and went into remission. Four years later, computed tomography results revealed multiple lung nodules and abnormal infiltration, and sustained and progressing hypogammaglobulinemia was observed. The pathological specimen of video-assisted thoracoscopic surgical lung biopsy demonstrated extensive invasion of lymphocytes with notable granuloma findings. Flow cytometric immunophenotyping analysis showed that lymphocytes were positive for CD3 and CD5; especially, CD3 was expressed in the cytoplasm. Southern blot analysis revealed rearrangements of the T-cell receptor Cβ1 gene. She was diagnosed with peripheral T-cell lymphoma, not otherwise specified, accompanied by notable granulomatous lesions. Conclusion Here, as a unique case of metachronous B-cell and T-cell lymphoma, we report a rare case of T-cell lymphoma that mainly affected the lungs with the presentation of notable granulomatous findings following AutoHSCT for EBV-positive DLBCL at the age of 53 years. These lung lesions of granulomatous T-cell lymphoma could be related to the underlying primary immunodeficiency background associated with sustained hypogammaglobulinemia.

Reports have described the excellent efficacies of new immunotherapeutic strategies, such as monoclonal antibody (mAb) therapies, in multiple myeloma (MM) patients. Signaling lymphocytic activation molecule family (SLAMF) molecules are expressed strongly on normal lymphocytes and plasma cells from MM patients. The anti-SLAMF7 mAb elotuzumab (ELO) has been approved for the treatment of relapsed/refractory MM (RRMM). In MM patients, a high serum soluble SLAMF7 (sSLAMF7) concentration is associated with aggressive clinical characteristics. This suggests a proliferative function of the SLAMF7-sSLAMF7 interaction that could be inhibited by ELO. SLAMF3 is also expressed strongly and constitutively on myeloma cells. We observed the aggressive characteristics of SLAMF3

Background Post-transplant lymphoproliferative disorders (PTLDs) are serious lymphoid and/or plasmacytic proliferations that occur after undergoing solid organ or hematopoietic stem cell transplantation (HSCT). In the context of HSCT, most reported PTLDs have occurred in patients who received allogenic HSCT (AlloHSCT), but only a few cases have been reported in autologous HSCT (AHSCT) recipients. Primary pulmonary T-cell lymphoma cases are also rare and have been reported mostly in case studies. Case presentation: A 53-year-old female patient initially presented with enlargement of the left cervical lymph nodes and was diagnosed as Epstein–Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL). She was treated with R-CHOP, R-ACES, and autologous HSCT (AHSCT) and went into remission. Four years later, computed tomography results revealed multiple lung nodules, and abnormal infiltration and sustained and progressing hypogammaglobulinemia was observed. The pathological specimen of video-assisted thoracoscopic surgical lung biopsy demonstrated extensive invasion of lymphocytes with notable granuloma findings. Flow cytometric immunophenotyping analysis showed that lymphocytes were positive for CD3 and CD5; especially, CD3 was expressed in the cytoplasm. Southern blot analysis revealed rearrangements of the T-cell receptor Cβ1 gene. She was diagnosed with peripheral T-cell lymphoma, regarded as T-cell PTLD accompanied by granulomatous lesion. Conclusion Here, we report a rare case of T-cell lymphoma that mainly affected the lungs with the presentation of notable granulomatous findings following AHSCT against EBV-positive DLBCL. This uncommon presentation of rare lung lesions of granulomatous T-cell lymphoma could be related to the manifestation of a PTLD associated with sustained hypogammaglobulinemia.

The signaling lymphocytic activation molecule family 3 (SLAMF3) is highly expressed on plasma cells from patients with multiple myeloma (MM) and induces high malignant potential by ERK signaling mediated via the interaction with adaptor proteins SHP2 and GRB2. This study focused on the single-nucleotide polymorphism (SNP) of the SLAMF3 gene (rs509749, 1804A>G, M602V) in MM. The SNP G allele was a major type, and the frequencies of the GG, GA, and AA genotypes were 61.8%, 29.4%, and 8.8%, respectively, in patients with MM, which was almost the same as in healthy the control group in the Japanese population. Interestingly, patients with GG genotypes had significantly shorter overall survival times than patients with GA/AA genotypes. Consistent with those results, SLAMF3-overexpressing KMS-34 cells with the G allele (V602) had higher cell proliferation potential and were more resistant to anti-MM agents than those with the A allele (M602). When those cells were subcutaneously inoculated into NOG mice, tumor sizes in mice receiving V602 cells rapidly increased, and survival was significantly shorter than in mice injected with M602 cells. Furthermore, SLAMF3 V602 molecules bound more tightly to SHP2 and GRB2, with increased SHP2 and ERK phosphorylation compared with M602 cells. The mRNA expression of cell cycle-related genes (CCND1 and CCNE1) and anti-apoptotic genes (BCL2L and p21) was increased in V602 cells compared with M602 cells. The results thus suggested that the G allele of SLAMF3 SNP rs509749 may be associated with MM disease progression.

PD-L1 expressed on tumor cells contributes to disease progression with evasion from tumor immunity. Plasma cells from multiple myeloma (MM) patients expressed higher levels of PD-L1 compared with healthy volunteers and monoclonal gammopathy of undetermined significance (MGUS) patients, and its expression is significantly upregulated in relapsed/refractory patients. Furthermore, high PD-L1 expression is induced by the myeloma microenvironment and PD-L1+ patients with MGUS and asymptomatic MM tend to show disease progression. PD-L1 expression on myeloma cells was associated with more proliferative potential and resistance to antimyeloma agents because of activation of the Akt pathway through PD-1-bound PD-L1 in MM cells. Those data suggest that PD-L1 plays a crucial role in the disease progression of MM.

