The randomized, phase III ALFA-0701 trial showed that a reduced and fractionated dose of gemtuzumab ozogamicin added to standard front-line chemotherapy significantly improves event-free survival ...(EFS) in adults with
acute myeloid leukemia (AML). Here we report an independent review of EFS, final overall survival (OS), and additional safety results from ALFA-0701. Patients (n=271) aged 50-70 years with
AML were randomized to receive conventional front-line induction chemotherapy (3+7daunorubicin+cytarabine) with/without gemtuzumab ozogamicin 3 mg/m
on days 1, 4, and 7 during induction. Patients in remission following induction therapy received 2 courses of consolidation therapy (daunorubicin+cytarabine) with/without gemtuzumab ozogamicin (3 mg/m
/day on day 1) according to their initial randomization. The primary end point was investigator-assessed EFS. Secondary end points included OS and safety. A blinded independent review confirmed the investigator-assessed EFS results August 1, 2011; hazard ratio (HR) 0.66; 95% Confidence Interval (CI): 0.49-0.89; 2-sided
=0.006, corresponding to a 34% reduction in risk of events in the gemtuzumab ozogamicin
control arm. Final OS at April 30, 2013 favored gemtuzumab ozogamicin but was not significant. No differences in early death rate were observed between arms. The main toxicity associated with gemtuzumab ozogamicin was prolonged thrombocytopenia. Veno-occlusive disease (including after transplant) was observed in 6 patients in the gemtuzumab ozogamicin arm and 2 in the control arm. In conclusion, gemtuzumab ozogamicin added to standard intensive chemotherapy has a favorable benefit/risk ratio. These results expand front-line treatment options for adult patients with previously untreated AML. (Trial registered at
).
Gemtuzumab ozogamicin (GO, Mylotarg
) consists of a humanized CD33-targeted antibody-drug conjugated to a calicheamicin derivative. Growing evidence of GO efficacy in acute myeloid leukemia (AML), ...demonstrated by improved outcomes in CD33-positive AML patients across phase I to III clinical trials, led to the Food and Drug Administration (FDA) approval on 1 September 2017 in CD33-positive AML patients aged 2 years and older. Discrepancies in GO recipients outcome have raised significant efforts to characterize biomarkers predictive of GO response and have refined the subset of patients that may strongly benefit from GO. Among them, CD33 expression levels, favorable cytogenetics (t(8;21), inv(16)/t(16;16), t(15;17)) and molecular alterations, such as
,
-internal tandem duplications and other signaling mutations, represent well-known candidates. Additionally, in depth analyses including minimal residual disease monitoring, stemness expression (LSC17 score), mutations or single nucleotide polymorphisms in GO pathway genes (
,
) and molecular-derived scores, such as the recently set up CD33_PGx6_Score, represent promising markers to enhance GO response prediction and improve patient management.
Abstract The evaluation of measurable residual disease (MRD) in acute myeloid leukemia (AML) using comprehensive mutation analysis by next-generation sequencing (NGS) has been investigated in several ...studies. However controversial results exist regarding the detection of persisting mutations in DNMT3A , TET2 , and ASXL1 (DTA). Benchmarking of NGS-MRD taking into account other molecular MRD strategies has to be done. Here, we performed error-corrected-NGS-MRD in 189 patients homogeneously treated in the ALFA-0702 study (NCT00932412). Persistence of non-DTA mutations (HR = 2.23 for RFS and 2.26 for OS), and DTA mutations (HR = 2.16 for OS) were associated with poorer prognosis in multivariate analysis. Persistence of at least two mutations in complete remission (CR) was associated with a higher cumulative incidence of relapse (CIR) (HR = 3.71, p < 0.0001), lower RFS (HR = 3.36, p < 0.0001) and OS (HR = 3.81, p = 0.00023) whereas persistence of only one mutation was not. In 100 analyzable patients, WT1 -MRD, but not NGS-MRD, was an independent factor for RFS and OS. In the subset of 67 NPM1 mutated patients, both NPM1 mutation detection ( p = 0.0059) and NGS-MRD ( p = 0.035) status were associated with CIR. We conclude that detectable NGS-MRD including DTA mutations correlates with unfavorable prognosis in AML. Its integration with alternative MRD strategies in AML management warrants further investigations.
In this study, we aimed to refine prognostication of older with acute myeloid leukemia (AML) after intensive chemotherapy. Five hundred and nine patients aged 60 years or older (median age, 68 years) ...were prospectively enrolled in the intensive Acute Leukemia French Association (ALFA)-1200 trial between 2012 and 2016, and 471 patient samples were submitted to multigene analysis. Mutations in any of 8 genes frequently altered in myelodysplastic syndromes (MDS), including ASXL1, SRSF2, STAG2, BCOR, U2AF1, EZH2, SF3B1, and ZRSR2, defined a secondary AML (sAML)-like disease, as reported. Of the samples analyzed, 48% included sAML-like gene mutations. These mutations were associated with a shorter event-free survival, both overall (hazard ratio, 1.46; 95% confidence interval, 1.19-1.79; P < .001) and within the European LeukemiaNet (ELN)-2017 intermediate-risk subgroup (hazard ratio, 1.52; 95% confidence interval, 1.01-2.28; P = .044), which excludes ASXL1-mutated cases by definition. We therefore included patients with intermediate-risk AML carrying sAML-like mutations in a single high-risk patients group together with adverse-risk patients with AML, whereas other intermediate-risk patients were included in a standard-risk group together with favorable-risk patients (high-risk/standard-risk patient ratio, 1.00). Using this 2-class risk assessment, we observed that transplantation prolonged overall survival from remission in patients with high-risk AML only, not in patients with standard-risk AML. Routine analysis of sAML-like gene mutations may thus improve the definition of high-risk older patients with AML, and better identify the half of older patients who clearly derive survival benefit from allogeneic transplantation in first remission. This trial was registered at www.clinicaltrials.gov as #NCT01966497.
