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The definition of sarcopenia assessed by computed tomography (CT) varies among different reports, and few studies have examined the effect of muscle mass loss on the prognosis of post-hematopoietic cell transplantation (HCT). We retrospectively evaluated 172 patients who underwent an initial allogeneic HCT for acute leukemia at our institution. They were divided into 3 groups according to muscle mass measured at the third lumbar vertebra as assessed by CT. Patients with low muscle mass had a worse performance status, higher comorbidity index and higher disease risk. There was a significant difference in 2-year overall survival between the 3 groups, and worse overall survival (OS) was associated with lower muscle mass (

High-dose methotrexate (MTX) is widely used for the treatment of hematological malignancies. Despite the application of routine supportive care measures, such as intensive fluid hydration and urine alkalinization, nephrotoxicity is still a problem. The present study aimed to evaluate the risk factors for MTX-induced nephrotoxicity. We retrospectively reviewed 88 patients who received a regimen consisting of high-dose MTX (1000 mg/m2) and cytosine arabinoside between 2006 and 2018. Nephrotoxicity (≥ grade 2) was observed in 11 patients. Nephrotoxicity was observed only in patients with a high MTX concentration. Other than the MTX concentration, the serum uric acid level and urine pH at day 1 were associated with nephrotoxicity. A multivariate analysis revealed that urine pH was an independent risk factor for MTX-induced nephrotoxicity. Urine pH

Gastrointestinal acute graft-versus-host disease (aGVHD) is a life-threatening complication that requires urgent and appropriate treatment. An endoscopic examination is considered the gold-standard for the diagnosis of gastrointestinal aGVHD. However, the prognostic value of endoscopy remains controversial. This study aimed to investigate the usefulness of pre-treatment macroscopic and histopathologic findings of upper and lower endoscopy with respect to predicting steroid-resistant gastrointestinal aGVHD. This retrospective study included 44 patients with gastrointestinal aGVHD who underwent endoscopy at the time of diagnosis and received systemic steroid treatment at our hospital. We graded the macroscopic and histopathologic findings using a previously validated 4-point scale. Univariate analyses of endoscopic grading revealed that a higher macroscopic grade in the ileum and higher histopathologic grades in the ileum and colon predicted a poor response to systemic steroids. In a multivariate analysis, macroscopic and histopathologic severity in the ileum were identified as significant prognostic factors that indicated resistance to steroid therapy. The presence of granulation tissue was also a strong independent predictor of resistance to steroid therapy. These findings suggest that both macroscopic and histopathologic findings in the ileum may be useful predictors of steroid-refractory gastrointestinal aGVHD and can indicate an immediate need to develop a second-line strategy.

The speed of neutrophil recovery following allogeneic hematopoietic cell transplantation (allo‐HCT) varies widely among patients. We retrospectively evaluated the slope of neutrophil recovery (N slope) in 120 patients who underwent a first unrelated bone marrow transplantation with granulocyte‐colony stimulating factor support between 2009 and 2018. The median N slope was 205.5 /µL/day. We classified patients into low (n = 59) and high (n = 61) N slope groups with a cut‐off value of 200 /µL/day. The high N slope group correlated with older patients, RIC regimen, high CD34+ cells and recent transplantation. The cumulative incidence of grade II to IV acute graft‐versus‐host disease (aGVHD) was significantly higher in the high N slope group than in the low N slope group (44.3% vs. 16.9%, P < 0.001). In multivariate analysis, high N slope was identified as a significant independent risk factor for grade II to IV aGVHD, irrespective of the involved organs. There were no differences in relapse, non‐relapse mortality, or overall survival between the two groups. In conclusion, the difference in N slope after allo‐HCT may predict the risk of aGVHD. Prevention and treatment of GVHD according to the changes in the neutrophil count may improve post‐transplant complications.

Leukemias are refractory hematopoietic malignancies, for which the development of new therapeutic agents requires in vivo studies using tumor-bearing mouse models. Although several organs are commonly examined in such studies to evaluate the disease course, the effectiveness of interventions and the localization of tumor cells in the affected organs are still unclear. In this study, we histologically examined the distribution of leukemia cells in several organs using two leukemic mouse models produced by the administration of two cell lines (THP-1, a human myelomonocytic leukemia, and A20, a mouse B cell leukemia/lymphoma) to severe immunodeficient mice. Survival of the mice depended on the tumor burden. Although A20 and THP-1 tumor cells massively infiltrated the parenchyma of the liver and spleen at 21 days after transplantation, A20 cells were hardly found in connective tissues in Glisson’s capsule in the liver as compared with THP-1 cells. In the bone marrow, there was more severe infiltration of A20 cells than THP-1 cells. THP-1 and A20 cells were widely spread in the lungs, but were rarely observed in the small intestine. These findings suggest that each leukemia model has a unique localization of tumor cells in several affected organs, which could critically affect the disease course and the efficacy of therapeutic agents, including cellular immunotherapies.

Cardiotoxicity after allogeneic stem cell transplantation (SCT) is associated with a high rate of mortality and worsening quality of life. The relation between daunorubicin dose and post- allogeneic stem cell transplantation (SCT) cardiotoxicity remains unclear. We retrospectively evaluated 171 patients with acute myeloid leukemia (AML) who underwent their first allogeneic SCT at our institution between 2005 and 2021. High-dose daunorubicin (50 mg/m

Tumor lysis syndrome (TLS) is a metabolic disorder caused by massive tumor lysis. Hypouricemic agents are administered to prevent TLS-related hyperuricemia and renal failure. We experienced three cases of urine xanthine crystals during TLS in patients with hematologic malignancies who received prophylactic febuxostat. Yellowish and pinkish deposits were observed in urinary tract catheters and urinary bags. Urine microscopy revealed that the deposits were xanthine crystals. In rapid tumor lysis, inhibition of xanthine oxidase can cause xanthine accumulation and urine xanthine crystallization. During TLS, urine xanthine crystals may be overlooked, so careful observation and management are required to avoid xanthine nephropathy.

Triplet regimens, such as lenalidomide, bortezomib, and dexamethasone (RVd) or thalidomide, bortezomib, and dexamethasone (VTd), are standard induction therapies for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). The addition of daratumumab to RVd and VTd has been investigated in the GRIFFIN and CASSIOPEIA trials, respectively, resulting in improvement in the rate of minimal residual disease (MRD) negativity. In this study, we conducted a cost-effectiveness analysis with a 10-year time horizon to compare first-line and second-line use of daratumumab for transplant-eligible patients with NDMM. Because long-term follow-up data for these clinical trials are not yet available, we developed a Markov model that uses MRD status to predict progression-free survival. Daratumumab was used either in the first-line setting in combination with RVd or VTd or in the second-line setting with carfilzomib plus dexamethasone (Kd). Quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios were calculated from a Japanese and US payer perspective. In the Japanese analysis, D-RVd showed higher QALYs (5.43 vs 5.18) and lower costs (¥64 479,793 vs ¥71 287 569) compared with RVd, and D-VTd showed higher QALYs (5.67 vs 5.42) and lower costs (¥43 600 310 vs ¥49 471,941) compared with VTd. Similarly, the US analysis demonstrated dominance of a strategy incorporating daratumumab in first-line treatment regimens. Given that overall costs are reduced and outcomes are improved when daratumumab is used as part of a first-line regimen, the economic analysis indicates that addition of daratumumab to first-line RVd and VTd regimens is a dominant strategy compared with reserving its use for the second-line setting.

