ABSTRACT
Background: In stage I/II natural killer (NK)/T-cell lymphoma, concurrent chemoradiotherapy (CCRT) had previously been shown to result in superior outcome compared with anthracycline-containing regimens, which have since been considered ineffective. The role of CCRT in comparison with approaches employing nonanthracycline-containing chemotherapy (CT) and sequential radiotherapy (RT) in such patients remains to be defined. Patients and methods: Three hundred and three untreated patients (207 men, 96 women; median age: 51, 18-86 years) with stage I/II NK/T-cell lymphoma who had received nonanthracycline-containing regimens were collected from an international consortium and retrospectively analyzed. Treatment included single modality (CT and RT), sequential modalities (CT + RT; RT + CT) and concurrent modalities (CCRT; CCRT + CT). The impact of clinicopathologic parameters and types of treatment on complete response (CR) rate, progression-free-survival (PFS) and overall-survival (OS) was evaluated. Results: For CR, stage (P = 0.027), prognostic index for NK/T-cell lymphoma (PINK) (P = 0.026) and types of initial treatment (P = 0.011) were significant prognostic factors on multivariate analysis. On Cox regression analysis, ECOG performance score (P = 0.021) and PINK-EBV DNA (PINK-E) (P = 0.002) significantly impacted on PFS; whereas ECOG performance score (P = 0.008) and stage (P < 0.001) significantly impacted on OS. For comparing CCRT ± CT and sequential CT + RT, CCRT ± CT patients (n = 190) were similar to sequential CT + RT patients (n = 54) in all evaluated clinicopathologic parameters except two significantly superior features (higher proportion of undetectable circulating EBV DNA on diagnosis and lower PINK-E scores). Despite more favorable pre-treatment characteristics, CCRT ± CT patients had CR rate, PFS and OS comparable with sequential CT + RT patients on multivariate and Cox regression analyses. Conclusions: In stage I/II NK/T-cell lymphomas, when effective chemotherapeutic regimens were used, CCRT and sequential CT + RT gave similar outcome.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Lymphoma, Extranodal NK-T-Cell/drug therapy , Lymphoma, Extranodal NK-T-Cell/radiotherapy , Adolescent , Adult , Aged, 80 and over , Chemoradiotherapy , Cohort Studies , Drug Administration Schedule , Female , Humans , Lymphoma, Extranodal NK-T-Cell/pathology , Male , Middle Aged , Neoplasm Staging , Prognosis , Young AdultABSTRACT
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.
Subject(s)
Core Binding Factors/genetics , Core Binding Factors/metabolism , DNA-Binding Proteins/genetics , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/metabolism , Mutation , Proto-Oncogene Proteins c-kit/metabolism , Proto-Oncogene Proteins/genetics , Adolescent , Adult , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Combined Modality Therapy , DNA Methylation , DNA Mutational Analysis , DNA-Binding Proteins/metabolism , Dioxygenases , Female , Hematopoietic Stem Cell Transplantation/methods , High-Throughput Nucleotide Sequencing , Humans , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/therapy , Male , Middle Aged , Prognosis , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-kit/genetics , Signal Transduction , Survival Analysis , Translocation, Genetic , Transplantation, Homologous , Young AdultABSTRACT
We conducted a 2-year multicentre prospective observational study to determine the epidemiology of and mortality associated with invasive fungal diseases (IFDs) among patients with haematological disorders in Asia. Eleven institutions from 8 countries/regions participated, with 412 subjects (28.2% possible, 38.3% probable and 33.5% proven IFDs) recruited. The epidemiology of IFDs in participating institutions was similar to Western centres, with Aspergillus spp. (65.9%) or Candida spp. (26.7%) causing the majority of probable and proven IFDs. The overall 30-day mortality was 22.1%. Progressive haematological disorder (odds ratio [OR] 5.192), invasive candidiasis (OR 3.679), and chronic renal disease (OR 6.677) were independently associated with mortality.
