To assess the clinical heterogeneity among patients with acute lymphoblastic leukemia (ALL) and various 11q23 abnormalities, we analyzed data on 497 infants, children and young adults treated between 1983 and 1995 by 11 cooperative groups and single institutions. The substantial sample size allowed separate analyses according to age younger or older than 12 months for the various cytogenetic subsets. Infants with t(4;11) ALL had an especially dismal prognosis when their disease was characterized by a poor early response to prednisone (P=0.0005 for overall comparison; 5-year event-free survival (EFS), 0 vs 23±12% s.e. for those with good response), or age less than 3 months (P=0.0003, 5-year EFS, 5±5% vs 23.4±4% for those over 3 months). A poor prednisone response also appeared to confer a worse outcome for older children with t(4;11) ALL. Hematopoietic stem cell transplantation failed to improve outcome in either age group. Among patients with t(11;19) ALL, those with a T-lineage immunophenotype, who were all over 1 year of age, had a better outcome than patients over 1 year of age with B-lineage ALL (overall comparison, P=0.065; 5-year EFS, 88±13 vs 46±14%). In the heterogeneous subgroup with del(11)(q23), National Cancer Institute-Rome risk criteria based on age and leukocyte count had prognostic significance (P=0.04 for overall comparison; 5-year EFS, 64±8% (high risk) vs 83±6% (standard risk)). This study illustrates the marked clinical heterogeneity among and within subgroups of infants or older children with ALL and specific 11q23 abnormalities, and identifies patients at particularly high risk of failure who may benefit from innovative therapy.

PURPOSE:To study the pharmacokinetics and pharmacodynamics of once- versus twice-daily oral etoposide in children with relapsed or refractory acute lymphoblastic leukemia (ALL).PATIENTS AND METHODS:Fifty-eight patients were randomly assigned to etoposide at 50 mg/m(2)/d with once- versus twice-daily doses for 22 days. On day 8, vincristine, asparaginase, and dexamethasone were started. Etoposide pharmacokinetics and pharmacodynamics were studied for 47, 28, and 26 patients on day 1, 8, and 22, respectively, of remission reinduction therapy.RESULTS:Of 48 patients with pharmacokinetic data, 42 (87.5%) achieved complete remission, three (6.3%) failed to achieve remission, and three (6.3%) died during induction. Median etoposide day 8 area under concentration-time curve (AUC) and cumulative AUC tended to be greater (P =.06 and P =.07, respectively) in patients (n = 23) who achieved complete remission (24 and 522 micro mol/L x h, respectively) than in patients (n = 3) who did not (14 and 303 micro mol/L x h, respectively). Three of eight patients with plasma concentrations exceeding 1.7 micro M (1 micro g/mL) for more than 8 hours daily, compared with one of 20 patients with concentrations exceeding 1.7 micro M for <or= 8 hours daily, were unable to receive all 22 days of etoposide because of toxicity. There was no difference in the AUC at day 1 or day 8 with once- versus twice-daily doses (P =.55 and P =.86, respectively).CONCLUSION:A pharmacodynamic relationship exists between systemic etoposide exposure and response to therapy when oral etoposide is used as part of remission induction regimens for relapsed or refractory childhood ALL.

CONTEXT:Traumatic or bloody lumbar puncture (LP) reduces the diagnostic value of the procedure and may worsen the outcome of patients with acute lymphoblastic leukemia (ALL). Little is known about the risk factors for traumatic and bloody LP.OBJECTIVES:To determine the risk factors for traumatic and bloody LP.DESIGN, SETTING, AND PATIENTS:Retrospective cohort study of 956 consecutive patients with newly diagnosed childhood ALL who were treated at a pediatric cancer center between February 1984 and July 1998.INTERVENTIONS:All patients underwent a diagnostic LP followed by a median of 4 LPs to instill intrathecal chemotherapy.MAIN OUTCOME MEASURE:Traumatic LP was defined as an LP in which cerebrospinal fluid contained at least 10 red blood cells (RBCs) per microliter and bloody LP as one in which the cerebrospinal fluid contained at least 500 RBCs per microliter.RESULTS:Of the 5609 LPs evaluated, 1643 (29%) were traumatic and 581 (10%) were bloody. The estimated odds ratios (ORs) and 95% confidence intervals (CIs) for traumatic LP were 1.5 (95% CI, 1.2-1.8) for black vs white race, 2.3 (95% CI, 1.7-3.0) for age younger than 1 year vs 1 year or older, 1.4 (95% CI, 1.2-1.7) for early vs recent (dedicated procedure area and general anesthesia) treatment era, 1.5 (95% CI, 1.2-1.8) for platelet count of 100 x 10(3)/ microL or more vs less than 100 x 10(3 )/ microL, 10.8 (95% CI, 7.7-15.2) for short (1 day) vs longer (>15 days) interval since the previous LP, and 1.4 (95% CI, 1.1-1.8) for the least vs the most experienced practitioners. Analyses for bloody LP yielded similar results.CONCLUSIONS:The unmodifiable risk factors for traumatic and bloody LP include black race, age younger than 1 year, a traumatic or bloody previous LP performed within the past 2 weeks, and a previous LP performed when the platelet count was 50 x 10(3)/ microL or less. Modifiable risk factors include procedural factors reflected in treatment era, platelet count of 100 x 10(3)/ microL or less, an interval of 15 days or less between LPs, and a less experienced practitioner.

