Dabigatran in the treatment and secondary prophylaxis of venous thromboembolism in children with thrombophilia.

In the phase 2b/3 DIVERSITY trial, 3 months treatment with dabigatran was noninferior to standard of care (SOC) for acute venous thromboembolism (VTE) in children. In a single-arm, phase 3, secondary VTE prevention study, up to 12 months dabigatran use was associated with favorable safety. Dabigatran is approved by the European Medicines Agency and US Food and Drug Administration for pediatric indications. We assessed primary composite efficacy (complete thrombus resolution and freedom from VTE recurrence/VTE-related death) in subgroups with thrombophilia vs those with negative/unknown thrombophilia status in the DIVERSITY trial and safety in both studies. Thrombophilia types were similar between the DIVERSITY trial (total population) and secondary prevention studies: factor V Leiden, 42% vs 33%; prothrombin mutation (G20210A), 19% vs 17%; antithrombin deficiency, 15% vs 20%; protein C/S deficiency, 23% vs 25%; and antiphospholipid antibodies, 18% vs 20% of patients, respectively. In DIVERSITY, 36% and 22% of thrombophilia subgroup patients treated with dabigatran and SOC, respectively, met the primary end point (Mantel-Haenszel-weighted rate difference, -0.135; 95% confidence interval, -0.36 to 0.08; noninferiority P = .0014); comparable to the total DIVERSITY trial population (46% vs 42%) showing dabigatran noninferiority to SOC. Within this subgroup, numerically fewer patients experienced VTE recurrence or progression of index thrombus in the dabigatran treatment group vs SOC. In the secondary prevention study, VTE recurrence at 12 months occurred in 2.8% of patients with thrombophilia vs 0% with negative/unknown thrombophilia. Safety profiles were consistent with those reported previously. Although they should be interpreted with caution, these exploratory findings suggest dabigatran could be an appropriate long-term anticoagulant for children with thrombophilia. These trials were registered at www.clinicaltrials.gov as #NCT01895777 and #NCT02197416.

Pilot Study of Adding Vincristine, Topotecan, and Cyclophosphamide to Interval-Compressed Chemotherapy in Newly Diagnosed Patients With Localized Ewing Sarcoma: A Report From the Children's Oncology Group.

BACKGROUND: The combination of topotecan and cyclophosphamide is active in relapsed Ewing sarcoma family of tumors (ESFT). The feasibility of adding these agents combined with vincristine (vincristine-topotecan-cyclophosphamide [VTc]) to standard five-drug chemotherapy with vincristine-doxorubicin-cyclophosphamide (VDC) and ifosfamide-etoposide (IE) administered in an interval-compressed (2-week instead of 3-week intervals) schedule was investigated. PROCEDURE: Newly diagnosed patients with localized ESFT < 31 years, with good performance status and adequate organ function were eligible. Seventeen alternating cycles of chemotherapy with VTc, VDC, and IE were administered at 2-week intervals. Local control (LC) of the primary tumor occurred following six cycles. Primary endpoints were the ability to deliver chemotherapy in an interval-compressed schedule, and the rate of grade 3 or greater nonhematologic toxicity and grade 4 hematologic toxicity, which delayed chemotherapy by ≥2 weeks. Secondary endpoints were event-free survival (EFS) and overall survival (OS). RESULTS: Thirty-five patients with a median age of 11 years were enrolled. The mean time to last dose of chemotherapy prior to LC was 12.6 ± 1.4 weeks and 45.5% of patients received intended chemotherapy without any delay prior to LC. There were no toxic deaths or unexpected toxicities. Five-year EFS was 79.6% (95% confidence interval [CI]: 61.8-89.7%) and 5-year OS was 88% (95% CI: 71.4-95.3%). CONCLUSIONS: The addition of VTc to standard therapy was tolerable with sufficient interval compression compared to historical standard 3-week cycles.

Identification of Discrete Prognostic Groups in Ewing Sarcoma.

