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Allogeneic hematopoietic cell transplantation (HCT) offers a possible cure for patients with relapsed and refractory non-Hodgkin lymphoma (NHL) through potentially beneficial graft versus lymphoma effects. However, allogeneic HCT is associated with high nonrelapse mortality (NRM). Fludarabine with reduced-intensity busulfan (Flu/Bu2) and myeloablative busulfan (Flu/Bu4) are commonly used in conditioning regimens for allogeneic HCT; however, data on their use in patients with NHL is limited. We investigated the effect of busulfan dose on outcomes by comparing Flu/Bu2 and Flu/Bu4 in patients with NHL who underwent allogeneic HCT. Our study included 415 adult patients with NHL who received Flu/Bu2 (315 patients) or Flu/Bu4 (100 patients) between January 2008 and December 2019. All patients were enrolled in the Transplant Registry Unified Management Program 2 of the Japanese Data Center for Hematopoietic Cell Transplantation. The primary endpoint was the 5-year overall survival (OS). To minimize potential confounding factors that may influence outcomes, we performed propensity score matching. The 5-year OS was 50.6% (95% confidence interval (CI), 39.4%–60.8%) and 32.2% (95% CI, 22.4–42.4%) in the Flu/Bu2 and Flu/Bu4 groups, respectively (p = 0.006). The hazard ratio comparing the two groups was 2.13 (95% CI, 1.30–3.50; p = 0.003). Both groups had a similar 5-year cumulative incidence of relapse (38.2% vs 41.3%; p = 0.581), and the Flu/Bu4 group had a higher cumulative incidence of 5-year NRM (15.7% vs 31.9%; p = 0.043). In this study, Flu/Bu4 was associated with worse OS compared with Flu/Bu2 because of high NRM in patients with NHL.

The main differentials in cases of sudden elevation of hepatic enzyme levels during immunochemotherapy are reactivation of hepatitis B virus or drug-induced liver injury. Here, we report a case of acute liver injury caused by hepatitis E virus (HEV) during chemotherapy for malignant lymphoma, wherein the patient was successfully treated and completed chemotherapy. A 57-year-old woman visited her local doctor because she felt light and tired. The patient underwent lower gastrointestinal endoscopy and was diagnosed with a malignant lymphoma of the small intestine (diffuse large B-cell lymphoma). The patient had a history of oral consumption of undercooked pork liver to improve anemia and was diagnosed with acute hepatitis E. Since the patient responded to chemotherapy, she was treated with single-agent ribavirin while continuing chemotherapy, resulting in a sustained virological response. Even during treatment with immunosuppressive drugs, if appropriate treatment for hepatitis E can be administered, the patient can be fully treated without interruption. The patient was able to complete chemotherapy adequately without interruption of treatment, which was a clinically beneficial result.

Thiotepa, an antineoplastic ethylenimine alkylating agent that can penetrate the central nervous system, was recently approved in Japan as high-dose chemotherapy prior to autologous hematopoietic stem cell transplantation (HSCT) for patients with malignant lymphoma. To further evaluate the safety and efficacy of thiotepa, a multicenter, open-label, non-comparative, expanded access program was undertaken in Japan, including a larger population of Asian patients with malignant lymphoma. Intravenous thiotepa (200 mg/m2/day) was administered over 2 h on days -4 and -3 before scheduled HSCT, plus intravenous busulfan (0.8 mg/kg) over 2 h every 6 h on days -8, -7, -6 and -5. In the safety analysis population (N = 51), 25 patients (49.0%) had primary central nervous system lymphomas. The most common treatment-emergent adverse event was febrile neutropenia (49/51 [96.1%]). No unexpected safety events were observed, and no event resulted in death or treatment modification. Forty-seven patients (92.2%) had engraftment (neutrophil count ≥ 500/mm3 for three consecutive days after bone-marrow suppression and HSCT). The survival rate at day 100 post-transplantation was 100%. These data confirm the safety of thiotepa prior to autologous HSCT for patients with malignant lymphoma. Trial registration: JapicCTI-173654. Supplementary Information The online version contains supplementary material available at 10.1007/s12185-021-03263-y.

To investigate which reduced-intensity conditioning (RIC)/reduced-toxicity conditioning (RTC) is superior for umbilical cord blood transplantation (UCBT) for lymphoid malignancies, we retrospectively compared three widely used RIC/RTC regimens: fludarabine/melphalan/total body irradiation (FM-TBI, n = 524), fludarabine/cyclophosphamide/total body irradiation (FC-TBI, n = 96), and fludarabine/busulfan/total body irradiation or melphalan (FB-based, n = 159). Among patients with acute lymphoblastic leukemia (ALL) (n = 314), there were no differences in overall survival (OS) by conditioning regimen. Among patients with malignant lymphoma (ML) (n = 465), FM-TBI and FC-TBI regimens had similar OS, whereas FB-based regimen had lower OS (hazard ratio [HR], 1.73; P

The JAK2V617F mutation is a driver mutation of myeloproliferative neoplasms (MPNs). V617F allele burden is considered a risk factor for complications associated with MPNs and is a predictor of prognosis. In Japan, V617F allele burden has been measured in laboratory settings using the i-densy

We evaluated 413 adult patients with lymphoma who underwent unrelated cord blood transplantation (UCBT) with fludarabine and melphalan (FM)-based reduced-intensity conditioning between 2002 and 2017 to investigate longitudinal changes in outcomes and the optimal melphalan dose and graft-versus-host disease (GVHD) prophylaxis regimen. Outcomes were compared between FM80/100 (melphalan dose: 80 or 100 mg/m

