bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II trial of dasatinib (DAS) in pediatric patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP).
Authors: Gore Lia , Kearns Pamela , Lee Maria Lucia , De Souza Carmino Antonio , Bertrand Yves , Hijiya Nobuko , Stork Linda C. , Chung Nack-Gyun , Cardenas-Cardos Rocio , Saikia Tapan , Fagioli Franca , Seo Jong-Jin , Landman-Parker Judith , Lancaster Donna , Place Andrew E. , Rabin Karen R. , Sacchi Mariana , Swanink Rene , Zwaan Michel 
Published: September 2018

10511 Background: Safe and effective treatment options for newly diagnosed (ND) or imatinib (IM) resistant/intolerant (R/I) pediatric CML pts are limited, and a large prospective study is needed. DAS has proven safety and efficacy in adults with ND or IM-R/I CML and is now being evaluated in a phase II trial of pediatric pts. Methods: CA180-226/NCT00777036 is an open-label nonrandomized prospective study of pts aged <18 y in 3 cohorts: (1) CML-CP R/I to IM treated with DAS tablets 60 mg/m2 QD, (2) IM-R/I CML-AP/BP or Ph+ ALL (enrollment closed early due to poor response), and (3) ND CML-CP treated with DAS tablets 60 mg/m2 or DAS 72 mg/m2powder for oral suspension (PFOS) QD. Primary objectives were major cytogenetic response (MCyR) for CML-CP R/I to IM and complete cytogenetic response (CCyR) for ND CML-CP (MCyR >30% and CCyR >55% considered of clinical interest). Results: 113 pediatric CML-CP pts were treated. Cumulative rate of MCyR >30% was reached as early as 3 mo (55%; [95% CI 36, 74]) for IM-R/I CML-CP. Cumulative rate of CCyR >55% was reached as early as 6 mo (64% [95% CI 53, 74] for ND CML-CP; 61% [95% CI 46, 74] for pts on tablets and 70% [95% CI 51, 84] for pts on PFOS). Estimated PFS by 48 mo was >75% for CML-CP R/I to IM and >90% for ND CML-CP. One CML-CP pt R/I to IM died 1 y after stopping DAS from gastrointestinal bleeding. AEs were consistent with those observed in adults, except no DAS-related pleural/pericardial effusion or pulmonary arterial hypertension (PAH) were reported here. Conclusions: In the largest prospective trial of pediatric pts with CML-CP, target responses were met early and increased over time with DAS treatment. The efficacy and safety of DAS were consistent with previous reports in adults, except no cases of pleural/pericardial effusion or PAH were observed. These results suggest DAS is safe and highly effective in the first- or second-line treatment of pediatric CML-CP. Clinical trial information: NCT00777036. [Table: see text]
Efficacy and safety of defibrotide (DF) to treat hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) after primary chemotherapy (CT): A post hoc analysis of final data.