Aprepitant (Apr) is an effective antiemetic agent for chemotherapy-induced nausea and vomiting (CINV). Current CINV guidelines recommend the antiemetic combination of a 5-HT3 receptor antagonist, Apr, and dexamethasone (Dex) for highly emetogenic chemotherapies. Apr inhibits CYP3A4 dose-dependently. Since Dex is metabolized by CYP3A4, the combined use of Apr and Dex inhibits Dex metabolism. CINV guidelines therefore recommend dose-reduction of Dex when Apr and Dex are used together. However, there is some controversy over whether or not Dex should be reduced when administered as an antitumor agent for lymphoid malignancies. We retrospectively compared the antitumor effect of Dex-containing chemotherapy in which Dex is administered at the usual dose without Apr (group A) or administered at a half-dose in combination with Apr (group B). We analyzed 62 consecutive patients with refractory or relapsed CD20 + B cell lymphoma who received R-DHAP therapy in our hospital, including 29 and 33 cases in groups A and B, respectively. The response rate at the end of the first course of R-DHAP was 62.1% and 54.5%, respectively (P = 0.61). As another endpoint to evaluate the effect of Dex, group B tended to show greater suppression of the lymphocyte count (P = 0.05). Therefore, decreasing the dose of Dex by half appeared to be reasonable when combined with Apr.

Background A treatment strategy is needed for hemodialysis-dependent patients with end-stage renal disease who have relapsed/refractory diffuse large B-cell lymphoma (DLBCL). We examined the feasibility of salvage chemotherapy followed by autologous stem-cell transplantation (ASCT) and busulfan as a conditioning regimen. Patients and Methods We provided a patient with refractory DLBCL who was receiving hemodialysis with modified salvage chemotherapies that were based on the mechanism of drug pharmacokinetics and an evaluation of the pharmacokinetics of busulfan. After chemotherapy, the patient underwent ASCT. Results The regimen was successfully administered without adverse events. Conclusion Chemotherapy followed by ASCT using a conditioning regimen of reduced melphalan and pharmacokinetically targeted busulfan is a promising strategy for treating patients with relapsed or refractory DLBCL who also have end-stage renal disease and are receiving hemodialysis.

Immune thrombocytopenia (ITP) has been reported to be associated with thrombotic events. The incidence of thrombosis in 303 newly diagnosed ITP patients in our institute between 2000 and 2016 was retrospectively reviewed. During a median follow-up of 3.6 years, 16 thrombotic events (12 arterial and four venous) occurred. The median platelet count at thrombotic events was 102 × 109/l. At 10 years, the cumulative thrombosis incidence was 10%. A univariate analysis showed that smoking, hypertension, male gender, a history of thrombosis, and atrial fibrillation (Af) were significantly associated with the occurrence of thrombosis, and a multivariate analysis identified smoking and Af as independent risk factors. The thrombotic risk was not increased by lupus anticoagulant positivity or ITP treatment. At 5 years, the cumulative incidence of bleeding and overall survival probability was 5.6% and 92%, respectively. This study demonstrates that smoking and Af were associated with an increased risk of thrombosis. Previously identified risk factors were not confirmed in these Japanese ITP patients.

The combination of dexamethasone, high-dose cytarabine, and cisplatin (DHAP) is used as salvage chemotherapy for relapsed or refractory lymphoma. It includes the administration of cisplatin in a single dose of 100 mg/m2, and renal toxicity is a common adverse event. In this study, we retrospectively analyzed the risk factors for renal toxicity (≥ grade 2) in 74 patients who received DHAP as salvage chemotherapy. Regarding maximal renal toxicities, 38 (51.4%), 6 (8.1%), and 1 (1.4%) patients had grade 2, 3, and 4 toxicities, respectively. Multivariate analyses revealed that overweight (body mass index ≥ 25) was an independent predictive factor for renal toxicity of ≥ grade 2 (odds ratio [OR] 4.08, P = 0.032). A subgroup analysis for patients with diffuse large B cell lymphoma treated with DHAP as second-line therapy (n = 44) confirmed that overweight was an independent risk factor (OR 5.28, P = 0.049). In conclusion, we demonstrated that overweight was an independent risk factor for renal toxicity of ≥ grade 2 in patients who received DHAP. Further clinical studies will be needed to identify a method to decrease renal toxicities after the administration of cisplatin.

Objective Peripherally inserted central catheters (PICCs) are widely used in patients with hematologic malignancies. However, the risks of PICC-related complications during chemotherapy for acute myeloid leukemia (AML) are not fully understood. Methods We conducted a retrospective review of 128 adult patients with AML who received induction therapy by way of PICC insertion between 2012 and 2019. Results The median duration of PICC insertion was 30 days. The incidence rate of catheter-related bloodstream infection (CRBSI) was 2.4% at 30 days, and women were more likely to suffer from CRBSI than men. Local reactions at the insertion site were observed in 56 patients; however, these events did not predict CRBSI. The incidence rates of catheter-related thrombosis (CRT) were 1.6% at 30 days. Obesity put patients at an increased risk for CRT. Unexpected PICC removal occurred in 59 patients, and women were at a higher risk of catheter removal than men. Conclusion Low PICC-related complication rates, possibly associated with high rates of catheter removal, were observed during intensive chemotherapy for AML. Women and obese patients require careful monitoring of their PICC. Procedures to achieve appropriate PICC removal without increasing the complication rate need to be considered.

Immune thrombocytopenia (ITP) can coexist with autoimmune thyroid disease. However, the detailed clinical features remain unknown. We retrospectively reviewed 248 patients with newly diagnosed ITP in our institute for whom we had thyroid function data at diagnosis between 2000 and 2019. Of the 248 patients with ITP, 74 patients also had thyroid disease, including 36 with overt thyroid disease (13 Graves' disease and 23 Hashimoto's thyroiditis) and 38 with subclinical thyroid disease (3 hyperthyroidism and 35 hypothyroidism). ITP and thyroid disease were concurrently diagnosed in 54 patients. Female sex and positivity for antinuclear antibodies (ANA) were significantly associated with thyroid diseases. Platelet-associated immunoglobulin G (PAIgG) levels in patients with Graves' disease were higher than those in patients with Hashimoto's thyroiditis. Platelet counts were similar among euthyroid patients and patients with thyroid disease. Thrombopoietin-receptor agonist was administered more frequently in patients with thyroid disease. The cumulative incidences of thrombosis and bleeding and overall survival did not differ between patients with and without thyroid disease. Treatment for thyroid disease in 22 patients improved thrombocytopenia in 21 patients, especially in 4 patients who were not treated for ITP. This study demonstrated that thyroid diseases were commonly found in patients with ITP. Treatment of the underlying thyroid disease may improve thrombocytopenia.

