Marker chromosome is a strong poor prognosis factor after allogeneic HSCT for adverse-risk AML patients.

INTRODUCTION: Chromosome analysis is necessary for the risk classification of acute myeloid leukemia (AML). Marker chromosome (MC) is a fragmented chromosome whose origin cannot be identified from other chromosomes and originates from marked genomic instability. Although AML with MC (MC+) has a poor prognosis even after intensive chemotherapy, its influence on the outcome after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is unclear. OBJECTIVE AND METHODS: We retrospectively analyzed 162 AML patients after allo-HSCT. To evaluate the significance of MC, we compared it with other chromosomal abnormalities. RESULT: Marker chromosome was detected in 14 (8.6%, MC+) patients (vs MC-, n = 158). The 2-year overall survival (OS) in MC+ vs MC- was 26.8% vs 62.2% (P = .0098). The 2-year cumulative incidence of relapse (CIR) in MC+ vs MC- was 80.4% vs 35.5% (P = .0004). Among adverse-risk AML (AD-AML, n = 36), AD-AML/MC+ (n = 11) demonstrated a poorer 2-year OS (9.1%, vs AD-AML/MC- n = 25, 58.3%, P = .0031) and higher 2-year CIR (89.6%, vs AD-AML/MC- 44.7%, P = .002). In multivariate analysis, MC (HR 3.08, 95% CI; 1.02-9.29, P = .046) and HCT-CI (HR 3.23, 95% CI; 1.00-10.4, P = .049) were independent risk factors for CIR among AD-AML. CONCLUSION: Our study suggests MC as a new independent factor for chromosome risk classification to further classify AD-AML.

Patient-based prediction algorithm of relapse after allo-HSCT for acute Leukemia and its usefulness in the decision-making process using a machine learning approach.

Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapy for high-risk acute leukemia (AL), some patients still relapse. Since patients simultaneously have many prognostic factors, difficulties are associated with the construction of a patient-based prediction algorithm of relapse. The alternating decision tree (ADTree) is a successful classification method that combines decision trees with the predictive accuracy of boosting. It is a component of machine learning (ML) and has the capacity to simultaneously analyze multiple factors. Using ADTree, we attempted to construct a prediction model of leukemia relapse within 1 year of transplantation. With the model of training data (n = 148), prediction accuracy, the AUC of ROC, and the κ-statistic value were 78.4%, 0.746, and 0.508, respectively. The false positive rate (FPR) of the relapse prediction was as low as 0.134. In an evaluation of the model with validation data (n = 69), prediction accuracy, AUC, and FPR of the relapse prediction were similar at 71.0%, 0.667, and 0.216, respectively. These results suggest that the model is generalized and highly accurate. Furthermore, the output of ADTree may visualize the branch point of treatment. For example, the selection of donor types resulted in different relapse predictions. Therefore, clinicians may change treatment options by referring to the model, thereby improving outcomes. The present results indicate that ML, such as ADTree, will contribute to the decision-making process in the diversified allo-HSCT field and be useful for preventing the relapse of leukemia.

Myeloablative and reduced-intensity conditioning in HLA-haploidentical peripheral blood stem cell transplantation using post-transplant cyclophosphamide.

We conducted two parallel prospective, multicenter, phase II studies to evaluate the safety and efficacy of HLA-haploidentical peripheral blood stem cell transplantation using post-transplant cyclophosphamide (PTCy-haploPBSCT) following myeloablative conditioning (MAC, n = 50) and reduced-intensity conditioning (RIC, n = 77). Event-free survival (EFS) at 1-year as for primary endpoint was 64% and 43% in the MAC and RIC groups, respectively. Neutrophil engraftment was achieved in 98% and 94% in the MAC and RIC groups, respectively. The incidences of grades II-IV and III-IV acute graft-versus-host disease (GVHD) were 18% and 8% in the MAC group, and 14% and 5% in the RIC group, respectively. Those of all grade and moderate to severe chronic GVHD at 2-year were 36% and 20% in the MAC group, and 27% and 20% in the RIC group, respectively. Overall survival (OS), EFS, nonrelapse mortality, and relapse rate at 2-year were 68%, 54%, 10%, and 36% in the MAC group, and 44%, 35%, 20%, and 45% in the RIC group, respectively. Notably, 83% and 86% of patients who survived without relapse stopped immunosuppressant at 2-year in the MAC and RIC groups, respectively. Our results indicate that both MAC and RIC are valid options for PTCy-haploPBSCT for adults with hematological malignancies.

Refinement of the Glasgow Prognostic Score as a pre-transplant risk assessment for allogeneic hematopoietic cell transplantation.

The Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) is a widely used tool for pre-transplant risk assessment. Allogeneic hematopoietic cell transplantation (HCT) is performed on patients with diverse backgrounds, highlighting the need for other predictors to complement the HCT-CI and support bedside decision-making. There is a strong body of evidence supporting the use of pre-transplant serum ferritin (SF) in risk assessments of allogeneic HCT. We additionally found that the Glasgow Prognostic Score (GPS), which assesses inflammatory biomarkers and predicts survival of patients with solid organ malignancies, is a useful predictive marker for overall survival (OS) and non-relapse mortality (NRM) in allogeneic HCT, independent of HCT-CI and SF. In this study, we refined the GPS by adding pre-transplant SF to improve its prognostic ability and enable better stratification; we call this revised index the HCT-specific revised Glasgow Prognostic Score (HCT-GPS). We observed that the HCT-GPS more accurately predicted NRM and early-term OS than the GPS. Moreover, the HCT-GPS provides an independent prognostic factor adjusted for the HCT-CI and disease status, and stratifies patients into four risk groups by OS and NRM. Thus, the HCT-GPS is a useful index for predicting early-term complications after allogeneic HCT in patients with hematopoietic diseases.

The Glasgow Prognostic Score as a pre-transplant risk assessment for allogeneic hematopoietic cell transplantation.

Evaluation methods, such as scoring systems for predicting complications in advance, are necessary for determining the adaptation of allogeneic hematopoietic cell transplantation (HCT) and selecting appropriate conditioning regimens. The Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI), which is based on functions of main organs, is a useful tool for pre-transplant risk assessments and has been widely applied in determining treatment strategies for patients with hematological diseases. However, as allogeneic HCT is performed on patients with diverse backgrounds, another factor, which reinforces the HCT-CI, is required to evaluate pre-transplant risk assessments. The Glasgow Prognostic Score (GPS), which assesses the combined C-reactive protein and albumin, was reported to predict survival of patients with solid-organ malignancies independently of receiving chemo/radiotherapy and stages of cancer. In this study, we applied the GPS for pre-transplant risk assessments for allogeneic HCT. The GPS successfully stratified the patients into three risk groups of overall survival (OS) and non-relapse mortality (NRM). Moreover, the GPS could predict outcomes independently of the HCT-CI for OS and NRM in multivariate analysis. The GPS is considered to be a useful tool and reinforces the HCT-CI for determining adaptation of allogeneic HCT for patients with hematopoietic neoplasms.

Donor Killer Immunoglobulin-Like Receptor Haplotype B/x Induces Severe Acute Graft-versus-Host Disease in the Presence of Human Leukocyte Antigen Mismatch in T Cell-Replete Hematopoietic Cell Transplantation.

Natural killer cells have been identified as a mediator of alloimmune reactions in allogeneic hematopoietic stem cell transplantation (HSCT). Killer immunoglobulin-like receptors (KIRs) are an important determinant of natural killer cell function. The relationship between KIR genotypes/haplotypes and clinical outcomes of allogeneic HSCT is complex and inconsistent among several reports. We assessed the clinical impact of KIR haplotype on T cell-replete allogeneic HSCTs performed in a single Japanese center for hematological malignancies (n = 106). A comparison of 2 groups, donor haplotypes A/A and B/x, revealed no significant differences in overall survival, relapse, and nonrelapse mortality. However, grade III to IV acute graft-versus-host disease (GVHD) occurred significantly more frequently in the KIR haplotype B/x group (A/A versus B/x: 4.9% versus 20.0%; P = .02). This was even more evident when HLA mismatch was present. The highest incidences of grade II to IV and grade III to IV acute GVHD were observed in patients who received allografts from HLA-mismatched donors with KIR haplotype B/x. These data highlight the importance of KIR genotyping in donor matching, especially when HLA mismatch allogeneic grafting is planned.

The Addition of Low-dose Thalidomide to Bortezomib and Dexamethasone for Refractory Multiple Myeloma.

Five cases were treated by adding daily low-dose thalidomide (50 mg) to bortezomib and dexamethasone therapy for refractory multiple myeloma. This therapy was effective in four cases, with an improvement of bone pain and regression of M-protein. One case was treated with cyclophosphamide, thalidomide, and dexamethasone, adding bortezomib after starting the three-drug combination therapy. This patient has remained in a stable disease state since the beginning of this therapy. Regarding the other four cases, a partial response and a prolonged survival for approximately one year were noted. Peripheral neuropathy did not increase after thalidomide addition. Adding low-dose thalidomide may safely improve the responses for multiple myeloma refractory to bortezomib and dexamethasone.

Fulminant Type 1 Diabetes Mellitus Associated with Coxsackie Virus Type A2 Infection: A Case Report and Literature Review.

