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.

Importance of Minimal Residual Disease Testing During the Second Year of Therapy for Children With Acute Lymphoblastic Leukemia

2003 ◽  
Vol 21 (4) ◽  
pp. 704-709 ◽  
Author(s):  
Glenn M. Marshall ◽  
Michelle Haber ◽  
Edward Kwan ◽  
Ling Zhu ◽  
Daniella Ferrara ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Univariate Analysis ◽  
Prognostic Significance ◽  
Maintenance Chemotherapy ◽  
Childhood All ◽  
Second Year ◽  
Minimal Residual

Purpose: A high level of minimal residual disease (MRD) after induction chemotherapy in children with acute lymphoblastic leukemia (ALL) is an indicator of relative chemotherapy resistance and a risk factor for relapse. However, the significance of MRD in the second year of therapy is unclear. Moreover, it is unknown whether treatment intervention can alter outcome in patients with detectable MRD. Patients and Methods: We assessed the prognostic value of MRD testing in bone marrow samples from 85 children at 1, 12, and 24 months from diagnosis using clone-specific polymerase chain reaction primers designed to detect clonal antigen receptor gene rearrangements. These children were part of a multicenter, randomized clinical trial, which, in the second year of treatment, compared a 2-month reinduction-reintensification followed by maintenance chemotherapy with standard maintenance chemotherapy alone. Results: MRD was detected in 69% of patients at 1 month, 25% at 12 months, and 28% at 24 months from diagnosis. By univariate analysis, high levels of MRD at 1 month, or the presence of any detectable MRD at 12 or 24 months from diagnosis, were highly predictive of relapse. Multivariate analysis showed that MRD testing at 1 and 24 months each had independent prognostic significance. Intensified therapy at 12 months from diagnosis did not improve prognosis in those patients who were MRD positive at 12 months from diagnosis. Conclusion: Clinical outcome in childhood ALL can be predicted with high accuracy by combining the results of MRD testing at 1 and 24 months from diagnosis.

Kinase-Activating Fusions in Pediatric High-Risk B-Lineage Acute Lymphoblastic Leukemia (ALL): a Report from the Dana-Farber Cancer Institute (DFCI) ALL Consortium

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1729-1729
Author(s):  
Thai Hoa Tran ◽  
Marian H. Harris ◽  
Jonathan V. Nguyen ◽  
Traci M. Blonquist ◽  
Kristen E. Stevenson ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Statistical Significance ◽  
Chromosomal Rearrangements ◽  
Univariate Analysis ◽  
Prognostic Significance ◽  
Multivariable Analysis ◽  
Philadelphia Chromosome ◽  
B Lineage