•Secondary AML-like gene mutations other than ASXL1 also identify a substantial subset of patients with intermediate-risk AML and a worse outcome.•In one-third of AML of the ELN 2017 intermediate-risk group, sAML-like mutations other than ASXL1 can be detected.
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Abstract
Background
Lesbian, gay, bisexual, trans and intersex (LGBTI) people experience significant health inequalities. Located within a European Commission funded pilot project, this paper ...presents a review of the health inequalities faced by LGBTI people and the barriers health professionals encounter when providing care.
Methods
A narrative synthesis of 57 papers including systematic reviews, narrative reviews, meta-analyses and primary research. Literature was searched in Cochrane, Campbell Collaboration, Web of Science, CINAHL, PsychINFO and Medline. The review was undertaken to promote understanding of the causes and range of inequalities, as well as how to reduce inequalities.
Results
LGBTI people are more likely to experience health inequalities due to heteronormativity or heterosexism, minority stress, experiences of victimization and discrimination, compounded by stigma. Inequalities pertaining to LGBTI health(care) vary depending on gender, age, income and disability as well as between LGBTI groupings. Gaps in the literature remain around how these factors intersect to influence health, with further large-scale research needed particularly regarding trans and intersex people.
Conclusion
Health inequalities can be addressed via changes in policy, research and in practice through health services that accommodate the needs of LGBTI people. With improved training to address gaps in their knowledge of LGBTI health and healthcare, health professionals should work in collaboration with LGBTI people to address a range of barriers that prevent access to care. Through structural change combined with increased knowledge and understanding, services can potentially become more inclusive and equally accessible to all.
Este estudio empleó el análisis de superficie de respuesta basado en un diseño compuesto central para evaluar una celda electrolítica de flujo tipo filtro prensa, acoplada a un concentrador ...parabólico compuesto solar, los cuales se usaron para llevar a cabo el tratamiento de 20 l de agua residual doméstica de 742 a 756 mg l-1 en demanda química de oxígeno, y de 248 a 253 mg l-1 en carbono orgánico total. Los ánodos usados en la celda electrolítica fueron de IrPbO, IrSnO y RuPbO, recubiertos mediante la técnica de los cloruros metálicos sobre placas de Ti y activados por descomposición térmica. El concentrador parabólico compuesto solar posee un área de 1 m², la cual fue expuesta por cuatro horas por día, recibiendo una radiación promedio de 889 Watts m-2. La degradación de los contaminantes se vio favorecida con la adición de TiO2 a concentraciones de 100 a 150 mg l-1, con efectos poco significativos al cambiar la concentración de 0.02 a 0.06 M de Na2SO4 del electrolito soporte. Los ensayos de la degradación fueron seguidos por el análisis del carbono orgánico total, con porcentajes de degradación de 5 a 30% al final del tratamiento, al aplicar intensidades de corriente de 10 a 30 A, con consumos energéticos desde 6 hasta 74 kW m-3.
Aims
We sought to assess whether global longitudinal strain (GLS) measured early during treatment with anthracyclines (at a cumulative dose of 150 mg/m2) can predict subsequent alterations in left ...ventricular ejection fraction.
Methods and results
Eighty-six patients with Hodgkin’s disease, non-Hodgkin’s lymphoma, or acute leukaemia and receiving anthracyclines were prospectively included. Patients underwent complete echocardiography on four occasions: baseline (V1); after reaching a cumulative dose of 150 mg/m2 (V2); end of treatment (V3); and 1 year follow-up (V4). Six patients developed cardiotoxicity, defined as a decrease in left ventricular ejection fraction of >10 percentage points, to a value <53%, at V4. GLS measured at V1 and V2 was significantly lower in the cardiotoxicity group vs. the controls (P = 0.042 and P = 0.01, respectively). Compared with GLS at V1, GLS obtained at V2 provided incremental predictive information and appeared to be the strongest predictor of cardiotoxicity (area under the receiver-operating-characteristic curve, 0.82). At a threshold of –17.45% for GLS measured at V2, the sensitivity and specificity of detecting cardiotoxicity were 67% (95% confidence interval 33–100) and 97% (95% confidence interval 94–100), respectively.
Conclusion
GLS greater than –17.45%, obtained after 150 mg/m2 of anthracycline therapy, is an independent predictor of future anthracycline-induced cardiotoxicity. These findings should encourage physicians to perform echocardiography earlier during treatment with anthracyclines.
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