Prognostic Significance of Copy Number Alterations in B-lineage Adult Acute Lymphoblastic Leukemia Patients Enrolled in Risk-adapted Protocols from the PETHEMA Group

2015 ◽  
Vol 15 ◽  
pp. S173-S174
Author(s):  
Jordi Ribera ◽  
Lurdes Zamora ◽  
Mireia Morgades ◽  
Isabel Granada ◽  
Neus Ruiz-Xivillé ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Copy Number ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Copy Number Alterations ◽  
Adult Acute Lymphoblastic Leukemia ◽  
B Lineage

Prognostic Significance Of Copy Number Alterations In B-Lineage Adult Acute Lymphoblastic Leukemia Patients Enrolled In Risk-Adapted Protocols From The Pethema Group

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2556-2556
Author(s):  
Jordi Ribera ◽  
Lurdes Zamora ◽  
Mireia Morgades ◽  
Ramon Guardia ◽  
Josep Sarrá ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Copy Number ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Advanced Age ◽  
Copy Number Alterations ◽  
Gene Deletions ◽  
B Lineage ◽  
Wbc Count

Abstract Introduction In the last years genome wide profilings have identified recurrent Copy Number Alterations (CNA) in genes potentially involved in the pathogenesis of Acute Lymphoblastic Leukemia (ALL). These studies have identified deletions in B-cell development genes (IKZF1, EBF1, PAX5, TCF3, etc.), cell cycle regulation genes (CDKN2A/B, RB1, TP53, etc.), glucocorticoid resistance genes (BTG1, CREBBP) and growth factor receptors genes (CRLF2, CSF2RA, IL3RA) among others. Some of these CNA (i.e. IKZF1, CDKN2A, CRLF2) have been reported to have prognostic significance in several pediatric series but there are very few data regarding their impact in B-lineage adult ALL. Our aim was to analyze the frequency and prognostic significance of CNA in a series of 125 B-lineage adult ALL patients treated according to risk-adapted protocols from the Spanish PETHEMA Group. Methods Bone marrow or peripheral blood (with significant blast burden) samples from 125 B-lineage adult ALL patients enrolled in risk-adapted protocols from the PETHEMA Group were analyzed at diagnosis. MLPA assays (MRC-Holland) were performed for the following genes: IKZF1, IKZF2, IKZF3, EBF1, CDKN2A/B, PAX5, ETV6, BTG1, RB1, hsa-miR-31, X/Y PAR1 region genes (CRLF2, CSF2RA, IL3RA) and 14q32.33 region genes (IGH D, MTA1, KIAA0284). Fragment analysis was made by Genescan in an ABI-3130 sequencer (Applied Biosystems). Data normalization provided a value indicative of the presence or absence of CNA: 0-0.20 homozygous deletion, 0.21-0.70 heterozygous deletion, 0.71-1.30 normal, 1.31-1.70 heterozygous duplication and 1.71-2.20 homozygous duplication. Results The median age [range] was 40 [15-74] years, 71 (57%) males, median WBC count 12.11 x109/L [0.4-388]. Immunophenotype: pro-B 14 (11%), common 71 (58%), pre-B 26 (21%), mature-B 10 (8%), unavailable 2 (2%). Cytogenetics: normal 16 (13%), hyperdiploid 6 (5%), hypodiploid 2 (2%), t(9:22) 20 (16%), t(1;19) 8 (6%), 11q23/MLL 11 (9%), 8q24/C-MYC 7 (5%), complex 1 (1%), iAMP21 2 (2%), other translocations or deletions 31 (25%), no growth 20 (16%). CNA frequencies of the 125 patients are shown in the table. IKZF1 deletions were significantly associated with EBF1 deletions, high WBC count and Philadelphia (Ph) chromosome. In the IKZF1 deleted cohort whole gene deletions were as frequent as Ik6 isoforms (28% each). A high codeletion rate was detected in genes located in 9p (CDKN2A/B with PAX5, CDKN2A/B with hsa-miR-31 and PAX5 with hsa-miR-31). CDKN2A/B also showed concomitant deletions with ETV6 while PAX5 showed codeletions with BTG1. CDKN2A/B and PAX5 deleted patients had higher WBC counts than non-deleted individuals. Clinical follow-up data was available for 123 patients of the whole series and for the 105 patients of the Ph-negative cohort. Multivariate analysis showed that advanced age, BTG1 deletions and EBF1 deletions were negative prognostic factors for achieving Complete Remission (CR) and WBC count and IKZF1 deletions significantly reduced CR duration in both cohorts. Interestingly, there were significant differences in relapse rates between whole and partial gene IKZF1 deletions. IKZF1 haploinsufficient patients had a probability of CR duration at 3 years of 83% ± 30% vs. 6% ± 12% of partial gene deletion carriers. Advanced age and IKZF1 deletions were predictors for overall survival in the Ph-negative cohort and age>30 years, IKZF1 deletions and hsa-miR-31 deletions were associated with poor prognosis in the whole series. Conclusions In B-lineage adult ALL, deletions of IKZF1, EBF1, BTG1 or hsa-miR-31 are markers with prognostic significance in addition to age and WBC count. Patients with partial IKZF1 gene deletions have a significantly higher probability of relapse than those with whole gene loss. These genetic abnormalities could help to better define prognostic subgroups in adult patients with B-lineage ALL. Supported by the grants PI10/01417 and RD12-0036-0029 from Instituto Carlos III and a grant from the Spanish Society of Hematology and Hemotherapy (2012). Disclosures: No relevant conflicts of interest to declare.

