Rituximab for High-Risk, Mature B-Cell Non-Hodgkin's Lymphoma in Children.

BACKGROUND: Rituximab added to chemotherapy prolongs survival among adults with B-cell cancer. Data on its efficacy and safety in children with high-grade, mature B-cell non-Hodgkin's lymphoma are limited. METHODS: We conducted an open-label, international, randomized, phase 3 trial involving patients younger than 18 years of age with high-risk, mature B-cell non-Hodgkin's lymphoma (stage III with an elevated lactate dehydrogenase level or stage IV) or acute leukemia to compare the addition of six doses of rituximab to standard lymphomes malins B (LMB) chemotherapy with standard LMB chemotherapy alone. The primary end point was event-free survival. Overall survival and toxic effects were also assessed. RESULTS: Analyses were based on 328 patients who underwent randomization (164 patients per group); 85.7% of the patients had Burkitt's lymphoma. The median follow-up was 39.9 months. Events were observed in 10 patients in the rituximab-chemotherapy group and in 28 in the chemotherapy group. Event-free survival at 3 years was 93.9% (95% confidence interval [CI], 89.1 to 96.7) in the rituximab-chemotherapy group and 82.3% (95% CI, 75.7 to 87.5) in the chemotherapy group (hazard ratio for primary refractory disease or first occurrence of progression, relapse after response, death from any cause, or second cancer, 0.32; 95% CI, 0.15 to 0.66; one-sided P = 0.00096, which reached the significance level required for this analysis). Eight patients in the rituximab-chemotherapy group died (4 deaths were disease-related, 3 were treatment-related, and 1 was from a second cancer), as did 20 in the chemotherapy group (17 deaths were disease-related, and 3 were treatment-related) (hazard ratio, 0.36; 95% CI, 0.16 to 0.82). The incidence of acute adverse events of grade 4 or higher after prephase treatment was 33.3% in the rituximab-chemotherapy group and 24.2% in the chemotherapy group (P = 0.07); events were related mainly to febrile neutropenia and infection. Approximately twice as many patients in the rituximab-chemotherapy group as in the chemotherapy group had a low IgG level 1 year after trial inclusion. CONCLUSIONS: Rituximab added to standard LMB chemotherapy markedly prolonged event-free survival and overall survival among children and adolescents with high-grade, high-risk, mature B-cell non-Hodgkin's lymphoma and was associated with a higher incidence of hypogammaglobulinemia and, potentially, more episodes of infection. (Funded by the Clinical Research Hospital Program of the French Ministry of Health and others; ClinicalTrials.gov number, NCT01516580.).

Improving the outcome for children with cancer: Development of targeted new agents.

The outcome for children with cancer has improved significantly over the past 60 years, with greater than 80% of patients today becoming 5-year survivors. Despite this progress, cancer remains the leading cause of death from disease in children in the United States, and significant short-term and long-term treatment toxicities continue to impact the majority of children with cancer. The development of targeted new agents offers the prospect of potentially more effective and less toxic treatment for children. More than a decade since imatinib mesylate was introduced into the treatment of children with Philadelphia chromosome-positive acute lymphoblastic leukemia, transforming its outcome, a range of targeted agents has undergone study in pediatric cancer patients. Early lessons learned from these studies include a better understanding of the adverse event profile of these drugs in children, the challenge of developing pediatric-specific formulations, and the continued reliance on successful development for adult cancer indications on pediatric drug development. The collaborative research infrastructure for children with cancer in the United States is well positioned to advance novel treatments into clinical investigations for a spectrum of rare and ultra-rare childhood cancers. A greater investment of resources in target discovery and validation can help drive much needed development of new, more effective treatments for children with cancer.

Pediatric cancer research: Surviving COVID-19.

A diverse panel of pediatric cancer advocates and experts, whose collective experience spans the continuum of international academic medicine, industry, government research, and cancer advocacy, recently discussed challenges for pediatric cancer research in the context of coronavirus disease 2019 (COVID-19). Specifically, this special report addresses the following focus areas: (a) the critical role that translational research has played in transforming pediatric cancer outcomes; (b) the current and potential future impact of COVID-19 on pediatric cancer research; (c) target areas of COVID-19 research that may have application in immunity, oncogenesis, and therapeutic discovery; and (d) future considerations and directions in maintaining pediatric cancer research during and after COVID-19.

