bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-term survival after alternative donor transplantation in children with acute leukemia.
Authors: Collins Chelsea Lee , Ahn Kwang Woo , Wang Zhiwei , Eapen Mary 
Published: March 2020

10006 Background: Most reports describing long-term survival after allogeneic transplantation are in adults after transplantation of bone marrow (BM) from HLA-matched siblings. This report compares long-term survival after transplantation of unrelated donor BM to that after umbilical cord blood (UCB) in children with acute leukemia. Methods: Included were patients aged less than 18 years with acute myeloid or lymphoblastic leukemia, alive and leukemia-free for at least 1 year after transplantation. Transplants occurred 2000-2009. Patients received BM grafts that were HLA-matched (N = 205) or mismatched at 1-HLA locus (N = 112) and UCB grafts that were matched (N = 55) or mismatched at 1 (N = 160) or 2 HLA-loci (N = 134). Multivariate Cox regression models were constructed to explore differences in survival between groups. UCB transplants were treated as a single group as there were no significant differences between HLA-matched and mismatched UCB grafts. Multivariate models held 3 treatment groups: HLA-matched BM, HLA-mismatched BM and UCB grafts. Results: The disease characteristics of the three groups were similar. There were differences in patient and transplant characteristics. Recipients of UCB transplants were younger, more likely non-Caucasian, and more likely to have received a non-irradiation-containing conditioning regimen, in-vivo T-cell depletion and GVHD prophylaxis with cyclosporine and either prednisone or mycophenolate. In multivariate analysis, the risks of long-term mortality were not significantly different after UCB and HLA-matched BM transplants (HR 0.83, p=0.41). Mortality risks were significantly higher after HLA-mismatched BM transplants compared to UCB (HR 1.66, p=0.03) and HLA-matched BM transplants (HR 2.00, p=0.008). In this cohort, surviving disease-free at least 1-year after transplantation, the 8-year probabilities of overall survival after UCB, HLA-matched and HLA-mismatched BM transplants were 78%, 81% and 68%. Conclusions: This is the first report to document long-term durability of UCB grafts. The data continue to support the use of UCB grafts either in the absence of an HLA-matched donor or when transplantation is needed urgently for children with acute leukemia.
Cytological and molecular remissions with blinatumomab treatment in second or later bone marrow relapse in pediatric acute lymphoblastic leukemia (ALL).
Authors: Gore Lia , Zugmaier Gerhard , Handgretinger Rupert , Locatelli Franco , Trippett Tanya M. , Rheingold Susan R. , Bader Peter , Borkhardt Arndt , Cooper Todd Michael , O'Brien Maureen Megan , Zwaan Christian M. , Fischer Anja , Whitlock James , von Stackelberg Arend 
Published: March 2020

10007 Background: Pediatric B-precursor acute lymphoblastic leukemia (ALL) in second or later relapse is an aggressive malignancy that needs therapeutic approaches with new mechanisms of action. Blinatumomab, a bispecific T-cell engaging (BiTE) antibody, has shown a hematological remission rate of 69% in adult patients with relapsed/refractory ALL. In order to establish a recommended dose in pediatric patients, a phase I multicenter trial was initiated. Methods: The primary endpoint is to determine the maximum tolerable dose defined by ≤1 of 6 patients experiencing dose limiting toxicity (DLT) within the 1st course of treatment. Up to 6 different dose levels of blinatumomab are being evaluated. Eligible patients must be <18 years old and have B-precursor ALL that is refractory or in second or later bone marrow relapse, or in any marrow relapse after allogeneic hematopoetic stem cell transplantation (HSCT). Blinatumomab is administered by continuous IV infusion over 28 days followed by a 14-day treatment-free interval (up to 5 cycles). To date, 3 dose levels have been explored (Table). Results: Seventeen patients have been treated thus far with a total of 32 cycles. One DLT (gastrointestinal hemorrhage) at dose level 2 (15 µg/m²/d) and two DLTs at dose level 3 (30 µg/m²/d; both cytokine release syndrome) with 1 death have been observed. One patient had generalized seizures on the 3rd day of the 2nd treatment cycle at the first dose level of 5 µg/m2/d, which was completely reversible. The patient successfully underwent an allogeneic HSCT after blinatumomab. Eight (47%) of the 17 patients reached a cytological complete remission in bone marrow and a molecular remission defined as MRD by PCR <10-4. Conclusions: A phase I trial of blinatumomab in patients with relapsed/refractory pediatric ALL has shown hematological and molecular remissions. Dose-limiting cytokine release syndrome has been noted. Alternative dosing regimens are being explored in current cohorts to refine the recommended dose of blinatumomab in this patient population. Clinical trial information: NCT01471782. [Table: see text]
Evaluation of early response by anatomic imaging to predict survival among patients with group III rhabdomyosarcoma: A report from the Children’s Oncology Group.
Authors: Hawkins Douglas S. , Rosenberg Abby R. , Lyden Elizabeth , Anderson James Robert , Rodeberg David A. , Wolden Suzanne L. , Kao Simon C , Parham David , Arndt Carola A. S. ,   Children's Oncology Group
Published: March 2020

