bluuebunny/crossref_metadata_2025 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.
Outcome of palbociclib based therapy in hormone receptor positive metastatic breast cancer patients after treatment with everolimus.
Authors: Dhakal Ajay , Matthews Christina , Zhang Fan , Levine Ellis Glenn , Edge Stephen B. , Salerno Kilian Elizabeth , O'Connor Tracy , Early Amy P. , Khoury Thaer , Takabe Kazuaki , Young Jessica S. , Opyrchal Mateusz
Published: September 2018

1054

Background: Resistance mechanisms to CDK 4/6 inhibition are not well defined. Outcome data on hormone receptor positive (HR+) metastatic breast cancer patients (MBCP) treated with palbociclib (PA) after treatment with everolimus (EV) are lacking. The PALOMA 3 trial (P3) showing benefit of PA plus fulvestrant (FU) compared to FU in HR+ MBCP after progression on endocrine therapy excluded women previously treated with EV. The aim of our study was to investigate the outcomes of HR+ MBCP with prior EV treatment on PA based therapy. Methods: This is a retrospective, single institute review of HR+, HER 2 nonamplified MBCP from Jan 2014 - Nov 2016 treated with PA after treatment with EV. Women who received EV for < 1 month or PA < 14 days were excluded. Progression free survival (PFS) was defined as the time from the initiation of PA to the date of progression as determined by treating physician based on radiological, biochemical and/or clinical criteria. Response rates were determined based on available radiological data. Clinical benefit was defined as a complete response (CR), partial response (PR) or stable disease of at least 24 weeks. Results: 23 patients with mean age 67 years (42 to 81) were identified. 95% were postmenopausal, 81% had ECOG performance status 0 or 1, 83% had visceral metastases, 95% had > 2 lines of prior endocrine therapy (ET), 82% shown prior sensitivity to ET, 82% received prior chemotherapy, of which 84% were in metastatic setting. Kaplan Meier estimate showed median PFS of 2.9 months (95% CI 2.0-4.2); median PFS of P3 PA cohort was 9.5 months (95% CI 9.2-11.0). Fisher’s exact test comparing study cohort with P3 PA cohort showed statistically significant differences in objective response (CR or PR) rates of 0/23 (0%) vs. 66/347 (19%, p = 0.02) & clinical benefit ratio of 4/23 (17.4%) vs. 231/347 (66.5%, p = 0.00). Conclusions: Outcomes with PA in HR+ EV treated MBCP were worse when compared to the P3 PA cohort data. Treatment with EV may lead to resistance to CDK inhibition. Though limited by size, our data suggests that use of PA after EV is associated with low response & clinical benefit rates. Further studies are necessary to confirm the findings to determine sequencing of targeted therapies.
A curative approach to central nervous system metastases of neuroblastoma.
Authors: Kramer Kim , Kushner Brian H. , Modak Shakeel , Pandit-Taskar Neeta , Tomlinson Ursula , Wolden Suzanne L. , Zanzonico Pat , John Humm L. , Haque Sofia , Souweidane Mark M. , Greenfield Jeffrey , Basu Ellen M. , Roberts Stephen S. , Carrasquillo Jorge A. , Lewis Jason Stuart , Lyashchenko Serge K. , Larson Steven M. , Cheung Nai-Kong V.
Published: September 2018

