RESUMEN
Thromboembolism frequently occurs during acute lymphoblastic leukemia (ALL) therapy. We prospectively registered thromboembolic events during the treatment of 1772 consecutive Nordic/Baltic patients with ALL aged 1 to 45 years who were treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol (July 2008-April 2017). The 2.5-year cumulative incidence of thromboembolism (N = 137) was 7.9% (95% confidence interval [CI], 6.6-9.1); it was higher in patients aged at least 10 years (P < .0001). Adjusted hazard ratios (HRas) were associated with greater age (range, 10.0-17.9 years: HRa, 4.9 [95% CI, 3.1-7.8; P < .0001]; 18.0-45.9 years: HRa, 6.06 [95% CI, 3.65-10.1; P < .0001]) and mediastinal mass at ALL diagnosis (HRa, 2.1; 95% CI, 1.0-4.3; P = .04). In a multiple absolute risk regression model addressing 3 thromboembolism risk factors, age at least 10 years had the largest absolute risk ratio (RRage, 4.7 [95% CI, 3.1-7.1]; RRenlarged lymph nodes, 2.0 [95% CI, 1.2-3.1]; RRmediastinal mass, 1.6 [95% CI, 1.0-2.6]). Patients aged 18.0 to 45.9 years had an increased hazard of pulmonary embolism (HRa, 11.6; 95% CI, 4.02-33.7; P < .0001), and patients aged 10.0 to 17.9 years had an increased hazard of cerebral sinus venous thrombosis (HRa, 3.3; 95% CI, 1.5-7.3; P = .003) compared with children younger than 10.0 years. Asparaginase was truncated in 38/128 patients with thromboembolism, whereas thromboembolism diagnosis was unassociated with increased hazard of relapse (P = .6). Five deaths were attributable to thromboembolism, and patients younger than 18.0 years with thromboembolism had increased hazard of dying compared with same-aged patients without thromboembolism (both P ≤ .01). In conclusion, patients aged at least 10 years could be candidates for preemptive antithrombotic prophylaxis. However, the predictive value of age 10 years or older, enlarged lymph nodes, and mediastinal mass remain to be validated in another cohort.
Asunto(s)
Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Asparaginasa/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Tromboembolia/inducido químicamente , Tromboembolia/prevención & control , Adolescente , Adulto , Factores de Edad , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Asparaginasa/uso terapéutico , Niño , Preescolar , Femenino , Humanos , Incidencia , Lactante , Masculino , Persona de Mediana Edad , Factores de Riesgo , Adulto JovenRESUMEN
BACKGROUND: The risk of venous thromboembolism is increased in adults and enhanced by asparaginase-based chemotherapy, and venous thromboembolism introduces a secondary risk of treatment delay and premature discontinuation of key anti-leukaemic agents, potentially compromising survival. Yet, the trade-off between benefits and harms of primary thromboprophylaxis in adults with acute lymphoblastic leukaemia (ALL) treated according to asparaginase-based regimens is uncertain. OBJECTIVES: The primary objectives were to assess the benefits and harms of primary thromboprophylaxis for first-time symptomatic venous thromboembolism in adults with ALL receiving asparaginase-based therapy compared with placebo or no thromboprophylaxis. The secondary objectives were to compare the benefits and harms of different groups of primary systemic thromboprophylaxis by stratifying the main results per type of drug (heparins, vitamin K antagonists, synthetic pentasaccharides, parenteral direct thrombin inhibitors, direct oral anticoagulants, and blood-derived products for antithrombin substitution). SEARCH METHODS: We conducted a comprehensive literature search on 02 June 2020, with no language restrictions, including (1) electronic searches of Pubmed/MEDLINE; Embase/Ovid; Scopus/Elsevier; Web of Science Core Collection/Clarivate Analytics; and Cochrane Central Register of Controlled Trials (CENTRAL) and (2) handsearches of (i) reference lists of identified studies and related reviews; (ii) clinical trials registries (ClinicalTrials.gov registry; the International Standard Randomized Controlled Trial Number (ISRCTN) registry; the World Health Organisation's International Clinical Trials Registry Platform (ICTRP); and pharmaceutical manufacturers of asparaginase including Servier, Takeda, Jazz Pharmaceuticals, Ohara Pharmaceuticals, and Kyowa Pharmaceuticals), and (iii) conference proceedings (from the annual meetings of the American Society of Hematology (ASH); the European Haematology Association (EHA); the American Society of Clinical Oncology (ASCO); and the International Society on Thrombosis and Haemostasis (ISTH)). We conducted all searches from 1970 (the time of introduction of asparaginase in ALL treatment). We contacted the authors of relevant studies to identify any unpublished material, missing data, or information regarding ongoing studies. SELECTION CRITERIA: Randomised controlled trials (RCTs); including quasi-randomised, controlled clinical, cross-over, and cluster-randomised trial