Abstract Background. Recurrent chromosomal rearrangements carry prognostic significance in pediatric B-lineage acute lymphoblastic leukemia (B-ALL). Recent genome-wide analyses identified a diverse spectrum of chromosomal rearrangements resulting in novel chimeric fusions associated with poor prognosis when treated with conventional chemotherapy. These fusions are observed more frequently in NCI High-Risk (HR) B-ALL compared with NCI Standard Risk (SR) patients. They often activate ABL and JAK-STAT signaling pathways and have demonstrated sensitivity to the relevant tyrosine kinase inhibitors (TKIs) in in vitro assays and ex vivomodels. The objective of this study was to determine the frequency of NCI HR B-ALL patients enrolled on DFCI ALL Consortium Protocol 05-001 with a kinase-activating fusion that would be amenable to TKI therapy and to describe their associated clinical characteristics and outcomes. Methods. Between 2005-2011, 219 NCI HR, Philadelphia chromosome (Ph)-negative, B-ALL patients were enrolled on DFCI ALL Consortium Protocol 05-001, 105 of whom had sufficient material to undergo kinase fusion testing by validated multiplex reverse transcription polymerase chain reaction (RT-PCR) assays. A total of 35 kinase fusions of ABL-class (ABL1, ABL2, PDGFRB, CSF1R), JAK2 and CRLF2 rearrangements were examined. IGH@-CRLF2 and EPOR rearrangements were not assessed. Fusion products were predicted by NCBI BLAST algorithms, confirmed by singleplex PCR and Sanger sequencing and aligned using CLC Main Workbench Version 7.6.1. IKZF1 deletion (del) status had previously been assessed by multiplex ligation-dependent probe amplification (MLPA). Fisher's exact test and the Wilcoxon rank sum test were used to compare patient characteristics to those with and without any identified fusion for categorical and continuous variables respectively. Event-free survival (EFS) and overall survival (OS) were estimated with the Kaplan-Meier method and compared using a log rank test. Univariate and multivariable Cox proportional hazards models of EFS were constructed. Results. Among 105 NCI HR, Ph-negative, B-ALL patients, 16 (15%) were found to harbor an ABL-class fusion (ETV6-ABL1: n=1; FOXP1-ABL1: n=1; SFPQ-ABL1: n=1; ZC3HAV1-ABL2: n=1) or a fusion activating the JAK-STAT pathway (P2RY8-CRLF2: n=8; PAX5-JAK2: n=4). Sixty-nine percent of patients with an identified fusion (Fusion +) had a concomitant IKZF1 del (n=11). Features associated with fusion-positivity were age of 10 years or older (p=0.003), male sex (p=0.03), Hispanic ethnicity (p=0.01) and IKZF1 del (p=0.0005) (Table 1). Fifty percent of Fusion+ patients experienced an event (induction death (n=1); induction failure (n=1); or relapse (n=6)) compared to 24% of patients without a fusion. The 5-year EFS and OS were 48% (95% CI 22-70%) and 68% (95% CI 39-85%) for Fusion+ patients compared to 78% (95% CI 67-85%) and 88% (95% CI 79-93%) for those without fusions (Figure 1). In univariate analysis, fusion-positivity (HR: 2.66, p=0.02) and IKZF1 del (HR: 3.21; p=0.0018) were each significantly associated with inferior EFS, while age and presenting leukocyte count were not. In multivariable analysis, IKZF1 del, but not fusion-positivity, retained statistical significance (HR: 2.64, p=0.02). Conclusion. Fifteen percent of NCI HR, Ph-negative, B-ALL patients enrolled on DFCI ALL Consortium 05-001 were found to have a kinase-activating fusion. Fusion+ patients frequently harbored concomitant IKZF1 deletion and had an inferior outcome. Future studies should focus on developing clinical strategies to rapidly identify these patients at diagnosis and to test whether the addition of the relevant TKIs to their treatment will improve their outcome. Disclosures Asselin: Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Sigma Tau Pharamceuticals: Consultancy. Loh:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding.

scholarly journals Biologic and prognostic significance of the presence of more than two mu heavy-chain genes in childhood acute lymphoblastic leukemia of B precursor cell origin

Blood ◽  
1986 ◽  
Vol 67 (3) ◽  
pp. 698-703 ◽  
Author(s):  
GR Kitchingman ◽  
J Mirro ◽  
S Stass ◽  
U Rovigatti ◽  
SL Melvin ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Heavy Chain ◽  
Lymphoblastic Leukemia ◽  
Clonal Evolution ◽  
Extra Chromosome ◽  
Prognostic Significance ◽  
Leukemic Cells ◽  
Chain Gene ◽  
Chromosome 14 ◽  
Childhood All

Abstract We examined the arrangement of the mu heavy-chain immunoglobulin (Ig) genes in the leukemic blast cell DNA of 93 children with acute lymphoblastic leukemia (ALL). All cases met morphologic and cytochemical criteria for ALL, lacked detectable T cell surface antigens, and expressed HLA-DR (Ia) antigens. Eighty-three of the 93 patients (89%) were positive for the common acute lymphoblastic leukemia antigen (CALLA), and 20 of 91 (22%) tested had detectable cytoplasmic immunoglobulin. As expected, the heavy-chain lg gene was rearranged in all cases, and the pattern of rearrangements was variable; 23 had one allele rearranged and one in the germ line configuration; 15 had one rearranged and one deleted; and 37 had two rearranged. Unexpectedly, in 18 patients the presence of more than two mu gene-hybridizing bands was detected. Combinations of enzymes and heavy-chain gene probes were used to confirm that the extra bands were not the result of underdigestion of the DNA or DNA restriction site polymorphism. In eight of the 18 patients, we identified an extra chromosome 14 as a possible cause of the extra bands' hybridizing to the mu heavy-chain constant-region probe. In the remaining ten patients, the presence of three or four bands hybridizing with the mu probe suggests the presence of two populations of leukemic cells that may have arisen either by separate leukemic transformation events or by clonal evolution of one clone into two related lines. Although preliminary (2-year follow-up), our data suggest that childhood ALL of B lineage with more than two mu heavy-chain genes, but without extra copies of chromosome 14, may be more resistant to therapy.