We evaluated clinical outcomes of disseminated intravascular coagulation (DIC) in patients with hematological malignancies treated with synthetic protease inhibitors (SPIs) and compared the effects of gabexate mesilate (FOY) and nafamostat mesilate (FUT). We retrospectively examined 127 patients [acute myeloid leukemia (n = 48), acute lymphoblastic leukemia (n = 25), and non-Hodgkin lymphoma (n = 54)] with DIC, who were diagnosed according to Japanese Ministry of Health, Labour and Welfare criteria and treated with SPIs [FOY (n = 55) and FUT (n = 72)] at our hospital from 2006 to 2015. The DIC resolution rates on days 7 and 14 were 42.6% and 62.4%, respectively. No significant differences were observed in DIC resolution rates between the FUT and FOY groups [40.3% vs. 45.5% (day 7), P = 0.586; 56.3% vs. 69.8% (day 14), P = 0.179, respectively]. Multivariate analysis revealed that response to chemotherapy was the only independent predictor of DIC resolution on days 7 and 14 (ORR 2.81, 95% CI 1.32-5.98, P = 0.007; ORR 2.51, 95% CI 1.12-5.65, P = 0.026). Resolution of DIC was correlated with improvement of background hematological malignancies, and no significant differences were observed between the two SPIs.

Wilms tumor gene 1 (WT1) is highly expressed in myelodysplastic syndrome (MDS) cells and is known to reflect the tumor burden in MDS. We evaluated the usefulness of WT1 mRNA levels for predicting the prognosis of MDS. At diagnosis, WT1 levels were strongly correlated with the percentage of blasts calculated based on non-erythroid cells, but not with that based on all nucleated cells (r = 0.57, p .05 vs r = 0.42, p = .13). Among the allogeneic transplant recipients, the presence of two consecutive WT1 levels ≥100 copies/μg RNA with a median interval of one month was associated with a 77.8% relapse rate at nine months from the first detection of a high WT1 level, and the median time to relapse was only 114 [36-257] days. WT1 levels at diagnosis were correlated with known prognostic factors. In addition, the presence of two consecutive high WT1 levels after allogeneic transplantation may predict early relapse of MDS.

We retrospectively examined 57 patients with multiple myeloma who underwent autologous stem cell transplantation (ASCT) at our institution. A receiver-operating characteristic curve (ROC) analysis showed that the reduction rate of quantitative serum monoclonal protein (M-protein) before ASCT and the difference in involved and uninvolved free light chains (dFLC) 30 days after ASCT, respectively, had the greatest predictive value for all patients (area under the curve [AUC] 0.791 and 0.660, respectively). Based on the ROC curve-based cutoff values of tumor burden parameters, progression-free survival (PFS) in the high serum M-protein reduction (≥90 %) group was significantly better than that in the low serum M-protein reduction group (

Double-hit lymphoma (DHL) is defined as lymphoma with concurrent BCL2 and MYC translocations. While the most common histological subtype of DHL is diffuse large B-cell lymphoma, the present patient had leukemic follicular lymphoma (FL). A 52-year-old man was admitted to our hospital due to general fatigue and cervical and inguinal lymph node swelling. The patient was leukemic and the pathological diagnosis of the inguinal lymph node was FL grade 1. Chromosomal analysis revealed a complex karyotype including a rare three-way translocation t(8;14;18)(q24;q32;q21) involving the BCL2, MYC, and IGH genes. Based on a combination of fluorescence in situ hybridization (FISH), using BCL2, MYC and IGH, and spectral karyotyping (SKY), the karyotype was interpreted as being the result of a multistep mechanism in which the precursor B-cell gained t(14;18) in the bone marrow and acquired a translocation between der(14)t(14;18) and chromosome 8 in the germinal center, resulting in t(8;14;18). The pathological diagnosis was consistently FL, not only at presentation but even after a second relapse. The patient responded well to standard chemotherapies but relapsed after a short remission. This patient is a unique case of leukemic DH-FL with t(8;14;18) that remained in FL even at a second relapse.

We retrospectively analyzed the relationship between white blood cell (WBC) count elevation after priming and clinical response in 115 patients with AML (61 untreated and 54 relapsed or refractory) treated with low-dose cytarabine, aclarubicin, and G-CSF priming. Receiver operating characteristic curve analysis showed that the ratio of maximum WBC count to pretreatment WBC count (WBCratio) was most strongly associated with complete remission (CR) in previously untreated patients among several parameters we analyzed in this study; however, the prediction accuracy was not clinically significant considering the area under the curve of 0.694. Based on the cutoff value of the WBCratio, CR rate and event-free survival in the high WBCratio group were significantly better than those in the low WBCratio group in untreated patients. Regarding the WBC differential counts, a high ratio of the maximum to pretreatment value of neutrophils rather than that of peripheral blasts was associated with a superior CR rate. In addition, an increase in blasts after G-CSF priming had a significant negative impact on CR rate in untreated patients. In conclusion, an increase in blast counts after G-CSF priming was not predictive of achieving CR.

Follicular lymphoma (FL) is a clinically and biologically heterogeneous disease. Therefore, it is important to identify factors that can predict its clinical outcome.We retrospectively evaluated the usefulness of soluble interleukin-2 receptor (sIL-2R) levels after R-CHOP (posttreatment sIL-2R) in 72 patients with newly diagnosed FL who had either a complete response (CR) or partial response. With the use of a recursive partitioning analysis, we determined the cut-off values of post- and pretreatment sIL-2R levels that were associated with disease progression, which corresponded to 486.5 and 5405 U/mL, respectively.The high posttreatment sIL-2R group showed a significantly inferior progression-free survival (PFS) compared to the low posttreatment sIL-2R group in all patients (3-year PFS 52.6% vs. 77.4%, P = 0.003), and in patients with CR (3-year PFS 57.1% vs. 82.1%, P = 0.034). Although a multivariate analysis showed that pretreatment sIL-2R, but not posttreatment sIL-2R, was an independently significant predictive factor for disease progression, among patients with low pretreatment sIL-2R levels, those with high posttreatment sIL-2R levels tended to have inferior PFS. There was a significant trend in PFS among the high pretreatment sIL-2R group, the low pre- and high posttreatment sIL-2R group, and the low pre- and low posttreatment sIL-2R group (P 0.001).Among patients with a low pretreatment sIL-2R level who exhibited a positive response to R-CHOP, the posttreatment sIL-2R level may help to identify those with a poor prognosis.

