Shinichiro Machida

Cytochrome P450 genetic polymorphisms influence the serum concentration of calcineurin inhibitors in allogeneic hematopoietic SCT recipients

Calcineurin inhibitors are necessary as immunosuppressants during hematopoietic SCT (HSCT) to prevent alloreactivity, but have unfortunate toxicities. So, we investigated the association of gene polymorphisms with the initial calcineurin inhibitor concentration and the subsequent drug dose from day 1 to day 28 among patients who underwent HSCT at a single institution. We analyzed 58 serial cases of Japanese patients receiving GVHD prophylaxis with CsA (21 cases) or tacrolimus (37 cases). We investigated eight single-nucleotide polymorphisms: rs4244285 (CYP2C19), rs15524, rs4646450, rs3800959, rs776746 (CYP3A5), rs1128503, rs2032582 and rs1045642 (MDR1). The CsA concentration was significantly higher when the genotype of CYP3A5 rs15524 was T/T (P=0.044) or rs776746 was G/G (P=0.027). The CYP3A5 rs776746 and rs4646450 genotypes were also associated with tacrolimus concentration (P=0.013 and P=0.0058, respectively). The dosage of tacrolimus was remarkably reduced from day -1 to day 28 when the patient had the CYP3A5 rs4646450 C/C and/or rs776746 G/G genotype (P=0.0010 and P=0.0021, respectively). In this study, we show that genetic variation has a predictable effect on the pharmacological responses to calcineurin inhibitors in HSCT patients.

Association of autoimmune disease-related gene polymorphisms with chronic graft-versus-host disease

Chronic graft‐versus‐host disease (GVHD) is the most common cause of poor outcomes after haematopoietic stem cell transplantation (HSCT), while the pathophysiology of chronic GVHD remains poorly understood. As both chronic GVHD and autoimmune disease share clinical features, we speculated that autoimmune disease‐related genes might be candidate chronic GVHD‐related genes. Recent large‐scale cohort studies showed that Fc receptor‐like 3 gene (FCRL3) single nucleotide polymorphism (SNP) and peptidylarginine deiminases citrullinating enzymes 4 gene (PADI4) haplotype were associated with autoimmune disease. The present study investigated the association between polymorphisms of these two genes and the incidence of chronic GVHD. We analysed 123 cases of Japanese human leucocyte antigen‐matched sibling recipients and their donors who underwent HSCT. Although PADI4, which is the rheumatoid arthritis‐specific related gene, was not associated with the occurrence of chronic GVHD, the recipient FCRL3‐169C/C genotype was significantly less frequent in chronic GVHD patients than in those without chronic GVHD (P = 0·0086). There was no relationship between FCRL3 polymorphism and acute GVHD. As FCRL3 is expressed by B cells and might have an important role in immunoregulation, this significant protective genetic effect raises the question of whether FCRL3 might also be involved in the pathogenesis of chronic GVHD.

Allogeneic hematopoietic stem cell transplantation for adult patients with mixed phenotype acute leukemia: results of a matched-pair analysis

Adult patients with mixed phenotype acute leukemia (MPAL) have a poor prognosis, and the therapeutic role of allogeneic stem cell transplantation (allo‐SCT) for MPAL remains to be elucidated. Thus, we retrospectively assessed the efficacy of allo‐SCT for MPAL. Eighteen patients with MPAL were identified from the transplant outcome database of Kanto Study Group for Cell Therapy (KSGCT). We also selected 215 patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) as control cohorts using an optimal matching method. The 5‐yr overall survival (OS) rate of patients with MPAL was 48.1%, and patients in remission at the time of transplant showed significantly better survival than those not in remission (5‐yr OS: 71.8% vs. 0%, P = 0.001). No significant differences were seen in OS when stratifying patients according to immunophenotype, cytogenetic abnormalities, or the type of induction therapy. The 5‐yr OS rate of patients with MPAL was not significantly different compared with AML control patients (48.1% vs. 48.1%; P = 0.855) or ALL control patients (48.1% vs. 37.8%; P = 0.426). These results suggested that allo‐SCT is an effective treatment for MPAL, especially early in the disease course, and innovative transplant approaches are warranted to improve the transplant outcome of patients with MPAL who are not in remission.