10545

Background: Neuroblastoma metastatic to the central nervous system (CNS NB) is associated with significant mortality (median survival < 6 months, < 10% survival at 36 months). Intraventricular compartmental radioimmunotherapy (cRIT) with radio-iodinated murine IgG1 monoclonal antibody 131I-8H9 targeting tumor cell-surface glycoprotein B7-H3 offers a therapeutic strategy. We analyzed overall survival of patients with CNS NB treated with intraventricular 131I-8H9 cRIT at Memorial Sloan Kettering Cancer Center (MSK) since 2003. Methods: After radiographic and/or pathologic confirmation of CNS NB, and assessment of adequate CSF flow, cRIT eligible patients underwent treatment on an IRB-approved protocol with either temozolomide/irinotecan-based CNS salvage regimen incorporating craniospinal radiation therapy, 131I-8H9 cRIT plus systemic immunotherapy (group 1), or non-regimen therapies with 131I-8H9 cRIT (group 2). cRIT administration involved a 2mCi tracer of 124I- or 131I-8H9 with nuclear imaging and CSF sampling for dosimetry followed by 1 or 2 therapeutic injections up to 70 mCi 131I-8H9. Disease surveillance included serial MR brain/spine, MIBG, CT, and bone marrow evaluation. Data are presented as overall survival after detection of CNS metastasis. Results: 105 patients with CNS NB were evaluated;80 patients (76%) were treated (57 group 1, 23 group 2). Of the 25 patients who were not eligible for cRIT, survival averaged 8.6 months. Of 19 patients with radiographic evidence of disease at the time of cRIT, 7 (36%) demonstrated post cRIT radiographic improvement. At analysis, 45/80 (56%) patients were alive 4.8–152 months (median 58 months) after CNS metastasis, including 36 (45%) at 36 months and 23 (29%) > 60 months. Subgroup analyses of 131I-8H9–treated patients identified age at NB diagnosis (≤18 months), relapse restricted to CNS and group 1 status as factors positively correlated with survival. Conclusions: 76% of patients with CNS NB treated at MSK received 131I-8H9 cRIT, and approximately half completed multimodality CNS salvage regimen with 131I-8H9 cRIT. Despite advanced CNS involvement, over 50% of patients treated with 131I-8H9 cRIT are still alive and nearly 50% have survived at least 36 months. Clinical trial information: NCT00089245.
Pazopanib therapy for adolescent and young adult desmoid tumors.
Authors: Agresta Laura , Nagarajan Rajaram , Szabo Sara , Turpin Brian , Kim Hee , Sorger Joel , Pressey Joseph Gerald
Published: September 2018

10547

Background: There is a lack of reliably effective medical therapies for desmoid tumors (DT). Surgical resection may be morbid, and even a complete resection does not preclude recurrence. Radiotherapy is associated with potentially severe late-effects, a risk that may be particularly detrimental in young patients. In a previous review of our single institution DT experience, we found that objective treatment responses to medical therapies were rare.However,we have recently observed promising effect from therapy with the tyrosine kinase inhibitor pazopanib in adolescent and young adult (AYA) patients with DT. Methods: Retrospective single institution chart review evaluating all pazopanib treatment in AYA patients with DT. Results: Five AYA patients, ages 15-21 years, with previously treated DT received pazopanib. Four patients with sporadic DT were documented by next generation sequencing to have mutations of CTNNB1, and 1 patient with intra-abdominal tumors following colectomy was known to carry a large germline interstitial chromosomal deletion (5q21.2q23.1) including the APC locus. The median duration of pazopanib treatment was 6 months at the time of analysis (range: 5-21), with treatment ongoing for 4 patients. None of the patients demonstrated progressive disease while on treatment. Best responses by Response Evaluation Criteria in Solid Tumors 1.1 (RECIST) were partial response in 3 of 5 and stable disease in 2 of 5 cases. One response was nearly complete. In one case of stable disease, tumor necrosis was evident on magnetic resonance imaging after 2 months on pazopanib. Four patients reported pain relief while on pazopanib, including one patient with stable disease. Pazopanib was discontinued in 1 patient after 18 months due to recurrent facial edema. Other grade 1-2 adverse effects responded to dose reduction. The only grade 3 adverse effect was increasing weakness in a patient with pre-existing myopathy; this patient tolerated pazopanib at a reduced dose. Conclusions: This is the first report of objective responses to pazopanib by RECIST criteria in AYA patients with DT. Given these benefits and relatively mild toxicity, we conclude that pazopanib therapy should be considered in this patient population.
A biomarker-guided approach to combining PARP inhibitors with radiotherapy in pediatric solid tumors.
Authors: Shelat Anang , Tinkle Christopher , Stewart Elizabeth , Federico Sara Michele , Bianski Brandon , Mellado-Lagarde Marcia
Published: September 2018

