scholarly journals Nonrandom abnormalities of chromosome 9p in childhood acute lymphoblastic leukemia: association with high-risk clinical features

Blood ◽  
1989 ◽  
Vol 74 (1) ◽  
pp. 409-415 ◽  
Author(s):  
SB Murphy ◽  
SC Raimondi ◽  
GK Rivera ◽  
M Crone ◽  
RK Dodge ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
High Risk ◽  
Clinical Features ◽  
Lymphoblastic Leukemia ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Cell Phenotype ◽  
Term Survival ◽  
Childhood All ◽  
Chromosome 9P

Abstract To assess the frequency and significance of nonrandom abnormalities of chromosome 9p in childhood acute lymphoblastic leukemia (ALL), we analyzed our experience with 398 consecutive cases with completely banded karyotypes. Forty cases (10%) with abnormalities of 9p were identified: 26 with deletions, nine with unbalanced translocations resulting in the loss of 9p material, and five with apparently balanced reciprocal translocations. As compared with children with ALL lacking 9p abnormalities, these 40 cases were significantly older, had higher initial circulating WBC counts, more “lymphomatous” disease characteristics (including presence of a mediastinal mass in 15%. T- cell phenotype in 26%, splenomegaly greater than 8 cm in 25%), an increased failure rate in the first 2 to 3 years after diagnosis, and a higher incidence of extramedullary relapse. Conversely, lymphomatous ALL cases were twice as likely (19% v 8%) to have an abnormality of chromosome 9p than ALL cases lacking lymphomatous features (P = .01). The finding of an abnormal chromosome 9p, however, was not specific for lymphomatous ALL or T-cell lineage, because most cases were neither lymphomatous nor T-cell, and the overall Kaplan-Meier distribution of treatment failures for abnormal 9p cases was not statistically significantly different from control ALL cases receiving the same treatment who lacked abnormalities of 9p (P = .06, by log-rank test). We conclude that nonrandom abnormalities of chromosome 9p, especially a breakpoint in 9p21–22, occur with increased frequency in childhood ALL in association with some high-risk clinical features. Despite this association, the chromosome anomaly is nonspecific in its syndrome delineation and confers no major adverse consequence on long-term survival of childhood ALL treated with modern therapy. However, due to an apparently increased hazard of involvement of the CNS (eight of 17 failures), it may be inadvisable to lessen the intensity of CNS preventive therapy for this group of patients.

scholarly journals Nonrandom abnormalities of chromosome 9p in childhood acute lymphoblastic leukemia: association with high-risk clinical features

Blood ◽  
1989 ◽  
Vol 74 (1) ◽  
pp. 409-415 ◽  
Author(s):  
SB Murphy ◽  
SC Raimondi ◽  
GK Rivera ◽  
M Crone ◽  
RK Dodge ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
High Risk ◽  
Clinical Features ◽  
Lymphoblastic Leukemia ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Cell Phenotype ◽  
Term Survival ◽  
Childhood All ◽  
Chromosome 9P

To assess the frequency and significance of nonrandom abnormalities of chromosome 9p in childhood acute lymphoblastic leukemia (ALL), we analyzed our experience with 398 consecutive cases with completely banded karyotypes. Forty cases (10%) with abnormalities of 9p were identified: 26 with deletions, nine with unbalanced translocations resulting in the loss of 9p material, and five with apparently balanced reciprocal translocations. As compared with children with ALL lacking 9p abnormalities, these 40 cases were significantly older, had higher initial circulating WBC counts, more “lymphomatous” disease characteristics (including presence of a mediastinal mass in 15%. T- cell phenotype in 26%, splenomegaly greater than 8 cm in 25%), an increased failure rate in the first 2 to 3 years after diagnosis, and a higher incidence of extramedullary relapse. Conversely, lymphomatous ALL cases were twice as likely (19% v 8%) to have an abnormality of chromosome 9p than ALL cases lacking lymphomatous features (P = .01). The finding of an abnormal chromosome 9p, however, was not specific for lymphomatous ALL or T-cell lineage, because most cases were neither lymphomatous nor T-cell, and the overall Kaplan-Meier distribution of treatment failures for abnormal 9p cases was not statistically significantly different from control ALL cases receiving the same treatment who lacked abnormalities of 9p (P = .06, by log-rank test). We conclude that nonrandom abnormalities of chromosome 9p, especially a breakpoint in 9p21–22, occur with increased frequency in childhood ALL in association with some high-risk clinical features. Despite this association, the chromosome anomaly is nonspecific in its syndrome delineation and confers no major adverse consequence on long-term survival of childhood ALL treated with modern therapy. However, due to an apparently increased hazard of involvement of the CNS (eight of 17 failures), it may be inadvisable to lessen the intensity of CNS preventive therapy for this group of patients.

