[Show abstract][Hide abstract] ABSTRACT: Objective:
Myelodysplastic syndromes (MDS) are a group of hematological neoplasms associated with ineffective hematopoiesis and that transform to acute leukemia. Distinguishing MDS from other cytopenias is sometimes difficult even for trained hematologists. WT1, the gene mutated in Wilms' tumor, was found expressed in acute myeloid leukemia and MDS. The amount of WT1 in peripheral blood and bone marrow (BM) is low in low-risk MDS subtypes, and is high in high-risk MDS subtypes. However, the role of WT1 in the differential diagnosis between MDS and other diseases showing cytopenia has not been fully addressed. The present study evaluated whether WT1 expression level can assist in the differential diagnosis of MDS from other cytopenias.
The amount of WT1 message was evaluated among 56 MDS patients and 47 patients with cytopenia for various other reasons (cytopenia VR) at the Nagasaki University Hospital.
The level of WT1 was significantly related to the percentage of blasts in BM among MDS cases, and the type of French-American-British classification of MDS; refractory anemia (RA) cases showed significantly lower WT1 level than patients with RA with excess blasts. WT1 level was significantly related to the prognostic risk categories of MDS by the International Prognostic Scoring System (IPSS) and the revised IPSS. Although the blast percentage in the BM of RA and cytopenia VR were both less than 5%, there was a significant difference in the level of WT1 between MDS and cytopenia VR.
WT1 might be a good marker to differentiate low blast percentage MDS and cytopenia VR.
Full-text · Article · Mar 2015 · Internal Medicine
[Show abstract][Hide abstract] ABSTRACT: Allogeneic hematopoietic SCT (allo-SCT) is a promising therapy that may provide long-term durable remission for adult T-cell leukemia-lymphoma (ATL) patients; however, the incidence of relapse associated with ATL remains high. To determine the clinical features of these patients at relapse, we retrospectively analyzed tumor lesions in 30 or 49 patients who relapsed following allo-SCT or chemotherapy (CHT), respectively, at three institutions in Nagasaki prefecture between 1997 and 2011. A multivariate analysis revealed that the development of abnormal lymphocytes in the peripheral blood of patients at relapse was less frequent after allo-SCT than after CHT (P<0.001). Furthermore, relapse with a new lesion only in the absence of the primary lesion was more frequent in allo-SCT (P=0.014). Lesions were more frequently observed in the central nervous systems of patients who relapsed with new lesions only (P=0.005). Thus, the clinical manifestation of relapsed ATL was slightly complex, especially in post-transplant patients. Our results emphasized the need to develop adoptive modalities for early and accurate diagnoses of relapsed ATL.Bone Marrow Transplantation advance online publication, 26 January 2015; doi:10.1038/bmt.2014.308.
No preview · Article · Jan 2015 · Bone Marrow Transplantation
[Show abstract][Hide abstract] ABSTRACT: Dear Editor,A 63-year-old male was admitted to our hospital with relapsed CC chemokine receptor 4 (CCR4)-positive adult T cell leukemia/lymphoma (ATL) (Fig. 1a). He received intravenous infusions of mogamulizumab (Moga), a defucosylated, humanized anti-CCR4 monoclonal antibody , once a week at a dose of 1.0 mg/kg. After the third infusion of Moga, morphologically abnormal lymphocyte count and human T cell leukemia virus type 1 (HTLV-1) proviral load  decreased from 4.8 × 109/L (32 % of white blood cell (WBC)) and 60.3 copies/100 peripheral blood mononuclear cells (PBMCs) to 0.33 × 109/L (4 % of WBC) and 17.0 copies/100 PBMCs, respectively. However, serum lactate dehydrogenase and soluble interleukin-2 receptor levels rose from 475 and 4,627 U/ml to 596 and 56,092 U/ml, respectively. His mediastinal and intra-abdominal lymph nodes also increased in size. Flow cytometric analysis (FCM) of his PB revealed that the majority of the remaining ATL cells were negative for CCR4 (Fig. 1a). ...