A 65-year-old Japanese man presented to our hospital in June 2013 with a 6-day history of fever and fatigue, a 24-h history of thirst, and polyuria. His temperature was 37.8°C and he was alert. However, laboratory tests revealed severe hyperglycemia, undetectable C-peptide levels, and diabetic ketoacidosis. Serum antibody testing confirmed a Coxsackie virus A2 infection. A variety of viral infections are reported to be involved in the development of fulminant type 1 diabetes mellitus (FT1D). Our patient is the first reported case of FT1D associated with Coxsackie virus A2 infection and supports the etiological role of common viral infections in FT1D.

Rapid Normalization of High Glutamic Acid Decarboxylase Autoantibody Titers and Preserved Endogenous Insulin Secretion in a Patient with Diabetes Mellitus: A Case Report and Literature Review.

A 59-year-old Japanese woman developed diabetes mellitus without ketoacidosis in the presence of glutamic acid decarboxylase autoantibody (GADA) (24.7 U/mL). After the amelioration of her hyperglycemia, the patient had a relatively preserved serum C-peptide level. Her endogenous insulin secretion capacity remained almost unchanged during 5 years of insulin therapy. The patient's GADA titers normalized within 15 months. The islet-related autoantibodies, including GADA, are believed to be produced following the autoimmune destruction of pancreatic beta cells and are predictive markers of type 1 diabetes mellitus. Therefore, the transient appearance of GADA in our patient may have reflected pancreatic autoimmune processes that terminated without progression to insulin deficiency.

Type 1 Diabetes Mellitus and Pernicious Anemia in an Elderly Japanese Patient: A Case Report and Literature Review.

We herein report the case of a 66-year-old Japanese man with acute-onset type 1 diabetes mellitus (T1D) accompanied by pernicious anemia. After 2 weeks of polyuria, the patient developed insulin-deficient hyperglycemia with diabetic ketoacidosis in the absence of verifiable islet-related autoantibodies and began insulin therapy in 2001. Eight years later, he developed gastric autoantibody-positive pernicious anemia and began methylcobalamin treatment. Previous studies have reported cases of slowly progressive autoimmune T1D concomitant with pernicious anemia. The present case suggests that potential associations with organ-specific autoimmune disorders should be considered during the long-term follow-up of T1D patients, even though verifiable islet-related autoantibodies are undetectable.

The association of level of reduction of Wilms' tumor gene 1 mRNA transcript in bone marrow and outcome in acute myeloid leukemia patients.

We focused on the level of reduction of Wilms' tumor gene 1 (WT1) mRNA in bone marrow as minimal residual disease during chemotherapies in adult acute myeloid leukemia (AML) patients. Forty-eight patients were enrolled in this study. Log levels of reduction of WT1 mRNA transcript after induction therapy compared with those at diagnosis were associated with disease-free survival (DFS) (P=0.0066) and overall survival (OS) (P=0.0074) in patients who achieved complete remission. Also log levels of reduction of WT1 mRNA transcript after final consolidation therapy compared with those at diagnosis were associated with DFS (P=0.015) and OS (P=0.012). By multivariate analysis, log levels of reduction of WT1 mRNA transcript after induction therapy and after final consolidation therapy compared with those at diagnosis were extracted as risk factors for outcome. Our results suggest that early and deep reduction of tumor burden may be important for the outcome of AML patients. In addition, it may be useful for the decision to proceed with allogeneic SCT as post-remission therapy.

Fulminant type 1 diabetes mellitus and fulminant viral myocarditis. A case report and literature review.

A 35-year-old Japanese woman was admitted with coma following flu-like symptoms. She was diagnosed with diabetic ketoacidosis and fulminant type 1 diabetes (FT1D) and received intravenous infusion of insulin and saline. The next day, the ketoacidosis disappeared, and she recovered consciousness. However, extensive ST-segment elevations in the electrocardiogram appeared with a positive troponin test, and the patient developed pulmonary edema on day 3. An echocardiogram showed globally reduced wall motion of the left ventricle and mild pericardial effusion. Despite medical therapy with intravenous furosemide, carperitide, and catecholamines, her cardiac function deteriorated rapidly, with the left ventricular ejection fraction decreasing to 26% within 7 hours, and progressed to cardiogenic shock that afternoon. The patient received mechanical circulatory support for 4 days with intra-aortic balloon pumping and percutaneous cardiopulmonary support, and recovered fully from circulatory failure. A paired serum antibody test showed a significantly elevated titer against parainfluenza-3 virus, indicating a diagnosis of fulminant viral myocarditis. She was discharged on multiple daily insulin injection therapy, and her subsequent clinical course has been uneventful. In summary, we present a case of concurrent FT1D and fulminant viral myocarditis. Parainfluenza-3 viral infection was confirmed serologically and was considered to be a cause of both the FT1D and fulminant myocarditis.

Late onset post-transfusion hepatitis E developing during chemotherapy for acute promyelocytic leukemia.

