This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Heerema, N. A. Articles by Uckun, F. M. Search for Related Content PubMed PubMed Citation Articles by Heerema, N. A. Articles by Uckun, F. M.

Abnormalities of Chromosome Bands 13q12 to 13q14 in Childhood Acute Lymphoblastic Leukemia

From the Department of Genetics, Parker Hughes Institute; Children’s Cancer Group ALL Biology Reference Laboratory and Parker Hughes Institute, St Paul; Division of Hematology-Oncology, Children’s Hospitals and Clinics, Minneapolis, MN; Group Operations Center, Children’s Cancer Group, Arcadia; Department of Preventive Medicine, University of Southern California; Department of Pediatric Hematology-Oncology, Children’s Hospital, Los Angeles, CA; Department of Pediatrics, Hematology-Oncology, University of Michigan, Ann Arbor, MI; Department of Pediatric Hematology-Oncology, University of Chicago, Chicago, IL; Children’s National Medical Center and the George Washington University School of Medicine, Washington, D.C.; Division of Oncology, Children’s Hospital of Philadelphia, PA; and Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY.

Address reprint requests to Nyla A. Heerema, PhD, c/o The Children’s Cancer Group, Attention Ms Lucia Noll, PO Box 60012, Arcadia, CA 91066-6012.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Contributing... REFERENCES

 
PURPOSE: Little is known about nonrandom deletions of chromosome bands 13q12 to 13q14 (13q12–14) in acute lymphoblastic leukemia (ALL). We determined the prognostic significance of cytogenetically identified breakpoints in 13q12–14 in children with newly diagnosed ALL treated on Children’s Cancer Group protocols from 1988 to 1995.

PATIENTS AND METHODS: Breakpoints in 13q12–14 were identified in 36 (2%) of the 1,946 cases with accepted cytogenetic data. Outcome analysis used standard life-table methods.

RESULTS: Seventeen patients (47%) with an abnormal 13q12–14 were classified, according to the National Cancer Institute (NCI), as poor risk, and 15 patients (42%) were standard risk; four (11%) were infants less than 12 months of age. Eight cases had balanced rearrangements of 13q12–14, 27 patients had a partial loss of 13q, and one had both a partial gain and a partial loss. The most frequent additional abnormalities among these patients were an abnormal 12p, a del(6q), a del(9p), a 14q11 breakpoint, and an 11q23 breakpoint. Nineteen patients were pseudodiploid, 10 were hyperdiploid, and seven were hypodiploid. Patients with an abnormal 13q12–14 had significantly worse event-free survival than patients lacking such an abnormality, with estimates at 6 years of 61% (SD = 14%) and 74% (SD = 1%), respectively (P = .04; relative risk = 1.74). Overall survival, however, was similar for the two groups (P = .25). The prognostic effect of an abnormal 13q was attenuated in a multivariate analysis adjusted for NCI risk status and ploidy (P = .72).

CONCLUSION: Aberrations of 13q12–14 may contribute to leukemogenesis of childhood ALL and confer increased risk of treatment failure but are associated with other poor-risk features.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Contributing... REFERENCES

 
CHROMOSOMAL aberrations involving chromosome bands 13q12 to 13q14 (13q12–14) have been described in various hematologic malignancies including chronic lymphocytic leukemia (CLL), acute and chronic myeloid leukemia, and myeloproliferative syndrome.^1-5 The observation of a high frequency of deletions of the D13S25 locus distal to the retinoblastoma gene in patients with B-cell CLL has suggested that disruption of a putative tumor suppressor gene is a critical leukemogenic event in this disease.^6-8 Translocation t(8;13)(p11;q12), resulting in fusion of the FGF gene on chromosome 8 and the ZNF198/RAMP/FIM gene on chromosome 13,^9-11 is a hallmark of a subset of atypical myeloproliferative disorders collectively referred to as the 8p11 myeloproliferative syndrome.¹² Rearrangements involving the ETV6 gene at chromosome band 12p13 and 13q12 have been found in patients with acute myeloid leukemia with t(12;13)(p13;q12).⁵ Recently, a putative gene at 13q12 involved in the t(12;13) fusion with ETV6 has been identified as the CDX2 homeobox gene.¹³ Other recent data demonstrated the occurrence of common breakpoints in 13q14 in patients with acute myeloid and lymphoid leukemias with t(12;13), t(10;13), and t(9;13).¹⁴

