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Primary Epstein-Barr virus (EBV)-positive nodal T/NK-cell lymphoma (PTCL-EBV) is a poorly understood disease which shows features resembling extranodal NK/T-cell lymphoma (ENKTL) and is currently not recognized as a distinct entity but categorized as a variant of primary T-cell lymphoma not otherwise specified (PTCL-NOS). Herein, we analyzed copynumber aberrations (n=77) with a focus on global measures of genomic instability and homologous recombination deficiency and performed gene expression (n=84) and EBV miRNA expression (n=24) profiling as well as targeted mutational analysis (n=16) to further characterize PTCL-EBV in relation to ENKTL and PTCL-NOS. Multivariate analysis revealed that patients with PTCL-EBV had a significantly worse outcome compared to patients with PTCL-NOS (P=0.002) but not to those with ENKTL. Remarkably, PTCL-EBV exhibited significantly lower genomic instability and homologous recombination deficiency scores compared to ENKTL and PTCL-NOS. Gene set enrichment analysis revealed that many immune-related pathways, interferon α/γ response, and IL6_JAK_STAT3 signaling were significantly upregulated in PTCLEBV and correlated with lower genomic instability scores. We also identified that NFκB-associated genes, BIRC3, NFKB1 (P50) and CD27, and their proteins are upregulated in PTCL-EBV. Most PTCL-EBV demonstrated a type 2 EBV latency pattern and, strikingly, exhibited downregulated expression of most EBV miRNA compared to ENKTL and their target genes were also enriched in immune-related pathways. PTCL-EBV also showed frequent mutations of TET2, PIK3CD and STAT3, and are characterized by microsatellite stability. Overall, poor outcome, low genomic instability, upregulation of immune pathways and downregulation of EBV miRNA are distinctive features of PTCL-EBV. Our data support the concept that PTCL-EBV could be considered as a distinct entity, provide novel insights into the pathogenesis of the disease and offer potential new therapeutic targets for this tumor.
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Infecções por Vírus Epstein-Barr , Linfoma Extranodal de Células T-NK , Linfoma de Células T Periférico , MicroRNAs , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/genética , Instabilidade Genômica , Herpesvirus Humano 4/genética , Humanos , Linfoma Extranodal de Células T-NK/diagnóstico , Linfoma Extranodal de Células T-NK/genética , Linfoma de Células T Periférico/diagnóstico , Linfoma de Células T Periférico/genética , MicroRNAs/genética , Regulação para CimaRESUMO
Natural killer (NK)/T-cell lymphomas failing L-asparaginse regimens have no known salvage and are almost invariably fatal. Seven male patients with NK/T-cell lymphoma (median age, 49 years; range, 31-68 years) for whom a median of 2 (range, 1-5) regimens (including l-asparaginase regimens and allogeneic hematopoietic stem-cell transplantation [HSCT] in 2 cases) failed were treated with the anti-programmed death 1 (PD1) antibody pembrolizumab. All patients responded, according to various clinical, radiologic (positron emission tomography), morphologic, and molecular (circulating Epstein-Barr virus [EBV] DNA) criteria. Two patients achieved complete response (CR) in all parameters. Three patients achieved clinical and radiologic CRs, with two having molecular remission (undetectable EBV DNA) but minimal EBV-encoded RNA-positive cells in lesions comprising predominantly CD3+CD4+ and CD3+CD8+ T cells (which ultimately disappeared, suggesting they represented pseudoprogression) and one having detectable EBV DNA despite morphologic CR. Two patients achieved partial response (PR). After a median of 7 (range, 2-13) cycles of pembrolizumab and a follow-up of a median of 6 (range, 2-10) months, all five CR patients were still in remission. The only adverse event was grade 2 skin graft-versus-host disease in one patient with previous allogeneic HSCT. Expression of the PD1 ligand was strong in 4 patients (3 achieving CR) and weak in 1 (achieving PR). PD1 blockade with pembrolizumab was a potent strategy for NK/T-cell lymphomas failing l-asparaginase regimens.
