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CD19-directed chimeric antigen receptor (CAR) T-cell therapy has been widely used and highly effective for B-cell lymphoid malignancies. Immune-mediated adverse effects such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) occur in the acute phase and are monophasic after CAR T-cell therapy. However, late-onset inflammatory and neurological toxicities have not been well studied. We encountered a patient with recurrent late-onset inflammatory toxicities and progressive dysautonomia after CD19-directed CAR T-cell therapy. A 69-year-old man was treated with CD19-directed CAR T-cell therapy for transformed follicular lymphoma. Triphasic inflammation with stomatitis, cytopenia, and non-infectious pneumonia was first observed 7 months after CAR T-cell infusion. Progressive dysautonomia was also observed and eventually fatal. Residual CAR T cells, predominantly central memory CD4+ cells, were detectable in peripheral blood approximately one year after CAR T-cell infusion. The cytokine profile with the lack of tumor necrosis factor-α, interferon-γ, and interleukin-1β elevation in the peripheral blood and cerebrospinal fluid was inconsistent with that of typical CRS or ICANS. The persistence of central memory CD4+ CAR T cells might be associated with unique manifestations of late-onset immune-mediated adverse effects. More cases should be accumulated to elucidate the mechanism and establish the optimal management strategy of late-onset immune-mediated toxicities previously unrecognized.

Lay abstract This case report describes a 72-year-old man with non-small-cell lung cancer who received four cycles of pembrolizumab-containing chemotherapy. He developed multiple immune-related adverse events (irAEs), which are significant side effects of immune checkpoint inhibitors (ICIs). Despite the discontinuation of pembrolizumab due to multiple irAEs, he developed immune-related hepatitis and neutropenia at 92 days and 118 days, respectively, after the final pembrolizumab dose. He received supportive care and immunosuppressive therapy and recovered from neutropenia. Recently, delayed development of irAEs was reported even in patients that discontinued ICIs; this is referred to as a delayed immune-related event (DIRE). This case developed strikingly delayed immune-related neutropenia as a DIRE. Clinicians should pay close attention to neutropenia as a possible life-threatening DIRE after ICI treatment.

There is currently no evidence that a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine might be associated with the development of autoimmune hemolytic anemia or disease progression in patients with mature B-cell neoplasm. Our patient was a 71-year-old man with indolent mature B-cell neoplasm who had been monitored for many years without treatment. After receiving the second dose of the BNT162b2 mRNA COVID-19 vaccine, he developed severe warm autoimmune hemolytic anemia. Although steroid therapy improved his anemia, he continued to develop IgM-monoclonal gammopathy, renal insufficiency, and splenomegaly. He was diagnosed with splenic marginal zone lymphoma after undergoing splenectomy. The splenectomy improved the patient's symptoms. We assessed his SARS-CoV-2 specific antibody response, but the patient's serologic response to the vaccine was impaired. In patients with mature B-cell neoplasm, a non-specific immune response after vaccination might be associated with paraneoplastic syndromes.

A combination of three post-transplant drugs, cyclophosphamide (PTCy), a calcineurin inhibitor, and mycophenolate mofetil, has long been used for prophylaxis of graft-versus-host-disease (GVHD) after HLA-haploidentical allogeneic hematopoietic cell transplantation (allo-HCT). Recently, this combination has been used following HLA-matched allo-HCT as well, but the optimal combination of drugs for GVHD prophylaxis in an HLA-matched setting remains unclear. This prospective phase II study evaluated the safety and efficacy of PTCy plus tacrolimus (TAC) for GVHD prophylaxis after allo-HCT from HLA-matched related donors (MRD) or HLA-matched unrelated donors (MUD). The cumulative incidences of grades II-IV and III-IV acute GVHD at 100 days post-transplantation were 18% and 5.9%, respectively, in the MRD group, and 18% and 9.1%, respectively, in the MUD group. The cumulative incidences of moderate to severe chronic GVHD at 1 year were 12% and 9.1% in the MRD and MUD groups, respectively. The 1-year overall survival rates in the MRD and MUD groups were 88% and 64%, respectively, and the 1-year GVHD-free, relapse free survival rates were 59% and 50%, respectively. These results suggest that GVHD prophylaxis with a less intensive double drug combination (PT/Cy and TAC) might be feasible after HLA-matched allo-HCT.Clinical Trial Notation This trial was a prospective single-center trial registered at the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR; identification number: UMIN000023890) and the Japan Registry of Clinical Trials (jRCTs051180143).

