Kosuke Yoshioka

The clinical features of fatal cyclophosphamide-induced cardiotoxicity in a conditioning regimen for allogeneic hematopoietic stem cell transplantation (allo-HSCT)

Cyclophosphamide (CY) cardiotoxicity induces a rare lethal complication associated with its use. The minimum dose for cardiac toxicity is still not known, although there are no reports of CY toxicity at doses of less than 100xa0mg/kg. There are few studies of CY cardiotoxicity that included a large number of patients who received high-dose CY for conditioning for allogeneic stem cell transplant (allo-HSCT). To elucidate the clinical course, complications, true incidence, and risk factors, the cardiac events of 811 patients who received more than a total of 100xa0mg/kg of CY as conditioning for allo-HSCT were analyzed. Twelve of 811 recipients (1.5xa0%) developed fatal cardiac failure induced by CY at a median of 4 (range 2–8) days after the first administration of CY. Regarding the dose of CY, 8.5, 1.2, and 0xa0% of the patients developed cardiac failure among the patients treated with a total of 200, 120, and 100xa0mg/kg CY, respectively. On echocardiography, the E/A ratio shows diastolic dysfunction but not the ejection fraction changed in the early course. Moreover, a short time to the first symptom after the administration of CY tended to be associated with early death (pu2009=u20090.09). Eleven patients died from progressive acute cardiac failure at day 7 (5–30) after the first administration of CY, and only one patient survived. In summary, fatal CY cardiotoxicity with allo-HSCT is a rare complication, but it is associated with high mortality. The possibility of CY-induced cardiotoxicity must be considered early after the administration of CY.

Clinical impact of pre-transplant gut microbial diversity on outcomes of allogeneic hematopoietic stem cell transplantation

Post-transplant microbial diversity in the gastrointestinal tract is closely associated with clinical outcomes following allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, little is known about the impact of the fecal microbiota before allo-HSCT. We analyzed fecal samples approximately 2xa0weeks before conditioning among 107 allo-HSCT recipients between 2013 and 2015. Microbial analysis was performed using 16S rRNA gene sequencing. Operational taxonomic unit-based microbial diversity was estimated by calculating the Shannon index. Patients were classified into three groups based on the diversity index: low (<2), intermediate (2, 3), and high (>3) diversity (18 (16.8%), 48 (44.9%), and 41 (38.3%) patients, respectively). There were no significant differences in the 20-month overall survival, cumulative incidence of relapse, and non-relapse mortality among three groups. The cumulative incidence of grade II to IV acute graft-versus-host disease (aGVHD) was similar among the three groups (low 55.6%; intermediate 35.4%; high 48.8%, pxa0=xa00.339, at day 100). Furthermore, we found no differences in the cumulative incidence of grade II to IV acute gastrointestinal GVHD among the three groups (low 38.9%; intermediate 21.3%; high 24.4%, pxa0=xa00.778, at day 100). Regarding the composition of microbiota before allo-HSCT, aGVHD patients showed a significantly higher abundance of phylum Firmicutes (pxa0<xa00.01) and a lower tendency for Bacteroidetes (pxa0=xa00.106) than non-aGVHD patients. Maintenance of Bacteroidetes throughout allo-HSCT may be a strategy to prevent aGVHD.

Gut microbiota and acute graft-versus-host disease

&NA; Although allogeneic stem cell transplantation (allo‐SCT) is a potentially curative treatment for various hematological diseases, acute graft‐versus‐host disease (GVHD) is a major cause of morbidity and mortality, and its management is clinically important. Advances in biological techniques have led to great progress in understanding the complex interactions between the host and the gut microbiota. The gut microbiota clearly modulates the immune response and is associated with the pathogenesis of various disorders. Also in allo‐SCT, both preclinical and clinical results indicate that the gut microbiota is closely associated with the development of acute GVHD and transplant outcomes. These results led to the idea that improvement in quantitative and/or qualitative abnormalities of microbiota (dysbiosis) may be a new treatment strategy for acute GVHD. Evaluations of therapies targeting the gut microbiota such as probiotics or fecal microbiota transplantation have just begun. Furthermore, intervention in the gut microbiota with a nutritional approach including prebiotics, postbiotics, and antibiotics selection may also be another promising treatment option for acute GVHD. Graphical abstract Figure. No caption available.

