scholarly journals Antimetabolite therapy for lesser-risk B-lineage acute lymphoblastic leukemia of childhood: a report from Children's Oncology Group Study P9201

Blood ◽  
2007 ◽  
Vol 110 (4) ◽  
pp. 1105-1111 ◽  
Author(s):  
Allen R. Chauvenet ◽  
Paul L. Martin ◽  
Meenakshi Devidas ◽  
Stephen B. Linda ◽  
Beverly A. Bell ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Statistical Significance ◽  
Great Majority ◽  
Intrathecal Chemotherapy ◽  
Oncology Group ◽  
Dna Index ◽  
Free Survival ◽  
Pediatric Oncology Group ◽  
B Lineage

AbstractPediatric Oncology Group (POG) protocol 9201 enrolled children with lesser-risk B-lineage acute lymphoblastic leukemia (ALL) defined by age (1-9), white blood cell count (WBC) less than 50 × 109/L (50 000/μL), DNA findings of trisomies 4 and 10 (or DNA index > 1.16), and lack of overt central nervous system (CNS) leukemia. After vincristine, prednisone, and asparaginase induction, 650 of 653 eligible patients attained remission (3 induction deaths) and received 6 courses of intravenous methotrexate (1 g/m2) with daily mercaptopurine. Weekly intramuscular methotrexate was added during maintenance; pulses of vincristine and prednisone were administered with periodic intrathecal chemotherapy. Treatment duration was 2.5 years. No alkylators, epipodophylotoxins, anthracyclines, or radiation were given. The 6-year event-free survival (EFS) was 86.6% with overall survival (OS) of 97.2%. Patients with less than 5% marrow blasts on induction day 15 had superior EFS. A difference not reaching conventional statistical significance (P = .068) was noted for superior outcomes in patients with trisomies of chromosomes 4 and 10 versus those lacking double trisomies. Sex, ethnicity, CNS status, and WBC were not predictive. This indicates the great majority of children with lesser-risk B-lineage ALL are curable without agents with substantial late effects.

scholarly journals Accumulation of high levels of methotrexate polyglutamates in lymphoblasts from children with hyperdiploid (greater than 50 chromosomes) B-lineage acute lymphoblastic leukemia: a Pediatric Oncology Group study

Blood ◽  
1992 ◽  
Vol 80 (5) ◽  
pp. 1316-1323 ◽  
Author(s):  
VM Whitehead ◽  
MJ Vuchich ◽  
SJ Lauer ◽  
D Mahoney ◽  
AJ Carroll ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Primary Component ◽  
Chromosome 9 ◽  
Dna Index ◽  
Free Survival ◽  
Continuation Therapy ◽  
Pediatric Oncology Group ◽  
B Lineage

Abstract Hyperdiploidy (greater than 50 chromosomes, or a DNA index greater than 1.16) confers a favorable prognosis in B-lineage acute lymphoblastic leukemia of childhood. Children with B-lineage acute lymphoblastic leukemia whose lymphoblasts at diagnosis accumulate high levels of methotrexate (MTX) and MTX polyglutamates (MTXPGs) in vitro experience a better event-free survival than those whose lymphoblasts do not (Blood 76:44, 1990). Lymphoblasts from 13 children with hyperdiploidy (greater than 50 chromosomes) accumulated high levels of MTX-PGs (1,095 and 571 to 2,346 pmol/10(9) cells [median and 25% to 75% intraquartile range]). These levels were higher than those in B-lineage lymphoblasts from 19 children with other aneuploidy (326 and 159 to 775 pmol/10(9) cells) and 15 children with diploidy (393 and 204 to 571 pmol/10(9) cells) (P = .0015). Chromosomal trisomies in hyperdiploid cases were highly nonrandom. Chromosome 9 was not one of the chromosomes involved in trisomies, even though this chromosome contains the gene for folate polyglutamate synthetase, which is the enzyme required for MTXPG synthesis. The correlation between MTXPG level and percentage of S- phase cells was weak, suggesting that increased levels of MTXPGs could not be attributed to elevated proportions of cells in active DNA synthesis. The ability of hyperdiploid lymphoblasts to accumulate high levels of MTXPGs may increase their sensitivity to MTX cytotoxicity, accounting in part for the improved outlook for hyperdiploid patients treated with regimens that emphasize MTX as a primary component of continuation therapy.

scholarly journals Accumulation of high levels of methotrexate polyglutamates in lymphoblasts from children with hyperdiploid (greater than 50 chromosomes) B-lineage acute lymphoblastic leukemia: a Pediatric Oncology Group study