This study characterized the outcomes of patients who underwent hematopoietic cell transplantation (HCT) for transformed follicular lymphoma (tFL), and clarified the association of low-dose anti-thymocyte globulin use with outcomes after allogeneic HCT. The retrospective study cohort included 74 consecutive patients who underwent autologous (n = 23) or allogeneic (n = 51) HCT at our center from 2000 to 2017. Compared with the allogeneic HCT group, the autologous HCT group underwent fewer systemic regimens before HCT (median 2 vs. 5, p < 0.001) and were more likely to have chemosensitive disease at HCT (100% vs. 82%, p = 0.05), while age, sex and HCT-specific comorbidity index were similar between the two groups. With a median follow-up of 5.8 years among survivors, the 5-year probability of progression-free survival was 64% after autologous HCT and 55% after allogeneic HCT (p = 0.21). The 5-year cumulative incidence of non-relapse mortality was 0% after autologous HCT and 9.5% after allogeneic HCT (p = 0.062). The 5-year cumulative incidence of disease progression was similar between autologous and allogeneic HCT (36% vs. 36%, respectively, p = 0.88). In the allogeneic HCT group, the use of low-dose anti-thymocyte globulin was associated with a lower incidence of severe acute GVHD but not with an increased risk of mortality or disease progression. More than half of patients with early phase chemosensitive tFL and approximately half of those with advanced-phase tFL achieved long-term progression-free survival with autologous and allogeneic HCT, respectively. Disease progression was the major cause of treatment failure after both types of HCT. Further strategies are needed to reduce the risk of disease progression.

To elucidate the incidence, causes, and risk factors associated with readmission due to transplant-related complications, we studied 213 consecutive patients who were discharged without progression of primary disease after their first allogeneic hematopoietic cell transplantation at our center between 2013 and 2016. The median patient age was 50 years (range, 18-71 years). Eighty-three patients had AML or MDS, 66 had lymphoma, 28 had ALL, 23 had ATL, and 13 had other diseases. The median duration of hospitalization for transplantation was 56 days (range 27-325 days). The cumulative incidences of readmission due to transplant-related complications were 8% at 30 days, 16% at 100 days, and 25% at 1 year after discharge. The most frequent cause of readmission was infection, followed by graft-versus-host disease throughout the first year. In multivariate analysis, steroid use at discharge was the only risk factor associated with readmission within 30 days, and steroid use at discharge, absolute lymphocyte count < 500/µl at discharge, and documented bacterial infection during admission were risk factors associated with readmission within 1 year. Our results indicated that factors during hospitalization or discharge, but not at transplantation, were associated with readmission. Patients with these risk factors should be monitored carefully after discharge.

The phase 3 ICARIA-MM trial showed that the addition of isatuximab improved the progression-free survival compared with pomalidomide/dexamethasone. However, the safety and efficacy of isatuximab for end-stage renal failure remains unclear. A 67-year-old man who started hemodialysis 5 years ago for diabetic nephropathy was diagnosed with International Staging System stage III multiple myeloma (MM) of IgD-λ type 3 years ago. After receiving a total of 7 treatment regimens, his free light chain (FLC) λ level increased from 419 to 2,070 mg/L, indicating progressive disease. Twelve days after starting isatuximab plus pomalidomide (3 mg daily) and dexamethasone (IsaPd), his FLC λ level rapidly decreased to 412 mg/L. The patient has now completed 7 courses of IsaPd with no adverse events, including infusion reactions and neutropenia. Isatuximab requires a lower dilution volume than daratumumab and can be safely and effectively administered to hemodialysis-dependent MM patients.

