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Journal of Clinical Oncology, Vol 26, No 13 (May 1), 2008: pp. 2186-2191 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.3552 Prospective Analysis of TEL Gene Rearrangements in Childhood Acute Lymphoblastic Leukemia: A Children's Oncology Group Study
From the Department of Oncology, St Jude Children's Research Hospital, Memphis, TN; Statistics and Data Center, Children's Oncology Group & University of Florida, Gainesville, FL; Pediatric Hematology/Oncology, Duke University, Durham, NC; Pediatric Hematology/Oncology, Medical College of Georgia, Augusta, GA; Pediatric Hematology-Oncology, University of Florida, Gainesville, FL; Department of Pediatrics, West Virginia University, Charleston, WV; Department of Pediatric Hematology-Oncology, Midwest Children's Cancer Center, Milwaukee, WI; and the Department of Pediatric Hematology-Oncology, University of Mississippi, Jackson, MS Corresponding author: Jeffrey E. Rubnitz, MD, PhD, Department of Oncology, Mail Stop 260, St Jude Children's Research Hospital, 332 N Lauderdale St, Memphis, TN 38105-2794; e-mail: jeffrey.rubnitz{at}stjude.org
Purpose To prospectively determine the prognostic significance of the TEL-AML1 fusion in children with acute lymphoblastic leukemia (ALL). Patients and Methods TEL gene status was determined for 926 patients with B-precursor ALL enrolled on the Pediatric Oncology Group ALinC 16 trials and patients were observed for a median time of 8 years. Results Rearrangements of the TEL gene were detected in 244 patients (26%). The estimated 5-year event-free survival rate (± SE) for patients with TEL rearrangements was 86% ± 2%, compared with 72% ± 2% for those with germline TEL (P < .0001). TEL rearrangements were associated with a superior outcome among patients with standard-risk ALL, high-risk ALL, and rapid early responses to therapy. In a multivariate analysis that included risk group, sex, and day 15 marrow status, TEL status was an independent predictor of outcome (P = .0002). Conclusion We conclude that TEL gene status should be incorporated into risk classification schemes and suggest that patients who have standard-risk features, the TEL-AML1 fusion, and rapid early responses to therapy, should be treated with antimetabolite-based therapy designed to maintain their high cure rates and avoid late effects.
The TEL-AML1 gene fusion, created by the t(12;21) (p12;q22), is the most common translocation in childhood acute lymphoblastic leukemia (ALL), occurring in approximately 25% of B-precursor cases.1-3 Soon after the fusion was cloned in 1995, several retrospective studies suggested that it was associated with an excellent outcome.4-6 We reported that among patients with ALL treated at St Jude Children's Research Hospital, TEL gene rearrangements, representing the TEL-AML1 fusion, were associated with a 5-year event-free survival (EFS) rate higher than 90%.4 In that study, the favorable impact of TEL rearrangements was independent of age and leukocyte count. Similarly, we demonstrated that TEL rearrangements were associated with an improved survival rate of patients treated on a Pediatric Oncology Group (POG) trial.5 The TEL-AML1 fusion was also associated with an outstanding outcome among patients treated on a Dana-Farber Cancer Institute (DFCI) trial.6 Investigators from St Jude and from DFCI also demonstrated a very low frequency of TEL-AML1 in patients with relapsed ALL, consistent with the excellent outcome of patients with this translocation.7,8 Despite the plethora of studies that suggest that TEL-AML1 is an independent favorable predictor of outcome and should be used in risk classification, questions remain regarding its true impact.9 For example, some reports demonstrated a high incidence (20% to 24%) of the TEL-AML1 fusion in relapsed patients with ALL, thereby casting doubt as to the prognostic significance of this genetic alteration.10,11 The retrospective nature of many of the studies and the short follow-up of others further suggested that a large prospective study should be performed. Hence, in 1996, investigators from the DFCI and from the POG simultaneously undertook prospective studies to determine the prognostic significance of the TEL-AML1 fusion in childhood ALL. The DFCI recently reported that TEL-AML1 is associated with an excellent outcome (5-year EFS, 89%), but that TEL-AML1 status is not an independent predictor of outcome.12 Herein we report the results of the POG study.
