Nucleophosmin 1 (<i>NPM1</i>) mutations in chronic myelomonocytic leukemia and their prognostic relevance

Vallapureddy, Rangit; Lasho, Terra L.; Hoversten, Katherine P.; Finke, Christy; Ketterling, Rhett P.; Hanson, Curtis A.; Gangat, Naseema; Tefferi, Ayalew; Patnaik, Mrinal M.

doi:10.1002/ajh.24861

Cited by 34 publications

(46 citation statements)

References 12 publications

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“…Rates of leukemic transformation (AML) vary among different series of CMML patients, with an approximated incidence of 15%‐20% . Risk factors identified have included high risk karyotype, PB blast %, circulating IMC, AMC >10 × 10 9 /L, ASXL1 , RUNX1 , NRAS , SETBP1 , DNMT3A and NPM1 mutations . In a large study of 171 patients with post CMML‐BT the median OS was 6 months, with 1‐,3‐,5‐year survival rates of 25%,9% and 6% respectively .…”

Section: Post Cmml‐blast Transormation (Cmml‐bt)mentioning

confidence: 99%

“…With the exception of a modest survival benefit from allogenic stem cell transplant (HCT; 5‐year survival 21%), all other treatment modalities, including AML‐like induction chemotherapy were associated with dismal outcomes (5‐year survival <10%) . Post‐BT survival was negatively impacted by PB blast percent, prior exposure to HMA, ELN (European Leukemia Net) high risk cytogenetics and a failure to reach a CR/CRi (complete remission/CR with incomplete recovery of counts) with BT‐directed therapies . Rare occurrences of CMML BT to blastic plasmacytoid dendritic cell neoplasms (BPDCN) secondary to specific molecular and copy number alterations have been documented, indicative of common clonal origins …”

Section: Post Cmml‐blast Transormation (Cmml‐bt)mentioning

confidence: 99%

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Chronic Myelomonocytic leukemia: 2020 update on diagnosis, risk stratification and management

2019

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Disease overview: Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes and myeloproliferative neoplasms, with an inherent risk for leukemic transformation (~15% over 3-5 years). Diagnosis: Diagnosis is based on the presence of sustained (>3 months) peripheral blood monocytosis (≥1 × 10 9 /L; monocytes ≥10%), along with bone marrow dysplasia. Clonal cytogenetic abnormalities occur in~30% of patients, while >90% have gene mutations. Mutations involving TET2 (~60%), SRSF2 (~50%), ASXL1 (~40%) and the oncogenic RAS pathway (~30%) are frequent; while the presence of ASXL1 and DNMT3A mutations and the absence of TET2 mutations negatively impact over-all survival. Risk stratification: Molecularly integrated prognostic models include; the Groupe Français des Myélodysplasies (GFM), Mayo Molecular Model (MMM) and the CMML specific prognostic model (CPSS-Mol). Risk factors incorporated into the MMM include presence of nonsense or frameshift ASXL1 mutations, absolute monocyte count>10 × 10 9 /L, hemoglobin <10 g/dL, platelet count <100 × 10 9 /L and the presence of circulating immature myeloid cells. The MMM stratifies CMML patients into four groups; high (≥3 risk factors), intermediate-2 (2 risk factors), intermediate-1 (1 risk factor) and low (no risk factors), with median survivals of 16, 31, 59 and 97 months, respectively.Risk-adapted therapy: Hypomethylating agents such as 5-azacitidine and decitabine are commonly used, with overall response rates of~40%-50% and complete remission rates of~7%-17%; with no impact on mutational allele burdens. Allogeneic stem cell transplant is the only potentially curative option, but is associated with significant morbidity and mortality.

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Section: Post Cmml‐blast Transormation (Cmml‐bt)mentioning

confidence: 99%

Section: Post Cmml‐blast Transormation (Cmml‐bt)mentioning

confidence: 99%

Chronic Myelomonocytic leukemia: 2020 update on diagnosis, risk stratification and management

2019

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“…Such cases show the characteristic morphologic features of CMML, but higher WBC and more severe anemia. They show increased tendency for AML progression and poorer prognosis so that a more aggressive clinical intervention may be indicated …”

Section: Diagnostic Workup Of Suspected Cases Of Cmmlmentioning

confidence: 99%

“…They show increased tendency for AML progression and poorer prognosis so that a more aggressive clinical intervention may be indicated. 61,62 Caution is advised in the interpretation of molecular results as some of these mutations, particularly those affecting epigenetic regulators (as TET2 and ASXL1) can be detected in otherwise healthy individuals without morphologic evidence of an underlying malignancy. This happens as a consequence of aging, a process is known as "clonal hematopoiesis of indeterminate potential" (CHIP) or aging hematopoiesis.…”