Posttransplant lymphoproliferative disorder (PTLD) after allogeneic hematopoietic cell transplantation (HCT) is usually donor derived, associated with Epstein-Barr virus (EBV), and of B-cell origin. T-cell PTLD (T-PTLD) after allogeneic HCT is extremely rare. Four of 1015 (0.39%) allogeneic HCT patients were diagnosed with T-PTLD; peripheral T-cell lymphoma-not otherwise specified, anaplastic large cell lymphoma, monomorphic T-cell PTLD and polymorphic PTLD with chronic active EBV infection-like symptoms. Three of the four patients developed T-PTLD within 6 months after HCT from HLA-mismatched unrelated donor. Three (75%) and 4 (100%) cases were positive for EBV-encoded small RNA in situ hybridization and EBV-DNA load in peripheral blood, respectively. Chimerism analysis showed that 75% of T-PTLD tissues (3/4) were recipient derived. T-PTLD was refractory to salvage chemotherapy and fatal in all four patients. Including the 10 patients in the literature, the median interval from HCT to diagnosis of T-PTLD was 5 months (range 1-72 months), 55% were negative for EBV, and 56% were recipient-derived. T-PTLD, which often occurred early after allogeneic HCT, was more likely to be EBV negative and recipient derived than B-cell PTLD after allogeneic HCT. Like T-PTLD after solid organ transplant, T-PTLD after allogeneic HCT demonstrated morphological heterogeneity and poor prognosis.

Monoclonal gammopathy of undermined significance (MGUS) is usually asymptomatic, and untreated follow-up is the standard treatment. However, MGUS progresses to multiple myeloma or related malignancy at a frequency of 1.5% per year. It is sometimes difficult to diagnose the progression of the disease via usual examinations. We herein report a case wherein rapid renal dysfunction led to a diagnosis of disease progression to multiple myeloma in a patient with MGUS that was asymptomatic for a long time. A 66-year-old woman developed rapid renal dysfunction requiring continuous hemodiafiltration 8 years after the diagnosis of IgA-κ type MGUS. A complete examination led to the diagnosis of IgA-κ type multiple myeloma. Chemotherapy was not effective, and she died due to sepsis on the 19th day of admission. A pathological autopsy revealed systemic amyloidosis and multiple abscesses positive for Staphylococcus aureus. An abnormal free light chain κ/λ ratio and M protein other than IgG are reportedly risk factors of disease progression of MGUS. In cases with these risk factors, it is important to always keep in mind the possibility of disease progression and to monitor the patient carefully for an early diagnosis.

We compared characteristics of myeloid neoplasms (MNs) following allogeneic hematopoietic cell transplantation (HCT) versus autologous HCT using a Japanese HCT registry database. Among 43 788 patients who underwent allogeneic (n = 18 874) or autologous HCT (n = 24 914) for non-myeloid malignancies or non-malignant diseases, 352 developed MNs. The cumulative incidence of MNs was lower after allogeneic HCT than after autologous HCT (0.3% vs. 1.8% at 10 years, respectively, p < .001). Compared with autologous HCT, MNs following allogeneic HCT developed in younger patients (median, 42 vs. 57 years old, respectively) and sooner after HCT (median, 16 vs. 33 months, respectively). Approximately half of MNs following allogeneic HCT were donor-derived and occurred later than recipient-derived MNs (median, 26 vs. 6 months, respectively, p = .003). In multivariate analysis, reduced-intensity conditioning and cord blood transplantation were associated with MN development after allogeneic HCT. Overall survival was similar in patients who developed MNs following allogeneic versus autologous HCT (18% vs. 22% at 5 years, respectively, p = .48). Patient age ≥ 55 years, the presence of previous HCT, AML subtype, and chromosome 5 or 7 abnormalities were adverse factors for overall survival after MN diagnosis. Further research is warranted to elucidate the mechanisms of MN development following allogeneic HCT.