No preview · Article · Oct 2014 · Annals of Hematology
[Show abstract][Hide abstract] ABSTRACT: Adult T-cell leukemia-lymphoma (ATL), an aggressive neoplasm etiologically associated with human T-lymphotropic virus type-I (HTLV-1), is a chemo-resistant malignancy. Heat shock protein 90 (HSP90) is involved in folding and functions as a chaperone for multiple client proteins, many of which are important in tumorigenesis. In this study, we examined NVP-AUY922 (AUY922), a second generation isoxazole-based nongeldanamycin HSP90 inhibitor, and confirmed its effects on survival of ATL-related cell lines. FACS analysis revealed that AUY922 induced cell-cycle arrest and apoptosis, while it also inhibited the growth of primary ATL cells, but not of normal peripheral blood mononuclear cells. AUY922 caused strong up-regulation of HSP70, a surrogate marker of HSP90 inhibition, and a dose-dependent decrease in HSP90 client proteins associated with cell survival, proliferation, and cell cycle in the G1 phase, including p-Akt, Akt, IKKα, IKKβ, IKKγ, Cdk4, Cdk6, and survivin. Interestingly, AUY922 induced down-regulation of the proviral integration site for Moloney murine leukemia virus (PIM) in ATL cells. The PIM family (PIM-1, -2, -3) are oncogenes that encode a serine/threonine protein kinase family. Since PIM kinases have multiple functions involved in cell proliferation, survival, differentiation, apoptosis and tumorigenesis, their down-regulation may play an important role in AUY922-induced death of ATL cells. In fact, SGI-1776, a pan-PIM kinase inhibitor, successfully inhibited the growth of primary ATL cells as well as ATL-related cell lines. Our findings suggest that AUY922 is an effective therapeutic agent for ATL, while PIM kinases may be a novel therapeutic target. This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Myelodysplastic syndromes (MDSs) is a hematological neoplasm defined by ineffective hematopoiesis, dysplasia of hematopoietic cells, and risk of progression to acute leukemia. MDS occurs as de novo or secondary, and chemoradiotherapy for cancers is thought to increase the risk of MDS among patients. Recently, an epidemiological study for MDS among A-bomb survivors was performed, and it clearly demonstrated that the exposure to external radiation significantly increased the risk of MDS. Precise epidemiological data among survivors have revealed important clinical factors related to the risk of leukemias. In this review, by comparing data for secondary MDS and leukemia/MDS among survivors, several factors which would affect the risk of MDS, especially secondary MDS, are discussed.
[Show abstract][Hide abstract] ABSTRACT: VCAP (vincristine, cyclophosphamide, doxorubicin, and prednisone)-AMP (doxorubicin, ranimustine, and prednisone)-VECP (vindesine, etoposide, carboplatin, and prednisone) is a standard regimen for aggressive adult T cell leukemia-lymphoma (ATL). However, the efficacy of this regimen has not been fully elucidated for patients aged 70 years or older. Here, we retrospectively analyzed elderly patients with aggressive ATL at Nagasaki University Hospital between 1994 and 2010 to assess treatment outcomes. Of 148 evaluable patients, 54 were aged 70 years or older at diagnosis. The median survival time (MST) and overall survival (OS) at 2 years in elderly patients were 10.6 months and 22.1 %, respectively. Thirty-four patients received VCAP-AMP-VECP as the initial treatment, although the doses were reduced for most patients. In these patients, MST and OS at 2 years were 13.4 months and 26.6 %, respectively. Eleven of 34 patients (32 %) received maintenance oral chemotherapy after two or three cycles of VCAP-AMP-VECP, and MST and OS at 2 years were 16.7 months and 32.7 %, respectively. Our results suggest that the VCAP-AMP-VECP regimen may be effective and that maintenance oral chemotherapy may be considered as a therapeutic option for elderly patients with aggressive ATL.