Correlation Between Clinical Features, CRLF2 Expression and Copy Number Alterations In Acute Lymphoblastic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4953-4953
Author(s):  
Juan Carlos Ponce Jarquin ◽  
Rosa M. Ayala ◽  
Ana Belen Dueñas Perez ◽  
Daniel Rueda ◽  
María Luisa Martin Ramos ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Copy Number ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Progression Free Survival ◽  
Copy Number Alterations ◽  
Free Survival ◽  
Risk Of Death ◽  
Increased Risk ◽  
Ph Chromosome

Abstract Background Acute lymphoblastic leukemia (ALL) is a heterogeneous disease comprising different genetic abnormalities. An increased cytokine receptor-like factor 2 (CRLF2) expression is associated with activating the JAK-STAT pathway and activation and leukemia initiation. Several studies have shown that some first events are insufficient to cause the development of ALL and other genetic changes are required. In 60% of cases, the altered genes are involved in lymphoid maturation (PAX, IKZF1, EBF, LEF1, BTALA/CD200, TOX), cell cycle control and tumour suppression (CDKN2A/B, PTEN, RB), or transcription factors and coactivators (ETV6, ERG, TBL1XR1). But the prognostic significance of deregulated CRLF2 mRNA expression in patients with CNA in the genes previously mentioned is not fully identified. Aims To analyze the frequency and prognostic significance of deregulated expression of  CRLF2 and the copy number alterations (CNA) in EBFF1, IKZF1, JAK2, CDKN, PAX, ETV, BTG1 and RB in a series of ALL patients enrolled in BFM, SHOP or PETHEMA clinical trials. Methods Bone Marrow samples at diagnosis from 69 ALL patients treated in Hospital Universitario 12 de Octubre, between January 2001 and December 2012, were studied by Multiplex ligation- dependent probe amplifications (MLPA) method was used to detect deletions or duplications of IKZF1, PAX5, ETV6, RB1, BTG1, EBF1 and CDKN2A-CDKN2B genes (SALSA MLPA kit P335-B1 ALL-IKZF1; MRC- Holland). Raw data was analyzed using Coffalyzer software (MRC-Holland) Results The median age was 22 years (0.9-88), 40 (58%) male and 29 (42%) female, median WBC count 70,753 x109/L (1,000 – 633,780). B-ALL subtype in 64 cases (92%) and T-ALL subtype in 5 cases (8%). Cytogenetics: 10 normal (14.5%), 16 hyperdiploid (20,5%), 8 t(9;22)(10.3%),4 cases 11q23/MLL (5.1%), and 24 (30.8%) with  other translocations or deletions and no growth (23.1%).  Cytogenetics risk was favourable in 25 cases (26.6%), intermediate in 10 cases (10.6%) and poor in 25 cases (26.6%). CRLF2 expression and CAN results are shown in table 1. CRFL2 over expression was found in 18 cases (23%), it was associated with deletions of IKZF1 (p0.013). Deletions of CDNK were associated with T-ALL subtype (p0.049) and with a tendency to deletions TEL group (p0.081). Deletions of PAX were associated with JAK2 deletions (p0.027) and with a tendency to IKZF1 deletions (p0.064). Rb deletions were associated with ph+ ALL (p0.001) and it had a tendency to the risk of death. Other molecular alterations found were gains of gen EBF 2 (2.6%), IKZF 2 (2.6%), CDKN 4 (5.1%), PAX 5(6.4%), BTG   2 (2.6%), RB 2 (2.6%). There was no association between hyperdiploid karyotype and any of the gene gains analyzed. Regarding survival, CDKN deletions 2A/ B were associated with decreasing of progression free survival P (0.051), independent of the presence of Ph chromosome. Deletions of IKZF1 showed an increased risk of death (p0.011) and tendency for deletions of PAX (p0.064). Conclusions Our findings are consistent with those of other published series. CDKN deletions 2A / B were associated with a decreased progression free survival, independent of the presence of Ph chromosome as described in other series. RB deletions are associated with ph + and have not been described previously, but these findings must be confirm with additional studies. Disclosures: No relevant conflicts of interest to declare.