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 Hypodiploidy is associated with a poor prognosis in childhood acute lymphoblastic leukemia

Blood ◽  
1987 ◽  
Vol 70 (1) ◽  
pp. 247-253 ◽  
Author(s):  
CH Pui ◽  
DL Williams ◽  
SC Raimondi ◽  
GK Rivera ◽  
AT Look ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Clonal Evolution ◽  
Lactic Dehydrogenase ◽  
Chromosomal Translocations ◽  
Leukemic Cells ◽  
Childhood All ◽  
Patients Âgés ◽  
Serum Lactic Dehydrogenase ◽  
Leukocyte Counts

Abstract Leukemic cells from 31 (7.6%) of 409 children with newly diagnosed acute lymphoblastic leukemia (ALL) had a hypodiploid karyotype. The patients' ages ranged from 0.8 to 17 years (median, 5 years) and their initial leukocyte counts from 1.0 to 132 X 10(9)/L (median, 12.7 X 10(9)/L). Modal chromosome numbers for the leukemic stem lines were 45 in 26 cases, 28 in two cases, and 26, 36 and 43 in one case each. Seven cases had one to three additional abnormal lines due to clonal evolution. Chromosome 20 was lost most frequently (nine cases). Structural abnormalities--including chromosomal translocations (21 cases), deletions (ten cases), duplications (two cases), or inversions (one case)--were common findings; the nonrandom translocations consisted of the t(1;19)(q23;p13.3) in two pre-B cases and tdic(9;12)(p1?1;p1?2) in three cases of common ALL. When compared with hyperdiploid cases (greater than 50 chromosomes), ALL with hypodiploidy was found to have a poorer outcome and was more likely to be associated with chromosomal translocations, higher serum lactic dehydrogenase levels, and age less than 2 or greater than or equal to 10 years. Moreover, patients with hypodiploid ALL fared as poorly as those with pseudodiploid karyotypes, even though their leukocyte counts and serum lactic dehydrogenase levels were lower and they had a comparable frequency of leukemic cell translocations. Hypodiploidy is therefore an unfavorable karyotypic feature in childhood ALL.

Early Responses to Chemotherapy of Normal and Malignant Hematologic Cells Are Prognostic in Children With Acute Lymphoblastic Leukemia

2005 ◽  
Vol 23 (10) ◽  
pp. 2264-2271 ◽  
Author(s):  
Stephen J. Laughton ◽  
Lesley J. Ashton ◽  
Edward Kwan ◽  
Murray D. Norris ◽  
Michelle Haber ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Induction Chemotherapy ◽  
Lymphoblastic Leukemia ◽  
Intensive Therapy ◽  
Prognostic Significance ◽  
Molecular Techniques ◽  
Response To Treatment ◽  
Relapse Prediction ◽  
Risk Of Relapse