Fit patients with peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL) in relapsed or refractory (R/R) disease status often receive salvage chemotherapy followed by autologous hematopoietic stem cell transplantation (autoHCT) or allogeneic HCT (alloHCT). However, there is no consensus on the type of HCT that should be applied for such patients. Herein, we retrospectively evaluated the survival outcome of 760 adult R/R PTCL-NOS or AITL patients who underwent the first HCT. Among them, 318 relapsed after first remission (REL) and 442 were refractory to the primary therapy (PIF). The 4-year overall survival (OS) of autoHCT and alloHCT was 50 and 50% for REL patients, and 52 and 49% for PIF patients, respectively. In the multivariable analysis, alloHCT tended to be associated with better progression-free survival (PFS) in REL (hazard ratio [HR] 0.74; 95% confidence interval [CI]: 0.53-1.03), and significantly better PFS in PIF (HR 0.64; 95% CI: 0.46-0.88) compared with autoHCT. The subgroup analysis with propensity-score matching showed that alloHCT was associated with better OS for REL-sensitive and PIF-nonremission disease. This study suggested that the advantage of alloHCT for R/R PTCL-NOS or AITL is different, depending on the disease status at HCT.

We retrospectively compared the outcomes of reduced-intensity conditioning (RIC) transplantation from matched related donors (MRD; n = 266), matched unrelated donors (MUD; n = 277), and umbilical cord blood (UCB; n = 513) for mature lymphoid malignancies. The 3-year overall survival rates for the MRD, MUD, and UCB groups were 54%, 59%, and 40%, respectively (P

Purpose Thiotepa is used in high-dose chemotherapy (HDT) before autologous hematopoietic stem cell transplantation (HSCT) to treat solid tumors and hematological malignancies. This Phase 1 study was conducted to establish the pharmacokinetics (PK) of thiotepa in a Japanese population. Methods HDT/HSCT was performed in pediatric patients (≥ 2 years) with solid tumors or brain tumors (thiotepa 200 mg/m2/day IV-infused over 24 h on HSCT Days − 12, − 11, − 5, and − 4 and melphalan 70 mg/m2/day IV-infused over 1 h on Days − 11, − 5, and − 4) and adult patients (≥ 16 years) with malignant lymphoma (thiotepa 200 mg/m2/day 2-h IV-infusion on HSCT Days − 4 and − 3 plus busulfan 0.8 mg/kg 2-h IV-infusion every 6 h from HSCT Days − 8 to − 5). Pharmacokinetics of thiotepa were assessed following initial dose. Safety and efficacy were also evaluated. Results Nine pediatric and 10 adult patients were enrolled. Mean volume of distribution (Vz) of thiotepa normalized with body surface area (BSA) was lower for pediatric patients (16.4 L/m2) compared with adult patients (26.4 L/m2) as expected due to the higher specific surface area of children. Clearance and biological half-life were similar between pediatric and adult patients. Two serious adverse events (cardiac arrest and pulmonary edema) were observed. Survival rate (Day 100 post-HSCT) was 77.8% (95% CI 36.5–93.9%) for pediatric patients and 100% for adult patients. Conclusion Thiotepa elimination was comparable in pediatric and adult patients with cancer. Lower Vz in pediatric compared with adult patients was expected. HDT with thiotepa prior to autologous HSCT was well tolerated. Study registration Japic CTI-163433. Electronic supplementary material The online version of this article (10.1007/s00280-019-03914-2) contains supplementary material, which is available to authorized users.

Objective: To differentiate patients with IgG4-related diseases (RD) from patients with other hyper IgG4 conditions who visit general medicine department.Methods: Fifty-six patients with high serum...

Alemtuzumab is the treatment choice for patients with T-prolymphocytic leukemia (T-PLL). However, patients with T-PLL have a poor prognosis, and the option of allogeneic hematopoietic cell transplantation (HCT) remains controversial in these patients. This study aimed to analyze the outcomes of allogeneic HCT among patients with T-PLL to identify the potential clinical efficacy of allogeneic HCT. We retrospectively analyzed data from 20 patients with T-PLL, including five patients with complex chromosomal abnormalities at diagnosis who received an allogeneic HCT between 2000 and 2016. The median follow-up of survivors was 51 months in allogeneic HCT from human leukemia antigen (HLA)-matched donors. All five patients with complex chromosomal abnormalities died after allogeneic HCT. Our data suggest that allogeneic HCT from an HLA-matched donor can be considered for patients with T-PLL without complex chromosomal abnormalities. New treatment strategies of allogeneic HCT are required to improve the safety and efficacy of allografting in patients with T-PLL and complex chromosomal abnormalities. Potential approaches that identify patients with T-PLL and complex chromosomal abnormalities for allogeneic HCT with better disease control may allow identification of individuals who are suitable for allogeneic HCT.

Background Although thrombocytopenia, anasarca, fever, reticulin fibrosis and organomegaly (TAFRO) syndrome was first described as a variant of idiopathic multicentric Castleman disease (CD), patients with TAFRO syndrome demonstrate more aggressive clinical features. Because these patients may present with fever of unknown origin, general physicians need to recognise its characteristic laboratory data and clinical features during hospitalisation. Aims to describe the features, symptoms and characteristics of TAFRO syndrome and to compare them to those of idiopathic CD. Methods This was a retrospective study of patients with histopathologically confirmed TAFRO syndrome and idiopathic multicentric CD who were diagnosed and managed between April 2012 and June 2018 in a Japanese university hospital's General Medicine Department. Results We found that the hospitalisations were significantly longer among patients with TAFRO syndrome compared to those with idiopathic CD (median: 87 days; range: 34–236 days vs median: 30 days; range: 13–59 days; P < 0.01). Patients with TAFRO syndrome were more likely to present with fever, abdominal pain and elevated inflammatory markers and be misdiagnosed with an infectious disease during the first hospital visit. Approximately 40% of patients with TAFRO syndrome had no radiographically enlarged lymph nodes. Conclusions TAFRO syndrome may present as an infectious disease with an aggressive clinical course. Our study highlights the importance of giving significance to chief complaints and laboratory data. Physicians need to recognise the clinical and laboratory features of this disease to avoid missing this potentially fatal disorder.

