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A Comparison of Early Intensive Methotrexate/Mercaptopurine With Leukemia (2001) 15, 1038–1045 2001 Nature Publishing Group All rights reserved 0887-6924/01 $15.00 www.nature.com/leu 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 SJ Lauer1, JJ Shuster2, DH Mahoney Jr3, N Winick4, S Toledano5, L Munoz5, G Kiefer6, JD Pullen7, CP Steuber3 and BM Camitta6 1Emory University School of Medicine, Atlanta, GA; 2Pediatric Oncology Group Statistical Office and Department of Statistics, University of Florida, Gainesville, FL; 3Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX; 4University of Texas Southwestern Medical Center, Dallas, TX; 5University Miami School of Medicine, Miami, FL; 6Midwest Children’s Cancer Center, Milwaukee, WI; and 7University of Mississippi Medical Center Children’s Hospital, Jackson, MS, USA A prospective, randomized multicenter study was performed to to their risk for relapse and treatment strategies designed to evaluate the relative efficacy of two different concepts for early improve event-free survival (EFS). intensive therapy in a randomized trial of children with B-pre- cursor acute lymphoblastic leukemia (ALL) at high risk (HR) for It is believed that the leading causes of relapse in children relapse. Four hundred and ninety eligible children with HR-ALL with higher risk ALL (HR-ALL) are inadequate cell kill and were randomized on the Pediatric Oncology Group (POG) 9006 emergence of drug-resistant clones. Clinical trials using early phase III trial between 7 January 1991 and 12 January 1994. intensive myelosuppressive combination chemotherapy as After prednisone (PDN), vincristine (VCR), asparaginase (ASP) post-induction consolidation were designed to maximize cell and daunorubicin (DNR) induction, 470 patients received either 2 kill and address drug resistance. Subsequently, improvement 12 intensive parenteral treatments of intermediate dose (1 g/m 9–20 each) methotrexate (MTX) and mercaptopurine (MP) over 24 in survival was realized for patients with HR-ALL. weeks (regimen A) or 12 intensive course of alternating myelos- Increased toxicity was also noted with the aggressive use of uppressive drug combinations given over 30 weeks (regimen myelosuppressive agents.9,13,14,16,18,19–22 However, prelimi- B). These drug combinations included MTX/MP, teniposide nary results from POG 8698 suggested that early intensifi- (VM-26)/cytosine arabinoside (AC) and VCR/PDN/DNR/AC/ASP. cation with the less toxic combination of intermediate-dose Central nervous system (CNS) prophylaxis was age-adjusted methotrexate (MTX) and mercaptopurine (MP) might be as triple intrathecal chemotherapy. Patients with CNS disease at effective as the more myelosuppressive combinations used in diagnosis were treated with craniospinal irradiation after the 13,17 intensive phase. Continuation was standard doses of MTX and another POG pilot study (POG 8398) for HR-ALL. MP for 2 years. This trial was closed early because of an appar- In 1991, the POG opened a group-wide randomized phase ent early difference favoring regimen B. Results show that 470 III clinical trial (POG 9006) to treat children with HR-ALL. The patients achieved remission (97%). Two hundred and thirty two primary objectives of this randomized trial were to compare were randomized to regimen A and 238 to regimen B. The esti- the efficacy and toxicity of regimen A: 12 early intensive mated 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% courses of antimetabolite-based chemotherapy (intermediate- (s.e. = 3.1%), P = 0.091. Toxicities were more frequent on regi- dose MTX/MP) vs regimen B: 12 early intensive courses of men B. In conclusion, for children with B-precursor ALL at high alternating myelosuppressive, non-cross-resistant combination risk to relapse, early intensification with myelosuppressive chemotherapy with MTX/MP as per the Goldie–Coldman combination chemotherapy was more toxic but produced no hypothesis.23 This paper reports the results of that trial. significant difference in EFS when compared to those treated with parenteral methotrexate and mercaptopurine. Leukemia (2001) 15, 1038–1045. Keywords: high risk childhood ALL; B-precursor ALL; early inten- Patients and methods sive chemotherapy Patients The POG 9006 phase III clinical trial accrued patients between 7 January 1991 and 12 January 1994. Approval by Introduction local institutional review boards and written informed consent were required before patient entry. Improvement in overall survival of children with acute lym- phoblastic leukemia (ALL) is in part due to a better under- standing of the biology of this malignancy and factors that are Eligibility associated with the success or failure to maintain remission. Irrespective of the therapeutic trial, common risk factors Eligibility for POG 9006 included (1) enrollment on the POG include age, WBC at diagnosis, leukemic cell surface antigen 