A prospective, randomized multicenter study was performed to evaluate the relative efficacy of two different concepts for early intensive therapy in a randomized trial of children with B-precursor acute lymphoblastic leukemia (ALL) at high risk (HR) for relapse. Four hundred and ninety eligible children with HR-ALL were randomized on the Pediatric Oncology Group (POG) 9006 phase III trial between 7 January 1991 and 12 January 1994. After prednisone (PDN), vincristine (VCR), asparaginase (ASP) and daunorubicin (DNR) induction, 470 patients received either 12 intensive parenteral treatments of intermediate dose (1 g/m2 each) methotrexate (MTX) and mercaptopurine (MP) over 24 weeks (regimen A) or 12 intensive course of alternating myelosuppressive drug combinations given over 30 weeks (regimen B). These drug combinations included MTX/MP, teniposide (VM-26)/cytosine arabinoside (AC) and VCR/PDN/DNR/AC/ASP. Central nervous system (CNS) prophylaxis was age-adjusted triple intrathecal chemotherapy. Patients with CNS disease at diagnosis were treated with craniospinal irradiation after the intensive phase. Continuation was standard doses of MTX and MP for 2 years. This trial was closed early because of an apparent early difference favoring regimen B. Results show that 470 patients achieved remission (97%). Two hundred and thirty two were randomized to regimen A and 238 to regimen B. The estimated 4-year event-free survival (EFS) for patients treated with regimen A is 61.6% (s.e. = 3.3%) and with regimen B is 69.4% (s.e. = 3.1%), P = 0.091. Toxicities were more frequent on regimen B. In conclusion, for children with B-precursor ALL at high risk to relapse, early intensification with myelosuppressive combination chemotherapy was more toxic but produced no significant difference in EFS when compared to those treated with parenteral methotrexate and mercaptopurine.
Improvement in overall survival of children with acute lymphoblastic leukemia (ALL) is in part due to a better understanding of the biology of this malignancy and factors that are associated with the success or failure to maintain remission. Irrespective of the therapeutic trial, common risk factors include age, WBC at diagnosis, leukemic cell surface antigen expression, cytogenetics, DNA index and early response to cytoreductive therapy.12345678 Based on these prognostic factors, children with newly diagnosed ALL can be stratified according to their risk for relapse and treatment strategies designed to improve event-free survival (EFS).
It is believed that the leading causes of relapse in children with higher risk ALL (HR-ALL) are inadequate cell kill and emergence of drug-resistant clones. Clinical trials using early intensive myelosuppressive combination chemotherapy as post-induction consolidation were designed to maximize cell kill and address drug resistance. Subsequently, improvement in survival was realized for patients with HR-ALL.91011121314151617181920 Increased toxicity was also noted with the aggressive use of myelosuppressive agents.91314161819202122 However, preliminary results from POG 8698 suggested that early intensification with the less toxic combination of intermediate-dose methotrexate (MTX) and mercaptopurine (MP) might be as effective as the more myelosuppressive combinations used in another POG pilot study (POG 8398) for HR-ALL.1317
In 1991, the POG opened a group-wide randomized phase III clinical trial (POG 9006) to treat children with HR-ALL. The primary objectives of this randomized trial were to compare the efficacy and toxicity of regimen A: 12 early intensive courses of antimetabolite-based chemotherapy (intermediate-dose MTX/MP) vs regimen B: 12 early intensive courses of alternating myelosuppressive, non-cross-resistant combination chemotherapy with MTX/MP as per the Goldie–Coldman hypothesis.23 This paper reports the results of that trial.
Patients and methods
The POG 9006 phase III clinical trial accrued patients between 7 January 1991 and 12 January 1994. Approval by local institutional review boards and written informed consent were required before patient entry.
Eligibility for POG 9006 included (1) enrollment on the POG 9000 classification study; (2) confirmation of B-precursor ALL by central reference laboratories;24 and (3) meeting the criteria for high risk B-precursor ALL. Those criteria were leukemic cell DNA index of ⩽1.16 (DNA content in leukemic cells: DNA content of normal G0/G1 cells) (DI) by central reference laboratory2526 and at least one of the following: (1) WBC ⩾10 000–99 000/μl, aged 1–2.99 years or ages 6–21 years; (2) WBC ⩾100 000/μl, aged 1–21 years; (3) all patients with CNS or overt testicular disease at diagnosis; or (4) leukemic cell chromosome translocations t(1;19) or t(9;22) confirmed by central reference laboratory.2728 Only patients who met criteria 1, 2, or 3 were eligible for randomization. Patients having t(1;19), or t(9;22) leukemia at diagnosis were not randomized because the numbers of these patients were predicted to be low and thus no statistically valid information would be obtained if they were randomized. All of these patients were assigned to regimen A and were excluded from this report. Patients <12 months of age were not eligible for this protocol.