Outcome of Patients with T-Cell Lymphoblastic Leukemia or Lymphoma: The GRAALL Experience.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2818-2818
Author(s):  
Stéphane Leprètre ◽  
Martine Escoffre-Barbe ◽  
Patrice Chevallier ◽  
Thibaut Leguay ◽  
Laurence Legros ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Early Response ◽  
Cell Phenotype ◽  
High Dose ◽  
Cns Involvement ◽  
Childhood All ◽  
High Risk Disease ◽  
Mediastinal Disease

Abstract In 2003, the GRAALL intergroup initiated two twin protocols for adult patients with acute lymphoblastic leukemia (ALL; ≥ 20% marrow blasts) or lymphoblastic lymphoma (LL; < 20% marrow blasts), namely the GRAALL-2003 and LL-2003 trials. Treatment strategy was inspired by childhood ALL trials, including corticosteroid prephase, 5-drug induction, high dose-intensity consolidation, late intensification, CNS prophylaxis with IT injections and cranial irradiation, and 2-year maintenance. An original induction reinforcement with sequential cyclophosphamide (HyperC) was offered to ALL patients with poor early response (cortico- and/or chemo-resistance) and to all LL patients. A total of 108 patients with T-cell phenotype have been treated (76 ALL and 32 LL; median age, 30 years; M/F sex ratio, 86/22; CNS+, 9; median follow-up, 2 years). Baseline characteristics were not different among ALL and LL subgroups, except for marrow blast percentage and mediastinal enlargement (47% vs 78% for ALL vs LL; P=.005), which correlated negatively, as well as for blood counts (WBC, 27 vs 8.7 × 109/L; platelets, 60 vs 328 × 109/L; Hb, 116 vs 134 g/L for ALL vs LL; P<.001). Bulky mediastinal disease was present in 57% LL vs 22% ALL patients (P=.002). Two patients (1 ALL, 1 LL) died early while the 106 remaining (98%) reached CR. With respect to mediastinal involvement, need for a salvage course with idarubicine and high-dose cytarabine to reach CR was more frequent in LL than in ALL patients (10 LL vs 2 ALL, P<.001). Allogeneic stem cell transplantation (SCT) was offered to patients with high-risk disease, defined here as CNS involvement, poor early response, or need for salvage. Among the 55 CR patients with high-risk disease (41 ALL, 14 LL), 26 received allogeneic SCT in first CR (20 ALL, 6 LL). Overall, 23/106 CR patients relapsed (18 ALL, 5 LL) while 8 died in first CR (7 ALL, 1 LL; 4 after SCT). At 2 years, estimated DFS and overall survival were 66% (64% vs 75% for ALL vs LL, P=.59) and 75% (74% vs 78% for ALL vs LL, P=.75), respectively. The only factors which influenced outcome in this risk-adapted strategy were need for salvage (higher relapse incidence) and CNS involvement (shorter survival). As compared to historical experiences, we report here a notable gain in outcome when treating patients with T-cell lymphoblastic disease, including lymphoma, with a pediatric-inspired ALL strategy. The efficacy of this approach leads to comparable outcome for both diseases. The systematic use of HyperC induction in LL patients was well tolerated, but the need for salvage therapy was more frequent in these patients possibly due to difficulty in early mediastinal response evaluation. The presence of CNS disease at diagnosis remains an unfavorable feature. The role of HyperC during induction and the place of allogeneic SCT in first CR deserve further evaluation in this new context.