The clinical significance of cytogenetic aberrations involving 13q12–14 in childhood acute lymphoblastic leukemia (ALL) is unclear. Most reports of such abnormalities involved only small numbers of patients.¹⁵ Therefore, we have examined the prevalence and clinical significance of cytogenetically identified breakpoints at 13q12–14 in a large cohort (N = 1,946) of children with ALL treated on contemporary intensive protocols of the Children’s Cancer Group (CCG).

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Contributing... REFERENCES

 
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.¹⁶ Immunophenotyping was performed centrally in the CCG ALL Biology Reference Laboratory by direct or indirect immunofluorescence and flow cytometry, as previously described.¹⁶ Patients were classified as B-lineage or T-lineage based on expression of CD19, CD24, CD2, CD3, CD5, and CD7, as previously described.¹⁷

The current study involved children with newly diagnosed ALL enrolled onto CCG risk-adjusted protocols between 1988 and 1995. Children 2 to 9 years of age with WBC counts less than 10,000/µL (low-risk ALL) were enrolled onto CCG-1881¹⁸; children 2 to 9 years of age with WBC counts 10,000 to 49,999/µL or age 12 to 23 months with WBC counts less than 50,000/µL (intermediate-risk ALL) were enrolled on CCG-1891.¹⁹ After completion of these studies, patients with low- or intermediate-risk ALL were enrolled onto a single protocol, CCG-1922, for National Cancer Institute (NCI) standard-risk ALL (age 1 to 9 years with WBC counts < 50,000/µL).²⁰ Children 1 to 9 years old with WBC counts 50,000/µL or age 10 years (NCI poor-risk group)²⁰ were assigned to CCG-1882.^21,22 Children with multiple unfavorable features²³ were enrolled onto the CCG-1901 protocol, and infants less than 12 months of age were treated on the CCG-1883 protocol.²⁴ All protocols were approved by the NCI and the institutional review boards of the participating CCG-affiliated institutions. Informed consent was obtained from parents, patients, or both, according to the guidelines of the Department of Health and Human Services. Event-free survival (EFS) and overall survival estimates at 6 years from study entry for the combined group of patients included in this analysis were 74% (SD = 1%) and 84% (SD = 1%), respectively.

Cytogenetic Analysis
Diagnostic karyotyping of leukemic cells was performed by institutional laboratories before initiation of therapy. Banded chromosomes were prepared from unstimulated peripheral blood or direct and 24-hour–cultured preparations of fresh bone marrow, as described previously.²⁵ Aberrations were designated according to the International System for Human Cytogenetic Nomenclature (1995).²⁶ Designation as an abnormal clone required the identification of two or more metaphase cells with identical structural abnormalities or extra chromosomes or three or more metaphase cells with identical missing chromosomes. Designation as normal required complete analysis of a minimum of 20 banded metaphases from bone marrow only. A minimum of two original karyotypes of each abnormal clone or of normal cells were reviewed by at least two members of the CCG Cytogenetics Committee.

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; 36 cases (2%) had an abnormality with a breakpoint in 13q12–14, and 1,910 cases (98%) lacked such an abnormality. Treatment assignments on the studies included in this analysis were not based on the presence of an abnormal 13q12–14. In general, treatment assignments were not based on any other cytogenetic abnormality, although patients with certain features, such as a t(9;22)(q34;q11) or a t(4;11)(q21;q23), may have been eligible for a bone marrow transplant in first remission. On CCG-1881, however, patients with a t(9;22)(q34;q11), a t(4;11)(q21;q23), a t(8;14)(q24;q32), a t(2;8)(p12;q24), or a t(8;22)(q24;q11) were nonrandomly assigned to more intensive therapy.

