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TAFRO syndrome was first described in 2010, standing for thrombocytopenia, anasarca, fever, reticulin fibrosis and organomegaly. Because the lymph node histopathology of TAFRO syndrome mimics idiopathic multicentric Castleman disease (iMCD), some researchers consider TAFRO syndrome to be a subtype of iMCD. However, the clinical features of TAFRO syndrome considerably differ from those of iMCD without TAFRO. The clinical features of patients with TAFRO syndrome with or without iMCD-histopathology are similar, and these patients require an accurate diagnosis and urgent treatment. Although a histological diagnosis, including a differential diagnosis, is important, lymph node involvement in patients with TAFRO syndrome is usually modest or sometimes absent. Furthermore, a bleeding tendency due to thrombocytopenia and severe anasarca hampers performing a biopsy. Nonetheless, patients with various other disorders may manifest TAFRO syndrome-like symptoms, making the differential diagnosis in borderline cases difficult. Therefore, the establishment of precise and specific biomarkers is important.

We compared the outcomes of autologous stem cell transplantation (auto-SCT) with those of allogeneic stem cell transplantation (allo-SCT) from a human leukocyte antigen-matched related donor in patients with Philadelphia chromosome-negative B-lineage acute lymphoblastic leukemia (ALL). Newly diagnosed patients who underwent allo-SCT (n = 486) or auto-SCT (n = 99) after achieving first complete remission (CR) were included. Propensity score matching (PS) and an inverse probability of the treatment weighting (IPTW) analysis were applied to compensate for imbalances in baseline characteristics. The 5 years rates of overall survival (OS) among those in the PS-matched cohorts were 57% [95% confidence interval (CI) 46-67%] for those who received allo-SCT and 44% (95% CI 33-54%) for those who received auto-SCT. Multivariable, propensity score-matched, and IPTW analyses all revealed no statistically significant differences in OS between the two groups [hazard ratios (HR) 0.81, 95% CI 0.53-1.27, p = 0.36; HR 0.84, 95% CI 0.40-1.78, p = 0.65; HR 0.71, 95% CI 0.25-2.02, p = 0.53, respectively]. Prospective trials that include autologous transplantation as a treatment option are needed to examine the potential of autologous transplantation.

The emergence of tyrosine kinase inhibitors as part of a front-line treatment has greatly improved the clinical outcome of the patients with Ph⁺ acute lymphoblastic leukemia (ALL). However, a portion of them still become refractory to the therapy mainly through acquiring mutations in the BCR-ABL1 gene, necessitating a novel strategy to treat tyrosine kinase inhibitor (TKI)-resistant Ph⁺ ALL cases. In this report, we show evidence that RUNX1 transcription factor stringently controls the expression of BCR-ABL1, which can strategically be targeted by our novel RUNX inhibitor, Chb-M'. Through a series of in vitro experiments, we identified that RUNX1 binds to the promoter of BCR and directly transactivates BCR-ABL1 expression in Ph⁺ ALL cell lines. These cells showed significantly reduced expression of BCR-ABL1 with suppressed proliferation upon RUNX1 knockdown. Moreover, treatment with Chb-M' consistently downregulated the expression of BCR-ABL1 in these cells and this drug was highly effective even in an imatinib-resistant Ph⁺ ALL cell line. In good agreement with these findings, forced expression of BCR-ABL1 in these cells conferred relative resistance to Chb-M'. In addition, in vivo experiments with the Ph⁺ ALL patient-derived xenograft cells showed similar results. In summary, targeting RUNX1 therapeutically in Ph⁺ ALL cells may lead to overcoming TKI resistance through the transcriptional regulation of BCR-ABL1. Chb-M' could be a novel drug for patients with TKI-resistant refractory Ph⁺ ALL.

We herein report a patient with primary effusion lymphoma-like adult T-cell leukemia/lymphoma (PEL-like ATL) that developed during hemodialysis. A 77-year-old man developed a fever and ascites. Elevated levels of LDH, calcium and sIL-2R along with antibodies to HTLV-1 were seen in his blood. Lymphoma cells in ascites were positive for HTLV-1 proviral DNA, but there were no neoplastic cells in peripheral blood or bone marrow and no lymphadenopathy. He was therefore diagnosed with PEL-like ATL, acute-type. After administration of Brentuximab Vedotin, his serum LDH, sIL-2R and atypical cells in ascites cytology decreased. The development of novel effective molecular-targeted therapies is warranted.

Background and aims Immunoglobulin 4 (IgG4)-related disease (IgG4-RD) is a lymphoproliferative disorder characterized by elevated serum IgG4 levels and tissue infiltration of IgG4-positive plasma cells. We analyzed the serum proteins, whose levels varied based on the disease state and treatment. Materials and methods Serum proteins from patients with IgG4-related disease and healthy subjects were resolved using two-dimensional electrophoresis, silver-stained, and scanned. Alternatively, the proteins were labeled with Cy2, Cy3, and Cy5 before electrophoresis. The proteins, whose expression differed significantly between patients and healthy individuals, and between before and after steroid treatment, were identified and validated using enzyme-linked immunosorbent assays. Results Pre-treatment sera from patients with IgG4-related disease was characterized by increased levels of immunoglobulins such as IgG1, IgG4; inflammatory factors such as α-1 antitrypsin (A1AT); and proteins associated with immune system regulation such as clusterin and leucine-rich α-2-glycoprotein (LRG-1). The serum levels of A1AT, LRG-1 and clusterin, during treatment with prednisolone for up to 12 months revealed that LRG-1 levels were halved after 1 month of treatment, comparable to those in healthy subjects; LRG-1 levels remained normal until the end of treatment. Conclusion LRG-1 could serve as a novel biomarker of IgG4-related diseases.

