Influence of cytogenetic and molecular findings on prognosis and response to treatment of patients with acute myeloid leukemia

La mayoría de las determinaciones moleculares detalladas según la ELN2017 resultan de difícil acceso en nuestro medio y el cariotipo mantiene su importancia al indicar el tratamiento de los pacientes con leucemia mieloide aguda. Nuestro objetivo fue evaluar la influencia del cariotipo y de los hallazgos moleculares disponibles en relación a la supervivencia global (SG) y respuesta al tratamiento. Se realizó un análisis retrospectivo de 688 pacientes (pertenecientes a 11 instituciones, diagnosticados entre ene-13/jun-19), de los cuales 592 (86%) fueron evaluables. Los 196 pacientes (p) con cariotipo alterado, 104 (55%) vinculables a síndromes mielodisplásicos, mostraron una distribución heterogénea según los nueve sistemas aplicados (adverso: rango 47%-CECOG-SWOG-MDACC hasta 99%-Keating). La mayoría de los sistemas fueron útiles para predecir SG, con superioridad para el definido por CECOG-SWOG-MDACC (intermedio 10 m vs adverso 6 m, HR1,6 p=0,007) y entre aquéllos que recibieron un trasplante de células progenitoras hematopoyéticas (TCPH) (intermedio no alcanzada-NA vs adverso 14,5 m, HR2,5 p=0,053). En cuanto al tratamiento con agentes hipometilantes en 1ª línea (N 41, a fin de homogeneizar), excluyendo o no a los que recibieron TCPH (N 4), ninguno fue útil para diferenciar SG (9 m), tasas de remisiones completas (RC) ni mejor respuesta. Al evaluar quimioterapia, los sistemas CECOG-SWOG-MDACC y ELN2010 fueron los mejores predictores censurando (13 vs 8 m, p=0,023 y 15 vs 8 m, p=0,018) o no hasta el TCPH (p=0,009 y p=0,005). Sin embargo, sólo el primero fue útil para diferenciar tasas de RC (51/70, 73% vs 28/54, 52%, p=0,023). Finalmente, se compararon los hallazgos frente a la t(15;17) (N 77, SG NA) tomando la categorización del CECOG-SWOG-MDACC para los cariotipos alterados: CBF (N 65, SG NA) HR1,6 p=0,184; cariotipo-normal/NPM1+/FLT3- (N 26, SG NA) HR2,3, p=0,057; cariotipo-normal/NPM1-/FLT3- (N 102, SG 14 m) HR4,2, p<0,001; cariotipo-alterado/intermedio (N 101, 10 m) HR5,6, p<0,001; cariotipo-normal/NPM1-/FLT3+ (N 21, 9 m) HR6,1, p<0,001; cariotipo-alterado/adverso (N 88, 6 m) HR8,2, p<0,001 y cariotipo-normal/NPM1+/FLT3+ (N 12, SG 7 m) HR9,9, p<0,001 (CEPBA disponible en N 62, no evaluable). La mayoría de los riesgos se incrementaron al excluir los TCPH. Los resultados obtenidos comprueban el buen pronóstico de los pacientes con t(15;17), rearreglos CBF y de NPM1+ con cariotipo normal. Mientras que la detección de FLT3+ se asoció con un pronóstico adverso, independiente de NPM1+. El sistema definido por el CECOG-SWOG-MDACC, el cual considera de mal pronóstico a los cariotipos complejos y -5/-7, es el que mejor refleja los parámetros evaluados. Sin embargo, las alteraciones recomendadas por la ELN2010 reord3q, 5q-, t(6;9); 11q23v y 17p-, también influirían en la SG frente al tratamiento con quimioterapia en 1ª línea.The ELN2017 stratification has proved useful in predicting the outcome for acute myeloid leukemia (AML). However, some molecular determinations detailed are limited in use in our media and the karyotype remains an important factor regarding therapy. Our aim was to evaluate the predictive capacity of different cytogenetic and molecular findings on the outcome of patients with AML. Data was informative in 592 patients (pt) (from a