Background Dimethyl fumarate (DMF), a fumaric acid derivative, is currently used worldwide as a therapeutic agent for autoimmune diseases, such as multiple sclerosis and psoriasis. As an activator of Nrf-2, DMF protects cells from oxidative stress by inducing anti-oxidant enzymes. In addition, a recent report in Science has shown that DMF catalytically inactivates GAPDH, thereby reduces glycolytic activity, and results in immune modulation in activated CD4+ T-cells. We have previously shown that DMF and its metabolite monomethyl fumarate (MMF) significantly inhibit 3H-thymidine uptake in activated T-cells. DMF also decreased the expression of proliferation marker Ki-67 and intracellular IFN-γ of activated T-cells in a dose dependent manner. These findings prompted us to investigate whether DMF can be used for the treatment of graft-versus host disease (GVHD) after hematopoietic stem cell transplantation. In the current study, we investigated whether, and if so, how DMF inhibits human T-cell immune response and suppress acute GVHD in vivo using a xenogeneic GVHD mouse model. Methods To induce acute GVHD, human peripheral blood mononuclear cells (hPBMCs) were intravenously injected into sublethally irradiated (250 cGy) NOG mice. We allocated the mice into two groups; DMF treatment and non-treatment (control mice). Mice in the DMF group were administered DMF orally (100 mg/kg) for consecutive 7 days (day -3 to +3), and compared with the control mice treated with the same volume of vehicle. Results First, we observed that DMF treatment prolonged the survival of mice (Figure 1). Supporting the result, histopathological analysis showed that the number of hPBMCs infiltrated in the lungs and liver was decreased in the DMF group. Next, to identify the alteration of donor human cell populations after DMF treatment, hPBMCs were retrieved from the lungs on day 9 after transplantation and were analyzed by flow cytometry. Consistent with the histological findings, the absolute number of hPBMCs (hCD45+), and also T-cells (hCD45+hCD3+), in the lungs was significantly lower in the DMF group compared with the control (p < 0.01) (Figure 2). Notably, the number of CD4+ T-cells, but not CD8+ T-cells, was decreased by the DMF treatment. The proportion of regulatory T-cells (Tregs) (hCD45+CD4+CD25+Foxp3+) was elevated in the DMF group, and this finding is consistent with existing reports that DMF may increase the proportion of Tregs. Furthermore, the expression level of PD-1 on hCD4+ T-cells was significantly lower in the DMF group. These results suggest that DMF treatment mainly regulates cell proliferation and functional differentiation of donor human CD4+ T-cells, leading to reduced severity of GVHD. Given that GAPDH and aerobic glycolysis have been shown as potential targets of DMF, we then measured glycolytic activity in human T-cells obtained from mice during GVHD. Extracellular acidification rate, an indicator of glycolytic activity, was monitored under basal conditions followed by sequential treatment with glucose, oligomycin, and 2-deoxy-D-glucose (a competitive inhibitor of glucose). Glycolytic activity after the addition of glucose was significantly lower in the T-cells of DMF group than in those of the control group (Figure 3). DMF treatment also led to a significant reduction in glycolytic capacity and glycolytic reserve. Furthermore, the oxygen consumption rate, an indicator of oxidative phosphorylation, was decreased in the DMF group, indicating that DMF disrupts mitochondrial energy production in T-cells, either directly or indirectly. Similar results were obtained from CD4+ T-cells. These results suggest that DMF treatment can negatively regulate aerobic glycolysis in alloreactive T-cells, leading to the mitigation of GVHD. Conclusion Oral administration of DMF ameliorates GVHD and prolongs the survival of mice by reducing donor CD4+ T-cell proliferation, while the number of Tregs is maintained. Our data suggests that DMF treatment drives donor T-cells into a metabolically inactive state by inhibiting aerobic glycolysis. This investigation provides pre-clinical data to use oral DMF as a prophylactic agent for acute GVHD. Disclosures Kanda: Daiichi Sankyo: Honoraria; Shire: Honoraria; Alexion Pharmaceuticals: Honoraria; Takeda Pharmaceuticals: Honoraria; Novartis: Honoraria; Kyowa Kirin: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Sumitomo Dainippon Pharma: Honoraria; Celgene: Honoraria; Otsuka: Honoraria, Research Funding; Chugai Pharma: Honoraria, Research Funding; Janssen: Honoraria; Astellas Pharma: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Merck Sharp & Dohme: Honoraria; Mochida Pharmaceutical: Honoraria; Mundipharma: Honoraria; Sanofi: Honoraria, Research Funding; Meiji Seika Kaisha: Honoraria; Bristol-Myers Squibb: Honoraria; Shionogi: Research Funding; Ono Pharmaceutical: Honoraria; Nippon Shinyaku: Honoraria, Research Funding.

The 1,3-beta-D-Glucan (BDG) assay is widely used for the diagnosis of fungal infections, especially in patients with hematologic malignancies. Some antimicrobials have been reported to cause false-positive results for BDG, but there has been no report on the effect of penicillin G (PCG) on BDG levels. We experienced a patient who developed false-positive BDG elevation during the administration of PCG for osteomyelitis due to Streptococcus pneumoniae infection. The serum BDG level increased up to 81.0 pg/ml during the continuous administration of PCG at 24 million units per day. However, chest and paranasal CT scan showed no evidence of fungal infection. The BDG level decreased to 38.0 pg/ml at 14 hours after the discontinuation of PCG. The amount of BDG in one vial of PCG inferred from these serum BDG levels is very similar to the actual BDG concentration in a vial of PCG. Therefore, during the administration of PCG, elevated BDG levels should be interpreted with caution, as they may be false-positive results.

The amount of infused CD34+ cells has been reported to be the strongest predictor of platelet recovery after autologous stem cell transplantation (ASCT). However, the timing of platelet recovery varies widely among patients even after the infusion of similar amounts of CD34+ cells. Therefore, we retrospectively assessed 99 patients who underwent their first ASCT for lymphoma or myeloma at our center. Thirteen patients (13%) did not achieve platelet engraftment, defined as a platelet count of at least 2.0 × 104/μL without transfusion, at day 28 after transplantation, whereas 58 of 60 patients (97%) who received at least 2.0 × 106/kg CD34+ cells achieved platelet engraftment within 28 days. Multivariate analysis identified the following significant risk factors for delayed platelet recovery: hemoglobin level and platelet count before stem cell harvest, body temperature of > 39 °C within 5 days after ASCT, and infusion of a small amount ( 39 °C within 5 days after ASCT were identified as independent factors for delayed platelet recovery. In summary, platelet recovery following ASCT was affected by insufficient hematopoietic recovery at stem cell harvest, a need for repeated apheresis, and high fever early after ASCT, particularly when the amount of infused stem cells was insufficient.