designs) comparing any parenteral/oral preemptive anticoagulant or mechanical intervention with placebo or no thromboprophylaxis, or comparing two different pre-emptive anticoagulant interventions in adults aged at least 18 years with ALL treated according to asparaginase-based chemotherapy regimens. For the description of harms, non-randomised observational studies with a control group were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Using a standardised data collection form, two review authors independently screened and selected studies, extracted data, assessed risk of bias for each outcome using standardised tools (RoB 2.0 tool for RCTs and ROBINS-I tool for non-randomised studies) and the certainty of evidence for each outcome using the GRADE approach. Primary outcomes included first-time symptomatic venous thromboembolism, all-cause mortality, and major bleeding. Secondary outcomes included asymptomatic venous thromboembolism, venous thromboembolism-related mortality, adverse events (i.e. clinically relevant non-major bleeding and heparin-induced thrombocytopenia for trials using heparins), and quality of life. Analyses were performed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. For non-randomised studies, we evaluated all studies (including studies judged to be at critical risk of bias in at least one of the ROBINS-I domains) in a sensitivity analysis exploring confounding. MAIN RESULTS: We identified 23 non-randomised studies that met the inclusion criteria of this review, of which 10 studies provided no outcome data for adults with ALL. We included the remaining 13 studies in the 'Risk of bias' assessment, in which we identified invalid control group definition in two studies and judged outcomes of nine studies to be at critical risk of bias in at least one of the ROBINS-I domains and outcomes of two studies at serious risk of bias. We did not assess the benefits of thromboprophylaxis, as no RCTs were included. In the main descriptive analysis of harms, we included two retrospective non-randomised studies with outcomes judged to be at serious risk of bias. One study evaluated antithrombin concentrates compared to no antithrombin concentrates. We are uncertain whether antithrombin concentrates have an effect on all-cause mortality (risk ratio (RR) 0.55, 95% confidence interval (CI) 0.26 to 1.19 (intention-to-treat analysis); one study, 40 participants; very low certainty of evidence). We are uncertain whether antithrombin concentrates have an effect on venous thromboembolism-related mortality (RR 0.10, 95% CI 0.01 to 1.94 (intention-to-treat analysis); one study, 40 participants; very low certainty of evidence). We do not know whether antithrombin concentrates have an effect on major bleeding, clinically relevant non-major bleeding, and quality of life in adults with ALL treated with asparaginase-based chemotherapy, as data were insufficient. The remaining study (224 participants) evaluated prophylaxis with low-molecular-weight heparin versus no prophylaxis. However, this study reported insufficient data regarding harms including all-cause mortality, major bleeding, venous thromboembolism-related mortality, clinically relevant non-major bleeding, heparin-induced thrombocytopenia, and quality of life. In the sensitivity analysis of harms, exploring the effect of confounding, we also included nine non-randomised studies with outcomes judged to be at critical risk of bias primarily due to uncontrolled confounding. Three studies (179 participants) evaluated the effect of antithrombin concentrates and six studies (1224 participants) evaluated the effect of prophylaxis with different types of heparins. When analysing all-cause mortality; venous thromboembolism-related mortality; and major bleeding (studies of heparin only) including all studies with extractable outcomes for each comparison (antithrombin and low-molecular-weight heparin), we observed small study sizes; few events; wide CIs crossing the line of no effect; and substantial heterogeneity by visual inspection of the forest plots. Although the observed heterogeneity could arise through the inclusion of a small number of studies with differences in participants; interventions; and outcome assessments, the likelihood that bias due to uncontrolled confounding was the cause of heterogeneity is inevitable. Subgroup analyses were not possible due to insufficient data. AUTHORS' CONCLUSIONS: We do not know from the currently available evidence, if thromboprophylaxis used for adults with ALL treated according to asparaginase-based regimens is associated with clinically appreciable benefits and acceptable harms. The existing research on this question is solely of non-randomised design, seriously to critically confounded, and underpowered with substantial imprecision. Any estimates of effect based on the existing insufficient evidence is very uncertain and is likely to change with future research.
