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© 2000 American Society for Clinical Oncology Six Months of Maintenance Chemotherapy After Intensified Treatment for Acute Lymphoblastic Leukemia of ChildhoodFrom the Department of Oncology, Kanagawa Children’s Medical Center, and Department of Pediatrics, Yokohama City University School of Medicine, Yokohama; Department of Pediatric Hematology/Oncology, The University of Tokyo, The Institute of Medical Science; The First Department of Pediatrics, Toho University School of Medicine; Departments of Pediatrics at Tokyo Medical and Dental University School of Medicine, Keio University School of Medicine, Juntendo University School of Medicine, Nippon Medical School, St Lukes International Hospital, and Teikyo University School of Medicine; Department of Hematology/Oncology, Tokyo Metropolitan Kiyose Children’s Hospital; Department of Hematology, National Children’s Hospital; and Environmental Epidemiology, National Children’s Med-ical Research Center, Tokyo; Department of Pediatrics, Ibaraki Children’s Hospital, Mito; Department of Hematology/Oncology, Saitama Children’s Medical Center, Iwatsuki; Department of Hematology/Oncology, Chiba Children’s Hospital, and Department of Pediatrics, Chiba University School of Medicine, Chiba; Department of Pediatrics, University of Shinshu School of Medicine, Matsumoto; Department of Hematology/Oncology, Gunma Children’s Medical Center, Maebashi; and Department of Pediatrics, Yamanashi Medical University, Kohfu, Japan. Address reprint requests to Yasunori Toyoda, MD, Kanagawa Children’s Medical Center, 2-138-4, Mutsukawa, Minami-ku, Yokohama, 232-8555, Japan.
PURPOSE: We postulated that intensification of chemotherapy immediately after remission induction might reduce the leukemic cell burden sufficiently to allow an abbreviated period of antimetabolite therapy. PATIENTS AND METHODS: Three hundred forty-seven children (ages 1 to 15 years) with previously untreated acute lymphoblastic leukemia (ALL) were enrolled onto the Tokyo L92–13 study, which excluded patients with mature B-cell ALL and patients less than 1 year old. One hundred twenty-four patients were classified as standard risk, 122 as high risk, and 101 as extremely high risk, according to age, peripheral-blood leukocyte count, selected genetic abnormalities, and immunophenotype. All subjects received four drugs for remission induction, followed by a risk-directed multidrug intensification phase and therapy for presymptomatic leukemia in the CNS. Maintenance chemotherapy with oral mercaptopurine and methotrexate was administered for 6 months, with all treatment stopped by 1 year after diagnosis. RESULTS: The mean (± SD) event-free survival (EFS) and overall survival rates for all patients were 59.5% ± 3.4% and 81.5% ± 2.2%, respectively, at 5.5 years after diagnosis. EFS rates by risk category were similar (60.2% ± 6.0% for standard risk, 57.7% ± 5.6% for high risk, and 62.5% ± 5.7% for extremely high risk), whereas overall survival rates differed significantly (91.2% ± 2.7%, 80.0% ± 4.1%, and 72.1% ± 4.5%, respectively, P < .0001 by the log-rank test). There were 107 relapses. Eighty-five (79.4%) of these 107 patients achieved second complete remissions, with subsequent EFS rates of 61.5% ± 7.9% (standard risk), 42.6% ± 8.1% (high risk), and 9.6% ± 6.4% (extremely high risk). Of the five risk factors analyzed, only the response to prednisolone monotherapy among extremely high-risk patients proved important. CONCLUSION: Early treatment intensification did not compensate for a truncated phase of maintenance chemotherapy in children with standard- or high-risk ALL. However, 6 months of antimetabolite treatment seemed adequate for extremely high-risk patients who were good responders to prednisolone and received intensified chemotherapy that included high-dose cytarabine early in the clinical course.
