Random survival forest model identifies novel biomarkers of event-free survival in high-risk pediatric acute lymphoblastic leukemia

Abstract We examined the prognostic impact of CD2 antigen expression for 651 patients with T-lineage acute lymphoblastic leukemia (ALL), who were enrolled in front-line Childrens Cancer Group treatment studies between 1983 and 1994. There was a statistically significant correlation between the CD2 antigen positive leukemic cell content of bone marrow and probability of remaining in bone marrow remission, as well as overall event-free survival (EFS) (P = .0003 and P = .002, log-rank tests for linear trend). When compared with patients with the highest CD2 expression level (> 75% positivity), the life table relative event rate (RER) was 1.22 for patients with intermediate range CD2 expression level (30% to 75% positivity) and 1.81 for “CD2-negative” patients (< 30% positivity). At 6 years postdiagnosis, the EFS estimates for the three CD2 expression groups (low positivity to high positivity) were 52.8%, 65.5%, and 71.9%, respectively. CD2 expression remained a significant predictor of EFS after adjustment for the effects of other covariates by multivariate regression, with a RER of 1.47 for CD2- negative patients (P = .04). Analysis of T-lineage ALL patients shows a significant separation in EFS after adjustment for the National Cancer Institute (NCI) age and white blood cell (WBC) criteria for standard and high-risk ALL (P = .002, RER = 1.67). The determination of CD2 expression on leukemic cells helped identify patients with the better and poorer prognoses in both of these risk group subsets. For standard risk T-lineage ALL, CD2-negative patients had a worse outcome (P = .0007, RER = 2.92) with an estimated 5-year EFS of 55.9% as compared with 78.3% for the CD2-positive patients. Thus, CD2 negativity in standard risk T-lineage ALL identified a group of patients who had a worse outcome than high-risk T-lineage ALL patients who were CD2 positive. The percentage of CD2 antigen positive leukemic cells from T- lineage ALL patients is a powerful predictor of EFS after chemotherapy. This prognostic relationship is the first instance in which a biological marker in T-lineage ALL has been unequivocally linked to treatment outcome.

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Obesity and Outcome in Pediatric Acute Lymphoblastic Leukemia

Journal of Clinical Oncology ◽

10.1200/jco.2006.07.7792 ◽

2007 ◽

Vol 25 (15) ◽

pp. 2063-2069 ◽

Cited By ~ 123

Author(s):

Anna M. Butturini ◽

Frederick J. Dorey ◽

Beverly J. Lange ◽

David W. Henry ◽

Paul S. Gaynon ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Newly Diagnosed ◽

Event Free Survival ◽

Prognostic Variables ◽

Free Survival ◽

Pediatric Acute Lymphoblastic Leukemia ◽

Cancer Group ◽

Hazard Ratios ◽

Nonobese Patients

PurposeTo evaluate the effect of obesity (defined as a body mass index > 95th percentile for age and sex at diagnosis) on outcome of pediatric acute lymphoblastic leukemia (ALL).Patients and MethodsWe retrospectively analyzed data from 4,260 patients with newly diagnosed ALL enrolled from 1988 to 1995 onto five concurrent Children's Cancer Group studies. Results were verified in a second cohort of 1,733 patients enrolled onto a sixth study from 1996 to 2002.ResultsThe 1988 to 1995 cohort included 343 obese and 3,971 nonobese patients. The 5-year event-free survival rate and risk of relapse in obese versus nonobese patients were 72% ± 2.4% v 77% ± 0.6% (P = .02) and 26 ± 2.4 v 20 ± 0.6 (P = .02), respectively. After adjusting for other prognostic variables, obesity's hazard ratios (HRs) of events and relapses were 1.36 (95% CI, 1.04 to 1.77; P = .021) and 1.29 (95% CI, 1.02 to 1.56; P = .04), respectively. The effect of obesity was prominent in the 1,003 patients ≥ 10 years old at diagnosis; in this subset, obesity's adjusted HRs of events and relapses were 1.5 (95% CI, 1.1 to 2.1; P = .009) and 1.5 (95% CI, 1.2 to 2.1; P = .013), respectively. In a second cohort of 1,160 patients ≥ 10 years old, obesity's adjusted HRs of events and relapses were 1.42 (95% CI, 1.03 to 1.96; P = .032) and 1.65 (95% CI, 1.13 to 2.41; P = .009), respectively. The effect of obesity on outcome was unrelated to changes in chemotherapy doses, length of intervals between chemotherapy cycles, or incidence and severity of therapy-related toxicity.ConclusionObesity at diagnosis independently predicts likelihood of relapse and cure in preteenagers and adolescents with ALL.