Definition of disease and response
CNS leukemia was diagnosed when the cerebrospinal fluid (CSF) WBC count was ⩾5 cells/μl and lymphoblasts were identified on a Wright-stained, cytocentrifuged slide examination without peripheral blood (PB) contamination. Complete remission (CR) was defined as a cellular bone marrow with fewer than 5% blasts and no evidence of leukemia at any other site.
The definition of relapse required: (1) bone marrow >25% lymphoblasts; (2) CNS ⩾5 WBC/μl of CSF and lymphoblasts identified on a Wright-stained examination without PB contamination; (3) extramedullary site with biopsy proven infiltrate with lymphoblasts; or (4) any combination of the above.
Five hundred and seventy-three newly diagnosed patients with B-precursor, HR-ALL were registered on POG 9006. After eligibility for this HR-ALL protocol was determined, 69 patients (45 t(1;19); 24 t(9:22)) were removed from randomization and assigned regimen A, 14 patients were ineligible for protocol therapy (wrong diagnosis) and 490 patients were randomized (Table 1) to receive one of two post-induction intensification therapies (Table 2).
Treatment and drug dose modification
Patients were randomized at diagnosis to one of two intensification schedules which have been previously outlined in detail.1317 Treatment regimens are listed in Table 2. Induction therapy was identical for both groups: vincristine (VCR), prednisone (PDN), E. coli L-asparaginase (ASP) and daunorubicin (DNR). Age-adjusted triple intrathecal therapy (TIT) with methotrexate (MTX), hydrocortisone (HDC) and cytosine arabinoside (AC) was administered on day 1 of induction. Patients with CNS disease at diagnosis were given three additional weekly doses of age-adjusted intrathecal MTX. Intensification started immediately after meeting the criteria for remission. Patients randomized or assigned regimen A began week 1 of intensification receiving intravenous (i.v.) intermediate-dose MTX infused over 24 h, followed by i.v. intermediate-dose MP infused over 6 h. On week 2, patients received intramuscular (i.m.) MTX on day 1 and MP by mouth (p.o.) daily for 7 days. The 2-week schedule was repeated 12 times over 24 weeks. The i.v. administration of MTX and MP required a 48-h hospitalization. Those patients randomized to regimen B received six courses of MTX and MP as in regimen A, three courses of teniposide (VM-26) and AC and three courses of DNR, AC, VCR, PDN and PEG-asparaginase (PEG-ASP) in an alternating fashion over 30 weeks. The DNR/AC and VM-26/AC courses required a 72-h hospitalization. Plasma MTX levels were monitored after each intermediate-dose MTX. Leucovorin (LCV) rescue began 48 h after the start of the methotrexate infusion and continued every 6 h for five doses or until plasma MTX was <0.1 μmol/l. All courses of chemotherapy during intensification began when the absolute neutrophil count was ⩾500/μl and platelet count was ⩾100 000/μl. If courses of DNR/AC or VM-26/AC resulted in prolonged neutropenia (<500/μl for >24 days), each myelosuppressive drug was reduced by 25% for the next course. Dose escalation was not permitted during any phase of this protocol.
Because of the known sensitivity of Down syndrome patients to MTX and myelosuppressive chemotherapy, they started with a 50% dose reduction of intermediate-dose MTX, DNR, AC and VM-26 during intensification. Subsequent courses of these agents were increased or decreased according to tolerance.
CNS prophylaxis was continued throughout intensification and continuation with age-adjusted TIT for a total of 18 doses for both regimens. Those children with CNS disease at diagnosis received additional IT chemotherapy (MTX) during induction (as above) and eight doses of TIT during intensification (regimen A or B). Following intensification these patients then received craniospinal irradiation: cranial volume, 2400 cGy in 16 fractions; and spinal axis, 1500 cGy in 10 fractions. No intrathecal chemotherapy was given following irradiation.