The cohort of patients with accepted cytogenetic data was similar to concurrently enrolled patients who did not have accepted cytogenetic data with respect to most presenting features, except that patients with accepted data were more likely to be white (81% v 71%, respectively; P = .001) and to have a T-lineage immunophenotype (15% v 11%, respectively; P = .001), WBC counts 50,000/µL (24% v 19%, respectively; P = .001), high platelet counts (23% v 19%, respectively; P = .002), and high hemoglobin levels (13% v 10%, respectively; P = .001). Importantly, similar percentages of patients in the two groups had a favorable early response to induction therapy (< 25% blasts in the marrow at day 7; P = .58), and more than 97% of each group achieved remission by the end of induction therapy (P = .23). Six-year EFS estimates were 73% (SD = 1%) and 75% (SD = 1%) for patients with or without accepted data, respectively (P = .20). Thus, the groups with and without accepted data are comparable with respect to treatment outcome and should not be biased with respect to analyses of treatment outcome. The 1,946 patients with accepted data represent one of the largest series of children studied for determination of the clinical significance of cytogenetic abnormalities in ALL.

Statistical Methods
Analyses were based on patient follow-up through September 29, 1998. Clinical, demographic, and laboratory features of patients with and without an abnormality of 13q12–14 were compared using ² tests for homogeneity of proportions. Outcome was analyzed using life-table methods and associated statistics. The primary end point examined was 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-Meier²⁷ life-table estimate of EFS and its SD²⁸ are provided for selected time points. An approximate 95% confidence interval can be obtained from the life-table estimate ± 1.96 SDs. Life-table comparisons of EFS outcome pattern for patient groups used the log-rank statistic.^28,29 P values are based on the pattern of outcome across the entire period of patient follow-up; P .05 are referred to as statistically significant, and values between .06 and .10 are considered to have borderline statistical significance. The multivariate prognostic significance of an abnormal 13q12-14 was assessed using a Cox regression model that included 13q12-14 status, NCI risk status, and ploidy status. Ploidy groupings (normal plus hyperdiploid with > 50 chromosomes v pseudodiploid, hyperdiploid with 47 to 50 chromosomes, and hypodiploid with 45 chromosomes v hypodiploid with < 45 chromosomes) were based on the similar EFS outcome for the classifications within each subgroup.³⁰

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Contributing... REFERENCES

 
Clinical Features of Children With ALL and Abnormalities of Chromosome Bands 13q12–14
Presenting features of patients with a 13q12–14 abnormality were similar to those of patients lacking such an abnormality, except that patients with an abnormal 13q12–14 were more likely to be less than 12 months or 10 years of age (P = .005), to have NCI poor-risk ALL²⁰ status (P = .009), or to have pseudodiploid, hypodiploid, or low hyperdiploid (47 to 50 chromosomes) leukemic-cell karyotypes (P = .001). Among the 22 patients with immunophenotypic data, 20 had B-lineage ALL.

Cytogenetic Features of Children With Abnormal Chromosome Bands 13q12–14
Specific breakpoints, losses, and gains of 13q are diagrammed in Fig 1. Karyotypes of patients with 13q12–14 breakpoints are listed in Table 1. The most frequent aberration resulting in a breakpoint at 13q12–14 was a partial deletion of chromosome 13, which occurred in 20 cases (56%). In addition, seven patients (19%) had partial loss of 13q because of an unbalanced translocation; one of these was an add (13). One patient had both a partial gain and a partial loss of 13q12–14. Partner chromosome breakpoints involved in the unbalanced translocations with 13q12–14 were 8p23 (which resulted in partial gain of 13q), 8q13, 9p13, 12p13, 15q13, 15q15, and 17p11.2. Eight cases had balanced rearrangements of 13q12–14, including one with the previously described t(12;13)(p13;q12) and one with a variant, t(4;11;13)(q21;q23;q14) of the t(4;11)(q21;q23), observed frequently in childhood ALL. Other partner chromosome breakpoints among patients with balanced rearrangements of 13q12–14 were 4q35; 7q22 and 16q24; 7q11 and 12q13; 10q24; 20q11; and 3p14 and 3p25. Four cases had partial loss of 13q12–14 resulting from a -13 and a derivative chromosome containing part of chromosome arm 13q.