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Socioeconomic status and event free survival in pediatric acute lymphoblastic leukemia: A population-based cohort study

Leukemia Research ◽

10.1016/j.leukres.2014.08.017 ◽

2014 ◽

Vol 38 (12) ◽

pp. 1407-1412 ◽

Cited By ~ 13

Author(s):

Sumit Gupta ◽

Rinku Sutradhar ◽

Astrid Guttmann ◽

Lillian Sung ◽

Jason D. Pole

Keyword(s):

Socioeconomic Status ◽

Cohort Study ◽

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Population Based ◽

Event Free Survival ◽

Free Survival ◽

Pediatric Acute Lymphoblastic Leukemia

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Unrelated donor stem cell transplantation compared with chemotherapy for children with acute lymphoblastic leukemia in a second remission: a matched-pair analysis

Blood ◽

10.1182/blood.v101.10.3835 ◽

2003 ◽

Vol 101 (10) ◽

pp. 3835-3839 ◽

Cited By ~ 107

Author(s):

Anja Borgmann ◽

Arend von Stackelberg ◽

Reinhard Hartmann ◽

Wolfram Ebell ◽

Thomas Klingebiel ◽

...

Keyword(s):

Stem Cell ◽

Acute Lymphoblastic Leukemia ◽

High Risk ◽

Stem Cell Transplantation ◽

Lymphoblastic Leukemia ◽

Matched Pair ◽

Event Free Survival ◽

Free Survival ◽

Matched Pair Analysis ◽

Pair Analysis

Abstract Allogeneic stem cell transplantation (SCT) is frequently considered as treatment for relapsed childhood acute lymphoblastic leukemia (ALL). For patients without a matched sibling donor, SCT from unrelated donors (UD-SCT) has been increasingly performed during the past years. However, UD-SCT–related mortality and morbidity is still considerable, and the question remains as to which patients are at such high risk of recurrence that UD-SCT is indicated and, conversely, which patients do not require transplantation for long-term disease control. A matched-pair analysis was performed among patients treated according to Acute Lymphoblastic Leukemia Relapse Berlin-Frankfurt-Münster (ALL-REZ BFM) Study Group protocols after first relapse with chemotherapy or UD-SCT. Altogether 81 pairs were identified that could be matched exactly for site of relapse and immunophenotype, and as closely as possible for duration of first remission, age, diagnosis date, and peripheral blast cell count at relapse. No significant difference in the probability of event-free survival (pEFS) between UD-SCT and chemotherapy existed regarding 28 pairs with an intermediate prognosis (0.39 ± 0.10 vs 0.49 ± 0.11,P = .105), whereas the pEFS was significantly different in the 53 pairs with a poor prognosis (0.44 ± 0.07 vs 0.00 ± 0.00, P < .001). The major reasons of treatment failure among patients who underwent UD-SCT were therapy-related death (TRD; 24/81) and relapses (20/81). In contrast, TRD rarely occurred in patients treated with chemotherapy alone (3/81), but relapse was much more common (62/81). In conclusion, UD-SCT provides better event-free survival for children with high-risk relapsed ALL. However, there is no clear advantage of UD-SCT in patients with intermediate prognosis.