Asunto(s)
Anticoagulantes/uso terapéutico , Antineoplásicos/efectos adversos , Asparaginasa/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Tromboembolia Venosa/prevención & control , Adulto , Anticoagulantes/efectos adversos , Antitrombinas/efectos adversos , Antitrombinas/uso terapéutico , Sesgo , Causas de Muerte , Humanos , Placebos/uso terapéutico , Tromboembolia Venosa/inducido químicamente , Tromboembolia Venosa/mortalidadRESUMEN
To examine the outcomes of allogeneic stem cell transplantation (HSCT) in first complete remission (CR1) compared with chemotherapy alone in a population-based setting, we identified a cohort of patients with acute myeloid leukemia (AML) aged 15 to 70 years diagnosed between 2000 and 2014 in Denmark. Using the Danish National Acute Leukemia Registry, we compared relapse risk, relapse-free survival (RFS), and overall survival (OS) between patients with unfavorable cytogenetic features receiving postremission therapy with conventional chemotherapy only versus those undergoing HSCT in CR1. To minimize immortal time bias, we performed Cox proportional hazards regression, included date of allogeneic HSCT as a time-dependent covariate, and stratified the results by age (<60 or ≥60 years) and cytogenetic risk group. Overall, 1031 patients achieved a CR1. Of these, 196 patients (19%) underwent HSCT. HSCT was associated with a lower relapse rate (24% versus 49%) despite a similar median time to relapse (287 days versus 265 days). In all subgroups, the risk of relapse was lower and both RFS and OS were superior in recipients of HSCT (OS, adjusted mortality ratios: all patients, .54 [95% confidence interval (CI), .42-.71]; patients age <60 years, .58 [95% CI, .42-.81]; patients age ≥60 years, .42 [95% CI, .26-.69]; patients with intermediate-risk cytogenetics, .63 [95% CI, .43-.87]; patients with adverse-risk cytogenetics, .40 [95% CI, .24-.67]). In conclusion, in this population-based nationwide cohort study, HSCT was associated with improved survival in both younger and older patients and in patients with both intermediate and adverse cytogenetic risk.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide Aguda/terapia , Adolescente , Adulto , Factores de Edad , Anciano , Estudios de Cohortes , Citogenética , Dinamarca , Femenino , Humanos , Leucemia Mieloide Aguda/epidemiología , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Recurrencia , Inducción de Remisión , Análisis de Supervivencia , Trasplante Homólogo , Adulto JovenRESUMEN
Arecent source data meta-analysis of randomized trials in adults assessing the immunoconjugate gemtuzumab ozogamicin combined with standard chemotherapy in acute myeloid leukemia showed a significant survival benefit in patients without an adverse karyotype. It is not clear whether the optimal dose should be 3 mg/m(2) or 6 mg/m(2) In this study, we randomized 788 patients to a single dose of gemtuzumab ozogamicin 3 mg/m(2) or 6 mg/m(2) with the first course of induction therapy. We found that the rate of complete remission was higher with 3 mg/m(2) [82% vs 76%; odds ratio 1.46 (1.04-2.06); P=0.03], but this was balanced by a higher rate of complete remission with incomplete peripheral blood count recovery in the 6 mg/m(2) treatment (10% vs 7%) resulting in similar overall response rate [89% vs 86%; hazard ratio 1.34 (0.88-2.04); P=0.17]. There was no overall difference in relapse or survival at four years between the arms: 46% vs 54%; hazard ratio 1.17 (0.94-1.45), P=0.5, and 50% versus 47%; hazard ratio 1.10 (0.90-1.34), P=0.3, respectively. The 30- and 60-day mortality was significantly higher in the 6 mg/m(2) recipients: 7% versus 3%; hazard ratio 2.07 (1.11-3.87), P=0.02, and 9% versus 5%; hazard ratio 1.99 (1.17-3.39), P=0.01, respectively, which in addition was associated with a higher rate of veno-occlusive disease (5.6% vs 0.5%; P<0.0001). Our conclusion from this trial is that there is no advantage in using a single dose of 6 mg/m(2) of gemtuzumab ozogamicin in combination with induction chemotherapy when compared with a 3 mg/m(2) dose, with respect to response, disease-free and overall survival, either overall, or in any disease subgroup. (AML17 was registered as ISRCTN55675535).
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Adolescente , Adulto , Anciano , Aminoglicósidos/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Niño , Preescolar , Femenino , Gemtuzumab , Humanos , Lactante , Recién Nacido , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Recurrencia , Inducción de Remisión , Análisis de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
In this study, we report the results from the largest cohort to date of newly diagnosed adult immune thrombocytopenia patients randomized to treatment with dexamethasone alone or in combination with rituximab. Eligible were patients with platelet counts ≤25×10(9)/L or ≤50×10(9)/L with bleeding symptoms. A total of 133 patients were randomly assigned to either dexamethasone 40 mg/day for 4 days (n = 71) or in combination with rituximab 375 mg/m(2) weekly for 4 weeks (n = 62). Patients were allowed supplemental dexamethasone every 1 to 4 weeks for up to 6 cycles. Our primary end point, sustained response (ie, platelets ≥50×10(9)/L) at 6 months follow-up, was reached in 58% of patients in the rituximab + dexamethasone group vs 37% in the dexamethasone group (P = .02). The median follow-up time was 922 days. We found longer time to relapse (P = .03) and longer time to rescue treatment (P = .007) in the rituximab + dexamethasone group. There was an increased incidence of grade 3 to 4 adverse events in the rituximab + dexamethasone group (P = .04). In conclusion, rituximab + dexamethasone induced higher response rates and longer time to relapse than dexamethasone alone. This study is registered at http://clinicaltrials.gov as NCT00909077.