The purpose of this study was to determine the frequency with which magnetic resonance (MR) imaging detects avascular necrosis of the bone (AVNB) in children with acute lymphoblastic leukemia (ALL) or advanced-stage non-Hodgkin lymphoma (NHL) who receive prednisone during remission induction, reinduction, and maintenance chemotherapy; to assess the clinical significance of these findings; and to identify factors predictive of AVNB. We prospectively obtained MR imaging of the hips and knees of 116 children who had completed at least 1 year of treatment for ALL or advanced-stage NHL on identical prednisone-containing regimens between December 1991 and October 1994. MR imaging findings of AVNB were compared with clinical outcomes, and the effect of therapeutic and patient factors on the frequency of AVNB was analyzed. The MR imaging findings of 17 of the 116 participating patients were consistent with AVNB. The most common clinical manifestation was joint pain (11 patients). Only one patient had progressive joint deterioration that necessitated surgical replacement. Only age 10 years or more at the time of the primary diagnosis was significantly associated with the development of AVNB ( P = 0.004). MR imaging showed changes consistent with AVNB in approximately 15% of this patient population. However, most patients in this study who had MR imaging signs of AVNB did not experience progressive joint destruction, even with continued prednisone therapy. Therefore, the clinical usefulness of MR imaging as a screening tool for AVNB in this set of patients remains uncertain.

PURPOSE:Development of antibodies and hypersensitivity to asparaginase are common and may attenuate asparaginase effect. Our aim was to determine the relationship between antiasparaginase antibodies or hypersensitivity reactions and event-free survival (EFS).PATIENTS AND METHODS:One hundred fifty-four children with acute lymphoblastic leukemia received Escherichia coli asparaginase 10,000 IU/m(2) intramuscularly three times weekly for nine doses during multiagent induction and reinduction phases and for seven monthly doses during continuation treatment. Erwinia asparaginase was used in case of clinical hypersensitivity to E coli but not for subclinical development of antibodies. Plasma antiasparaginase antibody concentrations were measured on day 29 of induction in 152 patients.RESULTS:Antibodies were detectable in 54 patients (35.5%), of whom 30 (55.6%) exhibited hypersensitivity to asparaginase. Of the 98 patients who had no detectable antibodies, 18 (18.4%) had allergic reactions. Patients with antibodies were more likely to have a reaction than those without antibodies (P <.001). Among the 50 patients who experienced allergic reactions (including two for whom antibodies were not measured), 36 (72.0%) were subsequently given Erwinia asparaginase; seven (19.4%) reacted to this preparation. EFS did not differ among patients who did and did not have antibodies (P =.54), with 4-year EFS (+/- 1 SE) of 83% +/- 6% and 76% +/- 5%, respectively. Similarly, EFS did not differ among patients who did and did not develop allergic reactions (P =.68), with 4-year estimates of 82% +/- 6% and 78% +/- 5%, respectively.CONCLUSION:In this setting, in which most patients with allergy were switched to another preparation, there was no adverse prognostic impact of clinical or subclinical allergy to asparaginase.

