11 results on '"Silverman, LB"'
Search Results
2. Treatment completion, asparaginase completion, and oncologic outcomes among children, adolescents and young adults with acute lymphoblastic leukemia treated with DFCI Consortium Protocols.
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Valtis YK, Flamand Y, Shimony S, Place AE, Silverman LB, Vrooman LM, Brunner AM, Sallan SE, Wadleigh M, Stone RM, DeAngelo DJ, and Luskin MR
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- Child, Humans, Adolescent, Young Adult, Antineoplastic Combined Chemotherapy Protocols adverse effects, Asparaginase therapeutic use, Precursor Cell Lymphoblastic Leukemia-Lymphoma
- Abstract
Adolescents and young adult (AYA) patients with acute lymphoblastic leukemia (ALL) face worse outcomes than children. While pediatric-inspired protocols have improved outcomes, the ability of patients to complete these intensive regimens and the reasons for discontinuation are unknown. We analyzed a cohort of 332 AYA patients (aged 15-49 years) and 1159 children (aged 1-14 years) with Ph-negative ALL treated on DFCI consortium protocols. We found that AYA patients completed treatment at lower rates than children (60.8% vs. 89.7%, p < 0.001), primarily due to higher rates of early treatment failure (14.5% vs. 2.4%, p < 0.001). Withdrawal from treatment for toxicity, social/personal, or unknown reasons was uncommon, but higher among AYA patients (9.3% vs 4.7%, p = 0.001). Patients who remained on assigned therapy for one year had favorable overall survival (AYA 5-year OS 88.9%; children 5-year OS 96.4%; p < 0.001). Among patients who continued treatment for 1 year, AYA patients completed asparaginase (defined as receiving 26+ weeks) at lower rates than children (79.1% vs. 89.6%, p < 0.001). Patients who received more weeks of consolidation asparaginase had higher overall and event-free survival. Efforts should focus on identifying patients at risk for early treatment failure and optimizing asparaginase delivery., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2024
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3. JAK3 mutations and mitochondrial apoptosis resistance in T-cell acute lymphoblastic leukemia.
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Bodaar K, Yamagata N, Barthe A, Landrigan J, Chonghaile TN, Burns M, Stevenson KE, Devidas M, Loh ML, Hunger SP, Wood B, Silverman LB, Teachey DT, Meijerink JP, Letai A, and Gutierrez A
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- Apoptosis, Glucocorticoids, Humans, Janus Kinase 3 genetics, Mutation, Proto-Oncogene Proteins c-bcl-2 genetics, T-Lymphocytes pathology, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma pathology
- Abstract
Resistance to mitochondrial apoptosis predicts inferior treatment outcomes in patients with diverse tumor types, including T-cell acute lymphoblastic leukemia (T-ALL). However, the genetic basis for variability in this mitochondrial apoptotic phenotype is poorly understood, preventing its rational therapeutic targeting. Using BH3 profiling and exon sequencing analysis of childhood T-ALL clinical specimens, we found that mitochondrial apoptosis resistance was most strongly associated with activating mutations of JAK3. Mutant JAK3 directly repressed apoptosis in leukemia cells, because its inhibition with mechanistically distinct pharmacologic inhibitors resulted in reversal of mitochondrial apoptotic blockade. Inhibition of JAK3 led to loss of MEK, ERK and BCL2 phosphorylation, and BH3 profiling revealed that JAK3-mutant primary T-ALL patient samples were characterized by a dependence on BCL2. Treatment of JAK3-mutant T-ALL cells with the JAK3 inhibitor tofacitinib in combination with a spectrum of conventional chemotherapeutics revealed synergy with glucocorticoids, in vitro and in vivo. These findings thus provide key insights into the molecular genetics of mitochondrial apoptosis resistance in childhood T-ALL, and a compelling rationale for a clinical trial of JAK3 inhibitors in combination with glucocorticoids for patients with JAK3-mutant T-ALL., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2022
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4. Hedgehog pathway mutations drive oncogenic transformation in high-risk T-cell acute lymphoblastic leukemia.
