207 results on '"Medeiros, Bruno"'
Search Results
2. An 8-year pragmatic observation evaluation of the benefits of allogeneic HCT in older and medically infirm patients with AML
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Sorror, Mohamed L., Gooley, Ted A., Storer, Barry E., Gerds, Aaron T., Sekeres, Mikkael A., Medeiros, Bruno C., Wang, Eunice S., Shami, Paul J., Adekola, Kehinde, Luger, Selina, Baer, Maria R., Rizzieri, David A., Wildes, Tanya M., Koprivnikar, Jamie, Smith, Julie, Garrison, Mitchell, Kojouri, Kiarash, Schuler, Tammy A., Leisenring, Wendy M., Onstad, Lynn E., Becker, Pamela S., McCune, Jeannine S., Lee, Stephanie J., Sandmaier, Brenda M., Appelbaum, Frederick R., and Estey, Elihu H.
- Abstract
We designed a prospective, observational study enrolling patients presenting for treatment of acute myeloid leukemia (AML) at 13 institutions to analyze associations between hematopoietic cell transplantation (HCT) and survival, quality of life (QOL), and function in: the entire cohort, those aged ≥65 years, those with high comorbidity burden, intermediate cytogenetic risk, adverse cytogenetic risk, and first complete remission with or without measurable residual disease. Patient were assessed 8 times over 2 years. Time-dependent regression models were used. Among 692 patients that were evaluable, 46% received HCT with a 2-year survival of 58%. In unadjusted models, HCT was associated with reduced risks of mortality most of the subgroups. However, after accounting for covariates associated with increased mortality (age, comorbidity burden, disease risks, frailty, impaired QOL, depression, and impaired function), the associations between HCT and longer survival disappeared in most subgroups. Although function, social life, performance status, and depressive symptoms were better for those selected for HCT, these health advantages were lost after receiving HCT. Recipients and nonrecipients of HCT similarly ranked and expected cure as main goal of therapy, whereas physicians had greater expectations for cure than the former. Accounting for health impairments negates survival benefits from HCT for AML, suggesting that the unadjusted observed benefit is mostly owing to selection of the healthier candidates. Considering patients’ overall expectations of cure but also the QOL burdens of HCT motivate the need for randomized trials to identify the best candidates for HCT. This trial was registered at www.clinicaltrials.gov as #NCT01929408.
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- 2023
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3. A randomized phase III study of standard versus high-dose cytarabine with or without vorinostat for AML
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Garcia-Manero, Guillermo, Podoltsev, Nikolai A., Othus, Megan, Pagel, John M., Radich, Jerald P., Fang, Min, Rizzieri, David A., Marcucci, Guido, Strickland, Stephen A., Litzow, Mark R., Savoie, M. Lynn, Medeiros, Bruno C., Sekeres, Mikkael A., Lin, Tara L., Uy, Geoffrey L., Powell, Bayard L., Kolitz, Jonathan E., Larson, Richard A., Stone, Richard M., Claxton, David, Essell, James, Luger, Selina M., Mohan, Sanjay R., Moseley, Anna, Appelbaum, Frederick R., and Erba, Harry P.
- Abstract
Prior experience indicated that use of higher doses of cytarabine during induction for acute myeloid leukemia (AML) with a histone deacetylase inhibitor resulted in high response rates. S1203 was a randomized multicenter trial for previously untreated patients aged 18–60 with AML which compared daunorubicin and cytarabine (DA), idarubicin with higher dose cytarabine (IA) and IA with vorinostat (IA + V). The primary endpoint was event free survival (EFS). 738 patients were randomized: 261 to each DA and IA arms and 216 to the IA + V arm. 96, 456, and 150 patients had favorable-, intermediate-, and unfavorable-risk cytogenetics, respectively. 152 were NPM1and 158 FLT3mutated. The overall remission rate was 77.5% including 62.5% CR and 15.0% CRi. No differences in remission, EFS, or overall survival were observed among the 3 arms except for the favorable cytogenetics subset who had improved outcomes with DA and postremission high dose cytarabine. A trend towards increased toxicity was observed with the IA and IA + V arms. The use of higher dose cytarabine during induction therapy in younger patients with AML, with or without vorinostat, does not result in improved outcomes. (Funded by the US National Institutes of Health and others, ClinicalTrials.gov number, NCT01802333.)
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- 2023
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4. Novel Data Analytics Identify Predictors of Quality-of-Life Trajectories in Patients with AML or High-Risk Myeloid Neoplasms
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Gauthier, Jordan, Furtuna, Bianca, Mangiavacchi, Jacopo, Gholami, Shahrzad, Lavista Ferres, Juan, Dodhia, Rahul, Fathi, Amir T., Brunner, Andrew M., Gerds, Aaron T., Sekeres, Mikkael A., Medeiros, Bruno C., Wang, Eunice S., Shami, Paul J, Adekola, Kehinde, Luger, Selina M., Baer, Maria R., Rizzieri, David A, Wildes, Tanya, Koprivnikar, Jamie L., Smith, Julie, Garrison, Mitchell A., Kojouri, Kiarash, Appelbaum, Frederick R., Percival, Mary-Elizabeth M., Lee, Stephanie J., and Sorror, Mohamed L.
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- 2022
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5. Novel Data Analytics Identify Predictors of Quality-of-Life Trajectories in Patients with AML or High-Risk Myeloid Neoplasms
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Gauthier, Jordan, Furtuna, Bianca, Mangiavacchi, Jacopo, Gholami, Shahrzad, Lavista Ferres, Juan, Dodhia, Rahul, Fathi, Amir T., Brunner, Andrew M., Gerds, Aaron T., Sekeres, Mikkael A., Medeiros, Bruno C., Wang, Eunice S., Shami, Paul J, Adekola, Kehinde, Luger, Selina M., Baer, Maria R., Rizzieri, David A, Wildes, Tanya, Koprivnikar, Jamie L., Smith, Julie, Garrison, Mitchell A., Kojouri, Kiarash, Appelbaum, Frederick R., Percival, Mary-Elizabeth M., Lee, Stephanie J., and Sorror, Mohamed L.
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- 2022
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6. Genomic landscape of patients with FLT3-mutated acute myeloid leukemia (AML) treated within the CALGB 10603/RATIFY trial
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Jahn, Nikolaus, Jahn, Ekaterina, Saadati, Maral, Bullinger, Lars, Larson, Richard A., Ottone, Tiziana, Amadori, Sergio, Prior, Thomas W., Brandwein, Joseph M., Appelbaum, Frederick R., Medeiros, Bruno C., Tallman, Martin S., Ehninger, Gerhard, Heuser, Michael, Ganser, Arnold, Pallaud, Celine, Gathmann, Insa, Krzykalla, Julia, Benner, Axel, Bloomfield, Clara D., Thiede, Christian, Stone, Richard M., Döhner, Hartmut, and Döhner, Konstanze
- Abstract
The aim of this study was to characterize the mutational landscape of patients with FLT3-mutated acute myeloid leukemia (AML) treated within the randomized CALGB 10603/RATIFY trial evaluating intensive chemotherapy plus the multi-kinase inhibitor midostaurin versus placebo. We performed sequencing of 262 genes in 475 patients: mutations occurring concurrently with the FLT3-mutation were most frequent in NPM1(61%), DNMT3A(39%), WT1(21%), TET2(12%), NRAS(11%), RUNX1(11%), PTPN11(10%), and ASXL1(8%) genes. To assess effects of clinical and genetic features and their possible interactions, we fitted random survival forests and interpreted the resulting variable importance. Highest prognostic impact was found for WT1and NPM1mutations, followed by white blood cell count, FLT3mutation type (internal tandem duplications vs. tyrosine kinase domain mutations), treatment (midostaurin vs. placebo), ASXL1mutation, and ECOG performance status. When evaluating two-fold variable combinations the most striking effects were found for WT1:NPM1(with NPM1mutation abrogating the negative effect of WT1mutation), and for WT1:treatment (with midostaurin exerting a beneficial effect in WT1-mutated AML). This targeted gene sequencing study provides important, novel insights into the genomic background of FLT3-mutated AML including the prognostic impact of co-mutations, specific gene–gene interactions, and possible treatment effects of midostaurin.
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- 2022
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7. Atezolizumab alone or in combination did not demonstrate a favorable risk-benefit profile in myelodysplastic syndrome
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Gerds, Aaron T., Scott, Bart L., Greenberg, Peter, Lin, Tara L., Pollyea, Daniel A., Verma, Amit, Dail, Monique, Feng, Yuning, Green, Cherie, Ma, Connie, Medeiros, Bruno C., Yan, Mark, Yousefi, Kasra, and Donnellan, William
- Abstract
We present primary results from the phase 1b GO29754 study evaluating the safety and tolerability of atezolizumab, a programmed death-ligand 1 inhibitor, alone and in combination with azacitidine, a hypomethylating agent (HMA), in patients with relapsed/refractory (R/R) or HMA-naïve myelodysplastic syndrome (MDS). Patients with R/R MDS received atezolizumab for 12 months (cohort A) or atezolizumab plus azacitidine for 6 cycles followed by atezolizumab as maintenance for 8 cycles (cohort B). Patients with HMA-naïve MDS received atezolizumab plus azacitidine until loss of clinical benefit (cohort C). Safety, activity, and exploratory end points were investigated. Forty-six patients were enrolled and received treatment (cohort A, n = 11; cohort B, n = 14; cohort C, n = 21). All patients experienced ≥1 adverse event (AE) on study, and all patients discontinued atezolizumab. In cohort A, 7 patients (63.6%) died, and no patients responded. In cohort B, 8 patients (57.1%) discontinued azacitidine, 11 (78.6%) died, and 2 (14.3%) responded. In cohort C, all 21 patients discontinued azacitidine, 13 died (61.9%), and 13 (61.9%) responded. The study was terminated by the sponsor before completion of recruitment because of the unexpected high early death rate in cohort C (6 [46.2%] of 13 deaths were due to AEs and occurred within the first 4 treatment cycles.). The high death rate and poor efficacy observed in this study do not support a favorable risk-benefit profile for atezolizumab as a single agent or in combination with azacitidine in R/R or HMA-naïve MDS. This trial was registered at www.clinicaltrials.gov as #NCT02508870.