10556

Background: Ewing sarcoma (EWS) expresses high levels of Schlafen-11 (SLFN11). SLFN11 disrupts checkpoint maintenance and may serve as a biomarker to assess sensitivity to Poly (ADP-ribose) polymerase 1 and 2 inhibitors (PARPi). The goal of this study is to evaluate SLFN11 protein expression in a panel of pediatric solid tumors and correlate levels of protein with sensitivity to PARP inhibition combined with ionizing radiation (IR), a component of therapy for many pediatric solid tumors and a potent inducer of DNA damage. Methods: SLFN11 mRNA and protein levels were assessed by quantitative RT-PCR, and immunohistochemistry, Western blot, and immunofluorescence microscopy, respectively. PARPi included: talazoparib (TAL), niraparib (NIR), veliparib (VEL), and olaparib (OLA). Approximately 30 minutes after addition of systemic therapy, graded doses of radiation were delivered and viability across a panel of pediatric solid tumor cell lines was measured using the ATP-based Cell TiterGlo assay and confirmed with the colony formation assay. Results: We found that SLFN11 mRNA and protein is expressed at high levels in EWS, and SLFN11 is also variably present in a subset of other pediatric solid tumor lines, including desmoplastic small round cell tumor, osteosarcoma, and rhabdomyosarcoma. In all tumor cells with detectable SLFN11 expression, viability was reduced by greater than 90% when exposed to 2Gy IR and 1-10nM TAL, whereas cells with undetectable levels of SLFN11 were 5-10 times less sensitive. Intriguingly, variation in the potentiation between specific PARPi and IR correlated with the ability to form drug-induced PARP-DNA adducts, with the strong PARP trapper TAL showing ~10-fold higher potency compared to the moderate trapper NIR, and ~300-fold more potency relative to the weak trapper VEL. Consistent with our PARPi findings, the toposiomerase 1 inhibitor irinotecan, which also forms DNA adducts, potentiated with IR similarly to TAL at concentrations < 10nM in tumor cells expressing detectable levels of SLFN11. Conclusions: SLFN11 is present in select pediatric solid tumors and may induce a DNA repair defect that is best exploited by combining low-doses of TAL and irinotecan with IR.
Diabetes risk in childhood cancer survivors: A population-based study.
Authors: Lega Iliana Carolina , Pole Jason D , Austin Peter , Lau Cindy , Nathan Paul C. , Baxter Nancy N.
Published: September 2018

10558

Background: Cure rates for childhood cancer have improved significantly over the last three decades. Diabetes has emerged as a delayed side-effect of treatment for childhood cancer. Methodologic limitations may have led to underestimation of the risk for diabetes in previous studies. Understanding the extent of diabetes risk and identifying risk factors for diabetes is imperative for improving screening and prevention strategies in this population. Methods: We used the Ontario population-based cancer registry and administrative health databases to evaluate the risk of diabetes in adult survivors of childhood cancer. Diabetes was measured using a validated algorithm. Survivors were compared to age and sex-matched controls from the general population using a multivariable, cause-specific hazard regression model where death and development of another cancer was treated as a competing risk. Results: We identified 10,438 1-year survivors of childhood cancer diagnosed prior to age 21 years between January 1st, 1990 and December 31st, 2010. Mean age at cancer diagnosis was 10.7 years (standard deviation [SD] 6.8) and the mean follow up was 11.2 years (SD 6.9). In multivariable models adjusted for rurality and income status, cancer survivors had a 55% increased rate of developing diabetes compared to matched controls (HR 1.55, 95% CI 1.31-1.83). Individuals treated for cancer between age 6-10 years (HR 4.01, 2.33-6.91) had the highest increased rate for diabetes among age categories. Leukemia (HR 2.39, 1.74-3.27) and lymphoma (HR 1.61, 1.12-2.31) was also associated with an increased risk for diabetes compared to the general population. Conclusions: Our study provides evidence of an increased risk for diabetes in adult survivors of childhood cancer. The increased risk is highest among those treated at younger ages, and after treatment for leukemia and lymphoma. Future research is warranted to identify optimal ways for diabetes screening and prevention in this population. Given the burden of cardiovascular disease in survivors, identifying and treating diabetes early may help improve overall morbidity and mortality.
Prospective study of UDP-glucuronosyltransferase (UGT) 2B17 genotype and exemestane (Exe) pharmacokinetics (PK) and pharmacodynamics (PD) in Asian, hormone receptor (HR) positive, metastatic breast cancer (MBC) patients.
Authors: Walsh Robert John , Lee Soo Chin , Seng Kok Yong , Wang Ling-Zhi , Ho Gwo Fuang , Ow Samuel Guan Wei , Kumarakulasinghe Nesaretnam Barr , Sundar Raghav , Lee Xiao Wen , Yap Hui-Ling , Jeyasekharan Anand Devaprasath , Pang Angela , Ho Jingshan , Tan Chee Seng , Lim Yi Wan , Malik Rozita Abdul , Wan Ishak Wan Zamaniah , Goh Boon Cher , Tai Bee Choo , Wong Andrea Li Ann
Published: September 2018