OVER THE PAST THREE decades, of treatment in children with acute lymphoblastic leukemia (ALL) has improved dramatically. At present, from 70% to nearly 80% of these patients can expect to be cured if treated on contemporary protocols.1-3 This improvement reflects progress in the development of effective therapy for presymptomatic leukemia in the CNS and other resistant forms of ALL, as well as better methods of supportive care.4-6 Remission maintenance therapy, usually consisting of mercaptopurine (6-MP) and methotrexate (MTX), is thought to play an important role in the clinical management of ALL, although its optimal duration remains controversial.7-10 In 1996, the Childhood ALL Collaborative Group reviewed the results of 42 major clinical studies conducted worldwide and concluded that a prolonged phase of maintenance therapy does in fact decrease the rate of leukemic relapse but also increases the risk of death during remission.9 We postulated that intensive chemotherapy given soon after the induction of complete remission might reduce the leukemic cell burden sufficiently to allow a shorter period of maintenance therapy. To test this hypothesis, the Tokyo Children’s Cancer Study Group (TCCSG) designed the L92-13 protocol for ALL, which specified four-drug induction treatment followed by intensive risk-directed chemotherapy and preventive CNS therapy (cranial irradiation or high-dose MTX). The duration of maintenance chemotherapy was reduced to 6 months, and all treatment was discontinued at 12 months after diagnosis.
Patients Between August 1992 and March 1995, 347 previously untreated children (ages 1 to 15 years) with a diagnosis of ALL were enrolled onto the L92-13 study. The protocol was approved by review boards of the participating institutions, with informed consent from patients or their parents or guardians. Patients with mature B-cell ALL and patients less than 1 year old were excluded. The diagnosis of ALL was based on the morphology of bone marrow or peripheral-blood leukocytes, as judged by French-American-British (FAB) criteria.11 Cell-surface antigens were detected by a standard immunofluorescence assay. Cases were subclassified as T-ALL (n = 39), B-cell precursor ALL (n = 264), ALL with myeloid-associated antigens (n = 22), or other (n = 22), according to the following criteria: T-ALL, if the leukemic cells were positive for CD5 and CD7 and negative for myeloid antigens; and B-precursor ALL, if the cells were positive for CD19 and HLA-DR. B-lineage cases were considered ALL with myeloid associated antigens if the leukemic cells were positive for CD13 and/or CD33. Karyotype analysis was performed by conventional methods after short-term culture. Metaphase preparations were stained to reveal Giemsa banding patterns. Patients were then assigned to standard-risk, high-risk, and extremely high-risk groups according to age, immunophenotype, selected genetic abnormalities and the initial leukocyte count in peripheral blood (Table 1). The male-to-female ratio was 1.04 (177 boys and 170 girls). Of the 347 patients enrolled, 124 (35.7%) were classified as standard risk, 122 (35.2%) as high risk, and 101 (29.1%) as extremely high risk. All patients older than 10 years were assigned to the extremely high-risk group after a protocol revision in 1994. Likewise, patients with CNS disease at diagnosis were treated with cranial irradiation (18 Gy) and upgraded to the next risk group. It should be stressed that our extremely high-risk group included many patients who would be classified simply as high risk at other centers.1
Treatment The treatment plan is outlined in Fig 1. Both the high-risk and extremely high-risk groups received oral prednisolone (PSL) alone at 60 mg/m2 per day for 1 week. Remission induction therapy uniformly consisted of vincristine (1.5 mg/m2 per week intravenously [IV]; maximum 2 mg), PSL (60 mg/m2 daily), L-asparaginase (6,000 U/m2 per day IV), and pirarubicin (20 mg/m2 IV weekly or biweekly for a total of two to four doses). MTX and hydrocortisone (HDC) were administered intrathecally to the standard-risk and high-risk groups, and the extremely high-risk group received triple intrathecal (IT) chemotherapy (MTX, HDC, and cytarabine [ara-C]) in age-adjusted doses, as follows: at 1 year, MTX 7.5 mg, HDC 15 mg, and ara-C 15 mg; at 2 years, MTX 10 mg, HDC 20 mg, and ara-C 20 mg; at 3 or more years, MTX 12.5 mg, HDC 25 mg, and ara-C 25 mg.