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- 2022
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8. Molecular landscape and prognostic impact of FLT3-ITD insertion site in acute myeloid leukemia: RATIFY study results
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Rücker, Frank G., Du, Ling, Luck, Tamara J., Benner, Axel, Krzykalla, Julia, Gathmann, Insa, Voso, Maria Teresa, Amadori, Sergio, Prior, Thomas W., Brandwein, Joseph M., Appelbaum, Frederick R., Medeiros, Bruno C., Tallman, Martin S., Savoie, Lynn, Sierra, Jorge, Pallaud, Celine, Sanz, Miguel A., Jansen, Joop H., Niederwieser, Dietger, Fischer, Thomas, Ehninger, Gerhard, Heuser, Michael, Ganser, Arnold, Bullinger, Lars, Larson, Richard A., Bloomfield, Clara D., Stone, Richard M., Döhner, Hartmut, Thiede, Christian, and Döhner, Konstanze
- Abstract
In acute myeloid leukemia (AML) internal tandem duplications of the FLT3gene (FLT3-ITD) are associated with poor prognosis. Retrospectively, we investigated the prognostic and predictive impact of FLT3-ITD insertion site (IS) in 452 patients randomized within the RATIFY trial, which evaluated midostaurin additionally to intensive chemotherapy. Next-generation sequencing identified 908 ITDs, with 643 IS in the juxtamembrane domain (JMD) and 265 IS in the tyrosine kinase domain-1 (TKD1). According to IS, patients were categorized as JMDsole (n= 251, 55%), JMD and TKD1 (JMD/TKD1; n= 117, 26%), and TKD1sole (n= 84, 19%). While clinical variables did not differ among the 3 groups, NPM1mutation was correlated with JMDsole (P= 0.028). Overall survival (OS) differed significantly, with estimated 4-year OS probabilities of 0.44, 0.50, and 0.30 for JMDsole, JMD/TKD1, and TKD1sole, respectively (P= 0.032). Multivariate (cause-specific) Cox models for OS and cumulative incidence of relapse using allogeneic hematopoietic cell transplantation (HCT) in first complete remission as a time-dependent variable identified TKD1sole as unfavorable and HCT as favorable factors. In addition, Midostaurin exerted a significant benefit only for JMDsole. Our results confirm the distinct molecular heterogeneity of FLT3-ITD and the negative prognostic impact of TKD1 IS in AML that was not overcome by midostaurin.
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- 2022
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9. Midostaurin reduces relapse in FLT3-mutant acute myeloid leukemia: the Alliance CALGB 10603/RATIFY trial
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Larson, Richard A., Mandrekar, Sumithra J., Huebner, Lucas J., Sanford, Ben L., Laumann, Kristina, Geyer, Susan, Bloomfield, Clara D., Thiede, Christian, Prior, Thomas W., Döhner, Konstanze, Marcucci, Guido, Voso, Maria Teresa, Klisovic, Rebecca B., Galinsky, Ilene, Wei, Andrew H., Sierra, Jorge, Sanz, Miguel A., Brandwein, Joseph M., de Witte, Theo, Niederwieser, Dietger, Appelbaum, Frederick R., Medeiros, Bruno C., Tallman, Martin S., Krauter, Jürgen, Schlenk, Richard F., Ganser, Arnold, Serve, Hubert, Ehninger, Gerhard, Amadori, Sergio, Gathmann, Insa, Döhner, Hartmut, and Stone, Richard M.
- Abstract
The prospective randomized, placebo-controlled CALGB 10603/RATIFY trial (Alliance) demonstrated a statistically significant overall survival benefit from the addition of midostaurin to standard frontline chemotherapy in a genotypically-defined subgroup of 717 patients with FLT3-mutant acute myeloid leukemia (AML). The risk of death was reduced by 22% on the midostaurin-containing arm. In this post hoc analysis, we analyzed the cumulative incidence of relapse (CIR) on this study and also evaluated the impact of 12 4-week cycles of maintenance therapy. CIR analyses treated relapses and AML deaths as events, deaths from other causes as competing risks, and survivors in remission were censored. CIR was improved on the midostaurin arm (HR = 0.71 (95% CI, 0.54–0.93); p= 0.01), both overall and within European LeukemiaNet 2017 risk classification subsets when post-transplant events were considered in the analysis as events. However, when transplantation was considered as a competing risk, there was overall no significant difference between the risks of relapse on the two randomized arms. Patients still in remission after consolidation with high-dose cytarabine entered the maintenance phase, continuing with either midostaurin or placebo. Analyses were inconclusive in quantifying the impact of the maintenance phase on the overall outcome. In summary, midostaurin reduces the CIR.
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- 2021
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10. Multisite 11-year experience of less-intensive vs intensive therapies in acute myeloid leukemia
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Sorror, Mohamed L., Storer, Barry E., Fathi, Amir T., Brunner, Andrew, Gerds, Aaron T., Sekeres, Mikkael A., Mukherjee, Sudipto, Medeiros, Bruno C., Wang, Eunice S., Vachhani, Pankit, Shami, Paul J., Peña, Esteban, Elsawy, Mahmoud, Adekola, Kehinde, Luger, Selina, Baer, Maria R., Rizzieri, David, Wildes, Tanya M., Koprivnikar, Jamie, Smith, Julie, Garrison, Mitchell, Kojouri, Kiarash, Leisenring, Wendy, Onstad, Lynn, Nyland, Jennifer E., Becker, Pamela S., McCune, Jeannine S., Lee, Stephanie J., Sandmaier, Brenda M., Appelbaum, Frederick R., and Estey, Elihu H.
- Abstract
Less-intensive induction therapies are increasingly used in older patients with acute myeloid leukemia (AML). Using an AML composite model (AML-CM) assigning higher scores to older age, increased comorbidity burdens, and adverse cytogenetic risks, we defined 3 distinct prognostic groups and compared outcomes after less-intensive vs intensive induction therapies in a multicenter retrospective cohort (n = 1292) treated at 6 institutions from 2008 to 2012 and a prospective cohort (n = 695) treated at 13 institutions from 2013 to 2017. Prospective study included impacts of Karnofsky performance status (KPS), quality of life (QOL), and physician perception of cure. In the retrospective cohort, recipients of less-intensive therapies were older and had more comorbidities, more adverse cytogenetics, and worse KPS. Less-intensive therapies were associated with higher risks of mortality in AML-CM scores of 4 to 6, 7 to 9, and ≥10. Results were independent of allogeneic transplantation and similar in those age 70 to 79 years. In the prospective cohort, the 2 groups were similar in baseline QOL, geriatric assessment, and patient outcome preferences. Higher mortality risks were seen after less-intensive therapies. However, in models adjusted for age, physician-assigned KPS, and chance of cure, mortality risks and QOL were similar. Less-intensive therapy recipients had shorter length of hospitalization (LOH). Our study questions the survival and QOL benefits (except LOH) of less-intensive therapies in patients with AML, including those age 70 to 79 years or with high comorbidity burdens. A randomized trial in older/medically infirm patients is required to better assess the value of less-intensive and intensive therapies or their combination. This trial was registered at www.clinicaltrials.gov as #NCT01929408.
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- 2021
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11. Multisite 11-year experience of less-intensive vs intensive therapies in acute myeloid leukemia
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Sorror, Mohamed L., Storer, Barry E., Fathi, Amir T., Brunner, Andrew, Gerds, Aaron T., Sekeres, Mikkael A., Mukherjee, Sudipto, Medeiros, Bruno C., Wang, Eunice S., Vachhani, Pankit, Shami, Paul J., Peña, Esteban, Elsawy, Mahmoud, Adekola, Kehinde, Luger, Selina, Baer, Maria R., Rizzieri, David, Wildes, Tanya M., Koprivnikar, Jamie, Smith, Julie, Garrison, Mitchell, Kojouri, Kiarash, Leisenring, Wendy, Onstad, Lynn, Nyland, Jennifer E., Becker, Pamela S., McCune, Jeannine S., Lee, Stephanie J., Sandmaier, Brenda M., Appelbaum, Frederick R., and Estey, Elihu H.
- Abstract
Less-intensive induction therapies are increasingly used in older patients with acute myeloid leukemia (AML). Using an AML composite model (AML-CM) assigning higher scores to older age, increased comorbidity burdens, and adverse cytogenetic risks, we defined 3 distinct prognostic groups and compared outcomes after less-intensive vs intensive induction therapies in a multicenter retrospective cohort (n = 1292) treated at 6 institutions from 2008 to 2012 and a prospective cohort (n = 695) treated at 13 institutions from 2013 to 2017. Prospective study included impacts of Karnofsky performance status (KPS), quality of life (QOL), and physician perception of cure. In the retrospective cohort, recipients of less-intensive therapies were older and had more comorbidities, more adverse cytogenetics, and worse KPS. Less-intensive therapies were associated with higher risks of mortality in AML-CM scores of 4 to 6, 7 to 9, and ≥10. Results were independent of allogeneic transplantation and similar in those age 70 to 79 years. In the prospective cohort, the 2 groups were similar in baseline QOL, geriatric assessment, and patient outcome preferences. Higher mortality risks were seen after less-intensive therapies. However, in models adjusted for age, physician-assigned KPS, and chance of cure, mortality risks and QOL were similar. Less-intensive therapy recipients had shorter length of hospitalization (LOH). Our study questions the survival and QOL benefits (except LOH) of less-intensive therapies in patients with AML, including those age 70 to 79 years or with high comorbidity burdens. A randomized trial in older/medically infirm patients is required to better assess the value of less-intensive and intensive therapies or their combination. This trial was registered at www.clinicaltrials.govas #NCT01929408.