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Burns MA, Liao ZW, Yamagata N, Pouliot GP, Stevenson KE, Neuberg DS, Thorner AR, Ducar M, Silverman EA, Hunger SP, Loh ML, Winter SS, Dunsmore KP, Wood B, Devidas M, Harris MH, Silverman LB, Sallan SE, and Gutierrez A
- Subjects
- Adolescent, Animals, Child, Child, Preschool, Female, Humans, Male, Oncogenes genetics, T-Lymphocytes physiology, Zebrafish, Carcinogenesis genetics, Cell Transformation, Neoplastic genetics, Hedgehog Proteins genetics, Mutation genetics, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma genetics, Signal Transduction genetics
- Abstract
The role of Hedgehog signaling in normal and malignant T-cell development is controversial. Recently, Hedgehog pathway mutations have been described in T-ALL, but whether mutational activation of Hedgehog signaling drives T-cell transformation is unknown, hindering the rationale for therapeutic intervention. Here, we show that Hedgehog pathway mutations predict chemotherapy resistance in human T-ALL, and drive oncogenic transformation in a zebrafish model of the disease. We found Hedgehog pathway mutations in 16% of 109 childhood T-ALL cases, most commonly affecting its negative regulator PTCH1. Hedgehog mutations were associated with resistance to induction chemotherapy (P = 0.009). Transduction of wild-type PTCH1 into PTCH1-mutant T-ALL cells induced apoptosis (P = 0.005), a phenotype that was reversed by downstream Hedgehog pathway activation (P = 0.007). Transduction of most mutant PTCH1, SUFU, and GLI alleles into mammalian cells induced aberrant regulation of Hedgehog signaling, indicating that these mutations are pathogenic. Using a CRISPR/Cas9 system for lineage-restricted gene disruption in transgenic zebrafish, we found that ptch1 mutations accelerated the onset of notch1-induced T-ALL (P = 0.0001), and pharmacologic Hedgehog pathway inhibition had therapeutic activity. Thus, Hedgehog-activating mutations are driver oncogenic alterations in high-risk T-ALL, providing a molecular rationale for targeted therapy in this disease.
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- 2018
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5. Long-term outcome of a pediatric-inspired regimen used for adults aged 18-50 years with newly diagnosed acute lymphoblastic leukemia.
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DeAngelo DJ, Stevenson KE, Dahlberg SE, Silverman LB, Couban S, Supko JG, Amrein PC, Ballen KK, Seftel MD, Turner AR, Leber B, Howson-Jan K, Kelly K, Cohen S, Matthews JH, Savoie L, Wadleigh M, Sirulnik LA, Galinsky I, Neuberg DS, Sallan SE, and Stone RM
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- Adolescent, Adult, Cytarabine administration & dosage, Doxorubicin administration & dosage, Drug Administration Schedule, Female, Humans, Karyotyping, Male, Methotrexate administration & dosage, Middle Aged, Precision Medicine, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma mortality, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Prednisone administration & dosage, Remission Induction, Survival Analysis, Treatment Outcome, Vincristine administration & dosage, Antineoplastic Combined Chemotherapy Protocols, Asparaginase administration & dosage, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
- Abstract
On the basis of the data suggesting that adolescents and young adult patients with acute lymphoblastic leukemia (ALL) have improved outcomes when treated on pediatric protocols, we assessed the feasibility of treating adult patients aged 18-50 years with ALL with the DFCI Pediatric ALL Consortium regimen utilizing a 30-week course of pharmacokinetically dose-adjusted E. coli L-asparaginase during consolidation. Between 2002 and 2008, 92 eligible patients aged 18-50 years were enrolled at 13 participating centers. Seventy-eight patients (85%) achieved a complete remission (CR) after 1 month of intensive induction therapy. With a median follow-up of 4.5 years, the 4-year disease-free survival (DFS) for the patients achieving a CR was 69% (95% confidence interval (CI) 56-78%) and the 4-year overall survival (OS) for all eligible patients was 67% (95% CI 56-76%). The 4-year DFS for the 64 patients who achieved a CR and were Philadelphia chromosome negative (Ph-) was 71% (95% CI 58-81%), and for all 74 Ph- patients the 4-year OS was 70% (95% CI 58-79%). We conclude that a pediatric-like treatment strategy for young adults with de novo ALL is feasible, associated with tolerable toxicity, and results in improved outcomes compared with historical regimens in young adult patients with ALL.
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- 2015
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6. Repression of BIM mediates survival signaling by MYC and AKT in high-risk T-cell acute lymphoblastic leukemia.