Subject(s)
Fungemia/epidemiology , Hematologic Diseases/complications , Adult , Asia, Southeastern/epidemiology , Aspergillus/isolation & purification , Candida/isolation & purification , Female , Fungemia/mortality , Humans , Male , Middle Aged , Pacific Islands/epidemiology , Prevalence , Prospective Studies , Survival AnalysisSubject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Dendritic Cell Sarcoma, Follicular/drug therapy , Paraneoplastic Syndromes/drug therapy , Pemphigus/drug therapy , Antibodies, Monoclonal, Murine-Derived/administration & dosage , Cyclosporine/administration & dosage , Dendritic Cell Sarcoma, Follicular/complications , Dendritic Cell Sarcoma, Follicular/diagnosis , Fatal Outcome , Female , Humans , Middle Aged , Paraneoplastic Syndromes/complications , Paraneoplastic Syndromes/diagnosis , Pemphigus/complications , Pemphigus/diagnosis , RituximabABSTRACT
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.
Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Killer Cells, Natural/pathology , Lymphoma, T-Cell/pathology , Lymphoma, T-Cell/therapy , Transplantation Conditioning/methods , Adolescent , Adult , Female , Humans , Male , Middle Aged , Transplantation, Homologous , Young AdultABSTRACT
BACKGROUND: Mantle cell lymphoma (MCL) is aggressive, and relapsed/refractory disease has poor outcomes. PATIENTS AND METHODS: Thirty-nine patients (men = 34, women = 5) at 64 (41-82) years of age with relapsed/refractory MCL, ineligible for high-dose chemotherapy and had received 2 (1-5) prior regimens, were treated with a continuous oral regimen, comprising oral arsenic trioxide (oral-As2O3), chlorambucil and ascorbic acid. RESULTS: Overall response rate was 49% (complete response, CR = 28%; partial response, PR = 21%). Only grade 1/2 toxicities were observed (hematologic: 56%, hepatic: 8%). Response was maintained in 11 patients (CR = 8; PR = 3), after a median of 24 (2-108) months. Independent prognostic factors for response were increased lactate dehydrogenase (P = 0.04) and unfavorable MCL international prognostic index (P = 0.04). At a median follow-up of 21 (1-118) months, the median progression-free survival (PFS) was 16 months, and overall survival (OS) 38 months. Independent prognostic factors for PFS were female gender (P = 0.002), and Eastern Cooperative Oncology Group (ECOG) performance score of 2 (P = 0.009). Independent prognostic factors for OS were female gender (P < 0.001), ECOG performance score of 2 (P = 0.03), non-response (P < 0.001), and disease progression after initial response (P = 0.05). CONCLUSION: An oral regimen of oral-As2O3, chlorambucil and ascorbic acid was active with minimal toxicity in relapsed/refractory MCL, achieving durable responses in â¼30% of cases.
Subject(s)
Arsenicals/therapeutic use , Lymphoma, Mantle-Cell/drug therapy , Oxides/therapeutic use , Salvage Therapy , Administration, Oral , Adult , Aged , Aged, 80 and over , Arsenic Trioxide , Arsenicals/administration & dosage , Humans , Lymphoma, Mantle-Cell/diagnostic imaging , Middle Aged , Oxides/administration & dosage , Positron-Emission Tomography , Recurrence , Survival AnalysisABSTRACT
Circulating Epstein-Barr virus (EBV) DNA is a biomarker of EBV-associated malignancies. Its significance in natural killer/T-cell lymphoma treated with the novel regimen SMILE was investigated. EBV DNA was quantified with a World Health Organization EBV standard in 910 plasma samples collected during 230 courses of SMILE in 56 patients. Median presentation EBV DNA was 1900 (0-1.4 × 10(7)) IU/ml. Presentation EBV DNA was significantly associated with tumor load and treatment response. To examine lymphoma chemosensitivity, EBV DNA changes after SMILE were evaluated. EBV DNA after SMILE (I) significantly correlated with tumor load and treatment response. Two dynamic parameters were further analyzed: negative EBV DNA after SMILE (I) and EBV DNA change patterns during treatment (A: persistently undetectable; B: persistently detectable
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , DNA, Viral/blood , Herpesvirus 4, Human/isolation & purification , Killer Cells, Natural/pathology , Lymphoma, T-Cell/drug therapy , Lymphoma, T-Cell/virology , Adolescent , Adult , Aged , Aged, 80 and over , Asparaginase/administration & dosage , Dexamethasone/administration & dosage , Etoposide/administration & dosage , Female , Humans , Ifosfamide/administration & dosage , Lymphoma, T-Cell/mortality , Lymphoma, T-Cell/pathology , Male , Methotrexate/administration & dosage , Middle Aged , PrognosisABSTRACT
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.