No preview · Article · Sep 2014 · International Journal of Hematology
[Show abstract][Hide abstract] ABSTRACT: Myelodysplastic syndrome (MDS) is a disorder of hematopoietic stem cells (HSCs) that is often treated with DNA methyltransferase 1 (DNMT1) inhibitors (5-azacytidine [AZA], 5-aza-2'-deoxycytidine), suggesting a role for DNA methylation in disease progression. How DNMT inhibition retards disease progression and how DNA methylation contributes to MDS remain unclear. We analyzed global DNA methylation in purified CD34+ hematopoietic progenitors from MDS patients undergoing multiple rounds of AZA treatment. Differential methylation between MDS phenotypes was observed primarily at developmental regulators not expressed within the hematopoietic compartment and was distinct from that observed between healthy hematopoietic cell types. After AZA treatment, we observed only limited DNA demethylation at sites that varied between patients. This suggests that a subset of the stem cell population is resistant to AZA and provides a basis for disease relapse. Using gene expression data from patient samples and an in vitro AZA treatment study, we identified differentially methylated genes that can be activated following treatment and that remain silent in the CD34+ stem cell compartment of high-risk MDS patients. Haploinsufficiency in mice of one of these genes (NR4A2) has been shown to lead to excessive HSC proliferation, and our data suggest that suppression of NR4A2 by DNA methylation may be involved in MDS progression.
No preview · Article · Aug 2014 · STEM CELLS TRANSLATIONAL MEDICINE
[Show abstract][Hide abstract] ABSTRACT: Cryoglobulinemia (Cg) in multiple myeloma (MM) is rare and no standard treatment has yet been established. Herein, we report a case of MM with Cg, successfully treated with a combination of lenalidomide and dexamethasone. A 76-year-old woman suffering from skin ulcerations, extremity pain and peripheral neuropathy was diagnosed as having IgG-kappa MM with Cg in 1992. She intermittently received conventional chemotherapy, immunosuppressant therapy and plasma exchange. Despite these treatments, Cg-related symptoms eventually became uncontrollable. She was admitted to our hospital in 2012 because of worsening skin symptoms involving both ankles. Plasmapheresis proved ineffective. Improvement of skin ulcerations and numbness was achieved with administration of lenalidomide at 25 mg daily with weekly dexamethasone, which also decreased the cryoglobulin level. The course of this patient suggests that lenalidomide plus dexamethasone is a promising treatment for MM with Cg.
No preview · Article · Aug 2014 · [Rinshō ketsueki] The Japanese journal of clinical hematology
[Show abstract][Hide abstract] ABSTRACT: Background
Common variable immune deficiency is the most frequently encountered immunodeficiency in adults, which is characterized by low levels of serum immunoglobulins. Common variable immune deficiency can present with inflammatory bowel disease-like colitis because of the dysregulated immune system; paradoxically activated T cell receptor pathways are thought to be pivotal in pathogenesis of common variable immune deficiency-related colitis. Treatment for severe complications, such as gastrointestinal bleeding, is not established. We report a case of common variable immune deficiency-related Crohn’s-like disease presenting massive melena, which was successfully treated by short course infliximab therapy.
A 26-year-old Japanese man with history of common variable immune deficiency presented with diarrhea, abdominal pain, and fever. Venous administration of antibiotics did not improve his symptoms. Colonoscopy revealed multiple longitudinal ulcers as well as cobblestone-like change in the ileum end and the ascending colon. Histopathological examination of biopsy specimen showed erosion and infiltration of T lymphocytes with lack of B cells. Intravenous hyperalimentation, mesalazine, and steroid did not improve the symptoms and the patient subsequently presented with massive melena. Colonoscopy revealed a protuberant vessel on one of the ulcers in the ascending colon. Endoscopic clipping was repeatedly performed for hemostasis, which was only temporarily successful. In an attempt to manage the bleeding and colitis, a trial of infliximab was given on week 0, week 2 and week 6. Gastrointestinal hemorrhage from the ulcer halted immediately after the first infliximab injection. Colonoscopy performed after the third infliximab showed remarkable improvement in the ileocolitis. No evidence of increased susceptibility to infections was observed and the patient has been in clinical remission for 3 years.
We present this case together with review of literature to share our experience of encountering common variable immune deficiency complicating severe Crohn’s-like disease and to support that infliximab is a safe and effective treatment that can promptly manage life-threatening intestinal hemorrhage in common variable immune deficiency-related colitis.