In allogeneic hematopoietic stem cell transplantation (allo-HSCT), the effects of patient and donor human leukocyte antigen (HLA) matching status on graft-versus-host disease (GVHD) have been extensively elucidated, but the effects of specific HLAs on acute GVHD remain unclear. Using data from a Japanese registry, we retrospectively analyzed 4392 patients with leukemia or myelodysplastic syndrome who received transplants from HLA-identical sibling donors to investigate the effects of HLAs on acute GVHD. From unbiased searches of HLA-A, -B, and -DR, HLA-B60 was significantly associated with an increased risk of grades II-IV acute GVHD (HR, 1.34; 95% CI, 1.13-1.59; P = 0.001). In contrast, HLA-B62 was significantly associated with a decreased risk of grades II-IV (HR, 0.73; 95% CI, 0.62-0.87; P 0.001) and III-IV acute GVHD (HR, 0.63; 95% CI, 0.46-0.87; P = 0.005). The risk of leukemia relapse was significantly higher in HLA-B62-positive patients than in HLA-B62-negative patients (HR, 1.23; 95% CI, 1.05-1.43; P = 0.01). Both HLA-B60 and -B62 did not affect overall survival. The findings of this study may by implication suggest the possibility that the effects of specific HLAs on transplant outcomes may reflect inherent biological features, and thus consideration of specific HLAs may be helpful to predict transplant outcomes.

The cost of tyrosine kinase inhibitors (TKIs) in the treatment of chronic myeloid leukemia (CML) is a substantial economic burden. In Japan, imatinib, dasatinib, and nilotinib are now approved as first-line treatment of CML in chronic phase. Recent “stop TKI” trials have shown that TKIs can be safely discontinued in nearly one-half of patients with sustained deep molecular response (DMR). In this study, we analyzed the cost-effectiveness of a simulated 10 years of CML treatment including stop TKI in both the United States and Japan. We constructed Markov models to compare 4 strategies in which treatment was initiated with imatinib, dasatinib, nilotinib, or any of these TKIs at the physician's discretion. Treatment was switched to another TKI in the case of intolerance or resistance to the initial TKI, and TKIs were discontinued if DMR persisted for 2 years. “Imatinib first” offered 7.34 quality-adjusted life years (QALYs) at the cost of $1 022 148 in the United States (US dollars) and ¥32 526 785 in Japan (Japanese yen). In comparison with imatinib first, the incremental cost-effectiveness ratio per QALY of “dasatinib first” (7.68 QALY, $1 236 052, ¥51 506 254), “nilotinib first” (7.64 QALY, $1 245 667, ¥39 635 598), and “physician's choice” (7.55 QALY, $1 167 818, ¥41 187 740) was $641 324, $696 717, and $666 634 in the United States and ¥54 456 325, ¥23 154 465, and ¥39 635 615 in Japan, respectively. None of the 3 strategies met the willingness-to-pay threshold. The results were robust to univariate and multivariate sensitivity analyses. Imatinib first was shown to be the most cost-effective approach even with the incorporation of stop TKI.

This study sought to investigate the impact of the soluble interleukin-2 receptor level in the relapsed or refractory phase (r/r sIL-2R) on the clinical outcome in patients with diffuse large B-cell lymphoma (DLBCL). We determined the optimal cutoff value of r/r sIL-2R for disease progression within 6 months from salvage chemotherapy to be 861 U/mL. The high r/r sIL-2R group exhibited a significantly lower survival rate than the low r/r sIL-2R group (1-year event-free survival [EFS], 22.6% vs. 55.7%

The BEAM regimen consisting of carmustine (BCNU), etoposide, cytarabine, and melphalan (MEL) is widely used before autologous hematopoietic stem cell transplantation (auto-HSCT) for lymphoma. However, intravenous BCNU is not available in Japan, and therefore, ranimustine (MCNU) has been used instead of BCNU (the MEAM regimen). We retrospectively analyzed the outcome of 79 adult patients who underwent auto-HSCT for lymphoma using this regimen in two centers, with 1- and 2-day dosing of MEL, respectively. Three-year overall survival (OS) and progression-free survival (PFS) probabilities were 77.3 and 56.5 % in the entire population and 71.7 and 58.0 % in patients with diffuse large B cell lymphoma. These outcomes were at least equivalent to those with the BEAM regimen. There was no regimen-related pulmonary toxicity. In a multivariate analysis, older age was the only factor that was significantly associated with for OS. In a comparison of the two MEL dosing schedules, while there was no significant differences in either OS or PFS, diarrhea was observed more frequently with 1-day dosing of MEL. In conclusion, the MEAM regimen appeared to be a promising conditioning regimen in auto-HSCT for lymphoma. A large prospective study is warranted to confirm the current findings.

We evaluated 121 patients with follicular lymphoma (FL) and analyzed the association between the soluble interleukin-2 receptor (sIL-2R) level at diagnosis and the cumulative incidence of transformation. By a receiver-operating characteristic analysis, we determined a cutoff value of sIL-2R for transformation at 4360 U/mL to classify patients into two groups. Patients in the high sIL-2R group showed a shorter progression-free survival (PFS) and shorter disease-specific survival (DSS) (p

Mesenchymal stromal cells (MSCs) have been shown to inhibit aerobic glycolysis in activated T cells, leading to increased autophagy. Although tryptophan depletion induced by indoleamine 2,3-dioxygenase (IDO) generated by MSCs has been suggested as a potential mechanism, we found that this inhibition was completely abolished when T cells were physically separated from MSCs using the Transwell system. Instead, in the current study, we demonstrate that programmed cell death 1 receptor (PD-1) and its ligand PD-L1, the expression of which is induced on activated T cells and MSCs, respectively, in response to IFN-γ are involved in this inhibition. Blockade of PD-1/PD-L1 interaction by blocking antibodies significantly restored glucose uptake, glycolytic activity, and cluster formation of activated T cells, whereas a specific inhibitor of IDO, 1-methyl-DL-tryptophan, had no effect. Neither surface nor cytoplasmic glucose transporter-1 expression on T cells was changed by MSCs. In addition, glycolytic gene expression in activated T cells was not inhibited despite the presence of MSCs. However, we found that hexokinase II (HK2) protein expression was markedly decreased in activated T cells that had been cocultured with MSCs. PD-1 blocking antibody restored HK2 expression. Taken together, our findings indicate that the PD-1/PD-L1 axis is involved in the MSC-mediated suppression of T cell glycolysis by negatively regulating HK2 activity at the protein level, but not at the mRNA level.