Purpose Improved cure rates for children with acute lymphoblastic leukemia (ALL) have resulted from better relapse prediction, using clinical and laboratory features at diagnosis, and more intensive therapy in high-risk patients. More recently, measurements of the variation in the response of malignant lymphoblasts to chemotherapy in vivo have further improved relapse prediction. It is unknown whether the variation in the response of nonmalignant hematologic cells after chemotherapy correlates with the response of lymphoblasts or risk of relapse. Patients and Methods We retrospectively evaluated myelosuppression during induction and consolidation chemotherapy in 227 children uniformly treated for ALL on consecutive Australian and New Zealand Children's Cancer Study Group protocols. The early response to treatment was assessed in a representative subset (n = 62) by determining minimal residual disease (MRD) level by molecular techniques on the end-of-induction bone marrow sample. Results We found that a slow rate of myeloid recovery at the end of induction chemotherapy, reflected in a low absolute neutrophil count (ANC), was highly predictive of relapse (P < .0001). Additionally, patients with a high end-of-induction MRD level had a high risk of relapse (P = .001). Multivariate analysis confirmed the independent prognostic significance of MRD and ANC at the end of induction chemotherapy (P < .05). There was no significant association between other measures of myelotoxicity and MRD or relapse. Conclusion We conclude that the responses of normal myeloid cells and malignant lymphoblasts to chemotherapy predict outcome by distinct mechanisms. While these results are promising, their use in the clinical setting needs to be examined in a future randomized controlled trial.

scholarly journals The Prevalent, Features and Prognostic Impact of Deletion p16 in Patients with Adult Acute Lymphoblastic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5351-5351
Author(s):  
Na Xu ◽  
Yulin Li ◽  
Xuan Zhou ◽  
Liu Xiaoli ◽  
Hongsheng Zhou ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Univariate Analysis ◽  
Prognostic Significance ◽  
Prognostic Impact ◽  
Newly Diagnosed ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Childhood All ◽  
Significant Difference

Abstract Background and objective: Deletion of chromosome 9p21 is a crucial event for acute lymphoblastic leukemia (ALL). 9p21.3 genes encode three cell cycle inhibitory proteins: p15INK4b, p16CDKN2A, and p14ARFT. Recently studies show that p16 (CDKN2A) alleles were hypermethylated at CpG islands in ALL patients and delation p16 was associated with poor prognosis in childhood ALL. However, the prognostic significance of the deletion p16 in adult ALL leukemia is controversial, so the aim of the present study was to investigate the prevalence, feature and specific prognostic relevance of delation p16 in Chinese ALL patients from a single center in China. Patients and Methods: A total of 513 newly diagnosed adult ALL patients were identified retrospectively from the database of ALL between January 2008 and December 2013 at our center. We Detected delation p16 by interphase fluorescence in ituhybridization (I-FISH) and analyzed their clinical data retrospectively. Results: Of 513 cases, the prevalence of having either heterozygous or homozygous p16 deletions was 32%. p16 deletion were identified in 27% of newly diagnosed Philadelphia positive(Ph+) patients by univariate analysis, patients with p16 deletion had no significant difference compared with wild-type patients in terms of sex, age, white blood cells (WBC) count at diagnosis,BM blast percentage,chromosome karyotype,extra infiltration and CR I rate. The patients with p16 deletion was more likely to relapse comparaed with wild-type patients (P=0.03), and at relapse, we found a strong trend in the detection rate of p16 loss (41%) compared with diagnosis (P=0.01), suggesting that loss of this genomic region may be involved in disease progression. Of note, in newly diagnosed Ph+ALL with delation p16 were likely relapse even in the patients who treated with allogeneic hematopoietic stem cell transplantation (P=0.03). In addition, deletion p16 were significantly associated with poor outcomes in terms of overall survival (P=0.01), disease free-survival (P< 0.001), and cumulative incidence of relapse (P< 0.001). Conclusion: In our study, the absence of p16 expression seems to a poor prognostic marker in adult ALL patients. However, how to improve the survival of these patients need further study. Disclosures No relevant conflicts of interest to declare.

scholarly journals Biologic and prognostic significance of the presence of more than two mu heavy-chain genes in childhood acute lymphoblastic leukemia of B precursor cell origin

Blood ◽  
1986 ◽  
Vol 67 (3) ◽  
pp. 698-703 ◽  
Author(s):  
GR Kitchingman ◽  
J Mirro ◽  
S Stass ◽  
U Rovigatti ◽  
SL Melvin ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Heavy Chain ◽  
Lymphoblastic Leukemia ◽  
Clonal Evolution ◽  
Extra Chromosome ◽  
Prognostic Significance ◽  
Leukemic Cells ◽  
Chain Gene ◽  
Chromosome 14 ◽  
Childhood All

