|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 2000 American Society for Clinical Oncology Prognostic Impact of Trisomies of Chromosomes 10, 17, and 5 Among Children With Acute Lymphoblastic Leukemia and High Hyperdiploidy (> 50 Chromosomes)From the Department of Genetics, Hughes Institute, and Children’s Cancer Group Acute Lymphoblastic Leukemia Biology Reference Laboratory, St. Paul; Department of Hematology-Oncology, Children’s Health Care, Minneapolis, MN; Department of Preventive Medicine, University of Southern California, and Department of Pediatric Hematology-Oncology, Children’s Hospital, Los Angeles; Group Operations Center, Children’s Cancer Group, Arcadia, CA; Department of Pediatric Hematology-Oncology, University of Michigan, Ann Arbor, MI; Department of Pediatric Hematology-Oncology, University of Chicago, Chicago, IL; Division of Oncology, Children’s Hospital of Philadelphia, PA; Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY; and Children’s National Medical Center and George Washington University School of Medicine, Washington, DC. Address reprint requests to Nyla A. Heerema, PhD, c/o The Children’s Cancer Group, Attn Lucia Noll, PO Box 60012, Arcadia, CA 91066-6012; nheerema{at}ih.org
PURPOSE: Children with acute lymphoblastic leukemia (ALL) and high hyperdiploidy (> 50 chromosomes) have improved outcome compared with other ALL patients. We sought to identify cytogenetic features that would predict differences in outcome within this low-risk subset of ALL patients. MATERIALS AND METHODS: High-hyperdiploid ALL patients (N = 480) were enrolled between 1988 and 1995 on Children’s Cancer Group (CCG) trials. Karyotypes were determined by conventional banding. Treatment outcome was analyzed by life-table methods. RESULTS: Patients with 54 to 58 chromosomes had better outcome than patients with 51 to 53 or 59 to 68 chromosomes (P = .0002). Patients with a trisomy of chromosome 10 (P < .0001), chromosome 17 (P = .0002), or chromosome 18 (P = .004) had significantly improved outcome compared with their counterparts who lacked the given trisomy. Patients with a trisomy of chromosome 5 had worse outcome than patients lacking this trisomy (P = .02). Patients with trisomies of both chromosomes 10 and 17 had better outcome than those with a trisomy of chromosome 10 (P = .09), a trisomy of chromosome 17 (P = .01), or neither trisomy (P < .0001). Multivariate analysis indicated that trisomy of chromosome 10 (P = .001) was the most significant prognostic factor for high-hyperdiploid patients, yet trisomy of chromosome 17 (P = .02) or chromosome 5 (P = .01) and modal chromosome number (P = .02) also had significant multivariate effects. CONCLUSION: Trisomy of chromosomes 10 and 17 as well as modal chromosome number 54 to 58 identify subgroups of patients with high-hyperdiploid ALL who have a better outcome than high-hyperdiploid patients who lack these cytogenetic features. Trisomy of chromosome 5 confers poorer outcome among high-hyperdiploid patients.
OUTCOME FOR children with acute lymphoblastic leukemia (ALL) has improved dramatically during the past two decades due to the adoption of multiagent, multiphase regimens with both intensive systemic and intensive intrathecal therapies.1-10 The various groups studying pediatric ALL currently allocate treatment to standard-risk, higher-risk, or infant patients on the basis of age and WBC count.11 Approximately 25% of all patients, however, are expected to experience adverse events while receiving current intensive therapies. Thus further intensification or modification of current therapies is warranted for these patients. In contrast, the toxicities associated with highly intensified regimens present untoward risks to patients who might be cured with existing intensive therapy. Therefore, improved criteria for allocating more or less intensive therapies should be sought.
Hyperdiploidy, defined as the presence of more than 50 chromosomes12-15 or a DNA index These observations motivated us to investigate the clinical, biologic, and cytogenetic features of a large group of high-hyperdiploid patients enrolled on recent trials of the Children’s Cancer Group (CCG). Our analyses indicate that although the high-hyperdiploid group as a whole has a favorable outcome when treated on our current intensive protocols, subsets of this group, defined by the presence or absence of trisomies of specific chromosomes, have better or worse outcomes than other high-hyperdiploid patients.