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Reynolds C, Roderick JE, LaBelle JL, Bird G, Mathieu R, Bodaar K, Colon D, Pyati U, Stevenson KE, Qi J, Harris M, Silverman LB, Sallan SE, Bradner JE, Neuberg DS, Look AT, Walensky LD, Kelliher MA, and Gutierrez A
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- Animals, Apoptosis drug effects, Apoptosis Regulatory Proteins antagonists & inhibitors, Bcl-2-Like Protein 11, Cell Line, Tumor, Humans, Imidazoles therapeutic use, Membrane Proteins antagonists & inhibitors, MicroRNAs physiology, Phosphatidylinositol 3-Kinases physiology, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma pathology, Proto-Oncogene Proteins antagonists & inhibitors, Quinolines therapeutic use, Signal Transduction physiology, Zebrafish, Apoptosis Regulatory Proteins physiology, Membrane Proteins physiology, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Proto-Oncogene Proteins physiology, Proto-Oncogene Proteins c-akt physiology, Proto-Oncogene Proteins c-myc physiology
- Abstract
Treatment resistance in T-cell acute lymphoblastic leukemia (T-ALL) is associated with phosphatase and tensin homolog (PTEN) deletions and resultant phosphatidylinositol 3'-kinase (PI3K)-AKT pathway activation, as well as MYC overexpression, and these pathways repress mitochondrial apoptosis in established T-lymphoblasts through poorly defined mechanisms. Normal T-cell progenitors are hypersensitive to mitochondrial apoptosis, a phenotype that is dependent on the expression of proapoptotic BIM. In a conditional zebrafish model, MYC downregulation induced BIM expression in T-lymphoblasts, an effect that was blunted by expression of constitutively active AKT. In human T-ALL cell lines and treatment-resistant patient samples, treatment with MYC or PI3K-AKT pathway inhibitors each induced BIM upregulation and apoptosis, indicating that BIM is repressed downstream of MYC and PI3K-AKT in high-risk T-ALL. Restoring BIM function in human T-ALL cells using a stapled peptide mimetic of the BIM BH3 domain had therapeutic activity, indicating that BIM repression is required for T-ALL viability. In the zebrafish model, where MYC downregulation induces T-ALL regression via mitochondrial apoptosis, T-ALL persisted despite MYC downregulation in 10% of bim wild-type zebrafish, 18% of bim heterozygotes and in 33% of bim homozygous mutants (P=0.017). We conclude that downregulation of BIM represents a key survival signal downstream of oncogenic MYC and PI3K-AKT signaling in treatment-resistant T-ALL.
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- 2014
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7. Sequencing histone-modifying enzymes identifies UTX mutations in acute lymphoblastic leukemia.
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Mar BG, Bullinger L, Basu E, Schlis K, Silverman LB, Döhner K, and Armstrong SA
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- Base Sequence, Female, Humans, Male, Histone Demethylases genetics, Mutation, Nuclear Proteins genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics
- Published
- 2012
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8. Long-term results of Dana-Farber Cancer Institute ALL Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1985-2000).
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Silverman LB, Stevenson KE, O'Brien JE, Asselin BL, Barr RD, Clavell L, Cole PD, Kelly KM, Laverdiere C, Michon B, Schorin MA, Schwartz CL, O'Holleran EW, Neuberg DS, Cohen HJ, and Sallan SE
- Subjects
- Adolescent, Child, Child, Preschool, Combined Modality Therapy, Female, Follow-Up Studies, Humans, Immunophenotyping, Infant, Infant, Newborn, Male, Precursor Cell Lymphoblastic Leukemia-Lymphoma mortality, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Prognosis, Remission Induction, Risk Factors, Survival Rate, Time Factors, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
- Abstract
The Dana-Farber Cancer Institute (DFCI) acute lymphoblastic leukemia (ALL) Consortium has been conducting multi-institutional clinical trials in childhood ALL since 1981. The treatment backbone has included 20-30 consecutive weeks of asparaginase during intensification and frequent vincristine/corticosteroid pulses during the continuation phase. Between 1985 and 2000, 1457 children aged 0-18 years were treated on four consecutive protocols: 85-01 (1985-1987), 87-01 (1987-1991), 91-01 (1991-1955) and 95-01 (1996-2000). The 10-year event-free survival (EFS)+/-s.e. by protocol was 77.9+/-2.8% (85-01), 74.2+/-2.3% (87-01), 80.8+/-2.1% (91-01) and 80.5+/-1.8% (95-01). Approximately 82% of patients treated in the 1980s and 88% treated in the 1990s were long-term survivors. Both EFS and overall survival (OS) rates were significantly higher for patients treated in the 1990s compared with the 1980s (P=0.05 and 0.01, respectively). On the two protocols conducted in the 1990s, EFS was 79-85% for T-cell ALL patients and 75-78% for adolescents (age 10-18 years). Results of randomized studies revealed that dexrazoxane prevented acute cardiac injury without adversely affecting EFS or OS in high-risk (HR) patients, and frequently dosed intrathecal chemotherapy was an effective substitute for cranial radiation in standard-risk (SR) patients. Current studies continue to focus on improving efficacy while minimizing acute and late toxicities.
