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Varicella zoster virus (VZV) reactivates more frequently in immunocompromised patients than immunocompetent subjects and is a significant cause of morbidity and mortality. Acyclovir is frequently used for treatment against VZV reactivation. However, long-term use of acyclovir can result in the emergence of VZV strain resistant to acyclovir. Here, we report a 67-year-old man with adult T-cell leukemia who suffered from herpes zoster with acyclovir-resistant VZV after long-term prophylaxis. The isolated viruses from his skin lesions were a mixture of acyclovir-resistant and acyclovir-susceptible strains. Sequence analysis showed the presence of thymidine kinase (TK) mutations in the resistant clones. Interestingly, oral administration of famciclovir, a prodrug form of penciclovir, resulted in resolution of his herpes zoster, although most acyclovir-resistant strains of VZV were reported to be resistant to penciclovir. This implied that a certain amount of susceptible VZV with wild-type viral TK gene was present in vivo , and that famciclovir could be phosphorylated intracellularly by the intact viral kinases. As famciclovir is more potent and longer-acting than acyclovir, the susceptible strains might have suppressed the generation and proliferation of the resistant in vivo. Even when VZV is developing resistance to acyclovir, famciclovir might be effective at least in the early resistant phase. [ABSTRACT FROM AUTHOR]

Abstract: Allogeneic hematopoietic cell transplantation (HCT), but not autologous HCT, can provide long-term remission in some patients with adult T cell leukemia-lymphoma (ATL). We retrospectively analyzed the effects of acute graft-versus-host disease (GVHD) among the 616 patients with ATL who survived at least 30 days after allogeneic HCT with other than cord blood grafts. Multivariate analyses treating the occurrence of GVHD as a time-varying covariate demonstrated an association between grade I-II acute GVHD and favorable overall survival (OS) (hazard ratio [HR], 0.634; 95% confidence interval [CI], 0.477 to 0.843), whereas grade III-IV acute GVHD showed a trend toward unfavorable OS (HR, 1.380; 95% CI, 0.988 to 1.927) compared with nonacute GVHD. In subsequent multivariate analyses of patients who survived at least 100 days after HCT (n = 431), the presence of limited chronic GVHD showed a trend toward favorable OS (HR, 0.597; 95% CI, 0.354 to 1.007), and extensive chronic GVHD had a significant effect on OS (HR, 0.585; 95% CI, 0.389 to 0.880). There were no significant interactions between myeloablative conditioning or reduced-intensity conditioning with OS even when acute GVHD was absent or present at grade I-II or grade III-IV or when chronic GVHD was absent, limited, or extensive. This study demonstrates the actual existence of graft-versus-ATL effects in patients with ATL regardless of whether myeloablative conditioning or reduced-intensity conditioning is used. [Copyright &y& Elsevier]

Adult T-cell leukemia-lymphoma (ATL) is an intractable mature T-cell neoplasm. We performed a nationwide retrospective study of allogeneic hematopoietic stem cell transplantation (HSCT) for ATL in Japan, with special emphasis on the ef-fects of the preconditioning regimen. This is the largest study of ATL patients receiv-ing HSCT. Median overall survival (OS) and 3-year OS of bone marrow or periph-eral blood transplantation recipients (n = 586) was 9.9 months (95% confidence interval, 7.4-13.2 months) and 36% (32%-41%), respectively. These values for recipients of myeloablative conditioning (MAC; n = 280) and reduced intensity con-ditioning (RIC; n = 306) were 9.5 months (6.7-18.0 months) and 39% (33%-45%) and 10.0 months (7.2-14.0 months) and 34% (29%-40%), respectively. Multivariate anal-ysis demonstrated 5 significant variables contributing to poorer OS, namely, older age, male sex, not in complete remission, poor performance status, and transplantation from unrelated donors. Although no significant difference in OS between MAC and RIC was observed, there was a trend indicating that RIC contributed to better OS in older patients. Regarding mortality, RIC was significantly associated with ATL-related mortality compared with MAC. In conclusion, allogeneic HSCT not only with MAC but also with RIC is an effective treatment resulting in long-term survival in selected patients with ATL. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic cell transplantation (HCT) is an effective treatment for adult T-cell leukemia (ATL), raising the question about the role of graft-versus-leukemia effect against ATL. In this study, we retrospectively analyzed the effects of acute and chronic graft-versus-host disease (GVHD) on overall survival, disease-associated mortality, and treatment-related mortality among 294 ATL patients who received allogeneic HCT and survived at least 30 days posttransplant with sustained engraftment. Multivariate analyses treating the occurrence of GVHD as a time-varying covariate demonstrated that the development of grade 1-2 acute GVHD was significantly associated with higher overall survival (hazard ratio [HR] for death, 0.65; P= .018) compared with the absence of acute GVHD. Occurrence of either grade 1-2 or grade 3-4 acute GVHD was associated with lower disease-associated mortality compared with the absence of acute GVHD, whereas grade 3-4 acute GVHD was associated with a higher risk for treatment-related mortality (HR, 3.50; P < .001). The development of extensive chronic GVHD was associated with higher treatment-related mortality (HR, 2.75; P = .006) compared with the absence of chronic GVHD. Collectively, these results indicate that the development of mild-to-moderate acute GVHD confers a lower risk of disease progression and a beneficial influence on survival of allografted patients with ATL. [ABSTRACT FROM AUTHOR]