We previously showed that the interaction of programmed death-ligand 1 (PD-L1) on multiple myeloma (MM) cells with PD-1 not only inhibits tumor-specific cytotoxic T-lymphocyte activity via the PD-1 signaling pathway but also induces drug resistance via PD-L1–mediated reverse signals. We here examined the regulation of PD-L1 expression by immunomodulatory drugs (IMiDs) and antimyeloma effects of the anti–PD-L1 antibody durvalumab in combination with IMiDs. IMiDs induced PD-L1 expression on IMiD-insensitive MM cells and plasma cells from patients newly diagnosed with MM. Gene-expression profiling analysis demonstrated that not only PD-L1, but also a proliferation-inducing ligand (APRIL), was enhanced by IMiDs. PD-L1 induction by IMiDs was suppressed by using the APRIL inhibitor recombinant B-cell maturation antigen (BCMA)-Ig, the antibody against BCMA, or an MEK/ERK inhibitor in in vitro and in vivo assays. In addition, its induction was abrogated in cereblon (CRBN)-knockdown MM cells, whereas PD-L1 expression was increased and strongly induced by IMiDs in Ikaros-knockdown cells. These results demonstrated that PD-L1 upregulation by IMiDs on IMiD-insensitive MM cells was induced by (i) the BCMA–APRIL pathway via IMiD-mediated induction of APRIL and (ii) Ikaros degradation mediated by CRBN, which plays a role in inhibiting PD-L1 expression. Furthermore, T-cell inhibition induced by PD-L1–upregulated cells was effectively recovered after combination treatment with durvalumab and IMiDs. PD-L1 upregulation by IMiDs on MM cells might promote aggressive myeloma behaviors and immune escape in the bone marrow microenvironment.

Myeloproliferative neoplasms (MPNs) including polycythemia vera (PV) and essential thrombocythemia (ET) have an increased risk of ischemic stroke. However, little is known about brain morphological changes and the cerebral vasculature in MPNs. The aim of the present study is to clarify the prevalence rates of brain infarcts (BIs) on magnetic resonance imaging (MRI) and to assess the detailed clinical and MRI characteristics in those patients.We prospectively enrolled patients with MPNs who underwent brain MRI between September 2017 and June 2019. BI patterns were characterized by the numbers and locations of BIs on MRI.A total of 101 patients were included in the present study. BIs were observed in 23 patients (23%). Multiple logistic regression analysis showed that age 60 years (odds ratio (OR) 7.34, 95% confidence interval (CI) 1.08-49.7, p = .041) and history of thrombosis (OR 40.6, 95% CI 7.97-207, p .0001) were independently associated with BIs, but not the JAK2V617F mutation. Of the 23 patients with BIs, eight patients (35%) had multiple territorial infarcts, and large vessel involvement was identified in five patients (22%). Two patients had thrombus formation in large vessels.Among patients with MPNs who underwent MRI, BIs were observed in 23% of patients followed up in our center. Older age and thrombosis history were independently associated with BIs. Some patients with MPNs may present with distinctive MRI findings including multiple territorial infarcts and thrombus formation in large vessels.

We evaluated the impact of FLT3-ITD, NPM1 mutations, and double mutant CEBPa (dmCEBPa) on overall survival (OS) after relapse in patients with cytogenetically intermediate-risk acute myeloid leukemia (AML) who were treated with chemotherapy alone in the first remission (CR1). Patients aged 16–65 years diagnosed with cytogenetically intermediate-risk AML, and who achieved CR1 were included. We retrospectively analyzed FLT3-ITD, NPM1 mutations and CEBPa using samples obtained at diagnosis, which therefore did not affect the therapeutic decisions. Among 235 patients who had achieved CR1, 152 relapsed, and 52% of them achieved second CR. The rate of achieving second CR was significantly higher (85%) in those with dmCEBPa. Patients with FLT3-ITD had significantly worse OS after relapse than those without (19% vs 41%, p = 0.002), while OS was comparable between patients with and without NPM1 mutations (37% vs 34%, p = 0.309). Patients with dmCEBPa had improved OS than those without (61% vs 32%, p = 0.006). By multivariate analysis, FLT3-ITD was independently associated with worse OS after relapse [hazard ratio (HR) 1.99, 95% CI 1.27–3.12, p = 0.003], and dmCEBPa with improved OS (HR 0.40, 95% CI 0.17–0.93, p = 0.033). Our data show that screening for these mutations at diagnosis is useful for facilitating effective therapeutic decision-making even after relapse.

This study presents the final report of the multicenter, prospective tyrosine kinase inhibitor discontinuation study, D‐STOP, after a 3‐year follow‐up of 54 patients with chronic CML who discontinued dasatinib after a sustained deep molecular response (DMR) for ≥2 years with dasatinib treatment. Estimated treatment‐free remission (TFR) rates at 12 and 36 months were 63.0% [95% confidence interval (CI): 48.7‐74.3] and 59.3% (95% CI: 45.0‐71.0), respectively. CD3−CD56+ NK, CD16+CD56+ NK, and CD57+CD56+ NK large granular lymphocyte (NK‐LGL), CD8+CD4– cytotoxic T cell, and CD57+CD3+ T‐LGL cell numbers were relatively elevated throughout the 24‐month consolidation only in failed patients who molecularly relapsed within 12 months. In successful patients, these subsets elevated transiently after 12 months, but returned to basal levels after 24‐month consolidation. Therefore, smaller changes in NK/T, particularly the NK subset throughout consolidation, reflected higher TFR rates. TFR rates of those patients exhibiting elevation in CD3−CD56+ NK >376 cells/μL, CD16+CD56+ NK > 241 cells/μL, or CD57+CD56+ NK‐LGL >242 cells/μL during consolidation compared with others were 26.7% (8.3%‐49.6%) vs 78.3% (55.4%‐90.3%), HR 0.032 (0.0027‐0.38; P = .0064), 31.2% (11.4%‐53.6%) vs 85.0% (60.4%‐94.9%), HR 0.039 (0.0031‐0.48; P = .011), or 36.8% (16.5%‐57.5%) vs 77.3% (53.7%‐89.8%), HR 0.21 (0.065‐0.69; P = .010), respectively. Therefore, silent responses of T/NK subsets to dasatinib throughout consolidation were significant for longer TFR. Elevated NK/T, particularly NK lymphocytes responsive to dasatinib, may be immunologically insufficient to maintain TFR. Their decline, subsequently replaced by altered lymphocyte population with less response to dasatinib during sustained DMR, might be immunologically significant. (D‐STOP, NCT01627132)., The figure shows that silent NK/T cell reactions against dasatinib, particularly that of NK cells, during sustained DMR before dasatinib discontinuation are significant for longer treatment‐free remission.