Mega-Analysis of 50 Years of Diagnosis and Therapy of Childhood Acute Lymphoblastic Leukemia in Bydgoszcz, Poland: From Prednisolone Therapy to Microarray Studies

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4688-4688
Author(s):  
Jan Styczynski ◽  
Agnieszka Jatczak-Gaca ◽  
Robert Debski ◽  
Andrzej Koltan ◽  
Mariusz Wysocki
Keyword(s):  
New York ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
International Strategy ◽  
Term Survival ◽  
Childhood All ◽  
Time Period ◽  
Number Of Patients ◽  
Analysis Of Results

Abstract Background: The beginnings of pediatric oncology in Bydgoszcz, Poland dates back to the year 1958. The first patient was treated with prednisolone only. Objective: Analysis of results of childhood acute lymphoblastic leukemia therapy in Bydgoszcz region in 1958–2008. Patients and methods: A total number of 570 children were diagnosed and treated over the period of 50 years, including: 215 children treated with different drugs and combinations in 1958–1972, 49 children treated with Memphis V–VII protocols in 1976–1983, 114 children treated with ALL-BFM83 or ALL-BFM86 protocols in 1983– 1995 and 192 children treated with ALL-BFM90, New York I–II or ALL-IC-2002 between 1995–2008. Results: A number of patients with „events” in respective time periods was: 205/215 (95.3%, in 1958–1972); 44/49 (89.8%, in 1976–1983), 54/114 (47.4%, in 1983–1995), 56/192 (29.2%, in 1995–2008). The values of 5-year pEFS in consecutive therapeutic periods were: p=0.012±0.008 (1958–1972), p=0.102±0.043 (in 1976–1983), p=0.526±0.047 (in 1983–1995), p=0.700±0.037 (in 1995–2008) (p&lt;0.0001). A median survival time was, respectively: 0.8 year (for patients treated in 1958–1972); 1.8 year (in1976–1983); 5.7 years (in 1983–1995); 7.4 years (for patients treated in 1995–2008). Conclusions: Complex therapy based on international strategy of multiagent total therapy and supportive care, has led to an improved long-term survival in childhood ALL in Bydgoszcz region, Poland, from 1% in sixties up to 70% nowadays Figure 1. pEFS in ALL with respect to time period Figure 1. pEFS in ALL with respect to time period

Early T-cell precursor leukemia: a subtype of high risk childhood acute lymphoblastic leukemia

2012 ◽  
Vol 6 (4) ◽  
pp. 416-420 ◽  
Author(s):  
Meilin Ma ◽  
Xiang Wang ◽  
Jingyan Tang ◽  
Huiliang Xue ◽  
Jing Chen ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Cell Precursor

Screening for Retrovirus Genomes in Childhood Acute Lymphoblastic Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4301-4301
Author(s):  
Abigail Morales-Sánchez ◽  
Juan Manuel Mejia-Arangure ◽  
Roberto Bernáldez-Ríos ◽  
Francisco Javier Álvarez-Rodríguez ◽  
Vilma Carolina Bekker-Méndez ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Mexico City ◽  
Graduate Program ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Causative Factor ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Childhood All

Abstract Abstract 4301 Background: Acute lymphoblastic leukemia (ALL) is the most common type of childhood malignancy worldwide and Mexico has one of the highest reported incidence rates at 49.5 cases per million. Infections have been strongly suggested to be a causative factor for ALL; however, the identity of the agent involved is presently unknown. In many animal species, members of the Retroviridae family are responsible for leukemias. The murine mammary tumor virus (MMTV) is associated with leukemia and breast cancer in mice and has been suggested to be associated with human breast cancer. The T-cell lymphotropic virus 1 (HTLV1) is the causative factor of adult T cell leukemia. In this study, we assessed whether MMTV and HTLV1/2 are also involved in childhood ALL. Materials and methods: 95 children from four Mexican states and Mexico City with untreated B cell ALL, aged 8 months to 16 years were included in the study. Bone marrow samples were screened using conventional PCR assays. Because the mutation rate is considerably high in retroviruses, false negatives due to inadequate primer recognition are likely. To avoid that, two sets of primers targeting different regions of the retroviral genomes were used and the PCR annealing temperatures were set at ≤ 55 °C. Also, the primers used in these assays had low similarity with human endogenous retroviral sequences to exclude false positives. The sensitivity of the MMTV PCR reactions was determined with plasmid DNA containing a region of the MMTV env gene and genomic DNA from CD1 mice spleens and for HTLV1/2 with DNA from the MJ cell line. Because ALL is defined by a frequency of at least 25% of leukemic blasts, the PCR sensitivities were set to detect in samples at least this frequency of infected cells. A nested PCR was also designed to confirm negative cases. Results: None of the samples were positive to any of the retroviruses. The study's statistical power to detect one or more MMTV or HTLV1/2 positive samples from our study population (N=95) for 20%, 15% or 10% hypothesized proportions of cases with genomic integration was quite high. Conclusion: Our study does not support the involvement of MMTV or HTLV1/2 in the etiology of childhood acute lymphoblastic leukemia in samples from Mexico. Acknowledgments and funding: This work was partially funded by the Mexican Institute of Social Security through its program “Apoyo Financiero para el Desarrollo de Protocolos de Investigación en Salud en el IMSS” and by the Graduate Program of Doctor Degree in Biomedical Sciences, Medicine Faculty, National Autonomous University of Mexico, Mexico City, Mexico. Disclosures: No relevant conflicts of interest to declare.