BACKGROUND: Although multiple prognostic variables have been proposed for Ewing sarcoma (EWS), little work has been done to further categorize these variables into prognostic groups for risk classification. PROCEDURE: We derived initial prognostic groups from 2,124 patients with EWS in the SEER database. We constructed a multivariable recursive partitioning model of overall survival using the following covariates: age; stage; race/ethnicity; sex; axial primary; pelvic primary; and bone or soft tissue primary. Based on this model, we identified risk groups and estimated 5-year overall survival for each group using Kaplan-Meier methods. We then applied these groups to 1,680 patients enrolled on COG clinical trials. RESULTS: A multivariable model identified five prognostic groups with significantly different overall survival: (i) localized, age <18 years, non-pelvic primary; (ii) localized, age <18, pelvic primary or localized, age ≥18, white, non-Hispanic; (iii) localized, age ≥18, all races/ethnicities other than white, non-Hispanic; (iv) metastatic, age <18; and (v) metastatic, age ≥18. These five groups were applied to the COG dataset and showed significantly different overall and event-free survival based upon this classification system (P < 0.0001). A sub-analysis of COG patients treated with ifosfamide and etoposide as a component of therapy evaluated these findings in patients receiving contemporary therapy. CONCLUSIONS: Recursive partitioning analysis yields discrete prognostic groups in EWS that provide valuable information for patients and clinicians in determining an individual patient's risk of death. These groups may enable future clinical trials to adjust EWS treatment according to individualized risk.

Regulatory barriers to clinical trial enrollment of adolescent and young adult oncology patients.

Adolescent and young adult (AYA) patients with cancer may face unique challenges if they and their families wish to participate in clinical oncology trials. Regulatory guidelines and funding requirements put in place to protect patients may actually raise barriers to enrollment in clinical trials. Hospital age guidelines may need to be readdressed to better suit the needs of AYA patients. Finally, the creation of the National Clinical Trials Network will provide new opportunities for pediatric and medical oncologists to collaborate in the care of AYA patients.

Children's Oncology Group's 2013 blueprint for research: adolescent and young adult oncology.

The discipline of Adolescent and Young Adult (AYA) Oncology addresses compelling medical and psychosocial needs of AYA patients across the spectrum of cancer survivorship. To be successful, extraordinary collaboration involving multiple scientific disciplines and specialties is required. While AYA Oncology is international in scope, recent AYA-focused studies conducted in the Children's Oncology Group (COG) have documented survival disparities, toxicity differences, and biological insights that provide the basis for new COG trials and initiatives for this population. This experience will be useful in leveraging the new United States National Cancer Institute Clinical Trials Network to transform AYA Oncology research.

A pilot study of low-dose anti-angiogenic chemotherapy in combination with standard multiagent chemotherapy for patients with newly diagnosed metastatic Ewing sarcoma family of tumors: A Children's Oncology Group (COG) Phase II study NCT00061893.

BACKGROUND: The aims of this study were to determine the feasibility of the combination of low dose, anti-angiogenic chemotherapy with standard therapy for patients with metastatic Ewing sarcoma (ES), and to obtain preliminary outcome data. PROCEDURES: Patients with metastatic ES were eligible. Therapy consisted of alternating cycles of ifosfamide-etoposide, and vincristine, doxorubicin, cyclophosphamide. Vinblastine and celecoxib were concomitantly administered. Surgical, radiotherapeutic, or combination local control therapy was given per institutional preference. RESULTS: Thirty-five eligible patients were enrolled. Ninety percent received at least 75% of planned vinblastine/celecoxib doses. There was no excess of neurologic, infectious, hemorrhagic, or cardiovascular toxicities. However, 7 of 21 patients who received pulmonary irradiation prior to experiencing pulmonary toxicity did develop grade 2 or greater pulmonary toxicity, including two deaths of apparent radiation pneumonitis. Fourteen of 16 patients with pelvic disease received local irradiation. Hemorrhagic cystitis developed in six patients, five of whom had received pelvic irradiation. The overall 24-month event free survival was 35% (19-51%); 71% (26-92%) for the seven with isolated pulmonary metastases, 26% (10-45%) for all others. CONCLUSION: The combination of vinblastine/celecoxib metronomic therapy with standard ES treatment was feasible according to the protocol definitions. However, excess toxicity in irradiated areas was noted and limits the usefulness of this protocol. The 24-month EFS for those with isolated pulmonary metastases is better than historical controls, although the number of patient number is small, follow up short and we are lacking contemporaneous controls.

Increasing diversity in pediatric hematology/oncology.