View larger version (25K): [in this window] [in a new window]   Fig 1. Aberrations of chromosome bands 13q12–14 in children with ALL. Lines to the right of the ideogram indicate regions of loss of 13q. Lines to left of the ideogram indicate regions of gains of 13q. Xs indicate breakpoints in balanced rearrangements; breakpoints within any particular part of a band are depicted in the middle.

Treatment Outcome
Patients with a breakpoint at 13q12–14 had significantly worse EFS than did patients lacking such abnormalities, with 6-year estimates of 61% (SD = 14%) and 74% (SD = 1%), respectively (P = .04; relative risk = 1.74; Fig 2). Overall survival, however, was not significantly different between patients with a breakpoint at 13q12–14 and patients without, with 6-year estimates of 74% (13%) and 82% (1%), respectively (P = .25; relative risk = 1.47)

View larger version (15K): [in this window] [in a new window]   Fig 2. Event-free survival for children with ALL and abnormalities of chromosome bands 13q12–14. EFS: estimates at 6 years for patients with and without 13q12 to 13q14 aberrations were 61% (SD = 14%) and 74% (SD = 1%), respectively (P = .04; relative risk = 1.74). The number of patients remaining in follow-up is shown in the inset.

A Cox regression analysis that included ploidy and NCI risk group was used to determine the multivariate effect of an abnormality of chromosome bands 13q12–14. Among patients with an abnormal 13q12–14, most were pseudodiploid (n = 19), low hyperdiploid (47 to 50 chromosomes; n = 9), or hypodiploid with 45 chromosomes (n = 6); one patient was hyperdiploid with more than 50 chromosomes, and one was hypodiploid with less than 45 chromosomes. In the multivariate analysis, the prognostic significance of an abnormal 13q12–14 was not maintained (P = .72; relative risk = 0.908; 95% confidence interval, 0.530 to 1.556). Ploidy seemed to have the most attenuating influence, reducing the unadjusted P from .04 to .46. NCI risk group attenuated the effect from P = .04 to .18. Within the NCI standard risk group, there was no difference in outcome for patients with or without an abnormal 13q12–14 (P = .91). Among NCI poor-risk patients, however, there was a trend for worse outcome for the 17 patients with an abnormal 13q12–14 (P = .11; relative risk = 1.79).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Contributing... REFERENCES

 
Although aberrations of 13q12–14, particularly t(8;13)(p11;q12), have been studied extensively in myeloid leukemias,^1-5 such abnormalities have been reported in only small numbers of children with ALL. A search of the Catalog of Chromosome Aberrations in Cancer (1998)¹⁵ revealed a total of 42 ALL patients with a breakpoint in 13q12–14. Among these 42 cases, there were 20 balanced rearrangements, 20 rearrangements resulting in partial deletions of 13q, and two rearrangements resulting in partial gain of 13q. In the current study, we observed a 13q12–14 breakpoint in 36 (2%) of 1,946 children with ALL. Approximately half of these patients were classified as poor risk by NCI criteria, although notably, there were no patients with a breakpoint at 13q12–14 who also had a Philadelphia chromosome.