Adult T-cell leukaemia (ATL) is a peripheral T-cell neoplasm caused by human T-cell leukaemia virus type I (HTLV-I). Several clinical observations suggest that some tumour-associated antigens in ATL may be recognised by the immune system. In this study, we performed the serological screening of an expression library to identify ATL-associated antigens by using materials from a unique ATL patient with long-term stable disease. Among five distinct genes isolated, serine/arginine protein kinase 1 ( SRPK1), which has been reported to have a restricted normal tissue distribution, was found to be overexpressed in most acute type ATL samples, but not in chronic type ATL or in normal peripheral blood mononuclear cells by real-time reverse transcription polymerase chain reaction. Interestingly, the overexpression of SRPK1 in aggressive types of ATL was more exclusively observed at the protein level than at the mRNA level. Autologous antibody to SRPK1 was confirmed in the ATL patient using Western blot analysis with plasma, but not detected in asymptomatic HTLV-I carriers or in healthy volunteers. These results indicate that SRPK1 may be useful for the development of therapeutic and diagnostic methods for patients with ATL. [ABSTRACT FROM AUTHOR]

Recently, a graft- versus-lymphoma (GVL) effect has been shown in patients allografted for mantle cell lymphoma (MCL), but the antigenic targets of this response remain unclear. We screened an MCL cDNA expression library with sera at GVL response after allogeneic haematopoietic stem cell transplantation and isolated five genes including APOBEC3B. Antibody responses to APOBEC3B were correlated with clinical response. Furthermore, APOBEC3B-specific T-cell response was induced with one of the HLA-A*0201 binding peptides. In addition, APOBEC3B mRNA appeared to be upregulated in some MCL. These findings warrant further investigation of APOBEC3B as a candidate gene eliciting an effective immune response against MCL. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) play an important role in innate and adaptive immunity. There are two major populations of blood DCs, myeloid DCs (myDCs) and plasmacytoid DCs (pcDCs). pcDCs are particularly important in antiviral as well as in general host defence, as they are the principal producers of type I interferons (IFNs). In this study, we analysed myDCs and pcDCs in healthy controls, human T-cell leukaemia virus type I (HTLV-I)-infected asymptomatic carriers (ACs), and patients with adult T-cell leukaemia (ATL). ATL patients had significantly decreased number of pcDCs and myDCs compared with controls. IFN- α production by peripheral blood mononuclear cells (PBMCs) was markedly reduced in ATL patients. Purified pcDCs from ACs were found to have impaired IFN- α-producing capacity, suggesting a functional defect in pcDCs in HTLV-I-infected individuals. Interestingly, pcDCs were shown to be susceptible to HTLV-I infection. Thus, impaired IFN- α production by pcDCs may contribute to the immunodeficiency observed in ATL. Furthermore, IFN- α-producing capacity was inversely correlated with HTLV-I proviral load in PBMCs from ACs, suggesting a role for pcDCs in maintaining the carrier state. Taken together, we hypothesize that the depletion and impaired IFN- α-producing capacity of blood DCs may contribute to the immunodeficiency in ATL and/or the development of ATL. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented related to the haematopoietic malignancies of allogenic stem cell transplantation with lymphoid neoplasm with eosinophilia.

The number of patients who are administered immunosuppressive agents has been increasing. Accordingly, more patients face higher risks for developing immunodeficiency-associated lymphoproliferative disorders (LPD). Although immunodeficiency-associated LPD are distinct from other lymphoid neoplasms in terms of their immunocompromised backgrounds, little is known about the impact of lymphopenia at diagnosis on survival in patients with these LPD. Seventy-one immunodeficiency-associated LPD in Kyoto University Hospital (post-transplant LPD (PTLD), n = 26; other iatrogenic immunodeficiency-associated LPD, n = 45) were reviewed and analyzed. The median age at diagnosis was 63 years (range, 3–83). Diffuse large B cell lymphoma was the most common subtype (n = 33), followed by Hodgkin lymphoma (n = 12), B cell monomorphic LPD not specified (n = 11), and polymorphic LPD or early-phase diseases (n = 15). The median follow-up period for survivors was 2.5 years and overall survival (OS) and progression-free survival (PFS) at 2.5 years were 75% and 67%, respectively. Multivariate analysis showed that lymphopenia (≤ 800/μL) at diagnosis predicted inferior OS (HR, 3.72; P = 0.043) and PFS (HR, 3.82; P = 0.012). Serum albumin values also strongly affected OS (> 3.18 g/dL vs. ≤ 3.18 g/dL; HR, 0.21; P = 0.010) and PFS (HR, 0.26; P = 0.013). Lymphopenia at diagnosis is suggested to predict inferior OS and PFS in patients with immunodeficiency-associated LPDs. Immunocompromised status might affect disease progression in these distinct lymphoid neoplasms growing under immunocompromised backgrounds. [ABSTRACT FROM AUTHOR]

