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All patients completed double induction with FLAG-IDA, and 27/30 (90%) patients completed all planned therapy (persistent thrombocytopenia, early relapse post-consolidation I, physician discretion). Of the 1096 patients enrolled in the COG trial AAML1031, MRD was available in 95% of patients and was negative (<0.05%) post-Induction I in only 75% of patients. Abbreviations AML Acute myeloid leukaemia ANC Absolute neutrophil count CNS Central nervous system COG Children's Oncology Group CR1 First complete remission EFS Event-free survival FLAG-IDA Fludarabine, cytarabine, idarubicin and G-CSF GO Gemtuzumab ozogamicin GCSF G-colony stimulating factor HDAc High-dose cytarabine HSCT Haematopoietic stem cell transplant IFI Invasive fungal infection LVSF Left ventricular shortening fraction MRC Medical Research Council MRD Minimal residual disease OS Overall survival TKI Tyrosine kinase inhibitor TRM Treatment-related mortality UK United Kingdom WBC White blood cell count DATA AVAILABILITY STATEMENT The data that support the findings of this study are available from the corresponding author upon reasonable request. [Extracted from the article]

New agent development rests on the fundamental assumption that candidate agents or drug combinations that induce objective responses after relapse will prevent relapse, if applied prior to relapse. However, cumulative experience now includes at least 5 examples of interventions with post-relapse objective response rates greater than 50% that failed to improve outcomes when applied prior to relapse. Emerging insights into oligoclonality provide some explanation. In acute lymphoblastic leukaemia, the predominant clones at relapse differ from the predominant clones at presentation. Arguably, the more highly proliferative clones that predominate at relapse differ in drug sensitivity from the less proliferative clones that escape primary therapy. Interventions effective against the predominant clones at relapse may have no effect on the antecedent escapee clones. Response is not sufficient in new agent development. Duration of response has attracted less attention because of variability in post-remission therapy but some patient subsets have such a uniformly dismal outcome that details of post-remission therapy may be irrelevant. Benchmarks are needed. Are recovering blasts members of the same clone or do they represent a new clone? When you eradicate the predominant clones you get a response. When you eradicate all clones, you get a cure. [ABSTRACT FROM AUTHOR]

Background: The objectives of this study were to assess the incidence of clinical allergy and end-induction antiasparaginase (anti-ASNase) antibodies in children with high-risk acute lymphoblastic leukemia treated with pegylated (PEG) Escherichia coli ASNase and to determine whether they carry any prognostic significance.Methods: Of 2057 eligible patients, 1155 were allocated to augmented arms in which PEG ASNase replaced native ASNase postinduction. Erwinia chrysanthemi (Erwinia) ASNase could be used to replace native ASNase after allergy, if available. Allergy and survival data were complete for 990 patients. End-induction antibody titers were available for 600 patients.Results: During the consolidation phase, 289 of 990 patients (29.2%) had an allergic reaction. There were fewer allergic reactions to Erwinia ASNase than to native ASNase (odds ratio, 4.33; P < .0001) or PEG ASNase (odds ratio, 3.08; P < .0001) only during phase 1 of interim maintenance. There was no significant difference in 5-year event-free survival (EFS) between patients who received PEG ASNase throughout the entire study postinduction versus those who developed an allergic reaction to PEG ASNase during consolidation phase and subsequently received Erwinia ASNase (80.8% ± 2.8% and 81.6% ± 3.8%, respectively; P = .66). Patients who had positive antibody titers postinduction were more likely to have an allergic reaction to PEG ASNase (odds ratio, 2.4; P < .001). The 5-year EFS rate between patients who had negative versus positive antibody titers (80% ± 2.6% and 77.7% ± 4.3%, respectively; P = .68) and between patients who did not receive any ASNase postconsolidation and those who received PEG ASNase throughout the study (P = .22) were significantly different.Conclusions: The current results demonstrate differences in the incidence rates of toxicity between ASNase preparations but not in EFS. The presence of anti-ASNase antibodies did not affect EFS. [ABSTRACT FROM AUTHOR]