Blood ◽  
1992 ◽  
Vol 80 (5) ◽  
pp. 1316-1323 ◽  
Author(s):  
VM Whitehead ◽  
MJ Vuchich ◽  
SJ Lauer ◽  
D Mahoney ◽  
AJ Carroll ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Primary Component ◽  
Chromosome 9 ◽  
Dna Index ◽  
Free Survival ◽  
Continuation Therapy ◽  
Pediatric Oncology Group ◽  
B Lineage

Hyperdiploidy (greater than 50 chromosomes, or a DNA index greater than 1.16) confers a favorable prognosis in B-lineage acute lymphoblastic leukemia of childhood. Children with B-lineage acute lymphoblastic leukemia whose lymphoblasts at diagnosis accumulate high levels of methotrexate (MTX) and MTX polyglutamates (MTXPGs) in vitro experience a better event-free survival than those whose lymphoblasts do not (Blood 76:44, 1990). Lymphoblasts from 13 children with hyperdiploidy (greater than 50 chromosomes) accumulated high levels of MTX-PGs (1,095 and 571 to 2,346 pmol/10(9) cells [median and 25% to 75% intraquartile range]). These levels were higher than those in B-lineage lymphoblasts from 19 children with other aneuploidy (326 and 159 to 775 pmol/10(9) cells) and 15 children with diploidy (393 and 204 to 571 pmol/10(9) cells) (P = .0015). Chromosomal trisomies in hyperdiploid cases were highly nonrandom. Chromosome 9 was not one of the chromosomes involved in trisomies, even though this chromosome contains the gene for folate polyglutamate synthetase, which is the enzyme required for MTXPG synthesis. The correlation between MTXPG level and percentage of S- phase cells was weak, suggesting that increased levels of MTXPGs could not be attributed to elevated proportions of cells in active DNA synthesis. The ability of hyperdiploid lymphoblasts to accumulate high levels of MTXPGs may increase their sensitivity to MTX cytotoxicity, accounting in part for the improved outlook for hyperdiploid patients treated with regimens that emphasize MTX as a primary component of continuation therapy.

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 Treatment of late bone marrow relapse in children with acute lymphoblastic leukemia: a Pediatric Oncology Group study

Blood ◽  
1993 ◽  
Vol 81 (3) ◽  
pp. 602-609 ◽  
Author(s):  
PD Sadowitz ◽  
SD Smith ◽  
J Shuster ◽  
MD Wharam ◽  
GR Buchanan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Pediatric Oncology ◽  
Lymphoblastic Leukemia ◽  
Randomized Study ◽  
Intrathecal Chemotherapy ◽  
Primary Therapy ◽  
Oncology Group ◽  
Continuation Therapy ◽  
Pediatric Oncology Group

Abstract Children with acute lymphoblastic leukemia (ALL) who have completed 2.5 to 3 years of initial chemotherapy have an off-therapy relapse rate of approximately 20%. In an attempt to improve the survival of children with a late bone marrow (BM) relapse (ie, occurring greater than 6 months after cessation of primary therapy), the Pediatric Oncology Group designed a randomized study to compare the efficacy of doxorubicin/prednisone and cytarabine/teniposide in a multidrug retreatment chemotherapy program. Treatment consisted of remission reinduction with vincristine, prednisone, and doxorubicin, central nervous system prophylaxis with triple intrathecal chemotherapy, and continuation therapy (for 132 weeks) with alternating cycles of oral 6- mercaptopurine/methotrexate and intravenous vincristine/cyclophosphamide. Patients received intermittent courses of either prednisone/doxorubicin (regimen 1) or teniposide/cytarabine (regimen 2) during continuation therapy and a late intensification phase with either vincristine, prednisone, and doxorubicin (regimen 1) or teniposide and cytarabine (regimen 2). One hundred two of 105 evaluable patients (97%) achieved a second complete remission. Twenty- eight of 50 patients on regimen 1 have failed compared with 28 or 52 patients on regimen 2 (log-rank analysis, P = .68), indicating that this trial was inconclusive as to which treatment regimen was superior. The overall 4-year event-free survival for children with a late BM relapse was 37% +/- 6%. Age less than 10 years at initial diagnosis (P < or = .001), white blood cell count less than 5,000/microL at relapse (P = .036) and duration of first remission greater than 54 months (P = .039) were independently associated with a more favorable outcome. While the randomized trial was inconclusive, prolonged second complete remissions were secured in more than one-third of children with a late BM relapse of ALL. The prognostic factors identified may help select children with a late BM relapse who can be successfully retreated with chemotherapy alone.

