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© 2003 American Society for Clinical Oncology Childhood T-Cell Acute Lymphoblastic Leukemia: The Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia Consortium Experience
From the Department of Pediatric Oncology and the Department of Biostatistical Science, Dana-Farber Cancer Institute; the Division of Hematology/Oncology, Children’s Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA; the Department of Pediatrics, Stanford University School of Medicine, Stanford, CA; the Department of Pediatrics, Division of Hematology/Oncology, University of Rochester Medical Center, Rochester, NY. Address reprint requests to Barbara Asselin, MD, 601 Elmwood Ave, Box 777, Rochester, NY 14642; e-mail: barbara_asselin{at}urmc.rochester.edu.
Purpose: T-cell acute lymphoblastic leukemia (T-ALL) accounts for 10% to 15% of newly diagnosed cases of childhood acute lymphoblastic leukemia (ALL). Historically, T-ALL patients have had a worse prognosis than other ALL patients. Patients and Methods: We reviewed the outcomes of 125 patients with T-ALL treated on Dana-Farber Cancer Institute (DFCI) ALL Consortium trials between 1981 and 1995. Therapy included four- or five-agent remission induction; consolidation therapy with doxorubicin, vincristine, corticosteroid, mercaptopurine, and weekly high-dose asparaginase; and cranial radiation. T-ALL patients were treated the same as high-risk B-progenitor ALL patients. Fifteen patients with T-cell lymphoblastic lymphoma were also treated with the same high-risk regimen between 1981 and 2000. Results: The 5-year event-free survival (EFS) rate for T-ALL patients was 75% ± 4%. Fourteen of 15 patients with T-cell lymphoblastic lymphoma were long-term survivors. There was no significant difference in EFS comparing patients with T-ALL and B-progenitor ALL (P = .56), although T-ALL patients had significantly higher rates of induction failure (P < .0001), and central nervous system (CNS) relapse (P = .02). The median time to relapse in T-ALL patients was 1.2 years versus 2.5 years in B-progenitor ALL patients (P = .001). There were no pretreatment characteristics associated with worse prognosis in patients with T-ALL. Conclusion: T-ALL patients fared as well as B-progenitor patients on DFCI ALL Consortium protocols. Patients with T-ALL remain at increased risk for induction failure, early relapse, and isolated CNS relapse. Future studies should focus on the identification of and treatment for T-ALL patients at high risk for treatment failure.
LYMPHOID MALIGNANCIES with the T-cell immunophenotype are associated with distinctive biologic behavior and clinical features and, historically, have had a worse prognosis when compared with B-progenitor lymphoblastic disease. Patients with T-cell acute lymphoblastic leukemia (T-ALL) are more likely than patients with B-progenitor acute lymphoblastic leukemia (ALL) to be older than 9 years at the time of presentation. They are also more likely to present with a leukocyte count above 50,000 cells/µL and a mediastinal mass.1,2 Since 1981, the Dana Farber Cancer Institute (DFCI) ALL Consortium has treated patients with T-ALL on the high-risk arm of its treatment protocols.3,4,5,6,7 We recently reviewed the results of DFCI ALL Consortium clinical trials conducted between 1981 and 1995.8,9 Here we focus on the outcome of patients with the T-cell immunophenotype, including 15 patients with lymphoblastic lymphoma treated according to the same protocols.
Patients Between 1981 and 1995, a total of 1,255 children with newly diagnosed ALL, excluding those with the mature B immunophenotype, were enrolled on four consecutive DFCI ALL Consortium protocols and were assessable for the results of treatment. A total of 125 patients (10%) had T-ALL. These patients expressed T-cell markers on more than 20% of blast cells. The enrollment of ALL patients and median follow-up by protocol can be found in Table 1  . Between 1981 and 2000, 15 previously untreated patients with lymphoblastic lymphoma were treated in accordance with these protocols. Three lymphoma patients were treated according to protocol 87-01, 10 were treated according to protocol 91-01, and two were treated according to protocol 95-01.