Outcome of risk-adapted therapy for pediatric acute lymphoblastic leukemia in Egypt.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 10044-10044
Author(s):  
Iman A. Sidhom ◽  
Abir Mokhles ◽  
Sonya Soliman ◽  
Khaled Shaaban ◽  
Sherine Salem ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Univariate Analysis ◽  
Risk Groups ◽  
Response To Therapy ◽  
Cell Phenotype ◽  
Free Survival ◽  
Egyptian Children

10044 Background: With modern risk directed therapy, >80% of children with acute lymphoblastic leukemia (ALL) in western countries are cured. The 5-year event free survival (EFS) and relapse free survival (RFS) of pediatric ALL patients in Egypt were 65% and 75% respectively in a previous study using an intensive treatment protocol for all patients. Aim: To improve cure rates of Egyptian children with ALL using risk adapted therapy. Methods: From July 2007 to December 2010, 706 patients aged 1-18 years with newly diagnosed ALL were treated at Children Cancer Hospital Egypt with a risk directed ALL protocol adopted from St Jude Total Study XV. Results: B-precursor phenotype was encountered in 75.8% and T-cell in 24.2%. Based on initial presentation and response to therapy measured by minimal residual disease (MRD), 42.6%, 45.8% and 11.6% of the patients were classified as low, intermediate and high risk respectively. The 5-year RFS and EFS were 88.2 ± 1.5% and 76.5 ± 1.7% respectively. Adverse events included 4.4% induction deaths, 2.5% failure to achieve induction remission (1.4% remained refractory), 6.8% deaths in remission, 9.2% relapses (3.1% hematological, 1.8% combined hematological and CNS, 4% isolated CNS, 0.3% isolated testicular), 0.9% abandonment of therapy and one patient had secondary myeloid leukemia. The median follow up for patients alive in CR was 43months (range 24–65). The 5-year RFS of the low, intermediate and high risk groups were 92.2 ± 2.4%, 85.3 ± 2.2% and 82.7 ± 4.8% respectively (p=0.001), while the 5-year EFS were 87.6 ± 2.5%, 78.2 ± 2.5% and 57.9 ± 5.7% respectively (p<0.001). Prognostic factors that had statistically significant unfavorable impact on both EFS and RFS by univariate analysis were age ≥10 years, TLC ≥100x109/L, T-cell phenotype, risk groups, MRD d42 ≥1% and MRD W7 ≥0.1%, while MRD d15 ≥1% had statistically significant unfavorable outcome on EFS only. By multivariate analysis, TLC and MRD W7 had prognostic significance on EFS and RFS, MRD d42 on EFS, while MRD d15 had marginal significance on EFS (p=0.055). Conclusions: Risk adapted therapy was effective in improving ALL survival among patients at our institution compared with previous trials, although the outcome remains lower than that in high income countries.

