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Current strategies to treat pediatric acute lymphoblastic leukemia rely on risk stratification algorithms using categorical data. We investigated whether using continuous variables assigned different weights would improve risk stratification. We developed and validated a multivariable Cox model for relapse-free survival (RFS) using information from 21199 patients. We constructed risk groups by identifying cutoffs of the COG Prognostic Index (PI COG ) that maximized discrimination of the predictive model. Patients with higher PI COG have higher predicted relapse risk. The PI COG reliably discriminates patients with low vs. high relapse risk. For those with moderate relapse risk using current COG risk classification, the PI COG identifies subgroups with varying 5-year RFS. Among current COG standard-risk average patients, PI COG identifies low and intermediate risk groups with 96% and 90% RFS, respectively. Similarly, amongst current COG high-risk patients, PI COG identifies four groups ranging from 96% to 66% RFS, providing additional discrimination for future treatment stratification. When coupled with traditional algorithms, the novel PI COG can more accurately risk stratify patients, identifying groups with better outcomes who may benefit from less intensive therapy, and those who have high relapse risk needing innovative approaches for cure., (© 2024. The Author(s).)

Chromosome aberrations have a major role in pediatric acute lymphoblastic leukemia (ALL) risk assignment. The Children's Cancer Group (CCG) and the Pediatric Oncology Group (POG) independently assessed the significance of trisomy for chromosomes 4, 10, and 17 in National Cancer Institute (NCI) Standard- and High-Risk ALL. Data from 1582 (CCG) and 3902 (POG) patients were analyzed. Eight-year event-free survivals (EFS) of 91% (CCG) and 89% (POG) (P < 0.001) were achieved in patients assigned to NCI Standard Risk whose leukemic cells had simultaneous trisomies 4, 10, and 17. Both groups showed the degree of favorable prognostic importance increased with the actual number of favorable trisomies. POG analyses also demonstrated hyperdiploidy (> or =53 chromosomes) was less of an independently significant prognostic factor in the absence of these key trisomies. This finding supported conclusions from previous CCG and POG studies that specific trisomies are more important than chromosome number in predicting outcome in pediatric B-precursor ALL. In NCI Higher Risk patients, the number of favorable trisomies was not prognostically significant, but showed the same trend. Moreover, specific trisomies 4, 10, and 17 remain associated with favorable prognosis in Standard-Risk B-precursor ALL, even in the context of very different treatment approaches between the groups.

Between May 1987 and January 1991, 1354 patients, 1-21 years old, with standard or poor prognosis B-lineage acute lymphocytic leukemia were treated on the Pediatric Oncology Group Study 8602. One thousand three hundred and twenty-three patients entered remission and 1051 patients were randomized on day 43 to an intensification regimen containing L-asparaginase and intermediate-dose methotrexate (regimen B) or cytarabine and intermediate dose methotrexate (regimen C). After completion of intensification at week 25, all patients received the same maintenance therapy until 3 years from diagnosis. Overall 5-year continuous complete remission (CCR) for regimen B was 72+/-2% (s.e.) and for regimen C, 73+/-2% (P = 0.72 by log-rank analysis). Significant differences between treatments for CCR, testicular, CNS relapses overall or with regard to phenotype (pre-B vs early pre-B), gender, or race were not detected. During intensification, regimen C had significantly more bacterial infections (P = 0.05) and days spent in the hospital (P < 0.001) compared with regimen B, while regimen B had significantly more allergic reactions (P < 0.0001). No significant differences in CCR were noted between patients with pre-B and early pre-B ALL (P = 0.22 stratified by risk group and treatment). This study was unable to detect statistical difference between asparaginase (regimen B) and cytarabine (regimen C) during the intensification phase of therapy in children with B-lineage acute lymphocytic leukemia.

T cell acute lymphocytic leukemia (T-ALL) and B-precursor ALL differ significantly in the clinical characteristics of the patients at presentation and in laboratory-defined characteristics of the leukemic cells. We assessed for pediatric patients with T-ALL the relative importance of prognostic factors previously demonstrated to predict outcome in B-precursor ALL. Presenting clinical and laboratory features were correlated with outcome for 441 children 12 months to 21 years of age with previously untreated T-ALL, registered on the Pediatric Oncology Group (POG) T3 protocol between 1986 and 1992. These T-ALL prognostic factor analyses were then compared to similar analyses for 1993 patients with B-precursor ALL enrolled during the same time period on the POG ALinC 14 protocol. Quantitative interaction between phenotype and each prognostic factor was studied to determine the relative importance of the prognostic factor for each of the two major immunophenotypes. We also analyzed the importance of maturational stage as a T-ALL prognostic factor, using a modified Ludwig definition of maturational stage. We conclude that several of the clinical and laboratory prognostic factors, which are used reliably for B-precursor ALL, are much less predictive in T-ALL (ie age, WBC, consensus risk group, hyperdiploidy, presence of trans- locations and CALLA expression). There was no significant difference between the phenotypes in the prognostic importance of race or gender. Our data demonstrate a significant difference in outcome among the three maturational stages of T-cell ALL, with the intermediate group faring best. Using traditional risk group criteria to stratify patients with T-ALL for therapy may not be appropriate.

