bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and activity of venetoclax in combination with high-dose cytarabine in children with relapsed or refractory acute myeloid leukemia.
Authors: Karol Seth E , Alexander Thomas , Das Gupta Soumyasri , Pounds Stanley B. , Canavera Kristin , Klco Jeffery M , Lacayo Norman James , Pui Ching-Hon , Opferman Joseph T , Rubnitz Jeffrey E 
Published: May 2019

10004 Background: Venetoclax is an orally available BCL-2 antagonist with demonstrated activity in adults with newly diagnosed or relapsed acute myeloid leukemia (AML). Here, we describe the first use of venetoclax 1) in combination with high-dose cytarabine and idarubicin 2) in patients 2-22 years old with relapsed AML. Methods: Patients with relapsed AML or AML refractory to at least two courses of induction therapy were enrolled in this Phase 1 study with a rolling-six design. All patients received venetoclax (240 or 360 mg/m2) on days 1-28 and low-dose (LD: 100 mg/m2 every 12 hours x 20 doses) or high-dose (HD: 1000 mg/m2 every 12 hours x 8 doses) cytarabine beginning on day 8 (Table). Patients who had previously received < 270 mg/m2 of doxorubicin equivalents also received idarubicin 12 mg/m2 on day 8 in dose level 4; other patients were enrolled on the expansion cohort at dose level 3. Non-hematologic CTCAE grade 3 or higher toxicities were intensity limiting (ILT), excluding those anticipated with HD cytarabine. Results: Among 18 evaluable patients, a single ILT (prolonged hematological suppression beyond day 50) was observed (Table). Toxicities were consistent with the underlying cytotoxic chemotherapy, with 14 patients experiencing a total of 40 grade 3 toxicities including 6 documented infections and 23 episodes of febrile neutropenia. There was 1 grade 4 fungal sepsis. The recommended phase 2 dose of venetoclax was 360 mg/m2 (max 600 mg) when combined with HD cytarabine or HD cytarabine/idarubicin. Of the 12 patients with > 50% reduction in blasts following the 7-day venetoclax window therapy, end-of-cycle marrow responses included 7 CR/CRi and 3 PR. Minimal residual disease negative remissions occurred in 4 patients. BH3 profiling of samples and a phase 2 expansion of both dose levels 3 and 4 to further characterize the promising activity of these combinations are underway. Conclusions: Venetoclax combined with cytarabine or cytarabine/idarubicin is active and well tolerated in pediatric patients with relapsed/ refractory AML. Clinical trial information: NCT03194932. [Table: see text]
Randomized use of anti-GD2 antibody dinutuximab beta (DB) long-term infusion with and without subcutaneous interleukin-2 (scIL-2) in high-risk neuroblastoma patients with relapsed and refractory disease: Results from the SIOPEN LTI-trial.
Authors: Lode Holger N. , Valteau-Couanet Dominique , Gray Juliet , Luksch Roberto , Wieczorek Aleksandra , Castel Victoria , Ash Shifra , Laureys Genevieve , Papadakis Vassilios , Owens Cormac , Garaventa Alberto , Manzitti Carla , Siebert Nikolai , Troschke-Meurer Sascha , Glogova Evgenia , Poetschger Ulrike , Ladenstein Ruth Lydia 
Published: May 2019