Authors: Kernan Nancy A. , Richardson Paul G. , Triplett Brandon , Grupp Stephan A. , Antin Joseph Harry , Messinger Yoav H. , Liang Wei , Hume Robin , Tappe William , Soiffer Robert 
Published: September 2018

10513 Background: VOD/SOS, which may be unpredictable and potentially life-threatening, is typically considered a complication of hematopoietic stem cell transplantation (HSCT); VOD/SOS with multi-organ dysfunction (MOD) may be associated with >80% mortality. DF is approved to treat hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT in the US and to treat severe hepatic VOD/SOS post-HSCT in the EU. However, VOD/SOS can occur after CT without HSCT. Methods: In an expanded-access protocol for patients (pts) with VOD/SOS post-HSCT or CT, with/without MOD (renal/pulmonary), DF 25 mg/kg/d (6.25 mg/kg q6h) was given a recommended ≥21 days. Post-CT subgroup survival was analyzed post hoc from the day DF was started (days 0–30 after start of CT) for 70 days (ie, up to 100 days, as follow-up was collected for 100 days post-CT). Results: Of 1154 VOD/SOS pts receiving DF, 137 (12%) developed VOD/SOS post-CT without HSCT. Among 82 pts (38 with MOD) treated by day 30 after start of CT, median age was 7.5 yrs (range, 0–68 years) and 66 (81%) were ≤16 yrs. Most common primary diseases were acute leukemias (65%). Kaplan-Meier estimated survival at day +70 was 74% overall (95% CI, 63–82%); 66% (49–79%) and 81% (66–90%) in pts with/without MOD, respectively. In the pediatric pts, estimated survival at day +70 was 80% (68–88%); in adult pts, 50% (25–71%). Adverse events (AEs) were reported in 54/82 pts (66%); 22 (27%) had AEs assessed as possibly related to DF, most commonly (≥2%) pulmonary or mouth hemorrhage (4% each) and hematochezia, nausea, encephalopathy, epistaxis, or hypotension (2% each). Hemorrhagic AEs of any relatedness (≥2%) were pulmonary (6%), epistaxis or mouth (4%), and hematochezia (2%). Related AEs led to discontinuation in 6 pts and were associated with 1 death (pulmonary hemorrhage, hypotension). Conclusions: The 74% survival rate at day +70 in pts with VOD/SOS receiving DF within 30 days of starting CT (80% in pts ≤16 yrs) is clinically encouraging. Of note is the 66% survival rate in pts with MOD. The safety profile was consistent with that previously reported in the overall population of this protocol. Support: Jazz Pharmaceuticals Clinical trial information: NCT00628498.
Subcortical brain volumes and neurocognitive function in survivors of childhood acute lymphoblastic leukemia (ALL) treated with chemotherapy-only.
Authors: Phillips Nicholas Steve , Glass John O , Scoggins Matthew , Cheung Yin Ting , Liu Wei , Ogg Robert J. , Mulrooney Daniel A. , Pui Ching-Hon , Robison Leslie L. , Reddick Wilburn E. , Hudson Melissa M. , Krull Kevin R. 
Published: September 2018

10517 Background: Brain deep grey nuclei and glucocorticoid receptor rich hippocampal subregions may be sensitive to neurotoxic effects of chemotherapy-only protocols for childhood ALL and associated with neurocognitive problems in long-term survivors. Methods: Brain MRIs and neurocognitive tests were obtained on 176 survivors (49% male, mean [range] age at diagnosis 6.8 [1-18] years, 14.5 [8-27] years at evaluation). MRI’s were also obtained on 82 healthy community controls (57% male, 13.8 [8-26] years at evaluation). General linear models were used to compare subcortical brain volumes between survivors and controls. Among survivors, gender stratified multivariable linear models were used to test associations between subcortical volumes, and serum concentration of dexamethasone (DEX) and high-dose methotrexate (HDMTX), adjusting for age at diagnosis, and intracranial volume (ICV). Volumes were also compared to neurocognitive tests. Results: Survivors had smaller volumes in bilateral thalami (p’s < 0.05) and hippocampal subregions (p’s < 0.001) compared to controls. After controlling for ICV, HDMTX exposure and younger age at diagnosis were associated with smaller bilateral thalami in male survivors (p’s < 0.05). DEX was associated with a smaller right thalamus in males (p = 0.04). Smaller hippocampi in both males and females were associated with younger age at diagnosis (p’s < 0.01). Smaller left thalamus was associated with worse verbal fluency scores in all survivors (p’s < 0.05). Smaller bilateral thalami and hippocampal subregions in girls were associated with worse processing speed, inhibition and cognitive flexibility; poor memory span correlated with smaller left CA1 and right thalamus volumes (all p’s < 0.05). Smaller bilateral thalami and right hippocampal subregions, in girls, correlated with slower processing speed (p’s < 0.05). In males, smaller left fimbria volume was correlated with poor attention (p = 0.03). Conclusions: ALL survivors have significantly smaller thalamic and hippocampal volumes compared to healthy community controls. In survivors, smaller volumes correlate with worse cognitive performance.
