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© 2002 American Society for Clinical Oncology Treatment of Childhood Acute Lymphoblastic Leukemia: Results of Dana-Farber ALL Consortium Protocol 87-01ByFrom the Division of Hematology/Oncology, Hopital Sainte Justine, Montreal, Quebec; Division of Pediatric Hematology/Oncology, McMaster University, Hamilton, Ontario, Canada; Departments of Pediatric Oncology and Biostatistical Science, Dana-Farber Cancer Institute; Divisions of Hematology/Oncology and Radiation Oncology and Department of Medicine, Children’s Hospital, Harvard Medical School, Boston, MA; Department of Pediatrics, Mt Sinai Medical Center, New York; Division of Pediatric Hematology/Oncology and Division of Pediatric Cardiology, University of Rochester Medical Center, Rochester, NY; Division of Pediatric Oncology, San Jorge Children’s Hospital, San Juan, Puerto Rico; Division of Pediatric Hematology/Oncology, Maine Children’s Cancer Program and Barbara Bush Children’s Hospital at Maine Medical Center, Portland, ME; Division of Pediatric Oncology, Ochsner Clinic, New Orleans, LA; and Department of Pediatrics, Stanford University School of Medicine, Stanford, CA. Address reprint requests to Stephen E. Sallan, MD, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; email: stephen_sallan{at}dfci.harvard.edu
PURPOSE: To improve efficacy and reduce toxic- ity of treatment for children with acute lymphoblas- tic leukemia. PATIENTS AND METHODS: Patients from all risk groups, including infants and those with T-cell disease, were treated between 1987 and 1991. Standard-risk (SR) patients did not receive cranial irradiation, whereas high-risk (HR) and very high-risk (VHR) patients participated in a randomized comparison of 18 Gy of cranial irradiation conventionally fractionated versus two fractions per day (hyperfractionated). RESULTS: At a median follow-up of 9.2 years, the 9-year event-free survival (EFS ± SE) was 75% ± 2% for all 369 patients, 77% ± 4% for the 142 SR patients, and 73% ± 3% for the 227 HR/VHR patients (P = .37 comparing SR and HR/VHR). The CNS, with or without concomitant bone marrow involvement, was the first site of relapse in 19 (13%) of the 142 SR patients: 16 (20%) of 79 SR boys and three (5%) of 63 SR girls. This high incidence of relapses necessitated a recall of SR boys for additional therapy. CNS relapse occurred in only two (1%) of 227 HR and VHR patients. There were no outcome differences found among randomized treatment groups. Nine-year overall survival was 84% ± 2% for the entire population, 93% ± 2% for SR children, and 79% ± 3% for HR and VHR children (P < .01 comparing SR and HR/VHR). CONCLUSION: A high overall survival outcome was obtained for SR patients despite the high risk of CNS relapse for SR boys, which was presumed to be associated with eliminating cranial radiation without intensifying systemic or intrathecal chemotherapy. For HR/VHR patients, inability to salvage after relapse (nearly all of which were in the bone marrow) remains a significant clinical problem.
THE OUTCOME for children with acute lymphoblastic leukemia (ALL) has steadily improved during the past two decades, resulting in an increased cure rate.1-6 Despite these advances, two challenging problems remain: how to further increase the cure rate for the 20% to 25% of children not cured by current regimens and how to minimize long-term sequelae for the children who are cured. Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocol 87-01 attempted to increase antileukemia efficacy by adding high-dose methotrexate during induction and to decrease toxicity by eliminating cranial radiation in standard-risk (SR) patients and using hyperfractionated radiation in high-risk (HR) and very high-risk (VHR) patients. We report the results of this protocol at a median follow-up time of 9.2 years.
DFCI ALL Consortium Protocol 87-01 was open to patient accrual from November 1987 to July 1991. Participating institutions (assessable patients) included DFCI and Children’s Hospital, Boston, MA (n = 87); University of Puerto Rico, San Juan, Puerto Rico (n = 76); Hopital Sainte Justine, Montreal, Quebec, Canada (n = 51); University of Rochester, Rochester, NY (n = 38); Maine Children’s Cancer Program, Portland, ME (n = 36); McMaster University, Hamilton, Ontario, Canada (n = 36); University of Massachusetts, Amherst, MA (n = 23); Mt Sinai Medical Center, New York, NY (n = 13), and Ochsner Clinic, New Orleans, LA (n = 9). Institutional review board approval was obtained at all participating institutions, and informed consent was obtained for each patient before initiation of treatment.
