Venetoclax combination therapy induces deep AML remission with eradication of leukemic stem cells and remodeling of clonal haematopoiesis

Vazquez, Romain; Breal, Claire; Zalmai, Loria; Friedrich, Chloé; Almire, Carole; Contejean, Adrien; Barreau, Sylvain; Grignano, Éric; Willems, Lise; Deau‐Fischer, Bénédicte; Franchi, Patricia; Vignon, Marguerite; Decroocq, Justine; Birsen, Rudy; Goldwirt, Lauriane; Kaltenbach, Sophie; Couronné, Lucile; Fontenay, Michaëla; Kosmider, Olivier; Bouscary, Didier; Chapuis, Nicolas

doi:10.1038/s41408-021-00448-w

Cited by 13 publications

(11 citation statements)

References 15 publications

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“…The preparation of library, sequencing and bioinformatics analysis are available in the previous work of our team 11 . The Exon 13 of ASXL1 (NM_015338.5) is entirely covered by our panel (Figure 1).…”

Section: Methodsmentioning

confidence: 99%

“…The majority of ASXL1 mutations are located in the last exon 13, causing truncation of downstream of the ASXH domain with a consequent loss of the PHD domain 2,3 . The most common genetic alteration in ASXL1 , which accounts for approximately half of all somatic truncating mutations, is the duplication of a single guanine, resulting in a frameshift and a premature stop codon and referred to p.Gly646Trpfs*12 or c.1934dupG 9‐11 …”

Section: Introductionmentioning

confidence: 99%

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PCR‐Fluo‐ASXL1‐FA: A fast, sensitive and inexpensive complementary method to detect ASXL1 mutations in haematological malignancies

Friedrich

Zalmai

Gay

et al. 2022

Int J Lab Hematology

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Introduction:The additional sex combs like 1 (ASXL1) gene is frequently mutated in a number of haematological neoplasms. The c.1934dupG, known to be the most common alteration in ASXL1, is associated with poor clinical outcome. A systematic determination of ASXL1 mutational status in myeloid malignancies is therefore necessary for prognostic stratification.Methods: Because direct sequencing is not sensitive and next-generation sequencing (NGS) is time-consuming, expensive and sometimes does not allow the detection of the c.1934dupG, we have developed a fragment analysis assay, complementary to NGS, that allows the detection of c.1934dupG mutation in addition to other nearby insertions/deletions of ASXL1 located close to it. We called this assay the "PCR-Fluo- ASXL1-FA."Results: First, we evaluated the efficiency of our approach compared to NGS and Sanger. We showed that "PCR-Fluo-ASXL1-FA" could detect all insertional mutations of ASXL1 located on its area, with a high sensitivity (1.5%). Then, we have illustrated the interest of this technique by three concrete cases.Discussion: In summary, we have established a fragment analysis approach, which can detect most ASXL1 mutations, in particular the c.1934dupG, in a sensitive, fast and inexpensive manner. We therefore recommend the synchronous use of this method with NGS, to ensure complete detection of all clinically relevant ASXL1 mutations in patients suffering with myeloid neoplasms.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PCR‐Fluo‐ASXL1‐FA: A fast, sensitive and inexpensive complementary method to detect ASXL1 mutations in haematological malignancies

Friedrich

Zalmai

Gay

et al. 2022

Int J Lab Hematology

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“…MRD negativity was obtained in 9 out of 11 tested patients in CRc (81.8%). Patients with persistent CRMRD- had a longer DoR than those with detectable MRD at even only one assessment at any time point during follow-up ( 31 ). A Chinese group that tested VEN in association with low dose DEC as post alloSCT maintenance for 20 high-risk AML and MDS patients, chose to perform a BM evaluation, with assessment of MRD monthly for the first six months of therapy and every two months or with longer intervals thereafter.…”

Section: Timing For Mrd Testing In Patients Receiving Low-intensity V...mentioning

confidence: 99%

MRD in Venetoclax-Based Treatment for AML: Does it Really Matter?

