Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel

Döhner, Hartmut; Estey, Elihu H.; Grimwade, David; Amadori, Sergio; Appelbaum, Frederick R.; Büchner, Thomas; Dombret, Hervé; Ebert, Benjamin L.; Fenaux, Pierre; Larson, Richard A.; Levine, Ross L.; Lo‐Coco, Francesco; Naoe, Tomoki; Niederwieser, Dietger; Ossenkoppele, Gert J.; Sanz, Miguel Á.; Sierra, Jorge; Tallman, Martin S.; Tien, Hwei‐Fang; Wei, Andrew H.; Löwenberg, Bob; Bloomfield, Clara D.

doi:10.1182/blood-2016-08-733196

Cited by 4,440 publications

(5,138 citation statements)

References 295 publications

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“…3,4 Here, viability in vitro assays revealed that both cytotoxic drugs, Ara-C and idarubicin, are equally toxic in different AML cell lines with an IC 50 of ~10 −7 M (Fig 1S). Exposure to Ara-C plus idarubicin (Ara-C/Ida) resulted in 80%–95% cell death of AML cell lines, measured by Annexin V staining (Figure 1A).…”

Section: Resultsmentioning

confidence: 78%

“…1,2 In contrast to acute lymphoblastic leukemia (ALL), treatment of AML has not improved substantially over the last two decades and many patients still fail to respond to standard intensive chemotherapy based on nucleoside analogs such as cytarabine (AraC) or fludarabine and anthracyclines such as idarubicin and daunorubicin. 3,4 Failure of current therapies to eradicate leukemia-initiating/propagating cells (LICs) and chemotherapy refractoriness are the major mechanisms underlying AML progression/relapse. In addition, the BM stroma has been involved in the pathogenesis of a variety of hematologic malignances including AML.…”

Section: Introductionmentioning

confidence: 99%

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IMiDs mobilize acute myeloid leukemia blasts to peripheral blood through downregulation of CXCR4 but fail to potentiate AraC/Idarubicin activity in preclinical models of non del5q/5q- AML

et al. 2018

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Treatment for acute myeloid leukemia (AML) remains suboptimal and many patients remain refractory or relapse upon standard chemotherapy based on nucleoside analogs plus anthracyclines. The crosstalk between AML cells and the BM stroma is a major mechanism underlying therapy resistance in AML. Lenalidomide and pomalidomide, a new generation immunomodulatory drugs (IMiDs), possess pleiotropic anti-leukemic properties including potent immune-modulating effects and are commonly used in hematological malignances associated with intrinsic dysfunctional BM such as myelodysplastic syndromes and multiple myeloma. Whether IMiDs may improve the efficacy of current standard treatment in AML remains understudied. Here, we have exploited in vitro and in vivo preclinical AML models to analyze whether IMiDs potentiate the efficacy of AraC/Idarubicin-based standard AML chemotherapy by interfering with the BM stroma-mediated chemoresistance. We report that IMiDs do not exert cytotoxic effects on either non-del5q/5q- AML cells nor BM-MSCs, but they enhance the immunomodulatory properties of BM-MSCs. When combined with AraC/Idarubicin, IMiDs fail to circumvent BM stroma-mediated resistance of non-del5q/5q- AML cells in vitro and in vivo but induce robust extramedullary mobilization of AML cells. When administered as a single agent, lenalidomide specifically mobilizes non-del5q/5q- AML cells, but not healthy CD34+ cells, to peripheral blood (PB) through specific downregulation of CXCR4 in AML blasts. Global gene expression profiling supports a migratory/mobilization gene signature in lenalidomide-treated non-del5q/5q- AML blasts but not in CD34+ cells. Collectively, IMiDs mobilize non-del5q/5q- AML blasts to PB through CXCR4 downregulation, but fail to potentiate AraC/Idarubicin activity in preclinical models of non-del5q/5q- AML.

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Section: Resultsmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 99%

IMiDs mobilize acute myeloid leukemia blasts to peripheral blood through downregulation of CXCR4 but fail to potentiate AraC/Idarubicin activity in preclinical models of non del5q/5q- AML

et al. 2018

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“…SPM-2 triplebody was present in the reactions at the concentrations shown in pM. A) Samples from patients with favorable AML subtype according to the ELN (European Leukemia Network) classification 2 . B) AML with intermediate-I ELN risk subtype.…”

Section: Resultsmentioning

confidence: 99%

“…The panel included patients with AML belonging to all genetic risk groups according to the ELN (European Leukemia Network) classification, 2 (Table 1). For in vitro cytolysis assays the target cells were labeled with calcein.…”

Section: Resultsmentioning

confidence: 99%

“…1 2 Prognosis for patients with relapsed disease is generally poor, and therefore, new treatment options are urgently needed. Recurrence of the disease is thought to be caused by Leukemia Stem Cells (LSCs) and leukemic progenitor cells which survived CT. 3–7 New treatment strategies attempting to reach prolonged and deeper remissions therefore need to aim at an improved elimination of AML LSCs.…”