Post-transplantation acute limbic encephalitis (PALE) is a rare, severe inflammatory disorder in the bilateral limbic system, including the hippocampus. To date, only a few studies have reported details, including risk factors for PALE; however, further clinical evidence of PALE, especially in cerebrospinal fluid human herpesvirus 6-negative cases, is warranted. In addition, data are sparse regarding the risk factors for calcineurin inhibitor (CNI)-induced encephalopathy (CNIE) following allogeneic hematopoietic cell transplantation (allo-HCT) in adults. Therefore, we examined the risk factors for and clinical details of PALE and CNIE. We retrospectively analyzed consecutive patients who underwent allo-HCT between January 2005 and November 2017. A total of 485 patients age 46 years (median) were eligible. In total, 14 PALE cases and 11 CNIE cases were identified. Multivariable analyses identified older age, use of an HLA-mismatched unrelated donor (URD), graft-versus-host disease (GVHD) prophylaxis with CNI and mycophenolate mofetil, and grade II-IV acute GVHD as significantly associated with an increased risk of PALE. In 13 patients who received high-dose methylprednisolone (mPSL) therapy, 6 (46%) responded to mPSL therapy, and 3 (23%) achieved complete remission at day 90 after mPSL administration. Furthermore, myelodysplastic syndrome (MDS), HLA-mismatched URD, and grade II-IV acute GVHD were significantly associated with an increased risk of CNIE. The 5-year nonrelapse mortality rate was 50% in PALE and 63% in CNIE, suggesting a very poor prognosis. In conclusion, this study provides evidence that HLA-mismatched URD and acute GVHD may independently contribute to the development of PALE, possibly in part through HLA-mismatch-derived alloimmune responses. Other than acute GVHD, we have identified MDS and HLA-mismatched URD as novel predictors of CNIE after allo-HCT.

NKG2D-mediated cytotoxicity is regulated by the single nucleotide polymorphism rs1049174, and its antitumor effect has been observed in various clinical settings. There are no previously published data on the influence of donor rs1049174 polymorphism on HLA-haploidentical allogeneic hematopoietic cell transplantation using post-transplantation cyclophosphamide (PTCy-haplo). We aimed to investigate the effect of donor NKG2D gene polymorphism on PTCy-haplo recipients. We retrospectively reviewed 91 consecutive PTCy-haplo recipients at our institution, and genotyped rs1049174 of the NKG2D gene in both donors and patients. In the patients who received PTCy without antithymocyte globulin (ATG) as graft-versus-host disease prophylaxis, the 2-year cumulative incidence of relapse/progression (RI) of PTCy-haplo from rs1049174 CC donors was lower than that from rs1049174 CG/GG donors (25.0% versus 52.4%; P = .041), and rs1049174 CC donors were associated with a decreased risk of relapse/progression (adjusted hazard ratio, 0.2; 95% confidence interval, 0.0 to 0.6; P = .007). Furthermore, a beneficial effect of rs1049174 CC donor on OS and RI was observed in non-acute myelogenous leukemia patients. This study demonstrates that receipt of PTCy-haplo from rs1049174 CC donors was associated with a decreased risk of relapse/progression in the patients who underwent PTCy-haplo without ATG. Future large-scale validation studies are needed to test the significance of donor NKG2D polymorphism in the development of a new donor selection algorithm for PTCy-haplo.

