Next-generation sequencing with a myeloid gene panel in core-binding factor AML showed KIT activation loop and TET2 mutations predictive of outcome.

Clinical outcome and mutations of 96 core-binding factor acute myeloid leukemia (AML) patients 18-60 years old were examined. Complete remission (CR) after induction was 94.6%. There was no significant difference in CR, leukemia-free-survival (LFS) and overall survival (OS) between t(8;21) (N=67) and inv(16) patients (N=29). Univariate analysis showed hematopoietic stem cell transplantation at CR1 as the only clinical parameter associated with superior LFS. Next-generation sequencing based on a myeloid gene panel was performed in 72 patients. Mutations in genes involved in cell signaling were associated with inferior LFS and OS, whereas those in genes involved in DNA methylation were associated with inferior LFS. KIT activation loop (AL) mutations occurred in 25 patients, and were associated with inferior LFS (P=0.003) and OS (P=0.001). TET2 mutations occurred in 8 patients, and were associated with significantly shorter LFS (P=0.015) but not OS. Patients negative for KIT-AL and TET2 mutations (N=41) had significantly better LFS (P<0.001) and OS (P=0.012) than those positive for both or either mutation. Multivariate analysis showed that KIT-AL and TET2 mutations were associated with inferior LFS, whereas age ⩾40 years and marrow blast ⩾70% were associated with inferior OS. These observations provide new insights that may guide better treatment for this AML subtype.

Allogeneic haematopoietic SCT for natural killer/T-cell lymphoma: a multicentre analysis from the Asia Lymphoma Study Group.

Eighteen patients (men=14; women=4) with natural killer (NK)/T-cell lymphomas (CR1, N=9; CR2, N=7; PR, N=1; progressive disease, N=1) undergoing allogeneic haematopoietic SCT (HSCT) (myeloablative, N=14; reduced intensity, N=4) were analyzed. With a median follow-up of 20.5 months, the 5-year OS was 57% and 5-year EFS was 51%. The use of the SMILE regimen pre-HSCT was the most important positive prognostic indicator, resulting in significantly superior OS and EFS (P<0.01). Acute GVHD had a significant negative impact on OS (P=0.03). CR1 and CR2 patients had similar survivals, but all patients who were not transplanted in remission died. Chronic GVHD, International Prognostic Index, disease stage, primary sites of involvement, conditioning regimen and source of HSC did not affect survival. Although allogeneic HSCT leads to reasonable survival for NK/T-cell lymphoma patients, results need to be compared with those in patients receiving L-asparaginase-containing regimens. Novel prognostic models incorporating biomarkers, such as circulating EBV DNA, are needed to identify high-risk patients who may benefit from allogeneic HSCT.

Antifungal drug usage in haematologic patients during a 4-year period in an Asian university teaching hospital.

BACKGROUND: Invasive fungal disease (IFD) is an important problem complicating the therapy of haematologic patients. AIM: This study aimed to provide data on the epidemiology of IFD in an Asian teaching hospital, as well as the prescription practice of antifungal drugs. METHOD: We conducted a retrospective review of 275 haematologic patients who were prescribed antifungal drugs in a 4-year period (2007-2010), of whom 130 (47%) had undergone haematopoietic stem cell transplantation. RESULTS: Antifungal prophylaxis with either fluconazole or itraconazole was given in 214 patients (78%). There were 414 prescriptions of antifungal drugs (including liposomal amphotericin B, voriconazole, caspofungin, micafungin, anidulafungin), of which 361 prescriptions were empirical. There were 14 patients with proven IFD, 11 of whom had breakthrough infection while on itraconazole prophylaxis. Interestingly, seven of these cases were due to infection by itraconazole-sensitive candida. CONCLUSION: These results provide important epidemiologic data necessary for the formulation of strategies for prevention and treatment of IFD in Asian patients.

Indolent T-cell large granular lymphocyte leukaemia after haematopoietic SCT: a clinicopathologic and molecular analysis.

