Cytogenetic findings in adult secondary acute myeloid leukemia (AML): frequency of favorable and adverse chromosomal aberrations do not differ from adult de novo AML

Preiss, Birgitte; Bergmann, Olav J.; Friis, Lone Smidstrup; Sørensen, Anne G.; Frederiksen, Michael; Gadeberg, Ole; Mourits-Andersen, Torben; Oestergaard, Birthe; Kerndrup, Gitte

doi:10.1016/j.cancergencyto.2010.06.013

Cited by 27 publications

(20 citation statements)

References 26 publications

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“…The proportion of patients with secondary AML found in our study (26.4%) was also higher compared to most previous studies [3,[20][21][22]. The proportion of patients with t-AML (7.7%) is slightly higher compared to most other studies [2,3,7,[19][20][21], which could be due to our rigorous reporting of the primary disease, also including nonmalignant diseases treated by chemotherapy and/or radiation. T-AML was defined as any exposure to a cytotoxic agent or radiation, regardless of dose or the time of exposure.…”

Section: Discussioncontrasting

confidence: 73%

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Characterization and prognostic features of secondary acute myeloid leukemia in a population‐based setting: A report from the Swedish Acute Leukemia Registry

et al. 2015

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Patients with secondary acute myeloid leukemia (AML) often escape inclusion in clinical trials and thus, population-based studies are crucial for its accurate characterization. In this first large population-based study on secondary AML, we studied AML with an antecedent hematological disease (AHD-AML) or therapyrelated AML (t-AML) in the population-based Swedish Acute Leukemia Registry. The study included 3,363 adult patients of which 2,474 (73.6%) had de novo AML, 630 (18.7%) AHD-AML, and 259 (7.7%) t-AML. Secondary AML differed significantly compared to de novo AML with respect to age, gender, and cytogenetic risk. Complete remission (CR) rates were significantly lower but early death rates similar in secondary AML. In a multivariable analysis, AHD-AML (HR 1.51; 95% CI 1.26-1.79) and t-AML (1.72; 1.38-2.15) were independent risk factors for poor survival. The negative impact of AHD-AML and t-AML on survival was highly age dependent with a considerable impact in younger patients, but without independent prognostic value in the elderly. Although patients with secondary leukemia did poorly with intensive treatment, early death rates and survival were significantly worse with palliative treatment. We conclude that secondary AML in a population-based setting has a striking impact on survival in younger AML patients, whereas it lacks prognostic value among the elderly patients.

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Section: Discussioncontrasting

confidence: 73%

“…The high median age of 71 years in this study demonstrate its true population-based nature with a median age substantially higher when compared with previous reports on secondary AML [2,6,8,18,19]. The proportion of patients with secondary AML found in our study (26.4%) was also higher compared to most previous studies [3,[20][21][22].…”

Section: Discussioncontrasting

confidence: 66%

Characterization and prognostic features of secondary acute myeloid leukemia in a population‐based setting: A report from the Swedish Acute Leukemia Registry

et al. 2015

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“…Del(7q) was persistently detected in 15 patients (including 13 patients who were ultimately diagnosed with therapy-related myeloid neoplasms), and became undetectable in 12 patients (11 who were not diagnosed with therapy-related myeloid neoplasms). Two patients (cases 15 and 17) showed clonal evolution with additional chromosomal abnormalities after 8 and 22 months respectively, and 2 patients (cases 18 and 36) had new unrelated clones that emerged after del(7q) disappeared, specifically case 18 showed 45,XY,der(6;7) (p10;q10) [4]/46,XY,add(11)(p15) [3]/46,XY [13], and case 36 showed 46,XY,del(11)(q22q23) [16]/46,XY [4].…”

Section: Follow-up and Outcomesmentioning

confidence: 99%

“…[1][2][3] Del(7q)/ − 7 occurs in~8% of de novo acute myeloid leukemia and~10% of de novo myelodysplastic syndromes. 1,4 Del(7q) has been classified as the intermediate-II risk group in de novo acute myeloid leukemia 5 and the intermediate risk group in de novo myelodysplastic syndromes, respectively.…”