Family history of cardiovascular disease and cardiovascular comorbidities risk in a pediatric cancer population.
Authors: Curtin Thomas Patrick , Kohlmann Wendy , Maese Luke Devon , Yu Zhe , Curtin Karen , Schiffman Joshua David 
Published: September 2018

10518 Background: Survival rates for childhood cancer patients have improved dramatically, but the growing survivor population suffers from increased treatment-related toxicity including high risk for cardiovascular disease (CVD). While the link between chemotherapy and radiation to cardiotoxicity is well established, few studies seek to determine if an underlying familial risk for cardiovascular disease contributes or predicts this risk. The Utah Population Database (UPDB) is a genealogical resource linked to statewide cancer diagnoses and electronic medical data in which family history is objectively determined. Methods: We calculated the risk of subsequent CVD (ICD-9 401-449) in relatives of 5602 pediatric cancer patients diagnosed at ages 0-19 in Utah from 1966-2013 with no congenital CVD-related anomalies (ICD-9 745-747, 758-759). We identified 964 patients with subsequent CVD diagnoses. Cox models provided recurrence-risk estimates in first-degree relatives of patients compared to relatives of 5:1 matched controls. Results: Pediatric cancer patients were at 5-fold risk of CVD compared to controls ( P< 10-15). In pediatric patients with subsequent CVD, first-degree relatives were at 30% increased CVD risk compared to relatives of cancer-free controls (HR = 1.31, 95%CI 1.16-1.47; P< 10-5). In pediatric patients without CVD, only parents exhibited slight CVD risk (HR = 1.08, 95%CI 1.03-1.14; P= 0.002). In 685,000 individuals with a non-congenital CVD history, pediatric cancers among their first-degree relatives were associated with a similar increased risk of subsequent CVD, compared to pediatric cancers among relatives of controls with no CVD events (HR = 1.39, 95%CI 1.18-1.64, P< 10-4). Conclusions: The UPDB is powerful for investigating comorbidities in cancer patients and their families without recall bias from self-reported family medical history. A family history of CVD may increase risk of CVD-related comorbidities among pediatric cancer patients by 30-40% beyond that observed in patients without a CVD family history. This finding suggests that in addition to a cancer family history, a CVD-related family history should be assessed in children diagnosed with cancer.
Complete dexrazoxane cardioprotection for cardiac function but incomplete female cardioprotection for cardiac structure in doxorubicin-treated osteosarcoma survivors: Hearts too small for the body.
Authors: Kopp Lisa M. , Bernstein Mark L. , Schwartz Cindy L. , Ebb David , Franco Vivian L , Hall David , Barkauskas Donald A. , Krailo Mark D. , Grier Holcombe E. , Meyers Paul A. , Wexler Leonard H. , Marina Neyssa , Womer Richard B. , Janeway Katherine A. , Gorlick Richard Greg , Lipshultz Steven E ,   Children's Oncology Group
Published: September 2018

10519 Background: Dexrazoxane is protective for lower-dose doxorubicin ( < 300 mg/m2) cardiotoxicity in childhood cancer, but the effect of dexrazoxane (DXRZ) administered with higher-dose (HD) doxorubicin (DOXO) is unknown. Methods: We evaluated patients from Children’s Oncology Group trials for localized (P9754) and metastatic (AOST0121) osteosarcoma (OS) who received HD DOXO (375-600 mg/m2) preceded by DXRZ (10:1 ratio), methotrexate, and cisplatin; some also received ifosfamide alone or ifosfamide/etoposide ± trastuzumab. Cardiotoxicity was identified by echocardiography and by serum N-terminal pro-brain natriuretic peptide (NT-proBNP) concentrations. Results: 81 DXRZ -treated OS patients ( age at enrollment = 13.7 years; range 3.8 - 23.7 years) had normal left ventricular (LV) systolic function as measured by LV fractional