Four women and three men after allogeneic (n=4) and autologous (n=3) haematopoietic SCT (HSCT) were observed to have an increase in T-cell large granular lymphocytes (T-LGLs) of CD3+CD8+ phenotype for a median of 41 (15-118) months. Clonal rearrangement of the T-cell receptor gene was verified by two PCR techniques and direct DNA sequencing, confirming that the cases were neoplastic and therefore classifiable as T-LGL leukaemia. In the allogeneic HSCT cases, T-LGL leukaemia was derived from donor T cells in three patients, as shown by DNA chimerism analysis, and recipient T cells in one patient who had graft failure previously. None of the patients showed cytopenia, autoimmune phenomenon or organ infiltration, which were features typical of de novo T-LGL leukaemia. Six patients had remained asymptomatic with stable large granular lymphocyte counts. One patient died from cerebral relapse of the original lymphoma. T-LGL leukaemias occurring post-HSCT are distinct from de novo T-LGL leukaemia and may have a different pathogenesis and clinical course. Patients did not require specific treatment, and the disease remained stable for long periods.

Effects of azithromycin in bronchiolitis obliterans syndrome after hematopoietic SCT--a randomized double-blinded placebo-controlled study.

Bronchiolitis obliterans syndrome (BOS) is an important complication after hematopoietic SCT (HSCT). Recent observations suggested that azithromycin might improve lung function in BOS after HSCT. We conducted a randomized double-blinded placebo-controlled study on azithromycin in patients with BOS after HSCT. The treatment group (n=10) received oral azithromycin 250 mg daily while the control group (n=12) received placebo daily for 12 weeks. Respiratory symptoms were assessed by the St George Respiratory Questionnaires and spirometry at baseline (drug commencement), 1, 2, 3 (drug cessation) and 4 months (1 month after drug cessation). There was no significant difference in the baseline demographic characteristics between the treatment and the control groups in age, gender, time from HSCT to BOS, time since diagnosis of BOS, chronic GVHD, baseline respiratory symptom scores and baseline forced expiratory volume in 1 s (FEV(1)). Throughout and after 3 months of treatment, there were no significant changes in respiratory symptom scores and FEV(1) measurements between the treatment and the control groups. In conclusion, there was no significant benefit of 3 months of oral azithromycin on the respiratory symptoms and lung function in patients with relatively late BOS after HSCT in this randomized placebo-controlled study.

A staged approach with vincristine, adriamycin, and dexamethasone followed by bortezomib, thalidomide, and dexamethasone before autologous hematopoietic stem cell transplantation in the treatment of newly diagnosed multiple myeloma.

Bortezomib-based regimens have significant activities in multiple myeloma (MM). In this study, we tested the efficacy of a total therapy with a staged approach where newly diagnosed MM patients received vincristine/adriamycin/dexamethsone (VAD). VAD-sensitive patients (> or =75% paraprotein reduction) received autologous hematopoietic stem cell transplantation (auto-HSCT), whereas less VAD-sensitive patients (<75% paraprotein reduction) received bortezomib/thalidomide/dexamethasone (VTD) for further cytoreduction prior to auto-HSCT. On an intention-to-treat analysis, a progressive increase of complete remission (CR) rates was observed, with cumulative CR rates of 48% after HSCT. Seven patients progressed leading to three fatalities, of which two had central nervous system disease. The 3-year overall survival and event-free survival were 75.1% and 48.3%, respectively. Six patients developed oligoclonal reconstitution with new paraproteins. In the absence of anticoagulant prophylaxis, no patients developed deep vein thrombosis. The staged application of VAD+/-VTD/auto-HSCT resulted in an appreciable response rate and promising survivals. Our approach reduced the use of bortezomib without compromising the ultimate CR rate and is of financial significance for less affluent communities.

Hematopoietic SCT activity in Asia: a report from the Asia-Pacific Blood and Marrow Transplantation Group.