Second allogeneic hematopoietic stem cell transplantation is a curative treatment option for patients with hematologic malignancies. However, it is unclear whether HLA discrepancy between graft and first donor has an impact on the outcome of second transplantation. We retrospectively analyzed 646 patients receiving second transplantation after an initial HLA mismatched transplantation. With regard to graft-versus-host, the one-allele mismatch (1 mismatch) group (SHR, 1.88; 95%CI: 0.79-4.45; P=0.163) and more than one-allele mismatch group (≥ 2 mismatch) (SHR, 1.84; 95%CI, 0.75–4.51; P=0.182) had higher risks of grade III–IV acute graft-versus-host disease (GvHD) compared to the HLA-matched (0 mismatch) group. In contrast, no difference in risk of acute GvHD was found among the 0, 1, and ≥ 2 mismatch group with respect to graft-versus-first donor. With regard to graft-versus-host, the ≥ 2 mismatch group showed a significantly higher risk of treatment-related mortality (SHR, 1.90; 95%CI, 1.04–3.50; P=0.038) compared to the 0 mismatch group, while the risk of relapse was slightly lower in the ≥ 2 mismatch group (SHR, 068; 95%CI, 0.44–1.06; P=0.086). In contrast, with regard to graft-versus-first donor, there were no significant differences in treatment-related mortality or relapse among the three groups. These findings suggested that HLA discrepancy between graft and host induces transplant-related immunological responses in second transplantation leading to an increase in treatment-related mortality, in contrast, the biological effects of HLA discrepancy between graft and first donor on outcome may be negligible.

We evaluated the impact of event-free survival (EFS) status at 24 months (EFS24) and 60 months (EFS60) after hematopoietic stem cell transplantation (HSCT) using registry data. Patients who underwent their first autologous HSCT (auto-HSCT) or allogeneic HSCT (allo-HSCT) for lymphoma between 1981 and 2018 were included. Overall survival was compared with that of the age-, sex, and calendar period–matched general population. A total of 14 977 patients, including 10 964 and 4013 who underwent auto-HSCT and allo-HSCT, respectively, were analyzed. Although patients who achieved EFS24 and EFS60 had favorable outcomes, most had significantly poorer survival rates than the general population. The standardized mortality ratios (SMRs) of patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) were significantly higher than that of the general population even after achieving EFS24 or EFS60. The SMRs of those after auto-HSCT were 2.5 to 3.5 and 2.7 to 3.7, respectively. The SMR was consistently highest in Hodgkin lymphoma (HL) patients after HSCT. By contrast, subsequent survival of patients with primary mediastinal large B-cell lymphoma, intravascular large B-cell lymphoma, or peripheral T-cell lymphoma, not otherwise specified, who achieved EFS60 after auto-HSCT, and those with extranodal natural killer/T-cell lymphoma who achieved EFS60 after allo-HSCT did not significantly differ from that of the general population, with SMRs of 1.6, 1.2, 1.8, and 1.3, respectively. Our results suggest that EFS24 and EFS60 were clinically useful end points after HSCT for lymphoma patients. Furthermore, patients with certain lymphoma subtypes who achieved EFS had a comparable prognosis with that of the general population and were potentially cured after HSCT.

Primary central nervous system (CNS) lymphoma (PCNSL) is a rare subtype of aggressive non-Hodgkin lymphoma originating within the CNS. Whole brain irradiation (WBRT) has been utilized in combination with high-dose methotrexate (HD-MTX), unfortunately with a high rate of late neurocognitive decline, particularly in the elderly. HD-MTX-based combination chemotherapy regimens have been developed as induction therapy for PCNSL and shown to improve response rates. Consolidation treatment, such as reduced-dose WBRT or high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (HDT-ASCT) is vital to controlling the disease. Two phase II trials randomizing PCNSL patients to WBRT or HDT-ASCT were recently published, showing comparable survival but better neurocognitive function in patients receiving HDT-ASCT. A key agent in HDT-ASCT for PCNSL is thiotepa, which, however, has been unavailable in Japan since 2011. Therefore, a clinical trial of HDT-ASCT with thiotepa was performed, and we are currently awaiting drug approval. Several targeted drugs are being trialed in patients with relapsed or refractory PCNSL. The treatment strategy of PCNSL is still developing to improve survival and reduce toxicity.

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

Although human leukocyte antigen (HLA) mismatch is often thought to be associated with a high incidence of cytomegalovirus (CMV) reactivation, it is not clear whether this process is mediated by HLA mismatch or other factors, such as acute graft-versus-host disease (aGVHD). Here we focused on cord blood transplantation (CBT) and examined the effects of HLA mismatch on the incidence of CMV reactivation while minimizing the effects of aGVHD. In a multivariate analysis considering aGVHD as a time-dependent covariate, a significant effect on the incidence of CMV reactivation was noted for HLA disparity (hazard ratio [HR]: 0.54 for 8/8 match compared with 3-allele mismatch) and development of aGVHD (HR: 1.26). Next, in an analysis excluding cases that developed aGVHD, the incidences of CMV reactivation for 8/8 match and 1-allele mismatch were low compared with those for other mismatches. These findings were supported by the multivariate analysis (HR: 0.49 for 8/8 match and 0.64 for 1-allele mismatch compared with 3-allele mismatch). Together, these results suggested that HLA mismatch was involved in CMV reactivation and was associated with high morbidity of opportunistic infection after CBT.

