Clinical impact of <i>NPM1</i>-mutant molecular persistence after chemotherapy for acute myeloid leukemia

Dillon, Richard; Ivey, Adam; Kuzich, James A.; Thiagarajah, Nisha; Sharplin, Kirsty; Kok, Chung Hoow; Tedjaseputra, Aditya; Rowland, James; Grove, Carolyn; Abro, Emad Uddin; Shortt, Jake; Hiwase, Devendra; Bajel, Ashish; Potter, Nicola; Smith, Matthew; Hemmaway, Claire; Thomas, Abin; Gilkes, Amanda F.; Russell, Nigel H.; Wei, Andrew H.

doi:10.1182/bloodadvances.2021005455

Cited by 28 publications

(25 citation statements)

References 11 publications

(20 reference statements)

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“…This fact may account for the still imperfect predictive accuracy of MRD as the status of antitumor immunity can critically affect disease progression, independent of the levels of residual leukemia. For instance, the spontaneous achievement of MRD negativity in post-chemotherapy MRD + AML patients bearing the NPM1 mutation [ 70 ] potentially mirrors the gradual eradication of the residual leukemic burden through the restoration of an effective antileukemic immune response after chemotherapy. The simultaneous assessment of the alterations of the leukemic clone and the immune system has the potential to overcome the limitations of current MRD methods.…”

Section: Discussionmentioning

confidence: 99%

MRD Monitoring by Multiparametric Flow Cytometry in AML: Is It Time to Incorporate Immune Parameters?

Pessach

Spyropoulos

Lamprianidou

et al. 2022

Cancers

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Acute myeloid leukemia (AML) is a heterogeneous group of clonal myeloid disorders characterized by intrinsic molecular variability. Pretreatment cytogenetic and mutational profiles only partially inform prognosis in AML, whereas relapse is driven by residual leukemic clones and mere morphological evaluation is insensitive for relapse prediction. Measurable residual disease (MRD), an independent post-diagnostic prognosticator, has recently been introduced by the European Leukemia Net as a new outcome definition. However, MRD techniques are not yet standardized, thus precluding its use as a surrogate endpoint for survival in clinical trials and MRD-guided strategies in real-life clinical practice. AML resistance and relapse involve a complex interplay between clonal and immune cells, which facilitates the evasion of the leukemic clone and which is not taken into account when merely quantifying the residual leukemia. Multiparameter flow cytometry (MFC) offers the possibility of capturing an overall picture of the above interactions at the single cell level and can simultaneously assess the competence of anticancer immune response and the levels of residual clonal cells. In this review, we focus on the current status of MFC-based MRD in diverse AML treatment settings and introduce a novel perspective of combined immune and leukemia cell profiling for MRD assessment in AML.

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Section: Discussionmentioning

confidence: 99%

MRD Monitoring by Multiparametric Flow Cytometry in AML: Is It Time to Incorporate Immune Parameters?

Pessach

Spyropoulos

Lamprianidou

et al. 2022

Cancers

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show abstract

“…Moreover, the use of MRD as a predictive tool which could aid in therapeutic decisions is even less established, with one prospective trial demonstrating the predictive value of MRD measurement in patients with RUNX1::RUNX1T1 AML for decision on AlloSCT after the second consolidation (see “updates in post remission therapy”) 89 . In addition, MRD negativity is not a sine qua non for cure, as relapse can occur in up to 30% of patients with MRD negativity 82,83 and not all patients with MRD positive disease will relapse, especially those with low level PCR‐MRD in patients with NPM1 or CBF mutations 90,91 . Thus, in our clinical practice, we use MRD as adjunct data among many others and not as a sole parameter to base our decisions.…”

Section: Updates In Risk Stratificationmentioning

confidence: 99%

“…MRD negativity by qPCR is defined as cycling threshold (Ct) ≥40 in ≥2 of 3 replicates. Due to low relapse risk when the end of treatment NPM1 or CBF AML qPCR is less than 2%, only values above that level are considered positive 74,88,90,91 . The incorporation of MRD as an endpoint also created new definitions for time to event outcomes other than OS, such as event free survival (EFS), relapse free survival (RFS), or cumulative incidence of relapse (CIR).…”

Section: Updates In Risk Stratificationmentioning

confidence: 99%

“…89 In addition, MRD negativity is not a sine qua non for cure, as relapse can occur in up to 30% of patients with MRD negativity 82,83 and not all patients with MRD positive disease will relapse, especially those with low level PCR-MRD in patients with NPM1 or CBF mutations. 90,91 Thus, in our clinical practice, we use MRD as adjunct data among many others and not as a sole parameter to base our decisions.…”