Five pediatric patients are described with acute lymphoblastic leukemia (ALL) who at presentation had clinical findings suggestive of B cell ALL and lymphoblasts with FAB L3 morphology and the characteristic t(8;14)(q24;q32). However, the leukemia cells of all five patients failed to express surface immunoglobulin (sIg) and kappa or lambda light chains. Based on initial immunophenotyping results consistent with B-precursor ALL, four of these cases were initially treated with conventional ALL chemotherapy. These four patients were switched to B cell ALL treatment protocols once cytogenetic results became available revealing the 8;14 translocation. The fifth case was treated with B cell ALL therapy from the outset. Four of the five patients are in complete remission at 64, 36, 29 and 13 months from diagnosis. One patient relapsed and died 6 months after initial presentation. These five unusual cases with clinical B cell ALL, the t(8;14), and FAB L3 morphology, but negative sIg, demonstrate the importance of careful and multidisciplinary evaluation of leukemic cells with morphology, cytochemistry, immunophenotyping and cytogenetic analysis. Future identification of patients with this profile will allow us to expand our knowledge regarding prognostic significance and optimal treatment for this rare subgroup of patients.

The t(12;21)(p13;q22) is the most common translocation in childhood B-precursor ALL. It results in a TEL-AML1 rearrangement and is associated with a good prognosis. Because many chromosomal alterations in leukemia are associated with distinct cell surface phenotypes, we investigated whether there was an association seen between surface marker expression and the TEL-AML1 rearrangement. Of 166 unselected cases of B-precursor ALL studied by Southern hybridization, 45 cases (27%) showed TEL rearrangement. Blasts of patients with TEL rearrangement were much more likely to be CD9-negative, CD45-positive, CD13 positive, and CD20 negative, but the predictive value of any of these markers for the rearrangement was very low. However, 93% of patients with the TEL rearrangement had blasts that were either negative or only partly positive for CD9; this phenotype was only seen in 27% of patients without the rearrangement. Only information about CD20 expression added to the predictive value of CD9 alone. The predictive value of the phenotype CD9 (negative or partly positive) and CD20 (negative or partly positive), for the TEL rearrangement was prospectively tested on an additional 223 cases, and found to be 88% sensitive and 71% specific for the rearrangement, with a positive predictive value of 47%. Hyperdiploidy, previously shown to correlate negatively with the rearrangement, was a slightly more sensitive indicator (94%) but had a much lower predictive value (28%). Three of eight cases found to be rearranged by Southern hybridization but lacking the characteristic phenotype failed to show evidence of the TEL-AML1 rearrangement by polymerase chain reaction, suggesting that at least some of the discordant cases may involve partner genes other than AML1 in the TEL rearrangement. We conclude that immunophenotyping is highly predictive of the TEL rearrangement. For every 100 patients with B-precursor ALL, we estimate that prescreening by phenotyping would eliminate the need for molecular testing on 57 patients and only two or three of an expected 24 patients with the TEL rearrangement would not be detected.

Purpose: To develop antimetabolite-based consolidation regimens that minimize acute and long-term toxicities and improve the survival rate of children with standard-risk B-lineage acute lymphocytic leukemia (ALL)., Patients and Methods: Seven hundred twenty-seven eligible patients with standard-risk early pre-B ALL were registered onto the study. Seven hundred sixteen patients attained a complete remission (CR) after induction therapy. Of these, 114 patients were randomized to a different regimen and were the subject of a separate report. Six hundred two patients were randomized to receive one the following regimens: intermediate-dose methotrexate (IDMTX) with leucovorin rescue on weeks 7, 10, 13, 16, 19, and 22 (regimen A); regimen A plus asparaginase (ASP) administered intramuscularly (i.m.) weekly for 24 weeks (regimen B); or regimen A plus a 24-hour infusion of cytarabine (AraC) with each IDMTX (regimen C). After consolidation, patients were placed on maintenance therapy through week 156. Regimens A and C were opened in February 1986, and regimen B in May 1987. Comparisons are based on concurrently randomized patients (May 1987 to January 1991 between regimens A and B, and February 1986 to January 1991 between regimens A and C)., Results: The 5-year continuous CR (CCR) rates were not significantly different: A versus B, 78.1% (3.9 +/- SE) versus 83.3% +/- 3.5% and A versus C, 79.4% +/- 3.2% versus 83.5% +/- 2.9%; P by one-sided log-rank tests were .27 and .34, respectively. Significant treatment differences were not found with regard to sex, rate of testicular and CNS relapse, or CNS complications. During consolidation, regimen C had significantly more bacterial infections (P = .0032) and days spent in the hospital (P < .001) compared with regimen A., Conclusion: We were unable to show a statistical advantage of adding either ASP or AraC to IDMTX in terms of improvement in event-free survival (EFS).

