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Subcutaneous Panniculitis-like T-cell lymphoma (SPTCL) is a rare subtype of childhood non-Hodgkin lymphoma. Subcutaneous Panniculitis-like T-cell lymphoma has an aggressive variant associated with the hemophagocytic syndrome (HPS). Patients without HPS show resolution of the disease with prednisone or immunosuppressive therapy unlike other T-cell lymphomas. One HIV-positive adolescent and one infant with multiple subcutaneous masses are presented and the literature is reviewed. Lesional cells were consistent with SPTCL alpha-beta type. Our cases, without HPS, showed complete resolution of their lesions when treated with non-aggressive therapies. Patients with SPTCL alpha-beta should be treated conservatively. [ABSTRACT FROM AUTHOR]

Therapy of relapsed pediatric acute lymphoblastic leukemia (ALL) Is hampered by low remission rates and high toxicity, especially in second and subsequent relapses. Our phase 1 study, T2005-003, showed that the combination of bor-tezomib with vincristine, dexamethasone, pegylated asparaginase, and doxorubicin had acceptable toxicity. We report the phase 2 expansion of this combination in patients with relapsed ALL who failed 2-3 previous regimens. Twenty-two pa-tients with relapsed ALL were treated with bortezomib combined with this regimen; their ages ranged from 1 to 22 years, and they had either B-precursor ALL (n = 20) or T-ceii ALL (n = 2). Grade 3 peripheral neuropathy developed in 2 (9%) patients. After 3 patients died from bacterial infec-tions, treatment with vancomycin, levo-floxacin, and voriconazole prophylaxis resulted in no further infectious mortality in the last 6 patients. Fourteen patients achieved complete remission (CR), and 2 achieved CR without platelet recovery, for an overall 73% response rate, meeting predefined criteria allowing for early clo-sure. B-precursor patients faired best with 16 of 20 (80%) CR + CR without platelet recovery, whereas the 2 patients with T-cell ALL did not respond. Thus, this combination of bortezomib with che-motherapy is active in B-precursor ALL, and prophylactic antibiotics may be use-ful in reducing mortality. Bortezomib mer-its further evaluation in combination therapy in pediatric B-precursor ALL. This study is registered at http://www.ciinicai trials.gov as NCT00440726. [ABSTRACT FROM AUTHOR]

Summary Gene expression profiling (GEP) of primary leukaemic cells (PLC) from 157 paediatric B-lineage acute lymphoblastic leukaemia (ALL) patients, including a direct comparison of matched pair initial diagnosis versus first relapse leukaemic specimens, provided previously unknown evidence that relapse clones are characterized by significantly higher expression levels of a CD22 exon 12 deletion (CD22ΔE12)-associated signature transcriptome than the PLC from newly diagnosed patients. In agreement with and validating these GEP results, reverse transcription polymerase chain reaction and Western blot analysis of PLC from 19 of 19 paediatric ALL patients in first bone marrow relapse occurring within 12 months of the completion of primary therapy confirmed them to be CD22ΔE12+. Likewise, PLC in diagnostic initial bone marrow specimens from seven of seven therapy-refractory newly diagnosed paediatric B-lineage ALL patients with <7 months event-free survival (EFS), including four patients with induction failures and three patients with early relapses, were CD22ΔE12+, whereas PLC from only one of five newly diagnosed paediatric B-lineage ALL patients with >18 months EFS was CD22ΔE12+. CD22ΔE12+ could be detected in PLC of therapy-refractory patients both at the time of initial diagnosis as well as at the time of documented treatment failure. Our study implicates the CD22ΔE12 genetic defect in the aggressive biology of relapsed or therapy-refractory paediatric B-lineage ALL. [ABSTRACT FROM AUTHOR]