Background: Sinusoidal obstruction syndrome (SOS) remains a significant, potentially lethal complication after allogeneic hematopoietic cell transplantation (allo-HCT). Although a liver biopsy is required to diagnose SOS accurately, it is not considered a mandatory evaluation due to its invasiveness. Therefore, the Seattle and Baltimore criteria with minor revisions have been widely used. However, the diagnostic accuracy of those criteria is insufficient. A noninvasive and more accurate diagnostic strategy is necessary. A number of studies have reported several candidate blood biomarkers for the diagnosis and prediction of SOS. However, which biomarkers or combination thereof are most useful for the diagnosis and prediction of SOS is unclear. We explored the best diagnostic and predictive biomarkers/combination among previously reported biomarkers for SOS using a stringent definition based on a liver biopsy. Methods: We performed this single-center prospective observational study in patients who received allo-HCT from April 2014 to February 2019. Seven biomarkers (PAI-1, P3P, ferritin, total bilirubin [T-bil], direct bilirubin [D-bil], brain natriuretic peptide [BNP], and protein C activity) were examined at pre-conditioning, at days 5 and 30, and at the onset of CTCAE grade ≥2 liver disorder after allo-HCT. We described how to diagnose definitive SOS (Fig. 1). A logistic regression (LR) model and the area under the receiver operating characteristic curves (AUC) were used to compare the seven biomarkers in the diagnosis and prediction of definitive SOS. The sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio for the SOS diagnosis and prediction were also calculated by the best cut-off values, using the Youden index. Results of statistical tests with a p < 0.05 were considered significant. Results: A total of 180 patients were included. The median age was 48 (range: 16-68) years old. Forty-eight patients developed CTCAE grade ≥2 liver disorders. Of these, 10 were diagnosed with definitive SOS. The results of LR and AUC analyses of the SOS diagnosis and prediction are shown in the Table. PAI-1, P3P, ferritin, T-bil, and D-bil were found to be significant diagnostic markers for SOS. Among these, PAI-1 showed the highest AUC (0.85; 95% confidence interval [CI], 0.67-1.00). Furthermore, PAI-1, P3P, ferritin, T-bil, D-bil, and BNP were significant predictors for SOS. Among these biomarkers, P3P showed the highest AUC (0.82; 95% CI, 0.67-0.97). To perform further comparisons using multivariable models in SOS prediction, we first constructed a base model including the times of allo-HCT, disease status, and conditioning intensity. The AUC of the base model was 0.66 (95% CI, 0.48-0.84). After adding P3P to the base model, the AUC significantly improved to 0.88 (95% CI, 0.76-1.00) (p = 0.049). In the kinetics analysis of biomarkers, notably, PAI-1 and P3P increased over the peri-transplant period only in patients with definitive SOS (Fig. 2). In contrast, those values in patients with liver disorders other than SOS or without liver disorders did not show significant kinetic characteristics in the allo-HCT period. Discussion: SOS is attributed to toxic injury of the sinusoidal endothelial cells. PAI-1 is a known endothelial factor, released when the endothelial cells are damaged. This could be why PAI-1 was considered useful for the SOS diagnosis. P3P has been shown to be a sensitive biomarker for liver fibrosis. Furthermore, fibrous alterations in the hepatic remodeling process are well-known significant features for patients with SOS. Thus, liver fibrosis may pathophysiologically be a risk factor for SOS, and P3P may allow clinicians to detect SOS-high-risk patients with high accuracy, even at the time of allo-HCT when preclinical liver fibrosis can exist. Conclusion: We demonstrated that PAI-1 and P3P were the most useful biomarkers for the diagnosis and prediction of SOS, respectively. Figure 1 Figure 1. Disclosures Okamura: NIPPON SHINYAKU CO.,LTD.: Honoraria. Koh: AstraZeneca: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; MSD: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria, Research Funding; Novartis: Honoraria; NIHON PHARMACEUTICAL CO., LTD: Honoraria; Asahi Kasei Corporation:: Research Funding; IQVIA Services Japan K.K.:: Research Funding. Takakuwa: Takeda Pharmaceutical Company Limited.: Honoraria; Bristol-Myers Squibb Comapany: Honoraria; Sanofi K.K.: Honoraria; Celgene Corporation: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Novartis: Honoraria; AbbVie GK: Research Funding; Celgene Corporation: Research Funding. Nakamae: Novartis: Honoraria. Nishimoto: Otsuka Pharmaceutical Co., Ltd.: Honoraria; CSL Behring: Honoraria; Kyowa Kirin Co., Ltd: Honoraria; "Bayer Yakuhin, Ltd ": Research Funding; Janssen Pharmaceutical K.K.: Research Funding. Nakashima: Amgen Astellas BioPharma K.K.: Honoraria; Amgen Inc: Honoraria; Novartis: Honoraria, Research Funding; JCR Pharmaceuticals Co., Ltd.: Honoraria; Pfizer Japan Inc.: Honoraria; Eisai Co., Ltd: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; SymBio Pharmaceuticals Limited.: Honoraria, Research Funding; Astellas Pharma Inc.: Research Funding; Celgene Corporation: Research Funding; AbbVie GK: Research Funding. Nakamae: Astellas Pharma Inc.: Honoraria; Otsuka Pharmaceutical Co., Ltd: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria; Simon-Kucher & Partners: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria; Novartis: Honoraria, Research Funding; Pfizer Japan Inc.: Honoraria; Bristol-Myers Squibb Company: Honoraria, Research Funding; Alexion: Research Funding; PPD-SNBL K.K: Research Funding; CMIC HOLDINGS Co., Ltd: Research Funding. Hino: Novartis: Honoraria, Research Funding; NIPPON SHINYAKU CO.,LTD.: Honoraria; Japan Blood Products Organization: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Sanofi: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria, Research Funding; AstraZeneca: Honoraria; Astellas Pharma Inc.: Honoraria; MSD: Honoraria, Research Funding; CSL Behring: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria, Research Funding; Meiji Seika Pharma Co., Ltd.: Honoraria; Eisai Co., Ltd: Honoraria, Research Funding; Kyowa Kirin Co., Ltd: Honoraria, Research Funding; Pfizer Japan Inc.: Honoraria, Research Funding; Bristol-Myers Squibb Comapany: Honoraria; Janssen Pharmaceutical: Honoraria; JCR Pharmaceuticals Co., Ltd.: Research Funding; ARKRAY: Research Funding; Asahi Kasei Corporation:: Research Funding; Abbott: Research Funding; TEIJIN PHARMA LIMITED.: Research Funding; SEKISUI MEDICAL CO., LTD.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; TAIHO PHARMACEUTICAL CO., LTD.: Research Funding; DAIICHI SANKYO COMPANY, LIMITED.: Research Funding; TOSOH CORPORATION: Research Funding.