10014 Background: We determined the role of scIL-2 combined with long term infusion (LTI) of DB in patients (pts) with high-risk relapsed/refractory neuroblastoma. Methods: 160 pts were enrolled into an open label SIOPEN Phase II clinical trial (EudraCT 2009-018077-31). Pts were randomly assigned to receive up to 5 cycles of 100 mg/m2 DB-LTI (d8-17) and 160 mg/m2 oral isotretinoin (d19-32) (81 pts) with and without 6x106IU/m2 scIL-2 (d1-5; 8-12) (79 pts). Endpoints were toxicity, response rates and 2yrs-event free and -overall survival. Results: Between 07/2014 and 07/2017, 160 pts from 11 countries were randomised. Median follow-up is 2.6 years. Pts were well balanced between arms according to stage, age, MYCN amplification, patients with relapse and remission status. The 2yrs-EFS and -OS for DB (81 pts) vs. DB combined with scIL-2 (79 pts) was 59%±6% vs 65%±6% (p = 0.721) and 79%±5% vs 84%±4% (p = 0.904). In 97 pts with evaluable disease, a response rate of 49% (9% CR, 40% PR) vs 52% (26% CR, 26% PR) after treatment with DB vs DB and scIL-2 was observed. Grade 3&4 fever (16% vs 46%, P = 0.000), allergic reaction (1% vs 14%, P = 0.004), hematological toxicity (46% vs 66%, P = 0.013) and neurotoxicity (0% vs 8%, p = 0.003) were significantly worse in the combination arm, but no difference was seen for capillary leak, gastrointestinal, liver enzyme elevation and pain. Paraplegia possibly related to the treatment was observed in 2 pts in the combination arm, none in the arm without scIL-2, and one resolved to baseline. A subgroup of 34 pts who had a relapse and measurable disease at treatment start, showed a 2yrs-EFS and -OS in DB (17 pts) vs DB combined with scIL-2 (17 pts) of 35%±12% vs 69%±12% (p = 0.116) and 59%±12% vs 81%±10% (p = 0.167). However, this trend was statistically not significant. Pharmacokinetic and HACA response between both arms was not different with overlapping antibody concentration-time curves and a HACA response of 15/81 (19%) (DB) vs 16/79 (20%) (DB and scIL-2). Conclusions: No significant difference in efficacy of DB combined with scIL-2 and increased toxicity in this arm suggests that this schedule of scIL-2 is of no additional benefit. Clinical trial information: 2009-018077-31.
Outcomes of adolescent males with extracranial malignant germ cell tumors compared with children and young adults: A report from the Malignant Germ Cell Tumors International Consortium (MaGIC) group.
Authors: Shaikh Furqan , Stark Daniel P. , Dang Ha , Xia Caihong , Krailo Mark D. , Stenning Sally Patricia , Pashankar Farzana D. , Rodriguez-Galindo Carlos , Olson Thomas Arthur , Hale Juliet , Depani Sarita , Stoneham Sara , Nicholson James , Murray Matthew , Amatruda James F. , Billmire Deborah F , Fonseca Adriana , Frazier A. Lindsay 
Published: May 2019

10022 Background: Adolescents with extracranial malignant germ cell tumors (GCTs) are often treated on the same regimens developed for children, but more closely resemble the clinical characteristics of young adult patients. We sought to determine whether event-free survival (EFS) for adolescents with GCTs was more like that of children or young adults. Methods: We assembled an individual patient database of ten GCT trials: seven conducted by pediatric cooperative groups and three by an adult group. We selected male patients aged 0-30 years old treated with platinum-based chemotherapy for non-seminomatous malignant GCTs of the testis, retroperitoneum, or mediastinum. We categorized age-group as children (0 to < 11 years), adolescents (11 to < 18 years), or young adults (18 to < 30 years old). We compared EFS among age groups, and adjusted for calculated IGCCCG risk-group using Cox proportional hazards analysis. Results: 593 patients met inclusion criteria, of whom 90 were children, 109 were adolescents, and 394 were young adults. The 5-year EFS for adolescents (72%; CI = 62-79%) was significantly lower than for children (90%; CI = 81-95%, p = 0.003) and for young adults (88%; CI = 84-91%, p < 0.001). Risk-group was significantly associated with EFS in the adolescent age-group (p = 0.002). In a Cox multivariable analysis, the difference between adolescents and children remained statistically significant (HR = 0.30, p = 0.001), but the difference between adolescents and young adults did not (HR 0.66, p = 0.114). Conclusions: EFS for adolescent patients with extracranial malignant GCTs was similar to young adults but significantly worse than children. This finding may have important implications for how adolescent patients are treated.
Outcome of children with malignant germ cell tumors by response status at the end of induction chemotherapy.
Authors: Fonseca Adriana , Villaluna Doojduen , Krailo Mark D. , Frazier A. Lindsay , Shaikh Furqan 
Published: May 2019

