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J Clin Oncol. 2012 May 10; 30(14): 1663–1669.
Published online 2012 March 12. doi:  10.1200/JCO.2011.37.8018
PMCID: PMC3383113

Improved Survival for Children and Adolescents With Acute Lymphoblastic Leukemia Between 1990 and 2005: A Report From the Children's Oncology Group

Abstract

Purpose

To 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 Methods

In 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.

Results

Five-year survival rates increased from 83.7% in 1990-1994 to 90.4% in 2000-2005 (P < .001). Survival improved significantly in all subgroups (except for infants age ≤ 1 year), including males and females; those age 1 to 9 years, 10+ years, or 15+ 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.

Conclusion

This 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.

INTRODUCTION

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy, comprising 25% of cancers occurring before age 15 years and 19% among those younger than age 20 years.1 The 5-year survival rate increased from less than 10% in the 1960s to 77% in 1985 to 1994.1 Survival rate has continued to increase over the past 10 to 15 years.211 The National Cancer Institute (NCI) SEER Program reported that 5-year survival for US patients younger than age 15 years with ALL increased from 80.2% to 87.5% between 1990-1994 and 2000-2004.12 Five-year survival rates for adolescents age 15 to 19 years increased from 41.0% in 1980-1984 to 61.1% in 2000-2004.13

The Children's Oncology Group (COG) includes more than 200 member institutions in the United States, Canada, Australia, and New Zealand. Unlike the SEER system, which tracks outcome in five representative states and four metropolitan areas that include approximately 10% of the US population, COG data include patients from all areas of the United States and Canada and provide an opportunity to assess outcome for children with ALL throughout these countries and to examine the prognostic impact of covariates not included in registry data. We report changes in survival among children enrolled onto COG ALL clinical trials between 1990 and 2005 and the extent to which different clinical and biologically defined patient subgroups benefited from treatment improvements.

PATIENTS AND METHODS

Patients

In all, 21,626 eligible children and adolescents younger than age 22 years enrolled onto one of 36 COG ALL clinical trials (Appendix Table A1, online only) between January 1, 1990, and December 31, 2005. Patients were treated on clinical trials that tested treatment intensifications and the need for cranial irradiation, and they used clinical and biologic prognostic variables, including genetic subtype and early treatment response, to risk stratify patients and assign therapies of varying intensity.18 We divided this period into three eras that included similar numbers of patients: 1990-1994 (7,304 patients; median follow-up, 9.13 years), 1995-1999 (7,169 patients; median follow-up, 8.02 years), and 2000-2005 (7,153 patients; median follow-up, 5.35 years). Most patients (92.2%) were treated in the United States, with 5.8% in Canada, and 2% elsewhere. Patients and/or a parent/guardian provided informed consent for clinical trial participation; trials were approved by institutional review boards at COG centers. We analyzed outcome on the basis of clinical features, including age and WBC count at diagnosis, sex, immunophenotype, race, and ethnicity as reported by the patient or parent.

Statistical Analyses

Overall survival estimates were obtained by using the Kaplan-Meier method,19 with SEs calculated by using the method of Peto and Peto.20 Survival time was calculated as the time from study entry to death or date of last contact. Comparisons of survival curves were performed by using the log-rank test.21 Survival curves were truncated at year 15. The cumulative incidence of death due to various causes was determined after adjusting for competing risks.22 Multivariate Cox regression analysis was used to identify prognostic factors affecting overall survival. Survival tree regression was used in both infant and non–infant subsets to identify prognostic factors and explore their association with overall survival.23,24 Data were frozen in September 2009.

Incidence rates for ALL were determined by using published SEER data with additional information on rates obtained directly from the National Institutes of Health and Information Management Services. Total numbers of ALL cases expected to occur in the United States during specific time periods was determined by applying these incidence rates to population statistics derived from US census data.

RESULTS

Overall 5- and 10-year survival rates increased significantly over time (Fig 1; P < .001). Five-year survival increased from 83.7% (SE, 0.4%) in 1990-1994 to 87.7% (SE, 0.4%) in 1995-1999 and to 90.4% (SE, 0.5%) in 2000-2005 (Table 1). Similar increases were seen in 10-year survival between 1990-1994 (80.1%; SE, 0.8%) and 1995-1999 (83.9%; SE, 1.3%; P < .001). For the eras from 1990 to 1999, approximately 84% of deaths occurred within 5 years of diagnosis and only 1% occurred more than 10 years following diagnosis (Appendix Tables A2 to A6, online only). Because of these factors and the more limited follow-up for the 2000-2005 era, subsequent analyses focused on 5-year survival.

Fig 1.
Overall survival probability by treatment era for patients enrolled onto Children's Oncology Group trials in 1990-1994, 1995-1999, and 2000-2005.
Table 1.
Five-Year Overall Survival of Patient Subsets by Era

Survival improved significantly in all subgroups examined except for infants ≤ 1 year old (Table 1 and Appendix Figs A1 to A6, online only): ages 1 to 9 years, 10+ years, and 15+ years; males and females; self-reported whites, blacks, and other races; self-reported Hispanics, non-Hispanics, and persons of unknown ethnicity; those with B-cell and T-cell ALL; and those with standard-risk (age 1 to 9.99 years; initial WBC < 50,000/μL) or high-risk (age ≥ 10 years and/or initial WBC ≥ 50,000/μL) features by using NCI/Rome25 criteria. The relative reductions in 5-year risk of death between the 1990-1994 and 2000-2005 eras were similar in all non–infant subgroups examined, ranging from 30% to 50% (Table 1). Because the results for infants differed from those of older children, we also analyzed data separately for infants and non–infants (Appendix Tables A7 and A8, online only).