10012 Background: The prognostic significance of response to induction therapy for rhabdomyosarcoma (RMS) by anatomic imaging (computerized tomographic [CT] or magnetic resonance imaging [MRI] scan) is controversial. We previously reported no relationship between early response and failure-free survival (FFS) for patients on IRS-IV. We repeated the same analysis using an independent cohort of patients with non-metastatic, initially unresected RMS treated on a more recent clinical trial. Methods: A total of 338 patients enrolled in Children’s Oncology Group study D9803 met the following inclusion criteria for this analysis: 1) non-metastatic, initially unresected (Group III); 2) embryonal (ERMS) or alveolar (ARMS) histology; 3) documented response to induction chemotherapy (excluding progressive disease) based on anatomic imaging; and 4) documented therapy beyond week 12. Response at week 12 was determined by the treating institution as complete response (CR, complete resolution), partial response (PR, decrease of >= 50% of the sum of the products of maximum perpendicular diameters), or no response (NR, between 50% reduction and 25% increase in the sum of the products of maximum perpendicular diameters). FFS was estimated using the Kaplan-Meier method, and comparisons between groups were made using the log-rank test. Results: Overall objective response rate (CR+PR) at week 12 of therapy was 85%, with similar responses for ERMS and ARMS. FFS was similar among all patients with CR, PR, or NR (p=0.49). Restricting the analysis to either ERMS or ARMS, there was no difference in FFS by histology (p=0.20 and p=0.45, respectively). Conclusions: These findings provide additional evidence that anatomic imaging assessment of early response to therapy among RMS patients does not predict outcome and should not be used to tailor subsequent therapy. Clinical trial information: NCT00003958. [Table: see text]
Survival in metastatic Ewing sarcoma (EWS) and rhabdomyosarcoma (RMS) following consolidation immunotherapy with autologous lymphocyte infusion, dendritic cell vaccines ± CYT107 (rhIL-7).
Authors: Mackall Crystal , Baird Kristin , Bernstein Donna B , Wood Bradford J , Steinberg Seth M. , Beq Stephanie , Croughs Therese , Sabatino Marianna , Stroncek Dave , Merchant Melinda S. 
Published: March 2020

10013 Background: Higher lymphocyte levels correlate with better survival in a variety of cancers, but it remains unclear whether there is a causal relationship between immune function and survival in cancer patients. A pilot study in high-risk pediatric sarcomas was undertaken to determine if a regimen designed to enhance immune reconstitution following standard cytotoxic therapy could improve survival. Methods: Forty-four patients (median 16 yrs, range 5-33) enrolled following a diagnosis of metastatic or late recurrent pediatric sarcoma, and underwent apheresis to collect mononuclear cells and tumor biopsy to generate tumor lysate, then received standard therapy at their home institution. After standard therapy, 29 patients received immunotherapy, comprising a single infusion of autologous lymphocytes depleted of CD4+CD25+regulatory T cells, plus dendritic cell vaccines pulsed with autologous tumor lysate and keyhole limpet hemocyanin (KLH, Q14d x 6). After the first 5 patients, CYT107 (rhIL-7, 20 mcg/kg SQ Q14d x 4) was added to the regimen. Intensive biologic analyses measured global and regulatory T cell immune reconstitution and vaccine responses. Results: This outpatient regimen was well tolerated with toxicities limited to rash, low-grade fever and mild constitutional symptoms. CYT107 dramatically enhanced global immune reconstitution and diminished regulatory T cell frequency. All patients developed immune responses to KLH and 31% developed immune responses to tumor lysate. Intent-to-treat analysis of all patients enrolled shows 56% 5-yr OS, with immunotherapy recipients having a 64% 5-yr OS (median f/u 30 mos, range 23-65). Intent-to-treat analysis of the subset of patients enrolled at the time of a new diagnosis of metastatic EWS or RMS shows 83% 5-yr OS and 54% 5-yr EFS (n=13, median f/u 35 mos, range 24-63), which is superior to previous outcomes reported for this population. Conclusions: A low intensity immunotherapy regimen focused on enhancing immune reconstitution following standard therapy may diminish recurrence in newly diagnosed metastatic EWS and RMS. Clinical trial information: NCT00923351.
The RIST design: A molecularly targeted multimodal approach for the treatment of patients with relapsed and refractory neuroblastoma.
Authors: Corbacioglu Selim , Steinbach Daniel , Lode Holger N. , Gruhn Bernd , Fruehwald Michael , Broeckelmann Mechthild , Suttorp Meinolf , Escherich Gabriele , Cario Gunnar , Ehlert Karoline , Meister Bernhard , Simon Thorsten , Debatin Klaus-Michael , Kuhlen Michaela , Feddersen Isa 
Published: March 2020