The diagnosis of ALL was made at each institution. Newly diagnosed patients who were younger than 18 years were eligible for entry. T-cell phenotype was determined if more than 20% of cells expressed a combination of T-cell antigens not present in normal blood. Biphenotypic leukemia was defined as coexpression of at least one myeloid antigen (CD33, CD13, CD14, or My8) on more than 10% of the CD10, CD20, and/or CD10 positive cells. CNS leukemia was defined as the presence of at least one blast on CSF cytospin, independent of CSF cell count before the initiation of CNS-specific therapy; evidence of leukemia involvement on ophthalmologic examination; or the presence of unexplained focal neurologic signs at the time of diagnosis. Thus both CNS 2 and CNS 3 patients were considered to have CNS disease at the time of diagnosis.7 Complete remission was defined as bone marrow with
Relapse was defined as the occurrence of any of the following at any time after remission was achieved:
Treatment Regimens
Therapy The 2-year treatment program consisted of four phases, begun 5 days after a single-agent investigational window (Table 1). Remission induction therapy and continuation therapy were the same for all patients, but postremission phases (CNS treatment and intensification treatment) differed by risk category. For SR and HR patients, CNS treatment began on the day that complete remission was attained. SR patients received a single dose of vincristine and 14 days of 6-mercaptopurine during this phase. HR patients received the same two drugs as well as a single dose of doxorubicin. Intensification therapy commenced after completion of the CNS phase, usually 3 weeks after attaining a complete remission. After intensification, continuation therapy was begun and continued until the completion of 24 months of complete remission. Treatment for VHR patients was the same as for HR patients, except that VHR patients received an additional cycle of therapy, including high doses of methotrexate and cytarabine, immediately after completion of remission induction and before CNS treatment. CNS treatment for infants was delayed until the age of 12 months.13
SR treatment.
After attaining a complete remission, CNS treatment consisted of intrathecal cytarabine (same doses as induction) and methotrexate (10 mg for children 2 to < 3 years of age; 12 mg for children HR treatment. After attaining a complete remission, CNS treatment included the same doses and frequency of intrathecal cytarabine and methotrexate as in SR treatment, except methotrexate doses were 8 mg for children 1 to less than 2 years of age. In addition, patients received 18 Gy of cranial radiation given over 12 to 14 days concurrent with the first four administrations of intrathecal drugs. Patients were randomly assigned to 10 daily fractions of 1.80 Gy each (standard fractionation) or 20 twice-daily fractions of .90 Gy each, separated by at least 6 hours (hyperfractionated) (Table 1). Intensification therapy included weekly E coli asparaginase as above and doxorubicin 30 mg/m2 every 3 weeks starting at the completion of induction until the cumulative dose was 360 mg/m2 or for 9 months of postremission therapy, whichever came sooner. Continuation therapy was the same as SR treatment with the following exceptions: the prednisone dose was 120 mg/m2/d and systemic methotrexate was omitted until completion of the intensification phase.
VHR treatment.
VHR treatment started with a 4-week high-dose intensification cycle begun at the time of complete remission. This cycle included vincristine 1.5 mg/m2 (maximum 2 mg) on days 1, 8, 15, and 22; mercaptopurine 50 mg/m2 PO at bedtime days 1 to 14; methotrexate 4 g/m2 as a 1-hour infusion (with leucovorin rescue beginning at hour 36) with concurrent intrathecal methotrexate (dosed by age) on days 1 and 8; cytarabine 3 g/m2 as a 3-hour infusion every 12 hours for six doses starting on day 18, and E coli asparaginase 25,000 IU/m2 administered intramuscularly on day 8, repeated 3 hours after the last dose of cytarabine on day 22, and then continued weekly until achievement of an absolute neutrophil count Recall therapy. In November 1992, 1.3 years after the protocol had closed for accrual, all boys who had received SR treatment (no cranial radiation) and remained in continuous complete remission were recalled to receive additional therapy because of the high observed incidence of CNS relapse (see below). Reinduction lasted 1 month and included weekly doses of vincristine, daily prednisone, doxorubicin 30 mg/m2 on days 1 and 2, methotrexate 4 g/m2 (with leucovorin rescue) given 8 hours after the last dose of doxorubicin, and intrathecal cytarabine (dosed by age) on days 1 and 15. CNS re-treatment included 18 Gy (standard fractionation) of cranial radiation with concurrent intrathecal therapy followed by intrathecal chemotherapy every 18 weeks until the end of treatment. Doses were the same as for HR treatment above. Continuation therapy consisted of a 3-week cycle of vincristine 2 mg/m2 (maximum 2 mg) on day 1, dexamethasone 6 mg/m2 PO on days 1 to 5, methotrexate 30 mg/m2 administered intramuscularly or intravenously on days 1, 8, and 15 (omitted on days of IT methotrexate), and mercaptopurine 50 mg/m2/d PO at bedtime on days 1 to 14. Duration of treatment differed by interval from first complete remission to start of recall treatment: 1 year from the completion of reinduction if the interval was greater than 1 year, or until 2 years of continuous complete remission if the interval was 1 year or less.