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confidence: 99%

Newly emerged isolated Del(7q) in patients with prior cytotoxic therapies may not always be associated with therapy-related myeloid neoplasms

et al. 2016

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Deletion 7q is a common chromosomal abnormality in myeloid neoplasms. Detection of del(7q) in patients following cytotoxic therapies is highly suggestive of an emerging therapy-related myeloid neoplasm. In this study, we describe 39 patients who acquired del(7q) as a sole abnormality in their bone marrow following cytotoxic therapies for malignant neoplasms. The median interval from cytotoxic therapies to detection of del(7q) was 40 months (range, 4-190 months). Twenty-eight patients showed an interstitial and 11 showed a terminal 7q deletion. Fifteen patients (38%) had del(7q) as a large clone and 24 (62%) as a small clone. With a median followup of 21 months (range, 1-135 months), 18 (46%) patients developed therapy-related myeloid neoplasms, including all 15 patients with a large del(7q) clone and 3/24 (12.5%) with a small clone. Of the remaining 21 patients with a small del(7q) clone, 16 showed no evidence of therapy-related myeloid neoplasms and 5 had an inconclusive pathological diagnosis. We conclude that isolated del(7q) emerging in patients after cytotoxic therapy may not always be associated with therapy-related myeloid neoplasms in about half of patients. The clone size of del(7q) is critical; a large clone is almost always associated with therapy-related myeloid neoplasms, whereas a small clone can be a clinically indolent or transient finding. Abnormalities of chromosome 7, either monosomy (−7) or deletion of the long arm (del(7q)), are the most common cytogenetic abnormalities detected in acute myeloid leukemia and myelodysplastic syndromes. 1-3 Del(7q)/ − 7 occurs in~8% of de novo acute myeloid leukemia and~10% of de novo myelodysplastic syndromes. 1,4 Del(7q) has been classified as the intermediate-II risk group in de novo acute myeloid leukemia 5 and the intermediate risk group in de novo myelodysplastic syndromes, respectively. 6 Therapy-related myeloid neoplasm is a late complication of cytotoxic therapies for primary malignant and non-malignant diseases. Cytogenetic abnormalities can be detected in more than 90% of patients with therapy-related myeloid neoplasms, and more than half of these patients have a complex karyotype. 7 Del(7q)/ − 7 presents in~50% of patients with therapy-related myeloid neoplasms and are often associated with prior exposure to alkylating agents or ionizing radiation. 1,[8][9][10][11][12][13] Any newly emerged cytogenetic abnormalities in patients with a prior history of cytotoxic therapies often raises the concern of development of therapy-related myeloid neoplasms, especially when the abnormalities include del(7q)/ − 7.In our practice, we have observed that some patients develop isolated del(7q) in their bone marrow following cytotoxic therapies, yet never develop therapy-related myeloid neoplasms with close follow-up. In order to better understand the

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“…3 Ϫ7/del(7q) is also found in myelodysplastic syndromes, AMLs arising from myeloproliferative neoplasms, the blast phase of chronic myelogenous leukemia, Ph ϩ acute lymphoblastic leukemia, and AMLs associated with inherited syndromes. [4][5][6][7][8][9][10] Ϫ7/del(7q) is an adverserisk prognostic indicator in myeloid disorders, and the long-term outcome for patients is typically poor. The median overall survival for patients with de novo AML or t-MNs with Ϫ7/del(7q) is ϳ 6 months.…”

Section: Introductionmentioning

confidence: 99%

CUX1 is a haploinsufficient tumor suppressor gene on chromosome 7 frequently inactivated in acute myeloid leukemia