A combination of three post-transplant drugs, cyclophosphamide (PTCy), a calcineurin inhibitor, and mycophenolate mofetil, has long been used for prophylaxis of graft-versus-host-disease (GVHD) after HLA-haploidentical allogeneic hematopoietic cell transplantation (allo-HCT). Recently, this combination has been used following HLA-matched allo-HCT as well, but the optimal combination of drugs for GVHD prophylaxis in an HLA-matched setting remains unclear. This prospective phase II study evaluated the safety and efficacy of PTCy plus tacrolimus (TAC) for GVHD prophylaxis after allo-HCT from HLA-matched related donors (MRD) or HLA-matched unrelated donors (MUD). The cumulative incidences of grades II–IV and III–IV acute GVHD at 100 days post-transplantation were 18% and 5.9%, respectively, in the MRD group, and 18% and 9.1%, respectively, in the MUD group. The cumulative incidences of moderate to severe chronic GVHD at 1 year were 12% and 9.1% in the MRD and MUD groups, respectively. The 1-year overall survival rates in the MRD and MUD groups were 88% and 64%, respectively, and the 1-year GVHD-free, relapse free survival rates were 59% and 50%, respectively. These results suggest that GVHD prophylaxis with a less intensive double drug combination (PT/Cy and TAC) might be feasible after HLA-matched allo-HCT. Clinical Trial Notation This trial was a prospective single-center trial registered at the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR; identification number: UMIN000023890) and the Japan Registry of Clinical Trials (jRCTs051180143).