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Effect of Blinatumomab vs Chemotherapy on Event-Free Survival Among Children With High-risk First-Relapse B-Cell Acute Lymphoblastic Leukemia

JAMA ◽

10.1001/jama.2021.0987 ◽

2021 ◽

Vol 325 (9) ◽

pp. 843

Author(s):

Franco Locatelli ◽

Gerhard Zugmaier ◽

Carmelo Rizzari ◽

Joan D. Morris ◽

Bernd Gruhn ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

High Risk ◽

B Cell ◽

Lymphoblastic Leukemia ◽

Event Free Survival ◽

Free Survival ◽

Cell Acute Lymphoblastic Leukemia ◽

First Relapse

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The Importance of Pharmacogenomic Variations in the Treatment of Children with Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood.v112.11.4847.4847 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4847-4847

Author(s):

Chung-Yi Hu ◽

Sheng-Kai Chang ◽

Yung-Li Yang ◽

Shu-Wha Lin ◽

Rong-Jing Chiu ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

High Risk ◽

Standard Error ◽

Poor Prognosis ◽

Lymphoblastic Leukemia ◽

Treatment Protocol ◽

Event Free Survival ◽

Free Survival ◽

Kaplan Meier

Abstract In adaptation of risk-directed combined chemotherapies, the initial remission rate in treatment of childhood acute lymphoblastic leukemia (ALL) has exceeded 95%. Hematological relapse during maintenance therapy, in which methotrexate (MTX) and thiopurine are applied, is the major cause of treatment failure. A retrospective study was performed to evaluate the role of pharmacogenomic effects in the treatment of children with ALL in the southern Chinese population. A total of 105 Taiwanese children with ALL, who received combined chemotherapy of different intensities based on risk-directed Taiwan Pediatric Oncology Group (TPOG)-ALL-93 protocols between Oct. 1993 to Dec. 2001, were recorded in long-term follow-up (6.5 to 13.7 years) for events (hematological relapse or death) occurrence (Figure 1). Seventeen genetic polymorphisms in 13 pharmacogenomic targets that implicated in MTX/thiopurine metabolism were analyzed by PCR-based restriction length polymorphism (RFLP) or sequence-specific oligonucleotide (SSO) probe hybridization. Pharmacogenomic polymorphisms were correlated with long-term event-free survival (EFS) of patients, with confounding effects adjusted by multivariate regression. Homozygosity of the 2677–3435 G-C allele in the multi-drug resistance gene (MDR-1, ABCB1) was highly associated with a significant reduction in long-term EFS in those patients treated with the standard risk protocol (TPOG-ALL-93-SR) (Figure 2). In the 36 patients receiving TPOG-ALL-93-SR treatment protocol, 6 out of 12 (50%) subjects carried homozygotic MDR1 2677–3435 G-C/G-C genotype suffered hematological relapse in 2 years, compared to 21 of 24 (88%) the non-homozygotic subjects remained event-free after 5 years (hazard ratio: 6.8, p=0.01). Among patients treated with the a high risk protocol (TPOG-ALL-93-HR) due to the presence of myeloid markers on the leukemic cells or manifested central nervous system leukemia, the thymidylate synthase (TYMS) enhancer 28-bp repeats 3R3R, and the glutathione-S-transferase M1 (GSTM1) null genotypes were associated with inferior clinical outcomes (p=0.029 and 0.058, respectively). Moreover, for patients with T-cell ALL that received the very high risk protocol (TPOG-ALL-97-VHR), the methionine synthase reductase (MTRR) 66AA genotype correlated with a superior prognosis compared to the AG or GG genotypes. These findings indicated independent pharmacogenomic determinants could be identified in subsets of Taiwanese children with ALL and correlated to the treatment outcome. In conclusion, we propose the pharmacogenomic determinants disclosed in the context of TPOG-ALL-93 protocols could be used to refine protocols for the treatment of pediatric ALL patients. Fig. 1 Kaplan-Meier plot depicting event-free survival of the ALL patients. The estimate of five-year event-free-survival (and the standard error) is illustrated for 105 patients received TPOG-ALL-93 protocols. Fig. 1. Kaplan-Meier plot depicting event-free survival of the ALL patients. The estimate of five-year event-free-survival (and the standard error) is illustrated for 105 patients received TPOG-ALL-93 protocols. Fig. 2 MDR1 2677–3435 G-C/G-C genotype identified a subset with poor prognosis in the 36 ALL patients received TPOG-ALL-93-SR treatment protocol. Fig. 2. MDR1 2677–3435 G-C/G-C genotype identified a subset with poor prognosis in the 36 ALL patients received TPOG-ALL-93-SR treatment protocol.