After induction of complete remission, the standard-risk group received early intensification therapy, ie, five doses of ara-C 75 mg/m2 per week for 3 weeks, daily doses of 6-MP 40 mg/m2 for 3 weeks, and one dose of mitoxantrone (MIT) 10 mg/m2 IV. High-risk patients received essentially the same regimen, except that cyclophosphamide (CPM) 1,000 mg/m2 IV was administered in place of MIT. In the standard-risk group, therapy for presymptomatic CNS leukemia consisted of two courses of high-dose MTX (3 g/m2) with leucovorin rescue, interspersed with IT MTX and HDC. Patients in the high-risk group were randomized to receive either high-dose MTX with IT MTX or 18-Gy cranial irradiation with IT MTX. Finally, the extremely high-risk group was treated with two courses of "early" high-dose ara-C (six doses at 2 g/m2 every 12 hours) with MIT 5 mg/m2 IV, followed by CNS irradiation with 18 Gy and early intensification with CPM, ara-C, and 6-MP. After CNS-directed therapy, patients underwent a reinduction phase with vincristine, PSL, L-asparaginase, and pirarubicin, followed by intermediate- or high-dose ara-C (500 mg/m2 per day for the standard-risk group, 1,000 mg/m2 per day for the high-risk group, and 2000 mg/m2 per day for the extremely high-risk group) with MIT (5 mg/m2/d IV for 2 days). Etoposide (150 mg/m2 per day for 4 days), L-asparaginase (1,000 mg/m2 per day for 4 days), and enocitabine, an ara-C derivative (150 mg/m2 per day for 4 days), were administered as reconsolidation therapy to the high-risk and extremely high-risk groups. Maintenance chemotherapy consisted of daily oral 6-MP (40 mg/m2 per day) and weekly MTX (25 mg/m2 orally) for the standard- and high-risk groups and 6-MP and MTX (75 mg/m2 IV) for the extremely high-risk group administered over 6 months. The total duration of therapy was 52 weeks for each group. Of the 25 patients who underwent elective hematopoietic stem-cell transplantation in first complete remission, nine received bone marrow from HLA-matched siblings, 15 received autologous peripheral-blood stem cells, and one received autologous bone marrow. The preparative regimen consisted of fractionated total-body irradiation (TBI) with either etoposide, CPM, or phenylalanine mustard, or the regimen consisted of busulfan, etoposide, CPM, or phenylalanine mustard without TBI. Prophylactic therapy for acute graft-versus-host disease in allograft recipients included cyclosporine and a short course of MTX. Fifty-six patients underwent hematopoietic stem-cell transplantation in second complete remission (41 allogeneic bone marrow recipients, four autologous bone marrow recipients, and 11 autologous peripheral-blood progenitor-cell recipients). A variety of preparative regimens, some including TBI, were used with this group .
Statistical Analysis
Remission Induction Remission induction rates in the three risk groups were similar: 98.4% in the standard-risk group, 95.9% in the high-risk group, and 93.1% in the extremely high-risk group. The overall rate was 96.0%. Sex was not a significant predictor of remission induction, whether tested in the individual risk groups or in the total study population (data not shown). Six patients died during remission induction, most from infectious complications
EFS and Overall Survival
Patterns of Relapse Of the 107 children who relapsed, 41 (38.3%) were in the standard-risk group, 43 (40.2%) were in the high-risk group, and 23 (21.5%) were in the extremely high-risk group. Their median times to relapse were 25.3 months (range, 3.1 to 56.2 months), 18.6 months (range, 4.2 to 52.1 months), and 12.4 months (range, 2.3 to 36.2 months). Sixty-eight (63.6%) of the 107 relapses occurred after cessation of treatment, primarily in the standard-risk group. Bone marrow was the most common site of relapse, followed by the testis and CNS (Table 2).