10023 Background: The management of pediatric malignant germ cell tumors (MGCTs) includes induction therapy with 3-4 cycles cisplatin, etoposide, bleomycin (PEb). The current practice recommends 2-3 cycles of PEb (total 6 cycles) as consolidation therapy if response is not complete at the end of induction, a significantly different approach than that used in adult patients who receive a standard number of cycles. Furthermore, there is no evidence supporting the addition of a consolidation phase with PEb in pediatric patients with MGCTs. Methods: We retrospectively reviewed all patients enrolled in a phase III, single-arm trial for low-risk and intermediate-risk MGCTs (AGCT0132). All patients received 3 cycles of PEb and underwent response assessment at the end of induction. Complete Response (CR) was defined as negative tumor markers and no viable residual lesion. Patients in CR were not to receive any further chemotherapy. Patients not in CR were prescribed 3 additional cycles of PEb as consolidation. Event-free survival (EFS) and Overall survival (OS) was calculated using the Kaplan-Meier method. Results: Among 210 patients enrolled, 193 patients had CR after 3 cycles of induction chemotherapy, and their post-induction 4yr-EFS and OS was 93% and 99%. Fifteen patients were not in CR at the end of the first 3 cycles and received additional chemotherapy, and their 4yr-EFS and OS was 51% and 60%. Conclusions: Children with MGCTs who have a partial response after the first 3 cycles of chemotherapy had an inferior outcome compared to those with a CR, despite receiving additional cycles of PEb chemotherapy. Thus, we conclude that consolidation is of unclear benefit. Although our results are limited by small sample size and lack of comparator, we propose that pediatric MGCT patients who fail to achieve a CR after standard induction chemotherapy should receive a salvage regimen with different agents rather than consolidation with more cycles of the same chemotherapy.
High-dose naxitamab plus stepped-up dosing of GM-CSF for high-risk neuroblastoma (HR-NB): Efficacy against histologically-evident primary refractory metastases in bone marrow (BM).
Authors: Kushner Brian H. , Modak Shakeel , Basu Ellen M. , Roberts Stephen S. , Cheung Nai-Kong V. 
Published: May 2019

10024 Background: Cure of HR-NB often requires ablating BM metastases that are chemoresistant and survive 131I-metaiodobenzylguanidine (MIBG) therapy. BM is ideal for immunotherapy with anti-GD2 antibodies including naxitamab (humanized-3F8; granted FDA’s breakthrough designation in 2018) because of excellent accessibility to antibody, complement, and effector cells. GM-CSF exerts a dose-response effect in antibody-dependent cellular cytotoxicity and significantly improves outcome with murine-3F8 ( JCO 2012;30:426). Methods: We evaluated HR-NB patients with histologically-evident chemoresistant disease in BM, but no soft tissue or prior progressive disease, for response to naxitamab+GM-CSF on protocol (NCT01757626). Cycles comprised naxitamab infused intravenously (30 minutes) x3 (Mon-Wed-Fri) and subcutaneously-administered GM-CSF starting 5 days pre-naxitamab in priming doses of 250µg/m2/day, then stepped-up to 500µg/m2/day beginning with antibody. Naxitamab was dose-escalated in the phase I portion and 9mg/kg/cycle (~270mg/m2/cycle, i.e., > 2.5x dosage of ch14.18) in the phase I/II expansion. BM was assessed post-cycle 2 in aspirates+biopsies from bilateral posterior and anterior iliac crests. Cycles were monthly but were deferred if human anti-human antibody (HAHA) developed. Results: The 19 patients enrolled through 5/2018 were 5m-to-19m (median 7.5m) post-diagnosis and age 2y10m-to-10y1m (median 5y2m). Included were 5 phase I and 14 phase I/II patients. Histology showed primitive NB in 12 and ganglioneuromatous cells in 7 patients. All (100%) patients achieved complete response (CR) in BM. 16 patients also had NB in bone/BM by 123I-MIBG scan; the latter showed CR in 12 (75%). 11 patients remained progression-free 20+-to-54+ (median 27+) months from enrollment, including 10 treated with anti-NB vaccine. HAHA developed in 2 patients post-cycle 2. Toxicities were as expected ( JAMA Oncol 2018;4:1729). Conclusions: Naxitamab+GM-CSF is effective against chemoresistant NB in BM, supporting further development of naxitamab which is proceeding in a pivotal international trial (NCT02502786). Clinical trial information: NCT01757626.
Frailty among childhood cancer survivors: A report from the Childhood Cancer Survivor Study (CCSS).
Authors: Hayek Samah , Gibson Todd M. , Leisenring Wendy , Guida Jennifer Lyn , Gramatges Maria Monica , Lupo Philip , Howell Rebecca M. , Oeffinger Kevin C. , Bhatia Smita , Edelstein Kim , Hudson Melissa M. , Robison Leslie L. , Nathan Paul C. , Yasui Yutaka , Krull Kevin R. , Armstrong Gregory T. , Ness Kirsten K. 
Published: May 2019

