Search

5-year overall survival rates have surpassed 90% for childhood acute lymphocytic leukaemia, but survivors are at risk for permanent health sequelae. Although event-free survival appropriately represents the outcome for cancers with poor overall survival, this metric is inadequate when cure rates are high but challenged by serious, persistent complications. Accordingly, a group of experts in paediatric haematology-oncology, representative of 17 international acute lymphocytic leukaemia study groups, launched an initiative to construct a measure, designated severe toxicity-free survival (STFS), to quantify the occurrence of physician-prioritised toxicities to be integrated with standard cancer outcome reporting. Five generic inclusion criteria (not present before cancer diagnosis, symptomatic, objectifiable, of unacceptable severity, permanent, or requiring unacceptable treatments) were used to assess 855 health conditions, which resulted in inclusion of 21 severe toxicities. Consensus definitions were reached through a modified Delphi process supplemented by two additional plenary meetings. The 21 severe toxicities include severe adverse health conditions that substantially affect activities of daily living and are refractory to therapy (eg, refractory seizures), are without therapeutic options (eg, blindness), or require substantially invasive treatment (eg, cardiac transplantation). Incorporation of STFS assessment into clinical trials has the potential to improve and diversify treatment strategies, focusing not only on traditional outcome events and overall survival but also the frequencies of the most severe toxicities. The two major aims of this Review were to: prioritise and define unacceptable long-term toxicity for patients with childhood acute lymphocytic leukaemia, and define how these toxicities should be combined into a composite quantity to be integrated with other reported outcomes. Although STFS quantifies the clinically unacceptable health tradeoff fo

Background: The aim of this study was to assess whether minimal residual disease (MRD) at the end of induction front-line treatment can serve as a surrogate endpoint for event-free survival (EFS) in childhood B-lineage acute lymphoblastic leukemia. Methods: The analysis was based on individual data of 4830 patients from two large phase III trials that asked a randomized question on the effect of different corticosteroids (dexamethasone vs prednisone) during induction chemotherapy on EFS. The association between MRD classified in three ordered categories (negative = 0, low positive = (>0 and <5 x 10(-4)), and positive = (>= 5 x 10(-4)] and EFS at the individual and trial levels was evaluated with the meta-analytic approach based on the Plackett copula model. Centers within trial were grouped according to geographical area, and a total of 28 units were identified for the analysis. Results: MRD at the end of induction was a poor surrogate for treatment effect on EFS at the trial level, with R-trial(2) = 0.09 (95% confidence interval [CI] = 0.00 to 0.29), whereas at the individual level it was strongly associated with EFS, with an odds ratio of 3.90 (95% CI = 3.35 to 4.44) of failure for patients with higher compared with lower MRD levels. Additional sensitivity and relevant subgroup analyses confirmed these findings at both trial- and patient-level association.Conclusions: Although MRD is a robust biomarker highly predictive of outcome for individual patients, clinicians and regulatory bodies should be cautious in using early MRD response in the context of complex multiagent acute lymphoblastic leukemia therapy as an early surrogate endpoint to predict the effect of a randomized treatment intervention on long-term EFS

Background: Infants with acute lymphoblastic leukemia (ALL) have a poor prognosis. Intensification of therapy has resulted in fewer relapses but increased early deaths, resulting in failure to improve survival. Procedure: AALL0631 is a Phase 3 study for infants (<366 days of age) with newly diagnosed ALL. Induction initially (Cohort 1) consisted of 3 weeks of therapy based on COG P9407. Due to excessive early mortality, induction was amended to a less intensive 5 weeks of therapy based on Interfant-99. Additionally, enhanced supportive care guidelines were incorporated with hospitalization during induction until evidence of marrow recovery and recommendations for prevention/treatment of infections (Cohort 2). Results: Induction mortality was significantly lower for patients in Cohort 2 (2/123, 1.6%) versus Cohort 1 (4/26, 15.4%; P=0.009). All induction deaths were infection related except one due to progressive disease (Cohort 2). Sterile site infections were lower for patients in Cohort 2 (24/123, 19.5%) versus Cohort 1 (15/26, 57.7%; P=0.0002), with a significantly lower rate of Gram positive infections during induction for patients in Cohort 2, P=0.0002. No clinically significant differences in grades 3-5 non-infectious toxicities were observed between the two cohorts. Higher complete response rates were observed at end induction intensification for Cohort 2 (week 9, 94/100, 94%) versus Cohort 1 (week 7, 17/25, 68%; P=0.0.0012). Conclusion: De-intensification of induction therapy and enhanced supportive care guidelines significantly decreased induction mortality and sterile site infections, without decreasing complete remission rates.