Outcome of a Risk-Adapted Treatment for Childhood Acute Lymphoblastic Leukemia in Thailand.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2248-2248
Author(s):  
Issarang Nuchprayoon ◽  
Panya Seksarn ◽  
Preeda Vanichsetakul
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
High Risk ◽  
Risk Group ◽  
Lymphoblastic Leukemia ◽  
High Risk Group ◽  
Low Risk ◽  
Childhood All ◽  
Satisfactory Outcome ◽  
Standard Risk

Abstract Acute lymphoblastic leukemia (ALL) is the most curable cancer in children. In developing country with limited resource and manpower like Thailand, where 3 pediatris hematologists take care of 100 new cancer children per year, it is a challenge to achieve satisfactory outcome. We treated ALL according to a risk-adapted modified CCG-105 protocols (standard or intensive induction of remission, consolidation, 1800 cGy CNS radiation, and maintenance therapy with or without delayed intensification, DI) since 1988. We reported here the outcome of childhood ALL treated with this protocol between 1997–2004. 181 children with newly-diagnosed ALL in this period were classified into B-precursor, or T-cell ALL by immunophenotyping with flow cytometry. B-precursor ALL were classified as low risk group (age 1–10 yr and initial white cell count (WBC) <20,000/μl), standard-risk (age 1–10 yr and WBC between 20,000–50,000/μl) and high-risk (age >10 yr or WBC >50,000/μl). The low-risk group were assigned to protocol B (CCG-105 standard induction without DI, n=69). The standard- and high-risk group were assigned to protocol C (CCG-105 intensive induction with DI, n=71). All T-cell ALL (n=21) were assigned to a T-cell protocol (DFCI 85-01 high-risk group) which includes high-dose methotrexate and asparaginase. Infantile ALL (n=9), mature B-cell ALL (n=3), a child with t(1;19), and 5 children who refused treatment or received other protocols of treatment were excluded from analysis. The remission rates were 98.5% for protocol B, 92.4% for protocol C, and 83.3% for T-cell disease. All remission failure were attributed to early deaths. The 5-yr event-free survival (EFS ±95% confidence interval) was 83.1 ± .7% for low-risk group treated with protocol B, 75.9 ± 6.0% for protocol C, and 68.6 ± 12.1% for T-cell ALL. These outcomes are significantly higher than our previous report. (Nuchprayoon I, Songnui T, Vanichsetakul P, Seksarn P. Treatment of childhood acute lymphoblastic leukemia in Thailand- outcome and cost analysis. Blood 96 (11 suppl 1): 435a) and can be attributed to a better risk classification, more intensified treatment for standard-risk group and T-cell ALL, and better supportive care. Satisfactory outcome of childhood ALL can be achieved in developing country with risk-adapted treatment strategy. Figure Figure

Long Term Results of the AIEOP-All-95 Trial for Childhood Acute Lymphoblastic Leukemia. An Insight on the Prognostic Value of Dna Index in the Frame of BFM-Based Chemotherapy.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1440-1440
Author(s):  
Maurizio Arico ◽  
Maria Grazia Valsecchi ◽  
Carmelo Rizzari ◽  
Elena Barisone ◽  
Andrea Biondi ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Prognostic Value ◽  
Lymphoblastic Leukemia ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Long Term Results ◽  
Entire Group ◽  
Treatment Burden ◽  
Dna Index ◽  
Childhood All

Abstract Between May 1995 and August 2000 the Associazione Italiana di Ematologia Oncologia Pediatrica (AIEOP) conducted the ALL-95 study for risk-directed, BFM-oriented therapy of childhood acute lymphoblastic leukemia (ALL), aimed at exploring treatment reduction in standard risk (SR) and intensification during continuation therapy in intermediate risk (IR) as randomized questions and treatment intensification in high risk (HR). The prognostic value of DNA index was explored in this setting. 1,744 patients were enrolled, 115 SR, 1,385 IR, and 244 HR risk. SR patients (DNA index ≥1.16 and &lt;1.60, age 1–5 and WBC&lt;20K, non-T, no high risk features), received a reduced induction therapy (no anthracyclines); IR patients were randomized to receive or not vincristine-dexamethasone (VCR-DEXA) pulses during maintenance; HR therapy was based on a conventional BFM schedule intensified with three chemotherapy blocks followed by double reinduction phase. The event-free-survival and overall survival probabilities at 10 years for the entire group were 72.5% (SE 1.3) and 83.6% (0.9); 85.0% (3.4) and 95.5% (2.0) in SR, 75.1% (1.5) and 87.5% (0.9) in IR, 51.0% (3.2) and 57.2% (3.3) in HR patients, respectively. Patients with favorable DNA index had superior EFS in both IR [83.8(2.7) versus 73.9(1.7)] and in HR [67.8(9.4) and 49.6(3.5)]. Of the 6 patients with DNA index. &lt;0.8 only 1 remained in remission. As for treatment burden there was no difference between SR patients, receiving only 3 drugs, and others in Induction IA. Highest treatment burden was reported during consolidation in HR patients. In reinduction, first protocol II had figures similar to those reported during protocol II given to non-HR patients, while second protocol II in HR patients was associated with higher treatment burden Treatment reduction, although appealing, should be applied with great caution not to endanger outstanding cure rate achieved with over 80% of patients in Italy during the second half of the 90s having been cured. Contribution of HSCT in front-line therapy remains limited. In this study, favorable DNA index was associated with better prognosis in IR and HR patients defined by clinical criteria and treated with BFM-oriented chemotherapy. Continuous effort put in the genetic studies could provide novel insights for treatment of subsets of childhood ALL refractory to modern chemotherapy.