Informed consent was obtained from parents or guardians before instituting therapy. Patients were enrolled from the following DFCI ALL Consortium institutions: DFCI/Children’s Hospital (Boston, MA; 1981 to 1995), Maine Medical Center/Maine Children’s Cancer Program (Portland, ME; 1981 to 1995), University of Rochester Medical Center (Rochester, NY; 1981 to 1995), Ochsner Clinic, New Orleans (New Orleans, LA; 1981 to 1995), University of Massachusetts (Worcester, MA; 1981 to 1995), University of Puerto Rico, San Juan (1981 to 1991), Eastern Maine Medical Center (Bangor, ME; 1981 to 1985), McMaster University Medical Center (Hamilton, Ontario, Canada; 1985 to 1995), Mount Sinai Medical Center (New York, NY; 1985 to 1995), San Jorge Children’s Hospital (San Juan, Puerto Rico; 1991 to 1995), Hospital Sainte Justine, (Montreal, Quebec, Canada; 1987 to 1995), and Le Centre Hospitalier de L’Universite, (Laval, Quebec, Canada; 1991 to 1995). All protocols were approved by the institutional review board of each participating institution.
Therapy
Statistical Methods Outcome events were induction failure, induction death, relapse, death during remission, and diagnosis of second malignancy. Patients without an outcome event were censored at the time of most recent follow-up. All patients were evaluated for survival. Survival was measured from the day of registration on the DFCI ALL Consortium protocol until death from any cause. Observations were censored for patients last known to be alive. Event-free survival (EFS) was defined to be the interval between the date of complete remission until the first relapse, second tumor or death; induction failure and induction deaths were considered to be events at time zero. Relapse-free survival was defined as the time interval between the date that complete response was established until the first relapse or death from any cause. Distributions of EFS and overall survival (OS) were estimated by the method of Kaplan and Meier and compared for statistical significance between subgroups using the log-rank test.10,11
Although the patients discussed here were enrolled on four different protocols, the variation in therapy and outcomes between protocols was minimal (Table 1
Patient Characteristics The distribution of presenting clinical characteristics of the 125 T-ALL patients and the outcomes associated with each presenting characteristic are summarized in Table 3 . Twenty-four (19%) of 125 were treated as VHR on 85-01 and 87-01 on the basis of presenting WBC count greater than 100,000/µL or age younger than 1 year. The remaining children with T-ALL were treated as HR. The presenting clinical characteristics of the lymphoblastic lymphoma patients are described in the Lymphoblastic Lymphoma subsection of the Response to Therapy section.
Response to Therapy Survival. OS at 5 years for the 125 T-ALL patients was 78% ± 4%, and 86% ± 1% for B progenitor ALL patients (P = .10). As shown in Figure 1 and Table 1 , the 5-year EFS was 75% ± 4% for T-ALL patients and 79% ± 1% for B-progenitor ALL patients (P = .56). Figure 2 shows EFS for T-ALL patients who went into complete remission, compared to B-progenitor patients who went into complete remission, highlighting that patients with T-ALL experienced earlier events, including induction failures and induction deaths. There were no significant differences in EFS for T-ALL patients between the four consecutive protocols (Table 1; P = .93).
Prognostic factors. As shown in Table 3 , there was no significant difference in EFS for T-ALL patients based on: age at diagnosis (P = .69), presenting leukocyte count (P = .57), sex (P = .45), presence of CNS disease at diagnosis (P = .26), presence of a mediastinal mass (P = .39), DFCI risk group (P = .27), or National Cancer Institute Consensus Risk criteria (P = .52).
Induction failure.
The CR rate for all 1,255 patients with ALL was 97% (Table 4
Induction deaths. During remission induction, 3.2% of patients with T-ALL and 0.7% of patients with B-progenitor ALL experienced toxicity-related death. T-ALL patients were 4.5 times more likely to suffer induction death on DFCI protocols than B-progenitor ALL patients (95% CI, 1.4 to14.8; P = .02). However, there was no statistically significant difference in the rate of induction death between T-ALL patients and patients with high-risk B-progenitor ALL (P = .08). Of the four T-ALL patients who died as a result of induction, one died before receiving any chemotherapy, having received emergency radiation therapy to the mediastinum, and three patients died as a result of infection or complications of severe infection (Table 5 ). Of note, all four patients would be classified as high-risk based on their age or WBC count, regardless of immunophenotype.
