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© 2000 American Society for Clinical Oncology Intensification With Intermediate-Dose Intravenous Methotrexate Is Effective Therapy for Children With Lower-Risk B-Precursor Acute Lymphoblastic Leukemia: A Pediatric Oncology Group StudyFrom the Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX; Pediatric Oncology Group Statistical Office and Department of Pediatrics, University of Florida, Gainesville, FL; Oklahoma University Health Sciences Center, Oklahoma City, OK; Emory University School of Medicine, Atlanta, GA; and Midwest Children’s Children’s Cancer Center, Milwaukee, WI. Address reprint requests to Donald H. Mahoney, Jr, MD, c/o Pediatric Oncology Group, 645 North Michigan Ave, Suite 910, Chicago, IL 60611; email dmahoney{at}msmail.his.tch.tmc.edu
PURPOSE: To determine whether early intensification with 12 courses of intravenous (IV) methotrexate (MTX) and IV mercaptopurine (MP) is superior to 12 courses of IV MTX alone for prevention of relapse in children with lower-risk B-lineage acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Six hundred fifty-one eligible patients were entered onto the study. Vincristine, prednisone, and asparaginase were used for remission induction therapy. Patients were randomized to receive intensification with IV MTX 1,000 mg/m2 plus IV MP 1,000 mg/m2 (regimen A) or IV MTX 1,000 mg/m2 alone (regimen C). Twelve courses were administered at 2-week intervals. Triple intrathecal therapy was used for CNS prophylaxis. Continuation therapy included standard oral MP, weekly MTX, and triple intrathecal therapy every 12 weeks for 2 years. RESULTS: Six hundred forty-five patients (99.1%) achieved remission. Three hundred twenty-five were assigned to regimen A and 320 to regimen C. The estimated 4-year overall continuous complete remission for patients treated with regimen A is 82.1% (SE = 2.4%) and for regimen C is 82.2% (SE = 2.6%; P = .5). No significant difference in overall outcome was shown by sex or race. Serious grade 3/4 neurotoxicity, principally characterized by seizures, was observed in 7.6% of patients treated with either regimen. CONCLUSION: Intensification with 12 courses of IV MTX is an effective therapy for prevention of relapse in children with B-precursor ALL who are at lower risk for relapse but may be associated with an increased risk for neurotoxicity. Prolonged infusions of MP combined with IV MTX did not provide apparent advantage.
EVENT-FREE SURVIVAL (EFS) of children with standard-risk acute lymphoblastic leukemia (ALL) approaches 80% with modern therapy.1 A major factor in this success has been the addition of postremission consolidation or intensification therapy. Various chemotherapeutic agents or combinations have been used during intensification, including antimetabolites, alkylating agents, epipodophyllotoxins, and anthracyclines.2-5 However, the optimum combination, dose, or schedule of agents has not been determined. For more than a decade, the Pediatric Oncology Group (POG) has been investigating dose intensification strategies using antimetabolite-based regimens for the prevention of relapse in children with ALL. Methotrexate (MTX) and mercaptopurine (MP), two of the most active antimetabolites used for the treatment of childhood ALL, have been the focus of these investigations. Intermediate-dose intravenous (IV) MTX, at doses ranging from 500 to 2,000 mg/m2, with leucovorin rescue provides high peak plasma concentrations of MTX, reaches sanctuary sites in the CNS and testes, and has been widely used in the treatment of childhood ALL.5-10 In two prior POG randomized clinical trials for children with standard-risk ALL, treatment regimens incorporating six courses of IV MTX during intensification resulted in 5-year continuous complete remission (CCR) rates in excess of 75%.11,12 Although several regimens have shown improved outcome with IV MTX, other studies have suggested that repetitive low-dose (LD) MTX can achieve critical threshold concentrations of MTX over time and produce comparable EFS rates at lower cost and less inconvenience.13
Dose intensification with MP has not been extensively studied. Oral MP is a core component of consolidation and maintenance chemotherapy for children with standard-risk ALL. MP acts synergistically with MTX. However, the bioavailability of oral MP is variable, the plasma half-life is short, and only one third of patients achieve plasma concentrations of MP greater than the minimal in vitro cytotoxic concentration.14-19 Prolonged IV infusions of MP at doses In early POG pilot studies for children with standard-risk ALL, intensification with 12 courses of IV MTX 1,000 mg/m2 over 24 hours followed by IV MP at 1,000 mg/m2 infused over 8 hours was associated with acceptable toxicity and produced a 7-year EFS rate of 82.4% (SE = 7.5%).21 In a POG pilot study of intensification with 12 courses of repetitive LD MTX and IV MP, similar toxicity and early EFS was observed.22 Based on the initial results of these trials, a prospective, randomized phase III trial was initiated. The primary objective was to determine whether early intensification with 12 courses of IV MTX/IV MP was superior to 12 courses of repetitive LD MTX/IV MP or 12 courses of IV MTX alone for prevention of relapse. The secondary objective was to determine immediate and delayed toxicities for each regimen. The results of the first phase of this randomized trial comparing IV MTX/IV MP against LD MTX/IV MP showed that IV MTX/IV MP was more effective than LD MTX/IV MP for prevention of relapse.23 We now present the results of the randomized trial comparing IV MTX/IV MP to IV MTX alone.