Background: Danaparoid sodium and synthetic protease inhibitors (SPIs) have been approved for the treatment of disseminated intravascular coagulation (DIC) in Japan. Objectives: To compare the clinical results of the treatment of DIC with danaparoid or SPIs. Methods: We retrospectively examined 188 patients with hematological malignancy-related DIC. Results: DIC resolution rate in the danaparoid group was higher than that in the SPIs group (61.5 vs. 42.6%; p = 0.031) on day 7. Multivariate analysis identified the response to chemotherapy as independent predictive factor for DIC resolution on day 7 (odds ratio, OR, 2.28; 95% confidence interval, CI, 1.21–4.31; p = 0.011). While there was no significant difference in the DIC resolution rate on day 14 (75.0 vs. 62.4%; p = 0.117), in a subgroup analysis of patients who did not show an improvement in the underlying disease, the danaparoid group showed a significantly better DIC resolution rate (OR 3.89; 95% CI 1.15–13.2; p = 0.030). There was no difference in the rate of cumulative mortality from bleeding within 28 days between the 2 groups (6.6 vs. 3.3%; p = 0.278). Conclusions: Danaparoid may be associated with more frequent resolution of DIC in patients with refractory underlying disease.

Diffuse large B-cell lymphoma (DLBCL) is a clinically heterogeneous disease. To evaluate the clinical relevance of the serum soluble interleukin-2 receptor (sIL-2R) level, we retrospectively analyzed 178 patients aged ≥60 years who were newly diagnosed with DLBCL. We determined the cutoff value of the sIL-2R level to be 1280 U/mL using the area under the receiver operating characteristic curve. The high sIL-2R group exhibited significantly inferior 5-year progression-free survival (PFS) (36.2% vs. 86.1%, p

TAFRO syndrome, a rare systemic inflammatory disease, can lead to multiorgan failure without appropriate treatment. Although thrombocytopenia is frequently seen in patients with TAFRO syndrome, little is known about its pathogenesis. Moreover, while recent studies have reported the presence of an anterior mediastinal mass in some patients, the pathological status of this remains unclear. Here, we report a case of fatal bleeding in a patient with TAFRO syndrome accompanied by an anterior mediastinal mass. A 55-year-old female was transferred to our hospital with a 2-week history of fever, epistaxis, and dyspnea. Laboratory tests revealed severe thrombocytopenia, computed tomography (CT) showed pleural effusions, and bone marrow biopsy revealed reticulin myelofibrosis. We suspected TAFRO syndrome, but the CT scan showed an anterior mediastinal mass that required a biopsy to exclude malignancy. She soon developed severe hemorrhagic diathesis and died of intracranial hemorrhage despite intensive treatment. She had multiple autoantibodies against platelets, which caused platelet destruction. An autopsy of the mediastinal mass revealed fibrous thymus tissues with infiltration by plasma cells. Our case suggests that thrombocytopenia could be attributed to antibody-mediated destruction and could be lethal. Hence, immediate treatment is imperative in cases of severe thrombocytopenia, even when accompanied by an anterior mediastinal mass.

Wilms' tumor 1 (WT1) mRNA expression is a universal marker of minimal residual disease in patients with acute myeloid leukemia (AML). The aim of this retrospective study was to evaluate the ability of serial measurement of peripheral blood WT1 mRNA levels to predict relapse in patients with AML in remission.From April 2012 to May 2015, 131 patients with AML were admitted to our hospital. Among them, 55 were examined for WT1 mRNA at least 3 times during complete remission to assess minimal residual disease, and thus were included in the following analyses.With a median follow-up duration of 921 days, 34 remained in remission, but their WT1 values frequently increased to 100 copies/μg RNA. Therefore, we focused on the 40 posttreatment observation periods of 37 patients who experienced high WT1 values (defined as those above 100 copies/μg RNA) at least once after they achieved remission. The cumulative incidence of hematologic relapse was 75.8% at 6 months in 26 patients with 2 consecutive high WT1 values, whereas just 1 of the 14 patients with only 1 high WT1 value relapsed (P .01). Similar results were obtained in subgroup analyses of allogeneic stem cell transplant recipients.Sequential monitoring of the WT1 mRNA is of value for the early detection of hematologic relapse in patients with AML in remission after chemotherapy or stem cell transplantation.

This retrospective analysis compared the efficacy of intensive induction therapy consisting of daunorubicin and cytarabine (DNR-AraC) to that of less-intensive therapy including low-dose cytarabine, aclarubicin and granulocyte colony-stimulating factor priming (CAG). Patients aged 60 years or older who were newly diagnosed as acute myeloid leukemia (AML) were analyzed. Sixty-four and 48 patients were treated with DNR-AraC and CAG, respectively. The complete remission rates, 3-year overall survival and event-free survival in the DNR-AraC group were significantly superior to those in the CAG group (65.6% vs. 29.2%, p

The early clearance of blast cells in peripheral blood (PB) during induction chemotherapy can predict the clinical outcome in acute leukemia. We retrospectively analyzed the kinetics of white blood cell (WBC) count, blast cell percentage (BCP), and blast cell count (BCC) in PB in 78 patients with de novo acute myeloid leukemia who underwent a uniform induction chemotherapy between December 2001 and December 2015 at Jichi Medical University. By a repeated-measures analysis of variance, the interaction of the decline in BCP with the achievement of complete remission (CR) was stronger than those of the decline in WBC or BCC. A receiver operating characteristic curve analysis for the achievement of CR showed that the areas under the curve for the decline in WBC, BCP, and BCC were 0.592, 0.703, and 0.634, respectively, and a decline in BCP of 9.25%/day within 4 or 5 days from induction chemotherapy was the optimal cutoff value. A multivariate analysis showed that a rapid decline in BCP (≥9.25%/day) was a significant predictive factor for CR, independent of the cytogenetic risk (p = 0.0096). A rapid decline in BCP during the first 5 days of induction chemotherapy may be a good predictor of CR. Copyright © 2015 John Wiley & Sons, Ltd.

Objective Myeloid/lymphoid neoplasms with fibroblast growth factor receptor-1 (FGFR1) rearrangement are hematopoietic stem cell disorders with a poor prognosis, but no established standard therapy. Methods We experienced a patient with T-lymphoblastic lymphoma (LBL) associated with FGFR1 rearrangement who underwent cord blood transplantation, but died of pulmonary complication. We collected the clinical data of patients with FGFR1 rearrangement from the medical literature and analyzed 45 patients, including our patient. Results The primary diagnoses were myeloproliferative neoplasm (MPN) or myelodysplastic syndromes (MDS) in 14 and acute leukemia or LBL in 31. In MPN and MDS patients, the cumulative incidence of transformation to blast phase (BP) at 12 months was 46.2%. The 1-year overall survival (OS) from diagnosis in all cases was 43.1%. With regard to the impact of treatment response on survival, the achievement of complete response with a landmark at 2 months after diagnosis of BP was associated with a superior OS (40.0% vs. 26.0% P = 0.011 for 1-year OS from BP). Allogeneic hematopoietic stem cell transplantation (HSCT) was performed in 13 patients, and the 1-year OS from allogeneic HSCT was 61.5%. The hazard ratio for mortality was 0.34 (95% CI, 0.08-1.51, P = 0.15) for allogeneic HSCT treated as a time-dependent covariate, which suggests that allogeneic HSCT may confer a clinical benefit. Conclusion The further accumulation of clinical data is needed to determine the optimal therapeutic approach for these neoplasms.