Various systems for predicting the prognosis of patients with myelodysplastic syndromes (MDS) have been developed. However, associations between performance status (PS) and prognosis of MDS require further investigation. To objectively assess the impact of PS on survival, we examined laboratory findings associated with PS, including serum levels of C-reactive protein (CRP), albumin (ALB), and total cholesterol (CHOL). Patients (n = 123; male 86, female 37; median age 74 yrs.) diagnosed with MDS or myelodysplastic/myeloproliferative neoplasms at Kanazawa Medical University Hospital between 2010 and 2020 were enrolled and grouped by cutoff values determined by receiver operating characteristic analysis: 0.44 mg/dL for CRP, 4.0 g/dL for ALB, and 120 mg/dL for CHOL. The median follow-up period was 17.6 months. Kaplan-Meier analysis revealed that overall survival (OS) in the high CRP, low ALB, and low CHOL groups was significantly shorter than in the low CRP, high ALB, and high CHOL groups, respectively. Multivariable analysis revealed that elevated serum CRP was an independent prognostic risk factor independent of gender, bone marrow blast percentage, and cytogenetics.

Tyrosine kinase inhibitor (TKI) administration after allogeneic hematopoietic stem cell transplantation (HSCT) may carry a survival benefit in Philadelphia chromosome‐positive acute lymphoblastic leukemia (Ph+ ALL). Therefore, we investigated whether TKI prophylaxis for negative‐minimal residual disease (MRD) after HSCT would improve patient outcomes in this nationwide retrospective cohort study. We included patients with Ph+ ALL who underwent their first allogeneic HSCT between 2001 and 2016, received TKI before HSCT, and achieved negative‐MRD status within 180 days after HSCT. Of 850 patients for inclusion, 50 patients received TKI prophylaxis, mostly imatinib or dasatinib (median dose: 400 mg with imatinib and 40 mg with dasatinib). In a multivariate analysis, disease status at HSCT was the sole risk factor for relapse (hazard ratio, 3.58; P

A 73-year-old man was referred to our hospital with a persistent fever, anemia, and a mass in the left pubic region. The findings of biopsy evaluations of the mass and a left inguinal lymph node were consistent with Castleman disease (CD) of plasma cell type. His serum interleukin 6 (IL-6) level was remarkably elevated, supporting the diagnosis of CD. However, imaging analyses revealed destruction of the pubic bone by the mass, which was atypical for CD. Therefore, another deeper biopsy was performed, which finally led to the diagnosis of IL-6-producing osteosarcoma. We conclude that clinicians should carefully exclude malignancies prior to making a CD diagnosis.

The optimal treatment for Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) in first complete remission (CR1) has not been established in the high-intensity chemotherapy era. The outcomes of patients with Ph-negative ALL who underwent allogeneic hematopoietic stem cell transplantation (HSCT) from a human leukocyte antigen-matched related or unrelated donor in CR1 (HSCT-MRD group and HSCT-MUD group) were obtained from a Japanese registry database. Patients aged 16–24 years and 25–65 years were analyzed separately, and their outcomes were compared to those of patients who continued high-intensity chemotherapy in CR1 in studies (202U group and 202O group) by the Japan Adult Leukemia Study Group (JALSG). In the HSCT-MRD group, patients younger than 25 years had lower overall survival (OS) than the 202U group, presumably due to the higher non-relapse mortality (NRM) in the HSCT-MRD group. Patients 25 years and older had similar OS to the 202O group. The lower relapse rate was counterbalanced by higher NRM in the HSCT-MRD group. In the HSCT-MUD group, patients in both age groups had similar OS to their corresponding groups in the JALSG studies. In conclusion, high-intensity chemotherapy may change the role of HSCT for Ph-negative ALL.

Minimal residual disease (MRD) monitoring by quantitative real-time reverse transcription PCR (qRT-PCR) is the standard of care in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL). We evaluated the impact of MRD status at hematopoietic cell transplantation (HCT) on relapse, as measured by a unified protocol at a central laboratory. Only patients with Ph-positive ALL who had minor transcripts (e1a2) and who underwent allogeneic HCT in first complete remission between 2008 and 2017 were included. First, patients with negative-MRD (n = 196) and positive-MRD (n = 61) at HCT were analyzed. As expected, MRD positivity at HCT was significantly associated with an increased risk of hematological relapse (hazard ratio [HR], 2.91; 95% CI 1.67–5.08; P

High-dose chemotherapy with autologous stem cell transplantation (HDC-ASCT) is an option for patients with peripheral T-cell lymphoma (PTCL); however, neither prospective nor retrospective studies support proceeding with ASCT upfront, and the timing of HDC-ASCT remains controversial. We retrospectively analyzed the risk factors for outcomes of 570 patients with PTCL, including PTCL not otherwise specified (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL), who received ASCT for frontline consolidation (n = 98 and 75, respectively) or alternative therapies after either relapse (n = 112 and 75) or primary induction failure (PIF; n = 127 and 83) between 2000 and 2015. Significant risk factors for overall survival (OS) after upfront ASCT were a ≥ 2 prognostic index for T-cell lymphoma (P 0.001) and partial response (PR) at ASCT (P = 0.041) in PTCL-NOS patients, and 60 years of age (P = 0.0028) and PR at ASCT (P = 0.0013) in AITL patients. Performance status of ≥ 2 at ASCT (P 0.001), receiving ≥ 3 regimens before ASCT (P = 0.018), and PR at ASCT (P = 0.018) in PTCL-NOS patients and 60 years of age at ASCT (P = 0.0077) in AITL patients were risk factors for OS after ASCT with a chemosensitive PIF status. Strategies that carefully select PTCL patients may allow identification of individuals suitable for ASCT.

