Clinical relevance of lymphoblast biological features in children with acute lymphoblastic leukemia.

1985 ◽  
Vol 3 (4) ◽  
pp. 477-484 ◽  
Author(s):  
D K Kalwinsky ◽  
P Roberson ◽  
G Dahl ◽  
J Harber ◽  
G Rivera ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Acute Lymphoblastic Leukemia ◽  
Clinical Features ◽  
Lymphoblastic Leukemia ◽  
Periodic Acid ◽  
Prognostic Significance ◽  
Time To Failure ◽  
Prognostic Information ◽  
Biological Features ◽  
Wbc Count

Improvements in therapy for childhood acute lymphoblastic leukemia (ALL) have led us to reevaluate the prognostic significance of lymphoblast characteristics at diagnosis. From application of univariate and multivariate statistical methods, we determined the relationship of five blast cell features to treatment outcome in 250 patients who were enrolled in two clinical trials at this center from May 1979 through April 1982. Karyotype ploidy, lymphoblast morphology, and immunophenotype were each significantly related to prognosis as measured by time to failure, while periodic acid-Schiff reactivity and glucocorticoid receptor number lacked prognostic implication for this patient population. In addition, clinical features of initial WBC count, age, and race were also significant independent variables in predicting treatment response. By multivariate analysis, both ploidy and morphology contributed prognostic information to a clinical model based on WBC count, age, and race. If the model was adjusted for impact of ploidy, however, French-American-British morphology no longer contributed additional prognostic information. Our findings suggest that many traditional biological features used to estimate prognosis in ALL can be discarded in favor of clinical features (leukocyte count, age, and race) and cytogenetics (ploidy) for planning of future clinical trials.

scholarly journals Prognostic Impact of t(4;11)(q21;q23)/KMT2A-AFF1-Positivity in 926 BCR-ABL1-Negative B-Lineage Acute Lymphoblastic Leukemia Patients Treated in Gimema Clinical Trials Since 1996

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1469-1469
Author(s):  
Alfonso Piciocchi ◽  
Monica Messina ◽  
Loredana Elia ◽  
Antonella Vitale ◽  
Stefano Soddu ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Acute Lymphoblastic Leukemia ◽  
Board Of Directors ◽  
Clinical Features ◽  
Lymphoblastic Leukemia ◽  
Educational Training ◽  
Advisory Committees ◽  
Survival Analyses ◽  
B Lineage ◽  
Wbc Count