Full-text · Article · Jun 2014 · BMC Research Notes
[Show abstract][Hide abstract] ABSTRACT: Myeloperoxidase (MPO) has been associated with both a myeloid lineage commitment and favorable prognosis in patients with acute myeloid leukemia (AML). DNA methyltransferase inhibitors (decitabine and zeburaline) induced MPO gene promoter demethylation and MPO gene transcription in AML cells with low MPO activity. Therefore, MPO gene transcription was directly and indirectly regulated by DNA methylation. A DNA methylation microarray subsequently revealed a distinct methylation pattern in 33 genes, including DNA methyltransferase 3 beta (DNMT3B), in CD34-positive cells obtained from AML patients with a high percentage of MPO-positive blasts. Based on the inverse relationship between the methylation status of DNMT3B and MPO, we found an inverse relationship between DNMT3B and MPO transcription levels in CD34-positive AML cells (P=0.0283). In addition, a distinct methylation pattern was observed in five genes related to myeloid differentiation or therapeutic sensitivity in CD34-positive cells from AML patients with a high percentage of MPO-positive blasts. Taken together, the results of the present study indicate that MPO may serve as an informative marker for identifying a distinct and crucial DNA methylation profile in CD34-positive AML cells.Leukemia advance online publication, 24 January 2014; doi:10.1038/leu.2014.15.
No preview · Article · Jan 2014 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
[Show abstract][Hide abstract] ABSTRACT: We retrospectively analyzed 81 relapsed or refractory adult T-cell leukemia-lymphoma (ATL) patients who received salvage therapy in our institution between 2000 and 2010. These patients had received chemotherapy, radiation, or hematopoietic stem cell transplantation (HSCT) as an initial treatment, and were then given chemotherapy, radiation, HSCT, or donor lymphocyte infusion (DLI) as salvage therapy. Median survival time was 3.9 months. Of 5 long-term survivors, who survived more than 2 years after the first salvage therapy, 4 patients received HSCT or DLI, and the other was given mogamulizumab as the salvage therapy. For patients with relapsed or refractory ATL, HSCT/DLI is a promising treatment for achieving long-term survival. Mogamulizumab may be the good choice for those who are ineligible for HSCT.
No preview · Article · Dec 2013 · [Rinshō ketsueki] The Japanese journal of clinical hematology
[Show abstract][Hide abstract] ABSTRACT: To investigate the long-term usefulness of immunosuppressive therapy (IST) for Japanese patients with lower-risk myelodysplastic syndromes, we retrospectively analyzed 29 MDS patients who were treated with cyclosporine A alone or with anti-thymocyte globulin at a single institute in Japan. A total of 58.6 % of patients showed hematological response to IST. Overall survival of all patients was 74.5 % at 5 years and 48.3 % at 10 years. The major adverse event was the elevation of creatinine level (grade 1 and 2). Eleven patients were still on IST at the time of analysis with, at least, some clinical benefits. Pneumonia was the most frequent cause of death (eight of 12 deaths), followed by bleeding (three of 12); most of the patients who died were non-responders. The presence of paroxysmal nocturnal hemoglobinuria-type cells was significantly associated with both response to IST and long-term survival by univariate analysis. The 10-year overall survival of responders (72.2 %) was significantly superior to that of non-responders (15.6 %, P < 0.0001). These results suggest that IST using cyclosporine A provides long-term benefit for Japanese patients with lower-risk MDS.
Full-text · Article · Nov 2013 · International journal of hematology
[Show abstract][Hide abstract] ABSTRACT: An appropriate trigger for BCR-ABL1 mutation analysis has not yet been established in unselected cohorts of chronic-phase chronic myelogenous leukemia patients. We examined 92 patients after 12 months of tyrosine kinase inhibitor (TKI) treatment in Nagasaki Prefecture, Japan. Univariate analysis revealed that significant factors associated with not attaining a major molecular response (MMR) were the presence of the minor BCR-ABL1 fusion gene, a low daily dose of TKI, and the emergence of BCR-ABL1 kinase domain mutations conferring resistance to imatinib. Factors associated with the loss of sustained MMR were a low daily dose of TKI and the emergence of alternatively spliced BCR-ABL1 mRNA with a 35-nucleotide insertion. Taken together, our results suggest that the search for BCR-ABL1 mutations should be initiated if patients have not achieved MMR following 12 months of TKI treatment.
