Unified classification and risk-stratification in Acute Myeloid Leukemia

Tazi, Yanis; Arango-Ossa, Juan E.; Zhou, Yangyu; Bernard, Elsa; Thomas, Ian; Gilkes, Amanda F.; Freeman, Sylvie; Pradat, Yoann; Johnson, Sean J.; Hills, Robert Kerrin; Dillon, Richard; Levine, Max F.; Leongamornlert, Daniel; Butler, Adam; Ganser, Arnold; Bullinger, Lars; Döhner, Konstanze; Ottmann, Oliver G.; Adams, Rachel; Döhner, Hartmut; Campbell, Peter J.; Burnett, Alan Kenneth; Dennis, Michael; Russell, Nigel H.; Devlin, Sean M.; Huntly, Brian J. P.; Papaemmanuil, Elli

doi:10.1038/s41467-022-32103-8

Cited by 94 publications

(122 citation statements)

References 66 publications

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“…Recent research demonstrated that ML applied to AML is able to predict new subgroups and prognostic scores [36 ▪ ]. Similarly, Papaemmanuil's work prototyped clinical decision support tools that deliver a personalized risk score based on cytogenetics and the mutational status of 32 genes [37 ▪▪ ].…”

Section: Future Directions In Acute Myeloid Leukamia: Integration Of ...mentioning

confidence: 99%

The role of next-generation sequencing in acute myeloid leukemia

Llop

Sargas

Barragán

2022

Current Opinion in Oncology

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Purpose of reviewThe development of high-throughput techniques like next-generation sequencing (NGS) has unraveled the genetic profile of cancer. In this review, we discuss the role of NGS on the diagnostic, risk stratification, and follow-up of patients with acute myeloid leukemia (AML).Recent findingsNGS has become an essential tool in clinical practice for AML management. Therefore, efforts are being made to improve its applications, automation, and turnaround time. Other high-throughput techniques, such as whole genome sequencing or RNA-sequencing, can be also used to this end. However, not all institutions may be able to implement these approaches. NGS is being investigated for measurable residual disease (MRD) assessment, especially with the development of error-correction NGS. New data analysis approaches like machine learning are being investigated in order to integrate genomic and clinical data and develop comprehensive classifications and risk scores.SummaryNGS has proven to be a useful approach for the analysis of genomic alterations in patients with AML, which aids patient management. Current research is being directed at reducing turnaround time and simplifying processes so that these techniques can be universally integrated into clinical practice.

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Section: Future Directions In Acute Myeloid Leukamia: Integration Of ...mentioning

confidence: 99%

The role of next-generation sequencing in acute myeloid leukemia

Llop

Sargas

Barragán

2022

Current Opinion in Oncology

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“…17 While some AML subtypes are characterized by recurrent genetic translocations or mutations associated with particular prognoses, most AMLs present a normal or complex karyotype, and identifying key factors that predict treatment resistance in these patients represents a major challenge. [17][18][19][20][21][22] Aside from disease stratification, AML also belongs to malignancies with the lowest mutational burdens, 23 and finding tumor-specific antigens for immunotherapeutic approaches remains very difficult as the frequency of mutations creating neoantigens is expected to be low. 24 In this context, HERV-derived antigens could represent a unique source of alternative tumor-specific antigens (i.e.…”

Section: Introductionmentioning

confidence: 99%

HERVs characterize normal and leukemia stem cells and represent a source of shared epitopes for cancer immunotherapy

et al. 2022

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Human endogenous retroviruses (HERVs) represent 8% of the human genome. The expression of HERVs and their immune impact have not been extensively studied in Acute Myeloid Leukemia (AML). In this study, we used a reference of 14 968 HERV functional units to provide a thorough analysis of HERV expression in normal and AML bone marrow cells. We show that the HERV retrotranscriptome accurately characterizes normal and leukemic cell subpopulations, including leukemia stem cells, in line with different epigenetic profiles. We then show that HERV expression delineates AML subtypes with different prognoses. We finally propose a method to select and prioritize CD8+ T cell epitopes derived from AML‐specific HERVs and we show that lymphocytes infiltrating patient bone marrow at diagnosis contain naturally occurring CD8+ T cells against these HERV epitopes. We also provide in vitro data supporting the functionality of HERV‐specific CD8+ T‐cells against AML cells. These results show that HERVs represent an important source of genetic information that can help enhancing disease stratification or biomarker identification and an important reservoir of alternative tumor‐specific T cell epitopes relevant for cancer immunotherapy.

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“…Acute myeloid leukemia (AML) is a term given to a rare, highly fatal, group of blood cancers 1 . The genetic etiology of AML has been well characterized [2][3][4][5] , and genomic analysis performed at the time of AML diagnostic evaluation can help predict response to therapy [6][7][8] , identify patients eligible for specific molecularly targeted therapies [9][10][11][12] , and stratify patients for risk of subsequent relapse and death in those who achieve an initial complete remission to therapy 3,13,14 .…”

Section: Introductionmentioning

confidence: 99%

Pre-MEASURE:FLT3-ITD and mutatedNPM1measurable residual disease before allogeneic transplant in adults with AML in first remission

Dillon

Gui

Ravindra

et al. 2022

Preprint

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BackgroundPrevention of relapse for adults with Acute Myeloid Leukemia (AML) in first remission (CR1) is the most common indication for allogeneic hematopoietic cell transplantation (alloHCT). Measurable residual disease (MRD) detection has been associated with higher relapse rates, but testing is not standardized. Establishment of validated AML MRD criteria would allow harmonization across centers facilitating clinical trials and generalizable practice guidelines.MethodsPatients aged 18 or older who underwent first alloHCT forFLT3, NPM1, IDH1, IDH2and/orKITmutated AML in CR1 were eligible for this multicenter study. Residual mutations detected in remission using ultra-deep error-corrected next-generation DNA-sequencing (NGS-MRD) associated with increased relapse risk were validated in a second independent cohort. The impact of baseline characteristics on NGS-MRD results was evaluated.ResultsPre-conditioning CR1 blood samples from 1075 patients were tested. Detection of residualNPM1and/orFLT3-ITD mutations before alloHCT was associated with worse outcomes after transplantation in both discovery (patients transplanted 2013-2017) and validation (patients transplanted 2018-2019) cohorts. In multivariate Cox regression analysis detection of residualNPM1m (relapse; HR: 4.9, 3.5-7.0, P<0.0001, survival; HR: 2.9, 2.2-4.0, P<0.0001), residualFLT3-ITD (relapse: HR: 4.2, 3.1-5.7, P<0.0001, survival; HR: 2.6, 2.0-3.6, P<0.0001), and receipt of non-melphalan containing reduced intensity conditioning were associated with inferior clinical outcomes.ConclusionsDetection of residualNPM1and/orFLT3-ITD mutations in the blood of patients undergoing alloHCT for AML in CR1 is associated with increased relapse and worse survival. In those undergoing reduced intensity conditioning, melphalan may reduce the risk associated with testing NGS-MRD positive prior to transplantation.

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Unified classification and risk-stratification in Acute Myeloid Leukemia

Cited by 94 publications

References 66 publications

The role of next-generation sequencing in acute myeloid leukemia

The role of next-generation sequencing in acute myeloid leukemia

HERVs characterize normal and leukemia stem cells and represent a source of shared epitopes for cancer immunotherapy

Pre-MEASURE:FLT3-ITD and mutatedNPM1measurable residual disease before allogeneic transplant in adults with AML in first remission

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