Deaths that occurred after induction failure or relapse were classified as leukemia related, and those that occurred without prior induction failure or relapse were deemed treatment related (Table 2 and Appendix Tables A9 and A10, online only). Among all patients, the 5-year cumulative incidence of death decreased from 16.35% in 1990-1994 to 9.6% in 2000-2005 (P < .001), and the 10-year cumulative incidence of death decreased from 19.86% in 1990-1994 to 16.07% in 1995-1999 (P < .001). This decrease was primarily due to reduction in the 5-year cumulative incidence of death following relapse/disease progression from 12.83% in 1990-1994 to 7.22% in 2000-2005 (P < .001), with similar reductions in 10-year rates between 1990-1994 and 1995-1999. Among infants (Appendix Table A9), the 5-year cumulative incidence of death changed little between 1990-1994 and 2000-2005 (52.1% v 50.3%; P = .45), but the causes of death changed considerably. The 5-year cumulative incidence of death following relapse/disease progression decreased from 43% in 1990-1994 to 27.2% in 2000-2005 (P < .001), and the cumulative incidence of treatment-related death increased from 3.9% in 1990-1994 to 13.9% in 2000-2005 (P < .001).

Table 2.
Cumulative Incidence of Death After Relapse/Disease Progression v Death As a First Event in COG ALL Trials

The highest relative risks of death occurred in known high-risk subgroups (Table 3). The relative risk of death was 2.3-fold (1990–1994) to 3.1-fold (2000–2005) higher for patients age 10+ years versus those age 1 to 9.99 years. The differences were even larger when those age 1 to 9.99 years were compared with infants age ≤ 1 year and adolescents age ≥ 15 years. We observed modest but statistically significant sex-based differences in survival, with males having a relative risk of death 1.2- to 1.3-fold higher than that of females. Self-described blacks had an increased relative risk of death compared with whites. Although information about ethnicity was not available for approximately 30% (6,509 of 21,626) of patients, self-described Hispanics (n = 2,589) had a higher relative risk of death than non-Hispanics. Leukemia immunophenotype was prognostic, with patients who had T-cell ALL having a higher relative risk of death than those with B-cell ALL. Patients with NCI high-risk ALL had a 2.4- to 3.6-fold higher relative risk of death than those with standard-risk ALL. However, because most patients have NCI standard-risk clinical features, a significant proportion of deaths occurred among the favorable prognosis subgroups (Table 4). Five-year survival of patients with NCI standard-risk ALL was 90% to 95% between 1990 and 2005 (Table 1 and Appendix Fig A6A), but approximately 36% of total deaths occurred among this subset.

Table 3.
Five-Year RR of Death by Era and Characteristic
Table 4.
Number of Deaths by Era and Presenting Characteristics

For patients older than age 1 year, era, sex, race, immunophenotype, and NCI risk group were all significant prognostic factors in the multivariate Cox regression model (Table 5). To better understand the most important factors predicting risk of death, we performed survival tree regression modeling (Appendix Fig A7A, online only). This analysis showed that NCI risk group was the most significant overall prognostic factor. Among NCI standard-risk patients, era (2000-2005 v 1990-1999) was the most significant prognostic factor. For NCI high-risk patients, age (1 to 14.99 v ≥ 15 years) was the most prognostic factor. Among NCI high-risk patients younger than age 15 years, race was the most significant prognostic factor, with survival for black/other being inferior to that of whites. For adolescents age ≥ 15 years, era was the most significant prognostic factor, with better survival rates in 1995-2005 compared with 1990 to 1994.

Table 5.
Multivariate Cox Regression Analysis for Patients Older Than Age 1 Year

For infants, age considered as a continuous variable was the most important prognostic factor (Appendix Fig A7B). The best age cutoff among infants was 92 days, with 5-year survival rates of 57.8% and 25.6% for age ≥ 92 days and less than 92 days, respectively (P < .001). Among infants ≥ 92 days old, WBC was the most significant predictor of survival, with higher WBC resulting in poorer outcome.

DISCUSSION

This study, which includes the largest childhood ALL cohort ever reported, documents progressive improvements in survival for children with ALL enrolled onto COG clinical trials between 1990-1994 and 2000-2005. Five-year survival increased from 83.7% to 90.4% during this time. The improved survival was explained primarily by an approximately 44% decrease in the risk of death following relapse/disease progression. Although we examined overall and not event-free survival (EFS) and cannot comment directly on changes in the incidence of relapse, a study of almost 10,000 children treated on COG ALL trials between 1988 and 2002, including 1,961 who relapsed, showed no significant improvements in survival after relapse over time.26 Taken together with results of COG ALL clinical trials showing significant improvements in EFS during this period, we believe that the major reason for improved survival was decreased risk of relapse.14,15,17