Asunto(s)
Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Dexametasona/administración & dosificación , Dexametasona/uso terapéutico , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Adulto , Edad de Inicio , Anciano , Algoritmos , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Dexametasona/efectos adversos , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Púrpura Trombocitopénica Idiopática/diagnóstico , Púrpura Trombocitopénica Idiopática/epidemiología , Recurrencia , Rituximab , Resultado del TratamientoRESUMEN
Upshaw-Schulman syndrome (USS) is due to severe congenital deficiency of von Willebrand factor (VWF)-cleaving protease ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 domains, nr 13) activity resulting in the presence of unusually large forms of VWF in the circulation, causing intravascular platelet clumping and thrombotic microangiopathy. Our patient, a 26-year-old man, had attacks of thrombotic thrombocytopenic purpura (TTP) with thrombocytopenia and a urine dipstick positive for hemoglobin (4+), often as the only sign of hemolytic activity. He had ADAMTS13 activity of <1% of normal plasma without the presence of inhibitors of ADAMTS13. ADAMTS13 deficiency was caused by two new mutations of the ADAMTS13 gene: a deletion of a single nucleotide in exon17 (c. 2042 delA) leading to a frameshift (K681C fs X16), and a missense mutation in exon 25 (c.3368G>A) leading to p.R1123H. This case report confirms the importance of the analysis of the ADAMTS13 activity and its inhibitor in patients who have episodes of TTP, with a very low platelet count and sometimes without the classic biochemical signs of hemolysis.
Asunto(s)
Proteínas ADAM/genética , Heterocigoto , Mutación , Púrpura Trombocitopénica Trombótica/diagnóstico , Púrpura Trombocitopénica Trombótica/genética , Proteínas ADAM/inmunología , Proteínas ADAM/metabolismo , Proteína ADAMTS13 , Adulto , Autoanticuerpos/inmunología , Análisis Mutacional de ADN , Activación Enzimática , Humanos , Masculino , LinajeRESUMEN
BACKGROUND: The prognosis of acute lymphoblastic leukemia is poorer in adults than in children. Studies have indicated that young adults benefit from pediatric treatment, although no upper age limit has been defined. DESIGN AND METHODS: We analyzed 749 patients aged 1-45 yr treated by the NOPHO ALL-2008 protocol. Minimal residual disease (MRD) on days 29 and 79, immunophenotype, white blood cell count (WBC), and cytogenetics were used to stratify patients to standard-, intermediate-, or high-risk treatment with or without hematopoietic stem cell transplantation. RESULTS: Adults aged 18-45 had significantly lower WBCs at diagnosis compared with children aged 1-9 and 10-17 yr, but significantly more adults were stratified to high-risk chemotherapy (8%, 14%, 17%; P < 0.0001) or high-risk chemotherapy with transplantation (4%, 13%, 19%; P < 0.0001). This age-dependent skewing of risk grouping reflected more T-ALL (11%, 27%, 33%, P < 0.0001), poorer MRD response day 29 (MRD < 0.1%: 75%, 61%, 52%; P < 0.0001), and more MLL gene rearrangements (3%, 3%, 10%; P = 0.005) in older patients. CONCLUSIONS: Even if identical diagnostics, treatment, and risk stratification are implemented, more adults will be stratified to high-risk therapy, which should be considered when comparing pediatric and adult outcomes.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Adolescente , Adulto , Niño , Preescolar , Análisis Citogenético , Dexametasona/administración & dosificación , Doxorrubicina/administración & dosificación , Esquema de Medicación , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Quimioterapia de Inducción , Lactante , Masculino , Cumplimiento de la Medicación , Metotrexato/administración & dosificación , Persona de Mediana Edad , Neoplasia Residual/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Prednisona/administración & dosificación , Sistema de Registros , Resultado del Tratamiento , Vincristina/administración & dosificación , Adulto JovenRESUMEN
We investigated trends of survival in a population-based cohort study of all 181 adults who received HCT for ALL in Denmark between 2000-2019. Patients had a median (min-max) age of 36 (18-74) years at HCT and were followed for a median of eight years. Overall survival (OS) improved over time with an estimated 2-year OS of 49% (CI 27-66%) in year 2000 versus 77% (CI 59-88%) in year 2019. More patients achieved cure over time (OR for cure per year 1.07, CI 1.00-1.15), while the rate of death in non-cured patients remained stable (HR of excess mortality per year 0.99, CI 0.93-1.06). Relapse decreased over time (HR 0.92 per year, CI 0.87-0.98), whereas non-relapse mortality did not change notably (HR 0.98 per year, CI 0.93-1.04). In conclusion, survival after HCT in adults with ALL has improved over the past two decades, primarily due to more patients achieving cure.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Adulto , Anciano , Estudios de Cohortes , Dinamarca/epidemiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Estudios Retrospectivos , Acondicionamiento Pretrasplante , Trasplante Homólogo , Adulto JovenRESUMEN
We describe a novel syndrome of severe toxic symptoms during intravascular hemolysis due to impaired hemoglobin scavenging in 2 children with acute myeloid leukemia undergoing CD33-directed therapy with the immunotoxin gemtuzumab ozogamicin (GO). A simultaneous high plasma hemoglobin, haptoglobin, and low bilirubin after septicemia-induced intravascular hemolysis indicated abrogated clearance of haptoglobin-hemoglobin complexes. This was further supported by low levels of plasma soluble CD163 and a concordant low number of CD163-expressing monocytes. We show that CD163 positive monocytes and macrophages from liver, spleen, and bone marrow coexpress CD33, thus suggesting that the GO-induced cellular cytotoxicity of CD33 positive cells eradicates a significant part of the CD163 positive monocytes and macrophages. The risk of severe toxic symptoms from plasma hemoglobin should be considered after CD33-targeted chemotherapy when the disease is complicated by a pathologic intravascular hemolysis. Furthermore, the cases provide further circumstantial evidence of a key role of (CD163-expressing) monocytes/macrophages in plasma hemoglobin clearance in vivo.