Fundamental problems with pediatric adaptive dosing of carboplatin using nuclear-medicine-based estimates of renal function.

BACKGROUND: Carboplatin is often adaptively dosed based on glomerular filtration rate (GFR), usually estimated by nuclear medicine tests. At least five pediatric adaptive dosing formulas have been developed. In an effort to standardize dosing in Children's Oncology Group protocols, we explored methodologic variation in GFR estimation and adaptive-dosing formula performance. PROCEDURE: Nuclear medicine GFR data from published series of ≥100 children with cancer were compared. Data from patients for whom body surface area, weight, GFR, and tracer half-life were available were used to compare formulas. RESULTS: Differences in methods used to estimate GFR in children with cancer resulted in highly variable population results, with median GFRs ranging from 96 to 150 mL/min/1.73m2 . The choice of adaptive formula had a major impact on calculated dose. When targeting an area under the curve of 7.9 mg/mL • min, the median difference between the formula yielding the lowest and highest carboplatin dose for individual subjects was 289 (range 96-1 737) mg/m2 . CONCLUSIONS: Wide variation in GFR obtained with nuclear-medicine-based tests in children with cancer primarily results from systematic methodologic errors. Formulas for calculating carboplatin dose produce additional and substantial variation that may place children with cancer at unnecessary risk for excessive toxicity or underdosing. These findings indicate a need for the development of a uniform, validated method for GFR determination in children that should be utilized in all centers. Currently, adaptive dosing of carboplatin based on GFR has serious limitations and in most clinical settings should arguably not be used in place of body-surface-area-based dosing.

Unintended consequences of evolution of the Common Terminology Criteria for Adverse Events.

BACKGROUND: Adverse events (AEs) on Children's Oncology Group (COG) trials are reported manually by clinical research assistants (CRAs). The Common Terminology Criteria for Adverse Events (CTCAE) was developed to provide standardized definitions for identifying and grading AEs. The CTCAE has expanded significantly over its five versions, but the impact of CTCAE definitional changes has not been examined. PROCEDURE: This study compared AE number and ascertainment among the first four CTCAE versions using a case vignette. Each CTCAE version was used to create a list of AEs and grades by two separate CRAs. RESULTS: The CTCAE expanded from 9 categories and 49 AEs in v1.0 to 26 categories and 790 AEs in v4.0. CRAs independently selected different approaches to AE ascertainment-comprehensive and parsimonious. The number of AEs identified in the parsimonious approach was stable with 10-14 in each CTC version. The comprehensive approach identified 9, 20, 29, and 37 AEs in CTC versions 1.0, 2.0, 3.0, and 4.0, respectively. Only approximately 65% of AEs were conclusively graded in versions 2.0 to 4.0 using the comprehensive approach. CONCLUSIONS: CTCAE has increased in complexity. Although this increased complexity allows for more granular AE reporting, these data demonstrate potential unintended negative consequences of increasing CTC AE complexity, including the risk of varying approaches to AE capture. A comprehensive evaluation of CTC AE definitions and CRA reporting practices across COG institutions and AEs are needed to improve the accuracy and efficiency of AE reporting.

Insights into pediatric rhabdomyosarcoma research: Challenges and goals.

Overall survival rates for pediatric patients with high-risk or relapsed rhabdomyosarcoma (RMS) have not improved significantly since the 1980s. Recent studies have identified a number of targetable vulnerabilities in RMS, but these discoveries have infrequently translated into clinical trials. We propose streamlining the process by which agents are selected for clinical evaluation in RMS. We believe that strong consideration should be given to the development of combination therapies that add biologically targeted agents to conventional cytotoxic drugs. One example of this type of combination is the addition of the WEE1 inhibitor AZD1775 to the conventional cytotoxic chemotherapeutics, vincristine and irinotecan.

Outcome of pediatric patients with acute lymphoblastic leukemia/lymphoblastic lymphoma with hypersensitivity to pegaspargase treated with PEGylated Erwinia asparaginase, pegcrisantaspase: A report from the Children's Oncology Group.