We examined the arrangement of the mu heavy-chain immunoglobulin (Ig) genes in the leukemic blast cell DNA of 93 children with acute lymphoblastic leukemia (ALL). All cases met morphologic and cytochemical criteria for ALL, lacked detectable T cell surface antigens, and expressed HLA-DR (Ia) antigens. Eighty-three of the 93 patients (89%) were positive for the common acute lymphoblastic leukemia antigen (CALLA), and 20 of 91 (22%) tested had detectable cytoplasmic immunoglobulin. As expected, the heavy-chain lg gene was rearranged in all cases, and the pattern of rearrangements was variable; 23 had one allele rearranged and one in the germ line configuration; 15 had one rearranged and one deleted; and 37 had two rearranged. Unexpectedly, in 18 patients the presence of more than two mu gene-hybridizing bands was detected. Combinations of enzymes and heavy-chain gene probes were used to confirm that the extra bands were not the result of underdigestion of the DNA or DNA restriction site polymorphism. In eight of the 18 patients, we identified an extra chromosome 14 as a possible cause of the extra bands' hybridizing to the mu heavy-chain constant-region probe. In the remaining ten patients, the presence of three or four bands hybridizing with the mu probe suggests the presence of two populations of leukemic cells that may have arisen either by separate leukemic transformation events or by clonal evolution of one clone into two related lines. Although preliminary (2-year follow-up), our data suggest that childhood ALL of B lineage with more than two mu heavy-chain genes, but without extra copies of chromosome 14, may be more resistant to therapy.

Clinical Significance of the Philadelphia Chromosome Positive Pediatric Acute Lymphoblastic Leukemia in Chinese.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4585-4585
Author(s):  
Qidong Ye ◽  
Long-Jun Gu ◽  
JingYan Tang ◽  
Huiliang Xue ◽  
Jing Chen ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Clinical Characteristics ◽  
Lymphoblastic Leukemia ◽  
Response To Therapy ◽  
Event Free Survival ◽  
Survival Curves ◽  
Childhood All ◽  
Free Survival ◽  
Wbc Count

Abstract Objective To explore the incidence, clinical characteristics and prognosis of childhood acute lymphoblastic leukemia (ALL) with t(9; 22). Methods All of the clinical characteristics of the 325 childhood ALL patients from November, 1998 to November, 2003 were analysised. The statistics was done by SPSS 10.0. Results There were 129 cases of high-risk ALLs in 325 Childhood ALL patients, with 95 males and 34 females. BCR-ABL fusion gene was found in 16 cases by RT-PCR, accounting for 4.9%. All of them were m-BCR-ABL. There were 12 males and 4 females among 16 Ph positive ALLs. The mean age at diagnosis was 8.54±3.36 (3.5 to 12.5) years, 50.0% of which were older than 10 years. The percents of patients who had initial WBC count more than 100×109/L, myeloid antigen coexpression, hypodiploidy, and ALL-L2 were 37.5%, 53.8%, 33.3%, and 62.5%, respectively. By comparison, the percents of age (older than 10 years), initial WBC count (more than 100×109/L), myeloid antigen coexpression, prednisone poor response (PPR), and CR over 35 days in the Ph positive ALLs were higher than that in the negative ALLs. No statistic difference was found in sex and L2 proportion between them. Moreover, no difference was found between Ph positive ALLs and negative high-risk ALLs in the mentioned parameters, except for the myeloid antigen coexpression. Four-year event-free survivals (EFS) and disease-free survivals (DFS) were 77.4% and 79.4, respectively, in Ph negative ALLs, but were 33.0% and 47.7%, respectively, in Ph positive ALLs (P<0.01). In Ph negative high-risk ALLs, the four-year EFS and DFS were 51.2% and 54.6%, respectively, both of which had no statistic difference between Ph positive cases. Only one Ph positive child received allogeneic BM transplantation, who remained in EFS at the time of this analysis. Conclusion The percent of t(9; 22) in Chinese childhood ALLs had no difference with the report abroad. There were statistic differences between Ph positive and negative childhood ALLs in age, initial WBC count, early response to therapy, and four-year EFS and DFS, but no difference was found between Ph positive ALLs and Ph negative high-risk ALLs, except for the immunophnotype. Aggressive treatment, such as high-dose chemotherapy with allogeneic BM transplantation should be considered for these patients to improve survival. Event-free survival curves for children with acute lymphoblastic leukemia Event-free survival curves for children with acute lymphoblastic leukemia