- Published
- 2010
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9. No prognostic effect of additional chromosomal abnormalities in children with acute lymphoblastic leukemia and 11q23 abnormalities.
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Moorman AV, Raimondi SC, Pui CH, Baruchel A, Biondi A, Carroll AJ, Forestier E, Gaynon PS, Harbott J, Harms DO, Heerema N, Pieters R, Schrappe M, Silverman LB, Vilmer E, and Harrison CJ
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- Child, Child, Preschool, Cohort Studies, Disease-Free Survival, Female, Humans, Incidence, Infant, Male, Prognosis, Chromosome Aberrations, Chromosomes, Human, Pair 11, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma mortality
- Abstract
This study characterized the additional chromosomal abnormalities (ACA) associated with 11q23 rearrangements in 450 infants and children with acute lymphoblastic leukemia (ALL) and examined the impact of these ACA on survival. Overall, 213 (47%) cases had ACA but the incidence varied according to patient age and 11q23 subgroup. Infants and patients with t(4;11)(q21;q23) had the lowest incidence of ACA (50/182 (27%) and 57/216 (26%) respectively), whereas patients with del(11)(q23) had the highest incidence (66/93 (71%)). Del(11)(q23) abnormalities were heterogeneous and occasionally secondary to t(9;22)(q34;q11.2). Thus, patients with del(11)(q23) comprised a separate biological entity, which was clearly distinct from those with an 11q23 translocation. The most frequent specific ACA were trisomy X (n = 38), abnormal 12p (n = 32), abnormal 9p (n = 28) and del(6q) (n = 19). The presence of ACA did not change the 5 year event-free survival estimates among children (56% (95% Cl 46-65%) vs 62% (54-69%)) or infants (22% (15-29%) vs 18% (9-29%)), nor when the different 11q23 subgroups were analyzed separately. This study has conclusively demonstrated that there is no prognostic effect of secondary chromosomal changes in association with 11q23 abnormalities in childhood ALL. However, characterization of these ACA is important to determine their potential role in initiation of MLL driven leukemogenesis.
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- 2005
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10. Secondary cytogenetic aberrations in childhood Philadelphia chromosome positive acute lymphoblastic leukemia are nonrandom and may be associated with outcome.
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Heerema NA, Harbott J, Galimberti S, Camitta BM, Gaynon PS, Janka-Schaub G, Kamps W, Basso G, Pui CH, Schrappe M, Auclerc MF, Carroll AJ, Conter V, Harrison CJ, Pullen J, Raimondi SC, Richards S, Riehm H, Sather HN, Shuster JJ, Silverman LB, Valsecchi MG, and Aricò M
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- Child, Chromosome Breakage, Chromosome Deletion, Cytogenetic Analysis, Disease-Free Survival, Female, Genetic Heterogeneity, Humans, Likelihood Functions, Male, Precursor Cell Lymphoblastic Leukemia-Lymphoma diagnosis, Precursor Cell Lymphoblastic Leukemia-Lymphoma mortality, Prognosis, Survival Analysis, Treatment Outcome, Chromosome Aberrations, Philadelphia Chromosome, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics
- Abstract
Additional chromosomal aberrations occur frequently in Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) of childhood. The treatment outcome of these patients is heterogeneous. This study assessed whether such clinical heterogeneity could be partially explained by the presence and characteristics of additional chromosomal abnormalities. Cytogenetic descriptions were available for 249 of 326 children with Ph+ ALL, diagnosed and treated by 10 different study groups/large single institutions from 1986 to 1996. Secondary aberrations were present in 61% of the cases. Chromosomes 9, 22, 7, 14, and 8 were most frequently abnormal. Most (93%) karyotypes were unbalanced. Three main cytogenetic subgroups were identified: no secondary aberrations, gain of a second Ph and/or >50 chromosomes, or loss of chromosome 7, 7p, and/or 9p, while other secondary aberrations were grouped as combinations of gain and loss or others. Of the three main cytogenetic subgroups, the loss group had the worst event-free survival (P=0.124) and disease-free survival (P=0.013). However, statistical significance was not maintained when adjusted for other prognostic factors and treatment. Karyotypic analysis is valuable in subsets of patients identified by molecular screening, to assess the role of additional chromosomal abnormalities and their correlation with clinical heterogeneity, with possible therapeutic implications.