Subject(s)
Antifungal Agents/therapeutic use , Hematologic Diseases/drug therapy , Hematologic Diseases/epidemiology , Hospitals, Teaching/trends , Mycoses/drug therapy , Mycoses/epidemiology , Adult , Aged , Aged, 80 and over , Asia/epidemiology , Female , Hospitals, Teaching/methods , Hospitals, University/trends , Humans , Male , Middle Aged , Retrospective Studies , Young AdultABSTRACT
The Sporopachydermia cereana species lives in decaying stems of cactus and is exceptionally rare as a human pathogen. A 57-year-old man with therapy-refractory acute promyelocytic leukaemia developed severe neutropaenia. After about 3 weeks of micafungin used as prophylaxis, he developed high fever, multiple pulmonary nodular infiltrates and a painful leg lesion. Blood culture yielded a yeast which was not identified by the Vitek 2 system. On ITS1-5.8S-ITS2 gene sequencing, the isolate was identified as S. cereana. Antifungal sensitivity by the Etest showed that the minimum inhibitory concentration for fluconazole was 0.75 µg/mL, and for anidulafungin, it was >32 µg/mL. He responded to liposomal amphotericin B but later died of Escherichia coli septicaemia. There were no cactus plants in the vicinity, suggesting that S. cereana might have alternative habitats.
Subject(s)
Antifungal Agents/therapeutic use , Chemoprevention/methods , Echinocandins/therapeutic use , Fungemia/diagnosis , Leukemia, Promyelocytic, Acute/complications , Lipopeptides/therapeutic use , Opportunistic Infections/diagnosis , Saccharomycetales/isolation & purification , DNA, Fungal/chemistry , DNA, Fungal/genetics , DNA, Ribosomal/chemistry , DNA, Ribosomal/genetics , DNA, Ribosomal Spacer/chemistry , DNA, Ribosomal Spacer/genetics , Escherichia coli Infections/complications , Escherichia coli Infections/diagnosis , Fatal Outcome , Fungemia/complications , Fungemia/microbiology , Fungemia/pathology , Humans , Immunocompromised Host , Male , Micafungin , Microbial Sensitivity Tests , Middle Aged , Neutropenia/complications , Neutropenia/diagnosis , Opportunistic Infections/complications , Opportunistic Infections/microbiology , Opportunistic Infections/pathology , Radiography, Thoracic , Saccharomycetales/classification , Saccharomycetales/genetics , Sepsis/complications , Sepsis/diagnosis , Sequence Analysis, DNA , Skin/pathology , Tomography, X-Ray ComputedABSTRACT
Internal tandem duplication (ITD) of the fms-like tyrosine kinase 3 (FLT3) gene is a gain-of-function mutation common in acute myeloid leukaemia (AML). It is associated with inferior prognosis and response to chemotherapy. Single base mutations at the FLT3 tyrosine kinase domain (TKD) also leads to a gain of function, although its prognostic significance is less well defined because of its rarity. The clinical benefits of FLT3 inhibition are generally limited to AML with FLT3-ITD. However, responses are transient and leukaemia progression invariably occurs. There is compelling evidence that leukaemia clones carrying both ITD and TKD mutations appear when resistance to FLT3 inhibitors occurs. Interestingly, the emergence of double ITD and TKD mutants can be recapitulated in vitro when FLT3-ITD+ leukaemia cell lines are treated with mutagens and FLT3 inhibitors. Furthermore, murine xenotransplantation models also suggest that, in some cases, the FTL3-ITD and TKD double mutants actually exist in minute amounts before treatment with FLT3 inhibitors, expand under the selection pressure of FLT3 inhibition and become the predominant resistant clone(s) during the drug-refractory phase. On the basis of this model of clonal evolution, a multipronged strategy using more potent FLT3 inhibitors, and a combinatorial approach targeting both FLT3-dependent and FLT3-independent pathways, will be needed to improve outcome.
