Antimetabolite therapy for lesser-risk B-lineage acute lymphoblastic leukemia of childhood: a report from Children's Oncology Group Study P9201

Abstract

Pediatric Oncology Group (POG) protocol 9201 enrolled children with lesser-risk Blineage acute lymphoblastic leukemia (ALL) defined by age (1-9), white blood cell count (WBC) less than 50 ؋ 10 9 /L (50 000/L), DNA findings of trisomies 4 and 10 (or DNA index > 1.16), and lack of overt central nervous system (CNS) leukemia. After vincristine, prednisone, and asparaginase induction, 650 of 653 eligible patients attained remission (3 induction deaths) and received 6 courses of intravenous methotrexate (1 g/m 2 ) with daily mercaptopurine.Weekly intramuscular methotrexate was added during maintenance; pulses of vincristine and prednisone were administered with periodic intrathecal chemotherapy. Treatment duration was 2.5 years. No alkylators, epipodophylotoxins, anthracyclines, or radiation were given. The 6-year event-free survival (EFS) was 86.6% with overall survival (OS) of 97.2%. Patients with less than 5% marrow blasts on induction day 15 had superior EFS. A difference not reaching conventional statistical significance (P ‫؍‬ . IntroductionB-lineage acute lymphoblastic leukemia (ALL) is the most common childhood malignancy in industrialized countries. 1 Multiple different treatments have produced cures for a majority of children with ALL. 2,3 A wide variety of prognostic factors have been used to separate patients into those of lesser risk and higher risk. The Pediatric Oncology Group (POG) previously recognized patients with "favorable" age and initial white blood cell count (WBC) by National Cancer Institute common risk group criteria 4 whose blasts have an elevated DNA index or trisomy of both chromosomes 4 and 10 in their leukemic cells to have an exceptionally good prognosis when treated with antimetabolite therapy, 5 a finding supported by other studies. 6,7 Because of the potential shortand long-term burden of therapy, POG 9201 was designed to extend this observation to a larger set of patients, attempting to clearly define a group of patients with an excellent prognosis even when treated with less-intensive treatment. Patients, materials, and methods PatientsThe POG 9201 protocol opened as a limited institution pilot study in June 1992 and as a nonrandomized single-arm phase 3 group-wide study in November 1994. The study met accrual goals and closed to new patient enrollment in November 1999. Patients eligible for enrollment were diagnosed with B-lineage ALL (confirmed by a central POG laboratory), aged 1 to 9 years, and had an initial WBC less than 50 ϫ 10 9 /L (50 000/L). Evidence of trisomies 4 and 10 was required if cytogenetics were abnormal (informative); it was assumed that "normal" cytogenetic studies might reflect lack of cell growth or division in the sample, and demonstration of a DNA index more than 1.16 was allowed as a surrogate marker; DNA index was determined by a POG reference laboratory and all cytogenetics were either determined centrally or centrally reviewed by one of the authors (A.J.C.). Fluorescence in situ hybridization (FISH), to determine trisomies of chromosomes 4 and 10, wa...

Intrathecal triple therapy decreases central nervous system relapse but fails to improve event-free survival when compared with intrathecal methotrexate: results of the Children's Cancer Group (CCG) 1952 study for standard-risk acute lymphoblastic leukemia, reported by the Children's Oncology Group

“…Contrary to the recent practice of some cooperative groups, the CNS-2 cohort did not receive additional doses of IT chemotherapy during induction on this study. 67,69,70 Interestingly, ITT reduced the iCNS relapse rate 5-fold compared with IT MTX in the CNS-2 subset. Excess BM relapses and poorer EFS did not occur in the CNS-2 cohort treated with ITT compared with IT MTX.…”

How I treat pediatric acute myeloid leukemia

“…62 However, it should be noted that phenotypic shifts or the emergence of a clone that was present only at low levels at the time of diagnosis may occasionally lead to false-negative results. 61 Flow-based MRD detection has been used successfully by investigators from the BFM study group, 63 the COG, 64,65 and St Jude. 9,66 In one of the first studies reported, Sievers et al demonstrated that immunophenotypic evidence of leukemic blasts at the time of morphologic remission was predictive of more rapid relapse.…”

Prospective Analysis of TEL Gene Rearrangements in Childhood Acute Lymphoblastic Leukemia: A Children's Oncology Group Study

“…13,14 These patients constituted a subset of all patients who had enrolled on these trials from November 15, 1994 to November 15, 1999. Definitive results regarding TEL status were obtained in 926 patients, who are the subject of this report.…”

“…Vincristine/prednisone pulses were given throughout continuation therapy and triple intrathecal therapy was used for central nervous system prophylaxis. 13 Patients with standard-risk ALL (POG 9605) received the same consolidation therapy as the low risk patients, but were randomly assigned, in a 2 × 2 factorial design, to receive divided dose oral methotrexate every other week versus standard weekly dose methotrexate during the first 6 months of continuation therapy and oral mercaptopurine in a single-dose versus divided dose fashion throughout continuation. Patients on 9201 and 9605 received no anthracyclines, epipodophyllotoxins, alkylating agents or cranial irradiation.…”