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Anticorpos Monoclonais Humanizados/uso terapêutico , DNA Viral/antagonistas & inibidores , Infecções por Vírus Epstein-Barr/terapia , Transplante de Células-Tronco Hematopoéticas , Linfoma Extranodal de Células T-NK/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adulto , Idoso , Antineoplásicos/uso terapêutico , Asparaginase/uso terapêutico , Infecções por Vírus Epstein-Barr/diagnóstico por imagem , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/imunologia , Expressão Gênica , Herpesvirus Humano 4/efeitos dos fármacos , Herpesvirus Humano 4/crescimento & desenvolvimento , Herpesvirus Humano 4/imunologia , Humanos , Linfoma Extranodal de Células T-NK/diagnóstico por imagem , Linfoma Extranodal de Células T-NK/genética , Linfoma Extranodal de Células T-NK/imunologia , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Estudos Retrospectivos , Resposta Viral Sustentada , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/virologia , Transplante Homólogo , Falha de TratamentoRESUMO
Deregulation of the DNA damage response (DDR) plays a critical role in the pathogenesis and progression of many cancers. The dependency of certain cancers on DDR pathways has enabled exploitation of such through synthetically lethal relationships e.g., Poly ADP-Ribose Polymerase (PARP) inhibitors for BRCA deficient ovarian cancers. Though lagging behind that of solid cancers, DDR inhibitors (DDRi) are being clinically developed for haematological cancers. Furthermore, a high proliferative index characterize many such cancers, suggesting a rationale for combinatorial strategies targeting DDR and replicative stress. In this review, we summarize pre-clinical and clinical data on DDR inhibition in haematological malignancies and highlight distinct haematological cancer subtypes with activity of DDR agents as single agents or in combination with chemotherapeutics and targeted agents. We aim to provide a framework to guide the design of future clinical trials involving haematological cancers for this important class of drugs.
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For patients with acute lymphoblastic leukemia (ALL) who relapse after allogeneic hematopoietic stem cell transplantation (HSCT), treatment options are limited, and the clinical course and prognostic factors affecting outcome have not been well characterized. We retrospectively analyzed outcomes of 123 adult patients with ALL who relapsed after a first HSCT performed at our center between 1993 and 2011. First-line salvage included second HSCT (n = 19), donor lymphocyte infusion with or without prior chemotherapy (n = 11), radiation therapy (n = 6), cytoreductive chemotherapy (n = 30), mild chemotherapy (n = 27), or palliative care (n = 23), with median postrelapse overall survival (OS) of 10 months, 6.5 months, 3 months, 4 months, 4 months, and 1 month, respectively. Despite a complete remission rate of 38% after first-line salvage in the treated patients, the OS rate remained limited with 1- and 2- year OS rates of 17% (95% confidence interval, 13 to 29) and 10% (95% confidence interval, 6 to 20), respectively. On univariate analysis, adverse factors for OS included active disease at the time of first HSCT and short time to progression from first HSCT (<6 months). There was no difference in the 6-month survival postrelapse in patients with isolated extramedullary relapse (44%) compared with combined extramedullary and bone marrow relapse (29%) or those with isolated bone marrow relapse (34%) (P = .8). Our data provide more insight into the disease behavior and treatment outcomes of ALL at relapse after HSCT against which future trials may be compared.
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Transplante de Células-Tronco Hematopoéticas , Agonistas Mieloablativos/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Condicionamento Pré-Transplante , Adolescente , Adulto , Idoso , Feminino , Humanos , Transfusão de Linfócitos , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Recidiva , Indução de Remissão , Estudos Retrospectivos , Análise de Sobrevida , Transplante Homólogo , Resultado do TratamentoRESUMO
Background: Hematopoietic stem cell transplantation (HSCT) has been performed in Singapore since 1985. Currently, more than 100 transplants are performed annually across the public and private sectors. In 2020, the COVID-19 pandemic resulted in unprecedented disruptions to global healthcare systems, and Singapore was no exception. In particular, the field of HSCT faced additional, unique challenges aside from those borne by the healthcare system at large, and appropriate measures were necessary to ensure that HSCT remained available to patients who needed it. Methods: The expert opinions of six hematologists from various institutions across Singapore were gathered through individual interviews and summarized. This was supplemented by a literature review on bone marrow donation and HSCT in Singapore. Main Findings and Conclusion: In Singapore, the COVID-19 pandemic has had significant implications for HSCT, ranging from the implementation of additional infection control measures in hospitals to an accelerated rise in haploidentical transplants. Further research is required to better understand and quantify these impacts, improve existing processes, and investigate the effects of COVID-19 and its treatment modalities on patients with HSCT.