Background Treatment-free remission (TFR), the ability to maintain a molecular response (MR), occurs in approximately 50% of patients with chronic myelogenous leukemia (CML) treated with tyrosine kinase inhibitors (TKIs). Methods A multicenter phase 2 trial (Delightedly Overcome CML Expert Stop TKI Trial: DOMEST Trial) was conducted to test the safety and efficacy of discontinuing imatinib. Patients with CML with a sustained MR of 4.0 or MR4.0-equivalent for at least 2 years and confirmed MR4.0 at the beginning of the study were enrolled. In the TFR phase, the international scale (IS) was regularly monitored by IS-PCR testing. Molecular recurrence was defined as the loss of MR4.0. Recurrent patients were immediately treated with dasatinib or other TKIs including imatinib. Results Of 110 enrolled patients, 99 were evaluable. The median time from diagnosis to discontinuation of imatinib was 103 months, and the median duration of imatinib therapy was 100 months. Molecular recurrence-free survival rates were 69.6%, 68.6% and 64.3% at 6, 12, and 24 months, respectively. After discontinuation of imatinib therapy, 26 patients showed molecular recurrence, and 25 re-achieved deep MR after dasatinib treatment. Molecular response MR4.0 was achieved in 23 patients within 6 months and 25 patients within 12 months. Multivariate analysis revealed that a longer time from diagnosis to discontinuation of imatinib therapy (p = 0.0002) and long duration of imatinib therapy (p = 0.0029) predicted a favorable prognosis. Conclusions This DOMEST Trial showed the feasibility of TKI discontinuation in a Japanese clinical setting.

In the opinion of the European LeukemiaNet (ELN), nucleophosmin member 1 gene mutation (NPM1 mut)–positive acute myeloid leukemia (AML) with an fms-like kinase 3-internal tandem duplication (FLT3-ITD) allele ratio (AR)

The signaling lymphocytic activation molecule family (SLAMF7; also known as CS1 or CD319) is highly expressed on plasma cells from multiple myeloma (MM) as well as natural killer (NK) cells and is a well-known therapeutic target of elotuzumab. The objective of this study was to evaluate the clinical significance of serum soluble SLAMF7 (sSLAMF7) levels in patients with MM (n=103) and furthermore the impact of sSLMF7 on the antitumor activity of anti-SLAMF7 antibody. Thirty-one percent of MM patients, but not patients with monoclonal gammopathy of undetermined significance and healthy controls, had detectable levels of serum sSLAMF7, which were significantly increased in advanced MM patients. Further, MM in sSLAMF7-postive patients exhibited aggressive clinical characteristics with shorter progression-free survival times in comparison with sSLAMF7-negative patients. In responders to MM therapy, the levels of sSLAMF7 were undetectable or decreased compared with those before treatment. In addition, the anti-SLAMF7 antibody-mediated antibody-dependent cellular cytotoxicity of NK cells against MM cell lines was inhibited by recombinant SLAMF7 protein. Thus, our findings suggest that high concentrations of sSLAMF7, which could transiently suppress the therapeutic effects of elotuzumab, may be a useful indicator of disease progression in MM patients.

A 73-year-old man presented with right lower back pain and dysuria. Right hydronephrosis and a large pelvic large mass were seen on computed tomography (CT). Although his prostate-specific antigen (PSA) was 0.5 ng/mL, an irregularly enlarged, stony, hard prostate was palpable on digital rectal examination. A prostate tumor was suspected, and a transrectal prostate biopsy and right transurethral ureteral stent placement were performed. Histological and immunohistochemical studies revealed diffuse large B-cell lymphoma. Positron emission tomography-computed tomography showed abnormal uptake in the stomach, cecum, right obturator lymph nodes, para-aortic lymph nodes, and dorsal left kidney. No abnormal findings were seen on bone marrow histology. Clinical stage IVA was confirmed according to Ann Arbor criteria. The patient achieved a complete response after 8 cycles of combination chemotherapy with rituximab, pirarubicin, cyclophosphamide, vincristine, and prednisolone.

BCOR gene is a transcription regulatory factor that plays an essential role in normal hematopoiesis. The wider introduction of next-generation sequencing technology has led to reports in recent years of mutations in the BCOR gene in acute myeloid leukemia (AML), but the related clinical characteristics and prognosis are not sufficiently understood. We investigated the clinical characteristics and prognosis of 377 de novo AML cases with BCOR or BCORL1 mutation. BCOR or BCORL1 gene mutations were found in 28 cases (7.4%). Among cases aged 65 years or below that were also FLT3-ITD-negative and in the intermediate cytogenetic prognosis group, BCOR or BCORL1 gene mutations were observed in 11% of cases (12 of 111 cases), and this group had significantly lower 5-year overall survival (OS) (13.6% vs. 55.0%, P = 0.0021) and relapse-free survival (RFS) (14.3% vs. 44.5%, P = 0.0168) compared to cases without BCOR or BCORL1 gene mutations. Multivariate analysis demonstrated that BCOR mutations were an independent unfavorable prognostic factor (P = 0.0038, P = 0.0463) for both OS and RFS. In cases of AML that are FLT3-ITD-negative, aged 65 years or below, and in the intermediate cytogenetic prognosis group, which are considered to have relatively favorable prognosis, BCOR gene mutations appear to be an important prognostic factor.

We analyzed the clinical responses to thyrosine kinase inhibitors (TKIs) and the molecular and cytogenetic characteristics of 18 chronic myeloid leukemia (CML) patients with 3-way chromosomal translocations. The patients were 14 men and 4 women, aged 23-75 years (median 57 years). The Sokal risk was low in 12 patients, intermediate in 4 patients, and high in 2 patients. Newly identified translocation breakpoints were seen in 7 of the 18 patients. Three patients had the same breakpoints of t(9;22;11)(q34;q11.2;q23). The best responses to TKIs were partial cytogenic response (PCyR) in 2 patients, complete cytogenic response (CCyR) in 3 patients, molecular response (MR) 3.0 in 7 patients, MR 4.0 in 3 patients, and MR 4.5 or higher in 3 patients. A total of 66.7% of patients did not achieve MR 4.0 or higher. In 3 patients in whom TKIs resulted in MR 4.5 or higher for more than 2 years, TKI treatment was discontinued. However, all of them exhibited a loss of MR3.0, at 2, 6, and 20 months after the discontinuation of treatment, respectively, and TKI treatment needed to be restarted. According to Kaplan-Meier survival curve analysis, the overall survival (OS) was 100 months in 56% of the patients. The 60-months cumulative incidences of CCyR, MR3.0, MR4.0 and MR4.5 were 88.9%, 72.2%, 33.3%, and 16.7%, respectively. In the 11 analyzable patients, the BCR-ABL1 mRNA subtype was e14a2 type in 4 patients and e13a2 type in 7 patients.