Background Dasatinib has shown promising anti-leukemic activity against chronic myeloid leukemia (CML). However, patients receiving dasatinib frequently require dose reductions and treatment interruptions (treatment alteration). Methods We prospectively analyzed the frequency and significance of treatment alteration during dasatinib therapy in patients with CML. In all patients, trough plasma concentrations of dasatinib (Cmin) at steady state were assessed on day 28 of therapy. Results 28% of patients had their doses reduced at a median of 42 days, and 25% of patients had temporarily interrupted at a median of 54 days after treatment initiation. The overall dasatinib treatment alteration-free rate at 1 year was 66%. Age was significantly correlated with Cmin on day 28 (p = 0.014), and the correlation remained significant after adjusting dasatinib dose (g), body weight (kg) (Cmin/D/W) (p = 0.026). In the univariate analysis, deep molecular response, advanced PS, higher Cmin/D/W were associated with a significantly higher risk of treatment alteration (HR 4.19, 95% CI: 1.06–16.60, p = 0.041; HR 5.26, 95% CI: 1.33–20.80, p = 0.018; and HR 10.15, 95% CI: 2.55–40.48, p = 0.001, respectively). In the multivariate analysis, advanced PS and higher Cmin/D/W were correlated with the incidence of treatment alteration (HR 4.78, 95% CI: 1.01–22.70, p = 0.049; HR 6.17, 95% CI: 1.17–32.50, respectively). Conclusion Current data demonstrate that patients treated with dasatinib who displayed a high Cmin/D/W value and/or advanced PS were at a high risk for altered treatment.

Allogeneic hematopoietic stem cell transplantation (HSCT) with the conventional cyclophosphamide and total body irradiation (CY/TBI) regimen is an essential therapeutic strategy for acute lymphoblastic leukemia (ALL) in adults. Medium-dose etoposide (VP16, 30-40 mg/kg) can be added to intensify this CY/TBI regimen and reduce relapse; however, differences in prognosis between the VP16/CY/TBI and CY/TBI regimens have not yet been fully analyzed. We conducted a retrospective cohort study using a Japanese transplant registry database to compare the prognosis between the VP16/CY/TBI (VP16, total 30-40 mg/kg) (N = 376) and CY/TBI (N = 1178) regimens in adult patients with ALL transplanted at complete remission (CR) between January 1, 2000 and December 31, 2014. Our analyses indicated that VP16/CY/TBI significantly reduced relapse compared with CY/TBI (risk ratio, 0.75; 95% confidence interval [CI], 0.56-1.00; P = .05) with a corresponding improvement in leukemia-free survival (hazard ratio [HR], 0.76; 95%CI, 0.62-0.93; P = .01), particularly in patients transplanted at CR1 with advanced-risk (positive minimal residual disease, presence of poor-risk cytogenetics, or an initial elevated leukocyte count) (HR, 0.75; 95%CI, 0.56-1.00; P = .05) or those transplanted beyond CR2 (HR, 0.58; 95%CI, 0.39-0.88; P = .01). The addition of VP16 did not increase post-transplant complications or nonrelapse mortality (HR, 0.88; 95%CI, 0.65-1.18; P = .38). This study is the first to reveal the efficacy of the addition of medium-dose VP16 to CY/TBI in high-risk ALL. To establish new myeloablative conditioning regimens including VP16, a large-scale prospective study is necessary.

To investigate better GVHD prophylaxis in reduced intensity conditioning umbilical cord blood transplantation (RIC-UCBT), we compared transplant outcomes after UCBT among GvHD prophylaxes using the registry data. We selected patients transplanted for AML or ALL with a calcineurin inhibitor and methotrexate (MTX)/mycophenolate mofetil (MMF) combination. A total of 748 first RIC-UCBT between 2000 and 2012 (MTX+ group, 446, MMF+ group, 302) were included. The cumulative incidence of neutrophil and platelet counts higher than 50 000/μL was significantly better in the MMF+ group (relative risk (RR), 1.55; P

Summary The efficacy of high-dose cytarabine (HDCA) plus cyclophosphamide/total-body irradiation (CY/TBI) has been proved in cord blood transplantation (CBT) for acute lymphoblastic leukaemia (ALL), but not in bone marrow or peripheral blood stem cell transplantation (BMT/PBSCT). In this cohort study, we compared the prognosis of CY/TBI (N = 1244) and HDCA/CY/TBI (N = 316) regimens in BMT/PBSCT for ALL. The addition of HDCA decreased post-transplant relapse, while significantly increasing non-relapse mortality (risk ratio, 1·33), and overall survival was not improved. The positive effects of HDCA reported in CBT cannot be extrapolated to BMT/PBSCT, and HDCA may not be recommended in these procedures.

This study investigated the efficacy of imatinib based therapy with intensified consolidation therapy in patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) to prevent early relapse. We conducted a phase II trial of imatinib-combined chemotherapy for newly diagnosed BCR-ABL-positive ALL in adults. Sixty-eight patients were included in the trial between October 2008 and December 2010. The median age was 49 years, with 28 patients55 years of age. Sixty-five patients achieved CR (95.6%). The estimated 2-year event-free survival (EFS) and overall survival (OS) were 62.3% and 67.4%, respectively. Allogeneic stem cell transplantation (allo-SCT) at initial CR was performed in 43 patients. Thirty-five of 39 patients55 years and 8 of 26 patients55 years underwent allo-SCT at first CR. The 3-year OS in patients55 years receiving allo-SCT at first CR, patients55 years receiving allo-SCT at first CR, patients55 years not receiving allo-SCT at first CR, and patients55 years not receiving allo-SCT at first CR were 80.4%, 41.1%, 32.5%, and 52.0%, respectively (P = 0.058). The three-year EFS in each group was 76.7%, 53.6%, not reached, and 26.4%, respectively (P = 0.150). A high CR rate was observed with imatinib-based chemotherapy allowing allo-SCT in a high proportion of patients, particularly those55 years. Moreover, intensified consolidation therapy reduced early relapse rates following induction therapy and resulted in improved OS and EFS rates following allo-SCT. This trial was registered with the UMIN (000001226).