PURPOSE Second malignant neoplasms (SMNs) after diagnosis of childhood acute lymphoblastic leukemia (ALL) are rare events. PATIENTS AND METHODS We analyzed data on risk factors and outcomes of 642 children with SMNs occurring after treatment for ALL from 18 collaborative study groups between 1980 and 2007. Results Acute myeloid leukemia (AML; n = 186), myelodysplastic syndrome (MDS; n = 69), and nonmeningioma brain tumor (n = 116) were the most common types of SMNs and had the poorest outcome (5-year survival rate, 18.1% ± 2.9%, 31.1% ± 6.2%, and 18.3% ± 3.8%, respectively). Five-year survival estimates for AML were 11.2% ± 2.9% for 125 patients diagnosed before 2000 and 34.1% ± 6.3% for 61 patients diagnosed after 2000 (P < .001); 5-year survival estimates for MDS were 17.1% ± 6.4% (n = 36) and 48.2% ± 10.6% (n = 33; P = .005). Allogeneic stem-cell transplantation failed to improve outcome of secondary myeloid malignancies after adjusting for waiting time to transplantation. Five-year survival rates were above 90% for patients with meningioma, Hodgkin lymphoma, thyroid carcinoma, basal cell carcinoma, and parotid gland tumor, and 68.5% ± 6.4% for those with non-Hodgkin lymphoma. Eighty-nine percent of patients with brain tumors had received cranial irradiation. Solid tumors were associated with cyclophosphamide exposure, and myeloid malignancy was associated with topoisomerase II inhibitors and starting doses of methotrexate of at least 25 mg/m(2) per week and mercaptopurine of at least 75 mg/m(2) per day. Myeloid malignancies with monosomy 7/5q- were associated with high hyperdiploid ALL karyotypes, whereas 11q23/MLL-rearranged AML or MDS was associated with ALL harboring translocations of t(9;22), t(4;11), t(1;19), and t(12;21) (P = .03). CONCLUSION SMNs, except for brain tumors, AML, and MDS, have outcomes similar to their primary counterparts.

Gene expression profiling was performed on 97 cases of infant ALL from Children's Oncology Group Trial P9407. Statistical modeling of an outcome predictor revealed 3 genes highly predictive of event-free survival (EFS), beyond age and MLL status: FLT3, IRX2, and TACC2. Low FLT3 expression was found in a group of infants with excellent outcome (n = 11; 5-year EFS of 100%), whereas differential expression of IRX2 and TACC2 partitioned the remaining infants into 2 groups with significantly different survivals (5-year EFS of 16% vs 64%; P < .001). When infants with MLL-AFF1 were analyzed separately, a 7-gene classifier was developed that split them into 2 distinct groups with significantly different outcomes (5-year EFS of 20% vs 65%; P < .001). In this classifier, elevated expression of NEGR1 was associated with better EFS, whereas IRX2, EPS8, and TPD52 expression were correlated with worse outcome. This classifier also predicted EFS in an independent infant ALL cohort from the Interfant-99 trial. When evaluating expression profiles as a continuous variable relative to patient age, we further identified striking differences in profiles in infants less than or equal to 90 days of age and those more than 90 days of age. These age-related patterns suggest different mechanisms of leukemogenesis and may underlie the differential outcomes historically seen in these age groups. (Blood. 2012; 119(8):1872-1881)

One of the challenges of incorporating molecularly targeted drugs into multi-agent chemotherapy (backbone) regimens is defining dose-limiting toxicities (DLTs) of the targeted agent against the background of toxicities of the backbone regimen. An international panel of 22 pediatric acute lymphocytic leukemia (ALL) experts addressed this issue (www.ALLNA.org). Two major questions surrounding DLT assessment were explored: (1) how toxicities can be best defined, assessed, and attributed; and (2) how effective dosing of new agents incorporated into multi-agent ALL clinical trials can be safely established in the face of disease- and therapy-related systemic toxicities. The consensus DLT definition incorporates tolerance of resolving Grade 3 and some resolving Grade 4 toxicities with stringent safety monitoring. This functional DLT definition is being tested in two Children's Oncology Group (COG) ALL clinical trials. © 2010 Wiley-Liss, Inc.