retrospective cohort of 688 pt diagnosed in 11 Argentine centers between Jan/13-Jun/19). The overall survival (OS) concerning genetic data was different: t(15;17), 77 pt, not reached (NR); CBF rearrangements, 65 pt, NR; normal karyotype, 254 pt, 13 m, and abnormal karyotype, 196 pt, 8 m; p<0.001. Regarding normal karyotype, combined data according to the ELN2010 showed differences in the outcome: NPM1+/FLT3-, 26 pt, NR; NPM1-/FLT3- , 102 pt, 14 m; NPM1-/FLT3+, 21 pt, 9 m; NPM1+/ FLT3+, 12 pt, 7 m; p=0.025 (CEPBA available 62 pt, no evaluable). Adverse karyotypes were heterogeneously distributed among 9 systems: 47% CECOG-SWOGMDACC to 99% Keating-classification, and 104 (55%) with changes related to myelodysplastic syndromes. The CECOG-SWOG-MDACC showed superiority to differentiate between intermediate vs adverse for OS (10 vs 6 m, p=0.004; HR1.6, p=0.007, Cox’s regression) and, in the limit, for those who undergone hematopoietic stem cell transplantation (HSCT) (NA vs 15 m, p=0.033; HR 2.5, p=0.053). Regarding hypomethylating agents (41 pt) as first line therapy none was useful to differentiate OS (9 m), complete remission (CR) or best response. When chemotherapy was evaluated, the CECOG-SWOG-MDACC and ELN2010 were similar censoring (13 vs 8 m, p=0.023 and 15 vs 8 m, p=0.018) or not censoring at HSCT (14 vs 8 m, p=0.009, and 16 vs 8 m, p=0.005). However, only the first one made a difference in CR rates (73% vs 52%, p=0.023), with a tendency for any therapy (p=0.057). Finally, all findings were compared, selecting t(15;17) as reference and applying the CECOGSWOG-MDACC: CBF HR1.6 p=0.184; normal karyotype NPM1+/FLT3- HR2.3, p=0.057; normal karyotype NPM1-/FLT3- HR4.2, p<0.001; intermediate HR5.6, p<0.001; normal karyotype NPM1-/ FLT3+ HR6.1, p<0.001; normal karyotype NPM1+/ FLT3+ HR9.9, p<0.001, and adverse HR8.2, p<0.001. These HRs increased when excluding HSCT, especially for FLT3+. Our results are in agreement with the favorable outcome of t(15;17), CBF rearrangement and NPM1+/FLT3- in those with normal karyotype, whereas FLT3+ was an adverse finding. Complex karyotypes, -5 and -7, according CECOG-SWOGMDACC, were associated with shorter OS and lower CR. However, when rearr3q, 5q-, t(6;9), 11q23v and 17p- were also included, according to ELN2010, they account for a shorter OS in those treated with chemotherapyFil: Belli, Carolina Bárbara. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Correa, Walter A.. Hospital Italiano; Argentina. Hospital Italiano de La Plata; ArgentinaFil: Gonzalez, Natalia Jacqueline. Gobierno de la Ciudad Autónoma de Buenos Aires. Hospital General de Agudos Carlos Durand; ArgentinaFil: Ferrari, Luciana. Fundación Para Combatir la Leucemia; ArgentinaFil: Dick, Hernán. Hospital Italiano de La Plata; ArgentinaFil: Cranco, Santiago. Instituto Alexander Fleming.; Argentina. Hospital Pediatrico Alexander Fleming; ArgentinaFil: Moirano, María. Provincia de Buenos Aires. Hospital Interzonal General de Agudos Gral. San Martín; ArgentinaFil: Rapan, Leticia. Sanatorio “Sagrado Corazón”; ArgentinaFil: Oliveira, Natalia. Hospital Nacional Profesor Alejandro Posadas; ArgentinaFil: Kornblihtt, Laura Inés. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Suero, Alejandro. Unidad Asistencial "Dr. César Milstein"; ArgentinaFil: Navickas, Alicia. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic; ArgentinaFil: Gimenez Conca, Alberto. Hospital Italiano; Argentin