Our cohort includes 18,501 (55.8%) of 33,139 US ALL cases in persons age 0 to 14.99 years predicted to occur between 1990 and 2005. Thus, our results are representative of survival following contemporary therapy in the United States and are consistent with previous reports of outcomes for children younger than age 15 years diagnosed with cancer between 1990 and 1994 enrolled onto COG trials.27,28 In contrast, only approximately 25% of adolescents age 15 to 19 years diagnosed with cancer were enrolled onto COG trials between 1990 and 1994.27 Our data are similar, with 33.5% (1,392 of 4,159) of US adolescents age 15 to 19.99 years predicted to develop ALL between 1990 and 2005 enrolling onto COG trials. There are a variety of reasons that children and adolescents with ALL might not be included in COG ALL trials, including participation in trials conducted by other centers,6,8 lack of an open study at the time of diagnosis, having the patient/parent decline participation, or failure to meet eligibility criteria. Most US children with ALL still enroll onto COG trials. In 2009, 1,951 (68%) of 2,869 US children and adolescents age 0 to 19.99 years predicted to develop ALL enrolled onto a COG trial, including 1,758 (69%) of 2,540 of those age 0 to 14.99 years and 168 (51%) of 329 of those age 15 to 19.99 years. The number of older adolescents with ALL enrolling onto COG trials has increased over time, which is an important trend, given the higher survival rates obtained with pediatric versus adult ALL trials for this age group.2931

Pulte et al12,13 reported survival for US children and adults diagnosed with ALL between 1990 and 2004 by using the SEER 9 Registries database, which includes about 30 million people. Our results show higher survival rates than the SEER-estimated 5-year survival of 87.5% from 2000-2004 for children younger than age 15 years and 61.1% for those age 15 to 19 years. We found 5-year survival rates of 91.4% for US children younger than age 15 years and 74.5% for those age 15 to 19 years in 2000-2005. It is unlikely that the slight difference in time period analyzed (SEER: 2000-2004 v COG: 2000-2005) accounts for these differences. There may be differences based on clinical trial enrollment because the SEER data include all patients reported to tumor registries in the specified areas, although the COG data are based on patients who met eligibility criteria and were offered and accepted clinical trial enrollment. The SEER 9 population is more urban and includes a higher percentage of foreign-born persons than the overall US population; these differences might contribute to observed differences in survival. There was a 13% absolute survival advantage for older adolescents in this COG cohort compared with the SEER estimates, consistent with the significant survival advantages for older adolescents with ALL treated on COG versus adult cooperative group trials.29 These data emphasize that optimal treatment for an older adolescent with ALL is referral to a pediatric center and enrollment onto a pediatric cooperative group trial.

In our analyses, survival improvements occurred in every subgroup analyzed with the exception of infants age ≤ 1 year (Table 1 and Appendix Figs A1 to A6). The magnitude of the decrease in risk of death between 1990-1994 and 2000-2005 was generally similar among non–infant subgroups and ranged from approximately 30% to 50%.

There were no survival improvements for infants enrolled onto COG ALL trials between 1990 and 2005 (Appendix Fig A1A). Infants contributed disproportionately to deaths because they accounted for only 2.1% (461 of 21,626) of patients but 8.0% (231 of 2,878) of deaths (P < .001). During this period, the COG pursued several strategies to attempt to increase survival for infants with ALL. Chemotherapy treatment was intensified significantly in the Children's Cancer Group (CCG) 1953 and COG P9407 trials, and the use of stem-cell transplantation in first remission was explored for those with MLL gene rearrangements. Stem-cell transplantation was not beneficial for infants in these COG ALL trials,16 and treatment intensification shifted the causes of death, with a significant decrease in death following relapse/disease progression but a parallel increase in death related to toxicity, with no net improvement in survival (Appendix Table A9). The Interfant99 infant ALL trial (1999–2005) obtained results similar to those of the COG trials, with 4-year EFS of only 48%.32 Although Interfant99 showed a benefit for stem-cell transplantation among a select high-risk subgroup of infants, survival was still poor for these patients.33 Infant ALL is a unique high-risk subset that requires new therapeutic strategies.

Survival for self-reported blacks with ALL improved significantly during the eras examined. The absolute difference in 5-year survival between blacks and whites decreased from 11.0% in 1990-1994 to 3.3% in 2000-2005. There are race-based differences in ALL biology, with blacks having a higher incidence of T-cell ALL and other high-risk features.34 Among the COG patients, 17.7% of blacks versus 9.5% of whites had T-cell ALL (P < .001) and 44.5% of blacks had NCI high-risk features versus 32.9% of whites (P < .001). Thus, black children and adolescents with ALL are predicted to have an inferior survival compared with whites because of the different percentages of ALL subtypes in the two racial groups. However, within these ALL subtypes, although patient numbers are small, our results show decreases in the racial outcome gap between 1990-1994 and 2000-2005. The absolute difference in 5-year survival for blacks versus whites with T-cell ALL decreased from 5.0% in 1990-1994 (94 blacks) to 0.02% in 2000-2005 (57 blacks). Similarly, for children with NCI high-risk B-cell ALL, the gap decreased from 11.1% in 1990-1994 (129 blacks) to 6.6% in 2000-2005 (53 blacks).