New recurring cytogenetic abnormalities and association of blast cell karyotypes with prognosis in childhood T-cell acute lymphoblastic leukemia: a Pediatric Oncology Group report of 343 cases

Blood ◽  
2000 ◽  
Vol 96 (7) ◽  
pp. 2543-2549 ◽  
Author(s):  
Nancy R. Schneider ◽  
Andrew J. Carroll ◽  
Jonathan J. Shuster ◽  
D. Jeanette Pullen ◽  
Michael P. Link ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Pediatric Oncology ◽  
Lymphoblastic Leukemia ◽  
Cell Lineage ◽  
Blast Cell ◽  
Derivative Chromosome ◽  
Oncology Group ◽  
Pediatric Oncology Group ◽  
B Lineage

Abstract To further define the cytogenetic differences between B-cell lineage (B-lineage) acute lymphoblastic leukemia (ALL) and T-cell lineage ALL (T-ALL) and to determine the prognostic value of cytogenetics in childhood T-ALL, the blast cell karyotypes of 343 cases of pediatric T-ALL, the largest series reported to date, were evaluated. Cytogenetics were performed in a single central laboratory, and the children were treated using a single Pediatric Oncology Group protocol. Clear differences between the karyotypic characteristics of B-lineage ALL and T-ALL were confirmed. This study suggests that there may be survival differences associated with some T-ALL blast cell karyotypes. Better survival is associated with only normal karyotypes and with t(10;14) (translocation of chromosomes 10 and 14); worse survival is associated with the presence of any derivative chromosome. Two new recurring chromosome aberrations previously not reported in T-ALL were found: del(1)(p22) and t(8;12)(q13;p13). Ten aberrations found in this series, which were reported only once previously in T-ALL, can now be considered recurring abnormalities in T-ALL. All 12 of these new recurring aberrations are targets for discovery and characterization of new genes that are important in T-cell development and leukemogenesis.

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.

scholarly journals Prospective Analysis of TEL Gene Rearrangements in Childhood Acute Lymphoblastic Leukemia: A Children's Oncology Group Study

2008 ◽  
Vol 26 (13) ◽  
pp. 2186-2191 ◽  
Author(s):  
Jeffrey E. Rubnitz ◽  
David Wichlan ◽  
Meenakshi Devidas ◽  
Jonathan Shuster ◽  
Stephen B. Linda ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Oncology Group ◽  
Free Survival ◽  
Pediatric Oncology Group ◽  
Gene Status ◽  
Group Sex ◽  
Cure Rates ◽  
Standard Risk

Purpose To prospectively determine the prognostic significance of the TEL-AML1 fusion in children with acute lymphoblastic leukemia (ALL). Patients and Methods TEL gene status was determined for 926 patients with B-precursor ALL enrolled on the Pediatric Oncology Group ALinC 16 trials and patients were observed for a median time of 8 years. Results Rearrangements of the TEL gene were detected in 244 patients (26%). The estimated 5-year event-free survival rate (± SE) for patients with TEL rearrangements was 86% ± 2%, compared with 72% ± 2% for those with germline TEL (P < .0001). TEL rearrangements were associated with a superior outcome among patients with standard-risk ALL, high-risk ALL, and rapid early responses to therapy. In a multivariate analysis that included risk group, sex, and day 15 marrow status, TEL status was an independent predictor of outcome (P = .0002). Conclusion We conclude that TEL gene status should be incorporated into risk classification schemes and suggest that patients who have standard-risk features, the TEL-AML1 fusion, and rapid early responses to therapy, should be treated with antimetabolite-based therapy designed to maintain their high cure rates and avoid late effects.

Extended triple intrathecal chemotherapy trial for prevention of CNS relapse in good-risk and poor-risk patients with B-progenitor acute lymphoblastic leukemia: a Pediatric Oncology Group study.

