Infectious complications in children with acute lymphoblastic leukemia treated with the Taiwan Pediatric Oncology Group protocol: A 16-year tertiary single-institution experience

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.

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

Blood ◽

10.1182/blood.v81.3.602.602 ◽

1993 ◽

Vol 81 (3) ◽

pp. 602-609 ◽

Cited By ~ 54

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.

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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 ◽

10.1182/blood.v96.7.2543 ◽

2000 ◽

Vol 96 (7) ◽

pp. 2543-2549 ◽

Cited By ~ 76

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.

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Treatment of CNS relapse in children with acute lymphoblastic leukemia: A Pediatric Oncology Group study.

Journal of Clinical Oncology ◽

10.1200/jco.1993.11.2.271 ◽

1993 ◽

Vol 11 (2) ◽

pp. 271-278 ◽

Cited By ~ 40

Author(s):

N J Winick ◽

S D Smith ◽

J Shuster ◽

S Lauer ◽

M D Wharam ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Pediatric Oncology ◽

Lymphoblastic Leukemia ◽

Treatment Protocol ◽

Intrathecal Therapy ◽

Oncology Group ◽

Treatment Comparison ◽

Cns Relapse ◽

Cranial Radiation ◽

Pediatric Oncology Group

PURPOSE To assess the efficacy and toxicity of chemotherapy and cranial radiation for the treatment of children with acute lymphoblastic leukemia (ALL) following first isolated CNS relapse. PATIENTS AND METHODS One hundred twenty children were treated on Pediatric Oncology Group (POG) protocol 8304. All children had received prophylactic CNS therapy during their initial treatment. The treatment protocol included a four-drug reinduction and six weekly doses of triple intrathecal therapy (TIT). Cranial radiation, 24 Gy, was followed by monthly TIT. Systemic consolidation and maintenance therapy included 6-week cycles of mercaptopurine/methotrexate (6MP/MTX) and vincristine/cyclophosphamide (VCR/CTX), with randomization to intervening pulses of prednisone/doxorubicin (PDN/DOX) or teniposide (VM26)/cytarabine (Ara-C) for a total of 88 weeks. RESULTS All 120 patients achieved a second complete remission. There have been 61 protocol failures. Thirty-five patients had a bone marrow relapse, four with simultaneous CNS involvement and one with concurrent testicular leukemia. Thirteen patients had a second isolated CNS relapse, 10 a testicular relapse, and two relapsed in other sites. One patient died in remission. Overall event-free survival (EFS) at 4 years was 46% +/- 7%. The toxicity associated with this protocol was minimal except for leukoencephalopathy, which occurred in 20 (17%) patients. The treatment comparison between VM26/Ara-C or PDN/DOX pulses showed a trend toward superior EFS (P = .12) in favor of VM-26/Ara-C. CONCLUSION To date, this represents the largest series of patients with ALL treated uniformly for an isolated CNS relapse. Since marrow relapse remains the primary site of failure, future protocols must intensify systemic therapy.

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Philadelphia chromosome and monosomy 7 in childhood acute lymphoblastic leukemia: a Pediatric Oncology Group study

Blood ◽

10.1182/blood.v77.5.1050.1050 ◽

1991 ◽

Vol 77 (5) ◽

pp. 1050-1056 ◽

Cited By ~ 47

Author(s):

C Russo ◽

A Carroll ◽

S Kohler ◽

M Borowitz ◽

M Amylon ◽

...

Keyword(s):

Bone Marrow ◽

Acute Lymphoblastic Leukemia ◽

Chronic Myelogenous Leukemia ◽

Pediatric Oncology ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Myelogenous Leukemia ◽

Oncology Group ◽

Monosomy 7 ◽

Pediatric Oncology Group

Abstract During an 8-year period, 3,638 children from institutions of the Pediatric Oncology Group (POG) were diagnosed with acute lymphoblastic leukemia (ALL). Fifty-seven patients had Philadelphia chromosome- positive (Ph1) ALL. Blast cells obtained at diagnosis from 13 of these 57 cases (23%) were also found to have partial or complete monosomy 7 (- 7). This subgroup of children with Ph1/-7 ALL was comprised primarily of older males with early B-lineage ALL. Bone marrow specimens from six Ph1/-7 patients were studied further using the polymerase chain reaction and primers that flank the ALL, and chronic myelogenous leukemia breakpoints to determine the molecular characteristic of the 9;22 translocation. Rearrangements were detected in RNA from bone marrow and/or peripheral blood cells of six patients, although four were in hematologic remission at the time of the analysis. Five cases showed the ALL breakpoint, while one child with Ph1/-7 showed the chronic myelogenous leukemia breakpoint. The induction failure rate was much higher in this subgroup (31%) as compared with Ph1-negative cases, and the projected duration of event-free survival reflected the aggressive nature of this subgroup because no children are projected to remain in remission at 2 years. ALL with both the 9;22 translocation and -7 appears to represent a unique and previously undescribed subgroup of childhood ALL associated with a particularly adverse outcome. Leukemic transformation in such patients may involve the interaction of a dominant oncogene (Ph1) and a tumor suppressor gene (- 7).

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

Journal of Clinical Oncology ◽

10.1200/jco.1998.16.8.2854 ◽

1998 ◽

Vol 16 (8) ◽

pp. 2854-2863 ◽

Cited By ~ 49

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.

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Poor prognosis of children with pre-B acute lymphoblastic leukemia is associated with the t(1;19)(q23;p13): a Pediatric Oncology Group study

Blood ◽

10.1182/blood.v76.1.117.117 ◽

1990 ◽

Vol 76 (1) ◽

pp. 117-122 ◽

Cited By ~ 157

Author(s):

WM Crist ◽

AJ Carroll ◽

JJ Shuster ◽

FG Behm ◽

M Whitehead ◽

...