Patients and Samples Bone marrow samples were obtained from patients sequentially enrolled on the POG 9400 classification/induction study from December 29, 1995, to June 16, 1998. Of the 1,501 patients subsequently enrolled on the three ALincC16 postinduction studies for B-precursor ALL (9201, 9605, and 9406), 1,150 had samples submitted for TEL testing.13,14 Because the 9400 classification study and the three therapeutic studies opened and closed to accrual at different times, and because some of the eligible patients were enrolled on pilot studies, the distribution of patients on the three ALinC16 studies does not add up to the total pre-B ALL population over a given period of time. Definitive results regarding TEL status were obtained in 926 patients, who are the subject of this report. At the time of diagnosis, patients were assigned to induction treatment based on National Cancer Institute (NCI) risk status15: patients with standard-risk ALL received a three-drug induction regimen (prednisone, vincristine, l-asparaginase), and patients with high-risk ALL received the same three drugs plus daunorubicin. At the completion of induction therapy, patients were further stratified into three risk groups for postinduction therapy. Patients with low-risk disease (POG 9201) were those with NCI standard-risk features and either simultaneous trisomy of chromosomes 4 and 10, or, in the absence of informative cytogenetics, a DNA index higher than 1.16. Patients with standard-risk disease (POG 9605) included those with NCI standard-risk features who lacked the low-risk characteristics and those with NCI high-risk features and both trisomies 4 and 10 or a DNA index higher than 1.16. Patients with high-risk ALL (POG 9406) included any patients with CNS3 status, a t(1;19), t(9;22), or t(4;11) and patients with NCI high-risk features who did not have trisomies 4 and 10 or a DNA index higher than 1.16. Postinduction therapy on POG 9201 consisted of consolidation therapy with intermediate dose methotrexate (1 gm/m2) given every 3 weeks for six doses and daily mercaptopurine. This was followed by continuation therapy with weekly standard dose methotrexate and daily mercaptopurine. Vincristine and prednisone pulses were given throughout continuation therapy and triple intrathecal therapy was used for CNS prophylaxis.13 Patients with POG standard-risk ALL (POG 9605) received the same consolidation therapy as the low-risk patients, but were randomly assigned, in a 2 x 2 factorial design, to receive divided dose oral methotrexate every other week versus standard weekly dose methotrexate during the first 6 months of continuation therapy and oral mercaptopurine in a single-dose versus divided dose fashion throughout continuation. Patients on 9201 and 9605 received no anthracyclines, epipodophyllotoxins, alkylating agents, or cranial irradiation. Patients with POG high-risk ALL (POG 9406) received multiagent intensified consolidation and continuation using rotating agents. The standard arm of 9406 used rotating courses of methotrexate (1 gm/m2) with intravenous mercaptopurine (1 gm/m2), followed by teniposide with standard dose cytarabine, followed by daunorubicin, standard-dose cytarabine, vincristine, prednisone, and l-asparaginase. On POG 9406, patients were randomly assigned in a 2 x 2 factorial design to determine whether 2.5 gm/m2 methotrexate was more effective than 1.0 gm/m2 and to determine whether substitution of high-dose cytarabine with PEG asparaginase for the teniposide with standard-dose cytarabine would give equally good or better EFS, with less chance of causing second malignancy. All three studies (POG 9201, 9605, and 9406) used triple intrathecal therapy until July 29, 1999, when the protocols were amended to give only intrathecal methotrexate. Genomic DNA was extracted, and the TEL gene status was analyzed as previously described.2 Written informed consent was obtained from patients or their legal guardians, and all studies were approved by the institutional review board at each collaborating site.
Study Design
Statistical Methods
Patient Characteristics A total of 2,676 patients were enrolled on the POG ALinC 16 therapeutic trials for B-precursor ALL: 692 patients with POG low-risk ALL were enrolled on POG 9201; 1,077 patients with POG standard-risk ALL were enrolled on POG 9605; and 907 patients with POG high-risk ALL were enrolled on POG 9406. Of these, 926 patients had adequate diagnostic bone marrow samples submitted for TEL gene analysis (152 on POG 9201, 470 on POG 9605, and 304 on POG 9406). The only differences in characteristics between patients who were and were not studied for TEL status were due to nonproportional sampling among studies, as the various treatment studies opened and closed at different times. In addition, there was no difference in outcome between patients who were and were not studied for TEL status (5-year EFS, 76% ± 1% v 77% ± 1%; P = .6). TEL gene rearrangements were present in 244 (26%) of 926 cases analyzed, including seven (5%) of 152 treated on POG 9201, 173 (37%) of 470 treated on POG 9605, and 64 (21%) of 304 treated on POG 9406 (Table 1).
