Genetic and genomic analysis of acute lymphoblastic leukemia in older adults reveals a distinct profile of abnormalities : analysis of 210 patients from the UKALL14 and UKALL60+ clinical trials
Despite being predominantly a childhood disease, the incidence of acute lymphoblastic leukemia (ALL) has a second peak in adults aged 60 years and over. These older adults fare extremely poorly with existing treatment strategies and very few studies have undertaken a comprehensive genetic and genomic characterization to improve prognosis in this age group. We performed cytogenetic, single nucleotide polymorphism (SNP) array and next-generation sequencing (NGS) analyses on samples from 210 patients aged ≥60 years from the UKALL14 and UKALL60+ clinical trials. BCR-ABL1-positive disease was present in 26% (55/210) of patients, followed by low hypodiploidy/near triploidy in 13% (28/210). Cytogenetically cryptic rearrangements in CRLF2, ZNF384 and MEF2D were detected in 5%, 1% and <1% of patients, respectively. Copy number abnormalities were common and deletions in ALL driver genes were seen in 77% of cases. IKZF1 deletion was present in 51% (40/78) of samples tested and the IKZF1plus profile was identified in over a third (28/77) of cases of B-cell precursor ALL. The genetic good-risk abnormalities high hyperdiploidy (n=2), ETV6-RUNX1 (no cases) and ERG deletion (no cases) were exceptionally rare in this cohort. RAS pathway mutations were seen in 17% (4/23) of screened samples. KDM6A abnormalities, including biallelic deletions, were discovered in 5% (4/78) of SNP arrays and 9% (2/23) of NGS samples, and represent novel, potentially therapeutically actionable lesions using EZH2 inhibitors. Outcome remained poor with 5-year event-free and overall survival rates of 17% and 24%, respectively, across the cohort, indicating a need for novel therapeutic strategies.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2022 |
|---|---|
| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:107 |
|---|---|
| Enthalten in: |
Haematologica - 107(2022), 9 vom: 01. Sept., Seite 2051-2063 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Creasey, Thomas [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
|---|
| Anmerkungen: |
Date Completed 08.09.2022 Date Revised 10.02.2024 published: Electronic Citation Status MEDLINE |
|---|
| doi: |
10.3324/haematol.2021.279177 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM333266404 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM333266404 | ||
| 003 | DE-627 | ||
| 005 | 20240210232409.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2022 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.3324/haematol.2021.279177 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1286.xml |
| 035 | |a (DE-627)NLM333266404 | ||
| 035 | |a (NLM)34788984 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Creasey, Thomas |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Genetic and genomic analysis of acute lymphoblastic leukemia in older adults reveals a distinct profile of abnormalities |b analysis of 210 patients from the UKALL14 and UKALL60+ clinical trials |
| 264 | 1 | |c 2022 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 08.09.2022 | ||
| 500 | |a Date Revised 10.02.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Despite being predominantly a childhood disease, the incidence of acute lymphoblastic leukemia (ALL) has a second peak in adults aged 60 years and over. These older adults fare extremely poorly with existing treatment strategies and very few studies have undertaken a comprehensive genetic and genomic characterization to improve prognosis in this age group. We performed cytogenetic, single nucleotide polymorphism (SNP) array and next-generation sequencing (NGS) analyses on samples from 210 patients aged ≥60 years from the UKALL14 and UKALL60+ clinical trials. BCR-ABL1-positive disease was present in 26% (55/210) of patients, followed by low hypodiploidy/near triploidy in 13% (28/210). Cytogenetically cryptic rearrangements in CRLF2, ZNF384 and MEF2D were detected in 5%, 1% and <1% of patients, respectively. Copy number abnormalities were common and deletions in ALL driver genes were seen in 77% of cases. IKZF1 deletion was present in 51% (40/78) of samples tested and the IKZF1plus profile was identified in over a third (28/77) of cases of B-cell precursor ALL. The genetic good-risk abnormalities high hyperdiploidy (n=2), ETV6-RUNX1 (no cases) and ERG deletion (no cases) were exceptionally rare in this cohort. RAS pathway mutations were seen in 17% (4/23) of screened samples. KDM6A abnormalities, including biallelic deletions, were discovered in 5% (4/78) of SNP arrays and 9% (2/23) of NGS samples, and represent novel, potentially therapeutically actionable lesions using EZH2 inhibitors. Outcome remained poor with 5-year event-free and overall survival rates of 17% and 24%, respectively, across the cohort, indicating a need for novel therapeutic strategies | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 700 | 1 | |a Barretta, Emilio |e verfasserin |4 aut | |
| 700 | 1 | |a Ryan, Sarra L |e verfasserin |4 aut | |
| 700 | 1 | |a Butler, Ellie |e verfasserin |4 aut | |
| 700 | 1 | |a Kirkwood, Amy A |e verfasserin |4 aut | |
| 700 | 1 | |a Leongamornlert, Daniel |e verfasserin |4 aut | |
| 700 | 1 | |a Papaemmanuil, Elli |e verfasserin |4 aut | |
| 700 | 1 | |a Patrick, Pip |e verfasserin |4 aut | |
| 700 | 1 | |a Clifton-Hadley, Laura |e verfasserin |4 aut | |
| 700 | 1 | |a Patel, Bela |e verfasserin |4 aut | |
| 700 | 1 | |a Menne, Tobias |e verfasserin |4 aut | |
| 700 | 1 | |a McMillan, Andrew K |e verfasserin |4 aut | |
| 700 | 1 | |a Harrison, Christine J |e verfasserin |4 aut | |
| 700 | 1 | |a Rowntree, Clare J |e verfasserin |4 aut | |
| 700 | 1 | |a Morley, Nick |e verfasserin |4 aut | |
| 700 | 1 | |a Marks, David I |e verfasserin |4 aut | |
| 700 | 1 | |a Fielding, Adele K |e verfasserin |4 aut | |
| 700 | 1 | |a Moorman, Anthony V |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Haematologica |d 1947 |g 107(2022), 9 vom: 01. Sept., Seite 2051-2063 |w (DE-627)NLM000081892 |x 1592-8721 |7 nnns |
| 773 | 1 | 8 | |g volume:107 |g year:2022 |g number:9 |g day:01 |g month:09 |g pages:2051-2063 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.3324/haematol.2021.279177 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 107 |j 2022 |e 9 |b 01 |c 09 |h 2051-2063 | ||