BACKGROUND: Erwinia asparaginase is a Food and Drug Administration approved agent for the treatment of acute lymphoblastic leukemia (ALL) for patients who develop hypersensitivity to Escherichia coli derived asparaginases. Erwinia asparaginase is efficacious, but has a short half-life, requiring six doses to replace one dose of the most commonly used first-line asparaginase, pegaspargase, a polyethylene glycol (PEG) conjugated E. coli asparaginase. Pegcristantaspase, a recombinant PEGylated Erwinia asparaginase with improved pharmacokinetics, was developed for patients with hypersensitivity to pegaspargase. Here, we report a series of patients treated on a pediatric phase 2 trial of pegcrisantaspase. PROCEDURE: Pediatric patients with ALL or lymphoblastic lymphoma and hypersensitivity to pegaspargase enrolled on Children's Oncology Group trial AALL1421 (Jazz 13-011) and received intravenous pegcrisantaspase. Serum asparaginase activity (SAA) was monitored before and after dosing; immunogenicity assays were performed for antiasparaginase and anti-PEG antibodies and complement activation was evaluated. RESULTS: Three of the four treated patients experienced hypersensitivity to pegcrisantaspase manifested as clinical hypersensitivity reactions or rapid clearance of SAA. Immunogenicity assays demonstrated the presence of anti-PEG immunoglobulin G antibodies in all three hypersensitive patients, indicating a PEG-mediated immune response. CONCLUSIONS: This small series of patients, nonetheless, provides data, suggesting preexisting immunogenicity against the PEG moiety of pegaspargase and poses the question as to whether PEGylation may be an effective strategy to optimize Erwinia asparaginase administration. Further study of larger cohorts is needed to determine the incidence of preexisting antibodies against PEG-mediated hypersensitivity to pegaspargase.

Dosing anticancer drugs in infants: Current approach and recommendations from the Children's Oncology Group's Chemotherapy Standardization Task Force.

An analysis of dose modifications for infants in 29 Children's Oncology Group protocols across 10 cancer types revealed 11 sets of criteria defining the infant population using age, weight, body surface area (BSA), or a combination of these parameters and eight dose modification methods. A new method of dosing anticancer drugs in infants was developed based on the rationale that prior modifications were implemented to reduce toxicity, which is not cancer-specific. The new method uses BSA dose banding in dosing tables for infants and children with a BSA <0.6 m2 and gradually transitions from body weight based to BSA-based dosing.

The impact of chemotherapy shortages on COG and local clinical trials: a report from the Children's Oncology Group.

BACKGROUND: Oncology drug shortage is associated with increased patient adverse events and decreased enrollment on clinical trials for adult patients; however, the impact of oncology drug shortages has not been well studied in children with cancer. PROCEDURE: The Children's Oncology Group (COG) distributed a 5-item survey to 226 COG site-specific principal investigators (PI's) and 14-item survey to 161 COG pharmacists to gather data the impact of chemotherapeutic shortages on clinical trials and patient care. RESULTS: The response rate was 66.4% (150/226) for PI's and 29.8% (48/161) for pharmacists. COG PI's reported daunorubicin (73%), methotrexate (56%), asparaginase/PEG-asparaginase (42%), doxorubicin (26%), thiotepa (21%), and cytarabine (20%) were most commonly in shortage, while COG pharmacists reported daunorubicin (80%), methotrexate (66%), vincristine (21%), thiotepa (41%), asparaginase/PEG-asparaginase (34%), and cytarabine (34%) were most commonly in shortage over the past two years. Pharmacists were twice as likely to report a shortage compared with PI's (OR 2.1, 95% CI: 1.6-2.7, P < 0.0001). Fifty percent (74/147) of COG PI's reported at least one patient enrolled on a clinical trial was impacted by drug shortage, and 66% (98/148) of COG PI's reported at least one patient had clinical care impacted by drug shortage. CONCLUSIONS: Chemotherapy shortages remain widespread across institutions, hinder clinical trials, and may contribute to adverse events in children with cancer. The increased frequency of chemotherapy shortages reported by pharmacists suggests that pharmacist efforts may mitigate negative impact chemotherapy shortages. Over half of pediatric institutions are implementing recommendations to address shortages, such as cross-institutional collaboration and center-level guidelines.