Following intensification all patients were given identical continuation therapy with standard-dose MTX and MP. Intensification and continuation lasted for a total of 130 weeks.
The plan for this study was to randomize 507 patients and monitor the patients until the last entrant would be at risk for 4 years. This plan allowed greater than 90% power to detect a 12% difference in 4-year continuous complete remission (CCR) rates (60% vs 72%), based on a two-sided logrank test at P = 0.05, proportional hazards, and a post-4-year hazard of 25% of the pre-4 year hazard.29 The Data Monitoring Committee (January 1994) closed the trial for an apparent early difference favoring regimen B (CCR at 2 years, A vs B, 70.8% (s.e. 7.7%) vs 82% (s.e. 6.1%), P = 0.0016. Accrual at the time of study closure was 490, 17 less than the planned accrual of 507). The committee recommended that the data be allowed to mature to the planned follow-up before publication.
Since both regimens used the same induction therapy, the primary end point was CCR, the time from achievement of a CR to failure (death, relapse, or second malignancy) or last contact. Event-free survival (EFS) results and site-specific failure results are also presented (Table 3). EFS is similar to CCR, except that the clock starts at registration and induction failures are counted. Actuarial comparisons were conducted by the logrank test. Actuarial curves were constructed by the method of Kaplan–Meier30 using standard errors of Peto et al.31 The cutoff for analysis was October 1998, the earliest cutoff where the planned follow-up was completed in all patients.
Readers are cautioned against overinterpretation of subsets and site-specific failure comparisons. The overall results should take priority in all subsets, because the study was not planned for these secondary analyses from a statistical power perspective. No subset demonstrated a qualitative interaction, where a result in favor of the overall inferior treatment occurred. We performed a Cox analysis32 to test for a quantitative interaction between treatment and sex. This tests for the equality of the treatment effect size between males and females.
Four hundred and ninety (490) patients were randomized to receive one of two post-induction therapies. Twenty patients did not achieve complete remission (CR) status: 15 due to induction failure and five were not evaluable for CR (refused therapy, one; toxicity, one; non-documentation, three) for a remission induction rate of 97% (470/485). Thus 470 of 485 patients achieved complete remission and were eligible for the randomized study question (regimen A, 232/243; regimen B, 238/247).
Patient outcomes by regimen are shown in Figures 1 and 2. The 4-year estimated EFS rate for randomized eligible patients treated with regimen A is 61.6% (s.e. = 3.3%) and with regimen B is 69.4% (s.e. = 3.1%), P = 0.091. The 4-year estimated overall CCR rate for patients with regimen A is 64% (s.e. = 3.4%) and with regimen B is 70.6% (s.e. = 3.1%), P = 0.22. This study was inconclusive with respect to efficacy. Based on the 5-year CCR, we are 95% confident that the true difference ranges from 6% favoring regimen A to 15% favoring regimen B. Logrank comparisons of treatment outcome by sites of failure and within gender and racial subgroups are listed in Table 3 and accounting of events is listed in Table 4. The estimated 4-year CCR rate for overall CNS (isolated and combined) relapse is 87.7% (s.e. = 3.3%) for regimen A and 85.4% (s.e. = 3.1%) for regimen B, P = 0.64. The estimated 4-year CCR rate for marrow relapse is 70.9% (s.e. = 4.1%) for regimen A and 75.3% (s.e. = 3.6%) for regimen B, P = 0.15. No significant difference in the incidence of testicular relapse by treatment regimen was observed, P = 0.22. The estimated overall EFS for the 16 randomized patients with CNS disease at diagnosis is 46.2% (s.e. = 16.9%). Only one of these patients had CNS involvement at relapse (combined BM + CNS). There was a higher failure rate for males than for females treated on regimen A. Although the treatment difference was significant (P = 0.036) for males and not statistically significant for females (P = 0.52), one should bear in mind that this was not a predesigned question. Also Cox analysis was conducted to compare the treatment effect size (hazards ratio) within males vs that within females. The estimated ratio of hazards ratios is 176% (95% confidence limits, 92% to 469%) males:females. Equivalent treatment effects (100%) fall within the confidence interval. Since no interaction could be demonstrated by this Cox analysis, the overall results should take priority over sex-specific results.