Clinical impact of CD25 expression on outcomes of allogeneic hematopoietic stem cell transplant for cytogenetically intermediate-risk acute myeloid leukemia

Approximately 50% of adult patients with acute myeloid leukemia (AML) do not show clonal chromosome aberrations at diagnosis, and although this group shows an intermediate prognosis, a minority of patients eventually become long-term survivors. [1]. Th is emphasizes the need for new molecular markers that can be used to predict disease aggressiveness and to determine the leukemic response to treatment, including allogeneic hematopoietic stem cell transplant (allo-HSCT) [2]. Recent data have shown that molecular analysis of the presence of mutated FMS-like tyrosine kinase-3 (FLT3), nucleophosmin 1 (NPM1), CCAAT/ enhancer-binding protein alpha (CEBPA), mixed lineage leukemia (MLL) or neuroblastoma RAS viral oncogene homolog (N-Ras) may be useful for this purpose [3]. However, molecular analyses may be costly and not always available, as not all the mutations are detected by sequencing. As an alternative approach, we may be able to focus on distinct clinical features that depend on specifi c genetic aberrations. For example, patients with a FLT3-internal tandem duplication (ITD) mutation tend to have higher white blood cell count and blast count [4], and moreover a high percentage of these patients may have high CD25 (the α -chain of the interleukin-2 [IL-2] receptor) antigen expression as observed with fl ow cytometry [5 – 7]. Recent studies have shown that CD25 is highly expressed in chemotherapy-resistant, cell cycle-quiescent leukemic stem cells, and high CD25 expression may be associated with an unfavorable outcome after conventional chemotherapy, including autologous and allogeneic transplant [5 – 7]. Th us, evaluation of CD25 expression may be an alternative, cost-eff ective non-molecular tool for cytogenetically intermediate (CI)-AML. Here we report the clinical impact of surface expression of the CD25 antigen on transplant outcomes in a total of 40 patients with CI-AML who underwent allo-HSCT in a single institution. In this study, intermediate-risk AML included patients with a normal or indeterminate karyotype. Bone marrow and peripheral blood samples from 40 patients with CI-AML were available for analysis of CD25 expression at the initial diagnosis. Th ese patients eventually underwent allo-HSCT in our institution between January 2001 and January 2013. We list the chemotherapies, conditioning regimens and outcomes (Supplementary Table I to be found online at http://informahealthcare.com/doi/ abs/10.3109/10428194.2014.974044). Patients with French – American – British (FAB) classifi cation M3 were excluded. Flow cytometry analyses were performed in-house using standard immunofl uorescence methods with monoclonal antibodies directed against CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD11b, CD13, CD14, CD19, CD20, CD25, CD33, CD34, CD38, CD41, CD56 and human leukocyte antigen (HLA)-DR antigens, and were considered to be positive if at least 20% of leukemic blasts expressed the antigen [5]. Th e cut-off level of CD25 depends on the report, for example 10% [6,7] and 20% [5]. Generally the cut-off level of 20% has been known as the standard, and we consider this as the best cut-off level to exclude false-positive results. Transplant procedures have been described in detail elsewhere [8]. Myeloablative conditioning mainly included busulfan (3.2 mg/kg for 4 days) and cyclophosphamide (60 mg/kg for 2 days). Th e main preparative regimen for the reduced-intensity procedure consisted of fl udarabine (30 mg/m 2 for 6 days), melphalan (40 mg/m 2

Hes1 upregulation contributes to the development of FIP1L1-PDGRA-positive leukemia in blast crisis.