Objective The aim of this study was to prospectively investigate the efficacy and safety profiles of low-dose dasatinib therapy (50 mg once daily). Methods Patients with chronic myeloid leukemia in the chronic phase (CML-CP) who were being treated with low-dose imatinib (≤200 mg/day), but were resistant to this agent were enrolled in the current study (referred to as the LD-CML study). Results There subjects included 9 patients (4 men and 5 women); all were treated with dasatinib at a dose of 50 mg once daily. Among 8 patients who had not experienced major molecular response (MMR; BCR-ABL1 transcript ≤0.1% according to International Scale [IS]) at study enrollment, 5 attained MMR by 12 months. In particular, 3 of 9 patients demonstrated a deep molecular response (DMR; IS ≤0.0069%) by 18 months. Five patients developed lymphocytosis accompanied by cytotoxic lymphocyte predominance. There was no mortality or disease progression, and all continue to receive dasatinib therapy at 18 months with only 2 patients requiring dose reduction. Toxicities were mild-to-moderate, and pleural effusion was observed in 1 patient (grade 1). Conclusion Low-dose dasatinib can attain MMR and DMR without severe toxicity in patients with CML-CP who are unable to achieve MMR with low-dose imatinib. Switching to low-dose dasatinib should therefore be considered for patients in this setting, especially if they are otherwise considering a cessation of treatment.