Patients Diagnosis of ALL required determination of lymphoblast morphology by Wright-Giemsa staining of bone marrow smears, negative lymphoblast staining for myeloperoxidase, and cell surface expression of two or more lymphoid differentiation antigens.25 Immunophenotyping was performed centrally in the CCG ALL Biology Reference Laboratory by indirect immunofluorescence and flow cytometry, as previously described.25,26 Patients were classified as B-lineage if  30% of the leukemic cells were positive for CD19 and/or CD24 and less than 30% were positive for any of the T-cell–associated antigens CD2, CD3, CD5, or CD7. Likewise, patients were classified as T-lineage if 30% of the isolated blasts were positive for any of the T-cell–associated antigens CD2, CD3, CD5, or CD7 and less than 30% were positive for CD19 and/or CD24.
The current study involved children with newly diagnosed ALL enrolled on CCG risk-adjusted protocols between 1988 and 1995. Children 2 to 9 years of age with WBC counts of less than 10,000/µL (low-risk ALL) were enrolled onto CCG-188127; children 2 to 9 years of age with WBC counts of 10,000 to 49,999/µL or age of 12 to 23 months and WBC counts of less than 50,000/µL (intermediate-risk ALL) were enrolled onto CCG-1891.4 After completion of these studies, patients with low- or intermediate-risk ALL were enrolled on a single protocol, CCG-1922,28 for standard-risk ALL (1 to 9 years old and WBC counts of < 50,000/µL) based on National Cancer Institute (NCI) criteria.11 Children who were 1 to 9 years old with WBC counts of
Cytogenetic Analysis
Between 1988 and 1995, a total of 5,120 children were entered onto the CCG studies included in this analysis. Among these, 1,946 cases had centrally reviewed and accepted cytogenetic data. Classification into ploidy groups was based on the karyotype of the simplest clone: 596 patients were considered normal, 114 patients were hypodiploid, 536 patients were pseudodiploid, 206 patients were low hyperdiploid (47 to 50 chromosomes), 480 patients were high hyperdiploid (51 to 68 chromosomes), and 14 patients had
Statistical Methods Multivariate analysis of the prognostic effect of high hyperdiploidy with selected trisomies was performed using a Cox regression model that included trisomies of all of the individual chromosomes, modal chromosome number, age, WBC count, and sex.35 Significance levels were based on the likelihood ratio test. The relative risks and 95% CIs associated with specific trisomies were estimated using the exponentiated maximum likelihood coefficient from the multivariate regression analysis. The current cohort of patients with accepted cytogenetic data was similar to concurrently enrolled patients who did not have accepted cytogenetic data with respect to many presenting features, although patients with accepted data were more likely to be white and to have high WBC counts, high platelet and hemoglobin levels, a large mediastinal mass, lymphadenopathy, a T-lineage immunophenotype, and a non-L1 French-American-British morphology. The actual percentages of patients with or without accepted cytogenetic data in these categories, however, did not seem to differ, thus the statistical differences may be due to the large sample size. Importantly, early treatment response, induction outcome, and 8-year EFS (73%, SD = 3%; 74%, SD = 2%; P = .22) were nearly identical for concurrently enrolled patients with or without accepted cytogenetic data.
Clinical and Biologic Features of Patients at Diagnosis Most presenting characteristics of high-hyperdiploid patients were significantly different from those of their non–high-hyperdiploid counterparts (Table 1). For example, compared with patients in all other ploidy groups, high-hyperdiploid patients were less likely to be older than 10 years of age (P < .0001), have WBC counts 50,000/µL (P < .0001), male sex (P = .002), Down’s syndrome (P = .03), markedly enlarged lymph nodes (P = .02), a mediastinal mass (P < .0001), hemoglobin levels 11.0 g/dL (P = .004), CNS disease at diagnosis (P < .0001), NCI poor-risk status (P < .0001),11 or T-lineage disease (P < .0001).