We retrospectively analyzed the cases of 14 patients (9 women, 5 men, mean age: 51.6 years) with cytomegalovirus (CMV) involvement in the esophagus, stomach, and/or duodenum diagnosed at a single center, to determine their endoscopic features and clinical backgrounds. Thirteen patients (92.9%) had hematologic disease; the other had rheumatoid arthritis. Of the former, 12 patients underwent allogeneic hematopoietic stem cell transplantation, and 9 of these patients had graft-versus-host disease (GVHD) before undergoing esophagogastroduodenoscopy (EGD). All 14 patients had been taking one or more immunosuppressive agents including cyclosporine (n=10), corticosteroids (n=9), mycophenolic acid (n=6), tacrolimus (n=3), and methotrexate (n=1). Tests for CMV antigenemia were positive in 11 patients (78.6%). EGD examinations revealed esophageal (n=3), gastric (n=9), and duodenal involvement (n=6). Macroscopically, esophageal lesions by CMV infection presented as redness (n=1), erosions (n=1), and ulcers (n=1). Gastric lesions manifested as redness (n=7), erosions (n=3), exfoliated mucosa (n=2), and verrucous erosions (n=1). Mucosal appearances in the duodenum varied: redness (n=2), ulcers (n=2), multiple erosions (n=2), single erosion (n=1), edema (n=1). CMV was detected even in the intact duodenal mucosa (n=1). In conclusion, physicians must recall the relevance of CMV infection when any mucosal alterations exist in the upper gastrointestinal tract of immunosuppressed patients.

Background Azacitidine (Aza) and donor lymphocyte infusion (DLI) therapy has recently been reported as an effective salvage therapy for relapsed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Despite the high response rate and relatively long period of remission, most patients relapse again. The immunologic mechanism of the response and limited efficacy remain unknown. Case Report Aza + DLI therapy was performed for a patient with therapy-related MDS (t-MDS), who had relapsed after allogeneic peripheral blood stem cell transplantation. We observed a powerful graft-versus-leukemia (GVL) effect accompanied by an evident Wilms tumor antigen 1 (WT1)-specific CD8 T-cell response. Remission continued for 15 months, but finally the patient relapsed. The kinetics of the WT1-specific CD8 T cells were inversely associated with WT1 messenger RNA (mRNA), suggesting a WT1-driven GVL effect. Discussion A difference of T-cell phenotype between the whole T cells and the WT1-specific CD8 T cells was observed. It is of note that the memory phenotype of the WT1-specific T cell was limited and decreased early. The immunoescape mechanism was partly supported by loss of the memory phenotype due to failure of expansion and differentiation. Conclusion Our data suggested that a WT1-specific T-cell response at least partly contributes to the GVL effect induced by Aza + DLI. A strategy for maximizing and maintaining the memory phenotype of the CTL may be required for durable remission.

Objective To analyze the clinical and endocrine characteristics of patients with primary adrenal lymphoma. Patients We retrospectively reviewed the cases of five patients with primary adrenal lymphoma who were treated in our hospital between April 2004 and March 2015. We investigated the characteristics of the clinical and pathological findings, treatment, prognosis and complications of adrenal insufficiency. Results Adrenal insufficiency, which was confirmed by the laboratory data at the initial presentation, was observed in two cases. One case was complicated by relative adrenal insufficiency during a course of chemotherapy. The plasma adrenaline and urinary adrenaline levels were decreased in four cases and three cases, respectively. Diffusion MRI was radiologically diagnostic. In all of the cases, the patients were pathologically diagnosed with diffuse large-B cell lymphoma and were treated with rituximab and CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone)-like chemotherapy. Two patients received central nervous system prophylaxis with high-dose methotrexate. Four of the patients survived and one patient died during the follow-up period. Conclusion The early detection of adrenal insufficiency and the administration of an appropriate dose of hydrocortisone are necessary during the course of chemotherapy as well as at the initial manifestation. The exclusion of adrenal dysfunction prior to invasive diagnostic procedures, such as CT-guided needle biopsy, is also critical.

Objective Stenotrophomonas maltophilia is an emerging nosocomial pathogen that causes fatal infections in critically ill or immunocompromised patients. S. maltophilia bacteremia (SMB) is a rare condition, and its clinical characteristics in Japanese settings are not well known. Methods The medical charts of patients with SMB were retrospectively reviewed at two medical facilities (Okayama University Hospital and Tsuyama Chuo Hospital) for seven years. The data were analyzed along with those previously reported from other Japanese facilities. Result A total of 181 patients (110 men and 71 women) were evaluated. The major underlying diseases included hematologic malignancy (36.5%), solid organ malignancy (25.4%), and neutropenia (31.5%). The recent use of carbapenem was seen in 56.9% of the cases in total, and more than one-third of the patients in our hospitals were treated with carbapenem at the onset of SMB. Of 28 (63.6%) of 44 cases treated for S. maltophilia, those who did not survive were more likely to have been treated with broad-spectrum antibiotics. A multivariate analysis revealed that a higher updated Charlson Comorbidity Index [odds ratio (95% confidence interval), 1.75 (1.11-2.75); p=0.015] and intubation [odds ratio (95% confidence interval), 12.6 (1.62-97.9); p=0.016] were associated with mortality in our cases. Pathogens were often resistant to ceftazidime but susceptible to minocycline, trimethoprim/sulfamethoxazole, and fluoroquinolones. The overall mortality rates within 30 and 90 days were 37.5% and 62.5%, respectively. Conclusion The clinical characteristics of SMB in Japanese cases were similar to those reported from other countries. Clinicians should be aware that breakthrough infection by S. maltophilia may occur during administration of carbapenem.