shortening and no heart failure. Female sex and longer follow-up since DOXO were associated with a significantly smaller LV dimension z-score normalized to BSA (μ = -1.20, 95%CI [-1.70, -0.70]). Similarly, in the one-third of patients treated > 81 days after minimal expected treatment (groups equally partitioned by time), significantly thinner LV posterior wall thickness for BSA (μ = -0.57, [-1.05, -0.09]) was found. Interventricular septal wall thickness (μ = -0.84, [-1.2, -0.48]) and LV mass (μ = -0.73, [-1.06, -0.40]) were significantly smaller for BSA than normal for both sexes. For females, these became significantly more abnormal with increasing length of follow-up. Females also showed progressive increases in NT-proBNP. Conclusions: DXRZ is cardioprotective for HD DOXO in terms of LV function and heart failure. Females had progressive abnormalities of LV structure, leading to smaller hearts for body size. This was associated with increasing cardiac stress, as measured by NT-proBNP. DXRZ protection was incomplete for HD DOXO effects on LV structure, resulting in higher LV stress and risk for late LV dysfunction. DXRZ should continue to be used in this population, including for females who exhibit more cardiotoxicity than males at specific cumulative DOXO doses.
Assessment of multiple endocrine therapies for metastatic breast cancer in a multicenter national observational study.
Authors: Le Saux Olivia , Lardy-Cleaud Audrey , Frank Sophie , Cottu Paul H. , Pistilli Barbara , Debled Marc , Vanlemmens Laurence , Leheurteur Marianne , Guizard Anne-Valérie , Laborde Lilian , Uwer Lionel , D'hondt Veronique , Berchery Delphine , Lorgis Veronique , Ferrero Jean-Marc , Perrocheau Genevieve , Courtinard Coralie , Chabaud Sylvie , Robain Mathieu , Bachelot Thomas Denis 
Published: September 2018

1052 Background: For HR+/HER2– metastatic breast cancer (mBC), International guidelines recommend multiple lines of endocrine therapy (ET) before starting chemotherapy. Few studies have assessed the efficacy of such strategy on large populations. Our objective was to evaluate multiple ET activity according to clinical and biological characteristics and type of ET. Methods: All patients (pts) who initiated treatment for a newly diagnosed mBC between January 2008 and December 2014 in all 18 French Comprehensive Cancer Centers were included in the real life ESME database. ESME collects retrospective data using a clinical trial-like methodology. Database lock was 8 Dec 2016. Primary endpoint of the current study was progression free survival (PFS) on successive ET lines. Only pts with ET alone were assessed (pts receiving ET after chemotherapy as maintenance therapy, or combined with targeted treatment were excluded). Results: 9921 pts out of 16703 in ESME, had HR+/HER2- mBC (median age 62.0 years[range 23-96]). 53.9% of pts had visceral and 80.1% non visceral disease at diagnosis. Median OS of HR+/HER2- pts was 42.15 months (95% CI, 40.93-43.27). As first-line therapy, 4123 pts (41.6%) received ET alone, while 2038 received chemotherapy alone (20.5%) and 3667 received both (37%). Median PFS for first-line ET (N=4123) was 11.3 months (95% CI, 10.6-11.9). Only 668 pts (16%) received subsequent lines of ET alone. Types of ET used are described in the table below. Successive PFS will be reported at the meeting. Conclusions: Those data show that ET is prescribed to less than 50% of patients with HR+/HER2- mBC in first line and only to a small minority in subsequent lines. This is not in line with existing guidelines (NCCN, ABC3). Real-life median PFS for first-line ET is consistent with median PFS reported in clinical trials (Nabholtz, 2000). [Table: see text]
Risk of subsequent breast cancer after radiotherapy according to hormone-receptor status: A nested case-control study in the Childhood Cancer Survivor Study (CCSS).
