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Survival in adult acute lymphoblastic leukaemia (ALL): A report from the Swedish ALL Registry.

ABSTRACT: OBJECTIVES:As new, effective therapies emerge for acute lymphoblastic leukaemia (ALL), the results of clinical trials need to relate to standard of care. METHODS:We used the population-based Swedish ALL Registry to evaluate characteristics, treatment and long-term outcome in 933 patients with diagnosis between 1997 and 2015. RESULTS:The median age was 53 years. The frequency of Philadelphia (Ph)-positive leukaemia was 34% of examined B-ALL with a peak incidence at 50-59 years. Five-year overall survival (OS) improved between 1997-2006 and 2007-2015; in patients 18-45 years from 50% (95% CI 43-57) to 65% (95% CI 58-72), 46-65 years from 25% (95% CI 18-32) to 46% (95% CI 37-55) and >65 years from 7% (95% CI 2.6-11) to 11% (95% CI 5.9-16) (P < 0.05). Men with Ph-neg B-ALL 46-65 years had inferior OS compared with women (P < 0.01). Standardised mortality ratio was 5.7 (95% CI 5.0-6.3) for patients who survived 5 years from diagnosis. In multivariable analysis, Ph-positive disease was not associated with impaired prognosis but with lower risk of death in 2007-2015. CONCLUSIONS:In a population-based cohort, OS has improved in adult ALL, especially for Ph-positive disease but for middle-aged men with Ph-negative B-ALL outcome was poor. Cure without late toxicity or relapse is still desired.

SUBMITTER: Lennmyr E

PROVIDER: S-EPMC6851994 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Survival in adult acute lymphoblastic leukaemia (ALL): A report from the Swedish ALL Registry.

Lennmyr Emma E Karlsson Karin K Ahlberg Lucia L Garelius Hege H Hulegårdh Erik E Izarra Antonio S AS Joelsson Joel J Kozlowski Piotr P Moicean Andreea A Tomaszewska-Toporska Beata B Lübking Anna A Hallböök Helene H

European journal of haematology 20190606 2

<h4>Objectives</h4>As new, effective therapies emerge for acute lymphoblastic leukaemia (ALL), the results of clinical trials need to relate to standard of care.<h4>Methods</h4>We used the population-based Swedish ALL Registry to evaluate characteristics, treatment and long-term outcome in 933 patients with diagnosis between 1997 and 2015.<h4>Results</h4>The median age was 53 years. The frequency of Philadelphia (Ph)-positive leukaemia was 34% of examined B-ALL with a peak incidence at 50-59 yea ...[more]

PMID: 31074910

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Project description:Relapsed acute lymphoblastic leukaemia (ALL) is a leading cause of death due to disease in young people, but the biological determinants of treatment failure remain poorly understood. Recent genome-wide profiling of structural DNA alterations in ALL have identified multiple submicroscopic somatic mutations targeting key cellular pathways, and have demonstrated substantial evolution in genetic alterations from diagnosis to relapse. However, DNA sequence mutations in ALL have not been analysed in detail. To identify novel mutations in relapsed ALL, we resequenced 300 genes in matched diagnosis and relapse samples from 23 patients with ALL. This identified 52 somatic non-synonymous mutations in 32 genes, many of which were novel, including the transcriptional coactivators CREBBP and NCOR1, the transcription factors ERG, SPI1, TCF4 and TCF7L2, components of the Ras signalling pathway, histone genes, genes involved in histone modification (CREBBP and CTCF), and genes previously shown to be targets of recurring DNA copy number alteration in ALL. Analysis of an extended cohort of 71 diagnosis-relapse cases and 270 acute leukaemia cases that did not relapse found that 18.3% of relapse cases had sequence or deletion mutations of CREBBP, which encodes the transcriptional coactivator and histone acetyltransferase CREB-binding protein (CREBBP, also known as CBP). The mutations were either present at diagnosis or acquired at relapse, and resulted in truncated alleles or deleterious substitutions in conserved residues of the histone acetyltransferase domain. Functionally, the mutations impaired histone acetylation and transcriptional regulation of CREBBP targets, including glucocorticoid responsive genes. Several mutations acquired at relapse were detected in subclones at diagnosis, suggesting that the mutations may confer resistance to therapy. These results extend the landscape of genetic alterations in leukaemia, and identify mutations targeting transcriptional and epigenetic regulation as a mechanism of resistance in ALL.

Dataset Information

Survival in adult acute lymphoblastic leukaemia (ALL): A report from the Swedish ALL Registry.

Publications

Survival in adult acute lymphoblastic leukaemia (ALL): A report from the Swedish ALL Registry.

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