Clonal dominance is an adverse prognostic factor in acute myeloid leukemia treated with intensive chemotherapy

Cerrano, Marco; Duchmann, Matthieu; Kim, Rathana; Vasseur, Loïc; Hirsch, Pierre; Thomas, Xavier; Quentin, Samuel; Pasanisi, Justine; Passet, Marie; Rabian, Florence; Rahmé, Ramy; Lengliné, Étienne; Raffoux, Emmanuel; Dhédin, Nathalie; Sébert, Marie; Maarek, Odile; Raimbault, Anna; Celli-Lebras, Karine; Adès, Lionel; Fenaux, Pierre; Boissel, Nicolas; Delhommeau, François; Soulier, Jean; Dombret, Hervé; Clappier, Emmanuelle; Sujobert, Pierre; Itzykson, Raphaël

doi:10.1038/s41375-020-0932-8

Cited by 17 publications

(15 citation statements)

References 38 publications

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“…11 Both mutations are early events and are associated with clonal dominance in single-cell genotyping studies, 47 a feature that is associated with a poorer prognosis in AML. 48 Mouse models suggest an epigenetic cooperation between the 2 alterations, leading to activation of a stem cell-like gene signature. 49 Following previous reports in refractory/relapsing IDH-mutated AML, 50,51 it will be interesting to further study the genetic landscape and molecular predictors in patients with relapsed IDH-mutated AML, to compare trials conducted in this population.…”

Section: Discussionmentioning

confidence: 99%

Prognostic significance of concurrent gene mutations in intensively treated patients withIDH-mutated AML: an ALFA study

Duchmann

Micol

Duployez

et al. 2021

Blood

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IDH inhibitors are effective in AML, and trials evaluating frontline combinations with intensive chemotherapy (IC) are ongoing. Data on the prognostic significance of co-occurring genetic alterations and allogeneic hematopoietic stem cell transplantation (HSCT) are conflicting in each IDH-mutated subgroup treated by IC, while this information is important for trial design and results interpretation. We retrospectively analyzed 127 IDH1, 135 IDH2R140 and 57 IDH2R172 newly diagnosed AML patients treated with IC in three Acute Leukemia French Association (ALFA) prospective trials. We addressed in each IDH subgroup the prognostic impact of clinical and genetic covariates, and the role of HSCT in eligible patients. In IDH1 patients, presence of NPM1 mutations was the only variable predicting improved OS in multivariate analysis (p < 0.0001). In IDH2R140, normal karyotype (p= 0.008) and NPM1 mutations (p = 0.01) predicted better OS. NPM1 mutations were associated with better DFS (p = 0.0009) whereas presence of DNMT3A mutations was associated with shorter DFS (p = 0.0006). In IDH2R172, platelet count was the only variable retained in the multivariate model for OS (p = 0.002). Among non-favorable ELN-2010 eligible patients, 71 (36%) achieved an HSCT in first complete remission (CR1) and had longer OS (p = 0.03) and DFS (p = 0.02) than not-transplanted patients. Future clinical trial testing frontline IDH inhibitors combined with IC may consider stratification on NPM1 mutational status, the main prognostic factor in IDH1 and IDH2R140 mutated AML. HSCT improve OS of non-favorable IDH1/2-mutated AML and should be fully integrated in the treatment strategy.

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Section: Discussionmentioning

confidence: 99%

Prognostic significance of concurrent gene mutations in intensively treated patients withIDH-mutated AML: an ALFA study

Duchmann

Micol

Duployez

et al. 2021

Blood

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“…Exome sequencing or targeted sequencing of panels including at least 50–100 genes recurrently mutated in AML can capture partial information on clonal structure. These approaches often compensate their limited coverage compared with WGS with greater depth, allowing more precise assessment of VAFs and more robust clustering of the variants captured [ 5 , 17 , 18 , 19 , 20 ]. Single-colony [ 5 , 6 , 21 ], plate-based single cell [ 22 , 23 ], and more recently, high-throughput, droplet-based genotyping protocols [ 24 , 25 ] have contributed to describe the exact clonal composition of AML ( Figure 1 ).…”

Section: Clonal Identity In Amlmentioning

confidence: 99%

“…Different indices exist to quantify alpha diversity [ 62 ]. The most frequently used are the number of clones [ 12 , 25 ], which is sometimes approximated by counting the number of mutations in the most recurrent AML oncogenes [ 17 , 63 ], Shannon’s index [ 17 , 24 , 25 ], and Simpson’s index [ 17 ].…”