Authors: Morton Lindsay M. , Veiga Lene , Curtis Rochelle E. , Withrow Diana , Inskip Peter , Oeffinger Kevin C. , Moskowitz Chaya S. , Neglia Joseph , Turcotte Lucie Marie , Howell Rebecca M. , Weathers Rita , Smith Susan A , Henderson Tara O. , Leisenring Wendy M. , Whitton John , Gibson Todd M. , Robison Leslie L. , Armstrong Gregory T. , Berrington De Gonzalez Amy 
Published: September 2018

10520 Background: Survivors of childhood cancer have a high absolute risk of subsequent breast cancer after chest-directed radiotherapy; however, it is not known if this risk differs by hormone-receptor status and radiation to the ovaries. Methods: We conducted a nested case-control study within the CCSS of 282 five-year survivors of childhood cancer with subsequent breast cancer and 1202 matched controls. Radiation dose to the location of the breast tumor (or corresponding location for controls) and mean dose to the ovaries were estimated from treatment records for each patient. Risk of radiation-related breast cancer was measured with the Excess Odds Ratio per Gray (EOR/Gy) and corresponding 95% confidence interval (CI), derived from conditional logistic regression. Results: The median age at subsequent breast cancer diagnosis was 39 years (range 21-58). Although 87% of cases and 70% of controls received radiotherapy, breast doses were higher in cases than controls (61% vs 24% breast dose > 10Gy), whereas ovarian doses were lower (7% vs 13% ovary dose > 5Gy). In the subset of cases (n = 159) with currently available estrogen receptor (ER) status (76% cases ER+, 24% cases ER-), there was a linear dose-response relation with radiation dose to the breast that was similar for ER+ (EOR/Gy = 0.51; 95%CI: 0.19-1.34) and ER- breast tumors (EOR/Gy = 0.41; 95%CI: 0.05-2.88). If the patient received an ovarian dose > 5Gy, this dose-response was significantly reduced for ER+ tumors but not for ER- tumors. Conclusions: Preliminary analyses demonstrate that radiation exposure to the breast to treat childhood cancer results in an increased risk of both ER+ and ER- breast cancers. The novel finding that only the risk of ER+ breast cancer is lowered if the ovaries are also exposed is consistent with known differences by hormone receptor status in the biological mechanisms of breast carcinogenesis.
Patient-reported quality of life (QOL) following CTL019 in pediatric and young adult patients (pts) with relapsed/refractory (r/r) b-cell acute lymphoblastic leukemia (B-ALL).
Authors: Dietz Andrew Charles , Grupp Stephan A. , Laetsch Theodore Willis , Stefanski Heather , Myers Gary Douglas , Bittencourt Henrique , Buechner Jochen , Nemecek Eneida R. , Martin Paul L. , Hiramatsu Hidefumi , Mechinaud Francoise , Yanik Gregory A. , De Moerloose Barbara , Wood Patricia Ann , Rasouliyan Lawrence , Zhang Yiyun , Thomas Simu K. , Shah Sweta , Harris Andrew 
Published: September 2018

10523 Background: The global ELIANA trial (NCT02435849) evaluates the efficacy and safety of CTL019, a single infusion of genetically modified autologous chimeric antigen receptor–expressing T cells targeting CD19+ cells in pediatric and young adult r/r B-ALL pts. Analyses show a complete response rate of 82% with or without complete blood count recovery ≤ 3 months. A serious adverse event rate of 71% was observed in ≤ 8 weeks of infusion, decreasing to 17% at > 8 weeks (Grupp S, et al. Blood. 