TEL-rearranged patients had a median age of 4.4 years (range, 1.4 to 19.7 years) and a median presenting leukocyte count of 12 x 109/L (range, 1 to 219 x 109/L), whereas those with germline TEL had a median age of 5.0 years (range, 1.1 to 21.1 years) and a median presenting leukocyte count of 12 x 109/L (range, 1 to 848 x 109/L). TEL rearrangements were detected in 29% of patients in the NCI standard-risk group and in 21% of patients in the NCI high-risk group (Table 1). Only 27% of patients with TEL rearrangements and 36% of patients with germline TEL (P = .0093) had high-risk ALL. Of the 22 patients who had TEL rearrangements and were at least 10 years old, 20 patients (91%) had presenting leukocyte counts less than 50 x 109/L.
Impact of TEL Rearrangements
Because we previously demonstrated that patients with trisomies 4 and 10 have an excellent outcome,19 we compared the outcome of patients with rearranged TEL with that of patients with trisomies 4 and 10 and patients with neither feature (Fig 2). Patients with TEL rearrangements had an outcome similar to that of patients with trisomies 4 and 10 (5-year EFS, 86% ± 2% v 82% ± 3%; P = .18), and both groups fared significantly better than did the group of patients with neither feature (5-year EFS, 69% ± 2%; overall P < .0001).
Impact of Early Response to Therapy Early response to therapy is one of the best predictors of outcome in childhood ALL.20,21 We therefore studied the association between day 15 bone marrow status and TEL gene rearrangements. Day 15 marrow status was available for 857of the patients with known TEL status. Of the 228 patients with a TEL rearrangement, 214 (94%) experienced rapid early responses, defined as M1 marrow at day 15, and 566 (90%) of 629 patients with germline TEL genes experienced such responses (P = .104). As expected, rapid early responses, compared with slow early responses (M2/M3 marrow at day 15), were associated with significantly improved outcomes for patients with rearranged TEL genes (5-year EFS, 87% ± 2% v 71% ± 12%; P = .043) and for those with germline TEL genes (5-year EFS, 75% ± 2% v 56% ± 6%; P < .0001). In addition, TEL rearrangements were associated with a superior outcome in patients with rapid early responses (5-year EFS, 87% ± 2% v 75% ± 2%; P = .0001; Fig 3A), but the difference in outcome did not attain statistical significance among those with slow early responses (5-year EFS, 71% ± 12% v 56% ± 6%; P = .16; Fig 3B).
Cox proportional hazards regression was used to determine the effect of TEL status on EFS. After adjustment for NCI risk group (standard risk v high risk), sex, and day 15 marrow status (M1 v M2/M3), TEL status was an independent predictor of outcome (hazard ratio [HR], 0.51; P = .0002; Table 2).
