levoleucovorin and Precursor-B-Cell-Lymphoblastic-Leukemia-Lymphoma

The Children's Oncology Group (COG) develops and implements multi-institutional clinical trials with the primary goal of assessing the efficacy and safety profile of treatment regimens for various pediatric cancers. However, the monetary costs of treatment regimens are not measured. AALL0232 was a COG randomized phase III trial for children with acute lymphoblastic leukemia that found that dexamethasone (DEX) was a more effective glucocorticoid than prednisone (PRED) in patients younger than 10 years, but PRED was equally effective and less toxic in older patients. In addition, high-dose methotrexate (HD-MTX) led to better survival than escalating doses of methotrexate (C-MTX). Cost data from the Pediatric Health Information System database were merged with clinical data from the COG AALL0232 trial. Total and component costs were compared between treatment arms and across hospitals. Inpatient costs were higher in the HD-MTX and DEX arms when compared to the C-MTX and PRED arms at the end of therapy. There was no difference in cost between these arms at last follow-up. Considerable variation in total costs existed across centers to deliver the same therapy that was driven by differences in inpatient days and pharmacy costs. The more effective regimens were found to be more expensive during therapy but were ultimately cost-neutral in longer term follow-up. The variations in cost across centers suggest an opportunity to standardize resource utilization for patients receiving similar therapies, which could translate into reduced healthcare expenditures.

Topics: Adolescent; Adult; Age Factors; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Cost-Benefit Analysis; Dexamethasone; Disease-Free Survival; Drug Administration Schedule; Drug Costs; Female; Follow-Up Studies; Health Expenditures; Hospital Costs; Hospitalization; Humans; Infant; Infant, Newborn; Leucovorin; Male; Methotrexate; Polyethylene Glycols; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Young Adult

Purpose Survivors of childhood acute lymphoblastic leukemia (ALL) are at risk for neurocognitive deficits that are associated with treatment, individual, and environmental factors. This study examined the impact of different methotrexate (MTX) and corticosteroid treatment strategies on neurocognitive functioning in children with high-risk B-lineage ALL. Methods Participants were randomly assigned to receive high-dose MTX with leucovorin rescue or escalating dose MTX with PEG asparaginase without leucovorin rescue. Patients were also randomly assigned to corticosteroid therapy that included either dexamethasone or prednisone. A neurocognitive evaluation of intellectual functioning (IQ), working memory, and processing speed (PS) was conducted 8 to 24 months after treatment completion (n = 192). Results The method of MTX delivery and corticosteroid assignment were unrelated to differences in neurocognitive outcomes after controlling for ethnicity, race, age, gender, insurance status, and time off treatment; however, survivors who were age < 10 years at diagnosis (n = 89) had significantly lower estimated IQ ( P < .001) and PS scores ( P = .02) compared with participants age ≥ 10 years. In addition, participants who were covered by US public health insurance had estimated IQs that were significantly lower ( P < .001) than those with US private or military insurance. Conclusion Children with high-risk B-lineage ALL who were age < 10 years at diagnosis are at risk for deficits in IQ and PS in the absence of cranial radiation, regardless of MTX delivery or corticosteroid type. These data may serve as a basis for developing screening protocols to identify children who are at high risk for deficits so that early intervention can be initiated to mitigate the impact of therapy on neurocognitive outcomes.

Topics: Adrenal Cortex Hormones; Adult Survivors of Child Adverse Events; Age Factors; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Cognition; Dexamethasone; Female; Humans; Insurance, Health; Intelligence; Leucovorin; Male; Medicaid; Memory, Short-Term; Methotrexate; Polyethylene Glycols; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Reaction Time; United States

Minimal residual disease (MRD) is highly prognostic in pediatric B-precursor acute lymphoblastic leukemia (B-ALL). In Children's Oncology Group high-risk B-ALL study AALL0232, we investigated MRD in subjects randomized in a 2 × 2 factorial design to receive either high-dose methotrexate (HD-MTX) or Capizzi methotrexate (C-MTX) during interim maintenance (IM) or prednisone or dexamethasone during induction. Subjects with end-induction MRD ≥0.1% or those with morphologic slow early response were nonrandomly assigned to receive a second IM and delayed intensification phase. MRD was measured by 6-color flow cytometry in 1 of 2 reference labs, with excellent agreement between the two. Subjects with end-induction MRD <0.01% had a 5-year event-free survival (EFS) of 87% ± 1% vs 74% ± 4% for those with MRD 0.01% to 0.1%; increasing MRD amounts was associated with progressively worse outcome. Subjects converting from MRD positive to negative by end consolidation had a relatively favorable 79% ± 5% 5-year disease-free survival vs 39% ± 7% for those with MRD ≥0.01%. Although HD-MTX was superior to C-MTX, MRD retained prognostic significance in both groups (86% ± 2% vs 58% ± 4% for MRD-negative vs positive C-MTX subjects; 88% ± 2% vs 68% ± 4% for HD-MTX subjects). Intensified therapy given to subjects with MRD >0.1% did not improve either 5-year EFS or overall survival (OS). However, these subjects showed an early relapse rate similar to that seen in MRD-negative ones, with EFS/OS curves for patients with 0.1% to 1% MRD crossing those with 0.01% to 0.1% MRD at 3 and 4 years, thus suggesting that the intensified therapy altered the disease course of MRD-positive subjects. Additional interventions targeted at the MRD-positive group may further improve outcome. This trial was registered at www.clinicaltrials.gov as #NCT00075725.