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- 2021
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12. Midostaurin in patients with acute myeloid leukemia and FLT3-TKD mutations: a subanalysis from the RATIFY trial
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Voso, Maria Teresa, Larson, Richard A., Jones, Dan, Marcucci, Guido, Prior, Thomas, Krauter, Jürgen, Heuser, Michael, Lavorgna, Serena, Nomdedeu, Josep, Geyer, Susan M., Walker, Alison, Wei, Andrew H., Sierra, Jorge, Sanz, Miguel A., Brandwein, Joseph M., de Witte, Theo M., Jansen, Joop H., Niederwieser, Dietger, Appelbaum, Frederick R., Medeiros, Bruno C., Tallman, Martin S., Schlenk, Richard F., Ganser, Arnold, Amadori, Sergio, Cheng, Yuan, Chen, YinMiao, Pallaud, Celine, Du, Ling, Piciocchi, Alfonso, Ehninger, Gerhard, Byrd, John, Thiede, Christian, Döhner, Konstanze, Stone, Richard M., Döhner, Hartmut, Bloomfield, Clara D., and Lo-Coco, Francesco
- Abstract
The results from the RATIFY trial (ClinicalTrials.gov: NCT00651261; CALGB 10603) showed that midostaurin combined with standard chemotherapy significantly improved outcomes in patients with FMS-like tyrosine kinase 3 (FLT3)–mutated acute myeloid leukemia (AML), compared with placebo. In this post hoc subgroup analysis from the trial, we evaluated the impact of midostaurin in 163 patients with FLT3-tyrosine kinase domain (TKD) mutations. At a median follow-up of 60.7 months (95% CI, 55.0-70.8), the 5-year event-free survival (EFS) rate was significantly higher in patients treated with midostaurin than in those treated with placebo (45.2% vs 30.1%; P = .044). A trend toward improved disease-free survival was also observed with midostaurin (67.3% vs 53.4%; P = .089), whereas overall survival (OS) was similar in the 2 groups. Patients with AML and NPM1mut/FLT3-TKDmut or core binding factor (CBF)–rearranged/FLT3-TKDmut genotypes had significantly prolonged OS with or without censoring at hematopoietic cell transplantation (HCT), compared with NPM1WT/CBF-negative AMLs. The multivariable model for OS and EFS adjusted for allogeneic HCT in first complete remission as a time-dependent covariable, revealed NPM1 mutations and CBF rearrangements as significant favorable factors. These data show that NPM1 mutations or CBF rearrangements identify favorable prognostic groups in patients with FLT3-TKD AMLs, independent of other factors, also in the context of midostaurin treatment.
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- 2020
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13. Midostaurin in patients with acute myeloid leukemia and FLT3-TKD mutations: a subanalysis from the RATIFY trial
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Voso, Maria Teresa, Larson, Richard A., Jones, Dan, Marcucci, Guido, Prior, Thomas, Krauter, Jürgen, Heuser, Michael, Lavorgna, Serena, Nomdedeu, Josep, Geyer, Susan M., Walker, Alison, Wei, Andrew H., Sierra, Jorge, Sanz, Miguel A., Brandwein, Joseph M., de Witte, Theo M., Jansen, Joop H., Niederwieser, Dietger, Appelbaum, Frederick R., Medeiros, Bruno C., Tallman, Martin S., Schlenk, Richard F., Ganser, Arnold, Amadori, Sergio, Cheng, Yuan, Chen, YinMiao, Pallaud, Celine, Du, Ling, Piciocchi, Alfonso, Ehninger, Gerhard, Byrd, John, Thiede, Christian, Döhner, Konstanze, Stone, Richard M., Döhner, Hartmut, Bloomfield, Clara D., and Lo-Coco, Francesco
- Abstract
The results from the RATIFY trial (ClinicalTrials.gov: NCT00651261; CALGB 10603) showed that midostaurin combined with standard chemotherapy significantly improved outcomes in patients with FMS-like tyrosine kinase 3 (FLT3)–mutated acute myeloid leukemia (AML), compared with placebo. In this post hoc subgroup analysis from the trial, we evaluated the impact of midostaurin in 163 patients with FLT3-tyrosine kinase domain (TKD) mutations. At a median follow-up of 60.7 months (95% CI, 55.0-70.8), the 5-year event-free survival (EFS) rate was significantly higher in patients treated with midostaurin than in those treated with placebo (45.2% vs 30.1%; P= .044). A trend toward improved disease-free survival was also observed with midostaurin (67.3% vs 53.4%; P= .089), whereas overall survival (OS) was similar in the 2 groups. Patients with AML and NPM1mut/FLT3-TKDmutor core binding factor (CBF)–rearranged/FLT3-TKDmutgenotypes had significantly prolonged OS with or without censoring at hematopoietic cell transplantation (HCT), compared with NPM1WT/CBF-negative AMLs. The multivariable model for OS and EFS adjusted for allogeneic HCT in first complete remission as a time-dependent covariable, revealed NPM1mutations and CBF rearrangements as significant favorable factors. These data show that NPM1mutations or CBF rearrangements identify favorable prognostic groups in patients with FLT3-TKD AMLs, independent of other factors, also in the context of midostaurin treatment.
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- 2020
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14. Single-cell mutational profiling enhances the clinical evaluation of AML MRD
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Ediriwickrema, Asiri, Aleshin, Alexey, Reiter, Johannes G., Corces, M. Ryan, Köhnke, Thomas, Stafford, Melissa, Liedtke, Michaela, Medeiros, Bruno C., and Majeti, Ravindra
- Abstract
Although most patients with acute myeloid leukemia (AML) achieve clinical remission with induction chemotherapy, relapse rates remain high. Next-generation sequencing enables minimal/measurable residual disease (MRD) detection; however, clinical significance is limited due to difficulty differentiating between pre-leukemic clonal hematopoiesis and frankly malignant clones. Here, we investigated AML MRD using targeted single-cell sequencing (SCS) at diagnosis, remission, and relapse (n = 10 relapsed, n = 4 nonrelapsed), with a total of 310 737 single cells sequenced. Sequence variants were identified in 80% and 75% of remission samples for patients with and without relapse, respectively. Pre-leukemic clonal hematopoiesis clones were detected in both cohorts, and clones with multiple cooccurring mutations were observed in 50% and 0% of samples. Similar clonal richness was observed at diagnosis in both cohorts; however, decreasing clonal diversity at remission was significantly associated with longer relapse-free survival. These results show the power of SCS in investigating AML MRD and clonal evolution.
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- 2020
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15. Impact of NPM1/FLT3-ITD genotypes defined by the 2017 European LeukemiaNet in patients with acute myeloid leukemia
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Döhner, Konstanze, Thiede, Christian, Jahn, Nikolaus, Panina, Ekaterina, Gambietz, Agnes, Larson, Richard A., Prior, Thomas W., Marcucci, Guido, Jones, Dan, Krauter, Jürgen, Heuser, Michael, Voso, Maria Teresa, Ottone, Tiziana, Nomdedeu, Josep F., Mandrekar, Sumithra J., Klisovic, Rebecca B., Wei, Andrew H., Sierra, Jorge, Sanz, Miguel A., Brandwein, Joseph M., de Witte, Theo, Jansen, Joop H., Niederwieser, Dietger, Appelbaum, Frederick R., Medeiros, Bruno C., Tallman, Martin S., Schlenk, Richard F., Ganser, Arnold, Serve, Hubert, Ehninger, Gerhard, Amadori, Sergio, Gathmann, Insa, Benner, Axel, Pallaud, Celine, Stone, Richard M., Döhner, Hartmut, and Bloomfield, Clara D.
- Abstract
Patients with acute myeloid leukemia (AML) harboring FLT3internal tandem duplications (ITDs) have poor outcomes, in particular AML with a high (≥0.5) mutant/wild-type allelic ratio (AR). The 2017 European LeukemiaNet (ELN) recommendations defined 4 distinct FLT3-ITD genotypes based on the ITD AR and the NPM1mutational status. In this retrospective exploratory study, we investigated the prognostic and predictive impact of the NPM1/FLT3-ITD genotypes categorized according to the 2017 ELN risk groups in patients randomized within the RATIFY trial, which evaluated the addition of midostaurin to standard chemotherapy. The 4 NPM1/FLT3-ITD genotypes differed significantly with regard to clinical and concurrent genetic features. Complete ELN risk categorization could be done in 318 of 549 trial patients with FLT3-ITD AML. Significant factors for response after 1 or 2 induction cycles were ELN risk group and white blood cell (WBC) counts; treatment with midostaurin had no influence. Overall survival (OS) differed significantly among ELN risk groups, with estimated 5-year OS probabilities of 0.63, 0.43, and 0.33 for favorable-, intermediate-, and adverse-risk groups, respectively (P< .001). A multivariate Cox model for OS using allogeneic hematopoietic cell transplantation (HCT) in first complete remission as a time-dependent variable revealed treatment with midostaurin, allogeneic HCT, ELN favorable-risk group, and lower WBC counts as significant favorable factors. In this model, there was a consistent beneficial effect of midostaurin across ELN risk groups.
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- 2020
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16. Impact of NPM1/FLT3-ITD genotypes defined by the 2017 European LeukemiaNet in patients with acute myeloid leukemia
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Döhner, Konstanze, Thiede, Christian, Jahn, Nikolaus, Panina, Ekaterina, Gambietz, Agnes, Larson, Richard A., Prior, Thomas W., Marcucci, Guido, Jones, Dan, Krauter, Jürgen, Heuser, Michael, Voso, Maria Teresa, Ottone, Tiziana, Nomdedeu, Josep F., Mandrekar, Sumithra J., Klisovic, Rebecca B., Wei, Andrew H., Sierra, Jorge, Sanz, Miguel A., Brandwein, Joseph M., de Witte, Theo, Jansen, Joop H., Niederwieser, Dietger, Appelbaum, Frederick R., Medeiros, Bruno C., Tallman, Martin S., Schlenk, Richard F., Ganser, Arnold, Serve, Hubert, Ehninger, Gerhard, Amadori, Sergio, Gathmann, Insa, Benner, Axel, Pallaud, Celine, Stone, Richard M., Döhner, Hartmut, and Bloomfield, Clara D.
