Prognostic significance of sex in childhood B-precursor acute lymphoblastic leukemia: a Pediatric Oncology Group Study.

1998 ◽  
Vol 16 (8) ◽  
pp. 2854-2863 ◽  
Author(s):  
J J Shuster ◽  
P Wacker ◽  
J Pullen ◽  
J Humbert ◽  
V J Land ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Pediatric Oncology ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Outcome Analysis ◽  
Oncology Group ◽  
Dna Index ◽  
Duration Of Symptoms ◽  
Pediatric Oncology Group ◽  
Wbc Count

PURPOSE In childhood B-precursor acute lymphoblastic leukemia (ALL), possible interactions among sex, time, and widely used prognostic factors (age, WBC count, and DNA index) were investigated for the first 5 years after diagnosis. PATIENTS AND METHODS All eligible patients aged 1 to less than 22 years, registered between February 1986 and September 1994 in two B-precursor ALL studies from the Pediatric Oncology Group (POG), were included in the analysis. Cutpoints for age (3.0, 5.0, and 10.0 years), WBC count (10, 50, and 100 x 10(9)/L), and DNA index (DI; 1.16) were defined. Four time periods after diagnosis (years 1, 2, 3, and 4 and 5 combined) were selected for the study of prognostic significance over time. The cut-off date for analysis was April 1996. RESULTS A total of 3,717 children (2,010 boys and 1,707 girls) were included in the outcome analysis. No major differences between the sexes were observed in age, duration of symptoms before registration, WBC count, hemoglobin level, platelet count, ploidy, presence of CNS disease at diagnosis, or induction failure rate. Event-free survival (EFS) differences between sexes became significantly different from 2 years following diagnosis. At 5 years, in all subsets analyzed, boys fared worse than girls, although not all differences were statistically significant. Major sex differences in EFS were observed in older children (10 to 22 years), in patients with intermediate WBC counts (10 to 50 x 10(9)/ L), and in children who fit both of these subgroups, in whom the 2-year EFS was almost 20% higher in girls than in boys, reaching a 38% difference at 5 years. CONCLUSION This study shows an outcome interaction among sex, time, and commonly used prognostic variables. The important sex difference observed at 2 and 5 years suggests that more intensive consolidation and/or maintenance therapy in some boys with B-precursor ALL should be investigated.

Ploidy of lymphoblasts is the strongest predictor of treatment outcome in B-progenitor cell acute lymphoblastic leukemia of childhood: a Pediatric Oncology Group study.

1992 ◽  
Vol 10 (4) ◽  
pp. 606-613 ◽  
Author(s):  
R Trueworthy ◽  
J Shuster ◽  
T Look ◽  
W Crist ◽  
M Borowitz ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Pediatric Oncology ◽  
Progenitor Cell ◽  
Leukocyte Count ◽  
Lymphoblastic Leukemia ◽  
Oncology Group ◽  
Dna Index ◽  
Pediatric Oncology Group ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Diploid Cells

PURPOSE Using the technique of recursive partitioning and amalgamation analysis with verification, the Pediatric Oncology Group (POG) investigated the independent prognostic significance of previously published prognostic factors significantly associated with event-free survival (EFS) in B-progenitor cell acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS Age, leukocyte count, sex, immunophenotype (expression of cytoplasmic immunoglobulin [Ig] and of surface antigens CD10 and CD34), and DNA index (ratio of the flow cytometry-determined DNA content of leukemia cells to that of normal diploid cells) were the variables used in the evaluation of four antimetabolite-based chemotherapy regimens in 1,535 children with the newly diagnosed B-progenitor cell ALL between February 1986 and May 1990. RESULTS There were three subgroups at widely different risks of treatment failure. A DNA index greater than 1.16 was the most prognostic feature. The final prognostic subgrouping was as follows: (1) DNA index greater than 1.16; (2) DNA index less than or equal to 1.16, age less than 11.0 years, and leukocyte count less than 50 x 10(9)/L; and (3) DNA index less than or equal to 1.16, (age greater than 11.0 years, and/or leukocyte count greater than 50 x 10(9)/L). These groups made up 20%, 53%, and 27% of the patients and had 4-year EFS rates (SE) of 90.1% (6.3%), 80.5% (5.1%), and 50.4% (7.6%), respectively. CONCLUSIONS Use of the DNA index, leukocyte count, and age--data that are relatively inexpensive and simple to obtain--may be sufficient to stratify patients with B-progenitor cell ALL for risk-directed therapy. Patients at an extremely low risk of failing therapy (approximately 20% of cases in this study) can thus be identified and spared the toxic short-term and late effects of more intensive therapies that may be needed for children with less favorable clinical and biologic features.

scholarly journals Frequency and prognostic significance of HRX rearrangements in infant acute lymphoblastic leukemia: a Pediatric Oncology Group study