Heterogeneity of Outcome Among Children With High-Hyperdiploid ALL The overall group of 480 high-hyperdiploid patients had an EFS at 8 years of 79% (SD = 5%), which was significantly better than patients with low hyperdiploidy (65%, SD = 10%), pseudodiploidy (66%, SD = 6%), or hypodiploidy (56%, SD = 15%; overall comparison for the four subgroups, P < .0001). High-hyperdiploid patients had similar outcome as patients with normal karyotypes (80%, SD = 5%; P = .95). By comparison, the 14 patients with modal number greater than 69, who were not included in this analysis, had an 8-year EFS similar to that of the high-hyperdiploid group (79%, SD = 16%). To begin to define subsets of high-hyperdiploid patients with better or worse outcome, we examined EFS within this group according to (1) modal chromosome number and (2) the presence of trisomies of individual chromosomes, both of which have been reported to influence outcome in patients with high-hyperdiploid ALL.22-24 Analyses of various modal number groupings indicated that groupings of patients with 51 to 53 (n = 113), 54 to 58 (n = 309), and 59 to 68 (n = 58) chromosomes had the greatest differences in outcome, with 8-year EFS of 69% (SD = 10%), 85% (SD = 6%), and 70% (SD = 19%), respectively (P = .0002). Overall survival also was significantly different among these subgroups (P = .02). Interestingly, early response (day 7) to induction therapy, which is an important prognostic factor for childhood ALL,36 was not prognostic within the subset of patients with modal number of 54 to 58 (P = .90; RR, M3 v M1 = 1.2). The univariate comparison of EFS for the entire group of high-hyperdiploid patients with or without trisomies of each of the individual 22 autosomes and the two sex chromosomes is shown in Table 2. A highly significant improvement in EFS was observed for the 301 patients with a trisomy of chromosome 10 (P < .0001; RR = 0.41), the 321 patients with a trisomy of chromosome 17 (P = .0002; RR = 0.47), and the 350 patients with a trisomy of chromosome 18 (P = .004; RR = 0.54). For patients with and without trisomy of chromosome 10, EFS estimates 8 years from study entry were 86% (SD = 6%) and 68% (SD = 8%; Fig 1). In contrast, significantly worse outcome was noted for the 97 patients with a trisomy of chromosome 5 (P = .02; RR 1.72) and the 80 patients with a trisomy of chromosome 9 (P = .045; RR = 1.63). For patients with and without trisomy of chromosome 5, 8-year EFS estimates were 70% (SD = 15%) and 81% (SD = 5%), respectively (Fig 2). No significant univariate effects on EFS were observed for trisomies of any of the other chromosomes. Similar results were observed when the analysis was restricted to the subset of 332 patients with B-lineage ALL, except that trisomy of chromosome 5 no longer had prognostic significance. The loss of significance of trisomy 5 among the B-lineage subset may be due to the reduced power achieved with this restricted sample size rather than to a real difference between B-lineage and T-lineage patients, because only six patients were classified as having T-lineage ALL, but 30% of patients lacked immunophenotypic data.
The majority of patients with a trisomy of chromosome 5 (93 of 97 patients), chromosome 9 (78 of 80 patients), chromosome 10 (282 of 301 patients), chromosome 17 (319 of 321 patients), and chromosome 18 (316 of 350 patients) had one extra copy of the trisomic chromosome. Similar findings were observed for all of the other chromosomes with the exception of chromosome 21: the majority of patients with a trisomy of chromosome 21 (332 of 470 patients) had more than one extra copy of chromosome 21. EFS for patients with one extra copy of chromosome 21 was similar to that of patients with more than one extra copy of chromosome 21 (P = .26; RR = 0.94). Thus trisomy of chromosome 21 was a nonsignificant risk factor regardless of the number of extra copies resulting in the trisomy.