- Abstract
Patients with acute myeloid leukemia (AML) harboring FLT3 internal tandem duplications (ITDs) have poor outcomes, in particular AML with a high (≥0.5) mutant/wild-type allelic ratio (AR). The 2017 European LeukemiaNet (ELN) recommendations defined 4 distinct FLT3-ITD genotypes based on the ITD AR and the NPM1 mutational status. In this retrospective exploratory study, we investigated the prognostic and predictive impact of the NPM1/FLT3-ITD genotypes categorized according to the 2017 ELN risk groups in patients randomized within the RATIFY trial, which evaluated the addition of midostaurin to standard chemotherapy. The 4 NPM1/FLT3-ITD genotypes differed significantly with regard to clinical and concurrent genetic features. Complete ELN risk categorization could be done in 318 of 549 trial patients with FLT3-ITD AML. Significant factors for response after 1 or 2 induction cycles were ELN risk group and white blood cell (WBC) counts; treatment with midostaurin had no influence. Overall survival (OS) differed significantly among ELN risk groups, with estimated 5-year OS probabilities of 0.63, 0.43, and 0.33 for favorable-, intermediate-, and adverse-risk groups, respectively (P < .001). A multivariate Cox model for OS using allogeneic hematopoietic cell transplantation (HCT) in first complete remission as a time-dependent variable revealed treatment with midostaurin, allogeneic HCT, ELN favorable-risk group, and lower WBC counts as significant favorable factors. In this model, there was a consistent beneficial effect of midostaurin across ELN risk groups.
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- 2020
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17. Cardiovascular, pulmonary, and metabolic toxicities complicating tyrosine kinase inhibitor therapy in chronic myeloid leukemia: Strategies for monitoring, detecting, and managing.
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Medeiros, Bruno C., Possick, Jennifer, and Fradley, Michael
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Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm, the incidence of which increases with age. Tyrosine kinase inhibitors (TKIs) are the mainstay of CML treatment, including imatinib, nilotinib, dasatinib, bosutinib, and ponatinib. Beyond matching patient disease profiles with TKI specificity, differences in the efficacy and toxicity profiles and a patient's comorbid risk factors should be considered when selecting the most appropriate agent. Our objectives are to review the incidence and severity of cardiovascular, metabolic, and pulmonary disorders associated with these TKIs, highlighting differences in adverse event profiles, suggested risk-mitigation strategies, and guidance for TKI selection in different settings. Patients receiving TKI agents for CML should be monitored for signs and symptoms of toxicity throughout therapy. Preemptive assessment, early toxicity recognition, and prompt management of cardiovascular, metabolic, and pulmonary toxicities can minimize treatment-limiting complications and improve outcomes in patients with CML. [ABSTRACT FROM AUTHOR]
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- 2018
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18. Effects of Education and Income on Treatment and Outcome in Patients With Acute Myeloid Leukemia in a Tax-Supported Health Care System: A National Population-Based Cohort Study.
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Granfeldt Østgård, Lene Sofie, Nørgaard, Mette, Medeiros, Bruno C., Friis, Lone Smidstrup, Schoellkopf, Claudia, Severinsen, Marianne Tang, Marcher, Claus Werenberg, Nørgaard, Jan Maxwell, and Østgård, Lene Sofie Granfeldt
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- 2017
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19. Genomic landscape of neutrophilic leukemias of ambiguous diagnosis
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Zhang, Haijiao, Wilmot, Beth, Bottomly, Daniel, Dao, Kim-Hien T., Stevens, Emily, Eide, Christopher A., Khanna, Vishesh, Rofelty, Angela, Savage, Samantha, Reister Schultz, Anna, Long, Nicola, White, Libbey, Carlos, Amy, Henson, Rachel, Lin, Chenwei, Searles, Robert, Collins, Robert H., DeAngelo, Daniel J., Deininger, Michael W., Dunn, Tamara, Hein, Than, Luskin, Marlise R., Medeiros, Bruno C., Oh, Stephen T., Pollyea, Daniel A., Steensma, David P., Stone, Richard M., Druker, Brian J., McWeeney, Shannon K., Maxson, Julia E., Gotlib, Jason R., and Tyner, Jeffrey W.
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Chronic neutrophilic leukemia (CNL), atypical chronic myeloid leukemia (aCML), and myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN-U) are a group of rare and heterogeneous myeloid disorders. There is strong morphologic resemblance among these distinct diagnostic entities as well as a lack of specific molecular markers and limited understanding of disease pathogenesis, which has made diagnosis challenging in certain cases. The treatment has remained empirical, resulting in dismal outcomes. We, therefore, performed whole-exome and RNA sequencing of these rare hematologic malignancies and present the most complete survey of the genomic landscape of these diseases to date. We observed a diversity of combinatorial mutational patterns that generally do not cluster within any one diagnosis. Gene expression analysis reveals enrichment, but not cosegregation, of clinical and genetic disease features with transcriptional clusters. In conclusion, these groups of diseases represent a continuum of related diseases rather than discrete diagnostic entities.
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- 2019
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20. Insect egg size and shape evolve with ecology but not developmental rate
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Church, Samuel, Donoughe, Seth, de Medeiros, Bruno, and Extavour, Cassandra
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Over the course of evolution, organism size has diversified markedly. Changes in size are thought to have occurred because of developmental, morphological and/or ecological pressures. To perform phylogenetic tests of the potential effects of these pressures, here we generated a dataset of more than ten thousand descriptions of insect eggs, and combined these with genetic and life-history datasets. We show that, across eight orders of magnitude of variation in egg volume, the relationship between size and shape itself evolves, such that previously predicted global patterns of scaling do not adequately explain the diversity in egg shapes. We show that egg size is not correlated with developmental rate and that, for many insects, egg size is not correlated with adult body size. Instead, we find that the evolution of parasitoidism and aquatic oviposition help to explain the diversification in the size and shape of insect eggs. Our study suggests that where eggs are laid, rather than universal allometric constants, underlies the evolution of insect egg size and shape. Analyses of insect eggs as well as genetic and life-history traits of insects show that where eggs are laid, rather than universal allometric constants, developmental rate or adult body size, underlies size and shape evolution.
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- 2019
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21. Real-World Impact of Physician and Patient Discordance on Health-Related Quality of Life in US Patients with Acute Myeloid Leukemia
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Horvath Walsh, L. Elise, Rider, Alex, Piercy, James, Pike, James, Wilson, Samuel, Pandya, Bhavik J., and Medeiros, Bruno C.
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Introduction: There is limited understanding concerning the health-related quality of life (HRQoL) in acute myeloid leukemia (AML) patients. Due to an overlap of symptoms, it can be difficult to separate disease versus treatment-related effects. Study objectives were to understand the impact of factors that might influence patients’ HRQoL, assess the degree of concordance in symptom reporting by patients and physicians, and assess the impact of any discordance on HRQoL in AML patients. Methods: Physicians in the USA captured demographics, current AML treatment and symptoms for 82 AML patients who completed the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu), 5-Dimension EuroQol Questionnaire (EQ-5D-3L) and Cancer Treatment Satisfaction Questionnaire (CTSQ). Effect size (ES) and clinically meaningful differences between AML subgroups were assessed, as was the impact of disagreement between patients and physicians regarding symptom recognition. Results: Clinically meaningful lower overall FACT-Leu scores were observed for: relapsed/refractory versus non-relapsed/refractory AML patients (92.5 vs. 103.7; P = 0.09; ES = 0.439), hypomethylating agent (HMA) monotherapy versus other therapies in patients with low treatment intensity (89.9 vs. 112.9; P = 0.0021; ES = 0.971) and presence/absence of FLT3-ITD mutation (85.5 vs. 100; P = 0.148; ES = 0.816). Differences in health state were also clinically meaningful between patients with/without FLT3-ITD; EQ-5D-Visual Analog Scale (VAS) (47.6 vs. 63.7; P = 0.0428; ES = 0.816). Patients were more likely than physicians to report bruising (κ= 0.1292), fatigue (κ= 0.0836), bleeding (κ= 0.0177), weight loss (κ= 0.0821) and appetite loss (κ= − 0.0246). FACT-Leu was associated with patient-physician discordance on bleeding (difference − 14.12; P = 0.046), weight loss (− 21.22; P = 0.001) and appetite loss (− 12.58; P = 0.027). Conclusions: HRQoL is generally low for AML patients, especially for particular subgroups. Discordance in symptom reporting between patients and physicians was common and associated with further negative impacts on HRQoL. There may be many reasons for this but better communication between physicians and patients may lead to shared objectives and improvement in patients’ HRQoL. Funding: Astellas Pharma, Inc.