Highlights • High lymphocyte area under the curve (AUC) was associated with a lower frequency of cytomegalovirus antigenemia. • High lymphocyte AUC was associated with a lower risk of treatment-related mortality. • Lymphocyte AUC could be a prognostic factor of immune-reconstitution after hematopoietic stem cell transplantation (HSCT). • High lymphocyte AUC was associated with a high frequency of human herpesvirus 6 (HHV-6) reactivation. • Rapid recovery of lymphocytes after HSCT might be associated with HHV-6 expansion. Abstract Viral infection is a serious complication that can greatly affect patient mortality and morbidity after allogenic hematopoietic stem cell transplantation (allo-HSCT). For the early identification of patients at high risk for viral infection, we evaluated the impact of lymphocyte area under the curve (AUC) value as a new predictive factor for early immune reconstitution after allo-HSCT against viral infection. This study included 286 patients who underwent their first allo-HSCT at Kyoto University Hospital between 2005 and 2017. Lymphocyte AUC from day 0 to day +15 was calculated in the analysis of human herpesvirus 6 (HHV-6), and lymphocyte AUC from day 0 to day +30 was calculated in the analysis of other viruses (cytomegalovirus [CMV], adenovirus, BK virus, JC virus, and varicella zoster virus). The risk factors for each viral reactivation/infection were assessed by multivariate analysis. The median age at transplantation was 51years (range, 17 to 68 years). The median lymphocyte AUC was 63/μL (range, 0 to 5620/μL) at day +15 and 3880 (range, 0 to 118,260/μL) at day +30. An increase in lymphocyte AUC was significantly associated with a high frequency of HHV-6 reactivation (P =.033) and a low frequency of CMV antigenemia (P =.014). No apparent association was found between lymphocyte AUC and reactivation/infection of other viruses. Aplastic anemia as a primary disease (hazard ratio [HR], 5.34; P <.001) and cord blood as a donor source (HR, 3.05; P =.006) were other risk factors for HHV-6 reactivation. Other risk factors for CMV antigenemia included the occurrence of acute graft-versus-host disease (HR 2.21; P <.001) and recipient age (HR 1.55; P =.017). Higher lymphocyte AUC at day +30 was significantly associated with low treatment-related mortality (HR,.47; P =.045). Lymphocyte AUC may be a good predictive factor for immune reconstitution against CMV reactivation. It also provides valuable information for predicting HHV-6 reactivation and treatment-related mortality. [ABSTRACT FROM AUTHOR]

Background: The preventive effect of laminar air flow (LAF) on aspergillosis has been observed in patients with hematological malignancies. However, the short follow-up period limits the interpretation of study results.Methods: To assess the preventive effect of long-term LAF use on aspergillosis in its long-term use, we retrospectively analyzed 124 acute leukemia patients at our hospital between January 2005 and March 2016. We compared the incidence of aspergillosis before (May 2008) and during the construction of a new building (June 2008-January 2010) and in the early (February 2010-March 2014) and late (April 2014-March 2016) periods after moving to a new hematology ward with an LAF system. The 2008 European Organization for Research and Treatment of Cancer and Mycosis Study Group criteria were used for the diagnosis of aspergillosis.Results: Fourteen patients were diagnosed with possible, probable, or definite aspergillosis. Cumulative incidence rates of aspergillosis at day 180 were 12.4, 24.9, 9.3, and 25.1% before construction, during construction, in the early period after moving to a new ward, and in the late period after moving to a new ward, respectively (p = 0.106). Multivariate analysis showed that the LAF system tended to reduce the risk of aspergillosis in the early period (before construction vs. early period; hazards ratio (HR) = 1.97, p = 0.463 and during construction vs. early period;HR = 3.42, p = 0.184), but the risk increased in the late period (late vs. early period, HR = 5.65, p = 0.035).Conclusions: Building construction might increase the risk of aspergillosis. Short-term LAF use might reduce aspergillosis risk, but its long-term use is inadequate, although we could not exclude the possibility of increased risks in the recent period due to continued improvements in the different areas of our hospital. Strict maintenance, more effective LAF system, and optimization of aspergillosis prophylaxis may be necessary. [ABSTRACT FROM AUTHOR]

Highlights • We hypothesized that the use and type of antibiotics had an impact on the occurrence of aGVHD through intestinal microbiota alterations. • The administration of fourth-generation cephalosporin had a strong impact on the onset of aGVHD. • We suggest that the impact of antibiotics on aGVHD may vary among the population. Abstract The intestinal microbiota plays an important role in the pathogenesis of acute graft-versus-host disease (aGVHD). During the course of hematopoietic stem cell transplantation (HSCT), the intestinal microbiota is influenced by the use of broad-spectrum antibiotics. However, the impact of the use and type of antibiotics on the microbiota composition and, subsequently, the onset of aGVHD remain poorly understood. We hypothesized that the use and type of antibiotics had an impact on the occurrence of aGVHD. We assessed 275 patients who underwent their first allogeneic HSCT between January 2005 and June 2015 at Kyoto University Hospital. We monitored the 6 most frequently administered antibiotics (fourth-generation cephalosporins, glycopeptides, piperacillin-tazobactam, carbapenems, aminoglycosides, and quinolones) administered between days –14 and +14 relative to HSCT and its duration. The primary endpoint was the cumulative incidence of grades II to IV aGVHD. The cumulative incidence of aGVHD was significantly higher in patients administered fourth-generation cephalosporins than in patients not receiving fourth-generation cephalosporins (grades II to IV: hazard ratio, 1.98; 95% confidence interval, 1.19 to 3.29; P =.0087; grades III to IV: hazard ratio, 8.03; 95% confidence interval, 1.07 to 60.51; P =.043). In contrast, there was no significant association between administration of other antibiotics and aGVHD incidence. As for organ-specific aGVHD, the cumulative incidence of gut aGVHD was significantly higher in patients who received fourth-generation cephalosporins than in those who did not (31% versus 16%, P =.018). In conclusion, we demonstrated that the administration of fourth-generation cephalosporins had a strong impact on the development of aGVHD. Graphical abstract Image, graphical abstract [ABSTRACT FROM AUTHOR]