Objective Stenotrophomonas maltophilia is an emerging nosocomial pathogen that causes fatal infections in critically ill or immunocompromised patients. S. maltophilia bacteremia (SMB) is a rare condition, and its clinical characteristics in Japanese settings are not well known. Methods The medical charts of patients with SMB were retrospectively reviewed at two medical facilities (Okayama University Hospital and Tsuyama Chuo Hospital) for seven years. The data were analyzed along with those previously reported from other Japanese facilities. Result A total of 181 patients (110 men and 71 women) were evaluated. The major underlying diseases included hematologic malignancy (36.5%), solid organ malignancy (25.4%), and neutropenia (31.5%). The recent use of carbapenem was seen in 56.9% of the cases in total, and more than one-third of the patients in our hospitals were treated with carbapenem at the onset of SMB. Of 28 (63.6%) of 44 cases treated for S. maltophilia, those who did not survive were more likely to have been treated with broad-spectrum antibiotics. A multivariate analysis revealed that a higher updated Charlson Comorbidity Index [odds ratio (95% confidence interval), 1.75 (1.11-2.75); p=0.015] and intubation [odds ratio (95% confidence interval), 12.6 (1.62-97.9); p=0.016] were associated with mortality in our cases. Pathogens were often resistant to ceftazidime but susceptible to minocycline, trimethoprim/sulfamethoxazole, and fluoroquinolones. The overall mortality rates within 30 and 90 days were 37.5% and 62.5%, respectively. Conclusion The clinical characteristics of SMB in Japanese cases were similar to those reported from other countries. Clinicians should be aware that breakthrough infection by S. maltophilia may occur during administration of carbapenem.

Autoimmune hemolytic anemia (AIHA) is secondary to underlying diseases, such as autoimmune diseases and lymphoid malignancies. Recently, solid cancers have also been reported to be associated with AIHA, although there is not much information available. In this study, we retrospectively examined the correlation between AIHA and onset of malignancy in 100 patients diagnosed with AIHA based on the broad definition of AIHA at our hospital and cooperating institutions from January 1, 1995 to May 31, 2016. Malignancies were detected in 52 of the 100 patients (hematological malignancies: 39 patients; solid cancers: 22 patients; total malignancies including multiple primary malignancies: 67 patients). Of the 67 patients with malignancies, 28 were diagnosed with malignancies within 6 months of AIHA diagnosis. All patients with cold agglutinin disease (CAD) were associated with malignancies. Compared with warm AIHA, solid cancers were significantly more common among the patients with CAD. These findings emphasize the importance of investigating the malignancies upon diagnosis of AIHA.

Castleman-Kojima disease, also known as idiopathic multicentric Castleman disease with TAFRO syndrome (iMCD-TAFRO), is a recently recognized systemic inflammatory disorder with a characteristic series of clinical symptoms, including thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O). Patients with iMCD-TAFRO often develop severe abdominal pain, elevated alkaline phosphatase levels, and systemic inflammation, but the etiological factors are unknown. To investigate the potential role of bacterial infection in the pathogenesis of iMCD-TAFRO, we performed polymerase chain reaction (PCR) for the bacterial 16S rRNA gene with DNA extracted from liver specimens of three patients with iMCD-TAFRO, four patients with amyotrophic lateral sclerosis, and seven patients with inflammatory conditions. Sequencing of the PCR product showed 99% DNA sequence identity with Campylobacter jejuni in all three patients with iMCD-TAFRO and in two patients with inflammatory conditions. Immunohistochemical and electron microscopy analyses could not identify C. jejuni in patients with iMCD-TAFRO. The findings indicated that C. jejuni infection is not the pathological cause of iMCD-TAFRO; however, this ubiquitous bacterium may play a role in uncontrolled systemic hypercytokinemia, possibly through the development of cross-reactive autoantibodies.

Acute myeloid leukemia (AML) with BCR-ABL1 is rare and has a poor prognosis with conventional chemotherapy or ABL tyrosine kinase inhibitors (TKIs) alone. We reported a case of AML with BCR-ABL1 patient who was successfully treated with dasatinib alone; additionally, we previously reported another case of long-term remission maintained with imatinib monotherapy. These results suggested that a treatment with a novel and significantly potent TKI may be effective in AML with BCR-ABL1 patients with low tumor burden and without additional chromosome aberrations and ABL kinase domain mutations.

Esophagogastroduodenoscopy revealed small duodenal lesions in a 56-year-old Japanese man and a 92-year-old Japanese woman with stage IV follicular lymphoma. Magnifying endoscopy examination revealed tiny white deposits in the second duodenal portion of the former patient and slightly enlarged duodenal villi in the latter. In both cases, biopsy revealed infiltration of follicular lymphoma cells and incipient formation of neoplastic follicles. Here, we discuss the usefulness of magnifying endoscopy and narrow-band imaging for the detection of small duodenal lesions in follicular lymphoma cases.