BACKGROUND: Diversity is necessary for the survival and success of both biological and social systems including societies. There is a lack of diversity, particularly the proportion of women and minorities in leadership positions, within medicine [Leadley. AAMC 2009. Steinecke and Terrell. Acad Med 2010;85:236-245]. In 2009 a group of ASPHO members recognized the need to support the career advancement of women and minority members. This article reports the results of a survey designed to characterize the comparative career pathway experience of women and minority ASPHO members. PROCEDURE: A group of ASPHO members modified a published Faculty Worklife survey [Pribbenow et al. High Educ Policy 2010;23:17-38] for use by Pediatric Hematologist-Oncologists (PHOs). A link to an online version of the survey was sent to all ASPHO members. RESULTS: Of 1,228 ASPHO members polled, 213 responded (17%). Women and minority PHOs reported less satisfaction than their counterparts on 70 of the 90 issues addressed in the survey including the hiring process, access to resources as well as integration and satisfaction with their organizations. Women also expressed greater dissatisfaction with issues of work-life balance, support for family obligations and personal health. CONCLUSIONS: The current literature suggests that there are significant disparities in career opportunities, compensation and satisfaction for women compared to men and minority compared to majority faculty in academic medicine [Nivet. J Vasc Surg 2010;51:53S-58S; Peterson et al. J Gen Intern Med 2004;19:259-265; DesRoches et al. Acad Med 2010;85:631-639; Castillo-Page. AAMC 2008]. Our data, derived from a survey of ASPHO members, suggests that this holds true for PHOs as well.

Localized purpura associated with lamotrigine.

Antiepileptic drug hypersensitivity syndrome consists of fever, rash, and internal organ involvement and usually occurs within the first 2 months of initiation of therapy. This report describes a 13-year-old female with a right frontal high-grade glioma and complex partial seizures who developed localized purpura after 23 months of lamotrigine monotherapy. This case study is the second report of localized purpura after prolonged lamotrigine treatment suggesting this may be an atypical lamotrigine-induced drug reaction.

Toxicity and efficacy of intensive chemotherapy for children with acute lymphoblastic leukemia (ALL) after first bone marrow or extramedullary relapse.

BACKGROUND: Approximately 25% of children newly diagnosed with acute lymphoblastic leukemia (ALL) will eventually experience leukemic relapse, with bone marrow being the most common site of recurrence. The ability to achieve a durable second remission is complicated by toxicity and resistant disease. We report a novel combination of chemotherapy for relapsed pediatric ALL. PROCEDURE: Thirty pediatric patients with relapsed medullary (n = 18) and extra-medullary (n = 12) ALL were enrolled at three pediatric institutions. Following receipt of induction and the first Block A and Block B of intensification, each patient was evaluated for toxicity, efficacy in achieving remission, and long-term survival. Additionally, minimal residual disease (MRD) detection by multidimensional flow cytometry (MDF) was performed. RESULTS: During induction, the major non-hematopoeitic toxicities were mucositis (30% of patients) and bacteremia (50% of patients). Two patients (7%) died of toxicity during induction. Toxicity during intensification Block 1A and 1B was markedly reduced. Eight-nine percent of patients with marrow disease achieved a remission following induction and intensification. The event-free survival (EFS) for all patients at 2 and 4 years were 60% (95% CI: 42-78%) and 49% (95% CI: 30-68%), respectively. CONCLUSIONS: This regimen for patients with relapsed ALL was successful in achieving a second remission for the majority of patients with acceptable toxicity.

Asparaginase pharmacokinetics after intensive polyethylene glycol-conjugated L-asparaginase therapy for children with relapsed acute lymphoblastic leukemia.

PURPOSE: Asparaginase therapy is an important component in the treatment of children with acute lymphoblastic leukemia. Polyethylene glycol-conjugated asparaginase (PEG-ASNase) has significant pharmacological advantages over native Escherichia coli asparaginase. We investigated the pharmacokinetics of PEG-ASNase, presence of antibodies to PEG-ASNase, and concentrations of asparagine in serum and cerebrospinal fluid (CSF) in combination chemotherapy for relapsed pediatric acute lymphoblastic leukemia. EXPERIMENTAL DESIGN: Twenty-eight pediatric patients with relapsed medullary (n = 16) and extramedullary (n = 11) acute lymphoblastic leukemia were enrolled at three pediatric institutions and had at least two serum and CSF samples obtained for analysis. Patients received induction therapy (including PEG-ASNase 2500 IU/m2 intramuscularly weekly on days 2, 9, 16, and 23) and intensification therapy (including PEG-ASNase 2500 IU/m2 intramuscularly once on day 7). Serum samples were obtained weekly during induction and intensification. CSF samples were obtained during therapeutic lumbar punctures during induction and intensification. RESULTS: Weekly PEG-ASNase therapy resulted in PEG-ASNase activity of >0.1 IU/ml in 91-100% of patients throughout induction. During intensification, PEG-ASNase on day 7 resulted in PEG-ASNase activity >0.1 IU/ml in 94% and 80% of patients on days 14 and 21, respectively. Serum and CSF asparagine depletion was observed and maintained during induction and intensification in the majority of samples. PEG-ASNase antibody was observed in only 3 patients. CONCLUSIONS: Intensive PEG-ASNase therapy in the treatment of relapsed acute lymphoblastic leukemia reliably results in high-level serum PEG-ASNase activity, and asparagine depletion in serum and CSF is usually achieved. Incorporation of intensive PEG-ASNase in future trials for recurrent acute lymphoblastic leukemia is warranted.