Patients The portion of the POG 9005 clinical trial, reported herein, accrued patients for randomization between IV MTX/IV MP (regimen A) and IV MTX alone (regimen C) as intensification therapy between May 1992 and September 1994. The original study was opened in January 1991, and compared IV MTX/IV MP with repetitive LD MTX/IV MP (regimen B). Because the study was accruing patients at a more rapid rate than anticipated, and because the next-generation ALL pilot study would not be completed before mid-1994, the POG trial was amended in May 1992, and a control arm—IV MTX (regimen C)—was introduced. Concurrent randomization between regimens A, B, and C continued to May 1993, when accrual was sufficient to answer the original study question (A v B), and the trial was reduced from a three-arm to a two-arm study. The report herein is restricted only to concurrently randomized patients. Approval by respective institutional review boards and written informed consent were required before patient entry. To be eligible for the POG 9005 trial, the patient had to (1) be enrolled onto the POG 9000 classification study 6 to 8 days before entry onto this treatment protocol; (2) be confirmed to have B-precursor ALL by the central reference laboratory at Duke University24; and (3) be negative for CNS disease at diagnosis. Finally, patients had to meet one or both of the following criteria: (1) age 1.00 to 10.99 years and WBC count less than 10,000/µL, or age 3.00 to 5.99 years and WBC count less than 100,000/µL; or (2) DNA index (DI) by the central reference laboratory greater than 1.16.25 These age and WBC criteria have been used by the POG to define risk groups since 1976.26 The POG has previously reported excellent outcome for children with B-precursor ALL and a DI greater than 1.16 when treated with antimetabolite therapy.27 On the basis of these observations, newly diagnosed patients who were classified as poor risk by age and WBC criteria, but with a DI greater than 1.16, were eligible for this trial. Patients were respectively stratified by those who failed to meet the age and WBC criteria versus all others. Patients with the t1;19 or t9;22 translocations were retrospectively excluded at day 28 and treated on the high-risk protocol, POG 9006.28,29
CR was defined as a cellular bone marrow with fewer than 5% blasts and no evidence of leukemia at any other site. CNS leukemia was diagnosed when the CSF cell count was
Treatment
The CNS prophylaxis during intensification therapy was identical for both regimens and included age-adjusted intrathecal MTX, administered during weeks 1, 2, 3, 7, 13, 19, and 25, and then every 12 weeks throughout continuation. On August 10, 1992, the CNS treatment schedule was changed to age-adjusted TIT, administered at the same scheduled intervals as intrathecal MTX alone. All patients previously registered and continuing on therapy and all newly diagnosed patients were immediately changed to this schedule. A higher-than-anticipated incidence of CNS relapse on an earlier POG pilot study in which intrathecal MTX alone was used prompted this change in therapy.22
Statistical Considerations Because both regimens used the same induction therapy, the primary end point was CCR, the time from achievementof a CR to failure (death, relapse, or second malignancy) or last contact. EFS results and site-specific failure results are also presented. EFS is similar to CCR, except that the clock starts at registration and induction failures count. Actuarial comparisons were conducted by the log-rank test.30 Actuarial curves were constructed by the method of Kaplan and Meier32 using SEs of Peto et al.30 The cutoff for analysis was October 17, 1998.
Six hundred fifty-one newly diagnosed patients with B-precursor ALL were eligible to be entered onto the study. Presenting characteristics are listed in Table 2. Complete remission was achieved in 645 (99.1%) of 651 patients. Three hundred twenty-five complete responders were assigned to regimen A (three failed to respond to induction), and 320 were assigned to regimen C (three failed to respond to induction).
Patient outcomes by risk stratum are shown in Fig 1. The 4-year estimated EFS rate for randomized eligible patients with good risk prognostic features and DI greater than 1.16 is 89.0% (SE = 2.6%); for good risk, DI  1.16 is 78.9% (SE = 2.4%); and poor risk, DI greater than 1.16 is 74.9% (SE = 7.4%).