In this prospective study of more than 900 patients with ALL treated on the POG ALinC 16 study with approximately 8 years of follow-up, we demonstrated that TEL status is a highly significant and independent predictor of outcome of patients overall and of patients with NCI standard-risk and high-risk ALL. This finding is in contrast to that in a recent report from DFCI, which found that NCI risk group, but not TEL status, was an independent predictor of outcome. In the DFCI study,12 TEL status was not significantly associated with better EFS within the standard-risk or the high-risk group; however, the power to detect a statistically significant difference was limited by relatively small numbers of patients in each group. In addition, the fact that the outcome of patients with germline TEL genes in the DFCI study (5-year EFS, 80%) was superior to that of patients with germline TEL genes in this study (5-year EFS, 72%) might have decreased the impact of TEL gene rearrangements. However, a confounding factor that may have contributed to the relatively poor outcome of patients with germline TEL in this study is the low proportion of patients with favorable trisomies in this study (19%) compared with the expected proportion among childhood B-precursor cases (approximately 23%). Nevertheless, these results suggest that the ALinC 16 therapy may have been inadequate for patients with high-risk ALL and no TEL rearrangements. In this study, patients with TEL rearrangements who had standard-risk ALL by NCI/Rome criteria had an excellent outcome in response to treatment with antimetabolite-based therapy (POG 9201 or 9605) that did not include anthracyclines, epipodophyllotoxins, alkylating agents, and cranial irradiation. This result suggests that current treatment protocols for this large group of patients should continue to be based on antimetabolites and to avoid agents that are associated with significant long-term sequelae. Patients with TEL rearrangements and high-risk ALL as defined by NCI/Rome criteria also had an excellent outcome, which may be attributed to the more intensive therapy that they received on POG 9406. The only subgroup of patients with TEL rearrangements and a relatively poor outcome (5-year EFS, 71%) was the approximately 5% of patients with slow early responses to therapy, who probably needed more aggressive or alternative therapies. What is the optimal therapy for children with ALL and the TEL-AML1 fusion? The strikingly similar outcomes of patients with TEL-AML1–positive ALL treated on this study, on the DFCI 95-01 trial,12 and at St Jude22 (EFS estimates of 86%, 89%, and 88%, respectively) indicate that different treatment strategies may result in equally good outcomes. Leukemic blasts from patients with TEL-AML1–positive ALL are sensitive to steroids, vincristine, and asparaginase in vitro,23 and it has been suggested that the outstanding outcome of such patients on DFCI trials is related to the intensive use of asparaginase.12 However, the lack of intensive asparaginase administration in ALinC 16 or in the St Jude trials suggests that the use of antimetabolite-based therapy or multiagent chemotherapy is also effective. Recent and ongoing cooperative group clinical trials will determine if the length of methotrexate infusion, the presence of a delayed intensification phase, or the addition of four doses of PEG asparaginase impact the outcome of these patients. In summary, our results demonstrate that early response to therapy, sex, NCI risk group, trisomies 4 and 10, and TEL status are all independent, significant predictors of outcome and should be used concurrently to determine risk classification in childhood ALL. We suggest that patients who have the TEL-AML1 fusion and rapid early responses to therapy should be treated with antimetabolite-based therapy designed to maintain their high cure rates and avoid late effects. In contrast, we believe that patients who have the TEL-AML1 fusion and slow responses to therapy might be candidates for more intensive treatment.
The author(s) indicated no potential conflicts of interest.
Conception and design: Jeffrey E. Rubnitz, Jonathan Shuster, Joanne Kurtzberg, Beverly Bell, Bruce Camitta, Jeanette Pullen Provision of study materials or patients: Joanne Kurtzberg, Beverly Bell, Allen Chauvenet, Bruce Camitta, Jeanette Pullen Collection and assembly of data: Jeffrey E. Rubnitz, David Wichlan, Jonathan Shuster, Beverly Bell, Allen Chauvenet, Jeanette Pullen Data analysis and interpretation: Jeffrey E. Rubnitz, David Wichlan, Meenakshi Devidas, Jonathan Shuster, Stephen B. Linda, Beverly Bell, Stephen P. Hunger, Ching-Hon Pui, Bruce Camitta Manuscript writing: Jeffrey E. Rubnitz, Joanne Kurtzberg, Beverly Bell, Stephen P. Hunger, Ching-Hon Pui, Bruce Camitta, Jeanette Pullen Final approval of manuscript: Jeffrey E. Rubnitz, Jonathan Shuster, Joanne Kurtzberg, Beverly Bell, Stephen P. Hunger, Allen Chauvenet, Ching-Hon Pui, Bruce Camitta, Jeanette Pullen
We thank Julia Cay Jones for expert editorial review.