Asunto(s)
Aminoglicósidos/toxicidad , Anticuerpos Monoclonales/toxicidad , Antígenos CD/sangre , Antígenos de Diferenciación Mielomonocítica/sangre , Hemoglobinas/metabolismo , Hemólisis , Leucemia Mieloide Aguda/complicaciones , Receptores de Superficie Celular/sangre , Anticuerpos Monoclonales Humanizados , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Gemtuzumab , Haptoglobinas/metabolismo , Humanos , Lactante , Leucemia Mieloide Aguda/tratamiento farmacológico , Masculino , Receptores Depuradores , SíndromeRESUMEN
Traditionally, patients with acute leukaemia are admitted to hospital during chemotherapy-induced pancytopenia, although a few recent reports have reported the feasibility and safety of outpatient treatment. We have developed an outpatient treatment programme for patients with acute leukaemia incorporating comprehensive patient education for self-care management at home during pancytopenia and involvement of patients in care of their tunnelled central venous catheter (CVC). During neutropenia, patients are treated with prophylactic ciprofloxacine, amoxicillin/clavulanic acid and fluconazole. Herein, we report the results of outpatient treatment of 60 patients with acute leukaemia (54 with acute myeloid leukaemia) followed prospectively in the period from March 2004 to 2007. After induction chemotherapy, outpatient treatment was possible after 48 of 73 induction courses, with no readmission in 19 of these (40%). A total of 129 consolidation courses were administered with outpatient treatment following 116 of these, with no readmission in 69 (59%). The median number of days spent at home with neutrophils below 0.5 x 10(9)/L was 8 d per course following induction and 12 d following consolidation chemotherapy. The predominant cause of readmission was neutropenic fever, in most instances of unknown origin. Coagulase-negative staphylococci and Enterococcus faecium were the most frequently identified bacteria in blood cultures, whereas only four positive blood cultures with multiresistant Escherichia coli were identified in the entire patient cohort, the latter exclusively observed in patients receiving antibiotic prophylaxis. The majority of the patients were able to take care of their CVC including change in dressing and heparin flushing. There were 12 CVC-related infections. There were no treatment-related deaths. We conclude that outpatient treatment of patients with acute leukaemia is feasible and safe.
Asunto(s)
Atención Ambulatoria/métodos , Antiinfecciosos/administración & dosificación , Leucemia/tratamiento farmacológico , Neutropenia/tratamiento farmacológico , Pancitopenia/tratamiento farmacológico , Enfermedad Aguda , Adolescente , Adulto , Anciano , Femenino , Humanos , Leucemia/sangre , Leucemia/microbiología , Masculino , Persona de Mediana Edad , Neutropenia/sangre , Neutropenia/microbiología , Pancitopenia/sangre , Pancitopenia/microbiología , Estudios ProspectivosRESUMEN
Mucormycosis is a life threatening infection in patients with haematological disease. We introduced a Mucorales-PCR and an aggressive, multidisciplinary management approach for mucormycosis during 2016-2017 and evaluated patient outcomes in 13 patients diagnosed and treated in 2012-2019. Management principle: repeated surgical debridement until biopsies from the resection margins were clean as defined by negative Blankophor microscopy, Mucorales-PCR (both reported within 24 h), and cultures. Cultured isolates underwent EUCAST E.Def 9.3.1 susceptibility testing. Antifungal therapy (AFT) (mono/combination) combined with topical AFT (when possible) was given according to the minimal inhibitory concentration (MIC), severity of the infection, and for azoles, specifically, it was guided by therapeutic drug monitoring. The outcome was evaluated by case record review. All patients underwent surgery guided by diagnostic biopsies from tissue and resection margins (195 samples in total). Comparing 2012-2015 and 2016-2019, the median number of patients of surgical debridements was 3 and 2.5 and of diagnostic samples: microscopy/culture/PCR was 3/3/6 and 10.5/10/10.5, respectively. The sensitivity of microscopy (76%) and Mucorales-PCR (70%) were similar and microscopy was superior to that of culture (53%; p = 0.039). Initial systemic AFT was liposomal amphotericin B (n = 12) or posaconazole (n = 1) given as monotherapy (n = 4) or in combination with isavuconazole/posaconazole (n = 3/6) and terbinafine (n = 3). Nine patients received topical amphotericin B. All received isavuconazole or posaconazole consolidation therapy (n = 13). Mucormycosis related six month mortality was 3/5 in 2012-2015 and 0/7 patients in 2016-2019 (one patient was lost for follow-up). Implementation of combination therapy (systemic+topical AFT/combination systemic AFT) and aggressive surgical debridement guided by optimised diagnostic tests may improve the outcome of mucormycosis in haematologic patients.