Multicentric Castleman disease (MCD) describes a heterogeneous group of disorders involving systemic inflammation, characteristic lymph node histopathology, and multi-organ dysfunction because of pathologic hypercytokinemia. Whereas Human Herpes Virus-8 (HHV-8) drives the hypercytokinemia in a cohort of immunocompromised patients, the etiology of HHV-8-negative MCD is idiopathic (iMCD). Recently, a limited series of iMCD cases in Japan sharing a constellation of clinical features, including thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O) has been described as TAFRO syndrome. Herein, we report clinicopathological findings on 25 patients (14 males and 11 females; 23 Japanese-born and two US-born), the largest TAFRO syndrome case series, including the first report of cases from the USA. The median age of onset was 50 years old (range: 23-72). The frequency of each feature was as follows: thrombocytopenia (21/25), anasarca (24/25), fever (21/25), organomegaly (25/25), and reticulin fibrosis (13/16). These patients frequently demonstrated abdominal pain, elevated serum alkaline phosphatase levels, and acute kidney failure. Surprisingly, none of the cases demonstrated marked hypergammoglobulinemia, which is frequently reported in iMCD. Lymph node biopsies revealed atrophic germinal centers with enlarged nuclei of endothelial cells and proliferation of endothelial venules in interfollicular zone. 23 of 25 cases were treated initially with corticosteroids; 12 patients responded poorly and required further therapy. Three patients died during the observation period (median: 9 months) because of disease progression or infections. TAFRO syndrome is a unique subtype of iMCD that demonstrates characteristic clinicopathological findings. Further study to clarify prognosis, pathophysiology, and appropriate treatment is needed.

Objective Due to their rarity, the endoscopic features and clinical backgrounds of colorectal follicular lymphoma lesions have not yet been fully investigated. The aim of this study was to reveal the characteristics of this disease entity. Methods A database search performed at the Department of Pathology of our institute identified 12 follicular lymphoma patients with involvement in the cecum, colon, and/or rectum. Data regarding the endoscopic, radiological, biological, and pathological examinations performed were retrospectively reviewed from their clinical records. Results The mean age of the patients (5 men, 7 women) was 58.7 years. Five patients were classified as being Lugano system stage I, while the other seven patients were stage IV. In all of the patients, colorectal follicular lymphoma presented with papular (n=4), polypoid (n=4), and flat elevated lesions (n=4). No erosions or ulcers were seen in any of the lesions. The initial pathological diagnoses included extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (n=2) and colitis/proctitis with infiltration of inflammatory cells (n=3), in addition to the correct diagnosis of follicular lymphoma (n=7). Conclusion Colorectal involvement of follicular lymphoma shows no erosions or ulcers. These lesions could be macroscopically observed as papular, polypoid and flat elevated lesions. Making a correct diagnosis of this disease based on the findings of biopsied samples is sometimes challenging. In such cases, multiple biopsies and/or endoscopic mucosal resection is required, in addition to appropriate consultation with pathologists.

BACKGROUND Transplant-associated thrombotic microangiopathy (TA-TMA) after hematopoietic stem cell transplantation (HSCT) remains a severe complication associated with underlying endothelial damage. TMA has a high mortality rate with no definite treatments and effective treatments are needed. STUDY DESIGN AND METHODS The study objective was to retrospectively analyze the outcome of patients receiving recombinant human soluble thrombomodulin (rTM), which has cytoprotective effects against calcineurin inhibitor–induced endothelial cell damage, or other therapeutics for TA-TMA from 254 consecutive HSCT recipients between 2009 to 2014 at a single institution. We hypothesized that patients receiving rTM as a first-line treatment would receive a benefit. RESULTS Sixteen patients were diagnosed as TA-TMA. Of these 16 patients, nine were treated with rTM (rTM group), and seven received treatment other than rTM (control group) as a first-line therapy. Seven of the nine patients in the rTM group recovered from TA-TMA without complications, but none in the control group recovered. The rTM group showed a significantly better overall survival after TA-TMA onset than did the control group (median, 123.0 days vs. 45.5 days, respectively; p = 0.045). The cumulative incidence of acute graft-versus-host disease was the same in both groups (56% vs. 57%, respectively; p = 0.52) on Day 100 after TA-TMA onset. CONCLUSION This is the first report evaluating rTM administration for TA-TMA compared with previous treatments. Our data suggests that rTM might offer a better clinical outcome in patients with TA-TMA.

Activated B cells have the capacity to present antigen and induce immune responses as potent antigen-presenting cells (APCs). As in other APCs, antigen presentation by B cells involves antigen internalization, antigen processing, and peptide loading onto MHC molecules. However, while the mechanism of antigen processing has been studied extensively in other APCs, this pathway remains elusive in B cells. The aim of this study was to investigate the MHC class II processing pathway in CD40-activated B cells (CD40Bs), as a model for activated, antigen-presenting B cells. Using CMV pp65 as a model antigen, we evaluated processing and presentation of the CD4 + T-cell epitope 509-523 (K509) by human CD40Bs in ELISPOT assays. As expected, stimulation of specific CD4 + T-cell clones was attenuated after pretreatment of CD40Bs with inhibitors of classic class II pathway components. However, proteasome inhibitors such as epoxomicin limited antigen presentation as well. This suggests that the antigen is processed in a non-classical, cytosolic MHC class II pathway. Further experiments with truncated protein variants revealed involvement of the proteasome in processing of the N and C extensions of the epitope. Access to the cytosol was shown to be size dependent. Epoxomicin sensitivity exclusively in CD40B cells, but not in dendritic cells, suggests a novel processing mechanism unique to this APC. Our data suggest that B cells process antigen using a distinct, non-classical class II pathway.