Tyrosine kinase inhibitors (TKIs) are standard therapy for chronic myeloid leukemia (CML). However, the effects of these agents on mature B cell lymphoma are not well known. We describe a 50-year-old man who was diagnosed with CML in the chronic phase and treated with imatinib. After 3 years of imatinib therapy that achieved a complete cytogenetic response of CML, he developed Philadelphia-negative follicular lymphoma (FL). Rituximab monotherapy induced a partial response of FL, and he subsequently achieved a major molecular response (MMR) of CML. Three years later, however, the MMR was lost, followed by the progression of FL. Imatinib was switched to nilotinib for the treatment of CML, while we chose watchful waiting for FL. He achieved MMR again under treatment with nilotinib for 8 months including one month of substitutional use of dasatinib due to adverse events, but thereafter nilotinib was switched to bosutinib due to hyperbilirubinemia. With the administration of second-generation TKIs (2G-TKIs) for a total of 18 months, he achieved a complete response to FL without antilymphoma treatment. This is the first report to suggest that 2G-TKIs may have direct or indirect effects on FL.

Background: Neutrophil recovery following allogeneic hematopoietic cell transplantation (allo-HCT) varies widely among patients. Some cases have a rapid increase in neutrophils and early engraft, while others show slow increase after neutrophils appearance and take time until engraftment. Such differences in neutrophil recovery may reflect the composition of the graft and affect the complications or prognosis after allo-SCT, though it has not been well documented in the literature. In this study, we retrospectively analyzed the influence of the slope of neutrophil recovery (N slope) following allo-HCT on post-transplant complications and prognosis. Methods: This study was a retrospective analysis of 120 patients with hematopoietic diseases who undergone first unrelated bone marrow transplantation at Jichi Medical University between January 2009 and December 2018. Patients who failed to achieve engraftment or did not receive granulocyte-colony stimulating factor were excluded. The N slope was defined as the increase of neutrophil counts from the last day of lowest neutrophil count after transplantation to the date of neutrophil engraftment. We evaluated the predictive value of N slope for acute graft-versus-host disease (GVHD) using the area under the receiver operating characteristic (ROC) curve and determined the cut-off value to maximize the sum of the sensitivity and specificity. Results: The median N slope was 205.5 /µL/day (range 26.4-7574). An ROC analysis showed that a cut-off value of N slope for grade II-IV acute GVHD was 207.5 /µL/day (sensitivity 0.73, specificity 0.6, AUC = 0.67, 95 % confidence interval (CI) = 0.59-0.79). Then, we classified patients into the low (n = 59) and high (n = 61) N slope groups according to the cut-off value of 200 /µL/day. The high N slope group correlated with older patients, RIC regimen, higher infused CD34+ cells ≥ 1.5 × 106/kg, and former transplantation between 2009 and 2013 compared with the low N slope group (p = 0.028, p = 0.003, p = 0.036 and p = 0.025, respectively). Cumulative incidence of grade II-IV acute GVHD at day 100 was significantly higher in the high N slope group than the low N slope group (44.3 % vs. 16.9%, p = 0.0007). With regard to the risk factors for grade II-IV acute GVHD, male, donor age ≥ 40 years, N slope ≥ 200 /µL/day and former transplantation between 2009 and 2013 were significant in univariate analysis. In multivariate analysis, donor age ≥ 40 years, N slope ≥ 200 /µL/day and former transplantation were identified as significant independent risk factors (hazard ratio (HR) 3.6, 95%CI 1.7-7.7, p = 0.001; HR 2.8, 95%CI 1.5-5.3, p = 0.002; HR 3.0; 95%CI 1.5-6.1, p = 0.02;, respectively). Cumulative incidence of grade III-IV acute GVHD at day 100 and chronic GVHD at 2 years did not differ in the high and low N slope groups (10.8 % vs. 5.1 %, p = 0.328; 63.3 % vs. 50.1 %, p = 0.12, respectively). In addition, there was no difference in relapse, non-relapse mortality and overall survival between the two groups (p = 0.76, p = 0.32, p = 0.65, respectively). Conclusion: The current study showed that a steeper slope of neutrophil recovery following HCT was associated with increased acute GVHD, though it did not affect relapse, NRM and OS. Early diagnosis and therapeutic intervention for acute GVHD may improve the outcome of patients with rapid neutrophil recovery. Disclosures Kanda: Chugai: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Ono: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; Nippon-Shinyaku: Research Funding; Takara-bio: Consultancy, Honoraria; CSL Behring: Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; CSL Behring: Research Funding; Mochida: Consultancy, Honoraria; Eisai: Consultancy, Honoraria, Research Funding; Taisho-Toyama: Research Funding; Otsuka: Research Funding; MSD: Research Funding; Takara-bio: Consultancy, Honoraria; Shionogi: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; Nippon-Shinyaku: Research Funding; MSD: Research Funding; Asahi-Kasei: Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Tanabe Mitsubishi: Research Funding; Celgene: Consultancy, Research Funding; Mochida: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Dainippon Sumitomo: Consultancy, Honoraria, Research Funding; Asahi-Kasei: Research Funding; Pfizer: Research Funding; Alexion: Consultancy, Honoraria; Sanofi: Research Funding; Celgene: Consultancy, Research Funding; Otsuka: Research Funding; Taiho: Research Funding; Novartis: Research Funding; Taiho: Research Funding; Taisho-Toyama: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Dainippon Sumitomo: Consultancy, Honoraria, Research Funding; Tanabe Mitsubishi: Research Funding; Sanofi: Research Funding; Novartis: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding.

The prognosis of patients with systemic lymphoma with central nervous system (CNS) involvement is very poor and there is no established standard therapy. We retrospectively analyzed 18 patients (4 untreated and 14 relapsed) with systemic lymphoma with CNS involvement who received methotrexate and cytarabine-based multiagent chemotherapy (modified Bonn protocol). Complete and partial responses were achieved in 56 and 22% of the patients, respectively. The 1-year overall survival (OS) and progression-free survival (PFS) was 81.0 and 39.2%, respectively. Patients with parenchymal involvement showed a better 1-year PFS than those with either leptomeningeal involvement or both. In a multivariate analysis, poor performance status (PS) was the only independent prognostic factor for the 1-year OS and PFS (HR 10.8, 95% CI 1.09-108, p = 0.042; HR 20.8, 95% CI 2.39-181, p = 0.006, respectively). Grade 4 neutropenia and thrombocytopenia occurred in 17 patients each (94%), but there were no grade 4 nonhematopoietic adverse events. The modified Bonn protocol resulted in relatively favorable response and survival, and provided clinical benefits to patients with good PS, in particular. This study demonstrated that the modified Bonn protocol could be a feasible and encouraging treatment approach for lymphoma with CNS and systemic involvement.