Prognostic Impact of Somatic Copy Number Alterations in Childhood B-Lineage Acute Lymphoblastic Leukemia

2020 ◽  
Vol 23 (1) ◽  
Author(s):  
Beatriz Rosales-Rodríguez ◽  
Juan Carlos Núñez-Enríquez ◽  
Juan Manuel Mejía-Aranguré ◽  
Haydeé Rosas-Vargas
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Copy Number ◽  
Lymphoblastic Leukemia ◽  
Prognostic Impact ◽  
Copy Number Alterations ◽  
B Lineage ◽  
Somatic Copy Number Alterations

scholarly journals Prognostic significance of copy number alterations in adolescent and adult patients with precursor B acute lymphoblastic leukemia enrolled in PETHEMA protocols

Cancer ◽  
2015 ◽  
Vol 121 (21) ◽  
pp. 3809-3817 ◽  
Author(s):  
Jordi Ribera ◽  
Mireia Morgades ◽  
Lurdes Zamora ◽  
Pau Montesinos ◽  
Inés Gómez-Seguí ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Copy Number ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Adult Patients ◽  
Copy Number Alterations

Clinical significance of translocation t(1;19) in childhood acute lymphoblastic leukemia in the context of contemporary therapies: a report from the Children's Cancer Group.

1998 ◽  
Vol 16 (2) ◽  
pp. 527-535 ◽  
Author(s):  
F M Uckun ◽  
M G Sensel ◽  
H N Sather ◽  
P S Gaynon ◽  
D C Arthur ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Newly Diagnosed ◽  
Event Free Survival ◽  
Free Survival ◽  
Cancer Group ◽  
Improved Outcomes ◽  
B Lineage ◽  
The Individual

PURPOSE The nonrandom translocation t(1;19) has been associated with poor outcome in pediatric B-lineage acute lymphoblastic leukemia (ALL). Because most patients treated by contemporary therapies now achieve improved outcomes, we have reassessed the prognostic significance of t(1;19). PATIENTS AND METHODS Cytogenetic data were accepted for 1,322 children (<21 years old) with newly diagnosed ALL enrolled between 1988 and 1994 on risk-adjusted studies of the Children's Cancer Group (CCG). Forty-seven patients (3.6%) were t(1;19) positive (+); 1,275 (96.4%) were t(1;19) negative (-). Clinical characteristics and treatment outcome were compared using standard methods. RESULTS Translocation (1;19)+ patients were more likely than t(1;19)- patients to be 10 years of age or greater (P < .001) or CD10+ CD19+ CD34- (P < .0001), or nonwhite (P = .02). Patients with a balanced t(1;19) were less likely to be hyperdiploid than patients with an unbalanced der(19)t(1;19). Event-free survival (EFS) was similar for the overall group of t(1;19)+ and t(1;19)- patients, with 4-year estimates of 69.5% (SD, 6.8%) and 74.8% (SD, 1.3%; P = .48), respectively. However, patients with unbalanced der(19)t(1;19) had significantly better outcomes than patients with balanced t(1;19): 4-year EFS were 80.6% (SD, 7.1%) and 41.7% (SD, 13.5%), respectively (P = .003). These differences were maintained within the individual studies analyses and after exclusion of t(1;19)+ patients whose cells were hyperdiploid with more than 50 chromosomes. CONCLUSION The overall group of t(1;19)+ patients, as well as the subgroup with an unbalanced der(19)+ (1;19) had outcomes similar to that of t(1;19)- patients, whereas patients with balanced t(1;19) had poorer outcomes. Thus, although the overall prognostic significance of t(1;19) has been obviated by contemporary risk-adjusted protocols, the balanced t(1;19) translocation remains an adverse prognostic factor.

scholarly journals PROGNOSTIC SIGNIFICANCE AND TREATMENT IMPLICATIONS OF MINIMAL RESIDUAL DISEASE STUDIES IN PHILADELPHIA-NEGATIVE ADULT ACUTE LYMPHOBLASTIC LEUKEMIA

2014 ◽  
Vol 6 (1) ◽  
pp. e2014062 ◽  
Author(s):  
Orietta Spinelli ◽  
Manuela Tosi ◽  
Barbara Peruta ◽  
Marie Lorena Guinea Montalvo ◽  
Elena Maino ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Adult Acute Lymphoblastic Leukemia ◽  
Cure Rates ◽  
Sensitive Individual ◽  
Minimal Residual ◽  
Risk Of Relapse

Acute lymphoblastic leukemia (ALL) is curable in about 40-50% of adult patients, however this is subject to ample variations owing to several host- and disease-related prognostic characteristics. Currently, the study of minimal residual disease (MRD) following induction and early consolidation therapy stands out as the most sensitive individual prognostic marker to define the risk of relapse following the achievement of remission, and ultimately that of treatment failure or success. Because substantial therapeutic advancement is now being achieved using intensified pediatric-type regimens, MRD analysis is especially useful to orientate stem cell transplantation choices. These strategic innovations are progressively leading to greater than 50% cure rates. 

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