Focal 22q11.22 Loss Combined with IKZF1 Alterations Predict Very Poor Outcome in Childhood Acute Lymphoblastic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 741-741
Author(s):  
D. Spencer Mangum ◽  
Soheil Shams ◽  
Jonathan M. Downie ◽  
Uta von Schwedler ◽  
Vladimir Rodic ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Differentially Expressed Genes ◽  
Lymphoblastic Leukemia ◽  
Genetic Alterations ◽  
Differentially Expressed ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Remission Induction ◽  
Childhood All ◽  
Poor Outcome

Abstract Abstract 741 Identifying prognostic biomarkers in childhood acute lymphoblastic leukemia (ALL) is imperative for risk-stratification and intensifying therapy for children at high risk of remission induction failure or relapse. IKZF1 deletions/mutations were recently shown to correlate with poor outcome in ALL, highlighting genetic alterations as prognostic markers (NEJM 360:470, 2009). We recently described focal deletions in VPREB1 located within the lambda variable chain region which are not part of normal light chain rearrangement in precursor B-cell ALL in a local Utah cohort and the TARGET cohort of high-risk ALL patients treated on the Children's Oncology Group P9906 trial. Upon further inspection, we identified a second focal deletion in chromosome 22q11.22, nearly 80 kilobases (Kb) upstream from VPREB1 in the same lambda region. We characterized and correlated this deletion with outcome in childhood ALL using the Utah Cohort (N=60), TARGET P9906 cohort (N=221), and St. Jude Children's Research Hospital cohort (SJCRH, N=298). Microarray data was analyzed (Utah = Molecular Inversion Probe 330K [Affymetrix]; TARGET = SNP 500K & U133A [Affymetrix]; SJCRH = SNP 500K/6.0 & U133A [Affymetrix]) by Nexus Copy Number and Nexus Expression (BioDiscovery, Inc.). Each cohort contains the focal 22q11.22 loss (Hemizygous: Utah = 21%, TARGET = 16%, SJCRH = 18%; and Homozygous: Utah = 7%, TARGET = 16%, SJCRH = 10%). It spans 142 Kb, with the most common recurring region just under 10 Kb in length. The deleted segment encodes no known genes. In the SJCRH cohort, 22q11.22 loss differs by subtype: Down's syndrome 93%, BCR-ABL1 47%, ETV6-RUNX1 46%, Pseudodiploid 38%, Hyperdiploid 30%, Other 33%, MLL 12%, TCF3-PBX1 12%, T-ALL 7%, Hypodiploid 0%. In the TARGET cohort, 22q11.22 loss confers a trend for worse event-free survival (EFS; P=0.17) and overall survival (OS; P=0.06). Compared to normal 22q11.22/IKZF1 (77% EFS) or IKZF1 alternations alone (45% EFS), combined 22q11.22 loss plusIKZF1 alterations drastically reduces EFS to 15% (P<0.0001). This pattern was validated in the larger SJCRH cohort with worse outcome for isolated 22q11.22 loss (EFS; P=0.03, and OS; P=0.02). Once again, compared to normal 22q11.22/IKZF1 (EFS 76%, OS 87%) or IKZF1 alterations alone (EFS 61%, OS 80%), 22q11.22 loss plusIKZF1 alterations reduces EFS to 23% (P<0.0001) and OS to 48% (P<0.0001). In the SJCRH cohort, multiple Cox regression including subtype, age, and WBC reveals that combined 22q11.22/IKZF1 alterations independently predict worse EFS (HR 5.568 [95% CI 2.6–11.7], P<0.0001) and OS (HR 4.989 [95% CI 1.8–13.9], P=0.0021). To understand the basis of this combined worse outcome, we analyzed paired gene expression data for the TARGET (N=198) and SJCRH (N=146) cohorts. We looked for differentially expressed genes in common between both cohorts and included only samples with 22q11.22 homozygous loss to capture the most pronounced effects of the deleted region. We compared: 1) 22q11.22 normal vs. 22q11.22 loss in IKZF1 normal samples, 2) IKZF1 normal vs. IKZF1 alterations in 22q11.22 normal samples, and 3) normal samples vs. combined 22q11.22/IKZF1 altered samples. CCND2 was upregulated 2.1-fold in isolated 22q11.22 loss samples, 1.4-fold in isolated IKZF1 altered samples, and increased to 2.6-fold in combined 22q11.22 loss plusIKZF1 altered samples. Of 23 genes affected by combined 22q11.22/IKZF1 alterations, 9 were associated with resistance to at least one of 4 commonly use antileukemic agents (prednisolone, vincristine, asparaginase, and daunorubicin) in primary ALL based on a previously published dataset (NEJM 351:533,2004; N=177). For example, CCND2 over-expression in diagnostic ALL blasts significantly associated with higher LC50 (resistance) for daunorubicin (P=0.002) and prednisolone (P=0.005). Gene Ontology enrichment for differentially expressed genes in combined 22q11.22/IKZF1 altered samples was significant for anti-apoptosis (P=0.001) and cell growth (P=0.005) biological processes. In summary, we discovered and validated that 22q11.22 loss independently contributes to worse outcome in pediatric ALL in the presence of IKZF1 genetic alterations. These combined alterations may be useful to identify patients with very poor outcomes in childhood ALL. Further work to understand the mechanism of the synergistic effect of combined 22q11.22 loss plusIKZF1 alterations is underway. Disclosures: Shams: BioDiscovery, Inc.: Employment.