The most common abnormality, occurring in 20 of the 36 patients was a deletion involving 13q12–14. Balanced and unbalanced rearrangements together accounted for the remaining cases. Multiple partner chromosome bands were involved with 13q12–14 in these rearrangements. Most patients had multiple abnormalities in addition to the 13q12–14 breakpoint, including recurrent abnormalities, such as a breakpoint in 15q13–15, an abnormal 12p, a del(6q), and an abnormal 9p. The high proportion of patients with a deletion of 13q12–14 supports the hypothesis forwarded with respect to CLL with del(13q) that a tumor suppressor gene may occur at this locus.^6-8 Alternatively, the observation of numerous cases with rearrangements involving 13q12–14 is consistent with reports of oncogenic fusion products resulting from rearrangements of 13q in cases of 8p11 myeloproliferative syndrome^9-11 as well as acute myeloid leukemia.¹³ Notably, all but one of the poor-risk patients with an abnormal 13q12–14 had deletions; whereas six of the 15 standard-risk patients had balanced translocations, and nine had unbalanced rearrangements, including deletions, resulting in partial loss of 13q. The clinical and biologic significance of these observations awaits further study. It is possible that deletions involving a putative tumor suppressor gene could result in a more aggressive leukemia than balanced rearrangements that result in activation of an oncogenic fusion transcript.

Compared with concurrently enrolled patients who lacked 13q12–14 abnormalities, patients with an aberration at 13q12–14 had significantly poorer EFS but similar overall survival. The predominant event for both groups was a marrow relapse. All events among patients with an abnormal 13q12–14 occurred early, within 2.7 years of study entry; whereas 30% of events among patients without a 13q12–14 abnormality occurred later. Among patients with NCI poor-risk status, there was a trend for worse outcome for those with an abnormal 13q12–14 compared with those lacking this abnormality. In addition, the prognostic effect of an abnormal 13q12–14 was attenuated in a multivariate analysis that included ploidy and NCI risk status, suggesting that additional poor-risk features contributed to the univariate effect of this cytogenetic aberration.

	APPENDIX Contributing Cytogeneticists

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Contributing... REFERENCES

 

	ACKNOWLEDGMENTS

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Contributing... REFERENCES

 
1. Panayiotidis P, Ganeshaguru K, Hoffbrand AV, et al: Deletion of 13q14.3 and not 13q12 is the most common genetic abnormality detected in chronic lymphocytic leukemia cells. Blood 89: 734-735, 1997 (letter)[Free Full Text]

2. Stilgenbauer S, Nickolenko J, Wilhelm J, et al: Expressed sequences as candidates for a novel tumor suppressor gene at band 13q14 in B-cell chronic lymphocytic leukemia and mantle cell lymphoma. Oncogene 16: 1891-1897, 1998[Medline]

3. Kempski H, MacDonald D, Michalski AJ, et al: Localization of the 8;13 translocation breakpoint associated with myeloproliferative disease to a 1.5 Mbp region of chromosome 13. Genes Chromosomes Cancer 12: 283-287, 1995[Medline]

4. Garcia-Marco JA, Navarro B, Caldas C: Confirmation of frequent somatic deletion of the 13q12.3 locus encompassing BRCA2 in chronic lymphocytic leukaemia. Br J Haematol 99: 708-709, 1997 (letter)[Medline]

5. Tosi S, Giudici G, Mosna G, et al: Identification of new partner chromosomes involved in fusions with the ETV6 (TEL) gene in hematologic malignancies. Genes Chromosomes Cancer 21: 223-229, 1998[Medline]

6. Hawthorn LA, Chapman R, Oscier D, et al: The consistent 13q14 translocation breakpoint seen in chronic B-cell leukaemia (BCLL) involves deletion of the D13S25 locus which lies distal to the retinoblastoma predisposition gene. Oncogene 8: 1415-1419, 1993[Medline]

7. Brown AG, Ross FM, Dunne EM, et al: Evidence for a new tumor suppressor locus (DBM) in human B-cell neoplasia telomeric to the retinoblastoma gene. Nat Genet 3: 67-72, 1993[Medline]

8. Chapman RM, Corcoran MM, Gardiner A, et al: Frequent homozygous deletions of the D13S25 locus in chromosome region 13q14 defines the location of a gene critical in leukemogenesis in chronic B-cell lymphocytic leukaemia. Oncogene 9: 1289-1293, 1994[Medline]