Keyword(s):

Treatment Outcome ◽

Acute Lymphoblastic Leukemia ◽

Pediatric Oncology ◽

Poor Prognosis ◽

Lymphoblastic Leukemia ◽

Chromosomal Translocations ◽

Oncology Group ◽

Childhood All ◽

Pediatric Oncology Group ◽

Worse Prognosis

Abstract The prognostic significance of chromosomal translocations, particularly t(1;19) (q23;p13), was evaluated in children with pre-B and early pre-B acute lymphoblastic leukemia (ALL). Patients were treated on a risk- based protocol of the Pediatric Oncology Group (POG) between February 1986 and May 1989. An abnormal clone was detected in 46% (130 of 285) of pre-B cases and 56% (380 of 679) of early pre-B cases. Translocation of any type was associated with a worse treatment outcome than other karyotypic abnormalities: 15 of 66 versus 3 of 64 failed therapy in the pre-B group (P = .001), and 37 of 141 versus 23 of 239 failed in the early pre-B group (P less than .001). The t(1;19) (q23;p13) occurred significantly more often in cases of pre-B ALL with a clonal abnormality than in early pre-B ALL cases (29 of 130 v 5 of 380, P less than .001). Among the 285 pre-B cases in which bone marrow was studied cytogenetically, those with t(1;19) had a significantly worse treatment outcome than all others (11 of 29 v 27 of 256 have failed therapy, P less than .001). This difference is significant (P less than .001) after adjustment for leukocyte count, age, and other relevant features. Cases with the t(1;19) also had a worse prognosis than pre-B patients with other translocations (4 of 37 have failed, P less than .01) or with any other karyotypic abnormality (7 of 101 have failed, P less than .001). We conclude that chromosomal translocations confer a worse prognosis for non-T, non-B-cell childhood ALL, and that the t(1;19) is largely responsible for the poor prognosis of the pre-B subgroup.

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A Comparison of Hepatotoxicity and Neutropenia in Children Given Oral Mercaptopurine on a Twice-Daily Versus Once-Daily Dosing Schedule for Acute Lymphoblastic Leukemia: A Pediatric Oncology Group Study.

Blood ◽

10.1182/blood.v104.11.994.994 ◽

2004 ◽

Vol 104 (11) ◽

pp. 994-994

Author(s):

R. Chesley ◽

B. A. Bell ◽

M. Devidas ◽

B. Bostrom ◽

G. Erdmann ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Pediatric Oncology ◽

Lymphoblastic Leukemia ◽

Phase Iii ◽

Oncology Group ◽

Dose Frequency ◽

Phase Dependence ◽

Continuation Therapy ◽

Pediatric Oncology Group ◽

Grade 3

Abstract Pediatric Oncology Group (POG) protocol 9605, a phase III study of standard risk acute lymphoblastic leukemia (ALL), was designed in part to compare daily (QD) versus twice-daily (BID) mercaptopurine (MP) dosing during intensification and continuation therapy. 1082 patients were enrolled between 1996 and 1999. MP is an important antimetabolite in the treatment of ALL. Due to its S-phase dependence and short half-life, dosing frequency may be crucial to toxicity and/or efficacy. MP is converted into two major metabolites, 6-thioguanine (TGN) and 6-methylthioinosinic acid (mMP). Correlations of toxicity and dose frequency were tabulated. Red blood cell (RBC) TGN and mMP levels measured in a randomized subpopulation (226/1082 patients) on POG 9605 found markedly elevated mMP in the QD versus BID group (2020 versus 1275 ng/8x108 RBC) with slightly higher levels of TGN in the QD group (42 versus 40 ng/8x108 RBC). Toxicity events occurring during treatment were recorded according to toxicity code, grade and week of therapy. Toxicity events for 1037/1082 patients were analyzed. For each toxicity, QD and BID groups were compared based on total number of events, number of individual patients, and average number of events per patient. A comparison of the incidence of neutropenia and hepatotoxicity between QD and BID groups became the focus. 518/1037 patients received 6MP 75 mg/m2 daily and 519/1037 patients received 6MP 37.5 mg/m2 twice daily. Decreased ANC were coded as grade 3 (0.5–0.9 x 103/mm3) or grade 4 (less than 0.5 x 103/mm3). Decreased WBC were coded as grade 3 (1.0–1.9 x 103/mm3) or grade 4 (less than 1.0 x 103/mm3). Elevated aminotransferase (ALT/AST) were coded as grade 3 (5.1–20 x normal) or grade 4 (greater than 20 x normal). For grade 4 neutropenia, the QD group had a significantly higher average number of events per patient than the BID group (4.67 versus 4.22, p=0.021). Also for grade 3 ALT/AST, the QD group had a significantly higher average number of events per patient than the BID group (2.40 versus 2.10, p=0.046). In previous studies, higher mMP levels were found to be correlated with elevated aminotransferases. The subpopulation (n=226/1082) data was analyzed to compare metabolite levels in patients who experienced various toxicities. In the QD arm, TGN was significantly elevated in those patients with grades 3 and 4 WBC (p=0.026) and grades 3 and 4 ANC (p=0.032). MMP was significantly elevated in those with grades 3 and 4 WBC (p=0.0066), grades 3 and 4 ANC (p=0.009) and grades 3 and 4 ALT/AST (p=0.0082). QD administration of 6MP is associated with increased levels of methylated metabolites, elevated ALT/AST and decreased ANC. Neutropenia correlates with elevations of both TGN and mMP. Hepatotoxicity correlates with elevations in mMP. Issues of adherence to dosing may also play a role. Implications for patient outcome await data maturation.

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