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Rituximab-based chemo-immunotherapy is currently the standard first-line treatment for Waldenstrom macroglobulinaemia (WM), while ibrutinib has emerged as an alternative. In the absence of randomised trials (RCTs) comparing these regimens, the optimal first-line treatment for WM remains uncertain. In this systematic review and meta-analysis, we sought to assess the efficacy and safety of first-line treatment regimens for WM. We searched key databases from January 2007 to March 2023, including phase II and III trials, including treatment-naïve WM patients treated with rituximab-based regimens or ibrutinib. Response rates, progression-free survival (PFS), overall survival (OS), and toxicities were evaluated. Four phase III and seven phase II trials were included among 736 unique records. Pooled response rates from all comparative and non-comparative trials were 46%, 33% and 26% for bendamustine rituximab (BR), bortezomib-dexamethasone, cyclophosphamide, rituximab (BDRC) and ibrutinib rituximab (IR), respectively. Two-year pooled PFS was 89%, 81% and 82% with BR, BDRC and IR, respectively. Neuropathy was more frequent with bortezomib, while haematologic and cardiac toxicities were more common with chemo-immunotherapy and ibrutinib-based regimens respectively. Our findings suggest that BR yields higher response rates than bortezomib or ibrutinib-based combinations. RCTs comparing BR against emerging therapies, including novel Bruton Tyrosine Kinase Inhibitors, are warranted.
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Macroglobulinemia de Waldenstrom , Humanos , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Rituximab/efeitos adversos , Bortezomib , Protocolos Clínicos , CiclofosfamidaAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Linfoma Extranodal de Células T-NK/tratamento farmacológico , Linfoma Anaplásico Cutâneo Primário de Células Grandes/tratamento farmacológico , Terapia de Salvação , Neoplasias Cutâneas/tratamento farmacológico , Infecções Tumorais por Vírus/tratamento farmacológico , Adolescente , Aloenxertos , Cloridrato de Bendamustina/administração & dosagem , Brentuximab Vedotin , Terapia Combinada , Resistencia a Medicamentos Antineoplásicos , Feminino , Transplante de Células-Tronco Hematopoéticas , Herpesvirus Humano 4/isolamento & purificação , Humanos , Imunoconjugados/administração & dosagem , Imunofenotipagem , Antígeno Ki-1/análise , Antígeno Ki-1/imunologia , Linfoma Extranodal de Células T-NK/terapia , Linfoma Extranodal de Células T-NK/virologia , Linfoma Anaplásico Cutâneo Primário de Células Grandes/terapia , Linfoma Anaplásico Cutâneo Primário de Células Grandes/virologia , RNA Viral/análise , Indução de Remissão , Neoplasias Cutâneas/terapia , Neoplasias Cutâneas/virologiaRESUMO
BACKGROUND: Patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) have limited treatment options and poor prognoses. Tisagenlecleucel, a chimeric antigen receptor (CAR) T-cell therapy has shown early promise in improving survival outcomes, but at a high upfront cost. This study evaluated the cost-effectiveness of tisagenlecleucel versus salvage chemotherapy for treating patients with r/r DLBCL who have failed at least 2 lines of systemic therapies. METHODS: A hybrid decision tree and three-state partitioned survival model (progression-free (PF), progressive disease and death) was developed from the Singapore healthcare payer perspective. Survival curves from JULIET trial and CORAL-1 extension study were extrapolated beyond trial period over a 15-year time horizon to estimate the underlying progression-free survival and overall survival parametric distributions for both arms. Health state utilities were retrieved from the literature, and direct costs were sourced from public healthcare institutions in Singapore. One-way probabilistic sensitivity analyses and scenario analyses were conducted to explore the impact of uncertainties and assumptions on cost-effectiveness results. RESULTS: Compared with salvage chemotherapy, tisagenlecleucel was associated with a base-case incremental cost-effectiveness ratio (ICER) US$508,530 (S$686,516) per quality adjusted life year (QALY) gained and US$320,200 (S$432,269) per life year (LY) gained. One-way sensitivity analysis showed the ICER was most sensitive to time horizon, PF utility and cost of tisagenlecleucel. Scenario analyses confirmed that the ICERs remained high under favorable assumptions and substantial price reduction was required to reduce the ICER. CONCLUSIONS: Our analysis showed tisagenlecleucel use in r/r DLBCL patients who failed at least 2 prior lines of systemic therapies was associated with exceedingly high ICER, which is unlikely to represent good use of healthcare resources. Comparative clinical evidence from the ongoing trials might provide more insight into future evaluations.