Intensive induction chemotherapy and delayed irradiation in the management of parameningeal rhabdomyosarcoma.

PURPOSE: To evaluate local control, event-free survival, and overall survival for patients with parameningeal (PM) rhabdomyosarcoma (RMS) treated with intensive chemotherapy and delayed irradiation. PATIENTS AND METHODS: Thirteen consecutive patients with PM RMS were treated with an institutional protocol from 1992 to 1998 at the University of Washington/Children's Hospital and Regional Medical Center and Deaconess Medical Center. Patients received intensive chemotherapy consisting of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide prior to radiotherapy. Irradiation was delayed, in contrast to current Intergroup Rhabdomyosarcoma Study Group (IRSG) recommendations. RESULTS: Median follow-up was 39 months. Eleven patients had high-risk features, including five with intracranial extension. All patients responded to the intensive chemotherapy, with 38% exhibiting a complete response and the remaining 62% a partial response. Radiation was administered a median of 21 weeks from initiation of chemotherapy. The Kaplan-Meier estimate of 5-year local control was 92%, with event-free survival and overall survival rates of 83%. CONCLUSIONS: With intensive induction chemotherapy, delayed irradiation for PM RMS does not compromise local control. Event-free survival and overall survival rates compare favorably with recently IRSG trials employing early irradiation. Delaying irradiation allows for intensification of chemotherapy and could permit response-based radiation volume and/or dose modifications, which could decrease treatment-related morbidity.

Peripheral blood stem cell support reduces the toxicity of intensive chemotherapy for children and adolescents with metastatic sarcomas.

BACKGROUND: To increase the dose intensity (DI) of chemotherapy for pediatric patients with metastatic sarcomas, including the Ewing sarcoma family of tumors (ESFT) and rhabdomyosarcoma (RMS), the authors tested the feasibility of an intensive regimen supported by granulocyte-colony stimulating factor (G-CSF) and peripheral blood stem cells (PBSC). METHODS: Twenty-three children and adolescents with metastatic sarcomas received vincristine, doxorubicin, cyclophosphamide, ifosfamide, sodium mercaptoethanesulfonate (mensa), and etoposide (VACIME) chemotherapy, consisting of 8 courses of vincristine 2 mg/m(2) on Day 0, doxorubicin 37.5 mg/m(2) per day on Days 0-1, cyclophosphamide 360 mg/m(2) per day on Days 0-4, ifosfamide 1800 mg/m(2) per day on Days 0-4, mesna 2400 mg/m(2) per day, and etoposide 100 mg/m(2) per day on Days 0-4. Doxorubicin was omitted in Courses 7 and 8. G-CSF was given after each course of therapy. Courses of therapy were repeated every 21 days or as soon as hematopoietic recovery permitted. PBSC were collected twice: first, after Course 2 (infused after Courses 3 and 4) and, second, after Course 4 (infused after Courses 5 and 6). Surgical resection followed Course 6, and radiotherapy followed Course 8. RESULTS: PBSC collections were adequate in 91% of all harvests. The mean DI was 82% (standard deviation, 14%) of the intended DI, which was greater than historic data without PBSC support. Seventeen patients (74%) achieved a complete response (CR), 12 patients with chemotherapy alone and 5 more patients after undergoing surgical resection. Fifteen patients developed progressive disease, with a 2-year event free survival (EFS) rate of 39% (95% confidence interval, 19-59%). Hematopoietic toxicity was severe and cumulative, although it was less than that seen previously without PBSC support. CONCLUSIONS: PBSC-supported multicycle chemotherapy is a feasible method to increase chemotherapy DI for pediatric patients with metastatic sarcomas. Although the CR rate compared favorably with previously reported response rates, the 2-year EFS rate was similar to that achieved with other intensive regimens.