Single nucleotide polymorphisms of cytarabine metabolic genes influence clinical outcome in acute myeloid leukemia patients receiving high-dose cytarabine therapy

Cytarabine arabinoside (Ara-C) is the most important agent for treating acute myeloid leukemia (AML). Here, we genotyped 11 single nucleotide polymorphisms (SNPs) of seven Ara-C metabolism-related genes in 39 AML patients who had received high-dose Ara-C as a single-agent treatment. Univariate analysis identified three SNPs that were significantly associated with shorter time-to-relapse (TTR): CTPS rs12144160 GG compared to AA/AG, DCTD rs9990999 AG/GG compared to AA, and SLC29A1 rs693955 CC compared to AA/AC. Multivariate analysis of TTR revealed the SLC29A1 rs693955 CC genotype and first induction failure to be significantly associated with a shorter TTR. The DCTD rs9990999 AG/GG and SLC29A1 rs693955 CC genotypes were also significantly associated with shorter duration of neutropenia. The results of our study suggest that SNP analysis can be an important tool in improving drug responsiveness and enabling a better understanding of this condition and the development of tailor-made treatments for AML patients who benefit from consolidated high-dose Ara-C therapy.

Clinical significance of pretransplant serum ferritin on the outcome of allogeneic hematopoietic SCT: A prospective cohort study by the Kanto Study Group for Cell Therapy

This prospective study aimed to investigate the influence of pretransplant serum ferritin levels on the outcomes of allogeneic hematopoietic SCT (HSCT). In total, 190 patients with acute leukemia or myelodysplastic syndrome were consecutively enrolled. The patients were divided into two groups: low-ferritin group (<1000 ng/mL) and high-ferritin group (⩾1000 ng/mL). The primary end point was the cumulative incidence of infection within 100 days after HSCT, which was similar between the two groups: bloodstream infection, 35 vs 38%, P=0.65; bacterial infection, 44 vs 41%, P=0.68; and fungal infection, 6 vs 8%, P=0.71. The 1-year adjusted probability of OS of the high-ferritin group was significantly lower than that of the low-ferritin group (76 vs 63%, P=0.017). Using receiver operating characteristic curve, the threshold of pretransplant serum ferritin levels for bloodstream infection was 1400 ng/mL; the threshold for OS, EFS and non-relapse mortality was 1349 ng/mL. In conclusion, pretransplant serum ferritin levels of ⩾1000 ng/mL did not influence the incidence of infection but adversely affected OS after HSCT. A higher threshold of pretransplant serum ferritin levels may predict HSCT outcomes.

Four hepatosplenic T-cell lymphoma cases of Japanese patients

Hepatosplenic T-cell lymphoma (HSTCL), a rare type of γδ T-cell lymphoma, is characterized by hepatosplenomegaly and cytopenias. It is associated with immunodeficiency and its age of onset is reportedly between the 20s and 30s. We herein report 4 Japanese HSTCL cases. Three of them, including an elderly case that was 74 years of age, were not at adolescence. No cases had a history of immunodeficiency. All other disease phenotypes were similar to the typical HSTCL cases. These findings suggest that there are a certain proportion of HSTCL patients who presented after middle age.

Strong effect of mogamulizumab on splenic residual disease of adult T cell leukemia/lymphoma

Dear Editor, A 54-year-old female complained of multiple subcutaneous masses. A histological study and southern blotting for HTLV1 proviral DNA led to a diagnosis of the acute type of ATLL. FDG accumulation was observed in the abdominal lymph nodes, liver, and spleen (Fig. 1, left panel). She received two cycles of multidrug chemotherapy, including vincristine, cyclophosphamide, doxorubicin, prednisone, ranimustine, vindesine, etoposide, and carboplatin (VCAP–AMP–VECP) [1]. A single residual ATLL lesion in the spleen remained following the administration of VCAP–AMP–VECP (Fig. 1, middle panel). Thereafter, the patient received intravenous infusions of mogamulizumab (1.0 mg/kg) once a week for 3 weeks and the splenic lesion completely disappeared (Fig. 1, right panel). The patient underwent umbilical cord blood transplantation (UCBT) following of cyclophosphamide (120 mg/kg) and total body irradiation (12 Gy). The HLA disparity was two loci mismatched at HLA-B and DR. The total nucleated cell and CD34-positive cell counts were 2.42× 10/kg and 0.75×10/kg, respectively. Prophylaxis for graftversus-host disease (GVHD) included tacrolimus and shortterm methotrexate. Neutrophil engraftment was achieved on day 23. STR-based chimerism testing performed on day 28 revealed BM cells to be 100 % of the donor type [2]. A skin rash emerged on day 30, and the patient was diagnosed with grade II acute GVHD. The acute GVHD immediately disappeared following the dose escalation of tacrolimus. However, after elevation of the total bilirubin level and the development of massive ascites on day 40, she died due to multiple organ failure on day 110. The autopsy results revealed widespread omission of hepatic cells and acute tubular necrosis. No findings of relapse of ATLL, GVHD, microthromboembolism, or veno-occlusive disease were observed.