Numerical Abnormalities of Children With High-Hyperdiploid ALL
Double Trisomies Involving Chromosome 10 High-hyperdiploid patients with a trisomy of chromosome 10, which had the most prognostic significance in the unadjusted univariate analysis described above, had multiple other trisomies, including extra copies of chromosomes 5, 17, or 18, which also were significant in the univariate analysis, or a trisomy of either chromosome 4 or chromosome 6, both of which were previously reported to confer decreased risk of treatment failure in childhood ALL.23,24 Indeed, patients whose leukemic cells harbored double trisomies of chromosomes 10 and 4, 10 and 6, 10 and 17, or 10 and 18 had significantly improved outcome compared with patients lacking the respective double trisomies. In the case of double trisomies of chromosomes 10 and 4, 10 and 6, and 10 and 18, however, the improved outcome was entirely attributable to the trisomy of chromosome 10. Patients with trisomies of both chromosomes 10 and 17, however, had improved outcome compared with patients with trisomy of chromosome 10 (P = .09; RR = 1.75), trisomy of chromosome 17 (P = .01; RR = 2.09), or neither of these trisomies (P < .0001; RR = 4.3; Fig 3). EFS estimates at 8 years were 89% (SD = 7%) for patients with trisomy of chromosome 10 and chromosome 17, 79% (SD = 12%) for patients with trisomy of chromosome 10 but not chromosome 17, 75% (SD = 9%) for patients with trisomy of chromosome 17 but not chromosome 10, and 59% (SD = 6%) for patients with neither trisomy of chromosome 10 nor chromosome 17. The subgroup of patients with modal number 54 to 58 who also had a double trisomy of chromosomes 10 and 17 had an 8-year EFS of 91% (SD = 7%).
Stratified Analysis of the Prognostic Significance of Trisomy of Chromosome 10 To begin to examine the relative prognostic effects of trisomy of chromosome 10, trisomies of other chromosomes, and other risk factors, we used stratified log-rank analyses of outcome (Table 4). Of the 301 patients with a trisomy of chromosome 10, there were 228 who had 54 to 58 chromosomes, 241 who were classified as having standard risk by NCI criteria, and 153 who had a rapid response (M1 or M2 marrow status at day 7) to induction therapy. Trisomy of chromosome 10 was a favorable risk factor within the subsets of patients with either 51 to 53 chromosomes (P = .005) or 54 to 58 chromosomes (P = .01) but lacked prognostic significance among patients with 59 to 68 chromosomes. Trisomy of chromosome 10 also was a highly significant favorable risk factor among the large group of high-hyperdiploid patients with standard-risk ALL as defined by NCI criteria (P = .0002) and had borderline significance in the small group of patients with NCI poor-risk status (P = .06). Interestingly, among the 349 patients with early (day 7 of induction therapy) marrow response data, trisomy of chromosome 10 was not prognostic for those who were M1 (P = .60), but did predict improved outcome among those who were M2 (P = .01) or M3 (P = .001). Conversely, as was observed within the subgroup with 54 to 58 chromosomes, day 7 marrow response was not a significant prognostic factor within the subset of patients with a trisomy of chromosome 10, chromosome 17, or trisomies of both chromosomes 10 and 17.
Trisomy of chromosome 10 also predicted improved outcome among patients with (P = .001) or without (P = .004) a trisomy of chromosome 4, with (P = .0003) or without (P = .05) a trisomy of chromosome 6, with (P = .01) or without (P = .003) a trisomy of chromosome 17, and with (P = .01) or without (P = .005) a trisomy of chromosome 18. Although trisomy of chromosome 10 was a significant favorable risk factor in patients lacking a trisomy of chromosome 5 (P < .0001), it had no effect among the 97 patients who had a trisomy of chromosome 5 (P = .36).