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- 2019
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22. Pracinostat plus azacitidine in older patients with newly diagnosed acute myeloid leukemia: results of a phase 2 study
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Garcia-Manero, Guillermo, Abaza, Yasmin, Takahashi, Koichi, Medeiros, Bruno C., Arellano, Martha, Khaled, Samer K., Patnaik, Mrinal, Odenike, Olatoyosi, Sayar, Hamid, Tummala, Mohan, Patel, Prapti, Maness-Harris, Lori, Stuart, Robert, Traer, Elie, Karamlou, Kasra, Yacoub, Abdulraheem, Ghalie, Richard, Giorgino, Ruben, and Atallah, Ehab
- Abstract
Pracinostat, a potent oral pan-histone deacetylase inhibitor with modest single-agent activity in acute myeloid leukemia (AML), has shown synergistic antitumor activity when combined with azacitidine. This single-group, multicenter phase 2 study assessed the safety and efficacy of pracinostat combined with azacitidine in patients who were at least 65 years old with newly diagnosed AML and who were ineligible for standard induction chemotherapy. Patients received pracinostat 60 mg/d, 3 d/wk, for 3 consecutive weeks, plus azacitidine 75 mg/m2 daily for 7 days in a 28-day cycle. Primary endpoints were complete remission (CR), CR with incomplete count recovery (CRi), and morphologic leukemia-free state (MLFS) rates of the combination. Secondary endpoints included safety, progression-free survival (PFS), and overall survival (OS) of the regimen. Fifty patients (33 de novo, 12 secondary, and 5 therapy-related AML) were enrolled. Twenty-six patients (52%) achieved the primary endpoint of CR (42%), CRi (4%), and MLFS (6%). Median OS and PFS were 19.1 months (95% confidence interval [CI], 10-26.5 months) and 12.6 months (95% CI, 10-17.7 months), respectively, with a 1-year OS rate of 62%. Forty-three patients (86%) experienced at least 1 grade 3 or worse treatment-emergent adverse event with the combination, with infections (52%), thrombocytopenia (46%), and febrile neutropenia (44%) reported as the most common toxicities. The 30- and 60-day all-cause mortality rates were 2% and 10%, respectively. DNA sequencing revealed somatic mutations at baseline, and clearance rates correlated with response to treatment. Pracinostat plus azacitidine is a well-tolerated and active regimen in the frontline treatment of older patients with AML unfit for intensive therapy. A larger controlled trial is ongoing. This trial was registered at www.clinicaltrials.gov as #NCT01912274.
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- 2019
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23. Pracinostat plus azacitidine in older patients with newly diagnosed acute myeloid leukemia: results of a phase 2 study
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Garcia-Manero, Guillermo, Abaza, Yasmin, Takahashi, Koichi, Medeiros, Bruno C., Arellano, Martha, Khaled, Samer K., Patnaik, Mrinal, Odenike, Olatoyosi, Sayar, Hamid, Tummala, Mohan, Patel, Prapti, Maness-Harris, Lori, Stuart, Robert, Traer, Elie, Karamlou, Kasra, Yacoub, Abdulraheem, Ghalie, Richard, Giorgino, Ruben, and Atallah, Ehab
- Abstract
Pracinostat, a potent oral pan-histone deacetylase inhibitor with modest single-agent activity in acute myeloid leukemia (AML), has shown synergistic antitumor activity when combined with azacitidine. This single-group, multicenter phase 2 study assessed the safety and efficacy of pracinostat combined with azacitidine in patients who were at least 65 years old with newly diagnosed AML and who were ineligible for standard induction chemotherapy. Patients received pracinostat 60 mg/d, 3 d/wk, for 3 consecutive weeks, plus azacitidine 75 mg/m2daily for 7 days in a 28-day cycle. Primary endpoints were complete remission (CR), CR with incomplete count recovery (CRi), and morphologic leukemia-free state (MLFS) rates of the combination. Secondary endpoints included safety, progression-free survival (PFS), and overall survival (OS) of the regimen. Fifty patients (33 de novo, 12 secondary, and 5 therapy-related AML) were enrolled. Twenty-six patients (52%) achieved the primary endpoint of CR (42%), CRi (4%), and MLFS (6%). Median OS and PFS were 19.1 months (95% confidence interval [CI], 10-26.5 months) and 12.6 months (95% CI, 10-17.7 months), respectively, with a 1-year OS rate of 62%. Forty-three patients (86%) experienced at least 1 grade 3 or worse treatment-emergent adverse event with the combination, with infections (52%), thrombocytopenia (46%), and febrile neutropenia (44%) reported as the most common toxicities. The 30- and 60-day all-cause mortality rates were 2% and 10%, respectively. DNA sequencing revealed somatic mutations at baseline, and clearance rates correlated with response to treatment. Pracinostat plus azacitidine is a well-tolerated and active regimen in the frontline treatment of older patients with AML unfit for intensive therapy. A larger controlled trial is ongoing. This trial was registered at www.clinicaltrials.govas #NCT01912274.
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- 2019
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24. CD25 Targeting Eliminates Regulatory T Cells and CD25+ Blasts in Acute Myeloid Leukemia
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Pousse, Laurene, Medeiros, Bruno C., Korfi, Koorosh, Berrera, Marco, Kumpesa, Nadine, Griesser, Vera, Eckmann, Jan, Karanikas, Vaios, Klein, Christian, and Amann, Maria
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- 2022
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25. CD25 Targeting Eliminates Regulatory T Cells and CD25+ Blasts in Acute Myeloid Leukemia
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Pousse, Laurene, Medeiros, Bruno C., Korfi, Koorosh, Berrera, Marco, Kumpesa, Nadine, Griesser, Vera, Eckmann, Jan, Karanikas, Vaios, Klein, Christian, and Amann, Maria
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- 2022
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26. FATORES DE INTERESSE PELA ÁREA FINANCEIRA: UMA AVALIAÇÃO COM ESTUDANTES DE ENSINO SUPERIOR EM ADMINISTRAÇÃO.
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de Paula, Cristiane Evelyn, Franco Danjour, Miler, Campelo Medeiros, Bruno, and Moreno Añez, Miguel Eduardo
- Abstract
Copyright of Revista de Administraçãao da UNIMEP is the property of Revista de Administracao da UNIMEP and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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- 2017
27. Is there a standard of care for relapsed AML?
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Medeiros, Bruno C.
- Abstract
Abstract Despite advances in treatment for acute myeloid leukemia (AML), the prognosis for patients with relapsed disease is extremely poor. The median overall survival for patients with relapsed AML ranges from 4–6 months and long-term survival from the time of relapse ranges from 5%–20%. Much of the difficulty in establishing a standard of care for relapsed AML is that the disease is clinically and genomically diverse. Nevertheless, significant progress has been made over the past 12 months with the approval of several agents, and the expectation is that additional therapies will be available soon. A brief review follows on the progress made in establishing a standard of care for relapsed AML. [ABSTRACT FROM AUTHOR]
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- 2018
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28. Functional genomic landscape of acute myeloid leukaemia
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Tyner, Jeffrey W., Tognon, Cristina E., Bottomly, Daniel, Wilmot, Beth, Kurtz, Stephen E., Savage, Samantha L., Long, Nicola, Schultz, Anna Reister, Traer, Elie, Abel, Melissa, Agarwal, Anupriya, Blucher, Aurora, Borate, Uma, Bryant, Jade, Burke, Russell, Carlos, Amy, Carpenter, Richie, Carroll, Joseph, Chang, Bill H., Coblentz, Cody, d’Almeida, Amanda, Cook, Rachel, Danilov, Alexey, Dao, Kim-Hien T., Degnin, Michie, Devine, Deirdre, Dibb, James, Edwards, David K., Eide, Christopher A., English, Isabel, Glover, Jason, Henson, Rachel, Ho, Hibery, Jemal, Abdusebur, Johnson, Kara, Johnson, Ryan, Junio, Brian, Kaempf, Andy, Leonard, Jessica, Lin, Chenwei, Liu, Selina Qiuying, Lo, Pierrette, Loriaux, Marc M., Luty, Samuel, Macey, Tara, MacManiman, Jason, Martinez, Jacqueline, Mori, Motomi, Nelson, Dylan, Nichols, Ceilidh, Peters, Jill, Ramsdill, Justin, Rofelty, Angela, Schuff, Robert, Searles, Robert, Segerdell, Erik, Smith, Rebecca L., Spurgeon, Stephen E., Sweeney, Tyler, Thapa, Aashis, Visser, Corinne, Wagner, Jake, Watanabe-Smith, Kevin, Werth, Kristen, Wolf, Joelle, White, Libbey, Yates, Amy, Zhang, Haijiao, Cogle, Christopher R., Collins, Robert H., Connolly, Denise C., Deininger, Michael W., Drusbosky, Leylah, Hourigan, Christopher S., Jordan, Craig T., Kropf, Patricia, Lin, Tara L., Martinez, Micaela E., Medeiros, Bruno C., Pallapati, Rachel R., Pollyea, Daniel A., Swords, Ronan T., Watts, Justin M., Weir, Scott J., Wiest, David L., Winters, Ryan M., McWeeney, Shannon K., and Druker, Brian J.
- Abstract
The implementation of targeted therapies for acute myeloid leukaemia (AML) has been challenging because of the complex mutational patterns within and across patients as well as a dearth of pharmacologic agents for most mutational events. Here we report initial findings from the Beat AML programme on a cohort of 672 tumour specimens collected from 562 patients. We assessed these specimens using whole-exome sequencing, RNA sequencing and analyses of ex vivo drug sensitivity. Our data reveal mutational events that have not previously been detected in AML. We show that the response to drugs is associated with mutational status, including instances of drug sensitivity that are specific to combinatorial mutational events. Integration with RNA sequencing also revealed gene expression signatures, which predict a role for specific gene networks in the drug response. Collectively, we have generated a dataset—accessible through the Beat AML data viewer (Vizome)—that can be leveraged to address clinical, genomic, transcriptomic and functional analyses of the biology of AML.
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- 2018
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29. Associations between cohabitation status, treatment, and outcome in AML patients: a national population-based study
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Østgård, Lene Sofie Granfeldt, Nørgaard, Mette, Medeiros, Bruno C., Severinsen, Marianne Tang, Friis, Lone Smidstrup, Marcher, Claus Werenberg, Schoellkopf, Claudia, and Nørgaard, Jan Maxwell
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- 2018
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30. Development and Validation of a Novel Acute Myeloid Leukemia–Composite Model to Estimate Risks of Mortality
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Sorror, Mohamed L., Storer, Barry E., Fathi, Amir T., Gerds, Aaron T., Medeiros, Bruno C., Shami, Paul, Brunner, Andrew M., Sekeres, Mikkael A., Mukherjee, Sudipto, Peña, Esteban, Elsawy, Mahmoud, Wardyn, Shylo, Whitten, Jennifer, Moore, Rachelle, Becker, Pamela S., McCune, Jeannine S., Appelbaum, Frederick R., and Estey, Elihu H.