High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (HDT-ASCT) is listed as a consolidation therapy option for primary central nervous system (CNS) lymphoma in the guidelines of western countries. The advantages of HDT-ASCT for primary CNS lymphoma as consolidation are believed to be high rates of long-term remission and lower neurotoxicity, even though its eligibility is limited to younger fit patients. In the Japanese guideline, HDT-ASCT for primary CNS lymphoma is however not recommended in daily practice, mainly because thiotepa was unavailable since 2011. The Japanese registry data for hematopoietic transplantation have shown that primary CNS lymphoma patients were treated with various HDT regimens and thiotepa-containing HDT was associated with better progression free survival (P=.019), lower relapse (P=.042) and a trend toward a survival benefit (Kondo E et al, Biol Blood Marrow Transplant 2019). A pharmacokinetic study of thiotepa(DSP-1958) in HDT-ASCT for lymphoma was conducted in 2017, and thiotepa was approved for HDT-ASCT in lymphoma this March, meaning that optimal HDT regimen for CNS lymphoma is now available in Japan. The treatment strategy of CNS lymphoma needs further development to improve survival and reduce toxicity.

High-dose chemotherapy (HDT) with autologous stem cell transplantation (ASCT) has been shown to improve the prognosis of patients with central nervous system (CNS) lymphoma. We queried the Japan Society for Hematopoietic Cell Transplantation Registry for 2006 to 2015 to analyze the outcomes of 102 patients with primary CNS lymphoma (PCNSL) who underwent first HDT/ASCT. The median patient age was 54 years (range, 20 to 74 years), and 65 patients were treated in an upfront setting. With a median duration of follow-up of 44 months, the 5-year overall survival (OS) and progession-free survival (PFS) were 54.9% and 38.4%, respectively. There were no significant differences in OS and PFS between upfront and salvage HDT/ASCT. Because thiotepa, a key agent in HDT/ASCT for PCNSL, has been unavailable since 2011 in Japan, the HDT regimens used were not uniform. Thiotepa-containing HDT was received by 16 out of 32 patients before 2010, but by only 2 of 70 patients after 2011. Thiotepa-containing HDT was associated with better PFS (P = .019), lower relapse (P = .042), and a trend toward a survival benefit. In multivariate analysis, noncomplete remission at HDT/ASCT was an independent predictor for OS (hazard ratio [HR], 2.40; 95% confidence interval [CI], 1.25 to 4.58; P = .008) and thiotepa-containing HDT remained significant for PFS (HR, .42; 95% CI, .19 to .95; P = .038). These results confirm the activity of thiotepa-containing regimens.

Background High sensitivity for detection of HIV-1 p24 antigen allows for early detection of primary HIV-1 infections. Objectives To evaluate the detection sensitivity and specificity of the Daina Screen® HIV Combo assay using clinical specimens in Japan where the pretest probability (prevalence) is low. Study design We screened 17,373 preoperative outpatient blood samples using 4th generation lateral flow immunochromatography Daina Screen® HIV Combo assay for simultaneously detecting anti-HIV-1/2 and HIV-1 p24 antigens. Results Of the samples tested, 24 were positive for HIV-1 p24 antigen and 49 for HIV-1/2 antibody. Of the 49 samples, 36 were WB and HIV-1 RNA negative, 10 were WB and HIV-1 RNA positive, and 3 were WB positive, HIV-1 RNA negative, and in-house HIV-1 proviral DNA positive. RT-PCR revealed that of the 24 samples that were p24 antigen positive, one sample was HIV-1 RNA positive, which was reconfirmed using an in-house HIV-1 provirus DNA assay. From the 17,300 HIV-1 p24 antigen and anti-HIV-1/2 negative samples, pools containing 10 negative samples each were tested for HIV-1 by RT-PCR; all results were negative. Conclusion The Daina Screen® HIV Combo assay had a sensitivity and specificity of 100% and 99.7%, respectively, which sufficiently detected HIV infection in the cohort.

A 73-year-old male with melena was admitted to our hospital. Computed tomography (CT) scan revealed the thickening of the jejunal and ileal walls and swelling of the mesenteric lymph nodes. Type II enteropathy-associated T-cell lymphoma (EATL) was diagnosed based on the pathological analysis of the resected specimen. Positron emission tomography and CT scan showed complete remission (CR) after surgery, and he further received CHOP therapy. However, 2 months after the completion of the therapy, the patient's disease relapsed, and he presented with abdominal pain. Ifosfamide, dexamethasone, etoposide, and cytarabine therapy was administered, and the second CR was observed in the patient. Subsequently, the patient was administered high-dose chemotherapy (MCEC) with autologous peripheral blood stem cell transplantation (auto-PBSCT). The treatment was well tolerated. Engraftment was performed on day9, and he was discharged on day17 after auto-PBSCT. However, at 6 months after auto-PBSCT, the second relapse of the disease was observed in the patient. He received salvage therapy; however, the patient died because of disease progression. Because of the dismal prognosis of EATL treated with conventional chemotherapy, the feasibility and efficacy of auto-PBSCT have been investigated. To the best of our knowledge, there is no report on an elderly patient (age70 years) with EATL who underwent auto-PBSCT. Thus, more data should be collected and analyzed to confirm that this therapy could be a promising treatment option for elderly patients with EATL.