9. Popovici C, Adelaide J, Ollendorff V, et al: Fibroblast growth factor receptor 1 is fused to FIM in stem-cell myeloproliferative disorder with t(8;13). Proc Natl Acad Sci USA 95: 5712-5717, 1998[Abstract/Free Full Text]

10. Smedley D, Hamoudi R, Clark J, et al: The t(8;13)(p11;q11-12) rearrangement associated with an atypical myeloproliferative disorder fuses the fibroblast growth factor receptor 1 gene to a novel gene RAMP. Hum Mol Genet 7: 637-642, 1998[Abstract/Free Full Text]

11. Reiter A, Sohal J, Kulkarni S, et al: Consistent fusion of ZNF198 to the fibroblast growth factor receptor-1 in the t(8;13)(p11;q12) myeloproliferative syndrome. Blood 92: 1735-1742, 1998[Abstract/Free Full Text]

12. MacDonald D, Aguiar RC, Mason PJ, et al: A new myeloproliferative disorder associated with chromosomal translocations involving 8p11: A review. Leukemia 9: 1628-1630, 1995[Medline]

13. Chase A, Reiter A, Burci L, et al: Fusion of ETV6 to the caudal-related homeobox gene CDX2 in acute myeloid leukemia with the t(12;13)(p13;q12). Blood 93: 1025-1031, 1999[Abstract/Free Full Text]

14. Coignet LJA, Lima CSP, Min T, et al: Myeloid and lymphoid-specific breakpoint cluster regions in chromosome 13q14 in acute leukemia. Blood 92: 71a, 1998 (abstr 288)

15. Miltelman F, Johansson B, Mertens F: Catalog of Chromosome Aberrations in Cancer [book on CD-ROM]. New York, NY, Wiley-Liss, 1998

16. 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[Abstract/Free Full Text]

17. Uckun FM, Sather HN, Gaynon P, et al: Clinical features and treatment outcome of children with myeloid antigen positive acute lymphoblastic leukemia: A report from the Children’s Cancer Group. Blood 90: 28-35, 1997[Abstract/Free Full Text]

18. 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 1051)

19. 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 2489)

20. 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]

21. 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[Abstract/Free Full Text]

22. 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]

23. Steinherz PG, Siegel SE, Bleyer WA, et al: Lymphomatous presentation of childhood acute lymphoblastic leukemia. Cancer 68: 751-758, 1991[Medline]

24. 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. J Clin Oncol 17: 445-455, 1999[Abstract/Free Full Text]

25. Heerema NA, Arthur DC, Sather H, et al: Cytogenetic features of infants less than 12 months of age at diagnosis of acute lymphoblastic leukemia: Impact of the 11q23 breakpoint on outcome—A report of the Childrens Cancer Group. Blood 83: 2274-2284, 1994[Abstract/Free Full Text]

26. ISCN: An International System for Human Cytogenetic Nomenclature, in Mitelman F (ed), Basel, Switzerland, Karger, 1995

27. Kaplan E, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958

28. 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]

29. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50: 163-170, 1966[Medline]

30. Heerema NA, Nachman JB, Sather HN, et al: Hypodiploidy with less than 45 chromosomes confers adverse risk in childhood acute lymphoblastic leukemia: A report from the Children’s Cancer Group. Blood 94: 4036-4045, 1999[Abstract/Free Full Text]

Submitted September 28, 1999; accepted June 16, 2000.

This article has been cited by other articles:

				D. A. Sweetser, C.-S. Chen, A. A. Blomberg, D. A. Flowers, P. C. Galipeau, M. T. Barrett, N. A. Heerema, J. Buckley, W. G. Woods, I. D. Bernstein, et al. Loss of heterozygosity in childhood de novo acute myelogenous leukemia Blood, August 15, 2001; 98(4): 1188 - 1194. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Heerema, N. A. Articles by Uckun, F. M. Search for Related Content PubMed PubMed Citation Articles by Heerema, N. A. Articles by Uckun, F. M.