The development of acute myeloid leukemia (AML) in patients with untreated chronic lymphocytic leukemia (CLL) is rare. We experienced a 65-year-old man who developed AML with aberrant CD7 expression and monoallelic CEBPA mutation during watchful waiting for CLL. He failed to achieve complete response (CR) by standard induction therapy for AML. We retrospectively reviewed 27 patients who developed AML with untreated CLL published between 1973 and 2016. The median age at diagnosis of AML was 68 years, and the median duration between the diagnoses of AML and CLL was 4.2 years. Diagnosis of AML and CLL was made simultaneously in 16 patients. The CR rate of AML was 42.9%, and the median survival was only 1.5 months after the diagnosis of AML. Patients who achieved CR tended to survive longer than those who did not. Our results demonstrated that the development of AML in patients with untreated CLL was associated with a poor response to chemotherapy and an extremely poor prognosis.

The combination of mitoxantrone (MIT), etoposide (ETP), and cytarabine (Ara-C) (MEC) is a frequently used salvage therapy for acute leukemia, but has been associated with severe myelosuppression. Therefore, we investigated the miniMEC regimen with reduced doses of AraC and MIT. Thirteen ALL and 44 AML patients, all relapsed or refractory, received miniMEC, which consisted of MIT at 8 mg/m2 for 3 d, ETP at 100 mg/m2 for 5 d, and Ara-C at 100 mg/m2 infused over 24 h for 7 d. CR + CRi was achieved in eight ALL patients (61.5%) and 16 AML patients (36.4%). Median duration of neutropenia was 30 d (range, 1–50). Thirty-one patients (54.4%) subsequently received allogeneic stem cell transplantation (SCT), and overall survival was significantly improved in this group (median OS 161 versus 481 d, p = 0.006). We concluded that miniMEC is a safe and effective bridging therapy to SCT.

The early clearance of blast cells in peripheral blood (PB) during induction chemotherapy can predict the clinical outcome in acute leukemia. We retrospectively analyzed the kinetics of white blood cell (WBC) count, blast cell percentage (BCP), and blast cell count (BCC) in PB in 78 patients with de novo acute myeloid leukemia who underwent a uniform induction chemotherapy between December 2001 and December 2015 at Jichi Medical University. By a repeated-measures analysis of variance, the interaction of the decline in BCP with the achievement of complete remission (CR) was stronger than those of the decline in WBC or BCC. A receiver operating characteristic curve analysis for the achievement of CR showed that the areas under the curve for the decline in WBC, BCP, and BCC were 0.592, 0.703, and 0.634, respectively, and a decline in BCP of 9.25%/day within 4 or 5 days from induction chemotherapy was the optimal cutoff value. A multivariate analysis showed that a rapid decline in BCP (≥9.25%/day) was a significant predictive factor for CR, independent of the cytogenetic risk (p = 0.0096). A rapid decline in BCP during the first 5 days of induction chemotherapy may be a good predictor of CR. Copyright © 2015 John WileySons, Ltd.

To better understand the biology of graft-versus-host disease (GvHD) after hematopoietic stem cell transplantation (HSCT) and develop novel treatment strategies, accurate and clinically relevant experimental animal models are indispensable. The majority of our understanding of this potentially lethal complication is based on mouse models of bone marrow transplantation in major histocompatibility complex antigens (MHC) and/or minor histocompatibility antigen mismatched settings. These mouse models of GvHD provide us with an immeasurable wealth of information; however, many findings obtained from mouse models are not necessarily correlated with clinical GVHD in humans. In addition, these mouse models are not suitable for predicting the effectiveness of recent human-specific therapies such as monoclonal anti-human antibodies and adaptive cell immunotherapies. To overcome these limitations, xenogeneic GvHD models using severe immunodeficient mice are currently being used in worldwide and allow us to investigate in vivo human immune reactions. The major aim of our study is to clarify the precise mechanism of immune response in vivo and to determine the principle components responsible for xenogeneic GvHD. We first observed that immunodeficient NOG mice receiving either no or sublethal irradiation consistently showed gradual body weight loss and eventual severe GvHD following injection of human unmanipulated peripheral blood mononuclear cells (PBMCs). Histopathology performed at the late phase of GvHD showed extensive infiltration of human CD45+ mononuclear cells, most of which were T-cells, and tissue destruction in lungs, bone marrow, liver, and spleen, with a smaller number detected in gut and skin unlike in human GvHD. We identified the infiltration of human T-cells exclusively in lungs and spleen before the onset of GvHD. Flow cytometric analysis showed a marked reduce of naïve (CD45RA+CCR7+) and central memory (CD45RA-CCR7+) T-cells and an increase of effector memory (CD45RA-CCR7-) T-cells within CD4+ subset in lungs, suggesting that xenogeneic response by human cells in lungs occur preceding systemic inflammation. Of note, the distribution of human cells was similar between intraperitoneal and intravenous injection. These results indicated that the acute lung injury is not associated with cell trapping within mouse pulmonary microvasculature by intravenous delivery. We next subdivided human lymphocyte subsets by magnetic cell sorting before adoptive transfer to characterize human cells responsive for xenogeneic GvHD development. CD4+ T-cells mediated more rapid and severe GvHD than did an equal number of CD8+ T-cells, whereas neither natural killer cells nor γδT cells caused any symptoms of GvHD. All antigen presenting cells (APCs)-depleted PBMCs mediated GvHD as well, suggesting that human T-cells are activated independently of their own APCs in this model. CFSE cell division assay showed more rapid proliferation of CD4+ rather than CD8+ T-cells. It is a noteworthy that the proliferation of and the expression of early activation marker CD69 on CD8+ T-cells was accelerated in the presence of CD4+ T-cells, indicating that CD4+ T-cells are required for the rapid and more efficacious response of CD8+ T-cells. We also found a strong increase of human IL-2, IFN-γ, and TNF-α in serum of mice injected with whole T-cells. In contrast, we observed very low levels of these inflammatory cytokines in mice injected with isolated CD8+ T-cells alone. Taken together, these results suggest that the early activation of human naïve CD4 T-cells by recognition of foreign antigen on mouse APCs following cytokine production play a critical role in triggering systemic inflammation in xenogeneic GvHD model. This in vivo response was confirmed in vitro by demonstrating that human CD4 T-cells rapidly proliferated and expressed CD69 with significantly increase of IL-2 and IFN-γ in response to mouse dendritic cells. These findings are helpful for adequate evaluation of immune response and creation of optimal experimental conditions in xenogeneic GvHD model. Disclosures Kanda: Otsuka Pharmaceutical: Honoraria, Research Funding.