Multivariate Analysis
Hyperdiploidy (> 46 chromosomes) occurs in an estimated 35% of children with ALL treated on recent studies of the CCG.21 As has been reported by others,16-20,37 patients with low hyperdiploidy (47 to 50 chromosomes) and high hyperdiploidy ( 51 chromosomes) have emerged as distinct subsets of the overall hyperdiploid group. In the current study, high hyperdiploidy predicts the most favorable outcome among those with cytogenetically abnormal leukemic clones, although patients with normal diploidy had equally favorable outcome. Compared with results from other reports, the apparent improvement in the normal diploid subset may be due to the combination of intensive treatment that is highly effective among normal diploid patients and the presence in such patients of a TEL-AML1 fusion transcript, which confers reduced risk of treatment failure in ALL.38-40 Indeed, in our recent analysis of 161 standard-risk ALL patients, 12 (21%) of 56 of those with a normal karyotype expressed a TEL-AML1 fusion transcript.41 Consistent with previous reports,22,24,42 high-hyperdiploid patients in this cohort had high frequencies of trisomies of 4, 6, 10, 14, 17, 18, 21, and X. The presence of a trisomy of chromosome 10, which occurred in 301 of the 480 patients, was identified as the strongest predictor of improved outcome within the overall group of high-hyperdiploid patients, both by univariate and multivariate analyses. However, our analyses also suggested a benefit for trisomy of chromosome 17, which occurred in 321 patients, as well as a modal chromosome number of 54 to 58, which occurred in 309 of the 480 patients. Moreover, the combination of a trisomy of chromosome 10 and a trisomy of chromosome 17 predicted improved outcome compared with either trisomy alone and particularly compared with outcome of patients lacking both trisomies. In addition, our analysis revealed a significant increase in risk for the smaller subset of high-hyperdiploid patients who had a trisomy of chromosome 5. Interestingly, we have also found that trisomy of chromosome 5 is a significant adverse risk factor among low-hyperdiploid patients, whereas neither trisomy of chromosome 10 nor trisomy of chromosome 17 is a significant prognostic factor.43 Previously, Harris et al24 reported that patients whose leukemic clones harbored both a trisomy of chromosome 10 and a trisomy of chromosome 4 had a low risk of treatment failure. Similarly, Jackson et al23 suggested that trisomy of chromosome 6 was a favorable risk factor for childhood ALL. In the current analysis of high hyperdiploid patients, however, we found no univariate prognostic significance for the presence of a trisomy of chromosome 4 or chromosome 6, regardless of the presence or absence of a trisomy of chromosome 10. Furthermore, neither trisomy of chromosome 4 nor trisomy of chromosome 6 attenuated the favorable prognostic significance of trisomy of chromosome 10.
The differences between the previous and current findings may be a result of the different comparison groups employed for analyses of treatment outcome in the two studies. In the study by Harris et al,24 trisomy of chromosome 10 was the strongest prognostic factor among all children studied, and trisomy of chromosome 4 was the strongest predictor among the subgroup of patients with a trisomy of chromosome 10. Trisomies of both chromosomes 4 and 10 were present in 180 patients with ploidy data: 161 of these patients had high hyperdiploidy, defined as DNA index The biologic basis for the improved outcome of children with high-hyperdiploid ALL is unclear, although some studies have begun to define characteristics that may contribute to increased killing of high-hyperdiploid leukemic blasts by chemotherapeutic agents. Uckun et al44 previously showed that hyperdiploid leukemic cells had a lower plating efficiency than did pseudodiploid leukemic cells or near-diploid leukemic cells with structural chromosome abnormalities, which suggests that hyperdiploid leukemia might be a less aggressive form of leukemia. Kaspers et al45 reported that hyperdiploid (DNA index between 1.16 and 1.35) leukemic cells showed a higher sensitivity than nonhyperdiploid cells to 6-mercaptopurine, 6-thioguanine, cytarabine, and L-asparaginase. Interestingly, although the median percentage of cells in S phase was higher for hyperdiploid cells, this parameter was not associated with increased sensitivity to any of the tested drugs. Whitehead et al42 as well as Synold et al46 reported that leukemic cells from high-hyperdiploid patients accumulated higher levels of polyglutamated metabolites of methotrexate than did cells from non–high-hyperdiploid patients.47 These polyglutamated derivatives act as potent inhibitors of dihydrofolate reductase, thymidylate synthetase, and the transformylases required for purine biosynthesis; thus increased levels would be expected to improve leukemic cell killing. Zhang et al48 reported that leukemic cells from B-precursor ALL patients with more than 52 chromosomes and three to five copies of chromosome 21 had a higher median level of RNA transcripts for the reduced folate carrier protein than did cells from normal diploid patients. Similarly, Belkov et al49 found that reduced folate carrier transcripts were higher in hyperdiploid B-lineage ALL patients than in nonhyperdiploid patients, whereas transcript levels in nonhyperdiploid B- and T-lineage patients were not significantly different. A recent report by Ito et al50 suggested that leukemic cells with 51 to 65 chromosomes were less likely than nonhyperdiploid cells to grow on stromal feeder cells in vitro. The poor cell survival was associated with apoptosis in most leukemic cells with 51 to 65 chromosomes. Thus the favorable outcome of children with high-hyperdiploid ALL may be due to their leukemic blasts’ high rate of apoptosis in suboptimal growth environments as well as their increased susceptibility to the antileukemic effects of antimetabolite chemotherapeutic agents. The biologic basis for the observed improved outcome of patients with trisomies of chromosomes 10 and/or 17 and the poorer outcome of patients with a trisomy of chromosome 5 may be due to the presence of genes on these chromosomes that contribute to the response of the leukemic cell to therapy. It will be of interest to continue to examine these subsets of patients in future studies to determine if these trisomies retain prognostic significance. Future molecular genetic studies may identify particular normal or abnormal genes that may contribute to the effects of these trisomies on outcome in pediatric ALL.