Introduction: Tyrosine kinase inhibitors (TKIs) dramatically improved the prognosis of chronic myelogenous leukemia (CML), as nearly half of CML patients presenting with a deep molecular response (DMR) over several years could achieve treatment-free remission. DASISION study reported dasatinib (DAS), a second-generation TKI was superior to imatinib to achieve faster and deeper response in treating newly-diagnosed chronic CML. However, standard initial dosage of 100 mg DAS/day might be too potent for patients aged >70 years with CML, possibly owing to the presence of other health conditions that threaten the life spans (e.g., lung and cardiovascular disease), thereby preventing TKI continuation. In this open-label, multicenter, single-arm, phase 2 study (DAVLEC), we evaluated the efficacy and safety of a reduced initial dose of DAS (20 mg/day) in the elderly with chronic CML. Patients and Methods: We included CML patients aged >70 years with an ECOG performance status of 0-2 and adequate organ function. After diagnosis, they began orally taking 20 mg of DAS per day. BCR-ABL mRNA values were measured and aligned to an international scale at a central laboratory to evaluate the drug's efficacy at 3, 6, 9, and 12 mo of therapy, per recommendations by European LeukemiaNet. The dosage was maintained in case of the optimal, increased by 20 mg/day when the warning appeared and could be decreased when an adverse event (AE) > grade 3 appeared. Patients were excluded if the respond was the failure or disease progression was detected. Primary endpoint was the cumulative major molecular response (MMR) rate at 12 mo. Secondary endpoints included the rates of the cumulative DMR, treatment discontinuation due to AEs, and failure to DAS treatment or disease progression. The non-inferiority of primary endpoint MMR (non-inferiority limit of 38%) was evaluated by binomial test with normal approximation. Other differences were investigated by Mann-Whitney tests, with p < 0.05 indicating significance. Results: Among the 56 patients enrolled from 25 centers, 4 declined participation, and so 52 (median age, 77.5 years) began taking 20 mg/day of DAS. In total, 73.1% of the patients had comorbidities. Median BCR-ABL values at 3, 6, and 12 mo were 1.47%, 0.23%, and 0.03%, respectively; cumulative MMR rate at 3, 6, 9, and 12 mo were 11.5%, 36.5%, 40.4%, and 59.6%, respectively. Calculated MMR at 12 mo was higher than 38%, a value selected based upon findings from the DASISION trial, accounting for a non-inferiority margin of 10% (p=0.047). At 12 mo, among the 31 patients achieving MMR, 23 were only given 20 mg DAS/day, and 14 and 7 respectively achieved MR4.0 and 4.5. Patients discontinued the study due to treatment failure (n=3), content withdrawal (n=2), drug-related AEs (Long QT Syndrome; n=1), or others (n=2). No patient discontinued it due to disease progression. Treatment-related AEs of all grades were noted in 96.2%and that of grade 3 or 4 events in 23.1% of the patients. Median dose interruptions for a median of 7 days (range: 5-36) were respectively noted in 3 and 2 patients due to hematological and non-hematological AEs. Furthermore, 4 patients experienced pleural effusion < grade 2, and 1 had lymphocytosis. Patients who achieved MMR at 12 mo (n=31) had a significantly lower BCR-ABL value at 3 mo (0.41% vs. 4.26%, p=0.0020) and a lower halving time from diagnosis to 3 mo (11.35 vs. 18.34 days, p=0.0050) than those who did not (n=21). Patients who achieved MMR by 12 mo with only 20 mg/day of DAS (n=23) had lower BCR-ABL values at 1 and 3 mo (25.51 vs. 63.63 %, p=0.00028; 0.33 vs. 5.89%, p Patients who achieved MMR at 12 mo (n=31) had higher plasma DAS concentration (23.5 vs. 8.0 ng/mL, p Conclusion: This study discovered that prescribing a starting very-low dose DAS (20 mg/day) while monitoring IS and AEs was a successful initial therapeutic strategy for the elderly with chronic CML comparable to previous studies using standard-dose. Notably, rapid BCR-ABL downregulation, early molecular responses at 1 and 3 mo, a shortened halving time from diagnosis to 3 mo, and sufficient increase in plasma DAS concentrations 2 h post-intake after 12 mo of treatment were key indicators for successful low-dose therapy. Disclosures Kumagai: Bristol-Myers Squibb: Honoraria; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria; Otsuka Pharmaceuticals: Honoraria, Speakers Bureau. Murai: Bristol Myers Squibb: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Novartis Pharma: Honoraria; Pfizer: Honoraria; CHUGAI Pharmaceutical Co., Ltd.: Honoraria; TAKEDA Pharmaceutical Co., Ltd.: Honoraria; DAIICHI SANKYO COMPANY, LIMITED.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria; Asahi Kasei Pharma Corporation.: Honoraria. Tanaka: Bristol-Myers Squibb: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Otsuka Pharmaceuticals: Honoraria. Nishiwaki: Kyowa-Kirin: Research Funding; Alexion: Honoraria. Inokuchi: Bristol-Myers Squibb: Research Funding. Yoshida: Bristol-Myers Squibb: Honoraria, Research Funding; Novartis KK,: Honoraria; Pfizer Japan Inc.: Honoraria; Otsuka Pharmaceutical.: Honoraria; AbbVie GK: Honoraria; Janssen Pharmaceutical KK: Honoraria; Nippon Shinyaku: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria. Uoshima: Janssen: Honoraria; Eisai: Honoraria. Usuki: MSD K.K.: Research Funding, Speakers Bureau; Eisai Co., Ltd.: Speakers Bureau; Alexion Pharmaceuticals, Inc.: Research Funding, Speakers Bureau; Pfizer Japan Inc.: Research Funding, Speakers Bureau; Kyowa-Kirin Co., Ltd.: Research Funding, Speakers Bureau; Nippon-Shinyaku Co., Ltd.: Research Funding, Speakers Bureau; Amgen-Astellas Biopharma K.K.: Research Funding; Mundipharma K.K.: Research Funding; Nippon-Boehringer-Ingelheim Co., Ltd.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Celgene K.K.: Research Funding, Speakers Bureau; Janssen Pharmaceutical K.K.: Research Funding; Ono Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Novartis Pharma K.K.: Research Funding, Speakers Bureau; Otsuka Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Sumitomo-Dainippon Pharma Co., Ltd.: Research Funding; Daiichi Sankyo Co., Ltd.: Research Funding, Speakers Bureau; SymBio Pharmaceuticals Ltd.: Research Funding, Speakers Bureau; Gilead Sciences, Inc.: Research Funding; AbbVie GK: Research Funding, Speakers Bureau; Astellas Pharma Inc.: Research Funding, Speakers Bureau; PharmaEssentia Japan KK: Research Funding, Speakers Bureau; Yakult Honsha Co., Ltd.: Research Funding, Speakers Bureau; Bristol-Myers-Squibb K.K.: Research Funding, Speakers Bureau; Apellis Pharmaceuticals, Inc.: Research Funding; Incyte Biosciences Japan G.K.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Sanofi K.K.: Speakers Bureau; Amgen K.K.: Research Funding. Kuroda: Otsuka Pharmaceutical: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; MSD: Research Funding; Abbvie: Consultancy, Honoraria; Ono Pharmaceutical: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Sysmex: Research Funding; Pfizer: Honoraria, Research Funding; Fujimoto Pharmaceutical: Current Employment, Honoraria, Research Funding; Taiho Pharmaceutical: Research Funding; Asahi Kasei: Research Funding; Shionogi: Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Janssen Pharmaceutical K.K: Consultancy; Bristol-MyersSquibb: Consultancy, Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Dainippon Sumitomo Pharma: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding. Ono: Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Kyowa Kirin Co., Ltd.: Honoraria, Research Funding; Novartis Pharma KK: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; DAIICHI SANKYO COMPANY, LIMITED.: Honoraria; Mundipharma K.K.: Honoraria; TAIHO PHARMACEUTICAL CO., LTD.: Research Funding; Merck Sharp & Dohme: Honoraria, Research Funding; Astellas Pharma Inc.: Honoraria; Eisai Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria, Research Funding; Pfizer Japan Inc.: Honoraria; Bristol-Myers Squibb Company: Honoraria; Celgene: Honoraria, Research Funding. Fujimaki: CSL Behring K.K.: Honoraria; Mundipharma K.K.: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Meiji Seika Pharma Co., Ltd.: Honoraria; Janssen Pharmaceutical KK: Honoraria; AbbVie GK: Honoraria; Bristol-Myers Squibb: Honoraria; Novartis KK: Honoraria; Nippon Shinyaku: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Pfizer Japan Inc.: Honoraria; Otsuka Pharmaceutical.: Honoraria. Shibayama: Chugai: Research Funding; Eizai: Speakers Bureau; Nippon Shinyaku: Speakers Bureau; Kyowa Kirin: Speakers Bureau; AbbVie: Research Funding; Celgene: Research Funding; Novartis: Research Funding, Speakers Bureau; Ono: Research Funding, Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Mundi Pharma: Speakers Bureau; Otsuka: Speakers Bureau; Sanofi: Research Funding, Speakers Bureau; AstraZeneca: Research Funding, Speakers Bureau; Takeda: Speakers Bureau. Kondo: Abbvie: Honoraria; Astellas Pharma Inc.: Consultancy, Honoraria; Otsuka Pharmaceutical: Consultancy, Honoraria, Research Funding; Novartis Pharma KK: Honoraria; Bristol-Myers Squibb Company: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Sanwa Kagaku Kenkyusho CO.,LTD: Consultancy; Pfizer: Honoraria. Minami: Bristol-Myers Squibb Company: Honoraria; Novartis Pharma KK: Honoraria; Pfizer Japan Inc.: Honoraria; Takeda: Honoraria; Astellas: Honoraria; Ono: Research Funding; CMIC: Research Funding. Kimura: Eisai: Speakers Bureau; Kyowa-Kirin: Research Funding, Speakers Bureau; PharmaEssentia: Speakers Bureau; Astellas: Speakers Bureau; Sanifi: Speakers Bureau; Gilead: Research Funding; Nippon-Boehringer-Ingelheim: Research Funding; Celgene: Research Funding, Speakers Bureau; Sumitomo-Dainippon: Research Funding; Chugai: Research Funding, Speakers Bureau; Mundi: Research Funding; Yakult: Research Funding, Speakers Bureau; MSD: Research Funding, Speakers Bureau; Ono: Research Funding, Speakers Bureau; SymBio: Research Funding, Speakers Bureau; Daiichi-Sankyo: Research Funding, Speakers Bureau; Janssen: Research Funding; Astellas-Amgen-Biopharma: Research Funding; Takeda: Research Funding, Speakers Bureau; Nippon-Shinyaku: Research Funding, Speakers Bureau; Amgen: Research Funding; Alexion: Research Funding, Speakers Bureau; Incyte: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Otsuka Pharmaceutical: Honoraria, Research Funding, Speakers Bureau; Ohara Pharmaceutical: Research Funding; Astellas Pharma: Research Funding; AbbVie: Research Funding, Speakers Bureau; Apellis: Research Funding.