- Abstract
IMPORTANCE: To our knowledge, this multicenter analysis is the first to test and validate (1) the prognostic impact of comorbidities on 1-year mortality after initial therapy of acute myeloid leukemia (AML) and (2) a novel, risk-stratifying composite model incorporating comorbidities, age, and cytogenetic and molecular risks. OBJECTIVE: To accurately estimate risks of mortality by developing and validating a composite model that combines the most significant patient-specific and AML-specific features. DESIGN, SETTING, AND PARTICIPANTS: This is a retrospective cohort study. A series of comorbidities, including those already incorporated into the hematopoietic cell transplantation–comorbidity index (HCT-CI), were evaluated. Patients were randomly divided into a training set (n = 733) and a validation set (n = 367). In the training set, covariates associated with 1-year overall mortality at a significance level of P < .10 constructed a multivariate Cox proportional hazards model in which the impact of each covariate was adjusted for that of all others. Then, the adjusted hazard ratios were used as weights. Performances of models were compared using C statistics for continuous outcomes and area under the curve (AUC) for binary outcomes. EXPOSURES: Initial therapy for AML. MAIN OUTCOMES AND MEASURES: Death within 1 year after initial therapy for AML. RESULTS: A total of 1100 patients, ages 20 to 89 years, were treated for AML between January 1, 2008, and December 31, 2012, at 5 academic institutions specialized in treating AML; 605 (55%) were male, and 495 (45%) were female. In the validation set, the original HCT-CI had better C statistic and AUC estimates compared with the AML comorbidity index for prediction of 1-year mortality. Augmenting the original HCT-CI with 3 independently significant comorbidities, hypoalbuminemia, thrombocytopenia, and high lactate dehydrogenase level, yielded a better C statistic of 0.66 and AUC of 0.69 for 1-year mortality. A composite model comprising augmented HCT-CI, age, and cytogenetic/molecular risks had even better predictive estimates of 0.72 and 0.76, respectively. CONCLUSIONS AND RELEVANCE: In this cohort study, comorbidities influenced 1-year survival of patients with AML, and comorbidities are best captured by an augmented HCT-CI. The augmented HCT-CI, age, and cytogenetic/molecular risks could be combined into an AML composite model that could guide treatment decision-making and trial design in AML. Studying physical, cognitive, and social health might further clarify the prognostic role of aging. Targeting comorbidities with interventions alongside specific AML therapy might improve survival.
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- 2017
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31. Epidemiology and Clinical Significance of Secondary and Therapy-Related Acute Myeloid Leukemia: A National Population-Based Cohort Study.
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Østgård, Lene Sofie Granfeldt, Medeiros, Bruno C., Sengeløv, Henrik, Nørgaard, Mette, Andersen, Mette Klarskov, Dufva, Inge Høgh, Friis, Lone Smidstrup, Kjeldsen, Eigil, Marcher, Claus Werenberg, Preiss, Birgitte, Severinsen, Marianne, Nørgaard, Jan Maxwell, and Granfeldt Østgård, Lene Sofie
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- 2015
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32. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia
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Stein, Eytan M., DiNardo, Courtney D., Pollyea, Daniel A., Fathi, Amir T., Roboz, Gail J., Altman, Jessica K., Stone, Richard M., DeAngelo, Daniel J., Levine, Ross L., Flinn, Ian W., Kantarjian, Hagop M., Collins, Robert, Patel, Manish R., Frankel, Arthur E., Stein, Anthony, Sekeres, Mikkael A., Swords, Ronan T., Medeiros, Bruno C., Willekens, Christophe, Vyas, Paresh, Tosolini, Alessandra, Xu, Qiang, Knight, Robert D., Yen, Katharine E., Agresta, Sam, de Botton, Stephane, and Tallman, Martin S.
- Abstract
Recurrent mutations in isocitrate dehydrogenase 2 (IDH2) occur in ∼12% of patients with acute myeloid leukemia (AML). Mutated IDH2 proteins neomorphically synthesize 2-hydroxyglutarate resulting in DNA and histone hypermethylation, which leads to blocked cellular differentiation. Enasidenib (AG-221/CC-90007) is a first-in-class, oral, selective inhibitor of mutant-IDH2 enzymes. This first-in-human phase 1/2 study assessed the maximum tolerated dose (MTD), pharmacokinetic and pharmacodynamic profiles, safety, and clinical activity of enasidenib in patients with mutant-IDH2 advanced myeloid malignancies. We assessed safety outcomes for all patients and clinical efficacy in the largest patient subgroup, those with relapsed or refractory AML, from the phase 1 dose-escalation and expansion phases of the study. In the dose-escalation phase, an MTD was not reached at doses ranging from 50 to 650 mg per day. Enasidenib 100 mg once daily was selected for the expansion phase on the basis of pharmacokinetic and pharmacodynamic profiles and demonstrated efficacy. Grade 3 to 4 enasidenib-related adverse events included indirect hyperbilirubinemia (12%) and IDH-inhibitor–associated differentiation syndrome (7%). Among patients with relapsed or refractory AML, overall response rate was 40.3%, with a median response duration of 5.8 months. Responses were associated with cellular differentiation and maturation, typically without evidence of aplasia. Median overall survival among relapsed/refractory patients was 9.3 months, and for the 34 patients (19.3%) who attained complete remission, overall survival was 19.7 months. Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib. This trial was registered at www.clinicaltrials.gov as #NCT01915498.
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- 2017
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33. Enasidenib in mutant IDH2relapsed or refractory acute myeloid leukemia
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Stein, Eytan M., DiNardo, Courtney D., Pollyea, Daniel A., Fathi, Amir T., Roboz, Gail J., Altman, Jessica K., Stone, Richard M., DeAngelo, Daniel J., Levine, Ross L., Flinn, Ian W., Kantarjian, Hagop M., Collins, Robert, Patel, Manish R., Frankel, Arthur E., Stein, Anthony, Sekeres, Mikkael A., Swords, Ronan T., Medeiros, Bruno C., Willekens, Christophe, Vyas, Paresh, Tosolini, Alessandra, Xu, Qiang, Knight, Robert D., Yen, Katharine E., Agresta, Sam, de Botton, Stephane, and Tallman, Martin S.
- Abstract
Recurrent mutations in isocitrate dehydrogenase 2 (IDH2) occur in ∼12% of patients with acute myeloid leukemia (AML). Mutated IDH2 proteins neomorphically synthesize 2-hydroxyglutarate resulting in DNA and histone hypermethylation, which leads to blocked cellular differentiation. Enasidenib (AG-221/CC-90007) is a first-in-class, oral, selective inhibitor of mutant-IDH2 enzymes. This first-in-human phase 1/2 study assessed the maximum tolerated dose (MTD), pharmacokinetic and pharmacodynamic profiles, safety, and clinical activity of enasidenib in patients with mutant-IDH2advanced myeloid malignancies. We assessed safety outcomes for all patients and clinical efficacy in the largest patient subgroup, those with relapsed or refractory AML, from the phase 1 dose-escalation and expansion phases of the study. In the dose-escalation phase, an MTD was not reached at doses ranging from 50 to 650 mg per day. Enasidenib 100 mg once daily was selected for the expansion phase on the basis of pharmacokinetic and pharmacodynamic profiles and demonstrated efficacy. Grade 3 to 4 enasidenib-related adverse events included indirect hyperbilirubinemia (12%) and IDH-inhibitor–associated differentiation syndrome (7%). Among patients with relapsed or refractory AML, overall response rate was 40.3%, with a median response duration of 5.8 months. Responses were associated with cellular differentiation and maturation, typically without evidence of aplasia. Median overall survival among relapsed/refractory patients was 9.3 months, and for the 34 patients (19.3%) who attained complete remission, overall survival was 19.7 months. Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib. This trial was registered at www.clinicaltrials.govas #NCT01915498.
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- 2017
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34. Identification of Interleukin-1 by Functional Screening as a Key Mediator of Cellular Expansion and Disease Progression in Acute Myeloid Leukemia
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Carey, Alyssa, Edwards, David K., Eide, Christopher A., Newell, Laura, Traer, Elie, Medeiros, Bruno C., Pollyea, Daniel A., Deininger, Michael W., Collins, Robert H., Tyner, Jeffrey W., Druker, Brian J., Bagby, Grover C., McWeeney, Shannon K., and Agarwal, Anupriya
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Secreted proteins in the bone marrow microenvironment play critical roles in acute myeloid leukemia (AML). Through an ex vivo functional screen of 94 cytokines, we identified that the pro-inflammatory cytokine interleukin-1 (IL-1) elicited profound expansion of myeloid progenitors in ∼67% of AML patients while suppressing the growth of normal progenitors. Levels of IL-1β and IL-1 receptors were increased in AML patients, and silencing of the IL-1 receptor led to significant suppression of clonogenicity and in vivo disease progression. IL-1 promoted AML cell growth by enhancing p38MAPK phosphorylation and promoting secretion of various other growth factors and inflammatory cytokines. Treatment with p38MAPK inhibitors reversed these effects and recovered normal CD34+cells from IL-1-mediated growth suppression. These results highlight the importance of ex vivo functional screening to identify common and actionable extrinsic pathways in genetically heterogeneous malignancies and provide impetus for clinical development of IL-1/IL1R1/p38MAPK pathway-targeted therapies in AML.
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- 2017
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35. Streetlights attract a broad array of beetle species
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de Medeiros, Bruno Augusto Souza, Barghini, Alessandro, and Vanin, Sergio Antonio
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Light pollution on ecosystems is a growing concern, and knowledge about the effects of outdoor lighting on organisms is crucial to understand and mitigate impacts. Here we build up on a previous study to characterize the diversity of all beetles attracted to different commonly used streetlight set ups. We find that lights attract beetles from a broad taxonomic and ecological spectrum. Lights that attract a large number of insect individuals draw an equally high number of insect species. While there is some evidence for heterogeneity in the preference of beetle species to different kinds of light, all species are more attracted to some light radiating ultraviolet. The functional basis of this heterogeneity, however, is not clear. Our results highlight that control of ultraviolet radiation in public lighting is important to reduce the number and diversity of insects attracted to lights.