Patient outcomes and events by regimen are listed in Table 3 and shown in Fig 2. There were 67 treatment failures for regimen A and 65 failures for regimen B. The 4-year estimated overall CCR for patients treated on regimen A was 82.1% (SE = 2.4%) and for regimen C was 82.2% (SE = 2.6%; P = .5).
Log-rank comparisons of treatment outcomes by sites of failure and within sex and racial subgroups are listed in Table 4. The estimated 4-year CCR rate for marrow disease is 87.1% (SE = 2.2%) for regimen A and 86.3% (SE = 2.4%) for regimen C (P = .45). The estimated 4-year CCR rate for overall CNS remission is 96.1% (SE = 1.3%) for regimen A and 97.1% (SE = 1.2%) for regimen C (P = .79). There was no significant difference in the incidence of CNS relapse in the few patients treated before the protocol change to TIT. The estimated 4-year CCR rate for testicular disease is 95.5% (SE = 2.1%) for regimen A and 94.5% (SE = 2.3%) for regimen C.
No significant difference in overall outcome was shown by sex or race. There was a trend toward a higher failure rate for patients stratified by poor prognosis features but with DI greater than 1.16 and treated on regimen C. Although the treatment difference was statistically significant, the patient numbers at risk are small, and this was not a predesigned study question, leading to the possibility of spurious significance from multiple testing. Common grade 3/4 toxicities reported during intensification, by treatment regimen, are listed in Table 5. During intensification, both regimens required 12 hospitalizations of approximately 48 hours for the delivery of therapy. Overall, toxicities were similar between regimens. Common grade 3/4 toxicities by treatment regimen occurring during maintenance therapy are listed in Table 6. During maintenance, patients received identical treatment with intramuscular MTX weekly and oral MP daily. No pulse therapy was given, and dose escalation of MTX or MP for patients based on WBC results was not required by protocol. Despite the similarity of treatments, there was a trend toward more infections and bilirubinemia in regimen A, but otherwise no significant differences were observed.
Neurotoxicity is listed in Table 7. Major neurotoxicity, principally seizures, was observed during intensification or maintenance therapy in 24 (7.4%) of 325 patients treated on regimen A and 25 (7.8%) of 320 patients treated on regimen C. Seizures occurred at a median time of 10 to 11 days after TIT during intensification or maintenance therapy. Computed tomography or magnetic resonance imaging evidence consistent with leukoencelphalopathy was observed in approximately 75% of these patients.33 Although there was an increased incidence of debilitating headaches for patients treated on regimen A compared with regimen C, the overall incidence of serious neurotoxicity was similar between regimens.
In this randomized clinical trial, we have shown that children with good-risk ALL, by POG risk criteria, attain an overall 4-year EFS rate exceeding 80% using 12 courses of IV MTX during early intensification. Although equivalence of the treatment arms with and without IV MP is a plausible outcome, a one-sided 95% confidence interval for 4-year complete continuous remission excludes advantages of more than 6% favoring IV MP. Hence, although the results are inconclusive with respect to the efficacy of IV MP, we can exclude the likelihood that it is of major benefit.
When outcomes by ethnic background, sex, and site of relapse are reviewed, there is no significant difference between treatment regimens. Isolated and combined testicular relapses occurred with equal frequency among patients treated on regimens A and C, and these outcomes were similar to results reported in prior POG trials.11,12 More than 95% of patients treated on POG 9005 remain in CNS remission for In 1996, the National Cancer Institute (NCI), together with the Pediatric Cooperative Groups, published a uniform approach to risk classification in childhood ALL.37 The POG 9005 trial did not prospectively use NCI consensus risk groups for subgroup analysis, because its accrual was completed around the time of the consensus risk conference. Subsets of both NCI consensus risk groups are included in this trial, which makes retrospective comparisons by consensus risk group potentially biased. Direct comparison is not valid, whereas the results of the antimetabolite-based POG 9005 trial are comparable with those of other regimens reported in the literature that use multiple agents.2,3,5,8,9 Using POG risk criteria, patients with good risk features by age and WBC and with DI greater than 1.16 had a 4-year EFS rate of 89.0% (SE = 2.6%). Because patients with ALL and good risk features may be at risk for late failures, these results may change with further follow-up. Trisomy of leukemic cell chromosomes 4 and 10 has been reported by the POG to be associated with lower risk for relapse.38 These observations were made after the start of the POG 9005 trial; therefore, patients with the combined trisomy entered onto this study were not prospectively stratified and thus are not analyzed separately. Several mechanisms may contribute to the success of MTX-based intensification for patients