Full-text · Article · Nov 2013 · Leukemia research
[Show abstract][Hide abstract] ABSTRACT: It has been reported that cord blood transplantation (CBT) for patients with aggressive adult T-cell leukemia/lymphoma (ATL) results in poorer outcomes than transplantation using other stem cell sources. To identify a subset of ATL in which CBT is feasible, we retrospectively analyzed 27 patients treated with CBT at three institutions in Nagasaki Prefecture, Japan. The estimated overall survival (OS) rate at 3 years was 27.4 %. Of 16 patients who received CBT during remission (complete, CR, or partial, PR), the OS rate at 3 years was 50 %, while during refractory periods (non-CR or non-PR), the OS rate was 9.1 %. Reduced intensity conditioning (RIC) was given to 18 patients, and myeloablative conditioning (MAC) was used in nine, with 3-year OS of 50.0 and 0 %, respectively. Of the 19 deaths, nine were due to progressive disease, eight (five MAC and three RIC) to infection, and two to multiple organ failure. These results suggest that CBT provides similar results with those in other transplantation procedures for selected ATL patients, such as those in CR or PR. Further studies are needed to evaluate the use of CBT in aggressive ATL.
No preview · Article · Mar 2013 · International journal of hematology
[Show abstract][Hide abstract] ABSTRACT: Myeloid ELF1-like factor (MEF/ELF4), a member of the ETS transcription factors, can function as an oncogene in murine cancer
models and is overexpressed in various human cancers. Here, we report a mechanism by which MEF/ELF4 may be activated by a
common leukemia-associated mutation in the nucleophosmin gene. By using a tandem affinity purification assay, we found that
MEF/ELF4 interacts with multifactorial protein nucleophosmin (NPM1). Coimmunoprecipitation and GST pull-down experiments demonstrated
that MEF/ELF4 directly forms a complex with NPM1 and also identified the region of NPM1 that is responsible for this interaction.
Functional analyses showed that wild-type NPM1 inhibited the DNA binding and transcriptional activity of MEF/ELF4 on the HDM2
promoter, whereas NPM1 mutant protein (Mt-NPM1) enhanced these activities of MEF/ELF4. Induction of Mt-NPM1 into MEF/ELF4-overexpressing
NIH3T3 cells facilitated malignant transformation. In addition, clinical leukemia samples with NPM1 mutations had higher human
MDM2 (HDM2) mRNA expression. Our data suggest that enhanced HDM2 expression induced by mutant NPM1 may have a role in MEF/ELF4-dependent
Preview · Article · Feb 2013 · Journal of Biological Chemistry
[Show abstract][Hide abstract] ABSTRACT: Although allogeneic hematopoietic stem cell transplantation (allo-SCT) is performed as a curative option in adult T-cell leukemia-lymphoma (ATL) patients, its high transplantation-related mortality raises a serious issue. The clinical features of infectious complications after transplantation are not well known. To analyze the impact of infections after allo-SCT for ATL, we retrospectively compared infectious complications in 210 patients (acute myeloid leukemia (AML), n=91; acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL), n=51; ATL, n=68) at three institutes in Nagasaki prefecture between 1997 and 2009. No patient received ganciclovir/foscarvir as prophylaxis, and most patients received antifungal prophylaxis with fluconazole or micafungin. The cumulative incidence of cytomegalovirus (CMV) infection at 3 years was 69.2% in ATL patients versus 54.4% in AML patients (p=0.0255). Cumulative infection-related mortality was significantly higher in ATL patients than that in the two other groups (ATL vs AML, p=0.0496; ATL vs ALL/LBL, p=0.0075), and most death-causing pathogens were bacteria and fungus. The appearance of CMV infection was negatively associated with infectious mortality in ATL patients, but the P-value for this association was near the borderline of significance (p=0.0569). In multivariate analysis, transplantation using unrelated bone marrow and episodes of CMV infection were associated with worse overall survival in ATL patients, but were not in either AML or ALL/LBL patients. Collectively, the impact of infectious complications after transplantation in ATL patients was different from that in AML and ALL/LBL patients, suggesting that a more intensive strategy for infection control in ATL patients is required to reduce infectious mortality.