Self-described ethnicity is another important risk factor in childhood ALL. Hispanics have inferior outcomes to non-Hispanics.35 Our study confirms this observation, with some differences in the magnitude of differences in the three eras (Tables 1 and and3).3). Importantly, there was much greater capture of information regarding self-described ethnicity in 2000-2005, with only 3.6% (261 of 7,153) of unknown ethnic group compared with 43.2% (6,284 of 14,473) in 1990-1999. We observed a 1.5-fold higher risk of death for Hispanics versus non-Hispanics in 2000-2005. A variety of reasons might account for the inferior outcome of Hispanics. For example, recent investigations have shown a much higher incidence of certain high-risk leukemia cell genomic alterations in Hispanics enrolled onto COG ALL trials.36

Simple demographic and clinical prognostic factors can identify patient subsets with significantly increased risk of death: infants, adolescents age ≥ 10 or ≥ 15 years, T-cell ALL, and NCI high-risk ALL. The relative risks of death for these subsets ranged from about two- to eight-fold higher than for lower-risk subsets (Table 3). However, 36% of total deaths occurred among patients with NCI standard-risk ALL. Thus, efforts to decrease ALL deaths must focus both on high-risk patient subsets and on the large subset of patients with favorable clinical characteristics. Detailed biologic characterization of lymphoblasts and host germline variability and sophisticated measurements of early treatment response can improve identification of ultra-low-risk patient subsets and identify patients at high risk of treatment failure.18,3647

We analyzed whether death occurred as a first event or after relapse/induction failure to investigate whether observed survival improvements were due to better front-line antileukemia therapy, better supportive care leading to a decrease in non–leukemia-related death, or both. Five to six times as many deaths occurred following relapse/disease progression compared with toxicity (Table 2). Although the cumulative incidence of deaths related to toxicity is relatively low at approximately 2%, it accounted for a higher percentage of overall deaths as the rate of death from leukemia decreases and was a particular problem among infants. Prevention of treatment-related deaths must be a critical component of efforts to improve childhood ALL survival.

Ten-year survival was 3% to 4% lower than 5-year survival in 1990-1999, when 84% of deaths occurred within 5 years, and only 1% occurred more than 10 years following diagnosis (Appendix Tables A2 to A4). Given this lower 10-year survival rate, the death rates observed in the 2000-2005 era (Appendix Tables A5 and A6), and the shape of the survival curves (Fig 1), we believe that it is extremely unlikely that there will be a significant increase in deaths beyond 5 years for patients diagnosed in 2000-2005, and we anticipate significant improvements in 10-year survival. We anticipate that the 10-year survival rate for children treated on COG ALL trials in 2006-2010 will approach or exceed 90%. The trend from 1990 to 2005 predicts an absolute 2% to 3% increment in survival during each 5-year era. More importantly, randomized COG ALL clinical trials conducted between 1995 and 2005 established superior treatment regimens that then became the baseline therapy for COG trials conducted in 2006 to 2010.4,5,14,15

This report underscores the remarkable improvements in the outcomes for childhood ALL since Farber et al48 first described temporary remissions in 1948. The ongoing discovery of important biologic subsets of ALL36,3840,46 will further refine risk stratification and facilitate the combination of molecularly targeted therapies with chemotherapy. As proof of principle, addition of imatinib to chemotherapy resulted in a dramatic increase in survival for pediatric Philadelphia chromosome–positive ALL.49 As these changes occur, it will remain essential to closely assess the survival for the majority of US children, adolescents, and young adults with ALL who are treated on COG clinical trials.

Acknowledgment

We thank the thousands of children and parents who participated in these clinical trials and the physicians, nurses, and other medical professionals who participated in their care as well as Sean Altekruse from the National Institutes of Health and Rashid Aminou from Information Management Services for their assistance with SEER data.

Appendix

Table A1.