Subject(s)
Antineoplastic Agents/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Animals , Humans , Leukemia, Myeloid, Acute/enzymologySubject(s)
Methicillin-Resistant Staphylococcus aureus , Pyomyositis/microbiology , Staphylococcal Infections/complications , Anti-Bacterial Agents/therapeutic use , Female , Humans , Middle Aged , Multimodal Imaging , Pyomyositis/diagnostic imaging , Pyomyositis/drug therapy , Radionuclide Imaging , Staphylococcal Infections/diagnostic imaging , Staphylococcal Infections/drug therapy , Vancomycin/therapeutic useSubject(s)
Hematopoietic Stem Cell Transplantation , Immunosuppressive Agents/administration & dosage , Living Donors , Multiple Myeloma/therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/etiology , Thalidomide/administration & dosage , Female , Humans , Male , Middle Aged , Transplantation, HomologousABSTRACT
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.
Subject(s)
Hematopoietic Stem Cell Transplantation/adverse effects , Leukemia, Large Granular Lymphocytic/etiology , Adult , Child , Cohort Studies , Female , Humans , Immunophenotyping , Leukemia, Large Granular Lymphocytic/genetics , Leukemia, Large Granular Lymphocytic/pathology , Male , Middle Aged , Risk Factors , Transplantation Conditioning/adverse effects , Transplantation, Autologous/adverse effects , Young AdultABSTRACT
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.
Subject(s)
Anti-Bacterial Agents/administration & dosage , Azithromycin/administration & dosage , Bronchiolitis Obliterans/drug therapy , Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Transplantation , Administration, Oral , Adult , Bronchiolitis Obliterans/etiology , Chronic Disease , Double-Blind Method , Female , Graft vs Host Disease/drug therapy , Graft vs Host Disease/etiology , Humans , Male , Middle Aged , Syndrome , Time Factors , Transplantation, HomologousABSTRACT
OBJECTIVE: To perform a multivariate analysis by Cox proportional hazard model of the impact of JAK2 V617F mutation on thrombosis and myeloid transformations in patients with essential thrombocythemia (ET). PATIENTS AND METHODS: The clinicopathologic features and outcome of a cohort of Chinese ET patients were retrospectively reviewed. JAK2 V617F mutation was detected by allele-specific polymerase chain reaction. Potential risk factors including JAK2 V617F that might impact on thrombosis and outcome were studied by multivariate analysis with Cox proportional hazard model. RESULTS: Of 141 patients studied, JAK2 V617F was found in 80 cases (57%). JAK2 V617F was positively correlated with hemoglobin and leukocyte count at diagnosis. Univariate analysis showed significant thrombotic risks to be JAK2 V617F (P=0.006), hemoglobin >13 g/dl (P=0.015), and age >55 years (P=0.011). However, in multivariate analysis, only age and hemoglobin were independent risk factors. JAK2 V617F was unrelated to survival or leukemic/myelofibrotic transformation. CONCLUSION: In Chinese patients with ET, JAK2 V617F was positively associated with age, hemoglobin, and leukocyte count, but was not an independent risk for thrombosis.
Subject(s)
Janus Kinase 2/genetics , Leukemia, Myeloid/genetics , Point Mutation , Thrombocythemia, Essential/complications , Thrombocythemia, Essential/genetics , Thrombosis/genetics , Adult , Aged , Aged, 80 and over , Aging , Female , Genetic Association Studies , Hemoglobins/analysis , Humans , Leukemia, Myeloid/etiology , Leukocyte Count , Male , Medical Records , Middle Aged , Multivariate Analysis , Retrospective Studies , Risk Factors , Survival Analysis , Thrombocythemia, Essential/mortality , Thrombocythemia, Essential/physiopathology , Thrombosis/etiology , Young AdultABSTRACT
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.