Supported in part by research grants including Children’s Cancer Group Chairman’s Grant no. CA-13539 and CA-60437 from the National Cancer Institute, National Institutes of Health, Bethesda, MD. We thank Diane Arthur, MD, for significant contribution to the collection of these data.
1. Clavell LA, Gelber RD, Cohen HJ, et al: Four-agent induction and intensive asparaginase therapy for treatment of childhood acute lymphoblastic leukemia. N Engl J Med 315:657-663, 1986[Abstract] 2. Chessells JM, Bailey C, Richards SM: Intensification of treatment and survival in all children with lymphoblastic leukaemia: Results of U.K. Medical Research Council trial UKALL X—Medical Research Council Working Party on Childhood Leukaemia. Lancet 345:143-148, 1995[Medline] 3. Eden OB, Lilleyman JS, Richards S, et al: Results of Medical Research Council Childhood Leukaemia Trial UKALL VIII (report to the Medical Research Council on behalf of the Working Party on Leukaemia in Childhood). Br J Haematol 78:187-196, 1991[Medline] 4. Lange B, Sather H, Weetman R, et al: Double delayed intensification improves outcome in moderate risk pediatric acute lymphoblastic leukemia (ALL): A Children’s Cancer Group study (CCG-1891). Blood 90:559a, 1997 (abstr)
5.
Nachman JB, Sather HN, Sensel MG, et al: Augmented post-induction therapy for children with high-risk acute lymphoblastic leukemia and a slow response to initial therapy. N Engl J Med 338:1663-1671, 1998 6. Nachman J, Sather HN, Cherlow JM, et al: Response of children with high-risk acute lymphoblastic leukemia treated with and without cranial irradiation: A report from the Children’s Cancer Group. J Clin Oncol 16:920-930, 1998[Abstract]
7.
Pui CH, Mahmoud HH, Rivera GK, et al: Early intensification of intrathecal chemotherapy virtually eliminates central nervous system relapse in children with acute lymphoblastic leukemia. Blood 92:411-415, 1998 8. Riehm H, Gadner H, Henze G, et al: Results and significance of six randomized trials in four consecutive ALL-BFM studies. Hamatol Bluttransfus 33:439-450, 1990[Medline] 9. Steinherz P, Gaynon P, Breneman J, et al: Treatment of acute lymphoblastic leukemia with bulky extramedullary disease and T-cell phenotype or other poor prognostic features: Randomized control trial from the Children’s Cancer Group. Cancer 82:600-612, 1998[Medline]
10.
Tubergen DG, Gilchrist GS, O’Brien RT, et al: Improved outcome with delayed intensification for children with acute lymphoblastic leukemia and intermediate presenting features: A Children’s Cancer Group phase III trial. J Clin Oncol 11:527-537, 1993 11. Smith M, Arthur D, Camitta B, et al: Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia. J Clin Oncol 14:18-24, 1996[Abstract] 12. Third International Workshop on Chromosomes in Leukemia (1980): Clinical significance of chromosomal abnormalities in acute lymphoblastic leukemia. Cytogenet 4:111-137, 1981
13.
Third International Workshop on Chromosomes in Leukemia: Chromosomal abnormalities and their clinical significance in acute lymphoblastic leukemia. Cancer Res 43:868-873, 1983 14. Secker-Walker LM, Chessells JM, Stewart EL, et al: Chromosomes and other prognostic factors in acute lymphoblastic leukaemia: A long-term follow-up. Br J Haematol 72:336-342, 1989[Medline]
15.
Raimondi SC: Current status of cytogenetic research in childhood acute lymphoblastic leukemia. Blood 81:2237-2251, 1993
16.