RESUMEN
The etiology of leukemia is largely unknown. Ecological data indicating trends in incidence and survival can provide information about changes in risk factors, can reflect underlying changes in diagnostic classification, and can measure therapeutic advances. From the records of the Danish Cancer Registry with registration starting from 1943, we calculated age-specific, period-specific, and age-standardized (world standard) incidence rates of chronic lymphoid leukemia (CLL), acute lymphoid leukemia (ALL), chronic myeloid leukemia (CML), and acute myeloid leukemia (AML) for persons above the age of 18. Kaplan-Meier survival curves and median survival times were calculated. Between 1943 and 2003, there were 26,036 cases of leukemia reported. The age-specific incidence rates of CLL, CML, and AML were higher for older men and women, while the incidence rates of ALL by age were more homogeneous. The age-standardized incidence rates during the study period increased for CLL and AML, increased less strongly for ALL, and decreased for CML in both men and women, although the incidence rates for women were almost always lower. Patients with CLL had the longest survival time in all age groups. The median survival time increased for all leukemia subtypes throughout the period of study most pronounced for CLL since 1950 and CML since 1990.
Asunto(s)
Leucemia/epidemiología , Adulto , Distribución por Edad , Dinamarca/epidemiología , Femenino , Humanos , Incidencia , Estimación de Kaplan-Meier , MasculinoRESUMEN
Purpose We investigated the effect on outcome of measurable or minimal residual disease (MRD) status after each induction course to evaluate the extent of its predictive value for acute myeloid leukemia (AML) risk groups, including NPM1 wild-type (wt) standard risk, when incorporated with other induction response criteria. Methods As part of the NCRI AML17 trial, 2,450 younger adult patients with AML or high-risk myelodysplastic syndrome had prospective multiparameter flow cytometric MRD (MFC-MRD) assessment. After course 1 (C1), responses were categorized as resistant disease (RD), partial remission (PR), and complete remission (CR) or complete remission with absolute neutrophil count < 1,000/µL or thrombocytopenia < 100,000/µL (CRi) by clinicians, with CR/CRi subdivided by MFC-MRD assay into MRD+ and MRD-. Patients without high-risk factors, including Flt3 internal tandem duplication wt/- NPM1-wt subgroup, received a second daunorubicin/cytosine arabinoside induction; course 2 (C2) was intensified for patients with high-risk factors. Results Survival outcomes from PR and MRD+ responses after C1 were similar, particularly for good- to standard-risk subgroups (5-year overall survival [OS], 27% RD v 46% PR v 51% MRD+ v 70% MRD-; P < .001). Adjusted analyses confirmed significant OS differences between C1 RD versus PR/MRD+ but not PR versus MRD+. CRi after C1 reduced OS in MRD+ (19% CRi v 45% CR; P = .001) patients, with a smaller effect after C2. The prognostic effect of C2 MFC-MRD status (relapse: hazard ratio [HR], 1.88 [95% CI, 1.50 to 2.36], P < .001; survival: HR, 1.77 [95% CI, 1.41 to 2.22], P < .001) remained significant when adjusting for C1 response. MRD positivity appeared less discriminatory in poor-risk patients by stratified analyses. For the NPM1-wt standard-risk subgroup, C2 MRD+ was significantly associated with poorer outcomes (OS, 33% v 63% MRD-, P = .003; relapse incidence, 89% when MRD+ ≥ 0.1%); transplant benefit was more apparent in patients with MRD+ (HR, 0.72; 95% CI, 0.31 to 1.69) than those with MRD- (HR, 1.68 [95% CI, 0.75 to 3.85]; P = .16 for interaction). Conclusion MFC-MRD can improve outcome stratification by extending the definition of partial response after first induction and may help predict NPM1-wt standard-risk patients with poor outcome who benefit from transplant in the first CR.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia de Inducción/métodos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Neoplasia Residual/tratamiento farmacológico , Neoplasia Residual/genética , Adolescente , Adulto , Anciano , Citarabina/administración & dosificación , Daunorrubicina/administración & dosificación , Femenino , Citometría de Flujo , Trasplante de Células Madre Hematopoyéticas , Humanos , Masculino , Persona de Mediana Edad , Mutación/genética , Proteínas Nucleares/genética , Nucleofosmina , Estudios Prospectivos , Factores de Riesgo , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Stringent complete remission (sCR) of acute myeloid leukemia is defined as normal hematopoiesis after therapy. Less sCR, including non-sCR, was introduced as insufficient blood platelet, neutrophil, or erythrocyte recovery. These latter characteristics were defined retrospectively as postremission transfusion dependency and were suggested to be of prognostic value. In the present report, we evaluated the prognostic impact of achieving sCR and non-sCR in the Danish National Acute Leukaemia Registry, including 769 patients registered with classical CR (ie, <5% blasts in the postinduction bone marrow analysis). Individual patients were classified as having sCR (n = 360; 46.8%) or non-sCR (n = 409; 53.2%) based on data from our national laboratory and transfusion databases. Survival analysis revealed that patients achieving sCR had superior overall survival (hazard ratio [HR], 1.34; 95% confidence interval [CI], 1.10-1.64) as well as relapse-free survival (HR, 1.25; 95% CI, 1.03-1.51) compared with those with non-sCR after adjusting for covariates. Cox regression analysis regarding the impact of the stringent criteria for blood cell recovery identified these as significant and independent variables. In conclusion, this real-life register study supports the international criteria for response evaluation on prognosis and, most importantly, documents each of the 3 lineage recovery criteria as contributing independently.
