ASXL1 mutated chronic myelomonocytic leukemia in a patient with familial thrombocytopenia secondary to germline mutation in ANKRD26

Botero, Juliana Perez; Oliveira, Jennifer L.; Chen, D; Reichard, Kaaren K.; Viswanatha, David S.; Nguyen, Phuong L.; Pruthi, Rajiv K.; Majerus, Julie A.; Gada, Purvi; Gangat, Naseema; Tefferi, Ayalew; Patnaik, Mrinal M.

doi:10.1038/bcj.2015.41

Cited by 32 publications

(10 citation statements)

References 11 publications

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“…There unfortunately exists no prospective data analyzing the risks and benefits for HCT in CMML. The response rates in retrospective studies have ranged from 17% to 50%, with corresponding treatment related mortality rates ranging from 12% to 52% (Table ) . The 10‐year OS of 85 patients who underwent HCT at Fred Hutchinson Cancer Center was 40%.…”

Section: Risk Adapted Therapymentioning

confidence: 99%

“…The European Group for Blood and Marrow Transplantation reported an OS of 42% for 283 patients with CMML that underwent HCT. None of the baseline factors including the conditioning regimen, age, disease status at transplant, cytogenetics, donor‐recipient gender match, HLA‐type of donor, stem cell source, T‐cell depletion or the development of GVHD affected the RFS or OS . A recent application of the CPSS in the HCT setting, assessed 209 adult patients from 2001 to 2012 with a median age of 57 years and followed for a median of 51 months .…”

Section: Risk Adapted Therapymentioning

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: Risk Adapted Therapymentioning

confidence: 99%

Section: Risk Adapted Therapymentioning

confidence: 99%

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

2019

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“…In addition to c. 473A > G, 11 other single nucleotide mutations within the 5 UTR mutation of ANKRD26 were confirmed to be pathogenic, they are c. Table 2). There was only one Noris et al, 2011;Pippucci et al, 2011;Perez Botero et al, 2015 c.-118 C > A 3(8) Noris et al, 2011Noris et al, , 2013Boutroux et al, 2015 C > G 1(1) Diep et al, 2019 C > T 7(25) Noris et al, 2011Noris et al, , 2013Pippucci et al, 2011;Marquez et al, 2014;Ouchi-Uchiyama et al, 2015;Diep et al, 2019 c. c.-125 T > G 3(5) Noris et al, 2011;Pippucci et al, 2011;Marconi et al, 2017 c.-126 T > C 1(7) Najm et al, 2013;Ventz et al, 2013 T > G 3(6) Noris et al, 2011Noris et al, , 2013 c.-127 A > G 3(13) Noris et al, 2011Noris et al, , 2013 A > T 8(30) Noris et al, 2011Noris et al, , 2013Pippucci et al, 2011;Boutroux et al, 2015;Vincenot et al, 2016 A > C 1(6) Guison et al, 2017 Del AT 1(6) Noris et al, 2013;Bluteau et al, 2014 c.-128 G > A 16(69) Noris et al, 2011Noris et al, , 2013Pippucci et al, 2011;Ferrari et al, 2016Ferrari et al, , 2017Zaninetti et al, 2017 G > C 2(4) Noris et al, 2013;…”

Section: Discussionmentioning

confidence: 99%

A Rare Big Chinese Family With Thrombocytopenia 2: A Case Report and Literature Review

et al. 2020

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Thrombocytopenia 2 (THC2) is one of the most prevalent forms of inherited thrombocytopenia. It is caused by a heterogeneous group of ANKRD26 gene mutation and shows a heterogeneous clinical and laboratory characteristics. We present a big Chinese family with 10 THC2 patients carrying c.-128G > T heterozygous substitution in the 5-untranslated region of the ANKRD26 gene. Although the platelets are fewer than 50 × 10 9 /L in 8 THC2 family members, only the proband and her son show a higher WHO bleeding score. The proband and her son are also beta-thalassemia carriers with heterozygous c.52A > T mutation of HBB, which might not be associated with the increased bleeding tendency since 3 other family members with low bleeding tendency also carried both ANKRD26 c.-128G > T and HBB c.52A > T mutations. However, the proband and her son also show hypofibrinogenaemia, which is likely the cause of their more severe clinical manifestation. HID1 c.442G > T mutation was detected not only in these two hypofibrinogenaemia family members but also in the other 8 family members with normal blood fibrinogen levels. Our study suggests that the co-occurrence of other inherited genetic conditions associated with blood coagulation might contribute to the heterogeneity of clinical and laboratory characteristics in THC2 patients. Considering the hematologic and myeloid malignancy predisposition of THC2 patients and a large population of immune thrombocytopenia in China, we urge more attention to be paid to the diagnosis of THC2 patients to avoid misdiagnosis and mistreatment.

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“…Loss of RUNX1 and friend leukemia integration 1 transcription factor (FLI1) and increased signaling of MPL have been implicated in the pathogenesis of myeloid malignancies in the patients with ANKRD26 mutations [4]. ASXL1-mutated chronic myelomonocytic leukemia has also been reported in a patient with ANKRD26-RT [6]. Zhang et al have previously described hereditary association between thrombocytopenia and hematological malignancies including one case of multiple myeloma in three families with germline ETV6 mutation [7], but there is no reported case of ANKRD26 RT and multiple myeloma.…”

Section: Discussionmentioning

confidence: 99%

Multiple Myeloma in a Patient with ANKRD26-Related Thrombocytopenia Successfully Treated with Combination Therapy and Autologous Stem Cell Transplant

Husnain

Wang

Valdes

et al. 2019

Case Reports in Hematology

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Ankyrin repeat domain-containing protein 26- (ANKRD26-) related thrombocytopenia is a rare, autosomal dominant condition caused by ANKRD26 gene mutation. ANKRD26-related thrombocytopenia is characterized by moderate thrombocytopenia with minimal bleeding, normal platelet size, and dysmegakaryopoiesis on bone marrow evaluation. ANKRD26 mutation has been previously associated with myeloid malignancies, including acute myeloid leukemia, myelodysplastic syndrome, and chronic myeloid leukemia. We report the first case of multiple myeloma in a patient with ANKRD26 related thrombocytopenia. The patient was successfully treated with contemporary combination therapy followed by melphalan-conditioned autologous stem cell transplant for his multiple myeloma despite preexisting thrombocytopenia.

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ASXL1 mutated chronic myelomonocytic leukemia in a patient with familial thrombocytopenia secondary to germline mutation in ANKRD26

Cited by 32 publications

References 11 publications

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

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

A Rare Big Chinese Family With Thrombocytopenia 2: A Case Report and Literature Review

Multiple Myeloma in a Patient with ANKRD26-Related Thrombocytopenia Successfully Treated with Combination Therapy and Autologous Stem Cell Transplant

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