Molecular genetics of B-precursor acute lymphoblastic leukemia

Mullighan, Charles G.

doi:10.1172/jci61203

Cited by 215 publications

(195 citation statements)

References 124 publications

(126 reference statements)

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“…The reason for the poor prognosis of early relapses is probably different disease biology. 19 Whereas late relapses may arise from slowly-cycling still chemotherapy-sensitive subclones of ALL, early relapses probably arise from selected, chemotherapy-resistant subclones that proliferate despite ongoing standard chemotherapy. 19,20 Interestingly, the rate of CR and OS among patients However, an analysis limited to those study groups or sites that provided data over the entire calendar period (i.e., from 1990 onward) showed no significant trends over time.…”

Section: Discussionmentioning

confidence: 99%

“…19 Whereas late relapses may arise from slowly-cycling still chemotherapy-sensitive subclones of ALL, early relapses probably arise from selected, chemotherapy-resistant subclones that proliferate despite ongoing standard chemotherapy. 19,20 Interestingly, the rate of CR and OS among patients However, an analysis limited to those study groups or sites that provided data over the entire calendar period (i.e., from 1990 onward) showed no significant trends over time. CR and OS also differed between study groups or centers, which may be due to differences in the distribution of patient or prognostic factors, such as US sites having patients with more lines of salvage and more patients treated from 1990-2000 than the European study groups or centers.…”

Section: Discussionmentioning

confidence: 99%

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International reference analysis of outcomes in adults with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia

et al. 2016

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A dults with relapsed/refractory acute lymphoblastic leukemia have an unfavourable prognosis, which is influenced by disease and patient characteristics. To further evaluate these characteristics, a retrospective analysis of 1,706 adult patients with Ph-negative relapsed/refractory B-precursor acute lymphoblastic leukemia diagnosed between 1990-2013 was conducted using data reflecting the standard of care from 11 study groups and large centers in Europe and the United States. Outcomes included complete remission, overall survival, and realization of stem cell transplantation after salvage treatment. The overall complete remission rate after first salvage was 40%, ranging from 35%-41% across disease status categories (primary refractory, relapsed with or without prior transplant), and was lower after second (21%) and third or greater (11%) salvage. The overall complete remission rate was higher for patients diagnosed from 2005 onward (45%, 95% CI: 39%-50%). One-and three-year survival rates after first, second, and third or greater salvage were 26% and 11%, 18% and 6%, and 15% and 4%, respectively, and rates were 2%-5% higher among patients diagnosed from 2005. Prognostic factors included younger age, longer duration of first remission, and lower white blood cell counts at primary diagnosis. This large dataset can provide detailed reference outcomes for patients with relapsed/refractory Ph-negative B-precursor acute lymphoblastic leukemia. clinicaltrials.gov identifier: 02003612 IntroductionOverall prognosis among adult acute lymphoblastic leukemia (ALL) patients has improved by optimisation of front-line therapy, 1 but outcomes remain poor for patients who relapse or are refractory to initial treatment. Reported rates of complete remission (CR) after salvage treatment range from 18%-45%, and median survival times range from 2-8 months, with less than 10% survival after 5 years in most studies.2-7 Achievement of CR and subsequent HSCT is the only curative option in relapsed adult ALL; 2,3,6 however, this can only be achieved in a subgroup For these reasons, new treatment options are needed for adult patients with relapsed/refractory (r/r) ALL, and a number of promising compounds are currently under clinical evaluation. 8,9 The rarity of adult r/r ALL, 10 combined with the very poor outcomes and non-standardised approaches of salvage therapies, make it difficult to conduct randomised trials of new compounds. Approvals of new treatments are therefore often based on evidence from phase 2 single-arm trials. 11-14To attain a more precise estimate of clinical practice outcomes in adult r/r ALL, and to evaluate important patient subgroups, we pooled data from major national study groups and large individual sites treating adult ALL from Europe and the United States to create the most extensive clinical dataset available in this population.The analysis aimed to describe patient characteristics and outcome parameters (achievement of CR, overall survival [OS] and realization of allogeneic HSCT) among adult patients with P...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

International reference analysis of outcomes in adults with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia

et al. 2016

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“…Along these lines, genes involved are EBF1, RAG1 and RAG2 genes, signal transduction genes like JAK/STAT or SLP65/BLNK, cytokine receptor genes like IL7R, FLT3, TSLP/CRLF2. Also of course, like in most other cancers, genes involved in cell proliferation/cell cycle like CDKN2A/ CDKN2B, RB1, TP53, or in control of cell death like BCL2, or BTG1, are also participating in many cases of human B-ALL (reviewed in 61,92,93 ).…”

Section: Mll-involving Translocations-based Gemmsmentioning

confidence: 99%

Genetically engineered mouse models of human B-cell precursor leukemias

2014

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“…46 Many of these alterations have not yet been shown to have clinical meaningfulness. One of the more common of these abnormalities is IKZF1 alterations, which occur in ϳ15% of pediatric ALL cases and are associated with an unfavorable prognosis.…”

Section: Disease Factorsmentioning

confidence: 99%

Clinically defining and managing high-risk pediatric patients with acute lymphoblastic leukemia

Alexander

2014

Hematology

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For children with acute lymphoblastic leukemia, the identification of those at higher risk of disease recurrence and modifying therapy based on this risk is a critical component to the provision of optimal care. The specific definitions of high-risk ALL vary across cooperative groups, but the themes are consistent, being largely based on leukemia biology and disease response. Intensification of conventional chemotherapy for those with high-risk disease has led to improved outcomes. It is anticipated that the development of rational targeted therapy for specific biologically unique subsets of children with leukemia will contribute to ongoing progress in improving the outcomes for children with acute lymphoblastic anemia. Learning Objectives• To understand current criteria used to identify children with high-risk ALL • To understand therapeutic strategies for children with highrisk ALL

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Molecular genetics of B-precursor acute lymphoblastic leukemia

Cited by 215 publications

References 124 publications

International reference analysis of outcomes in adults with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia

International reference analysis of outcomes in adults with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia

Genetically engineered mouse models of human B-cell precursor leukemias

Clinically defining and managing high-risk pediatric patients with acute lymphoblastic leukemia

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