Look AT, Roberson PK, Williams DL, et al: Prognostic importance of blast cell DNA content in childhood acute lymphoblastic leukemia. Blood 65:1079-1086, 1985
17.
Trueworthy R, Shuster J, Look T, et al: Ploidy of lymphoblasts is the strongest predictor of treatment outcome in B-progenitor cell acute lymphoblastic leukemia of childhood: A Pediatric Oncology Group study. J Clin Oncol 10:606-613, 1992 18. Bloomfield CD, Secker-Walker LM, Goldman AI, et al: Six-year follow-up of the clinical significance of karyotype in acute lymphoblastic leukemia. Cancer Genet Cytogenet 40:171-185, 1989[Medline]
19.
Raimondi SC, Roberson PK, Pui CH, et al: Hyperdiploid (47-50) acute lymphoblastic leukemia in children. Blood 79:3245-3252, 1992 20. Chessels JM, Swansbury GJ, Reeves B, et al: Cytogenetics and prognosis in childhood lymphoblastic leukaemia: Results of MRC UKALL X—Medical Research Council Working Party in Childhood Leukaemia. Br J Haematol 99:93-100, 1997[Medline] 21. Heerema N, Sather H, Reaman G, et al: cytogenetic studies of acute lymphoblastic leukemia: Clinical correlations results from the Children’s Cancer Group. Genet Technol 24:206-212, 1998 22. Raimondi SC, Pui CH, Hancock ML, et al: Heterogeneity of hyperdiploid (51-67) childhood acute lymphoblastic leukemia. Leukemia 10:213-224, 1996[Medline] 23. Jackson JF, Boyett J, Pullen J, et al: Favorable prognosis associated with hyperdiploidy in children with acute lymphocytic leukemia correlates with extra chromosome 6: A Pediatric Oncology Group study. Cancer 66:1183-1189, 1990[Medline]
24.
Harris MB, Shuster JJ, Carroll A, et al: Trisomy of leukemic cell chromosomes 4 and 10 identifies children with B-progenitor cell acute lymphoblastic leukemia with a very low risk of treatment failure: A Pediatric Oncology Group study. Blood 79:3316-3324, 1992
25.
Uckun FM, Muraguchi A, Ledbetter JA, et al: Biphenotypic leukemic lymphocyte precursors in CD2+CD19+ acute lymphoblastic leukemia and their putative normal counterparts in human fetal hematopoietic tissues. Blood 73:1000-1015, 1989 26. Uckun FM, Reaman GH, Steinherz PG, et al: Improved clinical outcome for children with T-lineage acute lymphoblastic leukemia after contemporary chemotherapy: A Children’s Cancer Group study. Leuk Lymphoma 24:57-70, 1996[Medline] 27. Hutchinson R, Bertolone S, Cooper H, et al: Early marrow response predicts outcome for patients with low risk ALL: Results of CCG-1881. Proc Am Soc Clin Oncol 13:319, 1994 (abstr) 28. Bostrom B, Gaynon P, Sather H, et al: Dexamethasone (DEX) decreases central nervous system (CNS) relapse in lower risk acute lymphoblastic leukemia (ALL). Proc Am Soc Clin Oncol 17:527a, 1998 (abstr 2024) 29. Reaman GH, Sposto R, Sensel MG, et al: Treatment outcome and prognostic factors for infants with acute lymphoblastic leukemia treated on two consecutive trials of the Children’s Cancer Group. Clin Oncol 17:445-455, 1999 30. Heerema NA, Palmer CG, Baehner RL: Karyotypic and clinical findings in a consecutive series of children with acute lymphocytic leukemia. Cancer Genet Cytogenet 17:165-179, 1985[Medline] 31. Mitelman F (ed): ISCN: An International System for Human Cytogenetic Nomenclature. Basel, Switzerland, Karger, 1995 32. Kaplan E, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958 33. Peto R, Pike MC, Armitage P, et al: Design and analysis of randomized clinical trials requiring prolonged observation of each patient: II. Analysis and examples. Br J Cancer 35:1-39, 1977[Medline] 34. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50:163-170, 1966[Medline] 35. Cox DR: Regression models and life tables. J R Stat Soc 34:187-220, 1972 36. Gaynon PS, Desai AA, Bostrom BC, et al: Early response to therapy and outcome in childhood acute lymphoblastic leukemia: A review. Cancer 80:1717-1726, 1997[Medline] 37. Groupe Francais de Cytogenetique Hematologique: Collaborative study of karyotypes in childhood acute lymphoblastic leukemias. Leukemia 7:10-19, 1993[Medline] 38. Rubnitz JE, Behm FG, Wichlan D, et al: Low frequency of TEL-AML1 in relapsed acute lymphoblastic leukemia supports a favorable prognosis for this genetic subgroup. Leukemia 13:19-21, 1999[Medline]
39.