2016;128(22) [abstract 221].). This analysis further evaluates the clinical benefit of CTL019. QOL was assessed before and after CTL019 infusion. Methods: Infused pts were 3-23 y/o with CD19+ B-ALL who were chemo refractory, relapsed after allogeneic stem cell transplant (SCT), or otherwise ineligible for SCT. Pts ≥ 8 y completed the Pediatric Quality of Life Inventory (PedsQL) and EuroQol EQ-5D at baseline and following CTL019 infusion. Minimal clinically important differences are estimated to be 4.4 and 7 to 10 for PedsQL and EQ-5D, respectively. Results: 62 of 81 enrolled pts were infused; 56% had relapsed after SCT with median of 3 prior therapies. At interim analysis, 50 pts were treated ≥ 3 months prior to data cutoff and eligible for primary efficacy analysis. A total of 39 pts were ≥ 8 y. Mean PedsQL total and EQ-5D VAS scores, respectively, were 58.4 and 69.4 at baseline. Mean changes from baseline for the PedsQL total and EQ VAS scores, respectively, were 13.9 and 13.7 at month 3 and 12.8 and 10.9 at month 6, supporting clinically meaningful improvements in QOL. Similar trends were observed with each PedsQL subscale. With EQ-5D, the proportions of pts reporting problems with mobility, self-care, usual activities, anxiety/depression, or pain/discomfort were notably decreased at months 3 and 6 compared with baseline. Conclusions: Clinically meaningful improvements in QOL were observed at 3 and 6 months after CTL019 therapy in pediatric and young adult r/r B-ALL pts, including fewer problems in each EQ-5D domain. These results suggest improved QOL after this one-time immunocellular therapy beyond the period of acute toxicities. Clinical trial information: NCT02435849.
Risk-adapted therapy utilizing upfront brentuximab vedotin (Bv) and rituximab (R) with reduced toxicity chemotherapy in children, adolescents, and young adults with Hodgkin lymphoma.
Authors: Hochberg Jessica , Klejmont Liana , Harrison Lauren , Flower Allyson , Shi Quihu , Basso Jaclyn , Cairo Mitchell S. 
Published: September 2018

10532 Background: Cure rates for CAYA patients with Hodgkin Lymphoma remain high, however are limited by significant toxicity of chemoradiotherapy. Brentuximab Vedotin and Rituximab have shown efficacy in relapsed HL. We hypothesize that the addition of both to combination chemotherapy will be safe in newly diagnosed HL preserving current EFS with elimination of more toxic chemoradiotherapy. Objective: To evaluate the safety and overall response and EFS of Brentuximab and Rituximab in combination with risk adapted chemotherapy in CAYA with newly diagnosed HL. Methods: Age 1-30 yrs with newly diagnosed classical HL given 3 to 6 cycles of chemoimmunotherapy: Brentuximab vedotin with Doxorubicin, Vincristine, Prednisone and Darcarbazine (Bv-AVPD) for Low risk patients or Doxorubicin, Vinblastine, Darcarbazine and Rituximab (Bv-AVD-R) for Intermediate/High risk. Early response measured by PET/CT scan following 2 cycles. Slow responders received an additional 2 cycles of Bv-AVD-R for Intermediate Risk or Ifosfamide/Vinorelbine for High Risk patients. Radiation therapy was given ONLY to those patients not in CR. Results: Total = 19 patients. Median age = 15yr (range 4-23yr). Risk = 2 low, 13 intermediate, 4 high. Toxcity = 1 episode of GrIII mucositis, 1 episode of GrIII infusion reaction to Brentuximab. 17 patients have completed therapy. All 17 patients achieved a complete response to therapy for a CR = 100%. Eleven (58%) have achieved a rapid early response. No patient has required radiation therapy. For 17 patients who have completed therapy, the EFS and OS is 100% with a median follow up time of 915 days (30 months). Conclusions: The addition of Brentuximab vedotin and Rituximab to combination chemotherapy for newly diagnosed Hodgkin Lymphoma appears to be safe. Our early results show significant promise with a CR rate of 100% and 58% rapid early response. We have successfully deleted toxic alkylator, topoisomerase inhibitor, bleomycin and radiation from this treatment regimen. The EFS/OS to date is 100% with a median follow up time of 2.5 years. Further follow up and a larger cohort is needed to determine long term outcomes of this approach. Clinical trial information: NCT02398240.