10017 Background: The prognosis for children with recurrent or refractory neuroblastoma (rNB) remains dismal. Novel therapeutic approaches are urgently needed. Methods: Based on promising in vitro data unselected patients with rNB were treated as compassionate use according to a multimodal approach (RIST design). The treatment consisted of metronomic courses of Rapamycin/Dasatinib (R/S) for 4 days followed by 5 days of Irinotecan and Temozolomide (I/T). Twenty-one patients (median age: 38 months) with stage IV (n=19) and stage III (n=2) disease, 5 with refractory disease, 8 with 1st and 8 with 2nd and 3rd relapses were included. Seven patients presented within 18 months after diagnosis (median age: 28 months). 18 patients were MIBG positive, 4 MYCN amplified. Dissemination was present in the bone in 15, bone marrow in 11 and lymph nodes in 6 patients, respectively. Results: The patients received a median of 16 courses of R/S (4 to 72) and 7 courses of I/T (4 to 65). 19 patients (90%) showed an initial response according to imaging criteria after a median of 7 R/S and 4 I/T courses (median treatment duration 12 weeks): CR in 12 (57%), a PR in 3 (14%) and a SD in 4 (19%). The median PFS was 90 weeks. The OS after a median of 148 weeks was 43% with 7 patients in CR, 1 VGPR and 1 in PR. There were no toxic deaths in this highly pretreated population. Grade III and IV toxicities (CTC 3.0) were thrombocytopenia in 81%, leukopenia in 76%, anemia in 71%, and diarrhea in 71% respectively. Conclusions: This RIST treatment design applied as a multimodal approach in a compassionate use setting exhibited very promising results considering the adequately long follow-up period of 3 years. This molecular targeted therapy design for rNB warrants confirmation in a prospective clinical trial.
Implementation and evaluation of clinical exome sequencing in childhood cancer care: The BASIC3 study.
Authors: Parsons Donald W. , Chintagumpala Murali M. , Berg Stacey L. , López-Terrada Dolores H. , Roy Angshumoy , Kerstein Robin A. , Scollon Sarah , Hilsenbeck Susan G. , Ramamurthy Uma , Eng Christine M. , Yang Yaping , Gibbs Richard A. , Wheeler David A. , Street Richard L. , McCullough Laurence B. , McGuire Amy L. , Monzon Federico A. , Plon Sharon E. ,   Baylor College of Medicine
Published: March 2020

10023 Background: Advances in sequencing technologies allow for provision of genome-scale data to oncologists and geneticists caring for pediatric cancer patients. The goal of the BASIC3 (Baylor Advancing Sequencing into Childhood Cancer Care) study is to determine the clinical impact of incorporating CLIA-certified tumor and constitutional exome sequencing into the care of children with newly diagnosed solid tumors. Methods: Blood and frozen tumor samples obtained at initial surgery are submitted for clinical exome sequencing (target enrollment 280 patients). Results are deposited into the electronic medical record and disclosed to families by their oncologist and a genetic counselor. Identification of germline cancer susceptibility mutations is compared with standard testing practices. Oncologists are surveyed on prioritization of treatment options in the hypothetical event of tumor recurrence before and after receiving tumor exome results. Patients will be followed for two years to assess the clinical utility of exome data. Preferences for reporting this complex information are obtained by interviews and audiorecording of disclosure visits. Results: Initial results reveal that41 of 49 (84%) ethnically diverse families have consented to enroll on study. Adequate tumor samples were available from 35 of 41 patients (85%), including 11 of 15 (73%) patients with CNS tumors and 24 of 26 (92%) with non-CNS tumors. Pathogenic germline cancer susceptibility mutations (TP53, MSH2) were reported in 2 of the first 11 patients, with a medically-actionable mutation in a gene (SCN5A) unrelated to cancer in 1 patient and 0-4 (median of 2) recessive carrier mutations per patient. Between 9 and 33 protein altering mutations (median of 11) have been identified in tumors, including known cancer genes such as TP53 and others with no known link to pediatric cancer. Conclusions: A robust clinical pipeline for exome sequencing of blood and tumor samples has been successfully developed with significant parental interest. Data assessing the clinical utility of both the tumor and constitutional exomes and the preferences of oncologists and parents for reporting of these results are under study. Supported by NHGRI 1U01HG006485.
Phase I/II study of brentuximab vedotin in pediatric patients (pts) with relapsed or refractory (RR) Hodgkin lymphoma (HL) or systemic anaplastic large-cell lymphoma (sALCL): Interim phase (ph) I safety data.
Authors: Neville Kathleen , Gore Lia , Mauz-Körholz Christine , Rosolen Angelo , Landman-Parker Judith , Sanchez de Toledo Jose , Beishuizen Auke , Keating Franklin Anna Rachel , Fasanmade Adedigbo , Wang Jingyuan , Huebner Dirk , Locatelli Franco 
Published: March 2020