with good risk features and DI greater than 1.16. Several investigators have shown a correlation between hyperdiploidy, increased intracellular accumulation of MTX and MTX polyglutamates, and EFS.39-42 Increased expression of reduced folate carrier protein, a marked propensity to undergo apoptosis, and an increased in vitro sensitivity to MP, thioguanine, L-asparaginase, and cytarabine, all have been demonstrated in hyperdiploid ALL blasts.43-45 Taken together, these observations suggest that antimetabolite-based regimens should be effective against hyperdiploid B-lineage ALL. Patients with good risk features but DI less than 1.16 and those with poor risk features and DI greater than 1.16 had 4-year EFS rates approaching 75% on POG 9005. Although precise comparisons cannot be made, intensification with 12 courses of IV MTX, as used in this trial, did not significantly decrease the rate of treatment failures when compared with previous POG trials that used six courses of IV MTX.11,12 Furthermore, the POG 9005 trial was associated with an increased incidence of acute neurotoxicity when compared with prior MTX-based POG trials.11,12 The reasons for these results are not clear. IV MTX at 1,000 mg/m2 may not result in optimum systemic exposure to MTX over time in nonhyperdiploid ALL.46 Development of MTX resistance by other mechanisms or potential overrescue with leucovorin may also contribute to treatment failures.47-50 The dose spacing of IV MTX courses together with the use of TIT in place of intrathecal MTX for CNS prophylaxis may have contributed to the increased neurotoxicity on this trial.33 In the POG 9005 trial, prolonged infusions of MP 1,000 mg/m2 were added to a backbone of IV MTX infusions with the objective to increase dose-intensity and prevent leukemic relapse. MP is a prodrug that must be converted to its nucleotide form intracellularly to exert a cytotoxic effect. Several studies have shown marked variability of MP plasma concentrations and erythrocyte thioguanine nucleotide levels using fixed, standard, oral dose schedules.16,17 Significant positive correlations between critical MP or thioguanine pharmacokinetic parameters, dose schedule, or combinations of MTX/MP parameters and disease outcome have been demonstrated by many, although not all investigators.51-54 Recently, Relling et al55 reported that higher dose-intensity of oral MP was the single most important determinant of overall EFS for all patients treated on St Jude Total XII. These data would suggest that dose intensification of MP might lead to improved EFS for children with ALL. In the POG 9005 trial, patients treated with IV MTX/MP experienced no apparent clinical advantage when compared with patients treated with IV MTX alone. The reasons for these results are not clear. In the POG 9005 trial, patients received IV MTX/IV MP every 2 weeks for the first 24 weeks of postinduction therapy but then returned to oral MP 50 mg/m2 daily for the remaining 106 weeks of maintenance therapy. Efficacy of MP therapy may be more dependent on adequate chronic exposure to the drug over a high percentage of weeks in continuation therapy. Cumulative dose of MP over time then becomes important for prevention of relapse.56 This may explain why relapses were rare during the first year on treatment and began to appear during second and third year of therapy. Preliminary results from Dutch ALL trials, with intensification including high-dose IV MP, also failed to demonstrate a benefit.57 In summary, the results of the POG 9005 trial indicate that early intensive therapy with 12 courses of IV MTX is effective for prevention of relapse in children with B-precursor ALL who are at lower risk for relapse. This clinical trial provides evidence that risk group stratification, based on favorable age, WBC, and ploidy, can identify patients with ALL who can be effectively treated with antimetabolite-based therapy without the need for anthracyclines, epipodyllotoxins, or alkylating agents. For patients with nonhyperdiploid ALL or other poor risk features, alternative strategies need to be considered. Further intensification of MTX dose and schedules may overcome difficulties with rapid drug clearance or less efficient intracellular MTX accumulation or MTX polyglutamate formation. However, there is a need for caution with dose intensification of MTX schedules, because increased acute or delayed neurotoxicity was observed when IV MTX and TIT schedules were closely spaced together in recent clinical trials.58 Because of concerns for neurotoxicity, current POG ALL trials have returned to intensification schedules with six courses of IV MTX given at 3-week intervals. The substitution of decadron for prednisone during remission induction,37 the addition of delayed intensification,59 and screening for early marrow response or minimal residual disease60,61 as indicators for further intensification of chemotherapy are approaches currently under investigation.
Participating Institutions 
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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
50 mg/m2/h are well tolerated and result in plasma concentrations between 1 and 10 µmol/L, which are cytocidal for leukemic cells in vitro.