Full-text · Article · Jan 2013 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
[Show abstract][Hide abstract] ABSTRACT: Adult T-cell leukemia/lymphoma (ATL) relapse is a serious therapeutic challenge following allogeneic hematopoietic stem cell transplantation (allo-SCT). Here, we retrospectively analyzed 35 patients who experienced progression of or relapsed persistent ATL after a first allo-SCT at three institutions in Nagasaki prefecture between 1997 and 2010. Twenty-nine patients were treated by the withdrawal of immune suppressants as the initial intervention, which resulted in complete remission (CR) in 2 patients. As the second intervention, 9 patients went on to receive a combination of donor lymphocyte infusion (DLI) and cytoreductive therapy, achieving CR in 4 patients. Of 6 patients who have already had their immune suppressants discontinued prior to the relapse, 3 patients with local recurrence received local cytoreductive therapy as the initial treatment, which resulted in CR for over 19 months. DLI-induced remissions of ATL were durable, with 3 cases of long-term remission over 3 years, and, interestingly, the emergence or progression of chronic graft-versus-host disease was observed in all of these cases. For all 35 patients, overall survival after relapse was 19.3% at 3 years. Our study suggests that induction of graft-versus-ATL effect may be crucial to obtain long-durable remission for ATL patients with relapse or progression after allo-SCT.
[Show abstract][Hide abstract] ABSTRACT: The percentage of myeloperoxidase (MPO)-positive blast cells is a simple and highly significant prognostic factor in AML patients.
It has been reported that the high MPO group (MPO-H), in which >50% of blasts are MPO activity positive, is associated with
favorable karyotypes, while the low MPO group (≤50% of blasts are MPO activity positive, MPO-L) is associated with adverse
karyotypes. The MPO-H group shows better survival even when restricted to patients belonging to the intermediate chromosomal
risk group or those with a normal karyotype. It has recently been shown that genotypes defined by the mutational status of
NPM1, FLT3, and CEBPA are associated with treatment outcome in patients with cytogenetically normal AML. In this study, we aimed to evaluate the
relationship between MPO positivity and gene mutations found in normal karyotypes. Sixty AML patients with normal karyotypes
were included in this study. Blast cell MPO positivity was assessed in bone marrow smears stained for MPO. Associated genetic
lesions (the NPM1, FLT3-ITD, and CEBPA mutations) were studied using nucleotide sequencing. Thirty-two patients were in the MPO-L group, and 28 patients in the
MPO-H group. FLT3-ITD was found in 11 patients (18.3%), NPM1 mutations were found in 19 patients (31.7%), and CEBPA mutations were found in 11 patients (18.3%). In patients with CEBPA mutations, the carrying two simultaneous mutations (CEBPA
double-mut) was associated with high MPO expression, while the mutant NPM1 without FLT3-ITD genotype was not associated with MPO activity. Both higher MPO expression and the CEBPA
double-mut genotype appeared to be associated with improved overall survival after intensive chemotherapy. Further studies are required
to determine the importance of blast MPO activity as a prognostic factor, especially in CEBPA wild-type patients with a normal karyotype.
Full-text · Article · Aug 2012 · International journal of hematology
[Show abstract][Hide abstract] ABSTRACT: The T315I BCR-ABL mutation in chronic myelogenous leukemia (CML) patients is responsible for up to 20% of all clinically observed resistance. This mutation confers resistance not only to imatinib, but also to second-generation BCR-ABL tyrosine kinases, such as nilotinib and dasatinib. A number of strategies have been implemented to overcome this resistance, but allogeneic stem cell transplantation remains the only established therapeutic option for a cure. A 61-year-old male was diagnosed with Philadelphia chromosome-positive chronic-phase CML in 2002. He was initially treated with imatinib and complete cytogenetic response (CCyR) was achieved 12 months later. However, after 18 months, a loss of CCyR was observed and a molecular study at 24 months revealed a T315I mutation of the BCR-ABL gene. At 30 months, imatinib/interferon-alfa (IFNα) combination therapy was initiated in an effort to overcome the resistance. Thirty months later, he re-achieved CCyR, and the T315I BCR-ABL mutation disappeared at 51 months. To our knowledge, this is the first case report showing the effectiveness of imatinib/IFNα combination therapy for CML patients bearing the T315I BCR-ABL mutation.
No preview · Article · Feb 2012 · International journal of hematology