• A rare Epstein–Barr virus-associated post-transplant lymphoproliferative disease. • Flow cytometric in situ hybridization was useful for detecting the infected cells. • Further research is needed to establish appropriate treatment strategies. A 69-year-old man who underwent cord blood transplantation seven years ago was admitted because of fever, elevated liver enzymes and thrombocytopenia. Bone marrow aspirate revealed hemophagocytic lymphohistiocytosis. Viral capsid antigen (VCA)-immunoglobulin (Ig) G, VCA-IgM, VCA-IgA, Epstein–Barr virus nuclear antigen-IgG, early antigen-diffuse-type and restricted-type (EA-DR) IgG, and EA-DR IgA titers were 2560, <10, 10, 40, 40, and <10, respectively. Real-time polymerase chain reaction assay of peripheral whole blood for Epstein–Barr virus-deoxyribonucleic acid (EBV-DNA) revealed 240,000 copies/μg DNA. Flow cytometric in situ hybridization assay confirmed that EBV-infected cells were NK-cells. Clonality evaluation by Southern blot assay of EBV-DNA terminal repeats proved to be bi-clonal. Accordingly, we made a diagnosis of NK-cell post-transplant lymphoproliferative disease with chronic active EBV infection-like clinical findings (CAEBV-like NK-cell PTLD). Although CAEBV-like PTLD is extremely rare, its prognosis seems to be very poor. The disease should be considered in such patients who present persistent or recurrent infectious mononucleosis-like symptoms after transplantation. [ABSTRACT FROM AUTHOR]

The article offers information about a patient who was presented with persistent fever and pancytopenia and reported pain in the pelvis and femora. According to medical examination that the patient had undertaken, the man had suffered from a primary bone marrow lymphoma, classified as diffuse large B-cell lymphoma.

Adenovirus (ADV)- or BK virus (BKV)-associated hemorrhagic cystitis (HC) is a common complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Several risk factors have been previously reported; however, it is unclear whether virus-associated HC can be transmitted. To clarify this point, we performed a retrospective cohort study on 207 consecutive patients who underwent allo-HSCT at Kyoto University Hospital between 2012 and 2018. We evaluated the incidence and risk factors of virus-associated HC and performed a phylogenetic analysis of the ADV partial sequence. The median age at transplantation was 50 (range, 17–68) years. Fifty-eight patients (28%) developed HC. ADVs were detected in 18 cases, BKVs were detected in 51, both were detected in 12, and only John Cunningham virus (JCV) was detected in 1 case. No factor was significantly associated with HC. However, both ADV- and BKV-HC occurred intensively between April 2016 and September 2017, which suggested possible nosocomial transmission of ADV and BKV. Genome sequencing of the hexon, E3, and penton regions of detected ADVs identified 7 cases of ADV type 11, 2 cases of type 35, and 3 cases of a type 79-related strain. A sequence analysis revealed that these strains in each type were almost identical, except for one case of a type 79-related strain. In conclusion, ADV-HCs with possible nosocomial transmission were described based on genotyping of the virus and partial sequencing of the viral genome. Although viral HC after allo-HSCT is thought to mainly be due to reactivation of a latent virus, nosocomial transmission of ADV or BKV should also be considered. [ABSTRACT FROM AUTHOR]

We report a case of 68-year-old man with stable polymyositis complicated with primary hepatic lymphoma (PHL) as other iatrogenic immunodeficiency-related lymphoproliferative disorders (OIIA-LPD). Multiple liver masses were diagnosed as diffuse large B-cell lymphoma (DLBCL) by biopsy. The LPD was associated with Epstein–Barr virus (EBV) reactivation, because EBV-DNA was detected in peripheral blood, and EBV antigen was detected in the tumour. He presented with high fever, cytopenia and hyperferritinemia, suggesting hemophagocytosis. Only discontinuation of methotrexate and tacrolimus resulted in a dramatic regression of the liver masses and improvement of fever and cytopenia. We review six cases of OIIA-LPD localised in the liver. All cases were DLBCL; 4/6 cases (67%) were positive for EBV staining, and 2/6 cases (33%) were improved after the discontinuation of immunosuppressants. Screening for EBV in blood and liver tumour is important, when a patient in immunosuppressive status presented with liver masses. [ABSTRACT FROM AUTHOR]

Benefit of high-dose cytarabine (HD-AraC) for acute myeloid leukemia (AML) prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains unknown. We retrospectively analyzed data from 79 non-core-binding-factor AML patients who underwent allo-HSCT in their first complete remission (CR1). In univariate analysis, HD-AraC (≥4 g/m2/day) before allo-HSCT improved disease-free survival (DFS) (p =.018), overall survival (OS) (p =.029), and cumulative incidence of relapse (CIR) (p =.033). Four-year DFS, OS, and CIR of patients receiving and not receiving HD-AraC were 79% vs. 49%, 82% vs. 56%, and 18% vs. 42%, respectively. In multivariate analysis, HD-AraC was a positive prognostic factor for DFS (hazard ratio (HR) = 0.36, 95% confidence interval (CI): 0.14–0.88), OS (HR = 0.37, 95% CI: 0.14–0.99), and CIR (HR = 0.38, 95% CI; 0.14–1.0). Our study demonstrates that HD-AraC before allo-HSCT at a dose ≥4 g/m2/day is effective for treating AML patients in CR1. [ABSTRACT FROM AUTHOR]