1993 ◽  
Vol 11 (5) ◽  
pp. 839-849 ◽  
Author(s):  
J Pullen ◽  
J Boyett ◽  
J Shuster ◽  
W Crist ◽  
V Land ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Pediatric Oncology ◽  
Lymphoblastic Leukemia ◽  
Intrathecal Chemotherapy ◽  
Oncology Group ◽  
Poor Risk ◽  
Cns Relapse ◽  
Risk Patients ◽  
Pediatric Oncology Group ◽  
Good Risk

PURPOSE The Pediatric Oncology Group (POG) acute leukemia in childhood (ALinC) 13 study tested two treatment regimens that used different CNS chemoprophylaxis for children older than 12 months with non-T, non-B acute lymphoblastic leukemia (ALL) and with no demonstrable CNS disease at diagnosis. PATIENTS AND METHODS With the first regimen, standard (S), six injections of triple intrathecal chemotherapy (TIC), consisting of methotrexate (MTX), hydrocortisone (HC), and cytarabine (ara-C), were administered during intensification treatment and at every-8-week intervals throughout the maintenance phase for 17 additional doses. The second regimen, standard and MTX pulses (SAM), also specified six TICs during intensification, but substituted every-8-week pulses of intermediate-dose parenteral methotrexate (IDM; 1 g/m2) for the 17 maintenance TIC injections, with a low-dose intrathecal (IT) MTX boost administered with the first four maintenance IDM pulses. Otherwise, systemic therapy on regimen SAM was identical to regimen S. There were 1,152 patients randomized to the S and SAM regimens after stratification by risk group (age/leukocyte count) and immunophenotype. RESULTS The 5-year probabilities (+/- SE) of an isolated CNS relapse were regimen S: good risk (n = 381), 2.8% +/- 1.3%; poor risk (n = 196), 7.7% +/- 3.2%; good + poor risk (n = 577), 4.7% +/- 1.5%; regimen SAM: good risk (n = 388), 9.6% +/- 2.2%; poor risk (n = 187), 12.7% +/- 4.2%; good + poor risk (n = 575), 10.9% +/- 2.2%. In poor-risk patients, approximately one third of the isolated CNS relapses occurred before preventive CNS therapy was begun at week 9. Hence, regimen S has provided better CNS preventive therapy for both good- and poor-risk patients (P < .001 overall). The difference is statistically significant for good-risk patients (P < .001), but not for poor-risk patients (P = .20). Neither treatment has shown a significant advantage in terms of general outcome. CONCLUSION TIC injections extended throughout the intensification and maintenance periods are superior to IDM pulses for prevention of CNS leukemia. Our results with TIC seem comparable with those achieved with other contemporary methods of CNS preventative therapy. Thus, extended TIC affords a reasonable alternative to CNS irradiation plus upfront IT MTX for patients with B-progenitor ALL.

scholarly journals Case-Control Study Suggests a Favorable Impact of TEL Rearrangement in Patients With B-Lineage Acute Lymphoblastic Leukemia Treated With Antimetabolite-Based Therapy: A Pediatric Oncology Group Study

Blood ◽  
1997 ◽  
Vol 89 (4) ◽  
pp. 1143-1146 ◽  
Author(s):  
Jeffrey E. Rubnitz ◽  
Jonathan J. Shuster ◽  
Vita J. Land ◽  
Michael P. Link ◽  
D. Jeanette Pullen ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Pediatric Oncology ◽  
Leukocyte Count ◽  
Lymphoblastic Leukemia ◽  
Intensive Therapy ◽  
Oncology Group ◽  
Pediatric Oncology Group ◽  
B Lineage ◽  
And Gender ◽  
Gene Status

Abstract TEL gene rearrangement is the most common genetic lesion in pediatric acute lymphoblastic leukemia (ALL), occurring in about 25% of B-lineage cases. We previously showed that, among patients treated on St Jude protocols, TEL rearrangement independently conferred an excellent prognosis. To extend these results to patients treated with antimetabolite-based therapy, we performed Southern blot analysis to determine the TEL gene status of 104 cases of B-lineage ALL treated on Pediatric Oncology Group 8602, matched on age, gender, and leukocyte count. There were 52 failures among the 77 patients with germline TEL, compared with only 8 failures among 27 patients in the rearranged group. Based on a two-sided logistic regression analysis, stratified for age (subdivided at 10 years), leukocyte count (subdivided at 50,000), and gender, the estimated odds of failing by 4 years in the germline TEL group is 5.4 times that of the rearranged TEL group, with 95% confidence from 1.9 to 15.6, two-sided P = .0009. Thus, the presence of a rearranged TEL gene is also associated with an improved survival among patients treated with antimetabolite-based therapy. Our results indicate that all newly diagnosed ALL patients should be screened for TEL gene rearrangements and suggest that these patients are candidates for less intensive therapy.

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