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Gastos em Saúde/estatística & dados numéricos , Imunoterapia Adotiva/economia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Receptores de Antígenos de Linfócitos T/uso terapêutico , Terapia de Salvação/economia , Análise Custo-Benefício , Nível de Saúde , Humanos , Imunoterapia Adotiva/métodos , Modelos Econométricos , Anos de Vida Ajustados por Qualidade de Vida , Singapura , Análise de SobrevidaRESUMO
Monoclonal paraproteinaemia is an increasingly common reason for referral to haematology services. Paraproteinaemias may be associated with life-threatening haematologic malignancies but can also be an incidental finding requiring only observation. Immunoglobulin M (IgM) paraproteinaemias comprise 15-20% of monoclonal proteins but pose unique clinical challenges. IgM paraproteins are more commonly associated with lymphoplasmacytic lymphoma than multiple myeloma and can occur in a variety of other mature B-cell neoplasms. The large molecular weight of the IgM multimer leads to a spectrum of clinical manifestations more commonly seen with IgM paraproteins than others. The differential diagnosis of B-cell and plasma cell dyscrasias associated with IgM gammopathies can be challenging. Although the discovery of MYD88 L265P and other mutations has shed light on the molecular biology of IgM paraproteinaemias, clinical and histopathologic findings still play a vital role in the diagnostic process. IgM secreting clones are also associated with a number of "monoclonal gammopathy of clinical significance" entities. These disorders pose a novel challenge from both a diagnostic and therapeutic perspective. In this review we provide a clinical overview of IgM paraproteinaemias while discussing the key advances which may affect how we manage these patients in the future.
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Background: Previous studies in Western populations, using immunohistochemistry (IHC) methods to subtype diffuse large B-cell lymphoma (DLBCL), suggest that germinal center B-cell lymphomas (GCBs) have improved outcomes. However, data in Asians have been limited and conflicting. This study aims to evaluate the prognostic impact of cell-of-origin (COO) subtyping by IHC and Lymph2Cx in South-East Asian (SEA) DLBCL patients, and to summarize the existing literature.Methods: A single-center retrospective analysis of 384 DLBCL patients diagnosed 2013-2018 who received Rituximab-based chemotherapy was performed. Hans and Lymph2Cx were used to assign COO and correlated with outcomes.Results: International Prognostic Index (IPI) score was associated with overall survival (OS) and progression-free survival (PFS). The 5-yr-OS for non-GCB versus GCB for COO by Hans was 70% versus 71% p=0.39, while 5-yr-OS for ABC versus GCB for COO by Lymph2Cx was 74% versus 92% p=0.19. The 5-yr-PFS for non-GCB versus GCB for COO by Hans was 65% versus 70% p=0.26, while 5-yr-PFS for ABC versus GCB for COO by Lymph2Cx was 64% versus 86% p=0.07.Conclusions: IPI is reaffirmed to be relevant in the rituximab era. COO by Hans has no prognostic significance, while subtyping by Lymph2Cx trends toward GCBs having better PFS and OS.
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Povo Asiático , Linfoma Difuso de Grandes Células B , Rituximab/administração & dosagem , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Singapura/epidemiologia , Taxa de SobrevidaRESUMO
BACKGROUND: The Revised International Staging System (R-ISS) has been widely adopted to prognosticate multiple myeloma. As a result, the continued utility of conventional metaphase karyotyping has been called into question. PATIENTS AND METHODS: A multi-center study for newly diagnosed patients with multiple myeloma who received novel agent(s) at induction was conducted. Conventional metaphase karyotype information was categorized based on ploidy. We evaluated the impact of ploidy on overall survival (OS) including multivariate analysis, taking into account the R-ISS stages, transplant status, age, and novel agent(s) used at induction. We also evaluated if it is possible to identify high-risk (HR) patients with conventional karyotyping when a fluorescence in situ hybridization analysis is not available. Results were validated in an independent cohort. RESULTS: There were 308 patients evaluable. Ploidy significantly affected the OS of patients with R-ISS stage II, with non-hyperdiploid patients doing the worst. In the multivariate analysis, ploidy was significantly associated with OS. R-ISS stage II patients with or without non-hyperdiploid karyotype had significantly different survival. We replaced HR fluorescence in situ hybridization abnormalities with HR metaphase karyotypic abnormalities (non-hyperdiploid karyotype). When compared with R-ISS, there was a high level of concordance in HR patients identified using HR karyotypic abnormalities. These results were validated with an independent cohort of 375 patients. CONCLUSION: Conventional metaphase karyotyping is an independent prognostic factor even in the setting of R-ISS.