We have previously shown that elevated expression of Hairy enhancer of split 1 (Hes1) contributes to blast crisis transition in Bcr-Abl-positive chronic myelogenous leukemia. Here we investigate whether Hes1 is involved in the development of other myeloid neoplasms. Notably, Hes1 expression was elevated in only a few cases of 65 samples with different types of myeloid neoplasms. Interestingly, elevated expression of Hes1 was found in two of five samples of Fip1-like1 platelet-derived growth factor receptor-α (FIP1L1-PDGFA)-positive myeloid neoplasms associated with eosinophilia. Whereas FIP1L1-PDGFRα alone induced acute T-cell leukemia or myeloproliferative neoplasms in mouse bone marrow transplantation models, mice transplanted with bone marrow cells expressing both Hes1 and FIP1L1-PDGFRα developed acute leukemia characterized by an expansion of myeloid blasts and leukemic cells without eosinophilic granules. FIP1L1-PDGFRα conferred cytokine-independent growth to Hes1-transduced common myeloid progenitors, interleukin-3-dependent cells. Imatinib inhibited the growth of common myeloid progenitors expressing Hes1 with FIP1L1-PDGFRα, but not with imatinib-resistant FIP1L1-PDGFRα mutants harboring T674I or D842V. In contrast, ponatinib efficiently eradicated leukemic cells expressing Hes1 and the imatinib-resistant FLP1L1-PDGFRΑ mutant in vitro and in vivo. Thus, we have established mouse models of FIP1L1-PDGFRA-positive leukemia in myeloid blast crisis, which will help elucidate the pathogenesis of the disease and develop a new treatment for it.

Central nervous system infection following allogeneic hematopoietic stem cell transplantation.

OBJECTIVE/BACKGROUNDnHere, we described the clinical characteristics and outcomes of central nervous system (CNS) infections occurring after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in a single institution over the previous 6 years.nnnMETHODSnCharts of 353 consecutive allogeneic transplant recipients were retrospectively reviewed for CNS infection.nnnRESULTSnA total of 17 cases of CNS infection were identified at a median of 38 days (range, 10-1028 days) after allo-HSCT. Causative pathogens were human herpesvirus-6 (n=6), enterococcus (n=2), staphylococcus (n=2), streptococcus (n=2), varicella zoster virus (n=1), cytomegalovirus (n=1), John Cunningham virus (n=1), adenovirus (n=1), and Toxoplasma gondii (n=1). The cumulative incidence of CNS infection was 4.1% at 1 year and 5.5% at 5 years.nnnCONCLUSIONnMultivariate analysis revealed that high-risk disease status was a risk factor for developing CNS infection (p=.02), and that overall survival at 3 years after allo-HSCT was 33% in patients with CNS infection and 53% in those without CNS infection (p=.04).

Comparison of transplant outcomes and economic costs between biosimilar and originator filgrastim in allogeneic hematopoietic stem cell transplantation

From January 2012 to September 2015, 49 patients received biosimilar filgrastim (BF) after allogeneic bone marrow transplantation (BMT, nxa0=xa031) or peripheral stem cell transplantation (PBSCT, nxa0=xa018) in our institution. To evaluate the clinical impact of BF on transplant outcomes of these patients, we compared hematological recovery, overall survival (OS), disease-free survival (DFS), transplantation-related mortality (TRM), cumulative incidence of relapse (CIR), and acute and chronic graft-versus-host disease (GVHD) with those of control patients who received originator filgrastim (OF) after BMT (nxa0=xa031) or PBSCT (nxa0=xa018). All cases were randomly selected from a clinical database in our institution. In both the BMT and PBSCT settings, neutrophil recovery (17 vs. 19xa0days in BMT; 13 vs. 15xa0days in PBSCT) and platelet recovery (27 vs. 31xa0days in BMT; 17 vs. 28xa0days in PBSCT) were essentially the same between BF and OF. They were also comparable in terms of OS, DFS, TRM, CIR, and the incidence of acute GVHD and chronic GVHD. On multivariate analysis, the use of BF in both BMT and PBSCT was not a significant factor for adverse transplant outcomes. Although BF significantly reduced filgrastim costs in both BMT and PBSCT, total hospitalization costs were not significantly different between BF and OF.

Toxic encephalopathy after exposure to azacitidine.