Clofarabine for injection is a second-generation nucleoside analog approved in the United States (Clolar) and Europe (Evoltra) for the treatment of pediatric relapsed or refractory acute lymphoblastic leukemia. This report describes the population pharmacokinetics of clofarabine and its metabolite 6-ketoclofarabine in adult and pediatric patients with hematologic malignancies or solid tumors. Clofarabine pharmacokinetics were best described by a 2-compartment model with linear elimination and first-order absorption after oral administration. Clofarabine was rapidly absorbed following oral administration with a mean absorption time of less than 2 h and bioavailability of 57.5%. The important covariates affecting clofarabine pharmacokinetics were age, weight, and estimated creatinine clearance (eCrCL). No difference in pharmacokinetics was observed between sexes, races, or disease type. The elimination half-life was dependent on all the covariates but was generally less than 7 h in all cases. A difference in clofarabine pharmacokinetics was observed between adults and children. For a pediatric patient 3 years old weighing 16 kg with an eCrCL of 138 mL/min/1.73 m, the population estimates for total systemic clearance and volume of distribution at steady-state were 18.3 L/h (1.14 L/h/kg) and 92.9 L (5.81 L/kg), respectively. α- and β-half-life were 0.9 and 4.4 h, respectively. For an elderly patient 82 years old weighing 96 kg with an eCrCL of 46 mL/min/1.73 m, the population estimates for CL and Vdss were 21.5 L/h (0.22 L/h/kg) and 257.4 L (268 L/kg), respectively. α- and β-half-life were 0.5 and 10.6 h, respectively. Because of the difference in pharmacokinetics, adults have higher exposure than children given a similar dose standardized to body surface area. The exact mechanism of this difference is not understood. As eCrCL decreased, exposure increased due to reduced total systemic clearance. In the case of moderate (eCrCL 30 to 60 mL/min/1.73 m) and severe (eCrCL <30 mL/min/1.73 m) renal impairment, dose reduction may be needed to maintain similar exposure in an equivalent patient of the same age, weight, and normal renal function after both oral and intravenous administration. 6-Ketoclofarabine was a minor metabolite with peak plasma concentrations occurring about 1 h after the start of the infusion and having a metabolite ratio averaging less than 5% and not more than 8% for any particular individual. 6-Ketoclofarabine was rapidly cleared from plasma with an average apparent half-life of 4.9 h (range 3.9 to 6.2 h). No accumulation of 6-ketoclofarabine was observed with predose samples all below the limit of quantification on Days 8 and 15. Further monitoring of 6-ketoclofarabine is not required in future studies. [ABSTRACT FROM AUTHOR]

Significant improvements in primary therapy for childhood acute lymphoblastic leukemia (ALL) have led to dramatic increases in cure rates over the past few decades. Relapsed ALL, however, remains more common than new diagnoses of many common pediatric malignancies. Outcomes for patients with relapsed ALL remain poor, especially for patients with early bone marrow relapse. However, most relapse patients do achieve a second complete remission, followed by therapeutic options including further chemotherapy and hematopoietic stem cell transplant. The level of minimal residual disease after achieving second remission or before transplant may predict outcomes. The substantial likelihood of achieving second remission with familiar drug combinations may discourage participation in formal relapse studies. The high likelihood of achieving a third remission may discourage participation in single-gent trials of new drugs, despite the critical need for novel agents with activity against resistant disease that may improve outcomes for recurrent ALL. [ABSTRACT FROM AUTHOR]

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Careful building upon past clinical trials and thoughtful application of our limited knowledge of pharmacology have provided steady improvement in outcome for newly diagnosed patients. Precise identification of the many patients who are unlikely to relapse with current effective regimens is required to avoid the morbidity of further intensification of therapy. Progress is sorely lacking for relapsed patients. Most patients who relapse die. Gene expression arrays and comparative genomic hybridization have further extended our appreciation of the known immunophenotypic and genetic diversity of childhood ALL. Insight into the molecular mechanisms of treatment failure may provide guidance for future efforts. [ABSTRACT FROM AUTHOR]

Thus PEG was administered immediately following the first infusion of 5 g/m SP 2 sp methotrexate and asparagine was depleted continuously through the remaining three doses of methotrexate. Erythrocyte MTXPG was assayed 2 or 3 weeks following each methotrexate infusion, likely prior to the subsequent methotrexate infusion. Subsequently, 5 g/m SP 2 sp methotrexate proved superior to "Capizzi" methotrexate PEG for B-ALL [[10]], while "Capizzi" methotrexate PEG proved superior for T-ALL [[11]]. 2 Capizzi RL, Summers WP, Bertino JR. L-asparaginase induced alteration of amethopterin (methotrexate) activity in mouse leukemia L5178Y. [Extracted from the article]

Acute lymphoblastic leukaemia (ALL) is the most common childhood cancer. Treatment has improved but relapsed ALL remains more common than new cases of many ‘common’ paediatric malignancies. We have salvage regimens with substantial complete remission (CR) rates and increasing access to haematopoietic stem cell transplantation, but most patients who relapse die. We need better therapies. Insights into pharmacology may guide more effective use of existing agents. Novel agents with activity against resistant lymphoblasts offer an appealing strategy. However, most candidate agents fail, despite enthusiastic investigators, intriguing mechanisms of action and ‘compelling’ preclinical data. A number of existing combinations provide a 40% complete response rate in second or third relapse. Yet survival in third remission is <10%. Novel agents must, most likely, be integrated into multiagent combinations that provide a higher CR rate or better quality CR's than our conventional combinations in order to contribute substantially to cure. The march from bench to bedside requires careful consideration of the intermediate steps. [ABSTRACT FROM AUTHOR]