Clinical Trials Included in Present Report

Trial No.Trial NameNCT IDAccrual ClosedReference
CCG 1881Treatment of Newly Diagnosed ALL in Children Aged 2-9 Inclusive With WBC < 10,000/μLDecember 15, 1992Hutchinson RJ, et al: J Clin Oncol 21:1790-1797, 2003
CCG 1882Treatment of Newly Diagnosed ALL in Children With a Poor Prognosis Excluding Infants and Patients With Lymphoma-Leukemia or FAB L3 BlastsJune 23, 1995Nachman JB, et al: N Engl J Med 338:1663-1671, 1998; Nachman J, et al: J Clin Oncol 16:920-930, 1998
CCG 1883Treatment of Newly Diagnosed ALL in Infants Less Than 12 Months of AgeAugust 25, 1993Reaman GH, et al: J Clin Oncol 17:445-455, 1999
CCG 1891Treatment of Newly Diagnosed ALL in Children With an Intermediate PrognosisJuly 20, 1990Lange BJ, et al: Blood 99:825-833, 2002
CCG 1901Phase III Protocol for the Treatment of Newly Diagnosed Childhood Acute Lymphoblastic Leukemia with Multiple Poor-Risk Factors Exclusive of FAB L3 LeukemiaSeptember 9, 1994Heath JA, et al: J Clin Oncol 21:1612-1617, 2003
CCG 1922Phase III Randomized Comparison of Intravenous vs Oral Mercaptopurine During Consolidation and of Prednisone vs Dexamethasone during Induction, Consolidation, and Maintenance in Children with Good-Prognosis and Intermediate-Prognosis ALL Receiving Standard ChemotherapyAugust 1, 1995Bostrom BC, et al: Blood 101:3809-3817, 2003
CCG-1952Randomized Comparisons of Oral Mercaptopurine vs. Oral Thioguanine and Intrathecal Methotrexate vs. Intrathecal Methotrexate/Cytarabine/Hydrocortisone for Standard Acute Lymphoblastic LeukemiaNCT00002744February 1, 2000Stork LC, et al: Blood 115:2740-2748, 2010
CCG 1953Treatment of Newly Diagnosed ALL in Infants < 1 Year of AgeAugust 31, 2000Hilden JM, et al: Blood 108:441-451, 2006
CCG-1961Treatment of Patients With Acute Lymphoblastic Leukemia With Unfavorable Features: A Phase III Group-Wide StudyNCT00002812May 1, 2002Seibel NL et al14
CCG 1962A Randomized Comparison of PEG and Native E. coli Asparaginases in the Standard Arm of CCG-1952 for Standard Risk ALLNovember 10, 1998Avramis VI, et al: Blood 99:1986-94, 2002
CCG-1991Escalating Dose Intravenous Methotrexate Without Leucovorin Rescue Versus Oral Methotrexate and Single Versus Double Delayed Intensification for Children With Standard Risk Acute Lymphoblastic LeukemiaNCT00005945January 31, 2005Matloub Y et al15
POG 8602Evaluation of Treatment Regimens in Acute Lymphoid Leukemia of Childhood (ALinC #14)January 7, 1991Harris MB, et al: Leukemia 14:1570-6, 2000
POG 8698Up Front Alternating Chemotherapy vs Up Front Intensive 6-Mercaptopurine/Methotrexate for Acute Lymphocytic Leukemia In Childhood - A Pediatric Oncology Group Pilot StudyJanuary 7, 1991Camitta B, et al: J Clin Oncol 12:1383-9, 1994
POG 8699Intensive Intravenous Treatment for Acute Lymphocytic Leukemia in Childhood - A Pediatric Oncology Group Pilot StudyJanuary 7, 1991Mahoney DH Jr, et al: Cancer 75:2623-31, 1995
POG 8704T-Cell #3 Protocol - A Pediatric Oncology Group Phase III StudyJanuary 9, 1992Amylon MD, et al: Leukemia 13:335-42, 1999
POG 9005Phase III Comparison of Intensification with Intr avenous Mercaptopurine plus Intermediate-Dose Intravenous Methotrexate vs Low-Dose Oral Methotrexate Following Induction with Prednisone/Vincristine/Asparaginase in Children with Low-Risk ALLSeptember 1, 1994Mahoney DH Jr, et al: J Clin Oncol 16:246-54, 1998
POG 9006Up-Front Intensive 6-Mercaptopurine/Methotrexate vs. Up-Front Alternating Chemotherapy for Acute Lymphocytic Leukemia in Childhood - A Randomized Pediatric Oncology Group Phase III StudyNovember 1, 1994Lauer SJ, et al: Leukemia 15:1038-45, 2001
POG 9086Phase I Pilot Study of Therapy for T-cell ALL or NHLApril 24, 1992
POG 9107Infant Leukemia Protocol - A Pediatric Oncology Groupwide Pilot StudyJune 15, 1993Maloney KW, et al: Leukemia 14:2276-85, 2000
POG 9201ALinC #16 Treatment for Patients With Lesser Risk Acute Lymphoblastic Leukemia—A Pediatric Oncology Group Phase III StudyNovember 15, 1999Chauvenet AR, et al: Blood 110:1105-11, 2007
POG 9202ALinC #16: Protocol for Patients with Standard Risk Acute Lymphoblastic Leukemia - A Pediatric Oncology Group Limited-Institution Pilot StudyOctober 1, 1994
POG 9203ALinC #16: Pilot Study for Patients with High-Risk ALL - A Pediatric Oncology Group Limited-Institution Pilot StudyApril 28, 1994Salzer WL, et al: J Pediatr Hematol Oncol 29:369-75, 2007
POG 9295T-Cell #4 “A” Pilot (With PEG-l-Asparaginase) - A Pediatric Oncology Group Limited-Institution Pilot StudyDecember 1, 1993
POG 9296T-Cell #4 Pilot “B” (With Intravenous Methotrexate/Intravenous 6-Mercaptopurine) - A Pediatric Oncology Group Limited-Institution Pilot StudyJune 15, 1993
POG 9297T-Cell #4 Pilot “C” (With Intermediate Dose Methotrexate/Intravenous 6-Mercaptopurine and High-Dose Cytosine Arabinoside) - A Pediatric Oncology Group Pilot StudyJune 15, 1993
POG 9398Efficacy of recombinant human granulocyte-colony stimulating factor in an Intensive Treatment for T-Cell Leukemia and Advanced-Stage Lymphoblastic Lymphoma of Childhood - A Pediatric Oncology Group-Wide Pilot StudyDecember 15, 1994
POG-9404Intensive Treatment for T-Cell Acute Lymphoblastic Leukemia and Advanced Stage Lymphoblastic Non-Hodgkin's Lymphoma: A Pediatric Oncology Group Phase III StudyNCT01230983September 10, 2001Asselin B, et al: Blood 118:874-883, 2011
POG 9405ALinC 16: Protocol for Patients with Newly Diagnosed Standard Risk Acute Lymphoblastic Leukemia (ALL)December 26, 1995
POG 9406ALinC 16: Protocol for Patients With Newly Diagnosed High Risk Acute Lymphoblastic Leukemia (ALL)November 15, 1999
POG 9407Induction Intensification and Allogeneic Bone Marrow Transplant In Infant ALL: A Children's Oncology Group Pilot StudyNCT00002756October 29, 2006Dreyer ZE et al16
POG 9605ALinC 16: Protocol for Patients With Newly Diagnosed Standard Risk Acute Lymphoblastic Leukemia (ALL)November 15, 1999
POG 9904ALinC #17 Treatment for Patients With Low Risk Acute Lymphoblastic Leukemia: A Pediatric Oncology Group Phase III StudyNCT00005585April 15, 2005Martin PL, et al: Pediatr Blood Cancer 51:58, 2008
POG 9905ALinC 17: Protocol for Patients With Newly Diagnosed Standard Risk Acute Lymphoblastic Leukemia (ALL): A Phase III StudyNCT00005596April 15, 2005Winick N et al17
POG 9906ALinC 17: Protocol for Patients With Newly Diagnosed High Risk Acute Lymphoblastic Leukemia (ALL) - Evaluation of the Augmented BFM Regimen: A Phase III StudyNCT00005603April 25, 2003Bowman WP, et al: Pediatr Blood Cancer 57:569-577, 2011
COG-AALL00P2The Use Of Modified BFM +/− Compound 506U78) (NSC# 686673) In an Intensive Chemotherapy Regimen For The Treatment Of T-Cell LeukemiaNCT00016302October 4, 2005Dunsmore KP, et al: J Clin Oncol 26:539s, 2008 (suppl; abstr 10002)
COG-AALL0232High Risk B-Precursor Acute Lymphoblastic LeukemiaNCT00075725January 21, 2011Larsen EC, et al: J Clin Oncol 29:6s, 2011 (suppl; abstr 3)