10026 Background: Childhood cancer survivors are at increased risk for frailty, which is a loss of physiological capacity that is typically observed among older adults. Aims: Estimate the prevalence of frailty among survivors, and examine direct and indirect effects of treatment, lifestyle, and chronic disease factors on frailty. Methods: CCSS participants who were > 5-year survivors of childhood cancer, diagnosed between 1970-1999 at <21 years of age (n=10,899, 48% male), and siblings (n=2,097, 42% male) were included. Frailty was defined from self-reported data at mean ages of 37.6±9.4 and 42.9±9.8 years for survivors and siblings, respectively, as ≥3 of the following: low lean mass, exhaustion, low energy expenditure, slow walking, and weakness. Results: The prevalence of frailty among survivors was higher compared to siblings (5.8%, 95% CI: 5.4-6.3% vs. 1.9%, 95% CI 1.4-2.5%). Prevalence was highest in survivors of CNS tumors (9.5%, 5.2-13.8%), bone sarcomas (8.1%, 5.1-11.1%) and Hodgkin lymphoma (7.5%, 4.9-10.1%). In models adjusted for sex, age at assessment, and race/ethnicity, treatment exposures were associated with frailty (Table). After adjusting for the presence of chronic diseases and lifestyle factors, these associations were attenuated. Conclusions: The prevalence of frailty among survivors (6.0% at 38 years of age) was similar to the general population aged ≥65 years (9.0%). Radiation, platinum, amputation and thoracotomy increased risk for frailty. Findings suggest interventions to prevent, delay onset, or remediate chronic disease and/or promote healthy lifestyle are needed to preserve function in this population. [Table: see text]
A phase II trial testing interventions to shorten time to diagnosis and reduce abandonment of treatment of children with Burkitt lymphoma in Kenya.
Authors: Langat Sandra , Njuguna Festus , Mostert Saskia , Lotodo Therese , Kigen Nikol , Boaz Odwar , Kaspers Gert Jan , Moormann Ann , Vance Gail , Loehrer Patrick J. , Vik Terry 
Published: May 2019

10032 Background: Burkitt Lymphoma (BL) is a common pediatric cancer in sub-Saharan Africa. Despite advances in care, prognosis is poor. The BL treatment protocol at our center in Kenya used since 2010, had a one-year survival of 29% (Martijn et al. BMJ Paed Open 2017). We hypothesized that financial burdens and delays in start of therapy impact outcomes. Methods: Our trial tested interventions aimed to: 1) Shorten time from presentation to start of treatment to improve survival; and 2) Support families during therapy to reduce abandonment. Initial eligibility included clinical suspicion of BL in a child 0-13 years of age. Patients with confirmed diagnosis of a mature B-cell lymphoma received support to complete therapy. Children with prior treatment of cancer were excluded. The trial was approved by human protection boards in Kenya and Indiana and consent was obtained prior to study entry. We enrolled 96 children with possible BL. Study personnel expedited routing of tissue samples to laboratories. Touch preps or smears were stained with Giemsa and reviewed by pathologists. Fresh tissue from all sources was used for flow cytometry. Tissue from core needle or incisional biopsies was processed for routine and immunohistochemical staining. Of 96 patients, 43 had BL confirmed by pathologic studies and were treated with combination chemotherapy given over 25 weeks. We paid families for transport costs for care, called after missed appointments, and provided direct monetary support (~$200 USD) for the 200 days children were on treatment. Results: Facilitating the biopsy shortened, by 3 days, the median time from admission to initiation of therapy for BL, because families did not need to raise funds for testing. Monetary support reduced abandonment of treatment by patients. Only 2 of 43 (5%) patients abandoned therapy, compared to abandonment by 22 of a cohort of 63 (35%) patients treated previously (p < 0.001). The combination of rapid diagnosis, early therapy, and financial support and communication with families improved event free survival of children with BL to 50% at 1 year (p = 0.045). Conclusions: Simple interventions to improve efficiency of diagnosis and reduce abandonment leads to improved outcomes for children with BL in Kenya.
Impact of low-income public insurance on survival for children and young adults with bone and soft tissue sarcomas.
Authors: Penumarthy Neela Lakshmi , Goldsby Robert , Penumarthy Lena 
Published: May 2019