• Allogeneic hematopoietic stem cell transplantation is beneficial for patients with mature T cell and natural killer cell neoplasms. • Cord blood transplantation (CBT) resulted in favorable outcomes with a lower risk of relapse. • CBT could be a preferred option, especially for patients with uncontrolled diseases. • Better control of lymphoma at transplantation is a key to improved outcomes. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the key strategy to cure patients with mature T and natural killer (NK) cell lymphomas/leukemia, especially those with relapsed/refractory diseases, there is no consensus strategy for donor selection. We retrospectively analyzed the outcomes of allo-HSCT in 111 patients in 15 Japanese institutions as a multi-institutional joint research project. Thirty-nine patients received bone marrow or peripheral blood stem cell transplantation from related donors (rBMT/rPBSCT), 37 received BMT/PBSCT from unrelated donors (uBMT/uPBSCT), and 35 received cord blood transplantation (CBT). Overall survival (OS) and progression-free survival (PFS) at 4 years were 42% and 34%, respectively. The cumulative incidences of relapse and nonrelapse mortality were 43% and 25%. In multivariate analysis, CBT showed comparable OS with rBMT/rPBSCT (rBMT/rPBSCT versus CBT: hazard ratio [HR], 1.63; P =.264) and better OS compared with uBMT/uPBSCT (HR, 2.99; P =.010), with a trend toward a lower relapse rate (rBMT/rPBSCT versus CBT: HR, 2.60; P =.010; uBMT/uPBSCT versus CBT: HR, 2.05; P =.082). This superiority of CBT was more definite in on-disease patients (OS: rBMT/rPBSCT versus CBT: HR, 5.52; P =.021; uBMT/uPBSCT versus CBT: HR, 6.80; P =.007). Better disease control was also strongly associated with better OS and PFS with lower relapse rate. In conclusion, allo-HSCT is beneficial for the survival of patients with mature T and NK cell lymphomas/leukemia if performed in a timely fashion. Since CBT showed favorable survival with a lower relapse risk, it could be a preferred alternative, especially in on-disease patients. [ABSTRACT FROM AUTHOR]

Aims: We performed the retrospective analysis to clarify the significance of drug monitoring for mycophenolic acid (MPA), the active form of mycophenolate mofetil (MMF), in prophylaxis for graft‐vs‐host disease (GVHD) in cord blood transplantation. Methods: We retrospectively analysed the data of 46 patients who underwent first cord blood transplantation and received GVHD prophylaxis with tacrolimus plus MMF. MPA levels were measured on days 7 and 21, and 24‐hour areas under the curve (AUC0–24) were estimated. Results: The engraftment and 3‐year overall survival rates of all patients were 94% and 78%, respectively. The cumulative incidence of sepsis before engraftment was higher in patients with AUC0–24 on day 7 of >60 μg h/mL than in other patients (33 vs 6%, P =.02). The cumulative incidence of grade II–IV acute GVHD was higher in patients with AUC0–24 on day 21 of ≤30 μg h/mL than in other patients (80 vs 50%, P =.04). The cumulative incidence of human herpesvirus 6 reactivation was higher in patients with AUC0–24 on day 21 of ≤48 μg h/mL (median) than in other patients (50 vs 19%, P =.03). Conclusion: Blood level of MPA was associated with risk of acute GVHD and infection. A prospective trial evaluating the benefit of personalized MMF dosing using MPA levels is needed. [ABSTRACT FROM AUTHOR]

• Loss of CD58 is a common mechanism for immune evasion in lymphoid malignancies. • EZH2 inhibitors restore epigenetically suppressed CD58 expression of lymphoma cells. • EZH2 inhibitors enhance IFN-γ production of T and NK cells against lymphoma cells. Loss of CD58 is a common mechanism for tumor immune evasion in lymphoid malignancies. CD58 loss is known to occur due to both genetic and non-genetic causes; therefore, we hypothesized that restoring CD58 expression in lymphoma cells may be an effective treatment approach. To explore the potential for restoring CD58 expression, we first screened 11 B-cell lymphoma lines and found that 3 had decreased CD58 expression. Among these, CD58 was genetically damaged in two lines but not in the third line. Using the cell line with downregulated CD58 without a genetic abnormality, we performed epigenetic library screening and found that two EZH2 inhibitors, EPZ6438 and GSK126, specifically enhanced CD58 expression. By examining the effect of three EZH2 inhibitors with different selectivity profiles in different B-cell lines, EZH2 inhibition was shown to have a common activity in upregulating CD58 expression. Restoring the expression of CD58 in lymphoma cells using an EZH2 inhibitor was shown to enhance interferon-γ production of T and NK cells against lymphoma cells. H3K27 was shown to be highly trimethylated in the CD58 promoter region, and EZH2 inhibition induced its demethylation and activated transcription of the CD58 gene. These results indicated that EZH2 is involved in the epigenetic silencing of CD58 in lymphoma cells as a mechanism for tumor immune escape, and EZH2 inhibitors are able to restore epigenetically suppressed CD58 expression. Our findings provide a molecular basis for the combination of an EZH2 inhibitor and immunotherapy for lymphoma treatment. [ABSTRACT FROM AUTHOR]