Supported in part by the St Jude Children's Research Hospital Cancer Center support grant P30 CA-21765; the Pediatric Oncology Group (POG) grant CA 30969; the POG Statistical Office grant U10 CA-29139; the Children's Oncology Group (COG) grant CA 98543; grant R21 CA-73983 from the National Institutes of Health; and by the American Lebanese Syrian Associated Charities. A complete listing of grant support for research conducted by Children's Cancer Group and POG before initiation of the COG grant in 2003 is available online at: http://www.childrensoncologygroup.org/admin/grantinfo.htm. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Romana SP, Mauchauffe M, Le Coniat M, et al: The t(12;21) of acute lymphoblastic leukemia results in a tel-AML1 gene fusion. Blood 85:3662-3670, 1995 2. Shurtleff SA, Buijs A, Behm FG, et al: TEL/AML1 fusion resulting from a cryptic t(12;21) is the most common genetic lesion in pediatric ALL and defines a subgroup of patients with an excellent prognosis. Leukemia 9:1985-1989, 1995[Medline] 3. Romana SP, Poirel H, Leconiat M, et al: High frequency of t(12;21) in childhood B-lineage acute lymphoblastic leukemia. Blood 86:4263-4269, 1995 4. Rubnitz JE, Downing JR, Pui CH, et al: TEL gene rearrangement in acute lymphoblastic leukemia: A new genetic marker with prognostic significance. J Clin Oncol 15:1150-1157, 1997 5. Rubnitz JE, Shuster JJ, Land VJ, et al: Case-control study suggests a favorable impact of TEL rearrangement in patients with B-lineage acute lymphoblastic leukemia treated with antimetabolite-based therapy: A Pediatric Oncology Group study. Blood 89:1143-1146, 1997 6. McLean TW, Ringold S, Neuberg D, et al: TEL/AML1 dimerizes and is associated with a favorable outcome in childhood acute lymphoblastic leukemia. Blood 88:4252-4258, 1996 7. 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[CrossRef][Medline] 8. Loh ML, Silverman LB, Young ML, et al: Incidence of TEL/AML1 fusion in children with relapsed acute lymphoblastic leukemia. Blood 92:4792-4797, 1998 9. Loh ML, Rubnitz JE: TEL/AML1-positive pediatric leukemia: Prognostic significance and therapeutic approaches. Curr Opin Hematol 9:345-352, 2002[CrossRef][Medline] 10. 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 11. Harbott J, Viehmann S, Borkhardt A, et al: Incidence of TEL/AML1 fusion gene analyzed consecutively in children with acute lymphoblastic leukemia in relapse. Blood 90:4933-4937, 1997 12. Loh ML, Goldwasser MA, Silverman LB, et al: Prospective analysis of TEL/AML1-positive patients treated on Dana-Farber Cancer Institute Consortium protocol 95-01. Blood 107:4508-4513, 2006 13. Chauvenet AR, Martin PL, Devidas M, et al: Anti-metabolite therapy for lesser risk B-lineage acute lymphoblastic leukemia of childhood: A report from Children's Oncology Group study P9201. Blood 110:1105-1111, 2007 14. Schultz KR, Pullen DJ, Sather HN, et al: Risk- and response-based classification of childhood B-precursor acute lymphoblastic leukemia: A combined analysis of prognostic markers from the Pediatric Oncology Group (POG) and Children's Cancer Group (CCG). Blood 109:926-935, 2007 15. 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] 16. Kaplan EL, Meier P: Non-parametric estimation for incomplete observations. Am Stat Assoc 53:457-481, 1958[CrossRef] 17. 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 18. Cox DR: Regression models and life-tables. J R Stat Soc B 34:187-220, 1972 19. 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 20. Pui CH, Campana D, Evans WE: Childhood acute lymphoblastic leukaemia: Current status and future perspectives. Lancet Oncol 2:597-607, 2001[CrossRef][Medline] 21. Pui CH, Evans WE: Treatment of acute lymphoblastic leukemia. N Engl J Med 354:166-178, 2006 22. Pui CH, Relling MV, Downing JR: Acute lymphoblastic leukemia. N Engl J Med 350:1535-1548, 2004 23. Ramakers-Van Woerden NL, Pieters R, Loonen AH, et al: TEL/AML1 gene fusion is related to in vitro drug sensitivity for L-asparaginase in childhood acute lymphoblastic leukemia. Blood 96:1094-1099, 2000 Submitted September 6, 2007; accepted January 7, 2008.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test. All tests were conducted at a significance level of 5%. 