Section: Introductionmentioning

confidence: 99%

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Dual-targeting triplebody 33-16-123 (SPM-2) mediates effective redirected lysis of primary blasts from patients with a broad range of AML subtypes in combination with natural killer cells

et al. 2018

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A number of agents designed for immunotherapy of Acute Myeloid Leukemia (AML) are in preclinical and early clinical development. Most of them target a single antigen on the surface of AML cells. Here we describe the development and key biological properties of a tri-specific agent, the dual-targeting triplebody SPM-2, with binding sites for target antigens CD33 and CD123, and for CD16 to engage NK cells as cytolytic effectors. Primary blasts of nearly all AML patients carry at least one of these target antigens and the pair is particularly promising for the elimination of blasts and leukemia stem cells (LSCs) from a majority of AML patients by dual-targeting agents. The cytolytic activity of NK cells mediated by SPM-2 was analyzed in vitro for primary leukemic cells from 29 patients with a broad range of AML-subtypes. Blasts from all 29 patients, including patients with genomic alterations associated with an unfavorable genetic subtype, were lysed at nanomolar concentrations of SPM-2. Maximum susceptibility was observed for cells with a combined density of CD33 and CD123 above 10,000 copies/cell. Cell populations enriched for AML-LSCs (CD34pos and CD34pos CD38neg cells) from 2 AML patients carried an increased combined antigen density and were lysed at correspondingly lower concentrations of SPM-2 than unsorted blasts. These initial findings raise the expectation that SPM-2 may also be capable of eliminating AML-LSCs and thus of prolonging survival. In the future, patients with a broad range of AML subtypes may benefit from treatment with SPM-2.

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DNA Sequencing to Detect Residual Disease in Adults With Acute Myeloid Leukemia Prior to Hematopoietic Cell Transplant

Dillon

Gui

Page

et al. 2023

JAMA

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ImportancePreventing relapse for adults with acute myeloid leukemia (AML) in first remission is the most common indication for allogeneic hematopoietic cell transplant. The presence of AML measurable residual disease (MRD) has been associated with higher relapse rates, but testing is not standardized.ObjectiveTo determine whether DNA sequencing to identify residual variants in the blood of adults with AML in first remission before allogeneic hematopoietic cell transplant identifies patients at increased risk of relapse and poorer overall survival compared with those without these DNA variants.Design, Setting, and ParticipantsIn this retrospective observational study, DNA sequencing was performed on pretransplant blood from patients aged 18 years or older who had undergone their first allogeneic hematopoietic cell transplant during first remission for AML associated with variants in FLT3, NPM1, IDH1, IDH2, or KIT at 1 of 111 treatment sites from 2013 through 2019. Clinical data were collected, through May 2022, by the Center for International Blood and Marrow Transplant Research.ExposureCentralized DNA sequencing of banked pretransplant remission blood samples.Main Outcomes and MeasuresThe primary outcomes were overall survival and relapse. Day of transplant was considered day 0. Hazard ratios were reported using Cox proportional hazards regression models.ResultsOf 1075 patients tested, 822 had FLT3 internal tandem duplication (FLT3-ITD) and/or NPM1 mutated AML (median age, 57.1 years, 54% female). Among 371 patients in the discovery cohort, the persistence of NPM1 and/or FLT3-ITD variants in the blood of 64 patients (17.3%) in remission before undergoing transplant was associated with worse outcomes after transplant (2013-2017). Similarly, of the 451 patients in the validation cohort who had undergone transplant in 2018-2019, 78 patients (17.3%) with residual NPM1 and/or FLT3-ITD variants had higher rates of relapse at 3 years (68% vs 21%; difference, 47% [95% CI, 26% to 69%]; HR, 4.32 [95% CI, 2.98 to 6.26]; P &lt; .001) and decreased survival at 3 years (39% vs 63%; difference, −24% [2-sided 95% CI, −39% to −9%]; HR, 2.43 [95% CI, 1.71 to 3.45]; P &lt; .001).Conclusions and RelevanceAmong patients with acute myeloid leukemia in first remission prior to allogeneic hematopoietic cell transplant, the persistence of FLT3 internal tandem duplication or NPM1 variants in the blood at an allele fraction of 0.01% or higher was associated with increased relapse and worse survival compared with those without these variants. Further study is needed to determine whether routine DNA-sequencing testing for residual variants can improve outcomes for patients with acute myeloid leukemia.

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Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel

Cited by 4,440 publications

References 295 publications

IMiDs mobilize acute myeloid leukemia blasts to peripheral blood through downregulation of CXCR4 but fail to potentiate AraC/Idarubicin activity in preclinical models of non del5q/5q- AML

IMiDs mobilize acute myeloid leukemia blasts to peripheral blood through downregulation of CXCR4 but fail to potentiate AraC/Idarubicin activity in preclinical models of non del5q/5q- AML

Dual-targeting triplebody 33-16-123 (SPM-2) mediates effective redirected lysis of primary blasts from patients with a broad range of AML subtypes in combination with natural killer cells

DNA Sequencing to Detect Residual Disease in Adults With Acute Myeloid Leukemia Prior to Hematopoietic Cell Transplant

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