Background: Systemic steroid is used to treat various transplant‐related complications after allogenic hematopoietic stem cell transplantation (allo‐HSCT). However, measures to evaluate its impact on infections are still limited. Hence, we examined the cumulative steroid dose used within 30 days after transplant as a predictor of future risk of infections. Methods: This study included 226 patients who underwent their first allo‐HSCT at Kyoto University Hospital between 2005 and 2015. Results: Sixty‐one patients received transplantation from related donors, 106 received unrelated BMT and 59 received unrelated single‐unit CBT. Patients were categorized into three groups according to the cumulative steroid dose in terms of prednisolone: no‐steroid group (n = 174), low‐dose group (≤7 mg/kg) (n = 22) and high‐dose group (>7 mg/kg) (n = 30). In a multivariate analysis, high‐dose steroid administration was associated with cytomegalovirus (CMV) antigenemia (HR 1.91, P = 0.037) and bacteremia (HR 2.59, P = 0.053). No impact was found on the occurrence of invasive fungal infection. Conclusion: High‐dose cumulative steroid could predict high risks of bacteremia and CMV antigenemia. Additional anti‐bacterial agents for fever and regular measurement of CMV antigen are recommended for whom with systemic steroid administration even after neutrophil engraftment. [ABSTRACT FROM AUTHOR]

Background: Blocking the PD-1 pathway induces immune-related adverse events (irAEs) which often involve the thyroid gland (thyroid irAEs). Clinical features of a thyroid irAE including its predictability and relationship to prognosis remain to be elucidated. Methods: Two hundred consecutive patients treated with nivolumab at Kyoto University Hospital between September 1, 2014 and August 31, 2017 were included in a retrospective cohort study. We systematically determined and classified subclinical and overt thyroid irAEs based on data collected of serum free T4 and TSH levels. Baseline characteristics and detailed clinical data were analyzed, and analyses of overall survival (OS) excluded patients censored within 1 month from the first administration of nivolumab. Results: Sixty-seven patients (33.5%) developed thyroid irAEs and these were divided into a subclinical thyroid irAE group (n = 40, 20.0%) and an overt thyroid irAE group (n = 27, 13.5%). Patients with thyroid uptake of FDG-PET before treatment showed high incidences of overt thyroid irAE (adjusted odds ratio 14.48; 95% confidence interval [CI] 3.12–67.19), while the same relationship was not seen with subclinical thyroid irAE. Regarding the total cohort, the thyroid irAE (+) group had a significantly longer median OS than the thyroid irAE (−) group (16.1 versus 13.6 months, hazard ratio [HR] 0.61; 95% CI 0.39–0.93). In 112 non-excluded patients with lung cancer, the thyroid irAE (+) group similarly had a longer median OS than the thyroid irAE (−) group (not reached versus 14.2 months, HR 0.51; 95% CI 0.27–0.92). However, this observation was not seen in 41 non-excluded patients with malignant melanoma (12.0 versus 18.3 months, HR 1.54; 95% CI 0.67–3.43). Conclusions: By thyroid uptake of FDG-PET, overt thyroid irAEs could be predicted before nivolumab therapy. Thyroid irAEs related to good prognosis in lung cancer but might be inconclusive in malignant melanoma. [ABSTRACT FROM AUTHOR]

Activation-induced cytidine deaminase (AID) plays important roles in the development of diffuse large B-cell lymphoma (DLBCL); however, its prognostic value remains controversial. Here, we evaluated AID expression in 71 DLBCL patients treated with R-CHOP by immunohistochemistry and investigated its prognostic significance. AID expression was detected in 40.8% of DLBCL samples and associated with IRF4 expression. Notably, AID expression correlated with shorter progression-free survival and overall survival for patients with high (3-5) international prognostic index (IPI) score. Moreover, it was a strong predictor of poor overall response to salvage therapy after relapse or disease progression, which may suggest its role in promoting the evolution of tumors into highly refractory disease at relapse. Our findings indicate that AID expression effectively discriminates between IPI-high score patients with different survival outcomes, and suggest that initial disease control would be particularly important for the treatment of IPI-high score patients with AID-positive DLBCL. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV)-associated post-transplantation lymphoproliferative disorders (PTLD) represent a heterogeneous group of EBV-driven abnormal lymphoid proliferations occurring after allogeneic hematopoietic stem cell transplantation [[1]-[3]]. Biopsy of the supraclavicular lymph node was performed for diagnosis, and the histology showed EBV-associated cHL-like PTLD with the presence of CD15, CD30, and EBER-positive tumor cells. [Extracted from the article]

Chromosomal translocations juxtaposing the class II homeobox gene I PRRX2 i with I NUP98 i loci have been reported in therapy-related acute myeloid leukemia (AML), but their clinical significance is unclear [[2]]. There have been some reports of AML development in rheumatoid arthritis patients treated with MTX, although it remains unclear whether low-dose MTX therapy may serve a role in pathogenesis of AML [[4]]. [Extracted from the article]

The number of patients eligible for allogeneic stem cell transplantation (allo-HSCT) has increased because of improvements in transplantation procedures. Among long-term survivors of allo-HSCT, chronic kidney disease (CKD) is a major cause of morbidity. We retrospectively analyzed the clinical data of 106 consecutive patients with a median age of 43 years (range, 17 to 73) who had undergone allo-HSCT at our institution between January 2001 and September 2009. Patients who died within 5 years after transplantation or had CKD at the time of transplantation were excluded from study. CKD was defined as a persistent decrease in the estimated glomerular filtration rate to below 60 mL/min/1.73 m 2 . CKD occurred in 32 patients (30.2%) at a median time of 55 months after transplantation. Three patients required maintenance hemodialysis. In multivariate analysis older age at the time of transplantation (hazard ratio [HR], 1.07/year; 95% confidence interval [CI], 1.02 to 1.13) and a history of acute kidney injury (AKI) within 100 days after transplantation (HR, 6.30; 95% CI, 2.21 to 17.9) were significant risk factors for CKD. Conditioning regimen, stem cell source, or the presence of acute/chronic GVHD was not significantly associated with CKD in this study. Patients with CKD had a lower overall survival rate (HR, 4.11; 95% CI, 1.3 to 13.0) than patients without CKD. Careful monitoring of renal function is required for long-term survivors after allo-HSCT, especially in patients who have experienced AKI and in older patients. [ABSTRACT FROM AUTHOR]

The article discusses the research on the therapeutic use of allogeneic hematopoietic stem cell transplantation in treating T cell/natural killer (NK) neoplasms. It mentions the remission and survival rate of patients with T cell lymphoma. It also mentions a graph on the outcome analysis of patients with T/NK-cell neoplasms after allogeneic hematopoietic stem cell transplantation.