BACKGROUND Donor lymphocyte infusion (DLI) is used for treatment of hematologic malignancy relapse or mixed chimerism after allogeneic hematopoietic stem cell transplantation. Although graft-versus-host disease is well recognized as one of the adverse effects of DLI, there are limited reports on noninfectious pulmonary complications (NIPCs) after DLI. CASE REPORT A 55-year-old woman with acute myeloid leukemia received DLI for conversion from recipient predominant to complete donor chimerism on Day +193 after allogeneic HSCT. Eight weeks later, she complained of dyspnea with fever; chest computed tomography revealed diffuse, bilateral, ground glass opacity and reticular appearance. She was diagnosed as having NIPC based on serum and bronchoalveolar lavage fluid (BALF) findings. She was successfully treated with prednisolone (PSL) and completely recovered. DISCUSSION We analyzed the cell profile from the BALF and 27 cytokines and chemokines in the serum using the Bio-Plex platform. The cells consisted of recipient predominant macrophages and T cells. The serum cytokine and chemokine profile showed significant elevation of interleukin (IL)−1β, IL-6, IL-8, tumor necrosis factor-α, macrophage inflammatory protein (MIP)−1α, and MIP-1β, which declined with the improvement of symptoms after initiation of PSL treatment. CONCLUSION Inflammatory effectors by recipient cells, rather than allogeneic responses by donor cells, played an important role in the pathogenesis of NIPCs after DLI in the present case.

Chronic graft-versus-host disease (GVHD) is a major cause of late death and morbidity after allogeneic hematopoietic cell transplantation. Recently, in addition to Th2 cells, Th1 and Th17 cells have been shown to contribute to chronic GVHD progression. IL-12 induces Th1 cells and IL-23 plays a role in stabilizing and/or amplifying Th17 cells, as well as in inducing IFN-γ/IL-17 double-producing cells. Because mAb targeting the p40 subunit common to both IL-12 and IL-23 can inhibit both IL-12R and IL-23R-mediated signaling, we investigated the effects of anti-p40 mAb on a well-defined chronic GVHD mice model. Treatment of anti-p40 mAb in allogeneic recipients significantly reduced the severity of clinical and pathological chronic GVHD. Intracellular staining revealed that IFN-γ single-positive (IL-17−) and IFN-γ/IL-17 double-positive cells were suppressed in anti-p40 mAb–treated allogeneic recipients compared with control recipients. The cytokine levels of IFN-γ and IL-17 were also decreased in serum from anti-p40 mAb–treated allogeneic recipients. T-bet expression of donor IL-17+ CD4+ T cells was reduced significantly in anti-p40 mAb–treated recipients, and this reduction in T-bet expression was associated with IL-22 production by donor T cells. These results suggested that anti-p40 mAb attenuated chronic GVHD via suppression of IFN-γ/IL-17–producing cells, and that targeting the IL-12/IL-23 pathway may represent a promising therapeutic strategy for preventing and treating chronic GVHD.

A 36-year-old Japanese woman presented with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) in the stomach. The gastric lesions only partially improved after eradication therapy for Helicobacter pylori. A fluorescence in situ hybridization analysis revealed no fusion genes of API2-MALT1, although trisomy of chromosome 18 was identified. Radiation therapy was initiated to treat the gastric lymphoma lesions, resulting in complete remission. However, MALT lymphoma recurred in the stomach 16 months later. This case indicates that intensive follow-up is required for MALT lymphoma associated with chromosomal aberrations in order to detect early relapse.

Objective Although high-dose methotrexate and whole-brain radiation therapy (WBRT) is the current standard for primary central nervous system lymphoma (PCNSL), it has a limited response rate and produces radiation-induced neurotoxicity. We report the effect of a combined treatment of high-dose methotrexate, cyclophosphamide, doxorubicin, vincristine and prednisolone (M-CHOP) for immunocompetent patients with PCNSL. Methods We analyzed 24 patients who had received M-CHOP administered in 28-day cycles with or without WBRT. The response rate to M-CHOP, overall survival (OS), and recurrence-free survival (RFS) were analyzed. Results Nine patients were treated with M-CHOP plus WBRT and 15 patients were treated with M-CHOP alone. Twenty-one patients achieved a complete response and three patients achieved a partial response to M-CHOP, for a 100% response rate. With a median follow-up of 70 months, the median OS and RFS were 33 and 13 months, respectively. The median OS for patients treated with M-CHOP plus WBRT and M-CHOP alone was 33 and 32 months, respectively. Of the 13 patients whose age was above 65 years, the median OS for the M-CHOP plus WBRT group (two patients) and the M-CHOP alone group (11 patients) was 14 and 32 months, respectively. Toxicities related to M-CHOP were mostly hematologic and generally mild to moderate. Two patients whose age was above 65 years in the M-CHOP plus WBRT group developed neurotoxicity. Conclusion Combined treatment with M-CHOP was well tolerated and produced a high response rate. Deferring WBRT was associated with reduced neurotoxicity without worsening the prognosis, especially in elderly patients.

Immune checkpoint inhibitors, such as anti-CTLA-4 and anti-PD-1 antibodies, have revolutionized cancer therapy, particularly in the treatment of malignant melanoma and lung cancer. Allogeneic hematopoietic stem cell transplantation (allo-HCT) is another form of immunotherapy and is being widely used to cure high-risk hematological malignancies. However, more than one-third of patients suffer a relapse after allo-HCT and often have a poor prognosis. A phase I/Ib study to assess the safety and efficacy of ipilimumab (anti-CTLA-4 antibody) for the treatment of relapsed hematological malignancies after allo-HCT has shown that induction treatment with ipilimumab led to remissions in some patients, including those with myeloid malignancies, without eliciting severe graft versus host disease (GVHD). The efficacy of treatment with anti-PD-1 antibodies before or after allo-HCT has been reported in some case reports and in one retrospective study, but one case of fatal GVHD caused by anti-PD-1 antibody therapy after allo-HCT raises a concern. Considering that remission status after transplantation is a strong prognostic factor in allo-HCT, immune checkpoint inhibitors might work better during post-remission consolidation than during induction. Further studies on immune checkpoint inhibitors in the treatment of hematological malignancies are warranted.