The population pharmacokinetics of plasma clofarabine and intracellular clofarabine triphosphate were characterized in pediatric patients with acute leukemias. Traditional model-building techniques with NONMEM were used. Covariates were entered into the base model using a forward selection significance level of .05 and a backwards deletion criterion of .005. Model performance, stability, and influence analysis were assessed using the nonparametric bootstrap and n-1 jackknife. Simulations were used to understand the relationship between important covariates and exposure. A 2- compartment model with weight (scaled to a 40-kg reference patient) modeled as a power function on all pharmacokinetic parameters (0.75 on clearance-related terms and 1.0 on volume-related terms) was fit to plasma clofarabine concentrations (n = 32). White blood cell (WBC) count, modeled as a power function (scaled to a WBC count of 10 × 103/μL), was a significant predictor of central volume with power term 0.128 ± 0.0314. A reference patient had a systemic clearance of 32.8 L/h (27% between-subject variability [BSV]), a central volume of 115 L (56% BSV), an intercompartmental clearance of 20.5 L/h (27% BSV), and a peripheral volume of 94.5 L (39% BSV). Intracellular clofarabine triphosphate concentrations were modeled using a random intercept model without any covariates. The average predicted concentration was 11.6 ± 2.62 μM (80% BSV), and although clofarabine triphosphate half-life could not be definitively estimated, its value was taken to be longer than 24 hours. The results confirm that clofarabine should continue being dosed on a per-square-meter or per-body-weight basis. [ABSTRACT FROM PUBLISHER]

Summary: Background: The prognosis and optimum treatment of childhood acute lymphoblastic leukaemia (ALL) with abnormalities of chromosomal band 11q23 are controversial. We aimed to identify prognostic factors that might help in planning future therapy, and to assess the effectiveness of haemopoietic stem-cell transplantation in patients with the t(4;11) translocation, which is associated with a particularly poor outcome. Methods: We reviewed data on 497 children and young adults who had ALL with various 11q23 abnormalities, including the translocations t(4;11), t(9;11), and t(11;19). All patients were treated with intensive chemotherapy, with or without haemopoietic stem-cell transplantation in first complete remission, by 11 study groups and single institutions from 1983 to 1995. Findings: Age was the most important prognostic factor. In a Cox's proportional-hazard model stratified by 11q23 abnormalities, infants younger than 1 year fared significantly worse than patients 1 year of age or older (hazard ratio for event-free survival 1.84 [95% CI 1.38-2.47], p=0.0001). Among infants, any category of 11q23 abnormality conferred a dismal outcome, whereas in older patients, t(4;11) and t(9;11) were associated with a worse outcome than were other 11q23 changes. In the largest subgroup--256 patients with t(4;11)--any type of transplantation was associated with significantly worse disease-free survival (1.61 [1.10-2.35], p=0.014) and overall survival (1.76 [1.08-2.45], p=0.004) compared with chemotherapy only. Even transplantation with stem cells from HLA-matched related or HLA-matched unrelated donors tended to be associated with a worse outcome than chemotherapy alone. Interpretation: The prognosis of acute lymphoblastic leukaemia with an 11q23 abnormality is particularly dismal in infants. Allogeneic transplantation with haemopoietic stem cells from an HLA-matched related donor does not seem to improve the clinical outcome in patients with t(4;11)-positive leukaemia. [ABSTRACT FROM AUTHOR]

Background: The prognosis and optimum treatment of childhood acute lymphoblastic leukaemia (ALL) with abnormalities of chromosomal band 11q23 are controversial. We aimed to identify prognostic factors that might help in planning future therapy, and to assess the effectiveness of haemopoietic stem-cell transplantation in patients with the t(4;11) translocation, which is associated with a particularly poor outcome.Methods: We reviewed data on 497 children and young adults who had ALL with various 11q23 abnormalities, including the translocations t(4;11), t(9;11), and t(11;19). All patients were treated with intensive chemotherapy, with or without haemopoietic stem-cell transplantation in first complete remission, by 11 study groups and single institutions from 1983 to 1995.Findings: Age was the most important prognostic factor. In a Cox''s proportional-hazard model stratified by 11q23 abnormalities, infants younger than 1 year fared significantly worse than patients 1 year of age or older (hazard ratio for event-free survival 1 84 [95% CI 1 38–2 47], p=0 0001). Among infants, any category of 11q23 abnormality conferred a dismal outcome, whereas in older patients, t(4;11) and t(9;11) were associated with a worse outcome than were other 11q23 changes. In the largest subgroup—256 patients with t(4;11)—any type of transplantation was associated with significantly worse disease-free survival (1 61 [1 10–2 35], p=0 014) and overall survival (1 76 [1 08–2 45], p=0 004) compared with chemotherapy only. Even transplantation with stem cells from HLA-matched related or HLA-matched unrelated donors tended to be associated with a worse outcome than chemotherapy alone.Interpretation: The prognosis of acute lymphoblastic leukaemia with an 11q23 abnormality is particularly dismal in infants. Allogeneic transplantation with haemopoietic stem cells from an HLA-matched related donor does not seem to improve the clinical outcome in patients with t(4;11)-positive leukaemia. [Copyright &y& Elsevier]

Examines the frequency of TEL-AML1 fusion transcripts in children diagnosed with acute lymphocytic leukemia (ALL). Risk of pseudodiplody among TEL AML1 versus standard risk ALL cases; Quality of remission of reverse transcriptase polymerase chain reaction; Cytogenic features of TEM AML versus standard risk ALL patients.