Common grades 3–4 toxicities are listed in Table 5. Significant neutropenia was the most common toxicity recorded (70% of patients) during the intensification phase. Regimen B had a 26% higher incidence of severe neutropenia when compared to regimen A. Hospitalizations for fever and neutropenia were 25% more frequent for patients treated with regimen B vs regimen A. Documented bacterial sepsis was 7% more frequent in regimen B. Drug fevers were also more frequent in regimen B due to the 72 h AC infusions. Allergic drug reactions to VM-26 and ASP were isolated to regimen B. There were five deaths during remission: two in regimen A (cardiac, one; infection, one) and three in regimen B (liver failure, one; infection, two). Therapy was discontinued permanently during treatment due to toxicity for 11 patients on regimen A and 22 patients on regimen B (P = 0.047, 11/232 vs 22/238, exact conditional chi-square). For regimen A, 153 patients modified or omitted a component of therapy to deal with toxicity vs 162 for regimen B.
The incidences of neurotoxic events (NTE) are presented in Table 6. There were 61 patients who had one or more grades 3–4 NTE (10.9%). The incidence was comparable between regimens A and B (31 vs 30). Seizures were the most common event (32 of 61 neurotoxic events). Clinicians judged the neurotoxic event to be methotrexate-associated (MTX-NTE) in 56 of the 61 patients (10% of all patients at risk). Of 31 patients with neurotoxicity who had brain MRI or CT scans following their event, 19 (61%) had imaging evidence for white matter changes/leukoencephalopathy. Eight patients were removed from this therapeutic trial because of unacceptable neurotoxicity.
Outcome for randomized subgroups include 14 patients with t(4;11): seven relapsed (CNS, three; BM, four), two went to bone marrow transplantation (BMT) and five remain in CR; eight Down syndrome patients: two died during induction (sepsis), one lost to follow-up and five remain in CR. Details of patients with t(1;19) or t(9;22) will be reported as part of a larger POG experience.
Early intensification is designed to continue cell kill and prevent the emergence of drug-resistant leukemia as a cause of treatment failure. The use of alternating myelosuppressive combination chemotherapy early in the post-induction period was tested in the POG 8398 pilot protocol.13 Significant but tolerable toxicity was encountered. Drug combinations were selected for their antileukemic effects in relapsed disease and for their relative non-cross-resistance as suggested by the Goldie–Coldman hypothesis.23 A more complete understanding of the mechanisms of drug resistance and cell kill prompted the addition of vincristine, prednisone and asparaginase to the drug combination daunorubicin/Ara-C. The VM-26 and Ara-C combination alternating with IDMTX/MP remained the same as in the POG 8398 pilot study. This intensive combination was compared in a randomized trial to the less toxic but equally efficacious anti-metabolite combination MTX/MP as supported by the POG 8698 pilot study.17
Results from this phase III trial were inconclusive with respect to efficacy. That is, children with HR-ALL treated with early intensive therapy using intermediate-dose MTX/MP alone showed no significant difference in EFS or CCR when compared to those similarly treated with alternating myelosuppressive combinations. The 4-year estimated EFS and CCR for the intermediate-dose MTX/MP alone compared to the multidrug combinations were 61.6 (3.3%) vs 69.4% (s.e. = 3.1%), P = 0.091 and 64% (s.e. = 3.4) vs 70.6 % (s.e. = 3.1%), P = 0.22, respectively. The randomized groups were matched for the risk factors age, gender, WBC and DI (Table 1). When outcome was compared between treatment regimens for sites of relapse and ethnicity, no significant differences were found (Table 3). However, for males the failure rate was lower in the alternating arm compared to the intermediate-dose MTX/MP arm (50 events vs 62 events) with a P = 0.036. This difference is not related to an increase in testicular relapse (11 vs 8, P = 0.22). Since gender was not a predesigned study question, the overall results take priority.
Regimen B was clearly more toxic than regimen A (Table 5). Grades 3–4 toxicities related to cytopenic events were 5% to 26% higher in regimen B. Hospitalizations for fever/neutropenia and bacterial sepsis were 25% and 7% more prevalent for regimen B. Drug fevers and allergic reactions were much higher for regimen B. There were 5 deaths while in remission (infectious (three), cardiac (one), and liver failure (one)), two on regimen A, and three on regimen B. The only second malignancy reported among the randomized patients was a brain tumor in a patient with CNS disease at diagnosis (regimen A) and who received craniospinal irradiation.