Castleman disease (CD) is a rare lymphoproliferative disorder that can be unicentric or multicentric. Multicentric CD (MCD) is further subdivided into human herpesvirus type-8-associated, POEMS syndrome-associated, and idiopathic (iMCD). TAFRO syndrome is a newly identified disorder of unknown etiology characterized by thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction, and organomegaly. The TAFRO syndrome is sometimes regarded as a subtype of iMCD (TAFRO-iMCD), whereas iMCD without TAFRO syndrome is considered "not otherwise specified" (iMCD-NOS). However, a proportion of patients with TAFRO syndrome have been diagnosed without lymph node biopsies (TAFRO syndrome without proven iMCD; TAFRO-w/op-iMCD). To clarify the clinical features of iMCD-NOS, TAFRO-iMCD, and TAFRO-w/op-iMCD, we retrospectively analyzed 220 patients extracted from the database of the Multicenter Collaborative Retrospective Study for Establishing the Concept of TAFRO Syndrome. The patients included 87 with iMCD-NOS, 63 with TAFRO-iMCD, and 19 with TAFRO-w/op-iMCD. Patients in all three groups exhibited anemia, hypoalbuminemia, and elevated serum C-reactive protein and interleukin-6 levels. No significant differences in clinical, laboratory, and prognostic features were noted between the TAFRO-iMCD, and TAFRO-w/op-iMCD groups. However, the iMCD-NOS group exhibited polyclonal hyper-γ-globulinemia. The five-year survival rates of patients in the iMCD-NOS and TAFRO-involved groups were 100% and 66.5%, respectively (dropping markedly during the first few months in the latter). The iMCD-NOS and the TAFRO-iMCD samples typically showed plasma cell and mixed-type histologies, respectively. Thus, iMCD can be classified into two distinct subtypes, iMCD-NOS and TAFRO-iMCD. As such, TAFRO-iMCD and TAFRO-w/op-iMCD may be considered the same entity, requiring prompt diagnosis and intensive care.

We conducted a retrospective analysis to compare outcomes in adult patients with acute lymphoblastic leukemia (ALL) who underwent allogeneic hematopoietic cell transplantation (allo-HCT) with conditioning regimens containing cyclophosphamide (CY) in combination with total body irradiation (TBI), oral busulfan (p.o. BU), or intravenous busulfan (i.v. BU). We used data for January 2000 to December 2012 from the Transplant Registry Unified Management Program of the Japan Society of Hematopoietic Cell Transplantation. We identified 2130 patients treated with TBI/CY (n = 2028), p.o. BU/CY (n = 60), or i.v. BU/CY (n = 42). Two-year overall survival (OS) and 2-year relapse-free survival rates were 69.0% and 62.1%, respectively, in the TBI/CY group, 55.9% and 54.2% in the p.o. BU/CY group, and 71.0% and 46.8% in the i.v. BU/CY group. In multivariate analysis, compared with TBI/CY, p.o. BU/CY, but not i.v. BU/CY, was associated with lower OS (hazard ratio [HR], 1.46; P = .047) and a higher incidence of sinusoidal obstruction syndrome (HR, 3.36; P = .030). No between-group differences were seen in the incidence of nonrelapse mortality, relapse, acute graft-versus-host disease (GVHD), or chronic GVHD. We suggest that i.v. BU/CY might be a possible alternative allo-HCT conditioning regimen for adults with ALL who are not suitable for TBI.

Cytogenetic abnormalities are well known and powerful independent prognostic factors for various hematologic disorders. Although the combination of chemotherapy with tyrosine kinase inhibitor (TKI) is now considered the standard of care in patients with Philadelphia chromosome–positive acute lymphoblastic leukemia, little is known about the impact of additional cytogenetic abnormalities (ACAs). Therefore, we retrospectively evaluated 1375 adult patients who underwent their first allogeneic hematopoietic stem cell transplantation in the TKI era. In this study, 224 patients had ACAs (16.3%). The ACAs that were seen in more than 20 cases (1.5%) were as follows: -7, der(22), der(9), +8, and +X. Overall survival at 4 years was 56.9% (95% confidence interval [CI], 49.4% to 63.7%) in the group with ACAs and 60.5% (95% CI, 57.3% to 63.5%) in the group without ACAs (P = .266). The cumulative incidence of relapse at 4 years was 28.9% (95% CI, 22.6% to 35.6%) in the group with ACAs and 21.9% (95% CI, 19.4% to 24.6%) in the group with Ph alone (P = .051). In multivariate analyses there were no statistically significant differences in the risk of overall mortality or risk of relapse between the groups with and without ACAs. In the subgroup analyses of specific ACAs, although the presence of +8 was associated with a higher relapse rate in univariate and multivariate analyses, no specific ACA was associated with poor overall survival. Further studies will be needed to verify the impact of specific ACAs on transplantation outcomes.

Introduction The addition of tyrosine-kinase inhibitor (TKI) to conventional chemotherapy followed by allogenic hematopoietic stem cell transplantation (HSCT) is a standard treatment for transplant-eligible patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Although TKI administration after HSCT may carry a survival benefit, available data are scarce. Objectives We conducted a nationwide retrospective study to evaluate whether TKI prophylaxis after allogenic HSCT in patients with negative-MRD would reduce relapse and improve overall survival. Methods In this nationwide retrospective cohort study, we included patients with Ph+ ALL who underwent their first allogenic HSCT between 2001 and 2016, received TKI before HSCT, and achieved negative-MRD status within 180 days after HSCT. Administration of TKI within 180 days after HSCT in a patient who maintained negative-MRD was defined as prophylactic TKI. Cox proportional hazards regression models were used to evaluate the impact of post-transplant TKI prophylaxis as a time-dependent covariate. Results We identified 850 patients for inclusion in this study. Fifty patients received TKI prophylaxis, mostly imatinib or dasatinib. TKI was more frequently administered in late time periods of HSCT or in cases of positive-MRD at HSCT. In a multivariate analysis, disease status at HSCT was the sole risk factor for relapse (hazard ratio, 3.58; P Conclusions Routine post-transplant TKI prophylaxis especially with imatinib is not recommended because this strategy yielded no clinical benefits. Since the risk of relapse in patients who did not achieve negative-MRD at HSCT was higher, even though they did achieve negative-MRD after HSCT, close monitoring and different post-transplant strategies using new-generation TKIs might be preferable in such patients.