Tyrosine kinase inhibitors (TKIs) improve the prognosis of patients with chronic myelogenous leukemia (CML) by inducing substantial deep molecular responses (DMRs); some patients could successfully discontinue TKI therapy after maintaining DMR for ≥1 year. In this cessation study, we investigated the optimal conditions for dasatinib discontinuation in patients who maintained DMR for ≥2 years. This study included 54 patients with CML who were enrolled in D-STOP multicenter prospective trial, had achieved DMR, and had discontinued dasatinib after 2-year consolidation. Peripheral lymphocyte profiles were analyzed by flow cytometry. The estimated 12-month treatment-free survival (TFS) was 62·9% (95% confidence interval: 48·5%–74·2%). During dasatinib consolidation, the percentage of total lymphocytes and numbers of CD3-CD56+ natural killer (NK) cells, CD16+CD56+ NK cells, and CD56+CD57+ NK-large granular lymphocytes (LGL) were significantly higher in patients with molecular relapse after discontinuation but remained unchanged in patients without molecular relapse for >7 months. At the end of consolidation, patients whose total lymphocytes comprised

TP53 gene abnormality has been reported to be an unfavorable prognostic factor in acute myeloid leukemia (AML). However, almost all studies of TP53 gene abnormality so far have been limited to mutation searches in the DNA binding domain. As there have been few reports examining both mutation and deletion over the full-length of the TP53 gene, the clinical characteristics of TP53 gene abnormality have not yet been clearly established. In this study, TP53 gene mutation was observed in 7.3% of the total 412 de novo AML cases (33 mutations in 30 cases), with mutation outside the DNA binding domain in eight cases (27%). TP53 gene deletion was observed in 3.1% of 358 cases. All cases had monoallelic deletion with TP53 gene mutation on the opposite allele. Multivariate analysis demonstrated that TP53 gene mutation in the DNA binding domain and outside the DNA binding domain was an independent poor prognostic factor for overall survival and relapse-free survival among the total cohort and it is also an unfavorable prognostic factor in FLT3-ITD-negative AML cases aged 70 years or below with intermediate cytogenetic prognosis. In stratified treatment, full-length search for TP53 gene mutation is therefore very important.

// Toshio Asayama 1 , Hideto Tamura 1 , Mariko Ishibashi 1 , Yasuko Kuribayashi-Hamada 1 , Asaka Onodera-Kondo 1 , Namiko Okuyama 1 , Akiko Yamada 1 , Masumi Shimizu 2 , Keiichi Moriya 1 , Hidemi Takahashi 2 and Koiti Inokuchi 1 1 Department of Hematology, Nippon Medical School, Tokyo, Japan 2 Department of Microbiology and Immunology, Nippon Medical School, Tokyo, Japan Correspondence to: Hideto Tamura, e-mail: tam@nms.ac.jp Keywords: myelodysplastic syndromes, Tim-3, galectin-9, acute leukemia, immune checkpoint molecule Received: January 24, 2017 Accepted: August 23, 2017 Published: October 04, 2017 ABSTRACT T-cell immunoglobulin mucin-3 (Tim-3), an inhibitory immune checkpoint receptor, is highly expressed on acute myeloid leukemia cells and its ligand galectin-9 is reported to drive leukemic progression by binding with Tim-3. However, it remains unclear whether the Tim-3–galectin-9 pathway is associated with the pathophysiology of myelodysplastic syndromes (MDS). Thus, we investigated the expression and function of Tim-3 and the clinical impact of its ligand galectin-9 in MDS. Tim-3 expression levels on MDS blasts by CD45/side-scatter or CD34/CD45 gating were increased as MDS progressed to the advanced stage. Tim-3 expression in the MDS blasts was upregulated in the presence of the cell culture supernatant of human stromal cells or the MDS-related cytokine transforming growth factor-β1. The proliferation of Tim-3 + MDS blasts was inhibited by the blockade of anti-Tim-3 antibody. Furthermore, plasma levels of galectin-9 were elevated as MDS progressed to the advanced stage in 70 MDS/acute leukemia transformed from MDS patients and was a prognostic factor in 40 MDS patients. Our data demonstrated that the Tim-3-galectin-9 pathway is associated with the pathogenesis and disease progression of MDS. These findings provide new insight into potential immunotherapy targeting the galectin-9–Tim-3 pathway in MDS.

Acute lymphoblastic leukemias (ALL) positive for KMT2A/AFF1 (MLL/AF4) translocation, which constitute 60% of all infant ALL cases, have a poor prognosis even after allogeneic hematopoietic stem cell transplantation (allo-HSCT). This poor prognosis is due to one of two factors, either resistance to TNFα, which mediates a graft-versus-leukemia (GVL) response after allo-HSCT, or immune resistance due to upregulated expression of the immune escape factor S100A6. Here, we report an immune stimulatory effect against KMT2A/AFF1-positive ALL cells by treatment with the anti-allergy drug amlexanox, which we found to inhibit S100A6 expression in the presence of TNF-α. In KMT2A/AFF1-positive transgenic (Tg) mice, amlexanox enhanced tumor immunity and lowered the penetrance of leukemia development. Similarly, in a NOD/SCID mouse model of human KMT2A/AFF1-positive ALL, amlexanox broadened GVL responses and extended survival. Our findings show how amlexanox degrades the resistance of KMT2A/AFF1-positive ALL to TNFα by downregulating S100A6 expression, with immediate potential implications for improving clinical management of KMT2A/AFF1-positive ALL. Cancer Res; 77(16); 4426–33. ©2017 AACR.

The clinical impact of KIT mutations in core binding factor acute myeloid leukemia (CBF-AML) is still unclear. In the present study, we analyzed the prognostic significance of each KIT mutation (D816, N822K, and other mutations) in Japanese patients with CBF-AML. We retrospectively analyzed 136 cases of CBF-AML that had gone into complete remission (CR). KIT mutations were found in 61 (45%) of the patients with CBF-AML. D816, N822K, D816 and N822K, and other mutations of the KIT gene were detected in 29 cases (21%), 20 cases (15%), 7 cases (5%), and 5 cases (4%), respectively. The rate of relapse-free survival (RFS) and overall survival (OS) in patients with D816 and with both D816 and N822K mutations was significantly lower than in patients with other or with no KIT mutations (RFS: p

Primary esophageal lymphoma is an extremely rare disease. We report a 76-year-old woman with esophageal lymphoma who achieved remission after Helicobacter pylori (HP) eradication. Esophagogastroduodenoscopy (EGD) revealed a mass in the lower esophagus, and she was diagnosed with stage IE mucosa-associated lymphoid tissue (MALT) lymphoma. She rejected any anti-lymphoma treatment except for HP eradication. Follow-up EGD demonstrated the disappearance of the esophageal MALT lymphoma 2 months after HP eradication, and she remained in remission for more than 3 years. Our results demonstrate that HP eradication may be effective as initial therapy in primary esophageal MALT lymphoma patients with HP infection.