Topics: Antineoplastic Agents; Asparaginase; Child; Child, Preschool; Dexamethasone; Disease-Free Survival; Dose-Response Relationship, Drug; Female; Flow Cytometry; Humans; Induction Chemotherapy; Kaplan-Meier Estimate; Leucovorin; Maintenance Chemotherapy; Male; Methotrexate; Neoplasm, Residual; Polyethylene Glycols; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Proportional Hazards Models; Risk Factors

To describe the incidence of acute neurotoxicity (NT) in children with lower risk B-precursor acute lymphoid leukemia (ALL) treated with intermediate-dose methotrexate (MTX) or divided dose oral MTX with or without intravenous (i.v.) mercaptopurine (MP) and extended intrathecal triple therapy.. Thirteen hundred four patients were entered onto Pediatric Oncology Group (POG) 9005, a randomized phase III trial, between January 11, 1991 and September 1, 1994. After remission induction, patients were randomized to one of three 24-week intensification schedules: regimen A, MTX 1,000 mg/m2 i.v. infused over 24 hours and MP 1,000 mg/m2 i.v. infused over 6 hours; regimen B, low-dose repetitive MTX 30 mg/m2 orally every 6 hours for six doses and i.v. MP; or regimen C, i.v. MTX alone. Intensification was given every 2 weeks for 12 courses. CNS prophylaxis was age-adjusted intrathecal MTX (ITM). In August 1992, the CNS prophylaxis was changed to age-adjusted triple intrathecal therapy (TIT). Reports of grades 3 and 4 acute NT were reviewed.. Acute NT was reported in 95 of 1,218 (7.8%) eligible patients treated on POG 9005. The incidence by regimen was regimen A, 46 of 543 patients (8.3%); regimen B, 13 of 354 patients (3.7%); and regimen C, 36 of 321 patients (11.2%) (P < .001). The majority of events were seizures and the median number of days to first occurrence of symptomatic NT after ITM or TIT was 10 to 11 days. Computed tomography (CT) or magnetic resonance imaging (MRI) evidence consistent with leukoencephalopathy (LE), with or without the presence of cerebral calcifications, was observed in 75% and 77.1 % of symptomatic patients treated on regimens A and C, respectively, but in only 15.4% of symptomatic patients treated on regimen B (P < .001). Factors associated with an increased incidence of NT included increased cumulative exposure with repeated i.v. MTX (regimens A and C v B), increased MTX-leucovorin (LCV) ratio (regimens A and C v B), and choice and timing of TIT therapy. The use of i.v. MP during intensification did not appear to contribute to these complications. The switch to TIT CNS prophylaxis was associated with an inferior overall 4-year continuous complete remission (CCR) (P=.031) when compared with ITM.. Intensification with repeated i.v. MTX in the setting of low-dose LCV rescue was associated with a higher risk for acute NT and LE, especially in patients who received concomitant TIT. The long-term consequences for affected patients remain unknown.

Topics: Acute Disease; Administration, Oral; Antidotes; Antineoplastic Combined Chemotherapy Protocols; Brain; Central Nervous System Diseases; Child; Child, Preschool; Female; Humans; Infant; Infusions, Intravenous; Injections, Spinal; Leucovorin; Magnetic Resonance Imaging; Male; Methotrexate; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Risk Factors; Tomography, X-Ray Computed

Emergency departments (EDs) are alert to the possibility of stroke and the need for early interventions to improve long-term clinical outcomes. However, new-onset hemiparesis in pediatric patients with leukemia may be due to a number of different etiologies, including most common side effects from chemotherapeutic agents. We present a case of a 15-year-old boy with pre-B acute lymphoblastic leukemia on chemotherapy, having recently received a high-dose methotrexate infusion in addition to intrathecal methotrexate therapy, who presented to our ED with acute right-sided hemiparesis. He was initially suspected as having a possible ischemic stroke. Magnetic resonance imaging (diffusion-weighted and fluid-attenuated inversion recovery sequence) demonstrated focal areas of diffusion restriction, an early sign of delayed-onset methotrexate neurotoxicity. Our patient received appropriate supportive care and leucovorin rescue with gradual clinical recovery, after a prolonged hospitalization and acute care rehabilitation over the course of several months. Our case illustrates the need for ED providers to consider methotrexate neurotoxicity in pediatric oncology patients presenting with acute neurologic changes.