ETV6, which encodes an ETS family transcription factor, is frequently rearranged in human leukemias. We show here that a patient with acute myeloid leukemia with t(7;11)(p15;p15) gained, at the time of relapse, t(11;12)(q12.1;p13) with a split ETV6 FISH signal. Using 3'-RACE PCR analysis, we found that ETV6 was fused to LPXN at 11q12.1, which encodes leupaxin. ETV6-LPXN, an in-frame fusion between exon 4 of ETV6 and exon 2 of LPXN, did not transform the interleukin-3-dependent 32D myeloid cell line to cytokine independence; however, an enhanced proliferative response was observed when these cells were treated with G-CSF without inhibition of granulocytic differentiation. The 32D and human leukemia cell lines each transduced with ETV6-LPXN showed enhanced migration towards the chemokine CXCL12. We show here for the first time that LPXN is a fusion partner of ETV6 and present evidence indicating that ETV6-LPXN plays a crucial role in leukemia progression through enhancing the response to G-CSF and CXCL12.

It is still a matter of debate whether detection of Epstein–Barr virus (EBV) DNA in pretreatment serum has clinical implications for diffuse large B‐cell lymphoma. For this study, we measured EBV DNA load in pretreatment serum from 127 diffuse large B‐cell lymphoma patients without any underlying immunodeficiency to evaluate its effects on clinical manifestations and prognosis. Anthracycline‐based chemotherapy in combination with rituximab was given as initial therapy for 119 patients (94%). Epstein–Barr virus DNA was detected in 15 patients (12%), who were older (P = 0.005) and tended to be at a more advanced disease stage (P = 0.053). They showed significantly worse progression‐free survival (PFS) and overall survival (OS) than other patients (P < 0.001 each). This effect remained significant (P = 0.004 and P = 0.027, respectively) after adjustment for age, lactate dehydrogenase, performance status, stage, and extranodal sites. The status of EBV‐encoded small RNA in situ hybridization was known for 123 patients; 6 of 8 positive patients (75%) and 9 of 115 negative patients (8%) had detectable EBV DNA in pretreatment serum. While patients positive for EBV‐encoded small RNA had significantly worse PFS and OS than negative patients (P = 0.001 and P = 0.029, respectively), EBV DNA detection in pretreatment serum was associated with poorer PFS and OS even for the 115 patients negative for EBV‐encoded small RNA (P < 0.001 each). These findings suggest that EBV DNA detection in pretreatment serum may have an adverse prognostic impact for patients with diffuse large B‐cell lymphoma.

Epstein-Barr virus (EBV)-encoded small RNA in situ hybridization (EBER-ISH) is a widely accepted method to evaluate EBV involvement in diffuse large B-cell lymphoma (DLBCL), although little is known regarding associations between EBV DNA load and the EBER status and whether EBV DNA load data provide additional clinical information. In this study, we quantified EBV DNA load in diagnostic specimens from DLBCL patients diagnosed at our hospital to evaluate clinical implications of EBV DNA load in diagnostic specimens as contrasted with EBER-ISH. Among 140 DLBCL patients without underlying immunodeficiency, 51 were evaluable for both EBER and EBV DNA load, 83 for EBER only and one for EBV DNA load only. The median EBV DNA load was 708 copies/µg. Although EBV DNA load was significantly higher for EBER-positive patients than for EBER-negative patients (p

The concentration of extracellular potassium in red blood cell concentrates (RCCs) increases during storage, leading to risk of hyperkalemia. A potassium adsorption filter (PAF) can eliminate the potassium at normal blood transfusion. This study aimed to investigate the potassium adsorption capacity of a PAF during rapid blood transfusion. We tested several different potassium concentrations under a rapid transfusion condition using a pressure bag. The adsorption rates of the 70-mEq/l model were 76·8%. The PAF showed good potassium adsorption capacity, suggesting that this filter may provide a convenient method to prevent hyperkalemia during rapid blood transfusion.

DEK-NUP214 gene fusion in acute myeloid leukemia (AML) is associated with poor prognosis. It is most often a sole translocation and more rarely observed as complex chromosomal forms. We describe an AML case with complex karyotype abnormalities involving chromosome bands 6p23, 6q13, 7p22, and 9q34. RNA sequencing analysis revealed that exon 17 of NUP214 (9q34) was fused to exon 2 of RAC1 (7p22). We also detected that the 5′-end of intron 1 of RAC1 was fused with the antisense strand of intron 5 of COL12A1 (6q13). RT-PCR analysis confirmed the expression of DEK-NUP214, NUP214-RAC1, RAC1-COL12A1, NUP214, and RAC1. These results suggest that the 5′- and 3′-ends of NUP214 from the breakpoint in the same locus were fused to RAC1 and DEK, respectively, and the 5′-end of RAC1 was fused to COL12A1. The reading frame of NUP214 was not matched with RAC1; however, high expression of the RAC1 protein was detected by Western blotting. This study identifies the variant complex fusion genesNUP214-RAC1 and RAC1- COL12A1 in a case of AML.

BACKGROUND: Transfusion of group O blood to non-O recipients, or transfusion of D- blood to D+ recipients, can result in shortages of group O or D- blood, respectively. This study investigated RBC utilization patterns at hospitals around the world and explored the context and policies that guide ABO blood group and D type selection practices.STUDY DESIGN AND METHODS: This was a retrospective study on transfusion data from the 2013 calendar year. This study included a survey component that asked about hospital RBC selection and transfusion practices and a data collection component where participants submitted information on RBC unit disposition including blood group and D type of unit and recipient. Units administered to recipients of unknown ABO or D group were excluded.RESULTS: Thirty-eight hospitals in 11 countries responded to the survey, 30 of which provided specific RBC unit disposition data. Overall, 11.1% (21,235/191,397) of group O units were transfused to non-O recipients; 22.6% (8777/38,911) of group O D- RBC units were transfused to O D+ recipients, and 43.2% (16,800/38,911) of group O D- RBC units were transfused to recipients that were not group O D-. Disposition of units and hospital transfusion policy varied within and across hospitals of different sizes, with transfusion of group O D- units to non-group O D- patients ranging from 0% to 33%.CONCLUSION: A significant proportion of group O and D- RBC units were transfused to compatible, nonidentical recipients, although the frequency of this practice varied across sites.

