A B S T R A C T PurposeTo examine population-based improvements in survival and the impact of clinical covariates on outcome among children and adolescents with acute lymphoblastic leukemia (ALL) enrolled onto Children's Oncology Group (COG) clinical trials between 1990 and 2005. Patients and MethodsIn total, 21,626 persons age 0 to 22 years were enrolled onto COG ALL clinical trials from 1990 to 2005, representing 55.8% of ALL cases estimated to occur among US persons younger than age 20 years during this period. This period was divided into three eras (1990-1994, 1995-1999, and 2000-2005) that included similar patient numbers to examine changes in 5-and 10-year survival over time and the relationship of those changes in survival to clinical covariates, with additional analyses of cause of death. ResultsFive-year survival rates increased from 83.7% in 1990-1994 to 90.4% in 2000-2005 (P Ͻ .001). Survival improved significantly in all subgroups (except for infants age Յ 1 year), including males and females; those age 1 to 9 years, 10ϩ years, or 15ϩ years; in whites, blacks, and other races; in Hispanics, non-Hispanics, and patients of unknown ethnicity; in those with B-cell or T-cell immunophenotype; and in those with National Cancer Institute (NCI) standard-or high-risk clinical features. Survival rates for infants changed little, but death following relapse/disease progression decreased and death related to toxicity increased. ConclusionThis study documents ongoing survival improvements for children and adolescents with ALL. Thirty-six percent of deaths occurred among children with NCI standard-risk features emphasizing that efforts to further improve survival must be directed at both high-risk subsets and at those children predicted to have an excellent chance for cure.

The more uniform approach to risk-based treatment assignment and to collection of specific prognostic factors should increase the efficiency of future ALL clinical research.

For this study, 118 children with standardrisk acute lymphoblastic leukemia (ALL) were given randomized assignments to receive native or pegylated Escherichia coli asparaginase as part of induction and 2 delayed intensification phases. Patients treated with pegaspargase had more rapid clearance of lymphoblasts from day 7 and day 14 bone marrow aspirates and more prolonged asparaginase activity than those treated with native asparaginase. In the first delayed intensification phase, 26% of native asparaginase patients had high-titer antibodies, whereas 2% of pegaspargase patients had those levels. High-titer antibodies were associated with low asparaginase activity in the native arm, but not in the pegaspargase arm. Adverse events, infections, and hospitalization were similar between arms. Event-free survival at 3 years was 82%. A population pharmacodynamic model using the nonlinear mixed effects model (NONMEM) program was developed that closely fit the measured enzyme activity and asparagine concentrations. Half-lives of asparaginase were 5.5 days and 26 hours for pegaspargase and native asparaginase, respectively. There was correlation between asparaginase enzymatic activity and depletion of asparagine or glutamine in serum. In cerebrospinal fluid asparagine, depletion was similar with both enzyme preparations. Intensive pegaspargase for newly diagnosed ALL should be tested further in a larger population. (Blood.

A B S T R A C T PurposeImatinib mesylate is a targeted agent that may be used against Philadelphia chromosome-positive (Phϩ) acute lymphoblastic leukemia (ALL), one of the highest risk pediatric ALL groups. Patients and MethodsWe evaluated whether imatinib (340 mg/m 2 /d) with an intensive chemotherapy regimen improved outcome in children ages 1 to 21 years with Phϩ ALL (N ϭ 92) and compared toxicities to PhϪ ALL patients (N ϭ 65) given the same chemotherapy without imatinib. Exposure to imatinib was increased progressively in five patient cohorts that received imatinib from 42 (cohort 1; n ϭ 7) to 280 continuous days (cohort 5; n ϭ 50) before maintenance therapy. Patients with human leukocyte antigen (HLA) -identical sibling donors underwent blood and marrow transplantation (BMT) with imatinib given for 6 months following BMT. ResultsContinuous imatinib exposure improved outcome in cohort 5 patients with a 3-year event-free survival (EFS) of 80% Ϯ 11% (95% CI, 64% to 90%), more than twice historical controls (35% Ϯ 4%; P Ͻ .0001). Three-year EFS was similar for patients in cohort 5 treated with chemotherapy plus imatinib (88% Ϯ 11%; 95% CI, 66% to 96%) or sibling donor BMT (57% Ϯ 22%; 95% CI, 30.4% to 76.1%). There were no significant toxicities associated with adding imatinib to intensive chemotherapy. The higher imatinib dosing in cohort 5 appears to improve survival by having an impact on the outcome of children with a higher burden of minimal residual disease after induction. ConclusionImatinib plus intensive chemotherapy improved 3-year EFS in children and adolescents with Phϩ ALL, with no appreciable increase in toxicity. BMT plus imatinib offered no advantage over BMT alone. Additional follow-up is required to determine the impact of this treatment on long-term EFS and determine whether chemotherapy plus imatinib can replace BMT.