Despite therapeutic advances over the past decades, multiple myeloma (MM) remains a largely incurable disease with poor prognosis in high-risk patients, and thus new treatment strategies are needed to achieve treatment breakthroughs. MM represents various forms of impaired immune surveillance characterized by not only disrupted antibody production but also immune dysfunction of T, natural killer cells, and dendritic cells, although immunotherapeutic interventions such as allogeneic stem-cell transplantation and dendritic cell-based tumor vaccines were reported to prolong survival in limited populations of MM patients. Recently, epoch-making immunotherapies, i.e., immunomodulatory drug-intensified monoclonal antibodies, such as daratumumab combined with lenalidomide and chimeric antigen receptor T-cell therapy targeting B-cell maturation antigen, have been developed, and was shown to improve prognosis even in advanced-stage MM patients. Clinical trials using other antibody-based treatments, such as antibody drug-conjugate and bispecific antigen-directed CD3 T-cell engager targeting, are ongoing. The manipulation of anergic T-cells by checkpoint inhibitors, including an anti-T-cell immunoglobulin and ITIM domains (TIGIT) antibody, also has the potential to prolong survival times. Those new treatments or their combination will improve prognosis and possibly point toward a cure for MM.

INTRODUCTION A cryptic form of dyskeratosis congenita (cDKC) has a gradual onset without the characteristic physical findings of DKC. cDKC is distinguished from other forms of bone marrow failure (BMF) through analysis of telomere shortening and gene mutations. Mutations in the telomerase reverse transcriptase (TERT) and telomere RNA component (TERC) genes have been detected in most Japanese cDKC patients. Therefore, we investigated the impact of each TERT and TERC mutation on telomerase activity. METHODS TERT and TERC mutants observed in DKC or cDKC patients were transfected into Saos-2 or VA13+TERT (TERT-expressing VA13 cells) cells to measure telomerase activity. RESULTS Telomerase activity in cells expressing a mutant detected in cDKC patients was significantly lower (P

A 51-year-old man was diagnosed with stage IV mantle cell lymphoma based on terminal ileum biopsy and treated with the R-CHOP regimen. Abdominal CT to assess continuous fever after three courses of R-CHOP revealed three low-density areas in the liver. PCR of the fluid obtained by percutaneous drainage revealed Entamoeba histolytica positivity, although the cultures were negative. Metronidazole treatment achieved cure. The patient was not a homosexual but had an 8-month stay in Lesotho 21 years ago, leading to the possibility that E. histolytica infection at the time continued as an asymptomatic colonization until the initiation of corticosteroid-containing chemotherapy.

Treatment outcomes for chronic myeloid leukemia (CML) have dramatically improved with the development of tyrosine kinase inhibitors (TKI). However, due to the improved prognosis for CML, problems have arisen from long-term administration of TKI. The present study sought to verify whether more patients could achieve treatment-free remission (TFR) after stopping the administration of dasatinib using dasatinib as frontline treatment. Treatment-naive chronic phase CML cases were treated with dasatinib as frontline treatment. Dasatinib treatment was stopped for 26 patients who achieved deep molecular response (DMR) within 24 months and were able to maintain DMR for an additional 2 years. Ten patients (38.5%) achieved DMR maintenance after 12 months. Recurrence was confirmed in 16 patients, and the median recurrence-free survival time was 5.1 months. The cumulative DMR rates at six and 12 months after restarting treatment were 84.6% and 100%, respectively. The results of this study demonstrated that the DMR maintenance rate after 12 months was 38.5%, which was not significantly different from previous TKI stop trials. The 2-year dasatinib administration period after reaching DMR did not contribute to improve TFR rates. These results suggest that the type of TKI is not associated with better TFR rates.

The signaling lymphocytic activation molecule family 3 (SLAMF3) is a member of the immunoglobulin superfamily expressed on T, B, and natural killer cells and modulates the activation and cytotoxicity of these cells. SLAMF3 is also expressed on plasma cells from patients with multiple myeloma (MM), although its role in MM pathogenesis remains unclear. This study found that SLAMF3 is highly and constitutively expressed on MM cells regardless of disease stage and that SLAMF3 knockdown/knockout suppresses proliferative potential and increases drug-induced apoptosis with decreased levels of phosphorylated ERK protein in MM cells. SLAMF3-overexpressing MM cells promote aggressive myeloma behavior in comparison with cytoplasmic domain-truncated SLAMF3 (ΔSLAMF3) cells. SLAMF3 interacts directly with adaptor proteins SH2 domain-containing phosphatase 2 (SHP2) and growth factor receptor bound 2 (GRB2), which also interact with each other. SLAMF3 knockdown, knockout, ΔSLAMF3, and SHP2 inhibitor-treated MM cells decreased phosphorylated ERK protein levels. Finally, serum soluble SLAMF3 (sSLAMF3) levels were markedly increased in advanced MM. Patients with high levels of sSLAMF3 progressed to the advanced stage significantly more often and had shorter progression-free survival times than those with low levels. This study revealed that SLAMF3 molecules consistently expressed on MM cells transmit MAPK/ERK signals mediated via the complex of SHP2 and GRB2 by self-ligand interaction between MM cells and induce a high malignant potential in MM. Furthermore, high levels of serum sSLAMF3 may reflect MM disease progression and be a useful prognostic factor. Implications: SLAMF3 may be a new therapeutic target for immunotherapy and novel agents such as small-molecule inhibitors.