Section: Origin Of Intraleukemic Heterogeneity and Clonal Evolutionmentioning

confidence: 99%

“…Thus, it is likely that most mutations have accumulated before initiation of the leukemia, as most of them are present in all AML cells in the sample, and there is a high correlation between the total number of mutations and the patient’s age [ 5 ]. Even when focusing on recurrent driver mutations, higher clonal diversity correlates with older patient age [ 17 , 24 ]. Of note, patients with clinically or molecularly defined secondary AML (sAML), who are usually older than de novo AML patients, have an increased number of genetic drivers [ 70 , 71 ].…”

Section: Origin Of Intraleukemic Heterogeneity and Clonal Evolutionmentioning

confidence: 99%

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Clonal Architecture and Evolutionary Dynamics in Acute Myeloid Leukemias

Duchmann

Laplane

Itzykson

2021

Cancers

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Acute myeloid leukemias (AML) results from the accumulation of genetic and epigenetic alterations, often in the context of an aging hematopoietic environment. The development of high-throughput sequencing—and more recently, of single-cell technologies—has shed light on the intratumoral diversity of leukemic cells. Taking AML as a model disease, we review the multiple sources of genetic, epigenetic, and functional heterogeneity of leukemic cells and discuss the definition of a leukemic clone extending its definition beyond genetics. After introducing the two dimensions contributing to clonal diversity, namely, richness (number of leukemic clones) and evenness (distribution of clone sizes), we discuss the mechanisms at the origin of clonal emergence (mutation rate, number of generations, and effective size of the leukemic population) and the causes of clonal dynamics. We discuss the possible role of neutral drift, but also of cell-intrinsic and -extrinsic influences on clonal fitness. After reviewing available data on the prognostic role of genetic and epigenetic diversity of leukemic cells on patients’ outcome, we discuss how a better understanding of AML as an evolutionary process could lead to the design of novel therapeutic strategies in this disease.

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“…In chronic lymphocytic leukemia, an increased number of sub-clonal driver mutations was associated with an inferior failure-free survival while an increase of clonal drivers was not. 29 In acute myeloid leukemia, clonal dominance has been associated with a worse prognosis, 30 while branched evolution of signaling mutations conveyed an inferior event-free survival compared to linear evolution. 31 These various associations between clonal architecture and clinical outcomes highlight the importance of understanding the underlying processes that drive clonal architecture.…”

Section: Introductionmentioning

confidence: 99%

To portray clonal evolution in blood cancer, count your stem cells

Lyne

Laplane

Perié

2021

Blood

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Clonal evolution, the process of expansion and diversification of mutated cells, plays an important role in cancer development, resistance and relapse. While clonal evolution is most often conceived of as driven by natural selection, recent studies uncovered that neutral evolution shapes clonal evolution in a significant proportion of solid cancers. In hematological malignancies, the interplay between neutral evolution and natural selection is also disputed. Because natural selection selects cells with a higher fitness-providing a growth advantage to some cells relative to others-the architecture of clonal evolution serves as indirect evidence to distinguish natural selection from neutral evolution and has been associated with different prognoses for the patient. Linear architecture, when the new mutant clone grows within the previous one, is distinctive of hematological malignancies and typically interpreted as driven by natural selection. Here we wish to discuss the role of natural selection and neutral evolution in the production of linear clonal architectures in hematological malignancies. While it is tempting to attribute linear evolution to natural selection, we argue that a lower number of contributing stem cells accompanied by genetic drift can also result in a linear pattern of evolution as illustrated by simulations of clonal evolution in hematopoietic stem cells. The number of stem cells contributing to long-term clonal evolution is not known in the pathological context and we advocate that estimating these numbers in the context of cancer and ageing is crucial to parsing out neutral evolution from natural selection, two processes that require different therapeutic strategies.

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Clonal dominance is an adverse prognostic factor in acute myeloid leukemia treated with intensive chemotherapy

Cited by 17 publications

References 38 publications

Prognostic significance of concurrent gene mutations in intensively treated patients withIDH-mutated AML: an ALFA study

Prognostic significance of concurrent gene mutations in intensively treated patients withIDH-mutated AML: an ALFA study

Clonal Architecture and Evolutionary Dynamics in Acute Myeloid Leukemias

To portray clonal evolution in blood cancer, count your stem cells

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