Despite great progress in curing childhood acute lymphoblastic leukemia (ALL), survival after relapse remains poor. We analyzed survival after relapse among 9585 pediatric patients enrolled on Children's Oncology Group clinical trials between 1988 and 2002. A total of 1961 patients (20.5%) experienced relapse at any site. The primary end point was survival. Patients were subcategorized by the site of relapse and timing of relapse from initial diagnosis. Time to relapse remains the strongest predictor of survival. Patients experiencing early relapse less than 18 months from initial diagnosis had a particularly poor outcome with a 5-year survival estimate of 21.0±1.8%. Standard risk patients who relapsed had improved survival compared with their higher risk counterparts; differences in survival for the two risk groups was most pronounced for patients relapsing after 18 months. Adjusting for both time and relapse site, multivariate analysis showed that age (10 þ years) and the presence of central nervous system disease at diagnosis, male gender, and T-cell disease were significant predictors of inferior post-relapse survival. It can be noted that there was no difference in survival rates for relapsed patients in earlier vs later era trials. New therapeutic strategies are urgently needed for children with relapsed ALL and efforts should focus on discovering the biological pathways that mediate drug resistance.

We performed a retrospective comparison of presenting features, planned treatment, complete remission (CR) rate, and outcome of 321 adolescents and young adults (AYAs) ages 16 to 20 years with newly diagnosed acute lymphoblastic leukemia (ALL) who were treated on consecutive trials in either the Children's Cancer Group (CCG) or the Cancer and Leukemia Group B (CALGB) from 1988 to 2001. CR rates were identical, 90% for both CALGB and CCG AYAs. CCG AYAs had a 63% event-free survival (EFS) and 67% overall survival (OS) at 7 years in contrast to the CALGB AYAs, in which 7-year EFS was only 34% (P < .001; relative hazard rate [RHR] ‫؍‬ 2.2) and OS was 46% (P < .001; RHR ‫؍‬ 1.9). While CALGB AYAs aged 16 to 17 years achieved similar outcomes to all CCG AYAs with a 7-year EFS of 55%, the EFS for 18-to 20-year-old CALGB patients was only 29%. Comparison of the regimens showed that CCG AYAs received earlier and more intensive central nervous system prophylaxis and higher cumulative doses of nonmyelosuppressive agents. There were no differences in outcomes of those who reached maintenance therapy on time compared with those who were delayed. Based on these observations, a prospective study for AYAs with ALL using the more successful approach of the CCG has been initiated.

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We previously reported preliminary findings that post induction imatinib mesylate (340 mg/m2/day), in combination with intensive chemotherapy, resulted in outcomes similar to blood and marrow transplant (BMT) for pediatric patients with Philadelphia chromosome-positive (Ph + ) acute lymphoblastic leukemia (ALL). We now report 5-year outcomes of imatinib plus intensive chemotherapy in 91 children (1–21 years) with and without allogeneic BMT (N = 91). We explore the impacts of additional chromosomal abnormalities and minimal residual disease (MRD) by flow cytometry on outcomes. The 5-year disease-free survival was similar for Cohort 5 patients, treated with chemotherapy plus imatinib (70% ± 12%, n = 28), sibling donor BMT patients (65% ± 11%, n = 21) and unrelated donor BMT patients (59 ± 15%; P = 0.60, n = 13). Patients with additional cytogenetic abnormalities had worse outcomes (P = 0.05). End induction (pre-imatinib) MRD was not prognostic for Cohort 5 or allogeneic BMT patients, although limited by small numbers. The re-induction rate following relapse was similar to other higher-risk ALL groups. Longer-term follow-up confirms our initial observation of substantially good outcomes for children and adolescents with Ph + ALL treated with imatinib plus intensive chemotherapy with no advantage for allogeneic BMT.