10037 Background: Racial and ethnic survival disparities have been described for many pediatric malignancies, but the impact of income has not been extensively explored. To assess whether socioeconomic status affects outcomes, we evaluated low-income public health insurance as a proxy. We analyzed how low-income public health insurance influences overall survival in children, adolescents, and young adults diagnosed with bone and soft tissue sarcomas. Methods: The University of California San Francisco Cancer Registry was used to identify patients age 0-39 diagnosed with bone or soft tissue sarcomas between 2000-2015. Low-income patients were defined as those with Medicaid, which is only available under state law to eligible low-income individuals or families, or those with no insurance. The comparison group included all other patients with private insurance, Medicare, or Tricare. Survival curves were computed using the Kaplan-Meier method and compared using log-rank tests and Cox models. Logistic regression was used to investigate the association of low-income public insurance and presence of metastatic disease at diagnosis. Results: A total of 1,106 patients were included in the analysis. 444 (40%) were considered low-income; of these, 428 (39%) had public insurance and 16 (1%) had no insurance. Low-income patients were more likely to both be racial/ethnic minorities and present with metastatic disease on multivariable analysis. Low-income patients had significantly worse 5-year OS (61% vs 71%, p = 0.0003). When stratified by localized, regional, or metastatic disease, low-income patients consistently had significantly worse 5-year OS (localized: 78% vs 84%, regional: 64% vs 73%, metastatic: 23% vs 30% respectively, p < 0.0001). Age and race/ethnicity did not significantly impact OS in this study population. Conclusions: Low-income patients with bone and soft tissue sarcomas had decreased overall survival. While these patients were more likely to have metastatic disease, disparities in survival were noted even within the localized and regional disease groups. The means by which insurance status impacts survival requires additional investigation, but may be through reduced access to care.
Evaluation of the multi-kinase inhibitor regorafenib in the Pediatric Preclinical Testing Consortium osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma in vivo models.
Authors: Harrison Douglas James , Gill Jonathan Benjamin , Roth Michael , Zhang Wendong , Teicher Beverly , Erickson Stephen W , Gatto Gregory , Kurmasheva Raushan , Houghton Peter , Smith Malcolm A. , Kolb E. Anders , Gorlick Richard Greg 
Published: May 2019

10038 Background: Regorafenib is a multi-kinase inhibitor, developed by adding a fluorine atom to the phenyl ring of sorafenib. Regorafenib inhibits multiple kinases including BRAF, FGFR1, KIT, PDGFRB, RAF, RET, and VEGFR1-3, many at a higher potency than sorafenib. Prior studies within the Pediatric Preclinical Testing Consortium (PPTC) demonstrated sorafenib exhibited intermediate activity for tumor growth inhibition in more than 50% of the sarcoma models tested at a dose of 60mg/kg by oral gavage daily (5 days/wk for 6 consecutive weeks). The in vivo effects of regorafenib were studied in the PPTC osteosarcoma (OS), rhabdomyosarcoma (Rh) and Ewing (EW) sarcoma xenograft models. Methods: The in vivo anticancer effects of regorafenib were assessed in a panel of 6 osteosarcoma models (OS2, OS9, OS31, OS33, OS36, OS60), two rhabdomyosarcoma models (Rh30, Rh41), and one Ewing sarcoma model (EW5). Regorafenib was administered by oral gavage at a dose of 30 mg/kg/day given daily for 21 consecutive days. Time to event and tumor volume responses were defined and analyzed utilizing standard PPTC statistical methods. Results: Regorafenib induced significant improvements in event-free survival (EFS) compared to control in 100% (9/9) of sarcoma models tested. Most models showed pronounced slowing of tumor growth compared to control during the 21 days of regorafenib treatment, with tumor growth generally approximating control rates soon after completion of regorafenib treatment. Three out of 8 sarcoma models demonstrated EFS T/C values > 2 (1/6 OS, 2/2 Rh, 0/1 EW). Minimum relative tumor volumes ranged from 0.74 to 1.60, with no models meeting criteria for objective response. Conclusions: Regorafenib induced modest inhibition of tumor growth in the PPTC sarcoma models evaluated. The overall pattern of response to the multi-kinase inhibitor regorafenib against the PPTC sarcoma models appears similar to that of the kinase inhibitor sorafenib, with pronounced slowing of tumor growth in some models that is limited to the period of agent administration being the primary treatment effect.