Acute neurotoxic events (NTE) (grades 3–4) were similar between regimens (Table 6). The overall methotrexate-associated NTE was 10%. These results are similar to those reported for the POG 9005 (standard risk ALL) where intermediate-dose MTX and TIT were used in a similar fashion.3334 Potential reasons for these neurotoxicities have been reviewed in a previous publication,34 but include the number of doses of i.v. intermediate dose MTX, the concomitant use of intermediate-dose MTX and TIT during intensification, the ratio of intermediate-dose MTX to leucovorin rescue and/or the lack of leucovorin following TIT during continuation. Patients in regimen A received 12 courses of intermediate-dose MTX in 24 weeks while those in regimen B received six courses in 30 weeks, yet the incidence of methotrexate associate NTE were similar (31 vs 30). This observation could be explained by the fact that both regimens prescribed the same number of TITs which, during the intensive phase, were only given during intermediate-dose MTX administration.
Overall outcome data from this clinical trial compare favorably with previous POG trials and those of other groups treating children for HR-ALL (62–75%).91011121314151617181920 Because risk group criteria differ among large cooperative groups treating childhood ALL, external comparisons are difficult and hazardous. However, 66% of the patients in this study would be considered high risk by the CTEP/NCI consensus risk group definition (age ⩾10 years, or WBC ⩾50 000) thus adding some validity to cross comparisons.35 The data show that sites of relapse are also consistent with other trials where bone marrow was identified as the primary site of failure. The incidence of isolated CNS relapse was 7% (34/490) and equivalent between regimens. As in previous POG trials, intrathecal and systemic chemotherapy provide excellent CNS prophylaxis and avoid the use of cranial irradiation.16343536
Recent trials from BFM, CCG and MRC UKALL reported improved results for HR-ALL patients when compared to previous trials.141937 Improvement was attributed to the use of blocks of intensive therapy (consolidation, intensification, VCR plus PDN pulses) over the first year of remission vs POG's intensive therapy limited to the first 6 months of treatment.
Reasons for lack of a significant difference between the two regimens may be attributed to one or more of the following: (1) the true difference may be less than the planned differences making the study power inadequate to be sensitive to the true difference; (2) using multiple blocks of intensification may be more important in improving outcome than the specific agents used;213738 (3) the alternating drug combinations did not adequately test the Goldie–Coldman hypothesis, ie the drugs selected were not equally effective nor non-cross-resistant. It is now well established that DNR and VM-26 share similar mechanisms of cell kill (topoisomerse II inhibition) and of resistance (multidrug resistance).394041 However, this clinical trial demonstrated that comparable efficacy can be achieved with antimetabolite therapy alone while avoiding many of the early and later toxicities of more myelosuppressive agents. Better treatment is still needed for patients at higher risk of relapse.
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This work was supported in part by the following grants from the National Cancer Institute, Bethesda, MD: CA 20549, CA 29139, CA 03161, CA 33625, CA 32053, CA 15989, CA 30969.
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Lauer, S., Shuster, J., Mahoney, D. et al. A comparison of early intensive methotrexate/mercaptopurine with early intensive alternating combination chemotherapy for high-risk B-precursor acute lymphoblastic leukemia: a Pediatric Oncology Group phase III randomized trial. Leukemia 15, 1038–1045 (2001). https://doi.org/10.1038/sj.leu.2402132
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Plasma Methotrexate, Red Blood Cell Methotrexate, and Red Blood Cell Folate Values and Outcome in Children With Precursor B-acute Lymphoblastic Leukemia
Journal of Pediatric Hematology/Oncology (2012)
Augmented therapy improves outcome for pediatric high risk acute lymphocytic leukemia: Results of Children's Oncology Group trial P9906
Pediatric Blood & Cancer (2011)
Long-term results of the pediatric oncology group studies for childhood acute lymphoblastic leukemia 1984–2001: a report from the children's oncology group
Randomized trial to compare LSA2L2-type maintenance therapy to daily 6-mercaptopurine and weekly methotrexate with vincristine and dexamethasone pulse for children with acute lymphoblastic leukemia
Pediatric Blood & Cancer (2010)