Treatment Outcome After Relapse Eighty-five (79.4%) of the 107 patients who relapsed achieved a second complete remission on a variety of chemotherapeutic regimens. This total included 70 (77.8%) of 90 patients with an isolated or combined bone marrow relapse. As of April 30, 1998, 42 patients (62.0%) with bone marrow–associated relapse remained in remission. Two of the three patients with an isolated CNS relapse had a second complete remission, as did all seven patients with an isolated testicular relapse, only two of whom have had a subsequent relapse. The postrelapse EFS and overall survival rates at 2 years were 61.5% ± 7.9% and 70.0% ± 8.9% for the standard-risk group, 42.6% ± 8.1% and 48.3% ± 9.0% for the high-risk group, and 9.6% ± 6.4% and 14.5% ± 7.7% for the extremely high-risk group, respectively.
Prognostic Factors
It was also of interest to test the prediction that a shorter duration of maintenance therapy might be adequate for girls but not for boys.3,12,13 Although girls did indeed seem to fare better in the high-risk and extremely high-risk groups (Fig 5), this trend has not attained statistical significance; the difference in outcome was much less pronounced among standard-risk patients.
The optimal length of maintenance chemotherapy for children with ALL has not been established. At most centers, patients are treated for 2.5 to 3 years with a combination of weekly MTX and daily 6-MP, an approach supported by numerous studies.12–15 We would stress, however, that the above practice is based on clinical trials incorporating fewer agents administered less intensively than is now the rule. Hence, we asked whether the duration of maintenance treatment could be truncated for patients who had received intensified chemotherapy immediately after remission induction. The results reported here indicate that 6 months of antimetabolite therapy is not adequate for most children with ALL, despite prior intensive treatment. One exception seems to be patients in the extremely high-risk group with fewer than 1,000 circulating blast cells/µL on day 8 of PSL monotherapy. Their estimated long-term EFS rate was 72.3% ± 6.9%, better than results in our standard- and high-risk groups and comparable to those achieved at other centers with extended maintenance therapy.16-20 We attribute this success to an early intensification phase incorporating high-dose ara-C, MIT, and cranial irradiation into a basic regimen of CPM, ara-C, 6-MP, and triple IT chemotherapy. Repeated use of high-dose ara-C may have produced the greatest therapeutic benefit, as this agent has shown increased activity against T-cell ALL, with or without a lymphomatous presentation.21-23 For extremely high-risk patients whose blast cells show resistance to corticosteroids, we suggest more aggressive postinduction therapy or hematopoietic stem-cell transplantation in first remission. These findings may extend to many patients classified as high risk at other centers, where the criteria for an extreme risk of failure are more conservative than ours.1 The clinical outcome of primary treatment in our standard- and high-risk groups was inferior to results in the immediately preceding trial (TCCSG ALL L89-12), in which the total duration of therapy was 2 years.24 Moreover, the excessive number of bone marrow and testicular relapses, many occurring after the cessation of therapy, suggests that longer-term drug exposure is needed to kill residual, slowly dividing leukemic cells or to suppress their growth, permitting apoptotic cell suicide.25 This notion is supported by the well-documented sensitivity of hyperdiploid B-lineage ALL cells to MTX and MTX polyglutamates26,27 and by the ability of long-term antimetabolite therapy to prevent testicular relapse.10,12 Conceivably, patients with the TEL-AML1 fusion gene, which accounts for 20% to 25% of childhood B-lineage ALL cases and is associated with an excellent prognosis,28-31 fared better on the standard-risk protocol than did others without this genetic feature. We plan to address this issue by examining the TEL-AML1 fusion transcripts of cryopreserved