Abbreviations: ALinC, acute leukemia in children; ALL, acute lymphoblastic leukemia; BFM, Berlin-Frankfurt-Munster; CCG, Children's Cancer Group; COG, Children's Oncology Group; FAB, French-American-British [leukemia classification system]; ID, identification; NCT, numbered clinical trial; NHL, non-Hodgkin's lymphoma; PEG, polyethylene glycol; POG, Pediatric Oncology Group.

Table A2.

Number of Patients Who Died Within 0-4.99, 5-9.99, and ≥ 10 Years of Diagnosis for Patients Enrolled in 1990-1999

Patient GroupTime to Death (years)
Total No. of Deaths
0-4.99
5-9.99
≥ 10
No. of Patients%No. of Patients%No. of Patients%
All patients2,04183.8536715.08261.072,434
Age group, years
    ≤ 115698.7321.2700158
    1-9.991,10379.327019.41181.291,391
    ≥ 1078288.369510.7380.9885
    10-14.9950087.116912.0250.87574
    ≥ 1528290.68268.3630.96311
Sex
    Male1,24883.2623215.48191.271,499
    Female79384.8113514.4470.75935
Race
    White1,25782.4824416.01231.511,524
    Black22486.493413.1310.39259
    Other56086.028913.6720.31651
Ethnicity
    Hispanic18484.793214.7510.46217
    Non-Hispanic84182.7816916.6360.591,016
    Unknown1,01684.616613.82191.581,201
Immunophenotype
    B cell1,42681.8629817.11181.031,742
    T cell33591.78256.8551.37365
Risk group
    Standard74676.7521422.02121.23972
    High1,13987.3515111.58141.071,304

Table A3.

Number of Patients Age ≤ 1 Year Who Died Within 0-4.99, 5-9.99, and ≥ 10 Years of Diagnosis for Patients Enrolled in 1990-1999

Patient GroupTime to Death (years)
Total No. of Deaths
0-4.99
5-9.99
≥ 10
No. of Patients%No. of Patients%No. of Patients%
Age, years
    ≤ 115698.7321.2700158
Sex
    Male7897.522.50080
    Female78100000078
Race
    White10398.121.900105
    Black910000009
    Other44100000044
Ethnicity
    Hispanic18100000018
    Non-Hispanic73100000073
    Unknown6597.0122.990067
Immunophenotype
    B cell12398.421.600125
    T cell210000002

Table A4.

Number of Patients Older Than Age 1 Year Who Died Within 0-4.99, 5-9.99, or ≥ 10 Years of Diagnosis for Patients Enrolled in 1990-1999

Patient GroupTime to Death (years)
Total
0-4.99
5-9.99
≥ 10
No. of Patients%No. of Patients%No. of Patients%
All patients1,88582.8236516.04261.142,276
Sex
    Male1,17082.4523016.21191.341,419
    Female71583.4313515.7570.82857
Race
    White1,15481.3224217.05231.621,419
    Black215863413.610.4250
    Other51685.018914.6620.33607
Ethnicity
    Hispanic16683.423216.0810.5199
    Non-Hispanic76881.4416917.9260.64943
    Unknown95183.8616414.46191.681,134
Immunophenotype
    B cell1,30380.5829618.31181.111,617
    T cell33391.74256.8951.38363

Table A5.