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Leucemia Mieloide Aguda/diagnóstico , Adulto , Anciano , Linaje de la Célula , Dinamarca/epidemiología , Humanos , Leucemia Mieloide Aguda/epidemiología , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Persona de Mediana Edad , Pronóstico , Sistema de Registros , Inducción de Remisión/métodos , Análisis de SupervivenciaRESUMEN
The increasing availability of genome-wide analysis has made it possible to rapidly sequence the exome of patients with undiagnosed or unresolved medical conditions. Here, we present the case of a 64-yr-old male patient with schistocytes in the peripheral blood smear and a complex and life-threatening coagulation disorder causing recurrent venous thromboembolic events, severe thrombocytopenia, and subdural hematomas. Whole-exome sequencing revealed a frameshift mutation (C3AR1 c.355-356dup, p.Asp119Alafs*19) resulting in a premature stop codon in C3AR1 (Complement Component 3a Receptor 1). Based on this finding, atypical hemolytic uremic syndrome was suspected because of a genetic predisposition, and a targeted treatment regime with eculizumab was initiated. Life-threatening hemostatic abnormalities would most likely have persisted had it not been for the implementation of whole-exome sequencing in this particular clinical setting.
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AIM OF DATABASE: The main aim of the Danish National Acute Leukemia Registry (DNLR) was to obtain information about the epidemiology of the hematologic cancers acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and myelodysplastic syndrome (MDS). STUDY POPULATION: The registry was established in January 2000 by the Danish Acute Leukemia Group and has been expanded over the years. It includes adult AML patients diagnosed in Denmark since 2000, ALL patients diagnosed since 2005, and MDS patients diagnosed since 2010. The coverage of leukemia patients exceeds 99%, and the coverage of MDS patients is currently 90%. MAIN VARIABLES AND DESCRIPTIVE DATA: Approximately, 250 AML patients, 25 ALL patients, and 230 MDS patients are registered in the DNLR every year. In January 2015, the registry included detailed patient characteristics, disease characteristics, treatment characteristics, and outcome data on more than 3,500 AML, 300 ALL, and 1,100 MDS patients. Many of the included prognostic variables have been found to be of high quality including positive predictive values and completeness exceeding 90%. These variables have been used in prognostic observational studies in the last few years. To ensure this high coverage, completeness, and quality of data, linkage to the Danish Civil Registration System and the Danish National Registry of Patients, and several programmed data entry checks are used. CONCLUSION: The completeness and positive predictive values of the leukemia data have been found to be high. In recent years, the DNLR has shown to be an important high-quality resource for clinical prognostic research.
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BACKGROUND: The Danish National Acute Leukemia Registry (DNLR) has documented coverage of above 98.5%. Less is known about the quality of the recorded data. OBJECTIVE: To describe the present coverage of the DNLR, its completeness, and accuracy of individual variables for acute myeloid leukemia (AML). Furthermore, as a second measure of true coverage of the DNLR, to estimate AML incidence in Denmark from DNLR data and compare it to incidence reported from other AML registries. PATIENTS AND METHODS: By the end of December 2011, the DNLR (established January 2000) included detailed data on a large, well-defined, and nonselected Danish population of 2,665 AML patients. We estimated positive predictive values (PPVs) and completeness for 30 variables, which included patient and disease characteristics, treatment, and treatment outcomes. We identified 260 AML patients (10% of all AML patients recorded in the DNLR). We used information from medical records as the gold standard. RESULTS: Using the Danish National Registry of Patients as a reference, the coverage of the DNLR was 99.6%. The PPVs of the individual variables ranged from 89.4% to 100%. The completeness of individual variables varied between 60.7% and 100%. Stratification by time of registration in the DNLR (before 2006 versus 2006 and later) revealed higher PPVs and lower frequencies of missing data from 2006. Sex-adjusted incidence rates were 6.2/100,000 person-years (95% confidence interval 5.8-6.6) in males and 4.9/100,000 person-years (95% confidence interval 4.5-5.4) in females. Yearly incidence rates of AML were higher than the incidence rates reported from Sweden (4.5 and 4.2/100,000) and the US (4.5 and 3.1/100,000 in Caucasians). CONCLUSION: With few exceptions, there were high values for PPVs and completeness of recorded data. Data accuracy and completeness have improved since the registry was established. The estimated incidence may indicate that the DNLR truly is more complete than other registries. In conclusion, the DNLR is a valuable resource for clinical research of AML.