Aim Small-scale clinical studies have reported on drug interactions between caspofungin (CPFG) and calcineurin inhibitors in healthy subjects; however, little is known about these interactions in allogeneic haematopoietic cell transplantation (allo-HCT) patients. Methods We retrospectively assessed the drug interactions and safety profiles in allo-HCT recipients treated concomitantly with CPFG and calcineurin inhibitors. Results Ninety-one consecutive cases were evaluated. There were no statistically significant differences in the plasma concentration/dose (C/D) ratios of tacrolimus (TAC) in 34 patients before and after co-administration with CPFG (median: 575.6–672.4, P = 0.200). In contrast, the median C/D ratio of cyclosporin A (CsA) in 16 patients was significantly elevated after co-administration with CPFG (median: 62.8–74.9, P = 0.016). There were no serious adverse effects on liver or renal function associated with the therapy. Conclusions Our data show that CPFG did not affect the pharmacokinetics of TAC and that it could mildly increase CsA blood concentrations in allo-HCT patients.

Chronic graft versus host disease (cGVHD) of the central nervous system is a rare condition that could occur after allogeneic hematopoietic stem cell transplantation (SCT) but has been poorly documented. Here, we report a patient diagnosed with recurrent acute disseminated encephalomyelitis (ADEM) with longitudinal extensive transverse myelitis (LETM) as cGVHD after HLA haploidentical peripheral blood SCT using posttransplantation cyclophosphamide for mixed-phenotype acute leukemia. We observed clinical and radiological improvement after the rituximab treatment of the condition that had been refractory to steroids. To the best of our knowledge, no report of cGVHD presented recurrent ADEM with LETM after allogeneic SCT and successfully treated with rituximab. Hence, ADEM should be included in the differential diagnosis of neurological symptoms in posttransplant patients with cGVHD.

Background Whether presepsin (soluble CD14-subtype) is better than other markers including procalcitonin (PCT), has not been adequately investigated in febrile neutropenia (FN). Methods We prospectively examined the utility of presepsin in FN in Cohort 1 (C1) and 2 (C2), between November 2010 and February 2012, and between November 2013 and January 2014, respectively. The purpose of this study was to investigate 1) the relative value of serum presepsin over serum PCT in C1, and 2) the relative value of plasma presepsin as compared with serum PCT, C-reactive protein, interleukin-6 and interleukin-8 with frequent, repeated sampling in C2. Results Seventy-nine FN episodes (C1, 75; C2, 4) were evaluable. In C1, when compared with control values, presepsin was significantly higher at onset of FN (P = 0.004), while PCT was not significantly higher (P = 0.54). The median value of serum presepsin within 72 h of onset of FN in subjects with fever of unknown origin, local infection, bacteremia and septic shock was 680 (reference 314) pg/ml, 763, 782 and 1359, respectively. In C2, the mean levels of plasma presepsin from onset of FN to 72 h were classified as negative in the two patients with no suspected site of infection, and those of the remaining two patients with clinically probable infections were positive (175, 131, 346 and 329 pg/ml, respectively). In contrast, the other markers did not discriminate between this two groups. Conclusions In FN, presepsin may be an earlier and more sensitive indicator of bacterial infection than PCT.

Background Therapy-related acute myeloid leukemia and myelodysplastic syndrome (t-AML/MDS) occur after hematopoietic cell transplantation (HCT). The incidence, risk factors and outcomes of t-AML/MDS among patients who underwent autologous or allogeneic HCT for a variety of disease have not been examined systemically. To address these questions, we conducted a retrospective cohort study using the Japanese national transplant registry database. Methods The study cohort included 43,790 patients of all ages who underwent autologous (n=24,916) or allogeneic HCT (n=18,874) for lymphoid malignancies, solid cancer and non-malignant diseases between 1977 and 2015 in Japan. Patients who had antecedent myeloid malignancies and those who had inherited disorders were excluded. Results With a median follow-up of 61 months among survivors, 354 patients developed t-AML/MDS, including 306 after autologous HCT and 48 after allogeneic HCT. The 10-year cumulative incidence of t-AML/MDS was 1.8% (95% CI, 1.6-2.0%) after autologous HCT and 0.3% (95% CI, 0.2-0.4%) after allogeneic HCT. The median patient age of t-AML/MDS diagnosis was higher in patients who had autologous HCT than those who had allogeneic HCT (59 vs 42 years, p Conclusions The incidence of t-AML/MDS was remarkably higher in patients who had autologous HCT than those who had allogeneic HCT. Risk factors and prognostic factors identified in this study would provide physicians with important information for counseling and managing patients about t-AML/MDS after HCT.