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Aberrações Cromossômicas , Transplante de Células-Tronco Hematopoéticas/mortalidade , Hibridização in Situ Fluorescente/métodos , Cariotipagem/métodos , Mieloma Múltiplo/patologia , Idoso , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Mieloma Múltiplo/genética , Mieloma Múltiplo/terapia , Estadiamento de Neoplasias , Estudos Retrospectivos , Taxa de Sobrevida , Transplante AutólogoRESUMO
Primary mediastinal large B-cell lymphoma (PMBCL) is a distinct clinico-pathological subtype of diffuse large B-cell lymphoma with unclear prognostic factors and limited clinical data. Optimal treatment and role for radiotherapy is not fully defined. We performed a multicenter retrospective review of 124 patients with newly diagnosed PMBCL between 2001 and 2016. Treatment regimens were R-CHOP (n = 41), R-CHOP + RT (n = 37), and DA-EPOCH-R (n = 46). 6% (n = 3) in the DA-EPOCH-R group received RT. With a median follow up of 45 months, the overall 5-year OS and PFS was 89.4% and 82.4%, respectively. The type of chemo-radiotherapy regimen, B symptoms and Ann-Arbor staging showed a significant association with OS on univariate analysis but only B symptoms remained prognostic (P = 0.012) after multivariate analysis. The chemo-radiotherapy regimen, Japanese IPI and Ann-Arbor stage was significantly associated with PFS in univariate analysis, but only chemo-radiotherapy regimen remained significant (P = 0.02) after multivariate analysis. Patients who received R-CHOP + RT or DA-EPOCH-R had better PFS than those receiving R-CHOP alone, with 5-year PFS of 90% vs 88.5% vs 56%, respectively (P = 0.02). In the subgroup analysis of patients with bulk (n = 71), R-CHOP alone (n = 21) had inferior 5-year PFS 56.6% compared to those who received R-CHOP + RT (n = 23) 91.3% or DA-EPOCH-R (n = 27) 92.6% (P = 0.007). In contrast, in patients without bulk (n = 42), there was no impact of treatment regimen on PFS (P = 0.25). In conclusion, R-CHOP + RT and DA-EPOCH-R provide excellent outcomes in patients with PMBCL. In patients with bulky disease, the use of DA-EPOCH-R may be preferable as it allows omission of RT without reduction in efficacy.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Neoplasias do Mediastino/tratamento farmacológico , Rituximab/administração & dosagem , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Esquema de Medicação , Etoposídeo/administração & dosagem , Etoposídeo/uso terapêutico , Feminino , Humanos , Linfoma Difuso de Grandes Células B/radioterapia , Masculino , Neoplasias do Mediastino/radioterapia , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/uso terapêutico , Estudos Retrospectivos , Rituximab/uso terapêutico , Análise de Sobrevida , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/uso terapêutico , Adulto JovemRESUMO
BACKGROUND: The WHO defines three categories of NK cell malignancies; extra nodal NK/T cell lymphoma (NKTCL), aggressive NK cell leukemia, and the provisional entity chronic lymphoproliferative disorder of NK cells (CLPD-NK). Although the flow cytometric (FC) phenotype of CLPD-NK has been described, studies on FC phenotype of NKTCL are limited. To the best of our knowledge ours is the first study to compare the phenotype of NKTCL, CLPD-NK, reactive NK lymphocytosis (RNKL), and normal NK cells using eight color (8C) FC. METHODS: Specimens analyzed using the Euroflow8C NK Lymphoproliferative Disorder (NKLPD) panel between 2011 and 2014 were identified from our database. All samples were analyzed on the FACSCantoII cytometer. NK cells were identified as CD45+, smCD3-, CD19-, CD56+ and normal T-cells served as internal controls. RESULTS: The majority of NKTCL were CD56 bright, CD16 dim, CD57-, and CD94+. CLPD-NK and RNKL were predominantly CD56+ or dim with positive expression of CD16 and CD57 and weak CD94 expression. Antigen based statistical analyses showed robust division of samples along the NKTCL/normal CD56 bright NK cell and CLPD-NK/RNKL/normal CD56 positive NK cell groups. CONCLUSIONS: It was concluded that FC can reliably distinguish NKTCL from CLPD-NK, normal NK cells of CD56+ phenotype, and RNKL. It was proposed that the typical phenotype for NKTCL is: CD56 bright, CD16 dim with positive CD2, CD7, CD94, HLADR, CD25, CD26, and absent CD57. This resembles the phenotype of the CD56 bright immunoregulatory subset of NK cells which we therefore hypothesize is the cell of origin of NKTCL. © 2017 International Clinical Cytometry Society.