Statistical Methods All analyses of randomized groups were by intent to treat according to randomized assignment. Data as of March 2000 were used for these analyses. The median follow-up was 9.2 years, and results were summarized in terms of 9-year EFS, 9-year OS, and 9-year cumulative incidence of CNS relapse. All P values were two-sided.
Patients
Two hundred seventeen patients (59%) had marrow lymphoblasts successfully evaluated for cytogenetic abnormalities. Sixty-eight were hyperdiploid, 102 were diploid, 13 were hypodiploid, and 34 were pseudodiploid. Of these, seven were t(9;22), three were t(1;19), and three were t(4;11). Two of the latter were infants younger than 1 year of age.
The results of all 369 patients as of March 2000 are listed in Table 3. Three hundred fifty-six patients (96%) achieved remission by day 60. Of the 13 patients who did not achieve complete remission, four died from infection during induction, one withdrew consent to participate beyond day six, and eight had refractory disease (only one of whom was alive at last follow-up19). Two hundred seventy-seven patients remained in continuous complete remission. Seventy-two patients experienced relapse and seven patients died in remission. The first site of relapse was bone marrow alone for 46 patients, CNS for 21 patients (15 isolated and six combined with another site), and other site(s) for five patients. Of the 21 CNS relapses, 19 had CSF findings compatible with CNS 3 and two others with CNS 2 (one SR boy and one VHR girl, both with isolated CNS relapses). Figure 1 shows the Kaplan-Meier plots for EFS and OS for the entire population of patients treated on Protocol 87-01. The 9-year EFS (± SE) for all 369 patients was 75% ± 2%, and the 9-year OS was 84% ± 2%.
SR Patients One hundred forty-one (> 99%) of 142 patients in the SR group attained complete remission, and 110 remained in continuous complete remission. Two patients died in remission and twenty-nine experienced relapse. The first site of relapse was marrow alone in nine patients, CNS in 19 patients (13 isolated and six combined with another site), and another site in one patient. As shown in Fig 2A, 9-year EFS was 77% ± 4% and OS was 93% ± 2%.
EFS was statistically significantly worse for SR boys compared with SR girls (P = .03), whereas OS was similar (P = .36) (Fig 3). The CNS was the first site of relapse for 16 (20%) of 79 SR boys (11 isolated and five CNS + bone marrow) and for three (5%) of 63 SR girls (two isolated and one CNS + bone marrow). The cumulative incidence of CNS as the first site of relapse was 20% ± 5% for SR boys and 5% ± 3% for SR girls (P = .007). All CNS relapses were observed within 4 years from initial diagnosis, and the median time to CNS relapse was 27 months (range, 13 to 44 months). The number of other events was similar when comparing SR boys with SR girls: four versus five bone marrow relapses, zero versus one induction death, one versus zero relapses at other sites, and two versus zero remission deaths, respectively.
SR Boys Eligible for Recall Therapy At the time that recall therapy was offered in November 1992, 13 of the 79 boys with SR disease had already relapsed in the CNS alone (n = 9) or CNS combined with marrow relapse (n = 4), three had isolated marrow relapses, one had a marrow combined with gingiva relapse, and one had died in remission. The median time to recall was 2.8 years (range, 1.4 to 4.8 years). Sixty-one SR boys were, therefore, eligible for recall therapy. One patient had an isolated CNS relapse discovered at the time of recall. Twenty other patients declined recall therapy, three of whom subsequently experienced relapse (one CNS alone, one marrow alone, and one CNS combined with marrow). Forty patients received recall therapy, although one of them declined cranial radiation. One boy died of liver failure during reinduction, whereas the remaining 39 patients continued in complete remission. One patient developed persistent quadriparesis from presumed toxic myelitis. None of the patients who received recall therapy experienced subsequent relapse. The median follow-up from the start of recall therapy (or refusal thereof) for the 56 SR boys who remained event-free was 6.3 years (range, 20 to 86 months).
Outcome After CNS Relapse of SR Boys
HR and VHR Patients
Comparison Between SR and HR/VHR Patients
Randomized Treatment Comparisons
The EFS distributions according to randomized cranial radiation fractionation plan for HR and VHR patients were not statistically significantly different (P = .52) (Table 4). CNS control was equivalent with the two fractionation schedules, as only two of the 227 HR/VHR patients had CNS as the first site of relapse, one of whom was randomized to standard fractionation and the other directly assigned to receive standard radiation.