Seeger K, Adams HP, Buchwald D, et al: TEL-AML1 fusion transcript in relapsed childhood acute lymphoblastic leukemia: The Berlin-Frankfurt-Munster Study Group. Blood 91:1716-1722, 1998
40.
Raimondi SC, Shurtleff SA, Downing JR, et al: 12p abnormalities and the TEL gene (ETV6) in childhood acute lymphoblastic leukemia. Blood 90:4559-4566, 1997 41. Heerema NA, Stork L, Crotty M-L, et al: TEL-AML1 expression in childhood acute lymphoblastic leukemia (ALL) is associated with rapid early response (RER) to induction chemotherapy. Blood 94:503a, 1999 (abstr)
42.
Whitehead VM, Vuchich MJ, Lauer SJ, et al: Accumulation of high levels of methotrexate polyglutamates in lymphoblasts from children with hyperdiploid (greater than 50 chromosomes) B-lineage acute lymphoblastic leukemia: A Pediatric Oncology Group study. Blood 80:1316-1323, 1992 43. Heerema NA, Sather HN, Sensel MG, et al: Low hyperdiploidy (47-50 chromosomes) in pediatric acute lymphoblastic leukemia (ALL). Blood 94:502a, 1999 (abstr) 44. Uckun FM, Kersey JH, Gajl Peczalska KJ, et al: Heterogeneity of cultured leukemic lymphoid progenitor cells from B cell precursor acute lymphoblastic leukemia (ALL) patients. J Clin Invest 80:639-646, 1987
45.
Kaspers GJ, Smets LA, Pieters R, et al: Favorable prognosis of hyperdiploid common acute lymphoblastic leukemia may be explained by sensitivity to antimetabolites and other drugs: Results of an in vitro study. Blood 85:751-756, 1995 46. Synold TW, Relling MV, Boyett JM, et al: Blast cell methotrexate-polyglutamate accumulation in vivo differs by lineage, ploidy, and methotrexate dose in acute lymphoblastic leukemia. J Clin Invest 94:1996-2001, 1994 47. Chu E, Allegra C: Antifolates, in Chabner B, Long D (eds): Cancer Chemotherapy and Biotherapy (ed 2). Philadelphia, PA,Lippincott-Raven, 1996, pp 39-44 48. Zhang L, Taub JW, Williamson M, et al: Reduced folate carrier gene expression in childhood acute lymphoblastic leukemia: Relationship to immunophenotype and ploidy. Clin Cancer Res 4:2169-2177, 1998[Abstract]
49.
Belkov VM, Krynetski EY, Schuetz JD, et al: Reduced folate carrier expression in acute lymphoblastic leukemia: A mechanism for ploidy but not lineage differences in methotrexate accumulation. Blood 93:1643-1650, 1999
50.
Ito C, Kumagai M, Manabe A, et al: Hyperdiploid acute lymphoblastic leukemia with 51 to 65 chromosomes: A distinct biological entity with a marked propensity to undergo apoptosis. Blood 93:315-320, 1999 Submitted September 2, 1999; accepted January 19, 2000. This article has been cited by other articles:
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
TOP
ABSTRACT
INTRODUCTION
2 tests for homogeneity of proportions. Outcome was analyzed using life-table methods and associated statistics. The primary end point examined was event-free survival (EFS) from study entry; events included induction failure (nonresponse to therapy or death during induction), leukemic relapse at any site, death during remission, or second malignant neoplasm, whichever occurred first. Patients not experiencing an event at the time of EFS analysis were censored at the time of their last contact. The Kaplan-Meier
.05 are referred to as statistically significant. Relative risk (RR) was calculated by the observed/expected method for log-rank analysis. 