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- 2017
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36. Increased plasma D-2-hydroxyglutarate in isocitrate dehydrogenase 2–mutated blastic plasmacytoid dendritic cell neoplasm.
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Rakheja, Dinesh, Fuda, Franklin, Vandergriff, Travis, Boriack, Richard, Medeiros, Bruno C., Frankel, Arthur E., and Weina Chen
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- 2015
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37. The inclusion of migrants in health impact assessments: A scoping review.
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Benkhalti Jandu, Maria, Canuto de Medeiros, Bruno, Bourgeault, Ivy, and Tugwell, Peter
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HEALTH impact assessment ,ENVIRONMENTAL impact analysis ,IMMIGRANTS ,ENVIRONMENTAL research ,STAKEHOLDERS ,ENVIRONMENTAL protection - Abstract
This article reports the findings of a scoping review assessing the extent and ways in which migrants have been included in health impact assessments (HIAs) and HIA evaluations worldwide. A total of 117 HIAs and two HIA evaluations were included. Only 14% of hand-searched HIAs mentioned migrants, 5% analysed migrants and only 2% included them in their recommendations. Nonetheless, migrants would be expected to be part of the analysis based on the reasons for which migrants were most commonly mentioned. Although the majority of HIAs included in the review mentioned migrants in baseline conditions and impact analysis steps, migrants were seldom included in recommendations. Furthermore, the use of frameworks or tools guiding the completion of an HIA was negatively associated with the inclusion of migrants in recommendations. This is a pivotal risk of frameworks not mentioning migrants. Although workshops and stakeholder engagement were a frequent way of including migrants in HIAs, this usually involved organizations representing migrants, and only seldom included members of the migrant community themselves. The main barriers to including migrants in the HIA impact analysis were the lack of available data on migrants and the significant additional resources required to gather and analyse additional data on migrants. Guidance is needed on ways to optimally include migrants in HIAs and ensure that recommendations for mitigation measures are optimal. [ABSTRACT FROM AUTHOR]
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- 2015
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38. Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies
- Author
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Lewinsohn, Maya, Brown, Anna L., Weinel, Luke M., Phung, Connie, Rafidi, George, Lee, Ming K., Schreiber, Andreas W., Feng, Jinghua, Babic, Milena, Chong, Chan-Eng, Lee, Young, Yong, Agnes, Suthers, Graeme K., Poplawski, Nicola, Altree, Meryl, Phillips, Kerry, Jaensch, Louise, Fine, Miriam, D’Andrea, Richard J., Lewis, Ian D., Medeiros, Bruno C., Pollyea, Daniel A., King, Mary-Claire, Walsh, Tom, Keel, Siobán, Shimamura, Akiko, Godley, Lucy A., Hahn, Christopher N., Churpek, Jane E., and Scott, Hamish S.
- Abstract
Recently our group and others have identified DDX41 mutations both as germ line and acquired somatic mutations in families with multiple cases of late onset myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML), suggesting that DDX41 acts as a tumor suppressor. To determine whether novel DDX41 mutations could be identified in families with additional types of hematologic malignancies, our group screened two cohorts of families with a diverse range of hematologic malignancy subtypes. Among 289 families, we identified nine (3%) with DDX41 mutations. As previously observed, MDS and AML were the most common malignancies, often of the erythroblastic subtype, and 1 family displayed early-onset follicular lymphoma. Five novel mutations were identified, including missense mutations within important functional domains and start-loss and splicing mutations predicted to result in truncated proteins. We also show that most asymptomatic mutation carriers have normal blood counts until malignancy develops. This study expands both the mutation and phenotypic spectra observed in families with germ line DDX41 mutations. With an increasing number of both inherited and acquired mutations in this gene being identified, further study of how DDX41 disruption leads to hematologic malignancies is critical.
- Published
- 2016
- Full Text
- View/download PDF
39. Novel germ line DDX41mutations define families with a lower age of MDS/AML onset and lymphoid malignancies
- Author
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Lewinsohn, Maya, Brown, Anna L., Weinel, Luke M., Phung, Connie, Rafidi, George, Lee, Ming K., Schreiber, Andreas W., Feng, Jinghua, Babic, Milena, Chong, Chan-Eng, Lee, Young, Yong, Agnes, Suthers, Graeme K., Poplawski, Nicola, Altree, Meryl, Phillips, Kerry, Jaensch, Louise, Fine, Miriam, D'Andrea, Richard J., Lewis, Ian D., Medeiros, Bruno C., Pollyea, Daniel A., King, Mary-Claire, Walsh, Tom, Keel, Siobán, Shimamura, Akiko, Godley, Lucy A., Hahn, Christopher N., Churpek, Jane E., and Scott, Hamish S.
- Abstract
Recently our group and others have identified DDX41mutations both as germ line and acquired somatic mutations in families with multiple cases of late onset myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML), suggesting that DDX41 acts as a tumor suppressor. To determine whether novel DDX41mutations could be identified in families with additional types of hematologic malignancies, our group screened two cohorts of families with a diverse range of hematologic malignancy subtypes. Among 289 families, we identified nine (3%) with DDX41mutations. As previously observed, MDS and AML were the most common malignancies, often of the erythroblastic subtype, and 1 family displayed early-onset follicular lymphoma. Five novel mutations were identified, including missense mutations within important functional domains and start-loss and splicing mutations predicted to result in truncated proteins. We also show that most asymptomatic mutation carriers have normal blood counts until malignancy develops. This study expands both the mutation and phenotypic spectra observed in families with germ line DDX41mutations. With an increasing number of both inherited and acquired mutations in this gene being identified, further study of how DDX41 disruption leads to hematologic malignancies is critical.
- Published
- 2016
- Full Text
- View/download PDF
40. Non-zero-sum game of transfusions: EOL in leukemia
- Author
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Medeiros, Bruno C.
- Published
- 2018
- Full Text
- View/download PDF
41. Non-zero-sum game of transfusions: EOL in leukemia
- Author
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Medeiros, Bruno C.
- Published
- 2018
- Full Text
- View/download PDF
42. New treatment approaches for older adults with multiple myeloma.
- Author
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Wildes, Tanya M., Vij, Ravi, Petersdorf, Stephen H., Medeiros, Bruno C., and Hurria, Arti
- Subjects
MULTIPLE myeloma treatment ,OLDER people ,PREDNISONE ,META-analysis ,THALIDOMIDE ,RANDOMIZED controlled trials - Abstract
Abstract: The incidence of multiple myeloma (MM) increases with age, and with the aging of the population, the number of adults with MM is expected to double in the next 20years. Novel agents, including the immunomodulatory agents thalidomide and lenalidomide, and the proteosome inhibitor bortezomib have dramatically changed the treatment of multiple myeloma in the past decade. The purpose of this review was to examine the recent clinical therapeutic trials in older adults with MM. A number of trials have evaluated the addition of novel agents to the traditional backbone of melphalan and prednisone. The combination of thalidomide with melphalan and prednisone has been evaluated in 7 randomized trials. The combination improves response rates and, in meta-analyses, survival, but at the expense of increased toxicity. Other combination regimens that include lenalidomide or bortezomib likewise are associated with higher response rates, but at the expense of greater toxicity. High dose dexamethasone is excessively toxic in older adults and should be avoided. The roles for high-dose therapy with autologous stem cell transplant or intermediate-dose melphalan with autologous stem cell transplant in older adults with MM in the era of modern therapy remain to be defined. In summary, there are a number of new therapeutic options for older adults with MM, allowing an individualized treatment strategy based on the patient''s comorbidities and goals of care. [Copyright &y& Elsevier]
- Published
- 2012
- Full Text
- View/download PDF
43. ASPECTGRID: ASPECT-ORIENTED FAULT-TOLERANCE IN GRID PLATFORMS.
- Author
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Medeiros, Bruno and Sobral, João
- Subjects
GRID computing ,COMPUTER programming ,COMPUTER programmers ,ASPECT-oriented programming ,COMPUTER systems ,DISTRIBUTED computing - Abstract
Migrating traditional scientific applications to computational Grids requires programming tools that can help programmers update application behaviour to this kind of platforms. Computational Grids are particularly suited for long running scientific applications, but they are also more prone to faults than desktop machines. The AspectGrid framework aims to develop methodologies and tools that can help Grid-enable scientific applications, particularly focusing on techniques based on aspect-oriented programming. In this paper we present the aspect-oriented approach taken in the AspectGrid framework to address faults in computational Grids. In the proposed approach, scientific applications are enhanced with fault-tolerance capability by plugging additional modules. The proposed technique is portable across operating systems and minimises the changes required to base applications. [ABSTRACT FROM AUTHOR]