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INTRODUCTION: This article presents the treatment results of 320 consecutive patients with malignant haematological diagnoses admitted to a tertiary intensive care unit at a Danish University hospital over a six-year period (2005-2010). With reference to international publications, we describe the development in treatment. MATERIAL AND METHODS: This was a retrospective observational study. RESULTS: The median age was 59 years. The median intensive care unit (ICU) stay was six days. A total of 88% required mechanical ventilation, and 72% received vasopressor treatment. The median Simplified Acute Physiology Score II score was 58. The ICU and one-year mortality rates were 44% and 77%, respectively, but mortality was significantly lower for patients aged 0-20 years. For patients aged 20-80 years, the mortality risk was independent of age. For the group of patients admitted acutely to the ICU with other diagnoses, the ICU- and the one-year mortality rate was 13% and 33%, respectively. CONCLUSION: Despite progress, the mortality rate for haematological patients in ICUs is high. We lack valid tools that allow us to differentiate between those who can benefit from intensive care and those for whom transfer to an ICU is futile. One patient out of five is alive after one year. This supports a strategy offering haematological patients intensive care on an equal footing with other patients. Follow-up studies of survivors, clarification of function level and quality of life are needed. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.
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Cuidados Críticos/métodos , Enfermedad Crítica , Neoplasias Hematológicas/terapia , Unidades de Cuidados Intensivos/estadística & datos numéricos , APACHE , Adolescente , Adulto , Anciano , Niño , Preescolar , Dinamarca , Femenino , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/mortalidad , Hematología/tendencias , Humanos , Lactante , Recién Nacido , Tiempo de Internación , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Medición de Riesgo , Triaje , Adulto JovenRESUMEN
PURPOSE: Interpatient variability in the pharmacokinetics (PK) of cytarabine, etoposide, and daunorubicin following body surface area-adjusted doses calls for studies that point to other covariates to explain this variability. The purpose of this study was to investigate such relationships and give insights into the PK of this combination treatment. METHODS: A prospective population PK study of twenty-three patients with acute myeloid leukemia was undertaken. Plasma concentrations of patients were determined by high-pressure liquid chromatography. PK models were developed with NONMEM; for daunorubicin, PK information from a prior study was utilized. RESULTS: Baseline white blood cell count (bWBC) influenced the PK for all drugs. A small, statistically insignificant improvement in model fit was achieved when a relationship between bWBC and daunorubicin central volume of distribution was included. The volume increased 1.9% for each increase in bWBC by 1 × 10(6) cells/mL. The clearances of etoposide and cytarabine were significantly increased and decreased, respectively, by increased bWBC. Tenfold changes in bWBC were needed for these relationships to have potential clinical relevance. A decrease in creatinine clearance of 60 mL/min resulted in a decrease in etoposide clearance of 32%. CONCLUSIONS: Population-based models characterized the PK for all three drugs. bWBC was a significant covariate for etoposide and cytarabine and showed a trend for daunorubicin. Linking the significant bWBC relationships and the relationship between kidney function and etoposide clearance to clinical end points would support dose individualization. Patients with above-normal creatinine clearances and high bWBC may receive sub-optimal treatment due to elevated etoposide clearances.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Leucemia Mieloide Aguda/tratamiento farmacológico , Modelos Biológicos , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Superficie Corporal , Cromatografía Líquida de Alta Presión , Creatinina/sangre , Creatinina/orina , Citarabina/administración & dosificación , Daunorrubicina/administración & dosificación , Relación Dosis-Respuesta a Droga , Etopósido/administración & dosificación , Femenino , Humanos , Leucemia Mieloide Aguda/patología , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Dinámicas no Lineales , Estudios Prospectivos , Distribución Tisular , Adulto JovenRESUMEN
Primary immune thrombocytopenia (ITP)--formerly known as idiopathic thrombocytopenic purpura--is an autoimmune disorder characterized by immune mediated thrombocytopenia. The aetiology of ITP remains unknown, but studies have shown that multiple immunological mechanisms are involved in the pathogenesis of ITP. This article aims to provide an overview of current treatment options, with particular emphasis on new biological therapies: rituximab, a monoclonal anti-CD20 antibody, and the thrombopoietin receptor agonists romiplostim and eltrombopag.