Background and aims. B-lineage acute lymphoblastic leukemia (B-ALL) carrying t(4;11)(q21;q23)/KMT2A-AFF1 accounts for roughly 10% of adult B-ALL, it is associated to pro-B immunophenotype and aggressive clinical features. However, the role of KMT2A-AFF1 in pediatric-like, minimal residual disease (MRD)-driven clinical trials and the impact of transplant in this poor prognostic subgroup are still debated. To address these issues we investigated the incidence, clinical features and outcome of KMT2A-AFF1-positive ALL treated in 6 consecutive GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) clinical trials. Materials and methods. Between November 1996 and September 2016, 926 BCR-ABL1-negative B-ALL patients were enrolled in the GIMEMA clinical trials LAL0496, LAL2000, LAL0904, LAL1104, LAL1308, LAL1913. The median follow-up is 25.4 months (range: 0.1-146.9). Starting from LAL2000, KMT2A-AFF1-positive patients were classified as high-risk and managed more intensively. LAL1308 and LAL1913 adopted a similar pediatric-like backbone, at variance from LAL0496, LAL2000 and LAL0904. Overall, median age was 34.3 (range, 14.1 - 81.9), there were 502 males (54.2%) and 424 females (45.8%) and the median WBC count was 8.80 x 109/L (range, 0.4- 872.3). Incidence, clinical features and outcome of KMT2A-AFF1-positive were analyzed in comparison with KMT2A-AFF1-negative B-ALL. MRD evaluation after induction treatment was available in 197 patients enrolled in the more recent protocols. Results. Overall, 97/926 (10.5%) samples harbored KMT2A-AFF1 fusion gene. The comparison between KMT2A-AFF1-positive and the 829 KMT2A-AFF1-negative B-ALL patients revealed that KMT2A-AFF1-positive patients had a higher median age (42 vs 32.5 years old, p<0.001), were more likely to be female (60/97 vs 364/829, p=0.001) and had a significantly higher median WBC count (70.7 vs 7.2 x 109/L, p<0.001). The complete remission (CR) rate did not differ between KMT2A-AFF1-positive and -negative patients (87.5% vs 81.5%, p=0.188). Notwithstanding, at 24 months, KMT2A-AFF1-positive patients had a significantly shorter survival than KMT2A-AFF1-negative in terms of median overall (OS, 20.3% vs 45.5%, p=0.003, Figure 1A), disease-free (DFS, 9.2% vs 34.3%, p<0.0001) and event-free survival (EFS, 9.5% vs 21.9%, p=0.03, Figure 1B). Of the KMT2A-AFF1-positive patients, 25 underwent transplant (18 received an allograft, 7 an autograft) and - in keeping with this - survival analyses were repeated after censoring for transplant and we found that KMT2A-AFF1-positive patients maintained a significantly worse OS (p<0.0001), DFS (p<0.0001), EFS (p=0.036). Similarly, the effect of KMT2A-AFF1-positivity was adjusted for treatment received and retained statistical significance (HR: 1.3, 95%CI: 1.0-1.7, p=0.050). Moreover, when survival analyses were restricted to the only KMT2A-AFF1-positive patients, we did not observe significant differences among the median survival across the various clinical trials (p=0.581). MRD quantification, with the caveat that the number of patients evaluated for MRD is small, showed that KMT2A-AFF1-positive and negative patients did not differ in the achievement of MRD-negativity: indeed, 8/26 (30.8%) KMT2A-AFF1-positive and 71/171 (41.5%) KMT2A-AFF1-negative patients were MRD-negative post-induction. Conclusions. The present study examined a cohort of 926 BCR-ABL1-negative B-ALL treated in Italian multicenter clinical trials. Overall, though not differing in the achievement of CR and MRD negativity, the analysis of survival curves confirms that KMT2A-AFF1-positive patients have a significantly shorter survival than KMT2A-AFF1-negative patients. This result holds true also when censoring for transplant, thus suggesting that allograft does not confer a survival advantage to KMT2A-AFF1-positive patients. Moreover, KMT2A-AFF1-positive patients perform poorly also in more intensive regimen, as emerged from the analysis of the GIMEMA LAL1913 clinical trial. These findings encourage the adoption of alternative strategies: among the available targeted therapies, preclinical models of KMT2A-leukemia show sensitivity to BCL2-inhibitors, thus providing the rationale for testing this approach in upcoming clinical trials for KMT2A-AFF1-positive patients. Figure Disclosures Chiaretti: Amgen: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Krampera:Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Di Raimondo:Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy. Bassan:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Vignetti:Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Educational Training; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Educational Training.

Prognostic significance of sex in childhood B-precursor acute lymphoblastic leukemia: a Pediatric Oncology Group Study.

1998 ◽  
Vol 16 (8) ◽  
pp. 2854-2863 ◽  
Author(s):  
J J Shuster ◽  
P Wacker ◽  
J Pullen ◽  
J Humbert ◽  
V J Land ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Pediatric Oncology ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Outcome Analysis ◽  
Oncology Group ◽  
Dna Index ◽  
Duration Of Symptoms ◽  
Pediatric Oncology Group ◽  
Wbc Count