Iron overload is considered a risk factor for mortality in patients with hematopoietic malignancies. Hepcidin is a key regulator of systemic iron balance. We previously reported dynamic changes of serum hepcidin-25 levels in patients with hematologic malignancies after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this study, we retrospectively analyzed the association of pretransplant hepcidin-25 levels with overall survival (OS), engraftment, and other clinical outcomes of allo-HSCT in patients with hematologic malignancies. A total of 166 patients were divided into two groups depending on their pretransplant serum hepcidin-25 levels; their median age was 49.5 years, and the median follow-up time was 46.8 months. At 3 years, the patients in the high-hepcidin group had a significantly lower OS than those in the low-hepcidin group (49.2 vs. 69.0%, respectively; P = 0.006). Multivariate analysis revealed that pretransplant serum hepcidin-25 level, sex, and disease status were independently associated with OS. The incidence of platelet engraftment was significantly lower in the high-hepcidin group than in the low-hepcidin group, whereas no significant differences were observed in neutrophil and reticulocyte engraftments between these groups. Hence, pretransplant serum hepcidin levels can be a marker for predicting delayed platelet recovery after allo-HSCT. [ABSTRACT FROM AUTHOR]

Adult T cell leukemia/lymphoma (ATL) is a peripheral T cell neoplasm of largely unknown genetic basis, associated with human T cell leukemia virus type-1 (HTLV-1) infection. Here we describe an integrated molecular study in which we performed whole-genome, exome, transcriptome and targeted resequencing, as well as array-based copy number and methylation analyses, in a total of 426 ATL cases. The identified alterations overlap significantly with the HTLV-1 Tax interactome and are highly enriched for T cell receptor-NF-κB signaling, T cell trafficking and other T cell-related pathways as well as immunosurveillance. Other notable features include a predominance of activating mutations (in PLCG1, PRKCB, CARD11, VAV1, IRF4, FYN, CCR4 and CCR7) and gene fusions (CTLA4-CD28 and ICOS-CD28). We also discovered frequent intragenic deletions involving IKZF2, CARD11 and TP73 and mutations in GATA3, HNRNPA2B1, GPR183, CSNK2A1, CSNK2B and CSNK1A1. Our findings not only provide unique insights into key molecules in T cell signaling but will also guide the development of new diagnostics and therapeutics in this intractable tumor. [ABSTRACT FROM AUTHOR]

Objectives Late-onset neutropenia after rituximab (RTX) therapy (R-LON) has been widely reported, but clinical studies on a large number of cases are limited. In this study, we aimed to investigate the incidence and risk factors of R-LON. Patients and methods In this study, we retrospectively analyzed data of 213 enrolled B-cell lymphoma patients (male 114; female 99) treated with RTX at a single institution. R-LON was defined as otherwise unexplained grade III–IV neutropenia after RTX. The median age of the patients was 62 years, and 129 of them were initially diagnosed at advanced stages (stage III–IV). Results R-LON occurred in 19 patients within a median of 121 (range, 49–474) days after the last RTX administration. The 1-year cumulative incidence was 9.0%. On univariate analysis, older age (>60 years), advanced stage, and purine analog or methotrexate administration were significant or borderline significant risk factors for R-LON, whereas sex, disease type, bone marrow invasion, combination with cytotoxic chemotherapeutic drugs, intensified therapy (compared with R-CHOP), prior autologous transplantation, and repeated RTX administration were not. On multivariate analysis, older age (hazard ratio (HR), 2.95) and advanced stage (HR, 3.56) were significant risk factors. Treatment with granulocyte colony-stimulating factor was feasible in grade IV R-LON patients with high risk of infection. Discussion and conclusion Careful follow-up is therefore necessary after B-cell lymphoma treatment, especially in high-risk patients with advanced disease or of older age. [ABSTRACT FROM AUTHOR]

A letter to the editor, which reports on the effectiveness of intra-arterial steroid infusion in the treatment of severe acute gastrointestinal graft-versus-host disease complicated by cytomegalovirus gastroenteritis, is presented.

Objective The objective of this study was to evaluate the therapeutic potential of bevacizumab with or without systemic chemotherapy for adult T-cell leukemia/lymphoma ( ATL) and clarify the significance of angiogenesis for ATL pathogenesis. Methods NOD/ Shi- scid, IL-2 Rγnull ( NOG) mice were used as recipients of tumor cells from a patient with ATL, which engraft and proliferate in a microenvironment-dependent manner. The ATL cells could be serially transplanted in NOG mice, but could not be maintained in in vitro cultures. Results Injection of bevacizumab alone significantly increased necrosis and decreased vascularization in the tumor tissue. Levels of human soluble interleukin two receptor in the serum (reflecting the ATL tumor burden) of bevacizumab-treated mice were significantly lower than in untreated mice. Although bevacizumab monotherapy showed these clear anti-angiogenesis effects, it did not prolong survival. In contrast, injection of bevacizumab together with cyclophosphamide, doxorubicin, vincristine, prednisolone ( CHOP) led to a significant prolongation of survival of the ATL mice relative to CHOP alone. Conclusions This is the first report to evaluate the efficacy of bevacizumab for ATL in a tumor microenvironment-dependent model. Bevacizumab therapy combined with chemotherapy could be a valuable treatment strategy for that subgroup of ATL probably depending to a large extent on angiogenesis via vascular endothelial growth factor. [ABSTRACT FROM AUTHOR]