Blood ◽  
1994 ◽  
Vol 84 (2) ◽  
pp. 570-573 ◽  
Author(s):  
JE Rubnitz ◽  
MP Link ◽  
JJ Shuster ◽  
AJ Carroll ◽  
N Hakami ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Pediatric Oncology ◽  
Lymphoblastic Leukemia ◽  
Cdna Probe ◽  
Prognostic Significance ◽  
High Rate ◽  
Chromosome Band ◽  
Oncology Group ◽  
Molecular Abnormalities ◽  
Pediatric Oncology Group

Abstract chromosome band 11q23, the location of the HRX gene, is a site of recurrent translocations in human malignancies. Infants with acute lymphoblastic leukemia (ALL) commonly have 11q23 translocations and have an especially poor prognosis despite intensive chemotherapy. We analyzed 96 cases of infant ALL treated on three consecutive Pediatric Oncology Group protocols to determine the frequency and prognostic significance of molecular rearrangements of HRX. Overall, 78 cases (81%) had HRX rearrangements detected by Southern blot analysis performed with a single HRX cDNA probe, whereas 18 cases (19%) had germline HRX. Of the 78 cases with HRX rearrangements, only 50 had abnormalities of 11q23 detected cytogenetically. Molecular abnormalities of HRX were associated with early treatment failure and a very poor outcome. Estimated event-free survival for patients with HRX rearrangements was 19% (SE, 7%) at 3 years, compared with 46% (SE, 17%) for patients with germline HRX (P = .033 by the two-sided logrank test). Therefore, infants with ALL and molecular abnormalities of HRX represent a group with an extremely high rate of failure who clearly need innovative or experimental treatment. Furthermore, cytogenetic analysis alone failed to detected 36% of HRX rearrangements, suggesting that molecular analysis be performed on all infants with ALL to identify this group of high-risk patients.

scholarly journals Prognostic Significance of Fluorescence Intensity of Surface Marker Expression in Childhood B-Precursor Acute Lymphoblastic Leukemia. A Pediatric Oncology Group Study

Blood ◽  
1997 ◽  
Vol 89 (11) ◽  
pp. 3960-3966 ◽  
Author(s):  
Michael J. Borowitz ◽  
Jonathan Shuster ◽  
Andrew J. Carroll ◽  
Michael Nash ◽  
A. Thomas Look ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Lymphoblastic Leukemia ◽  
Pediatric Oncology ◽  
Fluorescence Intensity ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Antigen Expression ◽  
Oncology Group ◽  
Color Flow ◽  
Pediatric Oncology Group

Abstract This report describes the prognostic significance of the intensity of surface membrane antigen expression in a series of 1,231 children older than 1 year with newly diagnosed B-precursor acute lymphoblastic leukemia (ALL) treated on Pediatric Oncology Group (POG) treatment protocols. All patients had dual-color flow cytometric immunophenotyping performed at a central reference laboratory with a standard panel of monoclonal antibodies. The flow cytometers used in the study were calibrated with a standard fluorescence microparticle that permitted conversion of relative fluorescence channels to standard units of mean equivalents of soluble fluorochrome (MESF). In univariate analysis, fluorescence intensity of CD45 and CD20 was significantly associated with event-free survival (EFS), whereas other markers showed no significant correlation with outcome. Patients whose blasts were greater than the 75th percentile of intensity for CD45 (corresponding to 18,000 MESF units with CD45-FITC, or about 8% of the intensity of normal lymphocytes) fared significantly worse than those with lower-density CD45, and those whose blasts were greater than the 25th percentile of intensity for CD20 (corresponding to 17,900 MESF units with CD20-PE) had a poorer EFS. The intensity of both CD45 and CD20 was independently correlated with outcome. There was no significant correlation between intensity of expression of either antigen and traditional clinical risk factors, ploidy, or t(9; 22) or t(1; 19). All patients with t(4; 11) had CD45 intensity greater than the 75th percentile, but CD45 intensity retained its prognostic significance after adjusting for t(4; 11). In multivariate analysis, both CD45 intensity greater than the 75th percentile and CD20 intensity greater than the 25th percentile were significantly correlated with poor outcome independently of previously reported poor prognostic factors including National Cancer Institute (NCI) risk group, ploidy, trisomies of 4 and 10, and adverse translocations including t(1; 19), t(9; 22), and t(4; 11). We conclude that in childhood B-precursor ALL, the intensity of expression of CD20 and CD45 provides prognostic information not available from simple consideration of antigen expression as positive or negative, and adds to that obtained from traditional clinical and biologic risk factors.

Treatment of occult or late overt testicular relapse in children with acute lymphoblastic leukemia: a Pediatric Oncology Group study.