The optimal conditioning regimen for elderly patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT) remains unclear. We retrospectively analyzed 1607 patients aged 50 years or older with acute myeloid leukemia (AML), acute lymphoblastic leukemia, or myelodysplastic syndrome (MDS) who underwent allo-HCT using fludarabine/busulfan (FB) or fludarabine/melphalan (FM) between 2007 and 2014. We compared the clinical outcomes among FB2 (busulfan at 6.4 mg/kg iv, n = 463), FB4 (busulfan at 12.8 mg/kg iv, n = 721), and FM140 (melphalan at 140 mg/m2, n = 423). The nonrelapse mortality (NRM) rates in the FB4 and FM140 groups were higher than that in the FB2 group (hazard ratio [HR], 1.63 [P

Varicella, characterized by a vesicular rash, occurs primarily in young children. Although older individuals can also be affected or vaccinated, outbreaks among adults are rare. We investigated a small outbreak of varicella in B-cell lymphoma patients for elucidation of risk factor of the disease. We experienced four cases of varicella after an index herpes zoster case. All varicella cases were confirmed varicella zoster virus (VZV) infection by PCR. All varicella cases occurred in diffuse large B-cell lymphoma patients receiving rituximab-containing chemotherapy. On the other hand, only three of the 18 non-varicella patients in the same room were receiving rituximab-containing chemotherapy (P = 0.005). All varicella patients had detectable serum anti-varicella zoster virus IgG antibodies before chemotherapy. Even in the presence of neutralizing antibodies to the virus, lymphoma patients treated with rituximab-containing chemotherapy can possibly become re-infected with varicella. These findings suggest that zoster patients should be strictly isolated in hematology and oncology ward, and prophylactic acyclovir should be considered for such patients when exposed to zoster/varicella.

We aimed to evaluate the impact of pretransplant imatinib administration on the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in adults with Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL). We retrospectively analyzed 738 patients with Ph(+) ALL that underwent allo-HSCT between 1990 and 2010 using data from the Transplant Registry Unified Management Program of the Japan Society of Hematopoietic Cell Transplantation. We compared the allo-HSCT outcomes between 542 patients who received imatinib before allo-HSCT during the initial complete remission period (imatinib cohort) and 196 patients who did not receive imatinib (non-imatinib cohort). The 5-year overall survival after allo-HSCT was significantly higher in the imatinib cohort than in the non-imatinib cohort (59% vs 38%; 95% confidence interval [CI], 31-45%; P < .001). Multivariate analysis indicated that pretransplant imatinib administration had beneficial effects on overall survival (hazard ratio [HR], 0.57; 95% CI, 0.42-0.77; P < .001), relapse (HR, 0.66; 95% CI, 0.43-0.99; P = .048), and nonrelapse mortality (HR, 0.55; 95% CI, 0.37-0.83; P = .005). In conclusion, our study showed that imatinib administration before allo-HSCT had advantageous effects on the clinical outcomes of allo-HSCT in patients with Ph(+) ALL.