blast cells from patients enrolled onto our L92-13 study. The optimal duration of maintenance chemotherapy may be shorter for girls than for boys.3,12,13 Chessells et al showed that boys with a high initial leukocyte count had a worse prognosis than girls, and Children’s Cancer Group investigators reported that sex was an important prognostic factor in their CCSG-141 and CCG-161 studies.15 In our analysis, sex lacked any demonstrable effect on the remission induction rates, but girls did seem to have an advantage over boys in maintaining complete responses, although the trend was not statistically significant. Of the 347 patients who were treated in this study, 107 relapsed, 90 (84.1%) in the bone marrow. Subsequent treatment, primarily allogeneic bone marrow transplantation, yielded 2 years or more of disease-free survival in approximately 40% of the group with marrow relapses. Thus, our 5.5-year overall survival estimate, 81.5% ± 2.2%, was comparable to results reported by others.1,2 The relatively high postrelapse EFS rates in the standard- and high-risk groups (61.5% ± 7.9% and 42.6% ± 8.1%, respectively) not only corroborate the inadequacy of initial maintenance chemotherapy but also suggest that early postremission treatment could have been more intensive. That only one adverse postremission event was caused by infection supports this notion. We conclude that major truncation of the maintenance phase of chemotherapy in childhood ALL patients is associated with unacceptably high rates of bone marrow and testicular relapse. However, children with extremely high-risk features who respond well to corticosteroid monotherapy may not require an extended phase of antimetabolite therapy after effective early treatment. Future efforts to shorten the duration of maintenance chemotherapy for standard-risk patients would likely benefit from the introduction of monthly pulses of vincristine and PSL.12,14 Alternatively, in light of the high salvage rates we obtained for standard-risk and high-risk patients, one might advocate that such groups be treated with abbreviated maintenance therapy, with the expectation that the total percentage of cured patients would ultimately be equivalent to results being achieved with more intensive regimens. This suggestion addresses a common complaint among leukemia therapists, ie, that many patients are being exposed to increasingly toxic therapy that affords them few clinical benefits.
Supported in part by a grant from the Children’s Cancer Association of Japan, Tokyo, Japan. We thank J. Gilbert for editorial assistance.
1. Pui CH, Evans WE: Acute lymphoblastic leukemia. N Engl J Med 339:605-615, 1998
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Reiter A, Schrappe M, Ludwig W-D, et al: Chemotherapy in 998 unselected childhood acute lymphoblastic leukemia patients: Results and conclusion of multicenter trial ALL-BFM 86. Blood 84:3122-3133, 1994 3. Riehm H, Gander H, Henze G, et al: Results and significance of six randomized trials in four consecutive ALL-BFM studies. Haematol Blood Transfus 33:439-449, 1990[Medline]
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Welte K, Reiter A, Mempel K, et al: A randomized phase-III study of the efficacy of granulocyte colony-stimulating factor in children with high-risk acute lymphoblastic leukemia: Berlin-Frankfurt-Münster Study Group. Blood 87:3143-3150, 1996
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Pui CH, Boyett JM, Hughes WT, et al: Human granulocyte colony-stimulating factor after induction chemotherapy in children with acute lymphoblastic leukemia. N Engl J Med 336:1781-1787, 1997 6. Urban C, Benesch M, Lackner H, et al: The influence of maximum supportive care on dose compliance and survival: Single-center analysis of childhood acute lymphoblastic leukemia and non-Hodgkin’s lymphoma treated within 1984-1993. Padiatr 209:235-242, 1997 7. Schmiegelow K, Pulcynska MK: Maintenance chemotherapy for childhood acute lymphoblastic leukemia: Should dosage be guided by white blood cell counts? Am J Pediatr Hematol Oncol 12:462-467, 1990[Medline] 8. Gale RP: Maintenance chemotherapy and cure of childhood acute lymphoblastic leukemia. Lancet 338:1315-1316, 1991[Medline] 9. Group CAC: Duration and intensity of maintenance chemotherapy in acute lymphoblastic leukaemia: Overview of 42 trials involving 12000 randomized children. Lancet 347:1783-1788, 1996[Medline] 10. Chessells J, Harrison G, Lilleymanc T, et al: Continuing (maintenance) therapy in lymphoblastic leukaemia: Lessons from MRC UKALL X. Br J Haematol 98:945-951, 1997[Medline] 11. Bennett JM, Catovsky D, Daniel MT, et al: Proposals for the classification of the acute leukaemias: French-American-British (FAB) co-operative group. Br J Haematol 33:451-458, 1976[Medline] 12. Bleyer WA, Sather HN, Nickerson HJ, et al: Monthly pulses of vincristine and prednisone prevent bone marrow and testicular relapse in low-risk childhood acute lymphoblastic leukemia: A report of the CCG-161 study by the Children’s Cancer Study Group. J Clin Oncol 9:1012-1021, 1991[Abstract] 13. Chessells JM, Richards SM, Bailey CC, et al: Gender and treatment outcome in childhood lymphoblastic leukaemia: Report from the MRC UKALL trials. Br J Haematol 89:364-372, 1995[Medline] 14. Eden OB, Lilleyman JS, Richards S, et al: Results of Medical Research Council Childhood Leukemia Trial UKALL VIII: Report to the Medical Research Council on behalf of the Working Party on Leukemia in Childhood. Br J Haematol 78:187-196, 1991[Medline]
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Uckun F, Sather H, 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 18. Steinherz PG, Gaynon PS, Breneman JC, et al: Treatment of patients with acute lymphoblastic leukemia with bulky extramedullary disease and a T-cell phenotype or other poor prognostic features: A randomized controlled trial from the Children’s Cancer Group. Cancer 82:600-612, 1998[Medline] 19. Nachman J, Sather H, Cherlow J, 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]
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Nachman J, Sather HN, Gaynon PS, et al: Augmented Berlin-Frankfurt-Münster therapy abrogates the adverse prognostic significance of slow early response to induction chemotherapy for children and adolescents with acute lymphoblastic leukemia and unfavorable presenting features: A report from the Children’s Cancer Group. J Clin Oncol 15:2222-2230, 1997 21. van den Berg H, Zsiros J, Venegerg A, et al: Favorable outcome after 1-year treatment of childhood T-cell lymphoma/T-cell acute lymphoblastic leukemia. Med Pediatr Oncol 30:46-51, 1998[Medline]
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Testi AM, Moleti ML, Giona F, et al: A single high dose of idarubicin combined with high-dose ARA-C (MSKCC ALL-3 protocol) in adult and pediatric patients with acute lymphoblastic leukemia: Experience at the University "La Sapienza" of Rome. Haematologica 82:664-667, 1997 23. Lauer SJ, Pinkel D, Buchanan GR, et al: Cytosine arabinoside/cyclophosphamide pulses during continuation therapy for childhood acute lymphoblastic leukemia: Potential selective effect in T-cell leukemia. Cancer 60:2366-2371, 1987[Medline] 24. Hanada R, Ikuta K, Ysuchida M, et al: Results of TCCSG ALL L-89-12-protocol. Jpn J Pediatr Hematol 9:222, 1995 (abstr) 25. Pui CH, Crist WM: Biology and treatment of acute lymphoblastic leukemia. J Pediatr 124:491-503, 1994 [Medline]
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Borkhardt A, Cazzaniga G, Viehmann S, et al: Incidence and clinical relevance of TEL/AML1 fusion genes in children with acute lymphoblastic leukemia enrolled in German and Italian multicenter therapy trials. Blood 90:571-577, 1997 Submitted May 12, 1999; accepted December 6, 1999. This article has been cited by other articles:
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
, MTX and intrathecal hydrocortisone; •, triple intrathecal.
.05. 
1,000 cells/µL had a 36.1% ± 10.5% EFS estimate, compared with 72.3% ± 6.9% for the 72 patients with lower counts (
1,000 circulating blasts/µL on day 8, the 5.5-year EFS estimate was 36.1% ± 10.5% (mean ± 2 SD), compared with 72.3% ± 6.9% for patients with fewer blasts on day 8.