1992 ◽  
Vol 10 (4) ◽  
pp. 624-630 ◽  
Author(s):  
M M Wofford ◽  
S D Smith ◽  
J J Shuster ◽  
W Johnson ◽  
G R Buchanan ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Pediatric Oncology ◽  
Lymphoblastic Leukemia ◽  
Oncology Group ◽  
Rank Analysis ◽  
Continuation Therapy ◽  
Significant Difference ◽  
Occult Disease ◽  
Pediatric Oncology Group ◽  
Wbc Count

PURPOSE The Pediatric Oncology Group (POG) designed a randomized two-arm protocol (8304) to improve the survival of children with acute lymphoblastic leukemia (ALL) who experience an isolated testicular relapse and to evaluate the efficacy of teniposide (VM-26) and doxorubicin as intensification agents during second remission. The outcome and toxicity observed in 80 patients with isolated testicular leukemia treated on POG 8304 are presented. PATIENTS AND METHODS The following are common features of POG 8304: (1) remission reinduction therapy with vincristine, prednisone, and doxorubicin; (2) bilateral testicular irradiation (2,600 cGy) during reinduction therapy; (3) CNS prophylaxis with intrathecal hydrocortisone, methotrexate (MTX), and cytarabine (Ara-C); and (4) continuation therapy (for 80 weeks) with alternating 6-week cycles of oral mercaptopurine (6-MP)/MTX and intravenous vincristine and cyclophosphamide. Treatment differences consisted of pulses (administered every 7 weeks) of either prednisone and doxorubicin (arm 1) or VM-26 and Ara-C (arm 2) during continuation therapy and a 4-week late intensification phase with either vincristine, prednisone, and doxorubicin (arm 1) or VM-26 and Ara-C (arm 2). RESULTS Fifty-five boys with ALL had isolated microscopic testicular leukemia detected by an elective biopsy at completion of initial treatment, and 25 had a late (greater than or equal to 6 months off-therapy) isolated overt testicular relapse. All patients with overt testicular leukemia attained a second clinical remission, and no patient with microscopic testicular leukemia progressed during reinduction. Of 42 patients on arm 1, 11 have relapsed compared with 18 of 38 patients on arm 2 (log-rank analysis, P = .22), indicating no significant difference between an anthracycline and an epipodophyllotoxin-Ara-C combination in the treatment of testicular leukemia. The overall 4-year event-free survival (EFS) among boys with occult testicular relapse was 53% +/- 8%. Age greater than 10 years at initial diagnosis, a WBC count greater than 50,000/microL at diagnosis, and black race were associated with a worse outcome. The 4-year EFS for boys with a late overt testicular relapse was 84% +/- 10%, and these patients fared significantly better than patients with occult disease (P = .007). CONCLUSION The treatment approach reported here can secure a prolonged second remission in many patients with occult or late overt testicular leukemia.

scholarly journals Frequency and prognostic significance of HRX rearrangements in infant acute lymphoblastic leukemia: a Pediatric Oncology Group study

Blood ◽  
1994 ◽  
Vol 84 (2) ◽  
pp. 570-573 ◽  
Author(s):  
JE Rubnitz ◽  
MP Link ◽  
JJ Shuster ◽  
AJ Carroll ◽  
N Hakami ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Pediatric Oncology ◽  
Lymphoblastic Leukemia ◽  
Cdna Probe ◽  
Prognostic Significance ◽  
High Rate ◽  
Chromosome Band ◽  
Oncology Group ◽  
Molecular Abnormalities ◽  
Pediatric Oncology Group

chromosome band 11q23, the location of the HRX gene, is a site of recurrent translocations in human malignancies. Infants with acute lymphoblastic leukemia (ALL) commonly have 11q23 translocations and have an especially poor prognosis despite intensive chemotherapy. We analyzed 96 cases of infant ALL treated on three consecutive Pediatric Oncology Group protocols to determine the frequency and prognostic significance of molecular rearrangements of HRX. Overall, 78 cases (81%) had HRX rearrangements detected by Southern blot analysis performed with a single HRX cDNA probe, whereas 18 cases (19%) had germline HRX. Of the 78 cases with HRX rearrangements, only 50 had abnormalities of 11q23 detected cytogenetically. Molecular abnormalities of HRX were associated with early treatment failure and a very poor outcome. Estimated event-free survival for patients with HRX rearrangements was 19% (SE, 7%) at 3 years, compared with 46% (SE, 17%) for patients with germline HRX (P = .033 by the two-sided logrank test). Therefore, infants with ALL and molecular abnormalities of HRX represent a group with an extremely high rate of failure who clearly need innovative or experimental treatment. Furthermore, cytogenetic analysis alone failed to detected 36% of HRX rearrangements, suggesting that molecular analysis be performed on all infants with ALL to identify this group of high-risk patients.

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