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- 2004
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11. Clinical heterogeneity in childhood acute lymphoblastic leukemia with 11q23 rearrangements.
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Pui CH, Chessells JM, Camitta B, Baruchel A, Biondi A, Boyett JM, Carroll A, Eden OB, Evans WE, Gadner H, Harbott J, Harms DO, Harrison CJ, Harrison PL, Heerema N, Janka-Schaub G, Kamps W, Masera G, Pullen J, Raimondi SC, Richards S, Riehm H, Sallan S, Sather H, Shuster J, Silverman LB, Valsecchi MG, Vilmer E, Zhou Y, Gaynon PS, and Schrappe M
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- Adolescent, Age Factors, Antineoplastic Combined Chemotherapy Protocols therapeutic use, B-Lymphocytes pathology, Child, Child, Preschool, Chromosomes, Human, Pair 19 ultrastructure, Chromosomes, Human, Pair 4 ultrastructure, Chromosomes, Human, Pair 9 ultrastructure, Cohort Studies, Combined Modality Therapy, DNA-Binding Proteins genetics, Disease-Free Survival, Drug Resistance, Neoplasm, Europe epidemiology, Female, Hematopoietic Stem Cell Transplantation, Histone-Lysine N-Methyltransferase, Humans, Infant, Leukocyte Count, Male, Myeloid-Lymphoid Leukemia Protein, Neoplastic Stem Cells pathology, Oncogene Proteins, Fusion genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma epidemiology, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Prednisone administration & dosage, Prognosis, Proportional Hazards Models, Retrospective Studies, Risk Factors, T-Lymphocytes pathology, Translocation, Genetic, Treatment Outcome, United States epidemiology, Chromosome Aberrations, Chromosomes, Human, Pair 11 ultrastructure, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Proto-Oncogenes, Transcription Factors
- Abstract
To assess the clinical heterogeneity among patients with acute lymphoblastic leukemia (ALL) and various 11q23 abnormalities, we analyzed data on 497 infants, children and young adults treated between 1983 and 1995 by 11 cooperative groups and single institutions. The substantial sample size allowed separate analyses according to age younger or older than 12 months for the various cytogenetic subsets. Infants with t(4;11) ALL had an especially dismal prognosis when their disease was characterized by a poor early response to prednisone (P=0.0005 for overall comparison; 5-year event-free survival (EFS), 0 vs 23+/-+/-12% s.e. for those with good response), or age less than 3 months (P=0.0003, 5-year EFS, 5+/-+/-5% vs 23.4+/-+/-4% for those over 3 months). A poor prednisone response also appeared to confer a worse outcome for older children with t(4;11) ALL. Hematopoietic stem cell transplantation failed to improve outcome in either age group. Among patients with t(11;19) ALL, those with a T-lineage immunophenotype, who were all over 1 year of age, had a better outcome than patients over 1 year of age with B-lineage ALL (overall comparison, P=0.065; 5-year EFS, 88+/-+/-13 vs 46+/-14%). In the heterogeneous subgroup with del(11)(q23), National Cancer Institute-Rome risk criteria based on age and leukocyte count had prognostic significance (P=0.04 for overall comparison; 5-year EFS, 64+/-+/-8% (high risk) vs 83+/-+/-6% (standard risk)). This study illustrates the marked clinical heterogeneity among and within subgroups of infants or older children with ALL and specific 11q23 abnormalities, and identifies patients at particularly high risk of failure who may benefit from innovative therapy.
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- 2003
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