Outcomes after allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia harboring t(7;11)(p15;p15)

Acute myeloid leukemia (AML) with chromosomal translocation between 7p15 and 11p15 [t(7;11)(p15;p15)], resulting in a fusion between the nucleoporin 98 and homeobox A9 genes (NUP98-HOXA9), is rare and has been reported sporadically in Asian countries. The NUP98-HOXA9 fusion gene can dysregulate hematopoietic precursor transcription, disrupt cell differentiation, enhance cell proliferation, and contribute to leukemogenesis. Although AML with t(7;11)(p15;p15) as the sole abnormality is classified as an intermediate-risk condition in recent cytogenetic stratifications, previous studies reported dismal outcomes, with a median survival of 8–13 months. Most patients in these studies underwent chemotherapy rather than allogeneic hematopoietic stem cell transplantation (HSCT). Moreover, the number of patients in each study was small. To date, no study has directly compared transplant outcomes between patients with AML harboring t(7;11)(p15;p15) and those with other AML variants. In this study, using nationwide registration data in Japan, we compared transplant outcomes of patients with AML harboring t(7;11)(p15;p15) with those of patients with intermediateor poor-risk AML variants. We also evaluated the risk factors for survival in patients with AML harboring t(7;11)(p15;p15) who underwent allogeneic HSCT. Clinical data were collected through the Transplant Registry Unified Management Program, which is the nationwide data registry of the Japan Society for Hematopoietic Cell Transplantation and the Japanese Data Center for Hematopoietic Cell Transplantation. The study endpoints were overall survival (OS), disease-free survival (DFS), relapse rate, and transplant-related mortality. Definitions of each endpoint, covariates considered in the univariate models for each analysis, and statistical methods are described in the Online Supplement. From 1986 through 2014, we identified 91 patients with AML harboring t(7;11)(p15;p15), 7,308 with intermediaterisk AML, and 2,406 with poor-risk AML with chromosomal changes other than t(7;11)(p15;p15). Among the survivors (n=4,278), the median follow-up period was 1,124 days. Patient and transplant characteristics are summarized in Online Supplementary Tables S1 and S2. At 3 years after allogeneic HSCT, OS and DFS probabilities were 40.1% and 37.8% in the t(7;11)(p15;p15) group; 48.0% and 44.8% in the intermediate-risk group; and 28.5% and 25.1% in the poor-risk group, respectively (Figure 1A,B). Patients in the poor-risk group exhibited significantly lower survival probabilities than those in the t(7;11)(p15;p15) group (OS, P=0.008; DFS, P=0.006),

Danaparoid reduces the incidence of hematopoietic stem cell transplantation-associated thrombotic microangiopathy

Danaparoid reduces the incidence of hematopoietic stem cell transplantation-associated thrombotic microangiopathy

Refractory acute promyelocytic leukemia successfully treated with combination therapy of arsenic trioxide and tamibarotene: A case report

A 40-year-old male developed refractory acute promyelocytic leukemia (APL) after various treatments including all-trans retinoic acid, tamibarotene, arsenic trioxide (As2O3), conventional chemotherapy, and autologous peripheral blood stem cell transplantation. We attempted to use both tamibarotene and As2O3 as a combination therapy, and he achieved molecular complete remission. Grade 2 prolongation of the QTc interval on the electrocardiogram was observed during the therapy. The combination therapy of As2O3 and tamibarotene may be effective and tolerable for treating refractory APL cases who have no treatment options, even when they have previously been treated with tamibarotene and As2O3as a single agent.