PURPOSE In childhood B-precursor acute lymphoblastic leukemia (ALL), possible interactions among sex, time, and widely used prognostic factors (age, WBC count, and DNA index) were investigated for the first 5 years after diagnosis. PATIENTS AND METHODS All eligible patients aged 1 to less than 22 years, registered between February 1986 and September 1994 in two B-precursor ALL studies from the Pediatric Oncology Group (POG), were included in the analysis. Cutpoints for age (3.0, 5.0, and 10.0 years), WBC count (10, 50, and 100 x 10(9)/L), and DNA index (DI; 1.16) were defined. Four time periods after diagnosis (years 1, 2, 3, and 4 and 5 combined) were selected for the study of prognostic significance over time. The cut-off date for analysis was April 1996. RESULTS A total of 3,717 children (2,010 boys and 1,707 girls) were included in the outcome analysis. No major differences between the sexes were observed in age, duration of symptoms before registration, WBC count, hemoglobin level, platelet count, ploidy, presence of CNS disease at diagnosis, or induction failure rate. Event-free survival (EFS) differences between sexes became significantly different from 2 years following diagnosis. At 5 years, in all subsets analyzed, boys fared worse than girls, although not all differences were statistically significant. Major sex differences in EFS were observed in older children (10 to 22 years), in patients with intermediate WBC counts (10 to 50 x 10(9)/ L), and in children who fit both of these subgroups, in whom the 2-year EFS was almost 20% higher in girls than in boys, reaching a 38% difference at 5 years. CONCLUSION This study shows an outcome interaction among sex, time, and commonly used prognostic variables. The important sex difference observed at 2 and 5 years suggests that more intensive consolidation and/or maintenance therapy in some boys with B-precursor ALL should be investigated.

Genetic Markers Add Significant Prognostic Information to Age and WBC Count in High-Risk, Ph-Negative, B-Precursor Adult Acute Lymphoblastic Leukemia (ALL): Study of 96 Patients Treated According to Risk-Adapted Protocols from the Pethema Group

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3798-3798
Author(s):  
Jordi Ribera ◽  
Lurdes Zamora ◽  
Eulàlia Genescà ◽  
Mireia Morgades ◽  
Pau Montesinos ◽  
...  
Keyword(s):  
High Risk ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Homozygous Deletion ◽  
Advanced Age ◽  
Prognostic Information ◽  
Independent Prognostic Significance ◽  
Multivariable Analyses ◽  
Wbc Count

Abstract Introduction Recurrent Copy Number Alterations (CNA) in genes potentially involved in the pathogenesis of ALL have been identified in genes involved in B-cell development, cell cycle regulation, proliferation, apoptosis and drug resistance. Their independent prognostic significance in adult ALL patients is controversial. The aim of this study was to analyze the prognostic significance of CNA in a series of 96 high-risk, Ph-negative, B-precursor adult ALL patients treated according to risk-adapted protocols from the Spanish PETHEMA Group. Methods 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. Univariable and multivariable analyses including the most relevant clinical parameters (age, WBC count, phenotype, cytogenetics, CNS involvement) were performed for CR attainment, CR duration and OS. Results The median age [range] of the 96 patients was 39 [15-72] years, 50 (52%) patients were males, with a median WBC count 14.3 x109/L [0.4-388]. Phenotype: early pre-B 19 (20%), common 51 (54%), pre-B 22 (24%), unknown 2 (2%). Cytogenetics: normal 18 (19%), hyperdiploid 5 (5%), hypodiploid 2 (2%), near haploid 6 (6%), t(1;19) 7 (8%), 11q23/MLL 11 (12%), complex 1 (1%), other 27 (29%), no growth 17 (18%). The most frequent CNA deletions involved CDKN2A/B (43/96, 45%), PAX5 (34/94, 36%), IKZF1 (32/95, 34%), hsa-miR-31 (25/96, 26%), 14q32.33 region (18/96, 19%), RB1 (17/96, 18%), EBF1(12/91, 13%) and X/Y PAR (10/96, 10%). The most frequent duplications involved X/Y PAR (11/96, 12%) and 14q32.33 region (7/96, 7%). The CR rate was 83% (80/96), the median (95%CI) of CR duration was 2.7 years (0-5.9) and the median (95%CI) of OS was 2.1 (1.0-3.2), being the median (range) follow-up of the series of 3.8 (0.6-8.0) years. Table 1 shows the results of univariable and multivariable analyses. By multivariable analyses advanced age and EBF1 deletions were significantly associated with less CR rate, WBC count and X/Y PAR duplication were associated with shorter CR duration, and advanced age and CDKN2A/Bdeletion were associated with shorter OS. Conclusions The CNA of EBF1, X/Y PAR1 genes and CDKN2A/Bhave independent prognostic significance in adult patients with high-risk, Ph-negative, B-precursor ALL. This study suggests that these genetic studies should be added to the initial work-up of these patients for more accurate prognostic assessment Supported by grants PI10/01417, RD12-0036-0029 from Instituto Carlos III, 2014 SGR225 (GRE) from Generalitat de Catalunya and a grant from the Spanish Society of Hematology and Hemotherapy (2012). Abstract 3798. Table 1. Results of the univariable and multivariable studies. Variable CR rate CR duration OS P (univ) OR (95%CI) P (univ) HR (95%CI) P (univ) HR (95%CI) Age 0.011 0.93 (0.89 - 0.98) NS - 0.005 1.03 (1.01 - 1.05) WBC NS - <0.001 1.01 (1.00 - 1.01) NS - IKZF1 * NS - 0.048 - NS - EBF1 * 0.025 0.11 (0.02 - 0.54) NS - NS - CDKN2A/B * NS - NS - 0.014 2.32 (1.35 - 4.00) X/Y PAR** NS - 0.013 4.26 (1.64 - 11.09) NS - *Normal versus deleted; ** Normal versus duplicated; NS: not significant Disclosures No relevant conflicts of interest to declare.