- Published
- 2012
44. Reacqua: A low-cost solar still system for the removal of antibiotics from contaminated effluents.
- Author
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Hoff, Rodrigo, Vogelmann, Eduardo Saldanha, Zapelini de Melo, Ana Paula, Deolindo, Carolina Turnes Pasini, Medeiros, Bruno Miguel de Souza, and Daguer, Heitor
- Subjects
SOLAR system ,ANTIBIOTICS ,OXYTETRACYCLINE ,SOLAR stills ,SEWAGE disposal plants ,ZONING ,WATER pollution ,BODIES of water - Abstract
The use of antibiotics in intensive animal production and human medical treatment can result in a significant discharge of those drugs and its transformation products in faeces and urine that contaminate water bodies. The effluents produced by poultry and pig production plants are often discharged without any treatment in the environment. These effluents can contain high levels of active drugs and several by-products. The contamination of water sources with these contaminants is of emerging concern for human health and the environment. The search for treatment processes capable of removing antibiotics from water is an urgent need, especially in rural zones that lack of wastewater treatment plants. A solar still system was used for removal and degradation of a mixture of several veterinary antibiotics widely used in poultry and pig intensive production. Water samples (10 L) containing enrofloxacin, oxytetracycline, sulfadimethoxine, sulfaquinoxaline, sulfamethazine, and sulfamethoxazole within the concentration range of 20–500 mg L
−1 were processed in the system. The experiment was carried out in filed conditions in duplicate (Summer and Winter). The occurrence of transformation products was also investigated to elucidate the degradation pathways. The system was able to remove antibiotics in a range from 99.73% to more than 99.99%. [Display omitted] • A simple and cheap solar still system was used to remove antibiotics from water. • Water containing high levels of 6 veterinary antibiotics were decontaminated. • All experiments were done in real field conditions with commercial products. • The occurrence of transformation products was also investigated. • The system was able to remove antibiotics from 99.73% to than 99.99%. [ABSTRACT FROM AUTHOR]- Published
- 2021
- Full Text
- View/download PDF
45. Activity of SL-401, a targeted therapy directed to interleukin-3 receptor, in blastic plasmacytoid dendritic cell neoplasm patients
- Author
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Frankel, Arthur E., Woo, Jung H., Ahn, Chul, Pemmaraju, Naveen, Medeiros, Bruno C., Carraway, Hetty E., Frankfurt, Olga, Forman, Stephen J., Yang, Xuezhong A., Konopleva, Marina, Garnache-Ottou, Francine, Angelot-Delettre, Fanny, Brooks, Christopher, Szarek, Michael, and Rowinsky, Eric
- Abstract
This is the first prospective study of treatment of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive hematologic malignancy derived from plasmacytoid dendritic cells that typically involves the skin and rapidly progresses to a leukemia phase. Despite being initially responsive to intensive combination chemotherapy, most patients relapse and succumb to their disease. Because BPDCN blasts overexpress the interleukin-3 receptor (IL3R), the activity of SL-401, diptheria toxin (DT)388IL3 composed of the catalytic and translocation domains of DT fused to IL3, was evaluated in BPDCN patients in a phase 1-2 study. Eleven patients were treated with a single course of SL-401 at 12.5 μg/kg intravenously over 15 minutes daily for up to 5 doses; 3 patients who had initial responses to SL-401 received a second course in relapse. The most common adverse events including fever, chills, hypotension, edema, hypoalbuminemia, thrombocytopenia, and transaminasemia were transient. Seven of 9 evaluable (78%) BPDCN patients had major responses including 5 complete responses and 2 partial responses after a single course of SL-401. The median duration of responses was 5 months (range, 1-20+ months). Further studies of SL-401 in BPDCN including those involving multiple sequential courses, alternate schedules, and combinations with other therapeutics are warranted. This trial is registered at clinicaltrials.gov as #NCT00397579.
- Published
- 2014
- Full Text
- View/download PDF
46. Activity of SL-401, a targeted therapy directed to interleukin-3 receptor, in blastic plasmacytoid dendritic cell neoplasm patients
- Author
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Frankel, Arthur E., Woo, Jung H., Ahn, Chul, Pemmaraju, Naveen, Medeiros, Bruno C., Carraway, Hetty E., Frankfurt, Olga, Forman, Stephen J., Yang, Xuezhong A., Konopleva, Marina, Garnache-Ottou, Francine, Angelot-Delettre, Fanny, Brooks, Christopher, Szarek, Michael, and Rowinsky, Eric
- Abstract
This is the first prospective study of treatment of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive hematologic malignancy derived from plasmacytoid dendritic cells that typically involves the skin and rapidly progresses to a leukemia phase. Despite being initially responsive to intensive combination chemotherapy, most patients relapse and succumb to their disease. Because BPDCN blasts overexpress the interleukin-3 receptor (IL3R), the activity of SL-401, diptheria toxin (DT)388IL3 composed of the catalytic and translocation domains of DT fused to IL3, was evaluated in BPDCN patients in a phase 1-2 study. Eleven patients were treated with a single course of SL-401 at 12.5 βg/kg intravenously over 15 minutes daily for up to 5 doses; 3 patients who had initial responses to SL-401 received a second course in relapse. The most common adverse events including fever, chills, hypotension, edema, hypoalbuminemia, thrombocytopenia, and transaminasemia were transient. Seven of 9 evaluable (78%) BPDCN patients had major responses including 5 complete responses and 2 partial responses after a single course of SL-401. The median duration of responses was 5 months (range, 1-20+ months). Further studies of SL-401 in BPDCN including those involving multiple sequential courses, alternate schedules, and combinations with other therapeutics are warranted. This trial is registered at clinicaltrials.govas #NCT00397579.
- Published
- 2014
- Full Text
- View/download PDF
47. Aggressive EBV-associated Lymphoproliferative Disorder
- Author
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Batra, Rashmi, Medeiros, Bruno C., Zehnder, James L., Warnke, Roger A., and Natkunam, Yasodha
- Abstract
A 19-year-old male patient presented with intermittent high fever and left cervical lymphadenopathy. The lymph node biopsy findings were interpreted as “Epstein-Barr virus (EBV)-associated lymphoproliferative disorder consistent with infectious mononucleosis.” No molecular studies were performed at that time. The patient was followed without treatment. Five months later, the patient again presented with fever, lymphadenopathy, and splenomegaly. The lymph node biopsy showed features of a diffuse large B-cell lymphoma. Molecular studies on this lymph node biopsy showed a clonal EBV population, although polymerase chain reaction studies failed to reveal a clonal B-cell or T-cell population. A concurrent bone marrow biopsy showed features consistent with hemophagocytic syndrome. He had elevated ferritin, soluble interleukin-2 receptors and persistent EBV viremia. The patient responded to Rituxan for a short period with undetectable EBV levels. Subsequent right cervical lymph node, liver, and jejunal biopsies showed involvement by diffuse large B-cell lymphoma and the patient expired soon thereafter.
- Published
- 2012
- Full Text
- View/download PDF
48. Targeting protein neddylation: a novel therapeutic strategy for the treatment of cancer
- Author
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Wang, Meng, Medeiros, Bruno C, Erba, Harry P, DeAngelo, Daniel J, Giles, Francis J, and Swords, Ronan T
- Abstract
Introduction:The NEDD8 (neural precursor cell-expressed developmentally downregulated 8) conjugation pathway regulates the post-translational modification of oncogenic proteins. This pathway has important potential for cancer therapeutics. Several proteins vital in cancer biology are regulated by protein neddylation. These observations led to the development of a small molecule inhibitor that disrupts protein neddylation and leads to cancer cell death and important activity in early phase clinical trials.Areas covered:This review provides an extensive coverage of cellular protein homeostasis with particular emphasis on the NEDD8 conjugation pathway. Insights into a new investigational drug that specifically disrupts the NEDD8 pathway are discussed. The clinical data for this agent are also updated.Expert opinion:Neddylation controls key cellular pathways found to be dysregulated in many cancers. Protein neddylation is a relatively under-explored pathway for pharmacologic inhibition in cancer. Selective disruption of this pathway has demonstrated clinical activity in patients with myeloid neoplasms and is worth exploring further in combination with other anti-leukemia agents.
- Published
- 2011
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- View/download PDF
49. Prognostic impact of monosomal karyotype in young adult and elderly acute myeloid leukemia: the Southwest Oncology Group (SWOG) experience
- Author
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Medeiros, Bruno C., Othus, Megan, Fang, Min, Roulston, Diane, and Appelbaum, Frederick R.
- Abstract
Monosomal karyotype (MK), defined as 2 or more monosomies, or a single monosomy in the presence of structural abnormalities, has recently been reported as identifying a distinct subset of acute myeloid leukemia (AML) patients with an extremely poor prognosis. In an effort to confirm this observation, we analyzed the prognostic impact of MK in 1344 AML patients between the ages of 16 and 88 years treated on Southwest Oncology Group protocols. MK was found in 176 (13%) patients. The proportion of patients with MK increased with age, being present in 4% of patients age 30 or younger, but in 20% of those over age 60. Ninety-eight percent of MK cases were within the unfavorable cytogenetic risk category and comprised 40% of this group. The complete remission rate in patients with unfavorable cytogenetics without MK was 34% versus 18% with MK (P< .01). The 4-year overall survival of patients with unfavorable cytogenetics but without MK was 13% in contrast to a 4-year survival of only 3% with MK (P< .01). Thus, MK defines a sizeable subset of patients with unfavorable cytogenetics who have a particularly poor prognosis.
- Published
- 2010
- Full Text
- View/download PDF
50. Prognostic impact of monosomal karyotype in young adult and elderly acute myeloid leukemia: the Southwest Oncology Group (SWOG) experience
- Author
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Medeiros, Bruno C., Othus, Megan, Fang, Min, Roulston, Diane, and Appelbaum, Frederick R.
- Abstract
Monosomal karyotype (MK), defined as 2 or more monosomies, or a single monosomy in the presence of structural abnormalities, has recently been reported as identifying a distinct subset of acute myeloid leukemia (AML) patients with an extremely poor prognosis. In an effort to confirm this observation, we analyzed the prognostic impact of MK in 1344 AML patients between the ages of 16 and 88 years treated on Southwest Oncology Group protocols. MK was found in 176 (13%) patients. The proportion of patients with MK increased with age, being present in 4% of patients age 30 or younger, but in 20% of those over age 60. Ninety-eight percent of MK cases were within the unfavorable cytogenetic risk category and comprised 40% of this group. The complete remission rate in patients with unfavorable cytogenetics without MK was 34% versus 18% with MK (P < .01). The 4-year overall survival of patients with unfavorable cytogenetics but without MK was 13% in contrast to a 4-year survival of only 3% with MK (P < .01). Thus, MK defines a sizeable subset of patients with unfavorable cytogenetics who have a particularly poor prognosis.
- Published
- 2010
- Full Text
- View/download PDF
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