Relapse. There were 14 relapses (11%) in the 125 patients with T-ALL. Seven involved marrow only, six involved the CNS only, and one was a combined marrow and extramedullary relapse (Table 4 ). T-ALL patients were less likely to experience a relapse than B-progenitor ALL patients, although the difference was not statistically significant (relative risk [RR], 0.6; 95% CI, 0.37 to 1.04; P = .06). However, the risk of CNS relapse was significantly higher in T-ALL patients (RR, 2.7; 95% CI, 1.4 to 5.4; P = .02). The median time of relapse for T-ALL patients was 1.2 years compared with 2.5 years for B-progenitor ALL patients (P = .001). Of the 14 children with T-ALL who experienced relapse, two (14%) were long-term survivors, compared with 65 of 203 children (32%) with B-progenitor ALL who experienced relapse (P = .24). Second malignancy and remission deaths. No T-ALL patients on DFCI protocols experienced second malignancy as a first event, compared with 10 B-progenitor patients (0.9%) who did. There were two remission deaths (2%) for T-ALL, compared with 38 remission deaths (3%) for B-progenitor ALL (P = .42). Lymphoblastic lymphoma. There were 15 patients (10 male and 5 female) with lymphoblastic lymphoma, treated according to DFCI-ALL Consortium protocols, who were deemed assessable for the results of treatment. Six patients were younger than 9 years at the time of diagnosis. Patients presented with advanced stage lymphoma and mediastinal disease. Only one patient had bone marrow involvement at presentation. All 15 patients went into complete remission, and 14 were long-term survivors. One female patient died from doxorubicin cardiotoxicity 8 months into therapy, and another patient relapsed but is a long-term survivor.
Historically, T-cell ALL in children has been associated with a worse prognosis than other sub-types of childhood ALL.1,2 However, EFS and OS rates for children with T-ALL treated on DFCI ALL Consortium protocols from 1981 to 1995 were comparable to those for children with B-progenitor ALL. The 5-year EFS rate for T-ALL patients treated on DFCI ALL Consortium protocols was 75%, which compares favorably with results reported for T-ALL patients treated contemporaneously on other regimens (with 5-year EFS rates ranging from 51% to 73%).12–15 Patients with advanced stage T-cell lymphoblastic lymphoma also responded well to this regimen, in accord with other studies which have reported favorable outcomes of such patients when treated with intensive ALL therapy.16 Unique features of DFCI ALL Consortium protocols that might have contributed to the improved outcome of T-ALL patients include consolidation with doxorubicin and weekly high-dose asparaginase, as well as frequent pulses of high-dose corticosteroids. The Pediatric Oncology Group reported that the inclusion of high-dose asparaginase consolidation on a backbone of intensive chemotherapy improved survival for patients with T-ALL,17 suggesting that the use of this agent may be beneficial in T-ALL. On that study, EFS was 68% for T-ALL patients who received asparaginase and 55% for those who did not. The most recent Pediatric Oncology Group protocol for patients with T-ALL and lymphoblastic lymphoma used a DFCI ALL Consortium backbone, with the addition of high-dose methotrexate during consolidation. Preliminary results have been favorable.18 Twenty-four T-ALL patients (19%) were classified as VHR and received an additional cycle of high-dose cytarabine and methotrexate on protocols 85-01 and 87-01. It seems unlikely that this additional cycle, which is no longer part of DFCI ALL Consortium protocols, significantly contributed to the favorable outcomes of children T-ALL on DFCI ALL Consortium protocols, given that children with T-ALL had similar EFS rates on protocols that did not include this cycle (protocols 81-01 and 91-01). Despite the relatively favorable outcome of patients with T-ALL on DFCI ALL Consortium protocols, such patients were at higher risk for induction failure, induction death, early relapse, and isolated CNS relapse, compared with B-progenitor patients. Higher rates of induction failure and early relapse in