INTRODUCTION Acute myelogenous leukemia (AML) in elderly patients is associated with an increased incidence of complications and treatment-related toxicity because of the frequency of comorbid disease and age-related deterioration in organ function. Despite advances in AML treatment in recent years, elderly patients have experienced limited benefit, and their outcomes remain poor. This study aimed to perform a comprehensive gene mutation analysis in elderly AML patients and identify gene mutations that could serve as prognostic factors. METHODS An analysis of gene mutations was performed for 281 AML patients, including 98 elderly patients aged 65 years or above. RESULTS Compared to younger AML patients, elderly patients showed a higher frequency of the following gene mutations: TP53 (P = 0.026), PTPN11 (P = 0.006), RUNX1 (P = 0.024), TET2 (P = 0.002), and ASXL1 (P = 0.023). The complete remission rate was significantly lower in DNMT3A mutation-positive cases (4.26%, P = 0.011) and TP53 mutation-positive cases (2.13%, P = 0.031) than in negative cases. The overall survival rate was significantly poorer in cases with FLT3-ITD (P = 0.003), DNMT3A (P = 0.033), or TP53 mutation (P

Background: Acute kidney injury (AKI) and chronic kidney disease (CKD) are considered common complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Objectives and Method: In this study, 114 patients who had undergone allo-HSCT were retrospectively analyzed to investigate the risk factors for onset of posttransplant AKI and CKD as defined by the new Kidney Disease Improving Global Outcomes criteria. Results: Seventy-four patients (64.9%) developed AKI and 25 (21.9%) developed CKD. The multivariate analysis showed that the risk factors for developing stage 1 or higher AKI were age ≥46 years at the time of transplant (p = 0.001) and use of ≥3 nephrotoxic drugs (p = 0.036). For CKD, the associated risk factors were disease status other than complete remission at the time of transplantation (p = 0.018) and onset of AKI after transplant (p = 0.035). The 5-year overall survival (OS) was significantly reduced by development of AKI (p < 0.001), but not CKD. Posttransplant AKI significantly increased the 5-year nonrelapse mortality (p < 0.001), whereas posttransplant CKD showed an increasing tendency, but the difference was not significant. Conclusions: Posttransplant AKI impacts OS, significantly increases the risk of CKD, and is significantly associated with disseminated intravascular coagulation and use of ˃3 nephrotoxic drugs.

B7 homolog 1 (B7-H1)–expressing myeloma cells not only inhibit myeloma-specific cytotoxic T lymphocytes (CTL), but also confer a proliferative advantage: resistance to antimyeloma chemotherapy. However, it remains unknown whether B7-H1 expressed on myeloma cells induces cellular responses associated with aggressive myeloma behaviors. To address this question, we analyzed the proliferation and drug sensitivity of B7-H1–expressing myeloma cells transfected with B7-H1–specific short-hairpin RNA or treated with programmed cell death (PD)-1-Fc–coupled beads. Knockdown of B7-H1 expression in myeloma cells significantly inhibited cell proliferation and increased apoptosis induced by the chemotherapeutic alkylating agent melphalan, with downregulation of the expression of cell cycle–related genes (CCND3 and CDK6) and antiapoptotic genes (BCL2 and MCL1). B7-H1 molecules thus contributed to myeloma cell-cycle progression and suppression of drug-induced apoptosis. B7-H1–expressing myeloma cells had a higher affinity for PD-1 than for CD80. PD-1-Fc bead–treated myeloma cells also became resistant to apoptosis that was induced by melphalan and the proteasome inhibitor bortezomib. Apoptosis resistance was associated with the PI3K/AKT pathway. Both myeloma cell drug resistance and antiapoptotic responses occurred through the PI3K/AKT signaling pathway, initiated from “reverse” stimulation of B7-H1 by PD-1. Therefore, B7-H1 itself may function as an oncogenic protein in myeloma cells. The interaction between B7-H1 on myeloma cells and PD-1 molecules not only inhibits tumor-specific CTLs but also induces drug resistance in myeloma cells through the PI3K/AKT signaling pathway. These observations provide mechanistic insights into potential immunotherapeutic benefits of blocking the B7-H1–PD-1 pathway. Cancer Immunol Res; 4(9); 779–88. ©2016 AACR.

The risk of complication of polycythemia vera (PV) and essential thrombocythemia (ET) by thrombosis in Japanese patients is clearly lower than in western populations, suggesting that genetic background such as race may influence the clinical features. This study aimed to clarify the relationship between genetic mutations and haplotypes and clinical features in Japanese patients with PV and ET. Clinical features were assessed prospectively among 74 PV and 303 ET patients. There were no clinical differences, including JAK2V617F allele burden, between PV patients harboring the various genetic mutations. However, CALR mutation-positive ET patients had a significantly lower WBC count, Hb value, Ht value, and neutrophil alkaline phosphatase score (NAP), and significantly more platelets, relative to JAK2V617F-positive ET patients and ET patients with no mutations. Compared to normal controls, the frequency of the JAK246/1 haplotype was significantly higher among patients with JAK2V617F, JAK2Ex12del, or MPL mutations, whereas no significant difference was found among CALR mutation-positive patients. CALR mutation-positive patients had a lower incidence of thrombosis relative to JAK2V617F-positive patients. Our findings suggest that JAK2V617F-positive ET patients and CALR mutation-positive patients have different mechanisms of occurrence and clinical features of ET, suggesting the potential need for therapy stratification in the future.

We report a case of the extremely rare condition Epstein-Barr virus (EBV)-positive T-cell lymphoproliferative disease (LPD) which occurred after umbilical cord blood transplantation. A 25-year-old Japanese man underwent cord blood transplantation from a male human leukocyte antigen 4/6-matched donor due to acute myeloid leukemia with trisomy 8. Bone marrow examination on day 30 showed chimerism with at least 90% donor cells and complete hematological response. Chronic symptoms of graft-versus-host disease appeared only on the skin and were successfully treated with cyclosporine alone. Three years later, however, the patient experienced repeated cold-like symptoms and was hospitalized with liver dysfunction. A high fever developed and was followed by significant edema of the right side of the face. The EBV DNA copy number in whole peripheral blood was 2×10(4)/mL. Liver biopsy showed invasion of EBV-infected CD8-positive T cells. Southern blotting analysis of the whole peripheral blood showed that the T-cell receptor Cβ1 rearrangement was positive. On the basis of these results, EBV-positive T-cell LPD was diagnosed and treated with prednisolone, cyclosporine, and etoposide, followed by cyclophosphamide, doxorubicin, vincristine, and prednisone. However, the patient died of cardiac function failure, pneumonia, and pulmonary hemorrhage, all of unidentified cause. Most cases of EBV-related LPD after hematopoietic stem cell transplantation consist of EBV-positive B-cell LPD, and, to our knowledge, de novo EBV-positive T-cell LPD subsequent to transplantation has not been previously reported.