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Stem-Cell Transplantation in Children With Acute Lymphoblastic Leukemia: A Prospective International Multicenter Trial Comparing Sibling Donors With Matched Unrelated Donors—The ALL-SCT-BFM-2003 Trial

Journal of Clinical Oncology ◽

10.1200/jco.2014.58.9747 ◽

2015 ◽

Vol 33 (11) ◽

pp. 1265-1274 ◽

Cited By ~ 97

Author(s):

Christina Peters ◽

Martin Schrappe ◽

Arend von Stackelberg ◽

André Schrauder ◽

Peter Bader ◽

...

Keyword(s):

Stem Cell ◽

Acute Lymphoblastic Leukemia ◽

High Risk ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Lymphoblastic Leukemia ◽

Event Free Survival ◽

Hematopoietic Stem ◽

Free Survival ◽

Unrelated Donors

Purpose Although hematopoietic stem-cell transplantation is widely performed in children with high-risk acute lymphoblastic leukemia (ALL), the influence of donor types is poorly understood. Thus, transplantation outcomes were compared in the prospective multinational Berlin-Frankfurt-Muenster (BFM) study group trial: ALL-SCT-BFM 2003 (Allogeneic Stem Cell Transplantation in Children and Adolescents with Acute Lymphoblastic Leukemia). Patients and Methods After conditioning with total-body irradiation and etoposide, 411 children with high-risk ALL received highly standardized stem-cell transplantations during the first or later remissions. Depending on donor availability, grafts originated from HLA-genoidentical siblings or from HLA-matched unrelated donors who were identified and matched by high-resolution allelic typing and were compatible in at least 9 of 10 HLA loci. Results Four-year event-free survival (± standard deviation [SD]) did not differ between patients with transplantations from unrelated or sibling donors (0.67 ± 0.03 v 0.71 ± 0.05; P = .405), with cumulative incidences of nonrelapse mortality (± SD) of 0.10 ± 0.02 and 0.03 ± 0.02 (P = .017) and relapse rates (± SD) of 0.22 ± 0.02 and 0.24 ± 0.04 (P = .732), respectively. Among recipients of transplantations from unrelated donors, no significant differences in event-free survival, overall survival, or nonrelapse mortality were observed between 9/10 and 10/10 matched grafts or between peripheral blood stem cells and bone marrow. The absence of chronic graft-versus-host disease had no effect on event-free survival. Engraftment was faster after bone marrow transplantation from siblings and was associated with fewer severe infections and pulmonary complications. Conclusion Outcome among high-risk pediatric patients with ALL after hematopoietic stem-cell transplantation was not affected by donor type. Standardized myeloablative conditioning produced a low incidence of treatment-related mortality and effective control of leukemia.