Growth plate abnormalities in pediatric cancer patients undergoing phase 1 anti-angiogenic therapy: a report from the Children's Oncology Group Phase I Consortium.

BACKGROUND: Pre-clinical studies suggest that anti-angiogenic agents may be toxic to the developing growth plate. The purpose of this study was to evaluate the incidence of growth plate abnormalities in children with refractory cancer undergoing anti-angiogenic therapy. PROCEDURE: Targeted radiographic studies from 53 subjects enrolled on six separate Children's Oncology Group Phase 1 and Pilot Consortium clinical trials evaluating new anti-cancer agents interfering with angiogenesis were reviewed. Subjects received tyrosine kinase inhibitors with anti-angiogenic effects (n = 35), monoclonal antibodies targeting vascular endothelial growth factor (VEGF) (n = 13), or angiopoietin (n = 5). Radiographs of their distal femur/proximal tibia were obtained at baseline. Follow-up radiographs were obtained after odd-numbered treatment cycles in patients with open growth plates who did not experience disease progression prior to cycle 3. RESULTS: Baseline and follow-up growth plate radiographs were acquired in 48/53 (90%) of patients. Five patients (9.4%), all of whom received a specific VEGF/VEGFR blocking agent (sunitinib [n = 1] or pazopanib [n = 4]), had growth plate abnormalities. Four patients had growth plate widening that was apparent on at least two successive radiographs, but was not confirmed by MRI. The fifth patient had progressive growth plate widening and evidence of physeal cartilage hypertrophy on MRI. Subsequent off treatment radiographs showed that the growth plate changes were reversible. CONCLUSION: Growth plate abnormalities occur in a small, but relevant number of patients undergoing anti-angiogenic therapy. These results support the need for growth plate monitoring in children with open growth plates who are receiving anti-angiogenic therapy, and for improved methods to assess toxicity of anti-angiogenic agents to the developing skeleton.

Comparison of in-patient costs for children treated on the AAML0531 clinical trial: A report from the Children's Oncology Group.

BACKGROUND: A better understanding of drivers of treatment costs may help identify effective cost containment strategies and prioritize resources. We aimed to develop a method for estimating inpatient costs for pediatric patients with acute myeloid leukemia (AML) enrolled on NCI-funded Phase III trials, compare costs between AAML0531 treatment arms (standard chemotherapy ± gemtuzumab ozogamicin (GMTZ)), and evaluate primary drivers of costs for newly diagnosed pediatric AML. PROCEDURE: Patients from the AAML0531 trial were matched on hospital, sex, and dates of birth and diagnosis to the Pediatric Health Information Systems (PHIS) database to obtain daily billing data. Inpatient treatment costs were calculated as adjusted charges multiplied by hospital-specific cost-to-charge ratios. Generalized linear models were used to compare costs between treatment arms and courses, and by patient characteristics. RESULTS: Inpatient costs did not differ by randomized treatment arm. Costs varied by course with stem cell transplant being most expensive, followed by Intensification II (cytarabine/mitoxantrone) and Induction I (cytarabine/daunorubicin/etoposide). Room/board and pharmacy were the largest contributors to inpatient treatment cost, representing 74% of the total cost. Higher AML risk group (P = 0.0003) and older age (P < 0.0001) were associated with significantly higher daily inpatient cost. CONCLUSIONS: Costs from external data sources can be successfully integrated into NCI-funded Phase III clinical trials. Inpatient treatment costs did not differ by GMTZ exposure but varied by chemotherapy course. Variation in cost by course was driven by differences in duration of hospitalization through room/board charges as well as increased clinical and pharmacy charges in specific courses.

Re-induction chemoimmunotherapy with epratuzumab in relapsed acute lymphoblastic leukemia (ALL): Phase II results from Children's Oncology Group (COG) study ADVL04P2.