The Incidence and Prognostic Significance of 9p21 Abnormalities In Pediatric Acute Lymphoblastic Leukemia Patients – the IWK Experience

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1705-1705
Author(s):  
Brett Gardiner ◽  
Barbara Morash ◽  
Christie Riddell ◽  
Hao Wang ◽  
Conrad V Fernandez ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Small Sample ◽  
Chromosome 9 ◽  
Prognostic Impact ◽  
Aberrant Methylation ◽  
Childhood All ◽  
Pediatric All

Abstract Abstract 1705 Background: Outcomes in acute lymphoblastic leukemia (ALL), the most common childhood malignancy, have improved significantly due to risk-based multi-agent chemotherapy strategies derived from diagnostic advances in cytogenetics and molecular biology. Characterization of recurrent genetic lesions has enabled further prognostic stratification on recent clinical trials. Abnormalities involving the short arm of chromosome 9 are well-documented in pediatric ALL. Three critical tumor suppressors: CDKN2a (p16INK4a), CDKN2b (p15INK4b) and p14ARF have been localized to band 9p21. While 9p21 abnormalities have been reported in 10% of childhood ALL, their prognostic significance remains uncertain and may depend on which of these genes are lost/inactivated. Moreover, 9p deletions may be cryptic and/or not readily identified by standard G-banding techniques. We investigated the incidence and prognostic significance of 9p21 abnormalities identified retrospectively in pediatric ALL patients. Methods: A total of 76 children were diagnosed with ALL at the IWK Health Centre in Halifax, Nova Scotia from 2000–2005. Cell pellets were available for analysis on 48 patients. Chart review was conducted retrospectively. Approval was obtained by the IWK Research Ethics Board. 9p21 abnormalities were assessed by two modalities: 1) fluorescence in-situ hybridization (FISH) using a commercial p16 probe; and 2) methylation specific multiplex ligation-dependent probe amplification (MS-MLPA), using SALSA MLPA kit ME024-A1 9p21 CDKN2A/2B region (MRC Holland). Results: Of the 48 samples studied by FISH, 18 (38%) had a 9p21 deletion, only 4 of which were previously identified by G-banding. MLPA was performed on 40 samples and identified a total of 18 (45%) patients with a 9p21 deletion, 5 of which were not identified by FISH. Aberrant methylation at CDKN2b (p15INK4b) was found by MLPA in 19 patients (46%). Overall, 32 of 48 (67%) patients were determined to have an abnormal 9p21, representing a substantially greater frequency than previously reported. The detection rate for deletions at 9p21 between FISH and MLPA, was not statistically different (p=0.31). Interestingly, all patients with T-cell disease (n=5) had an abnormal 9p21, suggesting an association between this immunophenotype and 9p21 abnormalities (p=0.02). Overall, 9p21 abnormalities were associated with National Cancer Institute (NCI) high risk criteria (p=0.04), specifically white blood cell count >50,000/μL at diagnosis (p=0.019) and a higher percentage of leukemic blasts in the peripheral blood (p=0.016). Only four B-cell lineage patients in our cohort relapsed, three of which had 9p21 abnormalities and one of these ultimately died of disease. Conclusions: Using FISH and MLPA, our study has revealed a much higher incidence of 9p21 abnormalities in childhood ALL than has previously been described. Moreover, our findings demonstrate an association with high risk features and possibly inferior prognosis. It is possible that the lack of consistent reports linking 9p21 abnormalities to prognosis are related to suboptimal ascertainment. A small sample size in our study prevents the conclusive determination of an independent prognostic impact. However, our results justify the need for a larger multi-center investigation to evaluate how 9p21 abnormalities might affect ALL outcome and possibly influence future risk stratification for determining treatment. Disclosures: No relevant conflicts of interest to declare.

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