Section: Molecular Abnormalitiesmentioning

confidence: 99%

How I investigate chronic myelomonocytic leukemia

Sangiorgio

Arber

Orazi

2019

Int J Lab Hematology

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The 2016 revised 4th edition of the World Health Organization classification of hematopoietic neoplasms updated the diagnostic criteria for chronic myelomonocytic leukemia (CMML). Persistent peripheral blood monocytosis of at least 1 × 109/L and a percentage of monocytes ≥10% of the circulating white blood cell count (WBC) are both prerequisite criteria for this diagnosis. CMML represents the prototype of “overlapping” myeloid neoplasms with concurrent myeloproliferative and myelodysplastic features. However, clinical presentation is heterogeneous, with cases showing prevailing “dysplastic” features and others a predominant “proliferative” phenotype. Accounting for this diversity, two variants of CMML are recognized: “dysplastic” CMML defined by WBC < 13 × 109/L and “proliferative” CMML with WBC ≥ 13 × 109/L often showing features mimicking a myeloproliferative neoplasm. Although not an official WHO category, the “oligomonocytic” variant of CMML is defined by relative monocytosis with an absolute monocyte count of 0.5‐0.9 × 109/L. It can be considered a “pre‐phase,” as it frequently anticipates the development of an overt, classic CMML. In an attempt at improving disease prognostication, the blast count based grading system for CMML of the WHO 2008 Classification has been expanded in 2016 to include a new “CMML‐0” category. Lastly, the large body of knowledge on the molecular events occurring in CMML has been used to assist diagnosis and assess prognosis. Despite the step forwards, diagnosis of CMML still remains one of exclusion as no clinical, pathologic or molecular findings are specific for this disease. The current review brings insight into the spectrum of CMML and provides practical advice to approach suspected cases of CMML.

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“…In comparison with those harboring the wt counterpart, NPM1-mutant CMML patients were more likely to be anemic, have a 'dysplastic CMML subtype', have an increased frequency of DNMT3A and FLT3-ITD, and a lower incidence of TET2 and ASXL1 mutations. 75 To better understand the molecular events following acquisition of the NPM1 mutation in CMML patient, Bolli and colleagues performed exome sequencing of bone marrow DNA at CMML diagnosis, AML diagnosis, and first CR. They found that DNMT3A and TET2 mutations were acquired first, followed by NPM1 and CEBPA mutations.…”

Section: Npm1 Mutations In Amlmentioning

confidence: 99%

Nucleophosmin1 (NPM1) abnormality in hematologic malignancies, and therapeutic targeting of mutant NPM1 in acute myeloid leukemia

Chen

2020

Therapeutic Advances in Hematology

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Nucleophosmin ( NPM1) is an abundant nucleolar protein that is implicated in a variety of biological processes and in the pathogenesis of several human malignancies. For hematologic malignancies, approximately one-third of anaplastic large-cell non-Hodgkin’s lymphomas were found to express a fusion between NPM1 and the catalytic domain of anaplastic lymphoma receptor tyrosine kinase. About 50–60% of acute myeloid leukemia patients with normal karyotype carry NPM1 mutations, which are characterized by cytoplasmic dislocation of the NPM1 protein. Nevertheless, NPM1 is overexpressed in various hematologic and solid tumor malignancies. NPM1 overexpression is considered a prognostic marker of recurrence and progression of cancer. Thus, NPM1 abnormalities play a critical role in several types of hematologic malignancies. This has led to intense interest in the development of an NPM1 targeting strategy for cancer therapy. The aim of this review is to summarize present knowledge on NPM1 origin, pathogenesis, and therapeutic interventions in hematologic malignancies.

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Nucleophosmin 1 (NPM1) mutations in chronic myelomonocytic leukemia and their prognostic relevance

Cited by 34 publications

References 12 publications

Chronic Myelomonocytic leukemia: 2020 update on diagnosis, risk stratification and management

Chronic Myelomonocytic leukemia: 2020 update on diagnosis, risk stratification and management

How I investigate chronic myelomonocytic leukemia

Nucleophosmin1 (NPM1) abnormality in hematologic malignancies, and therapeutic targeting of mutant NPM1 in acute myeloid leukemia

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