Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet

Döhner, Hartmut; Estey, Elihu H.; Amadori, Sergio; Appelbaum, Frederick R.; Büchner, Thomas; Burnett, Alan Kenneth; Dombret, Hervé; Fenaux, Pierre; Grimwade, David; Larson, Richard A.; Lo‐Coco, Francesco; Naoe, Tomoki; Niederwieser, Dietger; Ossenkoppele, Gert J.; Sanz, Miguel Á.; Sierra, Jorge; Tallman, Martin S.; Löwenberg, Bob; Bloomfield, Clara D.

doi:10.1182/blood-2009-07-235358

Cited by 3,033 publications

(2,937 citation statements)

References 290 publications

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“…The National Comprehensive Cancer Network guidelines recommend molecular characterization of several commonly mutated genes to allow for risk‐stratification and subsequent treatment paradigms 3, 4. Small molecule drugs are now emerging as an option for patients with AML to address the unmet clinical need, in addition to intensive chemotherapy regimens (e.g., cytarabine and daunomycin) and bone marrow transplantation.…”

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confidence: 99%

Sorafenib Dose Recommendation in Acute Myeloid Leukemia Based on Exposure‐FLT3 Relationship

Liu

Ivaturi

Sabato

et al. 2018

Clinical Translational Sci

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Sorafenib administered at the approved dose continuously is not tolerated long‐term in patients with acute myeloid leukemia (AML). The purpose of this study was to optimize the dosing regimen by characterizing the sorafenib exposure‐response relationship in patients with AML. A one‐compartment model with a transit absorption compartment and enterohepatic recirculation described the exposure. The relationship between sorafenib exposure and target modulation of kinase targets (FMS‐like tyrosine kinase 3 (FLT3)‐ITD and extracellular signal‐regulated kinase (ERK)) were described by an inhibitory maximum effect (Emax) model. Sorafenib could inhibit FLT3‐ITD activity by 100% with an IC50 of 69.3 ng/mL and ERK activity by 84% with an IC50 of 85.7 ng/mL (both adjusted for metabolite potency). Different dosing regimens utilizing 200 or 400 mg at varying frequencies were simulated based on the exposure‐response relationship. Simulations demonstrate that a 200 mg twice daily (b.i.d.) dosing regimen showed similar FLT3‐ITD and ERK inhibitory activity compared with 400 mg b.i.d. and is recommended in further clinical trials in patients with AML.

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mentioning

confidence: 99%

Sorafenib Dose Recommendation in Acute Myeloid Leukemia Based on Exposure‐FLT3 Relationship

Liu

Ivaturi

Sabato

et al. 2018

Clinical Translational Sci

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“…Clinical parameters were CR/CRi, defined as bone marrow blasts <5% with or without blood count recovery after induction therapy, RFS and OS [5]. Survival characteristics were analyzed by means of the Kaplan Meier method.…”

Section: Aml Maturity Scorementioning

confidence: 99%

“…Hence, in 2009 the European LeukemiaNet (ELN) proposed a standardized reporting system that risk stratifies patients according to their genetic subgroup. As of today, it is well established for early prognostic assessment in AML patients [5,4,6,7,3,[8][9][10]. Thus, patients in this cohort were primarily grouped according to these criteria [5].…”

Section: Introductionmentioning

confidence: 99%

Flow cytometric maturity score as a novel prognostic parameter in patients with acute myeloid leukemia

et al. 2015

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Abstract:The European LeukemiaNet (ELN) classification is widely accepted for risk stratification of patients with acute myeloid leukemia (AML). In order to establish immunophenotypic features that predict prognosis, the expression of single AML blast cell antigens has been evaluated with partly conflicting results; however, the influence of immunophenotypic blast maturity is largely unknown.In our study, 300 AML patients diagnosed at our institution between 01/2003 and 04/2012 were analyzed. A flow cytometric maturity score was developed in order to distinguish "mature" AML (AML-ma) from "immature" AML (AML-im) by quantitative expression levels of early progenitor cell antigens (CD34, CD117, and TdT).AML-ma showed significantly longer relapse-free survival (RFS) and overall survival (OS) than AML-im (p<0.001). Interestingly, statistically significant differences in RFS and OS were maintained within the Our novel flow cytometric score easily determines AML blast maturity and can predict clinical outcome. It remains to be clarified whether these results simply reflect an accumulation of favorable molecular phenotypes in the AML-ma subgroup or whether they rely on biological differences such as a higher proportion of leukemia stem cells and/or a higher degree of genetic instability within the AML-im subgroup.

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“…1,2 The antileukemic activity of myeloablative allo-SCT relies not only on the high dose of chemo/radiotherapy given during the conditioning regimen, but also on the immune-mediated graft-versus-leukemia (GVL) effect. 1,3,4 The biology of the GVL effect has been thought to involve reactions to polymorphic minor histocompatibility antigens expressed either specifically on hematopoietic cells (and thus not causing graft-versus-host disease (GVHD)) or more widely on a number of tissue cells. 5,6 Allo-SCT following reduced-intensity conditioning (RIC) is being increasingly used as treatment for patients with AML who are too old or too frail to tolerate high-dose conditioning regimens.…”

Section: Introductionmentioning

confidence: 99%

Impact of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation for acute myeloid leukemia: a report from the Acute Leukemia Working Party of the European group for blood and marrow transplantation

et al. 2012

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This report investigated the impact of graft-versus-host disease (GVHD) on transplantation outcomes in 1859 acute myeloid leukemia patients given allogeneic peripheral blood stem cells after reduced-intensity conditioning (RIC allo-SCT). Grade I acute GVHD was associated with a lower risk of relapse (hazards ratio (HR) ¼ 0.7, P ¼ 0.02) translating into a trend for better overall survival (OS; HR ¼ 1.3; P ¼ 0.07). Grade II acute GVHD had no net impact on OS, while grade III-IV acute GVHD was associated with a worse OS (HR ¼ 0.4, Po0.0.001) owing to high risk of nonrelapse mortality (NRM; HR ¼ 5.2, Po0.0001). In time-dependent multivariate Cox analyses, limited chronic GVHD tended to be associated with a lower risk of relapse (HR ¼ 0.72; P ¼ 0.07) translating into a better OS (HR ¼ 1.8; Po0.001), while extensive chronic GVHD was associated with a lower risk of relapse (HR ¼ 0.65; P ¼ 0.02) but also with higher NRM (HR ¼ 3.5; Po0.001) and thus had no net impact on OS. In-vivo T-cell depletion with antithymocyte globulin (ATG) or alemtuzumab was successful at preventing extensive chronic GVHD (Po0.001), but without improving OS for ATG and even with worsening OS for alemtuzumab (HR ¼ 0.65; P ¼ 0.001). These results highlight the role of the immune-mediated graft-versus-leukemia effect in the RIC allo-SCT setting, but also the need for improving the prevention and treatment of severe GVHD.

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Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet

Cited by 3,033 publications

References 290 publications

Sorafenib Dose Recommendation in Acute Myeloid Leukemia Based on Exposure‐FLT3 Relationship

Sorafenib Dose Recommendation in Acute Myeloid Leukemia Based on Exposure‐FLT3 Relationship

Flow cytometric maturity score as a novel prognostic parameter in patients with acute myeloid leukemia

Impact of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation for acute myeloid leukemia: a report from the Acute Leukemia Working Party of the European group for blood and marrow transplantation

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