et al. 2022

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The prognosis of newly diagnosed patients with acute myeloid leukemia is still unfavorable in the majority of cases within the intermediate and mainly adverse genetic risk group but also in a considerable fraction of favorable-risk patients, mainly due to recurrence of disease after complete remission achievement or, less frequently, primary refractoriness. Besides genetic classification at diagnosis, post-treatment prognostic factors include measurable residual disease evaluation in patients in complete remission and in most cases measurable residual disease (MRD) positivity predicts hematologic relapse potentially allowing early therapeutic intervention. Currently, the most commonly used methods for detection of minimal residual disease are multiparameter flow cytometry and quantitative PCR, applicable to around 90% and 50% of patients, respectively. In addition, in > 90% of acute myeloid leukemia (AML) patients, molecular aberrations can be identified by next-generation sequencing, a technology that is widely used in clinical practice for the initial mutational screening at the time of diagnosis but more often, for MRD detection because its flexibility allows almost every mutated gene to be used as an MRD marker. Threshold levels of residual disease and correlation with outcome have been thoroughly studied and established in younger patients treated with intensive induction and consolidation chemotherapy as well as after allogeneic transplantation. Yet, experience on MRD monitoring and interpretation in patients treated with low-intensity regimens, including new agents, is still limited. The updated armamentarium of anti-leukemic agents includes the BCL-2 inhibitor venetoclax, which demonstrated good tolerability, high response rates, and prolonged overall survival when combined with hypomethylating agents or low dose cytarabine in patients considered elderly/”unfit” to tolerate intensive regimens. Although remissions with negative minimal residual disease clearly translated into improved outcomes after intensive treatments, data supporting the same evidence in patients receiving low-intensity venetoclax-based treatments are not still consolidated. We here review and discuss more recent data on the minimal residual disease interpretation and role in AML patients treated with venetoclax-based combinations.

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“…A recurring theme herein is the incorporation of the BCL-2 inhibitor Venetoclax into combination regimens against AML LSCs. Indeed, clinical evaluation of AML patient LSC profiles has indicated that elderly AML patients may particularly benefit from Venetoclax combination therapy [ 239 ]. Apart from AML, in CML, combined blockade of BCL-2 by Venetoclax and BCR-ABL tyrosine kinase using a TKI effectively eradicates CML LSCs in vitro and in vivo [ 240 ].…”

Section: Potential Therapeutic Strategies To Combat Lscsmentioning

confidence: 99%

Properties of Leukemic Stem Cells in Regulating Drug Resistance in Acute and Chronic Myeloid Leukemias

Zhai

Jiang

2022

Biomedicines

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Notoriously known for their capacity to reconstitute hematological malignancies in vivo, leukemic stem cells (LSCs) represent key drivers of therapeutic resistance and disease relapse, posing as a major medical dilemma. Despite having low abundance in the bulk leukemic population, LSCs have developed unique molecular dependencies and intricate signaling networks to enable self-renewal, quiescence, and drug resistance. To illustrate the multi-dimensional landscape of LSC-mediated leukemogenesis, in this review, we present phenotypical characteristics of LSCs, address the LSC-associated leukemic stromal microenvironment, highlight molecular aberrations that occur in the transcriptome, epigenome, proteome, and metabolome of LSCs, and showcase promising novel therapeutic strategies that potentially target the molecular vulnerabilities of LSCs.

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Venetoclax combination therapy induces deep AML remission with eradication of leukemic stem cells and remodeling of clonal haematopoiesis

Cited by 13 publications

References 15 publications

PCR‐Fluo‐ASXL1‐FA: A fast, sensitive and inexpensive complementary method to detect ASXL1 mutations in haematological malignancies

PCR‐Fluo‐ASXL1‐FA: A fast, sensitive and inexpensive complementary method to detect ASXL1 mutations in haematological malignancies

MRD in Venetoclax-Based Treatment for AML: Does it Really Matter?

Properties of Leukemic Stem Cells in Regulating Drug Resistance in Acute and Chronic Myeloid Leukemias

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