T-ALL suggest that this subtype may be more inherently resistant to conventional ALL chemotherapeutic agents. Pieters et al have shown that T-ALL blasts demonstrate greater in vitro resistance to standard induction agents, such as glucocorticoids, vincristine, and asparaginase.19,20 Relative prednisone resistance was demonstrated in vivo on Berlin-Frankfurt-Muenster protocol 90, in which 36% of T-ALL patients demonstrated poor peripheral blood response after the prednisone prophase, compared with 5% of patients with common or pre–B-progenitor ALL.21 Barredo et al demonstrated that T-lineage lymphoblasts require a higher concentration of methotrexate to achieve the same intracellular levels as in B-lineage blasts.22 Although not at significantly higher risk for relapse in general, T-ALL patients were almost three times as likely to have CNS relapse. While the optimal method of CNS prophylaxis remains controversial, the increased risk for CNS relapse suggests that effective CNS prophylaxis for T-ALL patients is essential. All T-ALL patients treated on DFCI ALL Consortium protocols received cranial radiation and intrathecal chemotherapy. On other studies, the elimination of cranial radiation in patients with T-ALL has resulted in higher CNS relapse rates and lower EFS rates, especially for those with higher presenting leukocyte counts.23–25 Extended intrathecal chemotherapy and high-dose systemic therapy, without the use of cranial radiation, has provided effective CNS prophylaxis for subsets of patients with T-ALL, such as those with low presenting leukocyte counts (< 50 to 100,000/µL3) and favorable peripheral blood response to a prednisone prophase.24,26 Prior reports have suggested that patients with T-ALL may be at higher risk for secondary leukemias than those with B-progenitor ALL, especially after treatment with epipodophyllotoxins.16,27 We did not observe any second malignancy as a first event in T-ALL patients treated on DFCI ALL Consortium protocols, which include neither epipodophyllotoxins nor alkylating agents, in accord with our previously published results.28 T-ALL patients were at higher risk of induction death when compared with B-progenitor ALL patients treated on our protocols. However, there was no significant difference in the rates of induction death between high-risk B-progenitor and T-ALL patients, suggesting that increased risk of induction toxicity may reflect patient characteristics, such as age and presenting leukocyte count, rather than differences due to lymphoblast immunophenotype.1 Patients with T-ALL who experienced either induction failure or early relapse had a very poor outcome. It would be beneficial to identify high-risk T-cell patients at diagnosis or soon thereafter in order to modify their initial therapy with the goal of preventing early treatment failure. However, we have demonstrated that conventionally applied epidemiologic features fail to identify these patients. There were no significant differences in EFS for T-ALL patients based on age, presenting leukocyte blood cell count, sex, CNS involvement, or presence of a mediastinal mass. Thus, novel prognostic factors need to be identified in patients with T-ALL. Early response measures may be useful in differentiating good and poor-risk T-ALL patients. Initial response to prednisone prophase is one such predictor. For example, on a protocol conducted by the Berlin-Frankfurt-Muenster group, the EFS of T-ALL patients with a favorable prednisone response (78%) was superior to that of patients with a poor response (32%).20 Levels of minimal residual disease may also provide useful prognostic information. Cave et al reported high levels of minimal residual disease at the end of induction therapy correlated with risk of relapse in T-ALL patients.29 In the future, studies of gene expression profiles may potentially identify biologically distinctive, prognostically significant subsets of patients with T-ALL, as well as potential targets for novel therapies.30
The authors indicated no potential conflicts of interest.
Supported in part by grants from the National Institutes of Health (CA 68484 and 06516).