A high incidence of co-expression of myeloid-associated antigens in infant B-precursor Acute Lymphocytic Leukemia (B-ALL) has been reported, but the significance of this finding is uncertain. To further assess myeloid differentiation and its prognostic significance in this disease, we investigated the frequency of myeloperoxidase (MPO) gene expression in the blast cells from 43 infants with B-ALL registered in a Pediatric Oncology Group (POG) Pilot Study for Treatment of Infant ALL, utilizing a molecular probe for detection of MPO messenger RNA (mRNA) by Northern blot hybridization and a monoclonal antibody to detect MPO-protein by immunohistochemical staining. Sufficient RNA for Northern blot was extracted from 32 bone marrow or blood samples. In two cases, MPO mRNA was determined by a reverse transcriptase-polymerase chain reaction assay and was negative in both cases. MPO-specific transcripts (MPO+) were present in 19 of 34 (56%) samples analyzed. Immunoreactive MPO protein was positive in 13 of the 20 (65%) patients studied. No correlation was found between MPO gene expression and clinical or laboratory features, karyotypic patterns or clinical outcome. The high frequency of MPO gene expression demonstrated in this study suggests that leukemogenic events in many cases of infant B-ALL appear to involve a pluripotent stem cell not yet fully committed to lymphoid differentiation.

Purpose: To describe the occurrence of secondary acute myeloid leukemia (AML) in children with acute lymphoblastic leukemia (ALL) treated with etoposide (VP-16)., Patients and Methods: Two hundred five consecutive children with early B-lineage ALL were treated according to the Dallas/Fort Worth (DFW) protocol between January 1986 and July 1, 1991. Therapy included a four-drug induction followed by consolidation and continuation phases of nightly oral mercaptopurine (6-MP) and repetitive courses of divided-dose oral methotrexate (dMTX) and asparaginase (L-asp). Three doses of VP-16 and cytarabine (Ara-C) were given during consolidation and later, during continuation, two doses were given 3 to 4 days apart, every 9 weeks. Intrathecal (IT) chemotherapy was given throughout the treatment period., Results: Two hundred three of the 205 patients entered remission. Only eight of these 203 children have had a bone marrow relapse (ALL). However, 10 other children have developed secondary AML 23 to 68 months following the diagnosis of ALL. Overall event-free survival (EFS) at 4 years is 79.3% +/- 5.1%, with a risk of secondary AML at 4 years of 5.9% +/- 3.2%., Conclusion: This experience provides strong evidence for a link between epipodophyllotoxin therapy and secondary AML since none of these children received alkylating agent therapy or irradiation. This serious complication raises concern as to the appropriate use of epipodophyllotoxins in the treatment of childhood ALL.

To account for the superior prognosis of hyperdiploid, B-progenitor acute lymphoblastic leukemia (ALL), we investigated the influence of trisomy in 1021 children greater than or equal to 1 year old by recursive partitioning analysis. The patients were treated according to a stratified, randomized study testing antimetabolite-based therapies. Trisomies of several individual chromosomes were associated with a better prognosis in a univariate statistical analysis. Of greater importance, trisomy of both chromosomes 4 and 10 identified a subgroup of patients (n = 180) with an extremely favorable 4-year event-free survival (EFS). Combined trisomy of chromosomes 4 and 10 retained its prognostic significance after stratification of patients by DNA index, age, and leukocyte count. Among patients with a DNA index greater than 1.16, patients with trisomies of both chromosomes 4 and 10 had a 4-year EFS of 96.6% (n = 161, SE = 3.8%), whereas patients with neither or only one of these trisomies had a 4-year EFS of 70.4% (n = 73, SE = 11.5%). All 19 patients with a DNA index less than or equal to 1.16 but with trisomies of chromosomes 4 and 10 remain in remission, suggesting that favorable chromosome trisomy dominates in a situation in which the cellular DNA content of less than or equal to 1.16 predicts a less favorable outcome. We conclude that combined trisomy of chromosomes 4 and 10 independently predicts EFS among children with B-progenitor ALL. Patients within the B-progenitor group who have this feature (about 20% of those with clonal abnormalities) are likely to be cured with antimetabolite-based chemotherapy--an approach that should produce few significant late effects.