Is CDKN2A +/− CDKN2B and MTAP Inactivation of Prognostic Significance in B-Precursor Childhood Acute Lymphoblastic Leukemia? Results of EORTC Studies 58881 and 58951.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1076-1076
Author(s):  
Delphine Mirebeau ◽  
Cécile Acquaviva ◽  
Stefan Suciu ◽  
Raphaëlle Bertin ◽  
Alain Robert ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Promoter Methylation ◽  
Gene Dosage ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
High Risk Group ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
B Lineage ◽  
Wbc Count

Abstract Background: Deletions of the 9p21 chromosomal region which encompasses CDKN2A, a gene encoding both p16INK4a and p14ARF, are frequent in childhood acute lymphoblastic leukemia (ALL). Their prognostic relevance is controversial. Indeed, small retrospective series of patients were analysed so far, which usually mixed B- and T-lineage ALL. Moreover, the prognosis could vary according to the extent of the deletion since the inactivation of contiguous genes such as CDKN2B encoding p15INK4b or MTAP encoding methylthioadenosine phosphorylase, may influence chemosensitivity. Methods: 9p21 deletions were retrospectivelly studied in 227 children (aged 2 mo to 16 yrs) with B-lineage ALL, using a real-time PCR assay for CDKN2B, CDKN2A (e1b and e3), and MTAP gene dosage, and loss of heterozygosity analysis (Bertin et al., 2003). CDKN2A and CDKN2B inactivation by promoter methylation was also investigated. TEL-AML1 fusion was screened in 182 (80%) of these patients. All patients were enrolled in EORTC trials 58 881 or 58 951. Median follow-up was 6 years; total number of events was 55 and the overall 6-year EFS rate was 74%. Results: CDKN2A bi- and mono-allelic inactivation was found in 38 (17%), and 31 (14%) B-lineage ALL respectively. Patients with a bi-allelic inactivation did not differ from undeleted ones regarding age, sex, immunophenotype and response to prephase treatment, but tended to have a higher WBC count at diagnosis and were more often allocated to the NCI high risk group (42% vs 27%). Genetic defects, including TEL-AML1, were independent of 9p21 alteration with exception of hyperdiploidy (&gt;50 chromosomes) which was less frequent in patients with CDKN2A inactivation (5% vs 34%). The 6-year EFS rates of patients with bi-allelic, mono allelic and no inactivation did not differ significantly (68%, 80%, and 75% respectively). Bi-allelic CDKN2B inactivation by either deletion or promoter methylation was found in 36 (16%) patients and the 6-year EFS rate of these patients was similar to that of undeleted patients (71% vs 74%). MTAP bi-allelic inactivation was found in 24 (11%) of patients. Although MTAP deficient cells are in vitro very sensitive to methotrexate, the 6-year EFS rate (70% vs 75%) did not differ from that of MTAP positive patients even when the analysis was restricted to CDKN2A inactivated ALL. Conclusion: Although bi-alleic CDKN2A inactivation was more often associated with bad prognostic parameters in B-lineage ALL, it failed to significantly influence the outcome of the patients. We did not observe either any influence of the co-inactivation of CDKN2B and MTAP on the outcome. Considering that our study is the largest so far using molecular analysis of the 9p21 region, we assume that any bad prognosis associated with 9p21 alteration, if present, should be weak in B-lineage ALL, and would probably require larger cohorts of patients to be ascertained.

Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia.

1996 ◽  
Vol 14 (1) ◽  
pp. 18-24 ◽  
Author(s):  
M Smith ◽  
D Arthur ◽  
B Camitta ◽  
A J Carroll ◽  
W Crist ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Risk Category ◽  
Treatment Assignment ◽  
Uniform Approach ◽  
Wbc Count

PURPOSE To define more uniform criteria for risk-based treatment assignment for children with acute lymphoblastic leukemia (ALL), the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI) sponsored a workshop in September 1993. Participants included representatives from the Childrens Cancer Group (CCG), Pediatric Oncology Group (POG), Dana-Farber Cancer Institute (DFCI), St Jude Children's Research Hospital (SJCRH), and the CTEP. METHODS Workshop participants presented and reviewed data from ALL clinical trials, using weighted averages to combine outcome data from different groups. RESULTS For patients with B-precursor (ie, non-T, non-B) ALL, the standard-risk category (4-year event-free survival [EFS] rate, approximately 80%) will include patients 1 to 9 years of age with a WBC count at diagnosis less than 50,000/microL. The remaining patients will be classified as having high-risk ALL (4-year EFS rate, approximately 65%). For patients with T-cell ALL, different treatment strategies have yielded different conclusions concerning the prognostic significance of T-cell immunophenotype. Therefore, some groups/institutions will classify patients with T-cell ALL as high risk, while others will assign risk for patients with T-cell ALL based on the uniform age/WBC count criteria. Workshop participants agreed that the risk category of a patient may be modified by prognostic factors in addition to age and WBC count criteria, and that a common set of prognostic factors should be uniformly obtained, including DNA index (DI), cytogenetics, early response to treatment (eg, day-14 bone marrow), immunophenotype, and CNS status. CONCLUSIONS The more uniform approach to risk-based treatment assignment and to collection of specific prognostic factors should increase the efficiency of future ALL clinical research.

scholarly journals Incidence of TEL/AML1 Fusion Gene Analyzed Consecutively in Children With Acute Lymphoblastic Leukemia in Relapse

Blood ◽  
1997 ◽  
Vol 90 (12) ◽  
pp. 4933-4937 ◽  
Author(s):  
J. Harbott ◽  
S. Viehmann ◽  
A. Borkhardt ◽  
G. Henze ◽  
F. Lampert
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Treatment Strategies ◽  
Favorable Prognostic Factor ◽  
Structural Chromosomal Abnormality ◽  
Wbc Count

Abstract The translocation t(12; 21)(p13; q22) is difficult to detect by classic cytogenetics. However, using fluorescence in situ hybridization (FISH) and by screening for the TEL/AML1 rearrangement by the polymerase chain reaction (PCR), it has been demonstrated to be the most frequent known structural chromosomal abnormality in childhood acute lymphoblastic leukemia (ALL). It is closely correlated with a B-cell precursor (BCP) phenotype and is considered a favorable prognostic factor. However, little is known about the incidence of the translocation in relapsed patients and the duration of complete remission (CR) in children expressing the TEL/AML1 fusion gene. We therefore examined 49 bone marrow samples from children with ALL at first or second relapse that were consecutively mailed to our laboratory to test for the presence of t(12; 21) using reverse transcriptase (RT)-PCR. The TEL/AML1 rearrangement could be identified in nine of 44 (20%) of the patients, a result similar to the reported incidence at diagnosis. Most of the TEL/AML1–positive children showed no adverse clinical features at diagnosis (eg, white blood cell [WBC] count <100 × 109/L or age <10 years), and regarding these data, there were no differences versus children who were negative for the fusion gene. However, the period of remission was about 1 year longer in children expressing TEL/AML1 (P = .046), and the majority of relapses in this group appeared late (<2 years after diagnosis). Our findings therefore reinforce the urgent need for further prospective studies with a long follow-up period to determine the true prognostic significance of t(12; 21) and to avoid premature changes of treatment strategies.