We herein report the case of a leukemia patient who developed hepatitis E seven months after undergoing a transfusion with contaminated blood products. The latency period in this case was significantly longer than that of typical hepatitis E. Recently, chronic infection with hepatitis E virus (HEV) genotype 3 has been reported in immunocompromised patients. There is a possibility that our patient was unable to eliminate the virus due to immunosuppression following chemotherapy and the administration of steroids. The prevalence of HEV in healthy Japanese individuals is relatively high and constitutes a critical source of infection via transfusion. Hepatitis E is an important post-transfusion infection, and immunocompromised patients may exhibit a long latency period before developing the disease.

Manifestations of fulminant CD8 T-cell post-transplant lymphoproliferative disorder following the administration of rituximab for lymphadenopathy with a high level of Epstein-Barr Virus (EBV) replication after allogeneic hematopoietic stem cell transplantation.

We herein report the case of a 22-year-old woman with severe aplastic anemia who underwent allogeneic hematopoietic stem cell transplantation (HSCT). After HSCT, the Epstein-Barr virus (EBV)-DNA load in the peripheral blood gradually increased, and the patient presented with a fever and lymphadenopathy on day 56 post-HSCT. Although we administered rituximab, her clinical condition worsened. After rituximab treatment, CD8 T-cells emerged and became dominant in the peripheral blood, some of which were positive on an EBV-specific tetramer analysis. However, an open biopsy of the lymphadenopathy lesions revealed the CD8 T-cells to be infected with EBV, exhibiting proliferation with oligoclonality. The patient ultimately died of multiple organ failure on day 99 post-HSCT.

Successful treatment of severe newly diagnosed immune thrombocytopenia involving an alveolar hemorrhage with combination therapy consisting of romiplostim, rituximab and vincristine.

A 51-year-old man was admitted due to a severe bleeding tendency. After he was diagnosed with immune thrombocytopenia (ITP), several therapies, including steroids, steroid pulse, vincristine and rituximab, were administered; however, the patient's bleeding symptoms were not sufficiently controllable with these treatments. Subsequently, a diffuse alveolar hemorrhage was observed. Treatment with a thrombopoietin receptor agonist, romiplostim, was initiated to prevent lethal hemorrhaging, although the efficacy of thrombopoietic receptor agonists in such emergency situations has not been elucidated. The initiation of romiplostim achieved prompt remission in platelets. This case suggests that combination therapy with romiplostim, rituximab and vincristine is effective in cases of newly diagnosed severe therapy-resistant ITP.

Clinical factors predicting the response of acute graft-versus-host disease to corticosteroid therapy: an analysis from the GVHD Working Group of the Japan Society for Hematopoietic Cell Transplantation.

Systemic corticosteroid therapy is recommended as a first-line treatment for acute graft-versus-host disease (GVHD). We performed a retrospective study to identify the factors affecting the response of grade II to IV acute GVHD to systemic corticosteroid therapy using the Japanese national registry data for patients who received first allogeneic hematopoietic cell transplantation with bone marrow (BM) (n = 1955), peripheral blood stem cells (PBSCs) (n = 642), or umbilical cord blood (UCB) (n = 839). Of 3436 patients, 2190 (63.7%) showed improvement of acute GVHD to first-line therapy with corticosteroids. Various factors were identified to predict corticosteroid response. Interestingly, UCB (versus HLA-matched related BM) transplantation was significantly associated with a higher probability of improvement, whereas HLA-matched unrelated BM and HLA-mismatched stem cell sources other than UCB were significantly associated with a lower probability of improvement. HLA-matched related PBSC transplantation was not significantly different from HLA-matched related BM transplantation. Patients without improvement from corticosteroid therapy had a 2.5-times higher nonrelapse mortality and a .6-times lower overall survival rate. The present study demonstrated, for the first time, a higher probability of improvement in grade II to IV acute GVHD with systemic corticosteroid therapy in patients after UCB transplantation than in those after BM and PBSC transplantation. A prospective study is warranted.

Induction of apoptosis of leukemic cells by TRUE gene silencing using small guide RNAs targeting the WT1 mRNA.

TRUE gene silencing is a technology to eliminate specific cellular RNAs by using tRNase Z(L) and small guide RNA (sgRNA). Here we investigated how WT1-mRNA-targeting sgRNAs affect leukemic cells. We showed that sgRNA can be easily taken up by cells without any transfection reagents, and that the naked sgRNAs targeting the WT1 mRNA can reduce its mRNA levels and WT1 protein amounts in the WT1-expressing leukemic cells. Concomitantly, these sgRNAs efficiently induced apoptosis in these cells but not in WT1-nonexpressing cells. We also demonstrated that the reduction in the WT1 mRNA level is caused by its cleavage by tRNase Z(L).