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Proliferação de Células/fisiologia , Células Matadoras Naturais/fisiologia , Linfoma de Células T/fisiopatologia , Antígenos CD/metabolismo , Citometria de Fluxo/métodos , Humanos , Células Matadoras Naturais/metabolismo , Linfoma de Células T/metabolismo , Transtornos Linfoproliferativos/metabolismo , Transtornos Linfoproliferativos/fisiopatologia , FenótipoRESUMO
Febrile neutropenia (FN) is associated with substantial morbidity and necessitates empirical broad-spectrum antimicrobial treatment. In this prospective cohort study, a risk-guided management strategy for FN using empirical piperacillin/tazobactam (TZP) or a carbapenem was evaluated. The analysis involved 723 FN episodes in hospitalised adult patients, including those with severe sepsis or prior infection/colonisation with extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae. Propensity score matching analysis was used to adjust for baseline differences between treatment groups and produced 267 matched pairs. The primary outcome was all-cause mortality. Secondary outcomes were the incidences of drug-resistant Gram-negative (including ESBL-producing) and Gram-positive bacterial isolates and of invasive pulmonary aspergillosis (IPA) and their associated mortality. There was no difference in mortality between empirical carbapenem and TZP [18/267 (6.7%) vs. 14/267 (5.2%); Pâ¯=â¯0.466]. Higher incidences of drug-resistant Gram-negative isolates [77/267 (28.8%) vs. 26/267 (9.7%); P < 0.001], including ESBL-producing bacteria [57/267 (21.3%) vs. 16/267 (6.0%); P < 0.001], were observed in carbapenem-treated episodes where its use lowered mortality. Mortality rates for ESBL-positive infections were 5.3% (3/57) and 25.0% (4/16) (Pâ¯=â¯0.037) and for drug-resistant Gram-negative infections were 6.5% (5/77) and 23.1% (6/26) (Pâ¯=â¯0.018) in carbapenem- and TZP-treated episodes, respectively. More IPA was observed with carbapenem use [16/267 (6.0%) vs. 6/267 (2.2%); Pâ¯=â¯0.029]. Antifungal prophylaxis reduced the risk of death (odds ratioâ¯=â¯0.39, 95% confidence interval 0.17-0.87; Pâ¯=â¯0.017). Risk-guided carbapenem prescribing in FN correctly identified cases prone to drug-resistant Gram-negative infections and reduced the mortality in these episodes.