The hematopoietic SCT (HSCT) activity in nine Asian countries/regions was surveyed to overview the current situation. Data of 58 113 HSCTs (allogeneic: 63% vs autologous: 37%) performed between 1986 and 2006 by 432 transplant teams were collected. The number of HSCTs has been increasing in the past two decades in most countries/regions. The increase in allogeneic HSCTs is greater than in autologous HSCTs. The proportion of unrelated donors among allogeneic HSCTs in 2006 varied widely from <1% (Iran and Vietnam) to 62% (Japan). The use of each stem cell source, that is, BM, PBSC, cord blood and others (including co-infusion of BM and PBSC), also varied widely (36, 58, 0.1 and 6% in HSCT from related donors, respectively, and 53, 11, 35 and 1% in HSCT from unrelated donors, respectively). HSCTs have been continuously increasing for all indications except for chronic myelogenous leukemia and solid tumors. Hemoglobinopathy is a common indication among non-malignant diseases in many Asian countries/regions except for China, Japan and Korea. This survey clearly shows the recent progress of HSCTs in Asia and also some differences in donor and stem cell selection and disease application among countries/regions.

Defective phenotype of mesenchymal stem cells in patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) has been considered as stem cell disorder. The objective of this study was to examine the phenotype, growth and immunomodulatory effect of mesenchymal stem cells (MSCs) from SLE patients compared with those from age- and sex-matched healthy donors. MSCs were expanded from bone marrow aspirate and were examined for morphological appearance, quantified in different passages to determine growth rate and evaluated for ability of adipogenesis and osteogenesis. Telomerase activity was measured by telomerase repeat amplification protocol. The immunomodulatory effect of MSCs was evaluated by mixed lymphocyte reaction. MSCs from SLE patients were found to be bigger and flattened in appearance after passage 3 and demonstrated slower growth rate compared with fibroblast-like MSCs from normal controls. These cells were not able to reach confluence after passage 4. Telomerase activity was upregulated in five SLE patients mostly with active disease compared with two with negative expression with lesser activity. MSCs from SLE patients were, otherwise, comparable to normal controls in terms of their surface marker (CD73, CD90 and CD105) expression and extent of suppression on proliferation of allogeneic T lymphocytes. In conclusion, MSCs from SLE demonstrated early signs of senescence which may be a corollary of active lupus or a contributory factor to disease pathogenesis.

Long-term results of allogeneic bone marrow transplantation for 108 adult patients with acute lymphoblastic leukemia: favorable outcome with BMT at first remission and HLA-matched unrelated donor.

We analyzed the outcome of 108 adult acute lymphoblastic leukemia patients undergoing allogeneic bone marrow transplantation (BMT). Philadelphia (Ph) chromosome occurred in 35.2% patients at diagnosis. Two-thirds of patients received allogeneic BMT in first complete remission (CR1) BMT. Salvage BMT was performed in 21 and 16 patients at second complete remission (CR2) and beyond CR2. Donors were human leukocyte antigen-identical siblings in 87 patients, and match-unrelated donors in 21 patients. Conditioning contained total body irradiation (TBI) in 92.6% patients. Overall survival (OS) for BMT at CR1 and BMT beyond CR1 were 46.2 and 20.3% at 15 years. Multivariate analyses (including age, sex, disease status, donor type, acute graft-versus-host disease (aGVHD), stem cell source, cytogenetics, grade 1/2 aGVHD and TBI-containing conditioning regimen) identified age<35, BMT at CR1 and grade 1/2 aGVHD as favorable factors for OS. Disease-free survival (DFS) for BMT at CR1 and beyond CR1 were 45.8 and 15.9% at 15 years, respectively, with BMT at CR1, age<35 and grade 1/2 aGVHD being favorable factors for DFS. Importantly, conventional adverse risk factors such as the Ph chromosome, B-cell phenotype and high leukocyte count were not associated with inferior survivals. In summary, the adverse impact of Ph chromosome, B-cell phenotype and high leukocyte count was overcome by allogeneic BMT. Matched unrelated donor transplantation appears promising.

Percutaneous retrieval of a chronic foreign body with both intravascular and extravascular components.

Removal of unwanted intravascular foreign body is a useful but infrequent procedure carried out by interventional radiologists. We study a patient who had a long guidewire left in her body following central venous catheter placement by a surgeon. The guidewire was later found in situ, with both intravascular and extravascular components in continuity. We successfully removed the guidewire without causing any complications. Standard interventional techniques, Amplatz gooseneck snare (Microvena, White Bear Lake, MN, USA) and 6-Fr Multipurpose catheter were used.