Leucemias Agudas

Sobre: Leucemia linfoblástica aguda; Linfoma linfoblástico; Leucemia mieloide aguda; Leucemia promielocítica aguda y situaciones especiales.Fil: Agriello, Evangelina Edith. No especifíca;Fil: Belli, Carolina Bárbara. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Bullorsky, Laura. No especifíca;Fil: Cazap, Nicolás. No especifíca;Fil: Cranco, Santiago. No especifíca;Fil: Dick, Hernán. No especifíca;Fil: Fernandez, Isolda. No especifíca;Fil: Fischman, Laura. No especifíca;Fil: Funes, María Eugenia. No especifíca;Fil: Gimenez Conca, Alberto. No especifíca;Fil: González, Jacqueline. No especifíca;Fil: Lang, Cecilia. No especifíca;Fil: Mela Osorio, María José. No especifíca;Fil: Navickas, Alicia. No especifíca;Fil: Oliveira, Natalia. No especifíca;Fil: Rey, Irene. No especifíca;Fil: Rivas, Marta. No especifíca;Fil: Suero, Alejandro. No especifíca;Fil: Zanella, Lorena. No especifíca

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Effect of SGLT2 Inhibitors on Stroke and Atrial Fibrillation in Diabetic Kidney Disease: Results From the CREDENCE Trial and Meta-Analysis

BACKGROUND AND PURPOSE: Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus.METHODS: CREDENCE randomized 4401 participants with type 2 diabetes mellitus and chronic kidney disease to canagliflozin or placebo. Post hoc, we estimated effects on fatal or nonfatal stroke, stroke subtypes, and intermediate markers of stroke risk including AF/AFL. Stroke and AF/AFL data from 3 other completed large CVOTs and CREDENCE were pooled using random-effects meta-analysis.RESULTS: In CREDENCE, 142 participants experienced a stroke during follow-up (10.9/1000 patient-years with canagliflozin, 14.2/1000 patient-years with placebo; hazard ratio [HR], 0.77 [95% CI, 0.55-1.08]). Effects by stroke subtypes were: ischemic (HR, 0.88 [95% CI, 0.61-1.28]; n=111), hemorrhagic (HR, 0.50 [95% CI, 0.19-1.32]; n=18), and undetermined (HR, 0.54 [95% CI, 0.20-1.46]; n=17). There was no clear effect on AF/AFL (HR, 0.76 [95% CI, 0.53-1.10]; n=115). The overall effects in the 4 CVOTs combined were: total stroke (HRpooled, 0.96 [95% CI, 0.82-1.12]), ischemic stroke (HRpooled, 1.01 [95% CI, 0.89-1.14]), hemorrhagic stroke (HRpooled, 0.50 [95% CI, 0.30-0.83]), undetermined stroke (HRpooled, 0.86 [95% CI, 0.49-1.51]), and AF/AFL (HRpooled, 0.81 [95% CI, 0.71-0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate (P=0.01), with protection in the lowest estimated glomerular filtration rate (&lt;45 mL/min/1.73 m2]) subgroup (HRpooled, 0.50 [95% CI, 0.31-0.79]).CONCLUSIONS: Although we found no clear effect of SGLT2i on total stroke in CREDENCE or across trials combined, there was some evidence of benefit in preventing hemorrhagic stroke and AF/AFL, as well as total stroke for those with lowest estimated glomerular filtration rate. Future research should focus on confirming these data and exploring potential mechanisms. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02065791

Kidney and Cardiovascular Effects of Canagliflozin According to Age and Sex: A Post Hoc Analysis of the CREDENCE Randomized Clinical Trial

Rationale &amp; Objective: It is unclear whether the effect of canagliflozin on adverse kidney and cardiovascular events in those with diabetic kid-ney disease varies by age and sex. We assessed the effects of canagliflozin among age group categories and between sexes in the Canagli-flozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study.Study Design: Secondary analysis of a random-ized controlled trial. Setting &amp; Participants: Participants in the CREDENCE trial. Intervention: Participants were randomly assigned to receive canagliflozin 100 mg/d or placebo.Outcomes: Primary composite outcome of kid-ney failure, doubling of serum creatinine con-centration, or death due to kidney or cardiovascular disease. Prespecified secondary and safety outcomes were also analyzed. Out-comes were evaluated by age at baseline (&lt;60, 60-69, and &gt;_70 years) and sex in the intention-to-treat population using Cox regression models.Results: The mean age of the cohort was 63.0 &amp; PLUSMN; 9.2 years, and 34% were female. Older age and female sex were independently associ-ated with a lower risk of the composite of adverse kidney outcomes. There was no evidence that the effect of canagliflozin on the primary outcome (acomposite of kidney failure, a doubling of serum creatinine concentration, or death from kidney or cardiovascular causes) differed between age groups (HRs, 0.67 [95% CI, 0.52-0.87], 0.63 [0.4 8-0.82], and 0.89 [0.61-1.29] for ages &lt;60, 60-69, and &gt;_70 years, respectively; P = 0.3 for interaction) or sexes (HRs, 0.71 [95% CI, 0.5 4-0.95] and 0.69 [0.56-0.8 4] in women and men, respectively; P = 0.8 for interaction). No differences in safety outcomes by age group or sex were observed.Limitations: This was a post hoc analysis with multiple comparisons.Conclusions: Canagliflozin consistently reduced the relative risk of kidney events in people with diabetic kidney disease in both sexes and across age subgroups. As a result of greater background risk, the absolute reduction in adverse kidney outcomes was greater in younger participants.Funding: This post hoc analysis of the CREDENCE trial was not funded. The CREDENCE study was sponsored by Janssen Research and Development and was conducted collaboratively by the sponsor, an academic-led steering committee, and an academic research organization, George Clinical.Trial Registration: The original CREDENCE trial was registered at ClinicalTrials.gov with study number NCT02065791