McNerney

Brown

Wang

et al. 2013

Blood

139

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Key Points• CUX1 is a transcription factor encoded on a region of chromosome 7 that is frequently deleted in high-risk acute myeloid leukemia.• Haploinsufficiency of CUX1/ cut promotes hematopoietic overgrowth in both Drosophila melanogaster and human xenograft mouse models in vivo.Loss of chromosome 7 and del(7q) [؊7/del(7q)] are recurring cytogenetic abnormalities in hematologic malignancies, including acute myeloid leukemia and therapy-related myeloid neoplasms, and associated with an adverse prognosis. Despite intensive effort by many laboratories, the putative myeloid tumor suppressor(s) on chromosome 7 has not yet been identified. We performed transcriptome sequencing and SNP array analysis on de novo and therapy-related myeloid neoplasms, half with ؊7/del(7q). We identified a 2.17-Mb commonly deleted segment on chromosome band 7q22.1 containing CUX1, a gene encoding a homeodomain-containing transcription factor. In 1 case, CUX1 was disrupted by a translocation, resulting in a loss-of-function RNA fusion transcript. CUX1 was the most significantly differentially expressed gene within the commonly deleted segment and was expressed at haploinsufficient levels in ؊7/del(7q) leukemias. Haploinsufficiency of the highly conserved ortholog, cut, led to hemocyte overgrowth and tumor formation in Drosophila melanogaster. Similarly, haploinsufficiency of CUX1 gave human hematopoietic cells a significant engraftment advantage on transplantation into immunodeficient mice. Within the RNA-sequencing data, we identified a CUX1-associated cell cycle transcriptional gene signature, suggesting that CUX1 exerts tumor suppressor activity by regulating proliferative genes. These data identify CUX1 as a conserved, haploinsufficient tumor suppressor frequently deleted in myeloid neoplasms. (Blood. 2013;121(6):975-983) IntroductionLoss of chromosome 7 and del(7q) [Ϫ7/del(7q)] was first recognized as a frequent event in acute myeloid leukemia (AML) nearly 40 years ago. 1 Ϫ7/del(7q) occurs in 8% of de novo AML 2 and 50% of therapy-related myeloid neoplasms (t-MNs). 3 Ϫ7/del(7q) is also found in myelodysplastic syndromes, AMLs arising from myeloproliferative neoplasms, the blast phase of chronic myelogenous leukemia, Ph ϩ acute lymphoblastic leukemia, and AMLs associated with inherited syndromes. 4-10 Ϫ7/del(7q) is an adverserisk prognostic indicator in myeloid disorders, and the long-term outcome for patients is typically poor. The median overall survival for patients with de novo AML or t-MNs with Ϫ7/del(7q) is ϳ 6 months. 2,3 Loss of 1 or more tumor suppressor gene(s) (TSGs) is thought to contribute to leukemic growth in myeloid malignancies with Ϫ7/del(7q). Several groups have mapped a commonly deleted segment (CDS) of chromosome band 7q22 using polymorphic markers, conventional cytogenetic analysis, and FISH analysis. [11][12][13] In one study of 81 patients with malignant myeloid disorders characterized by chromosome 7 abnormalities, the CDS was mapped to a 2.52-Mb region of 7q22 by FISH using YAC clones. 11 However, deletion ...

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Cytogenetic findings in adult secondary acute myeloid leukemia (AML): frequency of favorable and adverse chromosomal aberrations do not differ from adult de novo AML

Cited by 27 publications

References 26 publications

Characterization and prognostic features of secondary acute myeloid leukemia in a population‐based setting: A report from the Swedish Acute Leukemia Registry

Characterization and prognostic features of secondary acute myeloid leukemia in a population‐based setting: A report from the Swedish Acute Leukemia Registry

Newly emerged isolated Del(7q) in patients with prior cytotoxic therapies may not always be associated with therapy-related myeloid neoplasms

CUX1 is a haploinsufficient tumor suppressor gene on chromosome 7 frequently inactivated in acute myeloid leukemia

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