Topics: Adolescent; Antidotes; Antimetabolites, Antineoplastic; Brain; Diffusion Magnetic Resonance Imaging; Humans; Leucovorin; Male; Methotrexate; Neurotoxicity Syndromes; Paresis; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma

Purpose To determine the prognostic significance of blasts, and of white and red blood cells, in CSF samples at diagnosis of acute lymphoblastic leukemia (ALL), a uniform CSF and risk group classification schema was incorporated into Children's Oncology Group B-cell ALL (B-ALL) clinical trials. Methods CSF status was designated as follows: CNS1, no blasts; CNS2a to 2c, < 5 WBCs/μL and blasts with/without ≥ 10 RBCs/μL or ≥ 5 WBCs/μL plus blasts, with WBCs ≥ 5 times the number of RBCs; CNS3a to 3c, ≥ 5 WBCs/μL plus blasts with/without ≥ 10 RBCs/μL or clinical signs of CNS disease. CNS2 status did not affect therapy; patients with CNS3 status received two extra intrathecal treatments during induction and augmented postinduction therapy with 18 Gy of cranial radiation. Results Among 8,379 evaluable patients enrolled from 2004 to 2010, 7,395 (88.3%) had CNS1 status; 857 (10.2%), CNS2; and 127 (1.5%), CNS3. The 5-year event-free and overall survival rates were, respectively, 85% and 92.7% for CNS1, 76% and 86.8% for CNS2, and 76% and 82.1% for CNS3 ( P < .001). In multivariable analysis that included age, race/ethnicity, initial WBC, and day-29 minimal residual disease < 0.1%, CSF blast, regardless of cell count, was an independent adverse predictor of outcome for patients with standard- or high-risk disease according to National Cancer Institute criteria. The EFS difference reflected a significant difference in the incidence of CNS, not marrow, relapse in patients with CNS1 versus CNS2 and/or CNS3 status. Conclusion Low levels of CNS leukemia, regardless of RBCs, predict inferior outcome and higher rates of CNS relapse. These data suggest that additional augmentation of CNS-directed therapy is warranted for CNS2 disease.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Central Nervous System Neoplasms; Cerebrospinal Fluid; Child; Clinical Trials as Topic; Cranial Irradiation; Dexamethasone; Disease-Free Survival; Erythrocyte Count; Female; Humans; Leucovorin; Leukocyte Count; Male; Methotrexate; Polyethylene Glycols; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Risk Factors; Survival Rate

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Chromosomes, Human, Pair 22; Chromosomes, Human, Pair 9; Cytarabine; Drug Interactions; Edema; Etoposide; Female; Humans; Imatinib Mesylate; Leucovorin; Methotrexate; Middle Aged; Piperazines; Pleural Effusion, Malignant; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Pyrimidines; Sodium Potassium Chloride Symporter Inhibitors; Translocation, Genetic

Topics: Acute Kidney Injury; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Drug Interactions; Female; Humans; Infusions, Intravenous; Leucovorin; Methotrexate; Migraine Disorders; Oxazolidinones; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Serotonin Receptor Agonists; Tryptamines

Topics: Adult; Aminophylline; Brain Diseases; Female; Humans; Leucovorin; Magnetic Resonance Imaging; Methotrexate; Neurotoxicity Syndromes; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Treatment Outcome

The purpose of this study was to determine if a correlation exists between clinical outcome and accumulation and polyglutamation of methotrexate by lymphoblasts in vitro in children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL).. The amount of accumulated methotrexate and of long-chain methotrexate polyglutamates (MTXPG(3-7)) by lymphoblasts was determined in 52 children newly diagnosed with BCP-ALL after incubation with 1 micromol/L [(3)H]MTX for 24 hours in vitro. All patients then received intensive multiagent chemotherapy that used divided-dose oral methotrexate during consolidation and intensive continuation and standard oral weekly methotrexate during maintenance.. Eight patients had a bone marrow relapse at a median of 40.4 months (range 18.5-48.3 months) after diagnosis. The median follow-up for the remaining 44 patients is 69.0 months (range 22-92.8 months). There was no significant difference in the amount of accumulated methotrexate (1450.0 +/- 896.3 vs. 640 +/- 472.5 pmol/10 cells) or of accumulated MTXPG (1450.0 +/- 919.4 vs. 617.4 +/- 482.7 pmol/10(9) cells) (median +/- semi-interquartile ranges) between patients who relapsed and those who remained in continuous complete remission. The estimated 5-year event-free survival rate for patients whose lymphoblasts accumulated more than 500 pmol MTXPG(3-7)/10(9) cells was 80.0% +/- 7.3% versus 90.5% +/- 6.4% for those whose lymphoblasts accumulated less than 500 pmol MTXPG(3-7)/10(9) cells.. In the context of effective prolonged divided-dose oral methotrexate-based therapy in the treatment of BCP-ALL, methotrexate accumulation and polyglutamation no longer seem to have prognostic significance.

Topics: Administration, Oral; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bone Marrow; Child; Cytarabine; Daunorubicin; Dexamethasone; Disease-Free Survival; Female; Humans; Hydrocortisone; Injections, Spinal; Karyotyping; Leucovorin; Life Tables; Lymphocytes; Male; Mercaptopurine; Methotrexate; Neoplastic Stem Cells; Polyglutamic Acid; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Pteroylpolyglutamic Acids; Recurrence; Remission Induction; Survival Analysis; Tumor Cells, Cultured; Vincristine