Safety of vaccinating sibling donors with live-attenuated varicella zoster vaccine before hematopoietic stem cell transplantation.

Reactivation of varicella zoster virus (VZV), clinically manifested as herpes zoster (HZ) is a common complication after hematopoietic stem cell transplantation (HSCT). The optimum prophylaxis for this disease has not been defined. In this study, we examined the effects of vaccinating donors with a live-attenuated vaccine with particular reference to their immune responses and the outcome of HSCT patients. Forty prospective HLA-matched sibling donors were vaccinated before HSCT. There were humoral immune responses in both sero-positive (P<0.01) and sero-negative (P=0.058) donors. Cellular immune response was assayed in 26 donors. Significant correlation was observed between cellular immune responses as enumerated by thymidine incorporation and interferon gamma secretion (P<0.001) and the latter was used in subsequent analyses. Significant response was observed in sero-negative (6/26) and a group of sero-positive (13/26) donors while 7/26 sero-positive donors showed no response. Thirty-four HSCT were performed. These patients have a lower, albeit insignificant, risk of HZ compared with historical controls and only 3/34 patients developed single dermatomal HZ at 6, 9 and 28 months after HSCT. No patients developed VZV-related mortality. Vaccinating donors with live-attenuated VZV vaccine was safe, but whether it confers a significant protection to the patients would require further study.

Long-term donor health and its relationship with outcome of allogeneic hematopoietic stem cell transplantation.

Data on long-term follow-up of donors for hematopoietic stem cell transplantation (HSCT) are limited. Donors of 612 adult allogeneic HSCT were studied, at a median of 81 (14-181) months post-HSC donation. Nine donors had severe health problems. Five donors died from aggressive malignancies or terminal illness, at a median of 41 (16-57) months post-donation. Notably, all their recipients had leukemic relapses. In contrast, donors of recipients in remission were all living. This observation might be due to an inherent depressed immunosurveillance in the donors, or selection of donors with suboptimal health for desperate patients with poor risks pre-HSCT.

Hepatitis B reactivation after withdrawal of pre-emptive lamivudine in patients with haematological malignancy on completion of cytotoxic chemotherapy.

BACKGROUND: The hepatic outcome of hepatitis B surface antigen (HBsAg) positive patients undergoing chemotherapy after withdrawal of pre-emptive lamivudine is unknown. AIMS: To examine the occurrence of hepatitis B virus (HBV) reactivation after withdrawal of pre-emptive lamivudine. METHODS: Pre-emptive lamivudine was started one week before initiation of chemotherapy in 46 consecutive HBsAg positive patients and continued for the entire duration of chemotherapy. Pre-emptive lamivudine was stopped at a median 3.1 (range 3.0-3.4) months after completion of chemotherapy. Patients were longitudinally followed up after withdrawal of pre-emptive lamivudine. RESULTS: Median time of follow up after withdrawal of lamivudine was 25.7 (range 5.7-75.7) months. Eleven of the 46 patients (23.9%) developed HBV reactivation after withdrawal of pre-emptive lamivudine. Eight of the 16 patients with high pre-chemotherapy HBV DNA (> or =10(4) copies/ml) compared with three of the 30 patients with low pre-chemotherapy HBV DNA (<10(4) copies/ml) developed HBV reactivation (50.0% v 10.0%, respectively; p<0.001). Hepatitis B e antigen positive patients were also more likely to develop HBV reactivation (5/11 (45.5%) v 6/35 (17.1%), respectively; p = 0.041). A high pre-chemotherapy HBV DNA (> or =10(4) copies/ml) was the most important risk factor for HBV reactivation after withdrawal of pre-emptive lamivudine on Cox proportional hazards analysis (relative risk 16.13, (95% confidence interval 2.99-87.01; p = 0.001). CONCLUSIONS: HBV reactivation is more likely to occur in patients with high pre-chemotherapy HBV DNA after withdrawal of pre-emptive lamivudine. A more prolonged course of antiviral therapy may be necessary in these patients after completion of chemotherapy in order to reduce post-chemotherapy HBV reactivation.