10028 Background: Brentuximab vedotin (ADCETRIS) is a novel antibody-drug conjugate that targets CD30, a cell surface antigen expressed by HL and sALCL. The ph 1 portion of this study evaluated safety, pharmacokinetics (PK), and recommended ph 2 dose (RP2D) of brentuximab vedotin in pediatric pts with RR CD30-expressing tumors. Methods: Ph 1/2, open-label, multicenter study in pts aged 2 to <18 years with RR HL or sALCL (5 to <18 years for HL). Pts received brentuximab vedotin by IV infusion once every 21 days (Q3wk). Ph 1 start dose was 1.4 mg/kg escalated to 1.8 mg/kg in a traditional 3+3 design. Results: 12 pts (median age 14.5 y; 10 HL; 2 sALCL) received brentuximab vedotin in the ph 1 portion (mg/kg/dose [n]: 1.4, [3]; 1.8 [9]). 1.8 mg/kg cohort was expanded from 6 to 9 pts to raise the ph 1 pediatric experience to 12 pts before the ph 2 portion. At data cut, pts had received a median of 3 cycles (range, 1–8). 11 pts (92%) had ≥1 treatment-emergent adverse event (TEAE): 2 at 1.4 mg/kg, 9 at 1.8 mg/kg. 6 pts (50%) had Gr ≥3 TEAE: 1 at 1.4 mg/kg, 5 at 1.8 mg/kg. The most frequent (≥15%) TEAE were nausea (50%), abdominal pain, diarrhea (25% each), upper abdominal pain, cough, fatigue, hypokalemia, leukopenia, decreased lymphocyte count, pain, paresthesia, vomiting, weight loss (17% each). 1 pt (8%) discontinued due to TEAE (Gr 3 hepatotoxicity). 7 serious AE (SAE) were reported in 4 pts at 1.8 mg/kg: Gr 2 supraventricular tachycardia unrelated to treatment in 1 pt; Gr 3 febrile neutropenia, Gr 3 hepatotoxicity and Gr 3 cardiac failure (not a cardiac event per later analysis) in 1 pt; Gr 3 bronchospasm and Gr 2 laryngeal edema in 1 pt; 1 cardiac arrest resulting in death, unrelated to treatment. 2 dose limiting toxicities were reported in 1 pt in the 1.8 mg/kg cohort (SAE: prolonged Gr 3 liver event, Gr 3 febrile neutropenia). PK data will be presented. Conclusions: Brentuximab vedotin is generally well tolerated in pediatric pts with RR CD30-positive HL or sALCL up to 1.8 mg/kg Q3wk. For the majority of pts, toxicities were generally mild to moderate and did not lead to discontinuation. 1.8 mg/kg is the RP2D for pediatric and adult pts. The ph 2 portion is ongoing. Clinical trial information: NCT01492088.
Impact of gender on efficacy and acute toxicity in standard risk localized (SR) Ewing sarcomas (ES) in the Euro-Ewing99-R1 trial.
Authors: Van Den Berg Hendrik , Paulussen Michael , Gaspar Nathalie , Lewis Ian , Dirksen Uta , Brennan Bernadette , Le Teuff Gwenael , Whelan Jeremy , Ranft Andreas , Michon Jean Marie , Ladenstein Ruth Lydia , Marec-Berard Perrine , Hjort Lars , Wheatley Keith , Judson Ian Robert , Oberlin Odile , Craft A. W , Juergens Herbert , Le Deley Marie-Cécile ,   Euro-E.W.I.N.G. 99
Published: March 2020