Key Clinical Message Currently, there is no standard treatment for neurolymphomatosis because of the scarcity of clinical studies. Here, we report the successful treatment of neurolymphomatosis caused by follicular lymphoma with bendamustine, which could be an effective treatment option for this condition. [ABSTRACT FROM AUTHOR]

Adult T-cell leukaemia (ATL) is caused by human T-cell leukaemia virus type I (HTLV-I). It has been suggested that cytokines play a role in the development and in the neoplastic cell growth of ATL. However, the precise mechanism involved in this process still remains unclear. Interleukin-21 (IL-21) and its receptor (IL-21R) have been recently described. In this study, we examined the expression of IL-21R and the effect of IL-21 on ATL cells. Real-time reverse transcription polymerase chain reaction showed that HTLV-I-infected cell lines and primary ATL cells expressed IL-21R mRNA. Cell surface expression of IL-21R on these cells was confirmed by flow cytometric analysis using a newly developed monoclonal antibody against human IL-21R. In contrast to the expression of IL-21R, IL-21 mRNA was scarcely detectable in these cells. Notably, IL-21 induced the proliferation of ATL-43T and ED-40515(+) cells, both of which were derived from leukaemic cell clones of ATL. Concerning the intracellular signalling pathways, IL-21 activated the phosphorylation of the signal transducers and activators of transcription (STAT)3 and STAT5. Taken together, these findings provide the first evidence that ATL cells express functional IL-21R, suggesting that it may contribute to the pathophysiology of ATL. In addition, the IL-21/IL-21R system may represent a new target for the treatment of ATL. [ABSTRACT FROM AUTHOR]

Background: Apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3G (APOBEC3G) is a host cellular protein with a broad antiviral activity. It inhibits infectivitiy of a wide variety of retroviruses by deaminating deoxycytidine (dC) into deoxyuridine (dU) in newly synthesized minus strand DNA, resulting in G-to-A hypermutation of the viral plus strand DNA. To clarify the mechanism of its function, we have examined the antiviral activity of APOBEC3G on human T-cell leukemia virus type 1 (HTLV-1), the first identified human retrovirus. Results: In this study, we have demonstrated that overexpressed as well as endogenous APOBEC3G were incorporated into HTLV-1 virions and that APOBEC3G inhibited the infection of HTLV-1. Interestingly, several inactive mutants of APOBEC3G also inhibited HTLV-1 and no Gto-A hypermutation was induced by APOBEC3G in HTLV-1 genome. Furthermore, we introduced the human immunodeficiency virus type 1 (HIV-1) vif gene into HTLV-1 producing cell line, MT-2, to antagonize APOBEC3G by reducing its intracellular expression and virion incorporation, which resulted in upregulation of the infectivity of produced viruses. Conclusion: APOBEC3G is incorporated into HTLV-1 virions and inhibits the infection of HTLV-1 without exerting its cytidine deaminase activity. These results suggest that APOBEC3G might act on HTLV-1 through different mechanisms from that on HIV-1 and contribute to the unique features of HTLV-1 infection and transmission. [ABSTRACT FROM AUTHOR]

Viral infection is more frequently reported in cord blood transplantation (CBT) than in transplantation of other stem cell sources, but its precise mechanism related to antiviral host defenses has not been elucidated yet. To evaluate the effect of human leukocyte antigen (HLA) class I allele-level incompatibility on viral infection in CBT, we conducted a single-center retrospective study. Total 94 patients were included, and viral infections were detected in 32 patients (34%) within 100 days after CBT. HLA-C mismatches in graft-versus-host direction showed a significantly higher incidence of viral infection (hazard ratio (HR), 3.67; p = 0.01), while mismatches in HLA-A, -B, or -DRB1 were not significant. Overall HLA class I mismatch was also a significant risk factor and the predictor of post-CBT viral infection (≥ 3 mismatches, HR 2.38, p = 0.02), probably due to the insufficient cytotoxic T cell recognition and dendritic cell priming. Patients with viral infection had significantly worse overall survival (52.7% vs. 72.1%; p = 0.02), and higher non-relapse mortality (29.3% vs. 9.8%; p = 0.01) at 5 years. Our findings suggest that appropriate graft selection as well as prophylaxis and early intervention for viral infection in such high-risk patients with ≥ 3 HLA class I allele-level mismatches, including HLA-C, may improve CBT outcomes. [ABSTRACT FROM AUTHOR]

We present a patient with virus‐associated hemorrhagic cystitis who underwent kidney and allogenic hematopoietic stem cell transplantations (allo‐HSCT). Six months post‐allo‐HSCT, adenovirus hemorrhagic cystitis occurred, which has been in remission after a single dose of intravesical cidofovir. This might cause prolonged neutropenia and nephrotoxicity, suggesting cidofovir absorption in the blood. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which discusses a case study of a 52 year old man who was suffering from severe anemia and mentions that the deletion of cyclin dependent kinase inhibitor (CDKN) 2A/2B for diffuse large B cell lymphoma (DLBCL) has the therapeutic characteristics.