9000 classification study; (2) confirmation of B-precursor ALL 24 expression, cytogenetics, DNA index and early response to by central reference laboratories; and (3) meeting the criteria cytoreductive therapy.1–8 Based on these prognostic factors, for high risk B-precursor ALL. Those criteria were leukemic < children with newly diagnosed ALL can be stratified according cell DNA index of 1.16 (DNA content in leukemic cells: DNA content of normal G0/G1 cells) (DI) by central reference laboratory25,26 and at least one of the following: (1) WBC >10 000–99 000/µl, aged 1–2.99 years or ages 6–21 years; Correspondence: SJ Lauer, c/o Pediatric Hematology-Oncology, 2040 > µ Ridgewood Drive, Suite 100, Atlanta, GA 30322, USA; Fax: 1 404 (2) WBC 100 000/ l, aged 1–21 years; (3) all patients with 727 4455 CNS or overt testicular disease at diagnosis; or (4) leukemic Received 16 November 2000; accepted 26 January 2001 cell chromosome translocations t(1;19) or t(9;22) confirmed Comparing early intensive therapies in high-risk ALL SJ Lauer et al 1039 by central reference laboratory.27,28 Only patients who met Treatment and drug dose modification criteria 1, 2, or 3 were eligible for randomization. Patients having t(1;19), or t(9;22) leukemia at diagnosis were not ran- Patients were randomized at diagnosis to one of two intensi- domized because the numbers of these patients were pre- fication schedules which have been previously outlined in dicted to be low and thus no statistically valid information detail.13,17 Treatment regimens are listed in Table 2. Induction would be obtained if they were randomized. All of these therapy was identical for both groups: vincristine (VCR), patients were assigned to regimen A and were excluded from prednisone (PDN), E. coli l-asparaginase (ASP) and daunorub- this report. Patients ,12 months of age were not eligible for icin (DNR). Age-adjusted triple intrathecal therapy (TIT) with this protocol. methotrexate (MTX), hydrocortisone (HDC) and cytosine arab- inoside (AC) was administered on day 1 of induction. Patients with CNS disease at diagnosis were given three additional Definition of disease and response weekly doses of age-adjusted intrathecal MTX. Intensification started immediately after meeting the criteria for remission. CNS leukemia was diagnosed when the cerebrospinal fluid Patients randomized or assigned regimen A began week 1 of (CSF) WBC count was >5 cells/µl and lymphoblasts were intensification receiving intravenous (i.v.) intermediate-dose identified on a Wright-stained, cytocentrifuged slide examin- MTX infused over 24 h, followed by i.v. intermediate-dose MP ation without peripheral blood (PB) contamination. Complete infused over 6 h. On week 2, patients received intramuscular remission (CR) was defined as a cellular bone marrow with (i.m.) MTX on day 1 and MP by mouth (p.o.) daily for 7 days. fewer than 5% blasts and no evidence of leukemia at any The 2-week schedule was repeated 12 times over 24 weeks. other site. The i.v. administration of MTX and MP required a 48-h hospi- The definition of relapse required: (1) bone marrow .25% talization. Those patients randomized to regimen B received lymphoblasts; (2) CNS >5 WBC/µl of CSF and lymphoblasts six courses of MTX and MP as in regimen A, three courses of identified on a Wright-stained examination without PB con- teniposide (VM-26) and AC and three courses of DNR, AC, tamination; (3) extramedullary site with biopsy proven infil- VCR, PDN and PEG-asparaginase (PEG-ASP) in an alternating trate with lymphoblasts; or (4) any combination of the above. 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 Randomization (LCV) rescue began 48 h after the start of the methotrexate infusion and continued every 6 h for five doses or until plasma Five hundred and seventy-three newly diagnosed patients with MTX was ,0.1 µmol/l. All courses of chemotherapy during B-precursor, HR-ALL were registered on POG 9006. After intensification began when the absolute neutrophil count was eligibility for this HR-ALL protocol was determined, 69 >500/µl and platelet count was >100 000/µl. If courses of patients (45 t(1;19); 24 t(9:22)) were removed from randomiz- DNR/AC or VM-26/AC resulted in prolonged neutropenia ation and assigned regimen A, 14 patients were ineligible for (,500/µl for .24 days), each myelosuppressive drug was protocol therapy (wrong diagnosis) and 490 patients were reduced by 25% for the next course. Dose escalation was not randomized (Table 1) to receive one of two post-induction permitted during any phase of this protocol. intensification therapies (Table 2). Because of the known sensitivity of Down syndrome patients to MTX and myelosuppressive chemotherapy, they Table 1 Presenting patient characteristics started with a 50% dose reduction of intermediate-dose MTX, Characteristics Regimen A Regimen B DNR, AC and VM-26 during intensification.
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