Reappraisal of the clinical and biologic significance of myeloid-associated antigen expression in childhood acute lymphoblastic leukemia.

1998 ◽  
Vol 16 (12) ◽  
pp. 3768-3773 ◽  
Author(s):  
C H Pui ◽  
J E Rubnitz ◽  
M L Hancock ◽  
J R Downing ◽  
S C Raimondi ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Antigen Expression ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Cell Precursor ◽  
Childhood All ◽  
Mll Gene ◽  
Blast Cells

PURPOSE To reassess the clinical and biologic significance of myeloid-associated antigen expression in childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS We prospectively studied 334 newly diagnosed cases of this disease, using a comprehensive panel of antibodies that represented five myeloid cluster groups (CD13, CD14, CD15, CD33, and CD65). Blast cells were tested for ETV6 and MLL rearrangement using Southern blot analysis. RESULTS CD13 was expressed in 13.7% of cases, CD14 in 1%, CD15 in 6.6%, CD33 in 16%, and CD65 in 9.7%. Approximately one third of cases (31.4%) expressed one or more of these antigens (B-cell precursor, 31.9%; T-cell, 28.8%), while 10.5% expressed two or more (B-cell precursor, 11.3%; T-cell, 6.1%). Among the B-cell precursor leukemias, myeloid-associated antigen expression was significantly associated with a lack of hyperdiploidy and rearrangements of ETV6 or MLL gene. Most of the cases with MLL rearrangements (82%) expressed CD65, CD15, and CD33, either alone or in combination, whereas 48% of those with a rearranged ETV6 gene expressed CD13, CD33, or both. Myeloid-associated antigen expression did not correlate with event-free survival, whether the analysis was based on any of the five antigens in our panel or on the three more commonly tested antigens (CD13, CD33, and CD65). Importantly, this finding was not affected by exclusion of patients with ETV6 or MLL gene rearrangements. CONCLUSION Even though blast cell expression of myeloid-associated antigen expression shows significant associations with specific genetic abnormalities, it lacks prognostic value in childhood ALL.

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