Section: Updates In Risk Stratificationmentioning

confidence: 99%

“…The definition of relapse remains bone marrow leukemia blasts ≥5%, any reappearance of peripheral leukemic blasts in two samples only values above that level are considered positive. 74,88,90,91 The incorporation of MRD as an endpoint also created new definitions for time to event outcomes other than OS, such as event free survival (EFS), relapse free survival (RFS), or cumulative incidence of relapse (CIR).…”

Section: Response and Outcomes Evaluationmentioning

confidence: 99%

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Acute myeloid leukemia: 2023 update on diagnosis, risk‐stratification, and management

2023

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Disease overview: Acute myeloid leukemia (AML) is a frequently fatal bone marrow stem cell cancer characterized by unbridled proliferation of malignant marrow stem cells with associated infection, anemia, and bleeding. An improved understanding of pathophysiology, improvements in measurement technology and at least 10 recently approved therapies have led to revamping the diagnostic, prognostic, and therapeutic landscape of AML.Diagnosis: One updated and one new classification system were published in 2022, both emphasizing the integration of molecular analysis into daily practice. Differences between the International Consensus Classification and major revisions from the previous 2016 WHO system provide both challenges and opportunities for care and clinical research.Risk assessment and monitoring: The European Leukemia Net 2022 risk classification integrates knowledge from novel molecular findings and recent trial results, as well as emphasizing dynamic risk based on serial measurable residual disease assessment. However, how to leverage our burgeoning ability to measure a small number of potentially malignant myeloid cells into therapeutic decision making is controversial.Risk adapted therapy: The diagnostic and therapeutic complexity plus the availability of newly approved agents requires a nuanced therapeutic algorithm which should integrate patient goals of care, comorbidities, and disease characteristics including the specific mutational profile of the patient's AML. The framework we suggest only represents the beginning of the discussion. | INTRODUCTIONAcute myeloid leukemia (AML) is a heterogenous disease that arises from uncontrolled proliferation of clonal hematopoietic cells. 1,2 It is the most common form of acute leukemia in adults, with a median age at diagnosis of 68 years. 3 The estimated 5-year OS is 30% 4 and differs greatly between various age groups, reaching 50% in younger patients but is less than 10% in patients older than age 60. 5 However, such statistics, based mainly on older trials, could be improving with the FDA approval of 11 new drugs or combinations since

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NPM1‐mutated acute myeloid leukemia: New pathogenetic and therapeutic insights and open questions

Falini

2023

American J Hematol

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The nucleophosmin (NPM1) gene encodes for a multifunctional chaperone protein that is localized in the nucleolus but continuously shuttles between the nucleus and cytoplasm. NPM1 mutations occur in about one‐third of AML, are AML‐specific, usually involve exon 12 and are frequently associated with FLT3‐ITD, DNMT3A, TET2, and IDH1/2 mutations. Because of its unique molecular and clinico‐pathological features, NPM1‐mutated AML is regarded as a distinct leukemia entity in both the International Consensus Classification (ICC) and the 5th edition of the World Health Organization (WHO) classification of myeloid neoplasms. All NPM1 mutations generate leukemic mutants that are aberrantly exported in the cytoplasm of the leukemic cells and are relevant to the pathogenesis of the disease. Here, we focus on recently identified functions of the NPM1 mutant at chromatin level and its relevance in driving HOX/MEIS gene expression. We also discuss yet controversial issues of the ICC/WHO classifications, including the biological and clinical significance of therapy‐related NPM1‐mutated AML and the relevance of blasts percentage in defining NPM1‐mutated AML. Finally, we address the impact of new targeted therapies in NPM1‐mutated AML with focus on CAR T cells directed against NPM1/HLA neoepitopes, as well as XPO1 and menin inhibitors.

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Clinical impact of NPM1-mutant molecular persistence after chemotherapy for acute myeloid leukemia

Cited by 28 publications

References 11 publications

MRD Monitoring by Multiparametric Flow Cytometry in AML: Is It Time to Incorporate Immune Parameters?

MRD Monitoring by Multiparametric Flow Cytometry in AML: Is It Time to Incorporate Immune Parameters?

Acute myeloid leukemia: 2023 update on diagnosis, risk‐stratification, and management

NPM1‐mutated acute myeloid leukemia: New pathogenetic and therapeutic insights and open questions

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