10031 Background: The randomized Euro-EWING99-R1 trial assessed noninferiority of cyclophosphamide- vs ifosfamide-based consolidation regimens (VAC vs VAI) in SR localized ES patients. Overall, efficacy of VAC was deemed acceptable compared to VAI, with hazard ratio of event HR = 1.12 [0.89 - 1.41]. Based on its gender-stratified randomization, influence of gender on efficacy and acute toxicity were additionally explored. Methods: Impact of gender on EFS, acute toxicity by course, switches between treatment arms, and cumulative dose of alkylating agents was evaluated in multivariable models, including terms to test for heterogeneity of treatment effect by gender. Analysis was performed on the intention to treat population. Results: 856 patients (509 males, 347 females) were recruited between 2000 and 2010: 425 VAI and 431 VAC. EFS did not significantly differ between genders (p=0.33), but a marginal interaction was seen between treatment and gender (p=0.083): VAC was associated with poorer EFS in males than VAI, HR(VAC/VAI) = 1.34 [0.96 - 1.86], whereas, in females, VAC was slightly better than VAI, HR = 0.83 [0.54 - 1.28]. Similarly, males had a worse EFS than females with VAC, HR(M/F) = 1.42 [0.97 – 2.08], whereas results by gender were very similar with VAI, HR = 0.91 [0.62 – 1.33]. Severe hematological toxicity was more frequent with VAC than VAI whereas tubular renal impairment was more frequent with VAI. Severe toxicity was more frequent in females than in males, whatever the toxicity type, with no significant interaction between treatment and gender effect. 30 patients switched from VAI to VAC (21 F, 9 M) mostly due to renal toxicity, and 3 from VAC to VAI (1 F, 2 M). A reduction of alkylating agent cumulative dose >20% was more frequent in females (15% vs 9%, p=0.01), with no major difference between VAI and VAC (13% vs 10%, p=0.21). Conclusions: The marginal interaction between gender and type of alkylating agent on EFS has to be validated on external data. Differences of acute toxicity rate and compliance are not sufficient explanation. Effects of gender-dependant polymorphism/activity of metabolic enzymes (e.g. known for CYP2B6) of ifosfamide vs cyclophosphamide should be explored. Clinical trial information: NCT00020566.
Barriers to survivorship care in the Consortium for New England Childhood Cancer Survivors (CONNECCS).
Authors: Schwartz Cindy L. , Hirway Priay , Ader Jeremy , Bradeen Heather Appleton , Grewal Satkiran S. , Huang Mary S , Kadan-Lottick Nina , Usmani Naheed , Kenney Lisa Brazzamano 
Published: March 2020

10035 Background: Although long-term adverse consequences of childhood cancer treatment may be mitigated by screening, prevention, and interventions, many survivors do not take advantage of survivorship care. We hypothesized that patients who are at risk for poor compliance with long-term follow-up are identifiable at diagnosis. Methods: To identify factors associated with poor follow-up compliance, 7 CONNECCS institutions evaluated a childhood acute lymphoblastic leukemia (ALL) survivor cohort diagnosed 1996-99. Data collected included: diagnosis year, age, race, ethnicity, gender, insurance, distance from center, CNS disease, and risk classification. Primary endpoints were compliance with 5 and 10-year follow-up. Differences in compliance were tested using chi-squared or t-tests. Logistic regression (including institution as a clustering variable) was used to calculate adjusted odds ratios (OR). Results: At diagnosis, the 358 ALL patients were: female (47%), age= 6.5 + 4.6 years, white/non-Hispanic (84%), black non-Hispanic (7%), high-risk (52%), CNS involvement (10%), privately insured (68%). Private insurance (OR 4.0; 95% CI 2.1-7.8) significantly increased the odds of 5-year compliance. Compliance with 10-year follow-up increased with private insurance (OR 3.3; 95% CI 1.4-8.1) but decreased with CNS disease (OR 0.36; 95% CI 0.31- 0.42) and with years of age (OR 0.93; 95% CI 0.88- 0.96). Conclusions: We evaluated predictors of long-term follow-up based on disease/demographic characteristics at diagnosis to identify cohorts in need of early interventions. In this regional cohort, patients from lower socioeconomic background (without private insurance) at diagnosis were less likely to participate in long-term follow-up care at 5 and 10 years from diagnosis. Older survivors and those with CNS disease were less likely to be in follow-up at 10 years. Future studies should investigate reasons why follow-up compliance is affected by 1) private insurance at diagnosis, 2) older age, and 3) CNS disease. Remediable causes might include: understanding of risk, adolescence/young adult transitions, and healthcare access.