PURPOSE:To improve outcome and study biology of childhood acute lymphoblastic leukemia (ALL) in El Salvador. PATIENTS AND METHODS:Between January 1994 and December 1996, 153 children of El Salvador had newly diagnosed ALL treated in a collaborative program between Hospital Benjamin Bloom and St. Jude Children's Research Hospital (SJCRH). Therapy was based on a modified SJCRH protocol, with uniform remission induction (prednisone, vincristine, L-asparaginase) followed-up by consolidation with teniposide/cytarabine and/or high-dose methotrexate. Continuation treatment was risk-stratified: 123 patients assigned to the high-risk group received weekly rotational drug pairs, and 16 assigned to the standard-risk group received daily 6-mercaptopurine, weekly methotrexate, and monthly pulses of vincristine plus dexamethasone. High risk was defined as: DNA index < 1.16, age 12 months or younger, white blood cell count > or = 50 x 10(9)/L, T-cell immunophenotype, anterior mediastinal mass, central nervous system leukemia at diagnosis, or t(4;11), t(1;19), or t(9;22). Duration of the continuation treatment was 2.5 years in both groups. The median age at diagnosis of all patients was 4.8 (range I d-17 yrs), median leukocyte count was 15 (range 1-766) x 10(9)/L, and sex distribution was equal. RESULTS:Immunophenotypes were early beta-progenitor in 79%, T-cell in 3.9%, and inconclusive in 17% of cases. DNA index was <1.16 in 80.5% and was > or = 1.16 in 19.5% of the 123 known cases. For the analyzes, patients who refused therapy (abandoned treatment) were considered to have treatment failure as of their last follow-up dates. Complete remission was achieved in 126 of 151 (82.4%) patients (11 abandoned therapy during induction). The overall 4-year event-free survival (EFS) rate +/- 1 standard error was 48 +/- 6%. The 4-year EFS rates in patients at high-risk and standard-risk were 46 +/- 7% (n = 121) and 69 +/- 15% (n = 16), respectively (P = 0.20). When patients who refused further treatment are censored, the corresponding 4-year estimates of EFS are 51 +/- 8% and 75 +/- 14%, respectively. CONCLUSIONS:These results suggest that the biology of childhood ALL in El Salvador appears to be similar to that seen in the United States. Risk-directed chemotherapy can successfully be used in developing countries, but risk factors must be carefully determined and applied.

CONTEXTPatients with thrombocytopenia are at risk for spontaneous or procedure-related hemorrhage. Whether such patients can safely undergo lumbar puncture (LP) without prophylactic platelet transfusion is unknown.OBJECTIVETo determine whether an association exists between thrombocytopenia and LP complications among children with acute lymphoblastic leukemia.DESIGN, SETTING, AND PATIENTSRetrospective review of the records of 958 consecutive children (median age, 5.5 years) with newly diagnosed acute lymphoblastic leukemia who were treated at a pediatric cancer center between February 1984 and July 1998.INTERVENTIONSAll patients underwent a diagnostic LP followed by a median of 4 LPs to instill intrathecal chemotherapy.MAIN OUTCOME MEASURESerious complications of LP occurring during the remission induction and consolidation treatment periods (when thrombocytopenia is likely to occur), defined as any neurologic, infectious, or hemorrhagic problems related to the procedure, reported by platelet count at the time of the procedure.RESULTSOf the 5223 LPs evaluated, 29 were performed at platelet counts of 10 x 10(9)/L or less, 170 at platelet counts of 11 to 20 x 10(9)/L, and 742 at platelet counts of 21 to 50 x 10(9)/L. No serious complications were encountered, regardless of the platelet count. The 95% confidence interval for the proportion of serious complications in the 199 patients with platelet counts of 20 x 10(9)/L or less was 0% to 1.75% and that for the 941 patients with platelet counts of 50 x 10(9)/L or less was 0% to 0.37%.CONCLUSIONSIn our study of children undergoing remission induction or consolidation therapy for acute lymphoblastic leukemia, serious complications of LP were not observed, regardless of platelet count. Prophylactic platelet transfusion is not necessary in children with platelet counts higher than 10 x 10(9)/L. Due to the small number of patients in our study with platelet counts of 10 x 10(9)/L or less, conclusions cannot yet be drawn for such patients. JAMA. 2000;284:2222-2224.

