Risk factors for relapse after allogeneic transplantation in acute myeloid leukemia

Ossenkoppele, Gert J.; Janssen, Jeroen; Loosdrecht, Arjan A. van de

doi:10.3324/haematol.2015.139105

Cited by 57 publications

(45 citation statements)

References 52 publications

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“…[5][6][7] Although the CR rate is 60-85% for younger patients (18-60 years old) who can achieve the most intensive treatment 8 , many patients achieving CR after the induction therapy die from later chemoresistant relapse. 9,[10][11][12][13][14] Design of better treatments that avert AML relapse is therefore of great importance.…”

Section: Introductionmentioning

confidence: 99%

Proteome and phosphoproteome changes associated with prognosis in acute myeloid leukemia

Aasebø

Berven

Bartaula-Brevik

et al. 2019

Preprint

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word count: 213 Number of figures and tables: 5 Number of references: 84 Key Points  V-ATPases and RNA processing proteins are downregulated and upregulated, respectively, in relapse patients  Relapse patients show higher activity of CSK2 and CDKs when compared to relapse-free patients AbstractAcute myeloid leukemia (AML) is a hematological cancer that mainly affects the elderly.Although complete remission (CR) is achieved for majority of the patients after induction and consolidation therapies, nearly two-thirds relapse within a short interval. Understanding biological factors that determine relapse has therefore become of major clinical interest in AML.We utilized liquid chromatography tandem mass spectrometry (LC-MS/MS) to identify protein changes and protein phosphorylation events associated with AML relapse in primary cells from 41 AML patients at time of diagnosis. Patients were defined as relapse-free if they had not relapsed within a 5-year clinical follow-up after AML diagnosis. Relapse was associated with increased expression of RNA processing proteins and decreased expression of V-ATPase proteins. We also observed an increase in phosphorylation events catalyzed by cyclin-dependent kinases (CDKs) and casein kinase 2 (CSK2). The biological relevance of the proteome findings was supported by cell proliferation assays using inhibitors of V-ATPase (bafilomycin), CSK2 (CX-4945), CDK4/6 (abemaciclib) and CDK2/7/9 (SNS-032). While bafilomycin preferentially inhibited the cells from relapse patients, the kinase inhibitors were less efficient in these cells.This suggests that therapy against the upregulated kinases also could target the factors inducing their upregulation rather than their activity. In conclusion, our study presents markers that could help predict AML relapse and direct therapeutic strategies.

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Section: Introductionmentioning

confidence: 99%

Proteome and phosphoproteome changes associated with prognosis in acute myeloid leukemia

Aasebø

Berven

Bartaula-Brevik

et al. 2019

Preprint

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“…Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults and, despite considerable progress in understanding the pathogenesis of the disease, its outcome is still adverse in many patients . The main reason of this unfavorable prognosis is the high frequency of relapse due to persistence of trace amounts of chemoresistant leukemic cells after therapy . Currently, the intensity of treatment, which may also include allogeneic hematopoietic stem cell transplantation, is based on risk stratification of patients at diagnosis.…”

Section: Introductionmentioning

confidence: 99%

Residual disease detection using targeted parallel sequencing predicts relapse in cytogenetically normal acute myeloid leukemia

et al. 2017

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Despite achieving complete remission after intensive therapy, most patients with cytogenetically normal (CN) AML relapse due to the persistence of submicroscopic residual disease. In this pilot study, we hypothesized that detection of leukemia-specific mutations following consolidation treatment using a targeted parallel sequencing approach predicts relapse. We included 34 AML patients of whom diagnostic material and remission bone marrow slides after at least one cycle of consolidation were available. Isolated DNA was screened for mutations in 19 genes using an Ion Torrent sequencing platform. Furthermore, the variant allelic frequency of distinct mutations was validated by digital PCR and sequencing using a barcoding approach. Twenty-seven out of 34 patients could be analyzed for mutation clearance. We identified 68 somatic mutations at diagnosis (median, 3 mutations per patient; range 1-5) and 22 of these were still detected in 16 patients after consolidation therapy with a reliable sensitivity of 0.5% (median, 1 mutation; range 0-3). The most frequent noncleared mutations were found in DNMT3A. However, as persistence of these mutations has recently been shown to be without any impact on relapse risk, we performed survival and relapse risk analysis excluding DNMT3A mutations. Importantly, persistence of non-DNMT3A mutations was associated with a higher risk of AML relapse (7/8 pts versus 6/19 pts; P = .013) and with a shorter relapse-free survival (333 days vs. not reached; log-rank P = .0219). Detection of residual disease by routine targeted parallel sequencing proved feasible and effective as persistence of somatic mutations other than DNMT3A were prognostic for relapse in CN AML.

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“…In another study by Araki and colleagues, where the MRD data from 359 adults with AML who received alloSCT retrospectively were analyzed, MRD-negative remission status was significantly associated with longer survival, both overall and progression-free[89]. Taking into account, the role of MRD in prediction of relapse in AML, some studies recently integrated MRD status before transplantation in prognostic models for allogeneic SCT in AML[90–92]. …”

Section: Treatment Of Amlmentioning

confidence: 99%

Frontline treatment of acute myeloid leukemia in adults

Tamamyan

Kadia

Ravandi

et al. 2017

Critical Reviews in Oncology/Hematology

117

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Recent years have highlighted significant progress in understanding the underlying genetic and epigenetic signatures of acute myeloid leukemia(AML). Most importantly, novel chemotherapy and targeted strategies have led to improved outcomes in selected genetic subsets. AML is a remarkably heterogeneous disease, and individualized therapies for disease-specific characteristics (considering patients’ age, cytogenetics, and mutations) could yield better outcomes. Compared with the historical 5-to 10-year survival rate of 10%, the survival of patients who undergo modern treatment approaches reaches up to 40–50%, and for specific subsets, the improvements are even more dramatic; for example, in acute promyelocytic leukemia, the use of all-trans retinoic acid and arsenic trioxide improved survival from 30–40% up to 80–90%. Similar progress has been documented in core-binding-factor-AML, with an increase in survival from 30% to 80% upon the use of high-dose cytarabine/fludarabine/granulocyte colony-stimulating factor combination regimens. AML treatment was also recently influenced by the discovery of the superiority of regimens with higher dose Ara-C and nucleoside analogues compared with the “7+3” regimen, with about a 20% improvement in overall survival. Despite these significant differences, most centers continue to use the “7+3” regimen, and greater awareness will improve the outcome. The discovery of targetable molecular abnormalities and recent studies of targeted therapies (gemtuzumab ozagomycin, FLT3 inhibitors, isocitrate dehydrogenase inhibitors, and epigenetic therapies), future use of checkpoint inhibitors and other immune therapies such as chimeric antigen receptor T-cells, and maintenance strategies based on the minimal residual disease evaluation represent novel, exciting clinical leads aimed to improve AML outcomes in the near future.

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Risk factors for relapse after allogeneic transplantation in acute myeloid leukemia

Abstract: Ferrata Storti Foundation

Cited by 57 publications

References 52 publications

Proteome and phosphoproteome changes associated with prognosis in acute myeloid leukemia

Proteome and phosphoproteome changes associated with prognosis in acute myeloid leukemia

Residual disease detection using targeted parallel sequencing predicts relapse in cytogenetically normal acute myeloid leukemia

Frontline treatment of acute myeloid leukemia in adults

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