Small-scale clinical studies have reported on drug interactions between caspofungin (CPFG) and calcineurin inhibitors in healthy subjects; however, little is known about these interactions in allogeneic haematopoietic cell transplantation (allo-HCT) patients.We retrospectively assessed the drug interactions and safety profiles in allo-HCT recipients treated concomitantly with CPFG and calcineurin inhibitors.Ninety-one consecutive cases were evaluated. There were no statistically significant differences in the plasma concentration/dose (C/D) ratios of tacrolimus (TAC) in 34 patients before and after co-administration with CPFG (median: 575.6-672.4, P = 0.200). In contrast, the median C/D ratio of cyclosporin A (CsA) in 16 patients was significantly elevated after co-administration with CPFG (median: 62.8-74.9, P = 0.016). There were no serious adverse effects on liver or renal function associated with the therapy.Our data show that CPFG did not affect the pharmacokinetics of TAC and that it could mildly increase CsA blood concentrations in allo-HCT patients.

Objective Recent studies suggest that presepsin (soluble CD14-subtype) is a useful diagnostic and prognostic marker for sepsis, with secretion by activated macrophages potentially dependent on phagocytosis of microorganisms. As "hemophagocytosis" is one of the major characteristics in patients with hemophagocytic syndrome (HPS), we hypothesized that presepsin may reflect the phagocytic activity and be a useful prognostic marker for HPS. Therefore, we aimed to assess the prognostic potential of presepsin in secondary HPS in adult patients with hematological malignancies. Methods Between April 2006 and August 2014, we retrospectively examined consecutive patients with HPS whose blood samples were available at our institution and compared the prognostic value of the following in HPS, singly and in combination: plasma presepsin, serum soluble interleukin (IL)-2 receptor (sIL-2R), ferritin, tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), IL-6 and IL-10. Results A total of 14 patients were enrolled. The median age of the patients was 46.5 years (range, 22-65). In univariable Cox models, there were no significant variables associated with the prognosis. However, in 12 evaluable patients, only the combination of higher median values of presepsin (>1,935 pg/mL) and sIL-2R (>4,585 U/mL) at the onset of HPS was significantly associated with the 90-day mortality (hazard ratio 14.5; 95% CI, 1.47-143.36; p=0.02). Conclusion These results suggest that a composite model of plasma presepsin and serum sIL-2R levels at the onset of HPS might be a novel predictor of the prognosis of patients with hematological malignancies and secondary HPS.

A 77-year-old man was diagnosed with cold agglutinin disease in 2004. He had been treated with prednisolone with stabilization of hemoglobin in the 6- to 8-g/dl range. However, his hemolytic anemia worsened, and computed tomography showed systemic lymphadenopathy in May 2012. A pathological diagnosis of small lymphocytic lymphoma was made based on an inguinal lymph node biopsy. Treatment was started with rituximab. However, there was no response to 6 doses of rituximab monotherapy. He next received 6 courses of bendamustine in combination with rituximab. This resulted in stabilization of hemoglobin and independence from transfusion support. To the best of our knowledge, this is only the second case report describing bendamustine plus rituximab treatment for non-Hodgkin lymphoma complicated by cold agglutinin disease. Our results in this case suggest bendamustine to potentially be a useful therapeutic option in patients with cold agglutinin disease.