Drug clearance is often higher in children than in adults, particularly when normalized to body weight. We previously showed that liver volume normalized to body weight was inversely related to age, but that the systemic clearance of a nonspecific cytochrome P450 (CYP) substrate (antipyrine) was higher in young children compared with adults even when normalized per liver volume. Our purpose herein was to evaluate whether P450 catalytic activities, expressed as maximal catalytic rates per milligram of microsomal protein, differed in up to 37 normal livers from subjects <10 (range 0.5-9 years of age), >10 but <60 years of age (range 10-59 years), and >60 year (range 63-93 years of age). There were no age-related differences in the oxidation of ethoxyresorufin (P = .83) (CYP1A2), ethoxycoumarin (P = .52) (CYP2E1 and other P450s), teniposide (P = .58), midazolam (P = .47) (CYP3A4/3A5), or paclitaxel (P = .24) (at the 17 alpha position, CYP2C8). Tolbutamide hydroxylation tended to be lower in children versus adults (P = .047) (CYP2C9), but did not reach statistical significance after correcting for multiple comparisons. No relationship was found to exist between age and microsomal recovery (P = .98); thus, recovery did not account for the lack of age-related differences in catalytic activity. We conclude that increased intrinsic cytochrome P450 activity is unlikely to account for increased clearance of most P450 drug substrates in children.

PURPOSE:Whether recent improvements in the treatment of childhood acute lymphoblastic leukemia (ALL) have nullified the adverse prognosis associated with male sex remains unclear. Therefore, we analyzed the survival experience and presenting clinical and laboratory features of boys and girls with newly diagnosed ALL who were treated at our institution over the past three decades.PATIENTS AND METHODS:One thousand one hundred fifty-one boys and 904 girls were treated in 13 consecutive Total Therapy studies between 1962 and 1994. An overview analysis was used to investigate the impact of sex on overall and event-free survival, both for the entire cohort and for subgroups defined by treatment era and blast-cell immunophenotype. Stratified analyses were performed to adjust for treatment protocol and known risk factors, and in the modern treatment era, for protocol, immunophenotype, and the DNA content of leukemic cells (ie, DNA index). The pharmacokinetics of methotrexate, teniposide, and cytarabine, as well as the thiopurine methyltransferase activity of erythrocytes, were compared between boys and girls treated on a single protocol.RESULTS:Compared with girls, boys were more likely to have T-cell ALL (20.9% v 10.7%, P < .001) and seemed less likely to have a favorable DNA index (17.8% v 25.1%, P = .072). There were no other statistically significant differences between the two sexes with respect to presenting features, including leukemic-cell genetic abnormalities, nor were there significant sex differences in the pharmacokinetics of methotrexate, teniposide, or cytarabine or in erythrocyte thiopurine methyltransferase activity. Girls clearly fared better than boys (P < .001) on protocols used during the early era of treatment (10-year event-free survival +/- 1 SE, 43.1%+/-2.1% v 31.5%+/-1.7%). Although prognosis improved for both sexes in the modern era, the difference in outcome between girls and boys persisted (P = .025) (10-year event-free survival, 73.4%+/-3.7% v 63.5%+/-4.0%). However, stratification of modern-era patients by protocol, immunophenotype, and DNA index mitigated statistical evidence of a sex difference in overall survival (P = .263) and event-free survival (P = .124).CONCLUSION:Although boys and girls alike have benefited from improvements in ALL therapy, these gains have not completely eliminated the sex difference in prognosis that has persisted since the early 1960s. The apparent difference in outcome is partially explained by differences between boys and girls in the distributions of ALL immunophenotype and DNA index.

PURPOSE:The CNS is an important sanctuary site in childhood acute lymphoblastic leukemia (ALL). CSF asparagine concentration reflects asparaginase systemic pharmacodynamics. We evaluated the time course of CSF asparagine depletion in children with ALL during and after a course of Escherichia coli asparaginase.PATIENTS AND METHODS:Thirty-one children (24 newly diagnosed and seven at relapse) received E coli asparaginase 10,000 IU/m2 intramuscularly three times weekly for six and nine doses, respectively, as part of multiagent induction chemotherapy. CSF asparagine levels were measured before, during, and after asparaginase dosing.RESULTS:The percentage of patients with undetectable (< 0.04 micromol/L) CSF asparagine was 3.2% (one of 31 patients) at baseline, 73.9% (17 of 23) during asparaginase therapy, and 56.3% (nine of 16) 1 to 5 days, 43.8% (seven of 16) 6 to 10 days, 20.0% (two of 10) 11 to 30 days and 0% (zero of 21) more than 30 days after asparaginase therapy. The proportion of patients with depleted CSF asparagine was higher during asparaginase therapy than at baseline (P < .001), 11 to 30 days (P = .003), and more than 30 days after asparaginase therapy (P < .001). Median CSF asparagine concentrations were 4.42 micromol/L before, less than 0.04 micromol/L during, and less than 0.04 micromol/L at 1 to 5 days, 1.63 micromol/L at 6 to 10 days, 1.70 micromol/L at 11 to 30 days, and 5.70 micromol/L at more than 30 days after asparaginase therapy, respectively. CSF depletion was more common in patients with low baseline CSF asparagine concentrations (P = .003).CONCLUSION:CSF asparagine concentrations are depleted by conventional doses of E coli asparaginase in the majority of patients, but they rebound once asparaginase therapy is completed.