BACKGROUND: Given the success of immunotherapeutic approaches in hematologic malignancies, the COG designed a phase I/II study to determine whether the addition of epratuzumab (anti-CD22) to an established chemotherapy platform improves rates of second remission (CR2) in pediatric patients with B-lymphoblastic leukemia (B-ALL) and early bone marrow relapse. PROCEDURE: Therapy consisted of three established blocks of re-induction chemotherapy. Epratuzumab (360 mg/m(2)/dose) was combined with chemotherapy on weekly × 4 (B1) and twice weekly × 4 [eight doses] (B2) schedules during the first re-induction block. Remission rates and minimal residual disease (MRD) status were compared to historical rates observed with the identical chemotherapy platform alone. RESULTS: CR2 was achieved in 65 and 66%, of the evaluable B1 (n = 54) and B2 patients (n = 60), respectively; unchanged from that observed historically without epratuzumab. Rates of MRD negativity (<0.01%) were 31% in B1 (P = 0.4128) and 39% in B2 patients (P = 0.1731), compared to 25% in historical controls. The addition of epratuzumab was well tolerated, with a similar toxicity profile to that observed with the re-induction chemotherapy platform regimen alone. CONCLUSIONS: Epratuzumab was well tolerated in combination with re-induction chemotherapy. While CR2 rates were not improved compared to historical controls treated with chemotherapy alone, there was a non-significant trend towards improvement in MRD response with the addition of epratuzumab (twice weekly for eight doses) to re-induction chemotherapy.

Declining childhood and adolescent cancer mortality.

BACKGROUND: To evaluate whether progress continues in identifying more effective treatments for children and adolescents with cancer, the authors examined both overall and disease-specific childhood cancer mortality rates for the United States, focusing on data from 2000 to 2010. METHODS: Age-adjusted US mortality trends from 1975 to 2010 were estimated using joinpoint regression analysis. Analyses of annual percentage change (APC) were performed on the same diagnostic groupings for the period restricted to 2000 through 2010 for groupings ages <20 years, <15 years, and 15 to 19 years. RESULTS: After a plateau in mortality rates during 1998 to 2002 (APC, 0.3%), the annual decline in childhood cancer mortality from 2002 to 2010 (APC, -2.4%) was similar to that observed from 1975 to 1998 (APC, -2.7%). Statistically significant declines in mortality rates from 2000 to 2010 were noted for acute lymphoblastic leukemia, acute myeloid leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, neuroblastoma, central nervous system cancers, and gonadal cancers. From 2000 to 2010, the rates of decline in mortality for the group ages 15 to 19 years generally were equal to or greater than the rates of decline for the group ages birth to 14 years. Improvements in treatment since 1975 resulted >45,000 cancer deaths averted through 2010. CONCLUSIONS: Cancer mortality for both children and adolescents declined from 2000 to 2010, with significant declines observed for multiple cancer types. However, greater than 1900 cancer deaths still occur each year among children and adolescents in the United States, and many survivors experience long-term effects that limit their quality of life. Continued research directed toward identifying more effective treatments that produce fewer long-term sequelae is critical to address these remaining challenges.

The Children's Oncology Group Childhood Cancer Research Network (CCRN): case catchment in the United States.

BACKGROUND: The Childhood Cancer Research Network (CCRN) was established within the Children's Oncology Group (COG) in July 2008 to provide a centralized pediatric cancer research registry for investigators conducting approved etiologic and survivorship studies. The authors conducted an ecological analysis to characterize CCRN catchment at >200 COG institutions by demographic characteristics, diagnosis, and geographic location to determine whether the CCRN can serve as a population-based registry for childhood cancer. METHODS: During 2009 to 2011, 18,580 US children newly diagnosed with cancer were registered in the CCRN. These observed cases were compared with age-specific, sex-specific, and race/ethnicity-specific expected numbers calculated from Surveillance, Epidemiology, and End Results (SEER) Program cancer incidence rates and 2010 US Census data. RESULTS: Overall, 42% of children (18,580 observed/44,267 expected) who were diagnosed with cancer at age <20 years were registered in the CCRN, including 45%, 57%, 51%, 44%, and 24% of those diagnosed at birth, ages 1 to 4 years, ages 5 to 9 years, ages 10 to 14 years, and ages 15 to 19 years, respectively. Some malignancies were better represented in the CCRN (leukemia, 59%; renal tumors, 67%) than others (retinoblastoma, 34%). There was little evidence of differences by sex or race/ethnicity, although rates in nonwhites were somewhat lower than rates in whites. CONCLUSIONS: Given the low observed-to-expected ratio, it will be important to identify challenges and barriers to registration to improve case ascertainment, especially for rarer diagnoses and older age groups; however, it is encouraging that some diagnoses in younger children are fairly representative of the population. Overall, the CCRN is providing centralized, real-time access to cases for research and could be used as a model for other national cooperative groups.