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The Outcome of Childhood High-Risk Acute Lymphoblastic Leukemia: 10 Years of Experience with the ALL-BFM 95 Protocol in Chinese Single Centre

Blood ◽

10.1182/blood.v124.21.5241.5241 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5241-5241

Author(s):

Yongsheng Ruan ◽

Xuedong Wu ◽

Chunfu Li ◽

Xiaoqin Feng

Keyword(s):

Acute Lymphoblastic Leukemia ◽

High Risk ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Poor Response ◽

Rank Test ◽

Event Free Survival ◽

Single Centre ◽

Hematopoietic Stem ◽

Free Survival

Abstract Objectives: To evaluate the effectiveness and the practicability of Acute Lymphoblastic Leukemia Berlin-Frankfurt-Münster 95 (ALL-BFM 95) protocol in treating childhood high-risk (HR) acute lymphoblastic leukemia (ALL) in Chinese single centre. Methods: A retrospective analysis of 47 children with novo high risk ALL from July 2003 and August 2013 was performed. These children treated by the ALL-BFM 95 protocol. Median follow-up time was 39 months (16~127months). Survival was evaluated by Kaplan Meier analysis and Log-Rank test. Results:Relapse-related death occurred in 12 of 47 patients (25.5%), and 5 of 47 patients (10.6%) were treatment-related mortality. Five-year probability of event-free-survival (pEFS) were found to be 62.4%. High risk ALL children only with prednisone poor response(PPR) has good outcome who’s Five-year probability of event-free-survival (pEFS) could reach to 80%. Children with hematopoietic stem cell transplantation (HSCT) after chemotherapy achieved significantly better pEFS than only chemotherapy (77.3% vs 51.6%，p=0.035). pEFS for B-cell precursor and T-cell ALL was 64.5% and 57.1%, respectively（P=0.633）. Conclusions: ALL-BFM 95 protocol can also improve the outcome of childhood high risk ALL in China. The leading causes of death were relapse. HSCT treatment had better outcome than only chemotherapy in high risk ALL children in CR1 phase. Disclosures No relevant conflicts of interest to declare.

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Escalating intravenous methotrexate improves event-free survival in children with standard-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group

Blood ◽

10.1182/blood-2010-12-322909 ◽

2011 ◽

Vol 118 (2) ◽

pp. 243-251 ◽

Cited By ~ 92

Author(s):

Yousif Matloub ◽

Bruce C. Bostrom ◽

Stephen P. Hunger ◽

Linda C. Stork ◽

Anne Angiolillo ◽

...

Keyword(s):

Overall Survival ◽

Acute Lymphoblastic Leukemia ◽

High Risk ◽

Lymphoblastic Leukemia ◽

Oncology Group ◽

Event Free Survival ◽

Free Survival ◽

Cancer Group ◽

Leucovorin Rescue ◽

Standard Risk

Abstract Children's Cancer Group-1991 selected 2 components from the Children's Cancer Group studies shown to be effective in high-risk acute lymphoblastic leukemia and examined them in children with National Cancer Institute standard-risk acute B-precursor lymphoblastic leukemia. These were (1) vincristine and escalating IV methotrexate (MTX) without leucovorin rescue during the interim maintenance (IM) phases and (2) addition of a second delayed intensification (DI) phase. Eligible patients (n = 2078) were randomly assigned to regimens containing either oral (PO) MTX, PO mercaptopurine, dexamethasone, and vincristine or IV MTX during IM phases, and regimens with either single DI or double DI. Five-year event-free survival (EFS) and overall survival for patients on the PO MTX arms were 88.7% ± 1.4% and 96% ± 0.9% versus 92.6% ± 1.2% and 96.5% ± 0.8% for those on the IV MTX arms (P = .009, P = .66). Five-year EFS and overall survival for patients who received single DI were 90.9% ± 1.3% and 97.1% ± 0.8% versus 90.5% ± 1.3% and 95.4% ± 3.8% for those who received double DI (P = .71, P = .12). No advantage was found for a second DI; however, replacement of PO MTX, PO mercaptopurine, vincristine, and dexamethasone during IM with vincristine and escalating IV MTX improved EFS.

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