The purpose of this study was to determine the incidence of and pharmacokinetic parameters associated with the development of transient encephalopathy following the administration of high-dose methotrexate and intrathecal chemotherapy in children with acute lymphoblastic leukemia (ALL). Two hundred and fifty-nine children with newly diagnosed ALL treated on one of two consecutive trials were analyzed. Presenting features in patients who developed transient encephalopathy were compared with those of patients who did not experience this event. For each patient who developed transient encephalopathy, methotrexate pharmacokinetic parameters were compared with those of matched controls. The cumulative incidence of acute encephalopathy was 3% (SE 1%) at 1 year and was associated with age greater than or equal to 10 years at diagnosis. Pharmacokinetic data did not differ between patients who developed transient encephalopathy and those who did not. The majority of patients had no long-term sequelae and were able to receive further courses of methotrexate without modification. Transient focal neurologic deficits occur in about 3% of children with ALL following the administration of intravenous and intrathecal methotrexate. These events cannot be predicted by pharmacokinetic parameters of methotrexate disposition. However, these events are generally benign, suggesting that patients who experience acute encephalopathy should continue to receive this important chemotherapeutic agent.

Standard prophylaxis and treatment of malignancy-associated hyperuricemia in the USA has been allopurinol with vigorous hydration, urinary alkalinization and osmotic diuresis. Urate oxidase, the enzyme that converts uric acid to allantoin (a readily excreted metabolite that has 5- to 10-fold higher solubility than uric acid), is an alternative therapy; however, few published findings support this practice. Between February 1994 and December 1996, we administered non-recombinant urate oxidase (Uricozyme) to 126 children with newly diagnosed non-B cell acute lymphoblastic leukemia (ALL) during the first 5 days of chemotherapy with methotrexate, 6-mercaptopurine or both. Their blood levels of uric acid and other indicators of tumor lysis were measured at diagnosis and during treatment and then compared with findings in 129 similarly treated historical controls who had received allopurinol to control hyperuricemia. Clinical responses to urate oxidase were also determined in eight patients with newly diagnosed B cell ALL or advanced-stage non-Hodgkin lymphoma. Patients treated with urate oxidase had rapid and significantly greater decreases in their blood uric acid levels than did the historical controls (median maximal level during treatment, 2.3 vs 3.9 mg/dl, P < 0.001). They also had lower creatinine (0.6 vs 0.7 mg/dl, P = 0.01) and blood urea nitrogen (11 vs 24 mg/dl, P < 0.001) levels. Similar findings were made in the eight cases of B cell ALL or non-Hodgkin lymphoma. None of the patients required dialysis for acute renal failure. Six (4.5%) of the 134 children given urate oxidase had allergic reactions, manifested primarily by urticaria, bronchospasm and hypoxemia. Thus, non-recombinant urate oxidase is a more effective uricolytic agent than allopurinol but is associated with acute hypersensitivity reactions, even in patients without a history of allergy.

To determine the frequency and prognostic significance of recently described genetic lesions in pediatric acute lymphoblastic leukemia (ALL), all cases with available leukemic cell samples treated on St Jude Study XII were analyzed by molecular techniques for alterations of the p16 , MLL and ETV6 genes. Homozygous p16 deletion was seen in 36 of 155 cases, including 14 of 23 T cell cases, but had no prognostic value. Rearrangement of MLL was seen in nine of 170 cases (5%) and conferred a poor prognosis, with a 5-year EFS estimate of only 11 ± 7%, compared with 74 ± 5% for the germline MLL group ( P = 0.0001). By contrast, rearrangement of ETV6 was found in 35 cases (21%) and was significantly associated with a better outcome (5-year EFS estimates: 87 ± 7% vs 64 ± 6%). In a Cox regression model adjusted for age, DNA index, race, leukocyte count, treatment group, and CNS status, ETV6 rearrangement retained independent prognostic significance (two-sided P value 0.012). Thus, in this uniformly treated group of patients, we confirmed the unfavorable prognostic significance of MLL rearrangement and demonstrated the favorable impact of ETV6 rearrangement, suggesting that these factors be added to ALL risk classification schemes.