Leukemia is the most common pediatric cancer. Despite great progress in the development of curative therapy, leukemia remains a leading cause of death from disease in childhood, and survivors are at life-long risk of complications of treatment. New agents are needed to further increase cure rates and decrease treatment-associated toxicities. The complex biology and aggressive nature of childhood leukemia, coupled with the relatively small patient population available for study, pose specific challenges to the development of new therapies. In this review, the authors discuss strategies and initiatives designed to improve access to new agents in the treatment of pediatric leukemia. Cancer 2015;121:1927-1936. © 2015 American Cancer Society. [ABSTRACT FROM AUTHOR]

Children and adolescents presenting with a markedly elevated white blood cell ( ME WBC) count ( WBC ≥200 × 109/l) comprise a unique subset of high-risk patients with acute lymphoblastic leukaemia ( ALL). We evaluated the outcomes of the 251 patients (12% of the study population) with ME WBC treated on the Children's Cancer Group-1961 protocol. Patients were evaluated for early response to treatment by bone marrow morphology; those with a rapid early response were randomized to treatment regimens testing longer and stronger post-induction therapy. We found that ME WBC patients have a poorer outcome compared to those patients presenting with a WBC <200 × 109/l (5-year event-free survival 62% vs. 73%, P = 0·0005). Longer duration of therapy worsened outcome for T cell ME WBC with a trend to poorer outcome in B- ALL ME WBC patients. Augmented therapy benefits T cell ME WBC patients, similar to the entire study cohort, however, there appeared to be no impact on survival for B- ALL ME WBC patients. ME WBC was not a prognostic factor for T cell patients. In patients with high risk features, B lineage disease in association with ME WBC has a negative impact on survival. [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]

In single-arm, two-stage phase II clinical trials to evaluate efficacy of cancer treatments using a response endpoint, one typically identifies a single reference response rate to be the null hypothesis benchmark. Patients eligible for the trial are assumed to have this response rate on average under the null hypothesis. When patients arise from subpopulations having different response rates, this single response rate reference may not be appropriate for the particular mix of patients actually enrolled on the trial. As a result, the Type I and Type II error rates conditional on the mix of enrolled patients may differ considerably from the unconditional error rates used to design the trial. We describe a method for designing two-stage Phase II studies that accounts for patient heterogeneity and effectively stabilizes conditional Type I and Type II error over the range of patient mixes that are likely to arise. Use of the design requires good estimates of the expected response rate within each population stratum as well as the stratum membership probabilities, but its properties are similar to and often preferable to the standard two-stage design even in situations where the underlying assumptions do not hold absolutely. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

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]

The author discusses a study by A. Bertaina and colleagues, published within the issue, on the use of bortezomib and chemotherapy to treat relapsed/refractory acute lymphoblastic leukemia of childhood. Topics include finding on the Therapeutic Advances in Childhood Leukaemia (TACL) trial on remission rates, how post-induction outcomes may be confounded, and the survival benefit of an inotuzumab-induced remission.

Children and adolescents presenting with a markedly elevated white blood cell (ME WBC) count (WBC ≥200 × 10(9) /l) comprise a unique subset of high-risk patients with acute lymphoblastic leukaemia (ALL). We evaluated the outcomes of the 251 patients (12% of the study population) with ME WBC treated on the Children's Cancer Group-1961 protocol. Patients were evaluated for early response to treatment by bone marrow morphology; those with a rapid early response were randomized to treatment regimens testing longer and stronger post-induction therapy. We found that ME WBC patients have a poorer outcome compared to those patients presenting with a WBC <200 × 10(9) /l (5-year event-free survival 62% vs. 73%, P = 0·0005). Longer duration of therapy worsened outcome for T cell ME WBC with a trend to poorer outcome in B-ALL ME WBC patients. Augmented therapy benefits T cell ME WBC patients, similar to the entire study cohort, however, there appeared to be no impact on survival for B-ALL ME WBC patients. ME WBC was not a prognostic factor for T cell patients. In patients with high risk features, B lineage disease in association with ME WBC has a negative impact on survival., (© 2014 John Wiley & Sons Ltd.)