Prognostic Factors
Comparison With Previous Protocols
These mature outcome data provided very good results for HR/VHR patients and two unexpected findings for SR patients. First, that a significant change in CNS treatment (elimination of cranial radiation without a concomitant increased intensity of systemic or intrathecal therapy) resulted in a marked increase in male but not female CNS relapses. Second, and relatedly, that the usual gold standard measure of clinical trial outcomes, EFS, was in this experience of less significance than OS among SR patients. HR/VHR patients treated on Protocol 87-01 had outcomes that compared favorably with those of contemporaneously conducted trials that treated all patients on a common therapy regimen.3,6 Thus we conclude that the major treatment elements of our program, which included multiple high doses of asparaginase for all patients as well as multiple doses of doxorubicin and higher doses of corticosteroids for HR/VHR patients, were efficacious. CNS disease control for HR/VHR patients was outstanding. We have reported late occurring toxicities of these interventions.21-27 Further investigations designed to assess the impact of these late toxicities within the context of disease control are ongoing. It should be noted that neuropsychologic tests for HR/VHR patients treated on Protocol 87-01 are within normal ranges at 7 years from diagnosis.28 We think that increasing outcome efficacy for patients with a higher risk of treatment failure will require identifying subpopulations with relatively refractory disease [for example, infants and patients whose leukemia cells express t(9;22)] and designing more disease-specific therapies. The high incidence of CNS relapses among SR boys was unexpected. Although both EFS and CNS disease-free survival for that group decreased compared with our previous experience, OS was not statistically significantly different, due to the fact that CNS salvage therapy was at least partially effective for these SR boys. Salvage therapy after relapse in HR/VHR patients, almost always bone marrow, was less effective as evidenced by the similarity between OS and EFS in the HR/VHR patients. The major treatment difference between this protocol and its predecessor was the deletion of cranial radiation in SR patients. Others have successfully eliminated radiation from the treatment of some children with ALL. Tubergen et al29 compared 18 Gy of radiation with intrathecal methotrexate alone every 12 weeks during maintenance therapy. Both groups of patients received six doses of intrathecal methotrexate in the initial weeks of treatment. Those authors found no overall differences in isolated CNS relapse rate or in EFS according to CNS treatment in patients younger than 9 years of age. They did report, however, a significant increase in isolated CNS relapse in patients who received intrathecal therapy without radiation and who received less intensive systemic therapy. The Tubergen study included some patients who met our SR criteria and others who would have been in our HR group. Pullen et al30 compared triple intrathecal therapy with intermediate dose intravenous methotrexate in children with ALL, some of whom would have met our criteria for SR treatment. Unlike our studies, their protocol excluded infants younger than 1 year of age and patients with T-cell ALL. They found that triple intrathecal therapy was significantly more effective in the prevention of isolated CNS relapse compared with intermediate-dose intravenous methotrexate. However, 5-year EFS for the triple intrathecal therapy arm was only 60%. Thus it is possible that if the competing risk of bone marrow relapse had been lower, more CNS events might have been observed. Our treatment differed from both of these studies in that different systemic therapy was used, no intrathecal methotrexate was used during induction, and the frequency of intrathecal therapy was every 18 weeks compared with every 12 weeks or 8 weeks.29,30 Our current studies, although still ongoing and premature, suggest that intrathecal therapy with three drugs given at 9-week intervals results in decreased CNS relapses in nonirradiated SR patients. Although we considered that our use of asparaginase might have interfered with the therapeutic effects of intrathecal methotrexate, we could not explain why this phenomenon would occur only in boys. Moreover, we recognized that any single component of therapy, such as cranial radiation, must be considered within the context of the entire treatment regimen. Finally, this study raises a question concerning the relative importance of EFS and OS outcome measures in clinical trials of children with ALL. Improving OS is the ultimate objective from the patient’s point of view. For the patient, improving EFS is important primarily from the quality-of-life perspective, because the diagnosis of relapse heralds another round of treatment and increases anxiety concerning the ultimate likelihood of therapeutic success. Historically, for the clinical investigator, EFS has been considered the gold standard, as it reflects antileukemia efficacy and treatment-related mortality and provides an accurate early indicator of survival outcome in almost all series. With the improved ability of modern treatment approaches to reduce the risk of relapse and the consequent increasingly important need to address issues of treatment intensity and late sequelae, we believe that OS, as well as EFS, also should be considered the gold standard for assessment of outcomes in childhood ALL. The goal of therapy should be to improve EFS and decrease toxicity. The risks and effects of primary and salvage therapies and their impact on OS must be better understood to make rational therapeutic decisions in the future.
Supported in part by grant nos. CA 68484 and CA 06515 from the National Cancer Institute, National Institutes of Health and Department of Health and Human Services, Bethesda, MD. We thank the children and parents who participated in Protocol 87-01. We also acknowledge the contributions of the dedicated nurses and doctors who cared for the patients; Molly Schwenn, MD, the principal investigator at the University of Massachusetts; and the study coordinators and data managers who enabled the conduct of this research study.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
5% blasts, absolute neutrophil count 
1,000/µL, platelets 