[Background] We previously demonstrated that allogeneic hematopoietic stem cell transplantation (HSCT) in the first complete remission (CR1) was recommended for adult patients wih Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) who have a human leukocyte antigen (HLA)-matched related (Leukemia 2011;25:259-265) or unrelated donor (Bone Marrow Transplant 2013;48:1077-1083). However, pediatric-inspired high-intensity chemotherapy dramatically improved the prognosis of adult patients with Ph-negative ALL. Therefore, the optimal treatment strategy for Ph-negative ALL in CR1 has not been established in the era of high-intensity chemotherapy. [Methods] Outcomes of patients with Ph-negative ALL who underwent HSCT from HLA-matched related or unrelated donor in CR1 performed between 2002 and 2011 (HSCT-MRD group and HSCT-MUD group, respectively) were obtained from the Transplant Registry Unified Management Program (TRUMP), which is the registry database of the Japanese Society for Hematopoietic Cell Transplantation (JSHCT). Patients aged between 16 and 24 and between 25 and 65 were analyzed separately, and their outcomes were compared with those of patients who did not receive HSCT in CR1 in clinical studies by Japan Adult Leukemia Study Group (JALSG), ALL-202U study in which patients received chemotherapy designed for pediatric patients (Blood Cancer J 2014;4:e252)(202U group) and ALL-202O study in which patients were randomly assigned to receive adult-type chemotherapy with high-dose or intermediate-dose methotrexate (MTX) therapy (Leukemia 2018;32:626-632)(202O group), respectively. Median durations between diagnosis to HSCT were obtained from the TRUMP data, and only patients who were disease-free more than each median duration were included from the JALSG studies. Risk stratifications were performed based on the white blood cell (WBC) count and cytogenetics. [Results] In patients aged less than 25 who underwent HSCT from related donor, the median duration between diagnosis to HSCT was 188 days. Overall survival (OS) in 202U group (N = 93) was significantly superior compared with OS in HSCT-MRD group (N = 102) (OS at 5 years: 81.8% vs 67.8%, P = 0.016) (Figure 1(A)), and which was attributed to the higher non-relapse mortality in HSCT-MRD group (NRM at 5 years: 1.4% vs 9.5%, P = 0.015). Disease-free survival (DFS) and relapse rate (RR) were similar between two groups (DFS at 5 years: 70.2% vs 62.5%, P = 0.115, and RR at 5 years: 28.4% vs 28.4%, P = 0.689). Higher OS was preserved in younger ( In patients aged more than 24 who underwent HSCT from related donor, the median duration between diagnosis to HSCT was 158 days. OS rate was not different between 202O group (N = 147) and HSCT-MRD group (N = 152) (OS at 5 years: 57.0% vs 60.2%, P = 0.114) (Figure 1(B)). The lower RR was counterbalanced by the higher NRM in HSCT-MRD group (RR at 5 years: 51.6% vs 30.0%, P < 0.001, and NRM at 5 years: 4.1% vs 15.2%, P = 0.015). No difference in OS was demonstrated among any subgroups. Superior DFS in HSCT-MRD group was observed only in high-risk patients (DFS at 5 years: 26.5% vs 57.2%, P = 0.003), but it diminished when only patients who actually received high-dose MTX were included in 202O group (DFS at 5 years: 36.4% vs 57.2%, P = 0.092). In patients aged more than 24 who underwent HSCT from unrelated donor, the median duration between diagnosis to HSCT was 214 days. OS rate was not different between 202O group (N = 138) and HSCT-MUD group (N = 104) (OS at 5 years: 60.0% vs 65.8%, P = 0.563). Superior DFS in HSCT-MUD group was observed even in all patients (DFS at 5 years: 47.2% vs 64.2%, P = 0.029). RR in HSCT-MUD group was lower (RR at 5 years: 14.3%) than that in HSCT-MRD group. [Discussions & Conclusions] High-intensity chemotherapy may change the role of HSCT for Ph-nagative ALL. Improved outcomes in HSCT-MUD group were observed, and it was partially because patients who had long CR before HSCT could underwent HSCT from MUD in CR1. Disclosures Kako: Bristol-Myers Squibb: Honoraria; Pfizer Japan Inc.: Honoraria. Tanaka:Bristol-Myers Squibb: Research Funding. Ichinohe:JCR Pharmaceuticals: Honoraria; Celgene: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Astellas Pharma: Research Funding; Chugai Pharmaceutical Co.: Research Funding; CSL Behring: Research Funding; Eisai Co.: Research Funding; Kyowa Hakko Kirin Co.: Research Funding; Ono Pharmaceutical Co.: Research Funding; Pfizer: Research Funding; Nippon Shinyaku Co.: Research Funding; MSD: Research Funding; Otsuka Pharmaceutical Co.: Research Funding; Repertoire Genesis Inc.: Research Funding; Sumitomo Dainippon Pharma Co.: Research Funding; Taiho Pharmaceutical Co.: Research Funding; Takeda Pharmaceutical Co.: Research Funding; Zenyaku Kogyo Co.: Research Funding; Alexion Pharmaceuticals: Honoraria; Bristol-Myers Squibb: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria. Kurahashi:Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Novartis Pharma Co., Ltd.: Honoraria; Takeda Pharmaceutical Co., Ltd: Honoraria; Bristol-Myers Squibb, Ltd.: Honoraria. Usui:Alexion Pharmaceuticals: Other: Personal Fees; Bristol-Myers Squibb: Other: Personal Fees, Research Funding; Kyowa-Hakko-Kirin Co.Ltd.: Other: Personal Fees; Astellas Pharma Inc.: Other: Personal Fees; Huya Bioscience International: Other: Personal Fees; Nippon Shinyaku Co.: Other: Personal Fees; SymBio Pharmaceuticals: Other: Personal Fees; Celgene Corporation: Other: Personal Fees; Pfizer: Other: Personal Fees, Research Funding; Takeda Pharmaceutical Co. Ltd: Other: Personal Fees; Cmic Co: Other: Personal Fees; Otsuka Pharmaceutical Co.Ltd.: Other: Personal Fees; AbbVie Inc: Other: Personal Fees. Kiyoi:Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Astellas Pharma Inc.: Honoraria, Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Pfizer Japan Inc.: Honoraria; Perseus Proteomics Inc.: Research Funding; Otsuka Pharmaceutical Co.,Ltd.: Research Funding; Bristol-Myers Squibb: Research Funding; Daiichi Sankyo Co., Ltd: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; FUJIFILM Corporation: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding. Matsumura:Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau; Otsuka Pharmaceutical: Consultancy, Research Funding; Pfizer: Research Funding, Speakers Bureau. Miyazaki:Chugai: Research Funding; Otsuka: Honoraria; Novartis: Honoraria; Nippon-Shinyaku: Honoraria; Dainippon-Sumitomo: Honoraria; Kyowa-Kirin: Honoraria. Atsuta:CHUGAI PHARMACEUTICAL CO., LTD.: Honoraria; Kyowa Kirin Co., Ltd: Honoraria.

The beneficial effect of rituximab for first-line treatment of diffuse large B-cell lymphoma (DLBCL) has been demonstrated by several randomized controlled trials. To clarify whether results for selected patient populations also apply to unselected patients, we analyzed long-term outcomes for all the 277 consecutive adults diagnosed with de novo DLBCL in a single center between 1998 and 2008. The study population included 147 and 130 patients diagnosed before (Cohort A) and after the advent of rituximab (Cohort B). Progression-free survival (PFS) was significantly better for Cohort B than for Cohort A (P = 0.005). For patients age 60 or younger, PFS did not differ significantly between Cohort A and Cohort B (P = 0.329), but for patients over 60, Cohort B showed superior PFS (P = 0.002). Patients with high or high-intermediate risk according to the International Prognostic Index score showed less improvement in PFS than did those with low or low-intermediate risk primarily because of still unfavorable outcomes of patients with poor performance status. These results indicate that the advent of rituximab has significantly improved outcome for unselected patients with DLBCL, and that improvement was greater for older patients. Further investigations are warranted in the hope of improving outcomes for younger patients with DLBCL.