Number of Patients Who Died Within 0-4.99 or 5-9.99 Years of Diagnosis for Patients Enrolled In 2000-2005

Patient GroupTime to Death (years)
Total No. of Deaths
0-4.99
5-9.99
No. of Patients%No. of Patients%
All patients61891.56578.44675
Age group, years
    ≤ 1731000073
    1-9.9928588.793611.21321
    ≥ 1026092.53217.47281
    10-14.9914093.33106.67150
    ≥ 1512091.6118.4131
Sex
    Male36390.75379.25400
    Female25592.73207.27275
Race
    White44590.82459.18490
    Black4892.3147.6952
    Other12593.9886.02133
Ethnicity
    Hispanic15491.12158.88169
    Non-Hispanic42591.4408.6465
    Unknown3995.1224.8841
Immunophenotype
    B cell48290.6509.4532
    T cell8197.5922.4183
Risk group
    Standard20388.652611.35229
    High34191.67318.33372

Table A6.

Number of Patients Who Died Within 0-4.99 or 5-9.99 Years of Diagnosis for Patients Older Than Age 1 Year Enrolled in 2000-2005*

Patient GroupTime to Death (years)
Total No. of Deaths
0-4.99
5-9.99
No. of Patients%No. of Patients%
All patients54590.53579.47602
Sex
    Male31889.583710.42355
    Female22791.9208.1247
Race
    White39089.664510.34435
    Black4591.8448.1649
    Other11093.2286.78118
Ethnicity
    Hispanic14290.45159.55157
    Non-Hispanic37390.31409.69413
    Unknown3093.7526.2532
Immunophenotype
    B cell41689.275010.73466
    T cell8197.5922.4183
*All the deaths that occurred in infants age ≤ 1 year who were enrolled in 2000-2005 occurred within 5 years of initial diagnosis.

Table A7.

Five-Year Overall Survival of Infants (age ≤ 1 year) by Era

Patient GroupNo.5-Year Survival ± SE (%)
% Reduction2000-2005 v 1990-1994P
1990-1994
1995-1999
2000-2005
%No. of Patients%No. of Patients%No. of Patients
Age, years
    ≤ 146147.9 ± 4.115448.1 ± 4.314853.2 ± 5.415910.4520
Sex
    Male23346.2 ± 5.68246.9 ± 6.56545.8 ± 7.086−1.9299
    Female22849.9 ± 6.17249.0 ± 5.78361.6 ± 8.07323.2754
Race
    White32246.4 ± 5.110150.1 ± 5.39954.3 ± 6.012215.5909
    Black251267
    Other11448.5 ± 8.24145.7 ± 7.74348.3 ± 12.3300.8509
Ethnicity
    Hispanic6364.3 ± 13.61438.5 ± 10.72254.0 ± 13.027−29.4606
    Non-Hispanic27452.9 ± 5.58354.8 ± 6.07653.8 ± 6.51152.9982
    Unknown12436.7 ± 6.75752.0 ± 7.25047.1 ± 14.01716.8070
Immunophenotype
    B cell38245.9 ± 4.811548.7 ± 4.812054.3 ± 5.614716.2434
    T cell6222

Table A8.

Five-Year Overall Survival of Non-Infants (older than age 1 year) by Era

Patient GroupTotal No. of Patients5-Year Survival ± SE (%)
% Reduction 2000-2005 v 1990-1994P
1990-1994
1995-1999
2000-2005
%No. of Patients%No. of Patients%No. of Patients
All patients21,16584.4 ± 0.47,15088.5 ± 0.47,02191.3 ± 0.46,99444< .001
Sex
    Male11,92283.4 ± 0.64,03586.9 ± 0.63,99290.9 ± 0.63,89545< .001
    Female9,24385.8 ± 0.63,11590.6 ± 0.63,02991.8 ± 0.73,09942< .001
Race
    White15,43787.0 ± 0.55,19689.7 ± 0.54,28992.0 ± 0.55,41238< .001
    Black1,44975.7 ± 2.050981.3 ± 1.851788.4 ± 2.142352< .001
    Other4,27977.8 ± 1.21,44587.3 ± 0.91,67589.2 ± 1.21,15951< .001
Ethnicity
    Hispanic2,52682.5 ± 1.853387.8 ± 1.465388.3 ± 1.11,34033.0036
    Non-Hispanic12,25487.9 ± 0.63,54389.3 ± 0.63,30192.3 ± 0.55,41036< .001
    Unknown6,38580.8 ± 0.73,07487.9 ± 0.63,06786.3 ± 2.924428< .001
Immunophenotype
    B cell16,51885.8 ± 0.54,95789.1 ± 0.45,71692.0 ± 0.55,84544< .001
    T cell1,82570.8 ± 1.774680.8 ± 1.762281.5 ± 2.245737< .001

Table A9.