From February 1986 to January 1991 the Pediatric Oncology Group (POG) treated 2404 children or adolescents with acute lymphoblastic leukemia (ALL) on immunophenotype (T-, B-, Pre-B, or Early pre-B-cell), age, and leukocyte count based treatment protocols (ALinC 14, T-cell 3, B-cell and infant leukemia studies). The immunophenotypic subgroups comprised 78.9% B-precursor cell, 15.1% T-cell, 2.0% B-cell, and 4% infant ALL. Patients with B-progenitor cell ALL were stratified by age and leukocyte count and randomized to receive induction therapy comprised of vincristine, prednisone, and asparaginase with triple intrathecal chemotherapy (methotrexate, hydrocortisone, cytarabine), followed by intensification with moderate-dose MTX (Regimen A), moderate-dose MTX plus asparaginase (Regimen B), moderate-dose MTX plus cytarabine given early (Regimen C), or moderate-dose MTX plus cytarabine given over the first 16 months of therapy (Regimen D). Continuation therapy comprised mercaptopurine and methotrexate with vincristine plus prednisone pulses. Central nervous system preventive treatment was continued for two years. Patients with T-cell or B-cell ALL or infants less than 1 yr old were treated on individual very intensive multiagent therapy protocols. The 4-year event-free survival for all patients was 66.4% +/- 2.4%; B-precursor ALL approximately 72%, T-ALL approximately 50%, B-ALL approximately 60%, and infants less than 1 yr old approximately 16.5%. We conclude that about two-thirds of newly diagnosed children with ALL can be cured with this approach which spares the majority of children exposure to alkylating agents, anthracyclines, epipodophylotoxins, and irradiation, diminishing the risks of serious acute and late effects.

We studied the blasts from 795 children greater than 1 year of age with newly diagnosed, untreated B-precursor acute lymphoblastic leukemia (ALL) for expression of the hematopoietic stem cell-associated antigen CD34. All cases were confirmed as B-lineage lymphoblastic leukemia by virtue of expression of CD19 and/or CD22, lack of T-cell antigens, and lack of surface-membrane immunoglobulin (Ig). The CD34 antigen was present in at least 10% of blast cells in 587 (73.8%) of the patients. There was no significant difference in presenting clinical characteristics between CD34+ and CD34- patients save for an increased incidence of CNS involvement at diagnosis in the latter. Patients with CD34+ leukemia were more likely to have blasts expressing CD22, CD9, and CD13 antigens but were less likely to coexpress CD20. Patients with pre-B (cytoplasmic mu) ALL were significantly more likely to lack CD34 on their blasts, while children with hyperdiploid ALL were more likely to be CD34+. Although remission induction rates were not significantly different between patients with CD34+ and CD34-ALL (P = .23), event-free survival was shorter for patients with CD34- leukemia (P = .0014). Even though CD34 expression was associated with certain other known prognostically favorable variables including hyperdiploidy and lack of cytoplasmic Ig, it had an independent favorable effect on treatment outcome, even after adjusting for competing prognostic factors.

Thirty-two children or adolescents had B cell acute lymphocytic leukemia (ALL) diagnosed by demonstration of surface immunoglobulin expression on greater than 10% of their bone marrow blasts. All patients had greater than 25% bone marrow lymphoblasts. Only five of 32 patients (16%) presented with an abdominal mass; however, 24 cases (75%) had FAB L3 morphology. By comparison with findings in common ALL, these 32 children were older (median age, 8 years) and had a higher incidence of central nervous system disease at presentation (22%); all but one were white, and 24 were males. Blast cells from individual cases expressed mu kappa (n = 13), mu lambda (n = 9), gamma kappa (n = 1), alpha kappa (n = 1), or mu with an undetermined light chain (n = 8). The most frequently identified cytogenetic abnormality was the classic B cell-associated t(8;14)(q23;q24) (n = 4); the t(1;19)(q23;p13.3), t(9;22)(q23;q11), and t(1;22) were observed in single cases. Twenty patients were treated uniformly on a single protocol designed for children with advanced B cell malignancy; therapy for the other 12 children varied. Nine children (28%) are surviving event-free; all but one for 3 years or more. We conclude that approximately 25% of children with B cell ALL are curable with intensive multiagent chemotherapy and that classification by immunophenotyping is superior to use of clinical and/or lymphoblast morphologic features.

A 57-year-old woman presented with L3 acute lymphoblastic leukemia demonstrating typical Burkitt's type morphology. Cytogenetic analysis revealed one of the variant translocations seen in Burkitt's lymphoma [t(8;22)] and a 14;18 translocation. Surface marker data at presentation and at autopsy demonstrated several B-cell markers, but absent surface immunoglobulins. The case presented here reveals a possible cytogenetic link between Burkitt's lymphoma and follicular center-cell lymphoma, and illustrates a variant surface marker profile for Burkitt's lymphoma.