Azacitidine (AZA) is a pyrimidine nucleoside analog of cytidine that has been shown to improve survival, reduce the risk of leukemic transformation and delay progression to acute myeloid leukemia (AML) in higher-risk myelodysplastic syndrome (MDS) [1,2]. AZA has become the standard of care for higher-risk MDS [3], and is generally well tolerated in patients, including the elderly [4]. Th e most common serious adverse events resulting in hospitalization are thrombocytopenia, febrile neutropenia, fever and pneumonia [5]. Aside from hepatic coma, severe central nervous system (CNS) complications have not been reported [6]. We report the case of a patient who showed disorientation and a depressed level of consciousness after AZA administration. A 59-year-old man was admitted with leukocytosis. His medical history consisted of mild diabetes mellitus (DM) without treatment, paroxysmal atrial fi brillation and sleep apnea syndrome (SAS) being treated using a bilevel positive airway pressure mask. On examination, he showed slight splenomegaly without lymphadenopathy. He was fully conscious, and neurological examination on admission showed normal results. Liver, kidney and heart functions were normal. Laboratory studies showed a hemoglobin level of 7.6 g/dL, and a white blood cell (WBC) count of 9.9 10 3 / μ L with 9% myeloblasts, 60.0% monocytes, 11% neutrophils and 18% mature lymphocytes. Th e platelet count was 12.5 x02 10 4 / μ L. Lactate dehydrogenase (LDH) was 519 U/L (normal range, 115 – 245 U/L). A bone marrow (BM) aspirate showed hypercellular marrow with 14.7% myeloblasts, 29.2% promonocytes and 38.4% monocytes. Myeloblasts showed the following immunophenotype: CD13 (40%); CD33 (99%); CD11b (95.4%); CD14 (86.9%); CD38 (99.4%); and human leukocyte antigen (HLA)-DR (99.6%). Cytogenetic study revealed a normal karyotype. AML with myelodysplasiarelated changes was diagnosed based on the World Health Organization classifi cation [7]. Th ese results suggested that leukemia would develop from chronic myelomonocytic leukemia. Th e patient was administered AZA intravenously for 7 days (75 mg/m 2 /day). Body surface area was 2.065 m 2

Diagnostic open brain biopsy following initial negative results of cerebrospinal fluid assessment for Toxoplasma

Cerebral toxoplasmosis is a rare but fatal complication after allogeneic hematopoietic stem cell transplantation (HSCT), and reaching an accurate antemortem diagnosis with pathological proof is difficult.1,2 We describe herein the clinical course of a patient with cerebral toxoplasmosis following allogeneic HSCT. The diagnosis was successfully made by aggressive open brain biopsy following initial negative results from cerebrospinal fluid (CSF) assessment for Toxoplasma. n nThis article is protected by copyright. All rights reserved.

Central Nervous System Involvement at the Time of Allogeneic Hematopoietic Stem Cell Transplantation Is Associated with a Poor Outcome in Patients with Acute Myeloid Leukemia

Recent reports suggested that central nervous system (CNS) involvement (CNS+) in patients with acute myeloid leukemia (AML) before allogeneic hematopoietic stem cell transplantation (allo-HSCT) is not an independent predictor of survival after allo-HSCT. However, these studies did not analyze minimal residual disease in the CNS at the time of allo-HSCT. We evaluated the effect of residual CNS+ on the transplant outcomes of 214 AML patients in a single institution. Twenty-one (10%) patients were diagnosed with CNS+ prior to allo-HSCT. Of these, 13 patients had CNS disease at the time of allo-HSCT. The patients in CNS+ AML remission at the time of allo-HSCT had better overall survival (OS) than the patients who were not in remission (2-year OS: 55% vs. 7.7%, pxa0=xa00.0001). In multivariate analyses, CNS+ at the time of allo-HSCT (hazard ratio (HR), 1.9; 95% confidence interval (CI), 1.05–3.59; pxa0=xa00.04), age over 50xa0years at the time of allo-HSCT, and non-complete remission disease status in bone marrow at the time of allo-HSCT were independent adverse factors for OS. However, a prior history of CNS+ before allo-HSCT did not independently affect OS (HR, 1.27; 95% CI 0.53–2.07; pxa0=xa00.6). Early diagnosis and eradication of CNS+ at the time of allo-HSCT may be necessary to improve the outcome for patients with CNS+ AML.