Cumulative Incidence of Death After Relapse/Disease Progression v Death As a First Event for Infants Age ≤ 1 Year by Cause in COG ALL Trials

Death As a First or Subsequent EventCumulative Incidence (%)
P
1990-19941995-19992000-2005Overall
5-year
    Relapse/disease progression or secondary malignancies as first event43.0315.8927.2128.92< .001
    Treatment-related death prior to relapse/disease progression3.9027.1713.8714.79< .001
    Unknown or unrelated5.218.885.726.56.2774
    Overall52.1451.9446.8050.27.4503
10-year
    Relapse/disease progression or secondary malignancies as first event43.7315.8929.20< .001
    Treatment-related death prior to relapse/disease progression3.9027.1714.79< .001
    Unknown or unrelated5.219.866.95.1454
    Overall52.8352.9250.93.6231

Abbreviations: ALL, acute lymphoblastic leukemia; COG, Children's Oncology Group.

Table A10.

Cumulative Incidence of Death After Relapse/Disease Progression v Death As a First Event for Patients Older Than Age 1 Year by Cause in COG ALL Trials

Death As a First or Subsequent EventCumulative Incidence (%)
P
1990-19941995-19992000-2005Overall
5-year
    Relapse/disease progression or secondary malignancies as first event12.188.896.749.40< .001
    Treatment-related death prior to relapse/disease progression2.121.391.281.60< .001
    Unknown or unrelated1.291.200.701.08< .001
    Overall15.5811.488.7212.07< .001
10-year
    Relapse/disease progression or secondary malignancies as first event15.2012.3812.62< .001
    Treatment-related death prior to relapse/disease progression2.131.421.62.0012
    Unknown or unrelated1.821.501.49.4130
    Overall19.1515.3115.74< .001

Abbreviations: ALL, acute lymphoblastic leukemia; COG, Children's Oncology Group.

Fig A1.

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Overall survival probability for patients with acute lymphoblastic leukemia of different ages enrolled onto Children's Oncology Group trials in 1990-1994, 1995-1999, and 2000-2005; (A) infants age ≤ 1 year, and persons age (B) 1 to 9.99 years, (C) 10 years or older, and (D) 15 years or older.

Fig A2.

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Object name is zlj9991022390003.jpg

Overall survival probability for (A) males and (B) females enrolled onto Children's Oncology Group trials in 1990-1994, 1995-1999, and 2000-2005.

Fig A3.

An external file that holds a picture, illustration, etc.
Object name is zlj9991022390004.jpg

Overall survival probability for (A) whites, (B) blacks, and (C) persons of other ethnicities enrolled onto Children's Oncology Group trials in 1990-1994, 1995-1999, and 2000-2005.

Fig A4.

An external file that holds a picture, illustration, etc.
Object name is zlj9991022390005.jpg

Overall survival probability for persons who reported themselves as (A) Hispanic, (B) non-Hispanic, or (C) unknown ethnicity enrolled onto Children's Oncology Group trials in 1990-1994, 1995-1999, and 2000-2005.

Fig A5.

An external file that holds a picture, illustration, etc.
Object name is zlj9991022390006.jpg

Overall survival probability by leukemia immunophenotype for patients with (A) B-cell and (B) T-cell acute lymphoblastic leukemia enrolled onto Children's Oncology Group trials in 1990-1994, 1995-1999, and 2000-2005.

Fig A6.

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Object name is zlj9991022390007.jpg

Overall survival probability by National Cancer Institute risk group for patients with (A) standard-risk (age 1-9.99 years and initial WBC count < 50,000/μL) and (B) high-risk (age 10 years or older and/or initial WBC count > 50,000/μL) acute lymphoblastic leukemia enrolled onto Children's Oncology Group trials in 1990-1994, 1995-1999, and 2000-2005.

Fig A7.

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Object name is zlj9991022390008.jpg

Survival tree regression analysis was performed by using complete data for (A) patients older than age 1 year (yr); and (B) infants age ≤ 1 year. NCI, National Cancer Institute; OS, overall survival.

Footnotes

Listen to the podcast by Dr Silverman at www.jco.org/podcasts

Supported by Chair's Grant No. U10 CA98543, Statistics and Data Center Grant No. U10 CA98413, Community Clinical Oncology Program Grant No. U10 CA95861, and Human Specimen Banking Grant No. U24 CA114766 to the Children's Oncology Group from the National Cancer Institute, National Institutes of Health, Bethesda, MD.

Presented as an abstract at the 40th Congress of the International Society of Pediatric Oncology, Berlin, Germany,October 2-6, 2008.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: Paul S. Gaynon, EUSA Pharma, sanofi-aventis, Teva Pharmaceutical Industries, Bristol-Myers Squibb (C) Stock Ownership: None Honoraria: Paul S. Gaynon, Enzon Pharmaceuticals, Sigma Tau Pharmaceuticals, Genzyme Research Funding: Paul S. Gaynon, Genzyme Expert Testimony: None Other Remuneration: None

AUTHOR CONTRIBUTIONS

Conception and design: Stephen P. Hunger, Meenakshi Devidas, Bruce M. Camitta, Naomi J. Winick, Gregory H. Reaman, William L. Carroll

Provision of study materials or patients: Naomi J. Winick

Collection and assembly of data: Meenakshi Devidas, Gregory H. Reaman, William L. Carroll

Data analysis and interpretation: All authors

Manuscript writing: All authors

Final approval of manuscript: All authors

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