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3. Silverman LB, Gelber R, Sallan SE, et al: Improved outcomes for children with acute lymphoblastic leukemia: Results of Dana-Farber Consortium Protocol 91-01. Blood 97:1211–1218, 2001 4. Clavell LA, Gelber R, Sallan SE, 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]
5. Niemeyer C, Gelber R, Sallan SE, et al: Low-dose versus high dose methotrexate during remission induction in childhood acute lymphoblastic leukemia (Protocol 81-01 Update). Blood 78:2514–2519, 1991 6. Schorin M, Blattner S, Sallan SE, et al: Treatment of childhood acute lymphoblastic leukemia: Results of Dana-Farber Cancer Institute/Children’s Hospital Acute Lymphoblastic Leukemia Consortium Protocol 85-01. J Clin Oncol 12:740–747, 1994[Abstract]
7. LeClerc JM, Billet AL, Sallan SE, et al: Treatment of childhood acute lymphoblastic leukemia: Results of Dana-Farber ALL Consortium Protocol 87-01. J Clin Oncol 20:237–246, 2002 8. Silverman LB, Gelber R, Sallan SE, et al: Induction failure in acute lymphoblastic leukemia of childhood. Cancer 85:1395–1404, 1999[CrossRef][Medline] 9. Silverman LB, Declerk L, Sallan SE, et al: Results of the Dana-Farber Cancer Institute Consortium Protocols for children with newly diagnosed acute lymphoblastic leukemia (1981–1995). Leukemia 14:2247–2256, 2000[CrossRef][Medline] 10. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481, 1958[CrossRef] 11. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50:163–170, 1966[Medline] 12. Schrappe M, Reiter A, Riehm H, et al: Long-term results of four consecutive trials in childhood ALL performed by the ALL-BFM study group from 1981 to 1995. Leukemia 14:2205–2222, 2000[CrossRef][Medline] 13. Maloney KW, Shuster JJ, Camitta BA, et al: Long-term results of treatment studies for childhood acute lymphoblastic leukemia: Pediatric Oncology Group studies from 1986–1994. Leukemia 14:2276–2286, 2000[CrossRef][Medline] 14. Eden OB, Harrison G, Gibson BES, et al: Long-term follow-up of the United Kingdom Medical Research Council protocols for childhood acute lymphoblastic leukemia, 1980–1997. Leukemia 14:2307–2320, 2000[CrossRef][Medline] 15. Gaynon PS, Trigg ME, Bleyer WA, et al: Children’s Cancer Group trials in acute lymphoblastic leukemia, 1983–1995. Leukemia 14:2142–2148, 2000[CrossRef][Medline]
16. Reiter A, Schrappe M, Riehm H, et al: Intensive ALL-type therapy without local radiotherapy provides a 90% event-free survival for children with T-cell lymphoblastic lymphoma: A BFM group report. Blood 95:416–421, 2000 17. Amylon MD, Shuster J, Murphy SB, et al: Intensive high dose asparaginase consolidation improves survival for pediatric patients with T cell acute lymphoblastic leukemia and advanced stage lymphoblastic lymphoma: A Pediatric Oncology Group study. Leukemia 13:335–342, 1999[CrossRef][Medline] 18. Asselin BL, Shuster JJ, Amylon M, et al: Improved event-free survival (EFS) with high dose methotrexate (HDM) in T-cell lymphoblastic leukemia and advanced lymphoblastic lymphoma (T-NHL): A Pediatric Oncology Group (POG) Study. Proc Am Soc Clin Oncol 20:367, 2001 (abstr 1464) 19. Pieters R, Kaspers G, Veerman A, et al: Cellular drug resistance profiles that might explain the prognostic value of immunophenotype and age in childhood acute lymphoblastic leukemia. Leukemia 7:392–397, 1993[Medline] 20. Pieters R, Boer M, Veerman A, et al: Relation between age, immunophenotype and in vitro drug resistance in 395 children with acute lymphoblastic leukemia: Implications for treatment of infants. Leukemia 12:1344–1348, 1998[CrossRef][Medline]
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26. Pui CH, Mahmoud HH, Evans WE, et al: Early intensification of intrathecal chemotherapy virtually eliminates central nervous system relapse in children with acute lymphoblastic leukemia. Blood 92:411–415, 1998 27. Pui CH, Behm FG, Murphy SB, et al: Secondary acute myeloid leukemia in children treated for acute lymphoid leukemia. N Engl J Med 321:136–142, 1989[Abstract] 28. Dalton VM, Gelber R, Sallan SE, et al: Second malignancies in patients treated for childhood acute lymphoblastic leukemia. J Clin Oncol 16:2848–2853, 1998[Abstract]
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30. Ferrando AA, Armstrong SA, Neuberg DS, et al: Gene expression signatures in MLL-rearranged T-lineage and B-precursor acute leukemias: Dominance of HOX dysregulation. Blood 102:262–268, 2003 Submitted September 22, 2002; accepted July 15, 2003.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
of .05. The Mann-Whitney test determined any differences in the time to relapse between the two groups. Descriptive statistics were also used to characterize the patients. Adjustments for multiple comparisons were not used. VHR patients were treated as HR patients for the purpose of this analysis. Results presented here are based on data available as of April 10, 2001, for protocols 81-01 and 91-01, and as of June 13, 2001, for protocols 85-01 and 87-01. 