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Antibacterianos/uso terapêutico , Bacteriemia/tratamento farmacológico , Carbapenêmicos/uso terapêutico , Infecções por Enterobacteriaceae/tratamento farmacológico , Neutropenia Febril/tratamento farmacológico , Combinação Piperacilina e Tazobactam/uso terapêutico , Antifúngicos/uso terapêutico , Bacteriemia/microbiologia , Farmacorresistência Bacteriana , Enterobacteriaceae/efeitos dos fármacos , Enterobacteriaceae/metabolismo , Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/mortalidade , Neutropenia Febril/microbiologia , Humanos , Aspergilose Pulmonar Invasiva/tratamento farmacológico , Aspergilose Pulmonar Invasiva/mortalidade , Estudos Prospectivos , Resistência beta-Lactâmica , beta-Lactamases/metabolismoRESUMO
BACKGROUND: The current standard of care for transplant-eligible myeloma patients is novel agent-based induction, followed by high-dose chemotherapy and autologous stem cell rescue. Chemo-mobilization of peripheral blood CD34+ stem cells (PBSCs) with pegylated filgrastim (pegfilgrastim), a sustained-duration formulation of filgrastim, has been used as an alternative to filgrastim in several studies involving heterogeneous cohorts of lymphoma and multiple myeloma (MM) patients and shown to be equivalent in PBSC yield and cost-effectiveness. The present study focused on the efficacy of pegfilgrastim in PBSC mobilization compared with filgrastim exclusively after novel agent-based induction in a homogeneous group of MM patients. PATIENTS AND METHODS: We analyzed the data from 89 patients with MM treated at 2 transplant centers in Singapore who had received novel agent-based induction chemotherapy, PBSC mobilization with vinorelbine/cyclophosphamide, high-dose melphalan conditioning, and autologous stem cell rescue. Of the 89 patients, 61 were included in the pegfilgrastim group and 28 in the filgrastim group, with a similar median age and disease characteristics. PBSC harvesting was performed at a similar median time of 9.51 ± 0.84 days for both, and the peak peripheral blood CD34+ stem cell count was 19.90 × 106/kg for pegfilgrastim and 32.50 × 106/kg for filgrastim (95% confidence interval, -4.36 to 0.70 × 106/kg). RESULTS: No significant difference was found in the median PBSC collection between the 2 groups (pegfilgrastim, 7.90 × 106/kg vs. filgrastim, 10.10 × 106/kg; P = .16). CONCLUSION: The present study has demonstrated that a single dose of pegfilgrastim is comparable to filgrastim in terms of the timing and efficacy of PBSC harvest and could potentially spare the patient 6 days of filgrastim injections. In addition, ours is the first study to compare these growth factors using vinorelbine/cyclophosphamide as mobilization chemotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Filgrastim/uso terapêutico , Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Mieloma Múltiplo/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , Transplante Autólogo/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Feminino , Filgrastim/farmacologia , Humanos , Masculino , Mieloma Múltiplo/patologia , Polietilenoglicóis/farmacologiaRESUMO
BACKGROUND: High dose Cyclophosphamide (Cy) and Vinorelbine Cyclophosphamide (Vino-Cy) are stem cell (SC) mobilisation options for patients with multiple myeloma (MM). We present a comparison of mobilisation outcomes using these regimens. PATIENTS AND METHODS: Vino-Cy patients received Vinorelbine 25â¯mg/m2 on day 1, cyclophosphamide 1500â¯mg/m2 on day 2, and pegylated GCSF on day 4 or GCSF 10â¯mcg/kg/day from day 4 onwards. Cy patients were given cyclophosphamide 4000â¯mg/m2 on day 1 and GCSF10â¯mcg/kg/day from day 5 onwards. The target CD34â¯+â¯SC collection was 5â¯×â¯106â¯per kg/BW. RESULTS: 149 patients were included. SC collection was lower in the Vino-Cy group (8.20â¯×â¯106/Kg BW) compared to the Cy group (11.43â¯×â¯106/Kg BW), with adjusted geometric mean ratio of 0.59 (95% CI 0.41 to 0.86, pâ¯=â¯0.006). Time taken to achieve an adequate PB SC count was shorter for Vino-Cy (9⯱â¯1â¯day compared to 12⯱â¯2â¯days for Cy, adjusted absolute mean difference -3.95, 95% CI -4.85 to -3.06, Pâ¯<â¯.001). Mobilisation related toxicities (in particular, neutropaenic fever) were greater for Cy. CONCLUSION: Vino-Cy is a potential alternative to Cy given the need for effective mobilisation protocols with acceptable toxicity.
Assuntos
Ciclofosfamida/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas/métodos , Mieloma Múltiplo/terapia , Células-Tronco de Sangue Periférico , Vinorelbina/administração & dosagem , Autoenxertos , Ciclofosfamida/efeitos adversos , Feminino , Filgrastim , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Transplante de Células-Tronco de Sangue Periférico , Vinorelbina/efeitos adversosRESUMO
Acute appendicitis is a clinical diagnosis typically presenting with right lower quadrant pain. We describe the case of an asymptomatic 53-year-old man with stage 2A diffuse large B-cell lymphoma, who underwent F-FDG PET/CT at the completion of chemotherapy. The scan showed complete lymphomatous disease remission. Incidentally, there was increased FDG uptake in a tubular structure adjacent to the cecum. Clinical examination was negative. Subsequently, the patient presented 6 days later with typical acute appendicitis symptoms. This case is interesting wherein increased FDG uptake in the appendix predated the appearance of clinical symptoms.