Impact of chromosomal translocations on prognosis in childhood acute lymphoblastic leukemia.

1991 ◽  
Vol 9 (12) ◽  
pp. 2183-2192 ◽  
Author(s):  
C M Rubin ◽  
M M Le Beau ◽  
R Mick ◽  
M A Bitter ◽  
J Nachman ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Intensive Therapy ◽  
Univariate Analysis ◽  
Prognostic Significance ◽  
Chromosomal Translocations ◽  
Leukemic Cells ◽  
Childhood All ◽  
Wbc Count

The presence of a chromosomal translocation in the leukemic cells at diagnosis of acute lymphoblastic leukemia (ALL) in children is associated with a high risk for treatment failure. We have reexamined the relationship between translocations and prognosis in 146 children with ALL who received risk-based therapy such that high-risk patients were treated with intensive drug schedules. In univariate analysis, multiple factors were associated with a relatively poor event-free survival (EFS) including age less than 2 years or greater than 10 years (combined group), WBC count greater than 10 x 10(9)/L, French-American-British (FAB) morphologic classification L2, absence of common ALL antigen (CALLA, CD10) expression, absence of hyperdiploidy with a chromosome number of 50 to 60, and presence of the specific translocations t(4; 11)(q21;q23) or t(9;22)(q34;q11) (combined group). However, there was no disadvantage with respect to EFS in patients with translocations compared with those who lacked translocations (73% at 4 years in both groups). Furthermore, when patients with specific cytogenetic abnormalities for which the prognostic significance has been well established (hyperdiploid 50 to 60, t(4;11), and t(9;22] were removed from the analysis, the remaining group with other translocations had a better EFS than the remaining group lacking translocations, although this was not statistically significant (81% v 65% at 4 years, P = .24). In a multivariate analysis, a model including WBC count and FAB classification was the strongest predictor of EFS. The presence or absence of translocations was not an independent predictor of EFS and did not contribute to the ability of any model to predict EFS. In conclusion, when effective intensive therapy is used to treat childhood ALL with high-risk clinical features, categorization of patients on the basis of chromosomal translocations without attention to the specific abnormality is not useful as a prognostic factor.

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.

scholarly journals Prognostic importance of chromosome number in 136 untreated children with acute lymphoblastic leukemia

Blood ◽  
1982 ◽  
Vol 60 (4) ◽  
pp. 864-871 ◽  
Author(s):  
DL Williams ◽  
A Tsiatis ◽  
GM Brodeur ◽  
AT Look ◽  
SL Melvin ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Chromosome Number ◽  
Leukocyte Count ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cell ◽  
Time To Failure ◽  
Prognostic Information ◽  
Prognostic Group ◽  
Induction Failure

Abstract Leukemia cell karyotypes were determined at diagnosis for 136 of 159 consecutive patients with acute lymphoblastic leukemia (ALL) who were followed for up to 35 mo. Ninety patients (67%) had abnormal karyotypes. Five chromosome categories were designated, based on the distribution of modal numbers: hyperdiploid greater than 50 (n = 41), hyperdiploid 47–50 (n = 18), pseudodiploid (n = 28), normal (n = 46), and hypodiploid (n = 3). Treatment response was assessed for the categories in terms of time to failure (induction failure, first relapse, or death). Children in the hyperdiploid greater than 50 category had the best responses to treatment, with only 2 failures, and those in the pseudodiploid category had the poorest (p less than 0.001). The remaining 3 chromosome categories had intermediate responses and formed a third prognostic group. This same influence of chromosome number on time to failure was evident within the 2 clinical prognostic groups: high risk, signified by a leukocyte count greater than 100 X 10(9)/liter, meningeal leukemia, mediastinal mass, or the presence of blasts that formed rosettes with sheep erythrocytes at 37 degrees C, and standard risk, indicated by the absence of these features. The influence of chromosome number on time to failure was also the same within the historically favorable prognostic group that had common ALL. Results of a multivariate analysis indicated that chromosome number was the strongest single predictor of outcome (p less than 0.001) and was the only variable that added significant prognostic information to leukocyte count (p less than 0.001). The combination of chromosome number and leukocyte count should more clearly distinguish patients with ALL at low or high risk of relapse.

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