The prognosis for adult acute lymphoblastic leukemia (ALL) patients with central nervous system (CNS) involvement (CNS+) who received allogeneic hematopoietic stem cell transplantation (allo-SCT) remains unclear. We retrospectively compared the outcomes of allo-SCT for patients with CNS involvement and for patients without CNS involvement (CNS−) using a database in Japan. The eligibility criteria for this study were as follows: diagnosis of ALL, aged more than 16 years, allo-SCT between 2005 and 2012, and first SCT. Data for 2582 patients including 136 CNS+ patients and 2446 CNS− patients were used for analyses. As compared with CNS− patients, CNS+ patients were younger, had worse disease status at SCT and had poorer performance status (PS) at SCT (P < 0.01). Incidence of relapse was higher in CNS+ patients (P = 0.02), and incidence of CNS relapse was also higher (P < 0.01). The probability of 3-year overall survival (OS) was better in CNS− patients (P < 0.01) by univariate analysis. However, in patients who received SCT in CR, there was no difference in the probability of OS between CNS+ and CNS− patients (P = 0.38) and CNS involvement did not have an unfavorable effect on OS by multivariate analysis. CNS+ patients who achieved CR showed OS comparable to that of CNS− patients.

High dose chemotherapy followed by autologous stem cell transplantation (SCT) has been shown to be effective therapy for patients with relapsed lymphoma responsive to standard-dose salvage chemotherapy. Here we report a patient in second complete remission (CR) from relapsed follicular lymphoma (grade 3) who was successfully treated with peripheral blood stem cells (PBSC) that had been harvested in first CR 10 years before. One of six frozen bags was thawed and submitted for progenitor cell assays. Because the number of progenitors was considered to be sufficient for engraftment, autologous SCT was performed without further stem cell harvest. At infusion, the viability of all nucleated cells (ANC) of the 5 remaining bags was 61.4%. She was expected to receive 2.87

既に治療法として確立している造血幹細胞移植に用いる細胞処理のガイドラインを，日本輸血・細胞治療学会と日本造血細胞移植学会との共同指針として今回初めて策定した．欧米のFACT-JACIE基準を参考にする一方で，移植施設が小規模で分散し移植に係るコメディカルの少ないわが国の状況を踏まえて，多くの施設が受容し得る内容とした．ただし，必ずしも現在の大半の施設が満たす基準ではなく「目指すべき基準（理想的な基準）」の内容も含めた．構成は，1目的，2対象，3細胞の採取，4責任者と作業者，5設備・機器，6細胞処理（プロセシング），7払い出し，8保存と解凍，9検体保存，10投与，11廃棄，12雑則からなり，教育的観点から「付」として代表的な細胞処理法に関して，解説，標準作業手順書（SOP）サンプル，記録シートサンプル，結果シートサンプルなどを設けた．今後この指針が多くの場面で運用されるように努めるとともに，現場に即した指針となるように改訂を重ねていく必要がある．また，将来的に欧米の最新の指針と同等の基準となり，また輸血・細胞処理部門認定や有害事象の監視体制を構築するのに活用されることが期待される．

The optimal treatment for adult Philadelphia chromosome-negative acute lymphoblastic leukemia [Ph(−)ALL] during first complete remission (CR1) remains a matter of debate. One treatment option for Ph(−)ALL is autologous hematopoietic stem cell transplantation (auto-SCT).[1][1],[2][2] Previous

Acute promyelocytic leukemia (APL) is the most curable subtype of acute myeloid leukemia. Second complete remission (CR2) can be easily achieved with several therapeutic options even after relapse. However, the optimal strategy to treat APL in CR2 is still controversial. We retrospectively compared the outcome of autologous (auto) and allogeneic (allo) hematopoietic stem cell transplantation (HSCT) for patients with APL in CR2 or CR3. Fifteen patients received auto and 13 received allo HSCT between 1999 and 2004 at eight hospitals belonging to the Nagoya Blood and Marrow Transplantation Group. Four-year disease-free survival (DFS) and overall survival (OS) for autografted patients were 68.9 and 75.8%, whereas those for allografted patients were 46.2 (P = 0.350) and 46.2% (P = 0.185), respectively. Three autografted patients and one allografted patient relapsed, and one autografted patient and five allografted patients died without leukemia relapse. Among 14 autografted patients who were evaluated for MRD with molecular analysis, relapse occurred in one with positive MRD (n = 2) and two with negative MRD (n = 12). These data suggest that auto HSCT is very effective for APL in CR2 or CR3, and may be preferable to allo HSCT for a portion of patients. Prospective studies are required to define the role of auto HSCT in the treatment of relapsed APL.

We describe the clinical outcome of autologous bone marrow transplantation (ABMT) for patients with Philadelphia chromosome —positive acute lymphoblastic leukemia (Ph-ALL). Between 1985 and 2000, 14 patients in first complete remission underwent transplantation. In all cases, harvested marrow was purged with a cocktail of complement and monoclonal antibodies to common acute lymphoblastic leukemia antigen (CALLA). Eight patients died following BMT: 2 patients from interstitial pneumonia and 6 from disease recurrence. For the 6 surviving patients in continuous remission, the median follow-up period was 96 months. The probability of disease-free survival and the rate of relapse at 5 years were 41.7% and 51.4%, respectively. Minimal residual disease (MRD) was assayed quantitatively with patient-specific D-JH probes in 6 of 14 cases. A higher residual tumor burden at marrow harvest was associated with subsequent relapse. Efforts to reduce the MRD burden before harvesting stem cells should improve the clinical outcome of ABMT.

The net benefits of induction therapy for older adults with acute myeloid leukemia (AML) remain controversial. Because AML in older adults is a heterogeneous disease, it is important to identify those who are unlikely to benefit from induction therapy based on information available at the initial assessment. We used next-generation sequencing to analyze TP53 mutation status in AML patients aged 60 years or older, and evaluated its effects on outcomes. TP53 mutations were detected in 12 of 77 patients (16 %), and there was a significant association between TP53 mutations and monosomal karyotype. Patients with TP53 mutations had significantly worse survival than those without (P = 0.009), and multivariate analysis identified TP53 mutation status as the most significant prognostic factor for survival. Neverthelsess, TP53-mutated patients had a 42 % chance of complete remission and a median survival of 8.0 months, which compares favorably with those who did not undergo induction therapy, even in the short term. These results suggest that screening for TP53 mutations at diagnosis is useful for identifying older adults with AML who are least likely to respond to chemotherapy, although the presence of this mutation alone does not seem to justify rejecting induction therapy.