Preclinical evaluation of the PARP inhibitor, olaparib, in combination with cytotoxic chemotherapy in pediatric solid tumors.

BACKGROUND: Poly(ADP-ribose) polymerase (PARP) signals DNA damage and facilitates DNA repair. PARP inhibitors are being evaluated in cancers with defective DNA repair mechanisms or in combination with cytotoxic therapy or radiation. We evaluated the PARP inhibitor, olaparib, in combination with chemotherapy using in vitro and in vivo pediatric solid tumor models. PROCEDURE: The IC50 of olaparib alone and in combination with cytotoxic agents was determined in 10 pediatric solid tumor cell lines. Synergy was assessed using the combination index of Chou-Talalay. Olaparib alone and in combination with topotecan/cyclophosphamide was evaluated in xenograft models of Ewing sarcoma (RD-ES) and neuroblastoma (NGP). PAR activity was evaluated in cell lines and tumor lysates. RESULTS: Olaparib induced growth inhibition, median (range) IC50 = 3.6 (1-33.8) µM, and inhibited PAR activity in pediatric solid tumor cell lines. The addition of olaparib to DNA damaging agents resulted in additive to synergistic interactions. In RD-ES and NGP xenografts, olaparib inhibited PAR activity by 88-100% as a single agent and 100% when administered with cyclophosphamide/topotecan. Although the addition of olaparib did not antagonize the activity of cyclophosphamide/topotecan, clear evidence of synergy could not be demonstrated. CONCLUSIONS: In pediatric solid tumor cell lines, clinically achievable concentrations of single agent olaparib caused growth inhibition. Although the in vitro data demonstrated synergistic efficacy of olaparib when added to the camptothecins and alkylating agents, synergy was not discernible in vivo. Clinical trials of PARP inhibitors in combination DNA damaging agents are necessary to establish the role of PARP inhibitors in childhood cancer.

Phase 1 trial of temsirolimus in combination with irinotecan and temozolomide in children, adolescents and young adults with relapsed or refractory solid tumors: a Children's Oncology Group Study.

BACKGROUND: mTOR inhibitors have activity in pediatric tumor models. A phase I trial of the mTOR inhibitor temsirolimus (TEM) with irinotecan (IRN) and temozolomide (TMZ) was conducted in children with recurrent/refractory solid tumors, including central nervous system (CNS) tumors. METHODS: Escalating doses of intravenous (IV) TEM were administered on days 1 and 8 of 21-day cycles. IRN (50 mg/m(2)/dose escalated to a maximum of 90 mg/m(2)/dose) and TMZ (100 mg/m(2)/dose escalated to a maximum of 150 mg/m(2)/dose) were administered orally (PO) on days 1-5. When maximum tolerated doses (MTD) were identified, TEM frequency was increased to weekly. RESULTS: Seventy-one eligible pts (median age 10.9 years, range 1.0-21.5) with neuroblastoma (16), osteosarcoma (7), Ewing sarcoma (7), rhabdomyosarcoma (4), CNS (22) or other (15) tumors were enrolled. Dose-limiting hyperlipidemia occurred in two patients receiving oral corticosteroids. The protocol was subsequently amended to preclude chronic steroid use. The MTD was identified as TEM 35 mg/m(2) IV weekly, with IRN 90 mg/m(2) and TMZ 125 mg/m(2) PO on days 1-5. At higher dose levels, elevated serum alanine aminotransferase and triglycerides, anorexia, and thrombocytopenia were dose limiting. Additional ≥ grade 3 regimen-related toxicities included leukopenia, neutropenia, lymphopenia, anemia, and nausea/vomiting. Six patients had objective responses confirmed by central review; three of these had sustained responses through ≥ 14 cycles of therapy. CONCLUSION: The combination of TEM (35 mg/m(2)/dose IV weekly), IRN (90 mg/m(2)/dose days 1-5) and TMZ (125 mg/m(2)/dose days 1-5) administered PO every 21 days is well tolerated in children. Phase 2 trials of this combination are ongoing.