1056

Background: The active metabolite of Exe, 17-dihydroexemestane (17DhExe), is glucuronidated by UGT2B17 to inactive exemestane-17-O-glucuronide (Exe17- O-glu). UGT2B17*2/*2null genotype is 7 times more common in Asians than Caucasians and leads to reduced Exe glucuronidation in vitro. We studied Exe PK and PD in MBC patients genotyped for UGT2B17. Methods: Eligible patients (HR+ MBC; ≥1 line of endocrine therapy) received Exe 25mg OD till progression. UGBT2B17 genotype was correlated with day 29 (D29) steady-state PK (Exe and metabolites), change in PD biomarkers (estrone and androstenedione) at D29 vs baseline (BL), objective response rate (ORR) [sum of complete and partial responses], and clinical benefit rate (CBR) [response or stable disease ≥ 24 weeks]. Results: In 64 patients enrolled, CBR was 25%; ORR was 3%. Frequencies of UGT2B17*2/*2, UGT2B17*1/*2 and UGT2B17*1/*1 were 72%, 26% and 2%, respectively. PD and PK data were available for 54 and 53 patients respectively. Mean Exe17- O-glu AUC and Cmax were significantly lower, and mean 17DhExe Cmax numerically higher in patients with UGT2B17*2/*2 vs other genotypes (Table 1). 17DhExe Cmax was higher in patients with clinical benefit vs none (5.6 vs 3.8 ng/ml, p=0.02). Frequency of desired PD effect (rise in androstenedione and fall in estrone at D29 vs BL) was 22%. Exe plasma active index (PAI) [Table 1] was higher in patients with a fall in D29 estrone vs those without (14.7 vs 9.5, p=0.05). Conclusions: UGT2B17 genotype affects Exe PK and may have significant PD correlates. Larger studies to examine effects on clinical treatment efficacy are needed. Clinical trial information: NCT01655004. [Table: see text]
Late complications among adult survivors of neuroblastoma in the St. Jude Lifetime Cohort Study (SJLIFE).
Authors: Wilson Carmen Louise , Cook Cathleen Marie , Brinkman Tara M. , Huang Sujuan , Furman Wayne Lee , Bhakta Nickhill , Robison Leslie L. , Ness Kirsten K. , Hudson Melissa M.
Published: September 2018

10561

Background: Assessment of late outcomes in neuroblastoma survivors has generally consisted of self-reported health events within retrospective cohorts. We aimed to characterize the health outcomes of a clinically-assessed cohort of long-term survivors of neuroblastoma diagnosed between 1963-2003. Methods: In a cohort of 239 ten-year survivors of neuroblastoma, of whom 137 (57%) underwent comprehensive clinical assessments, chronic conditions were graded using a modified version of the Common Terminology Criteria of Adverse Events, version 4.03. Comparisons were made using 272 clinically assessed community controls. Log-binomial regression was used to compare the prevalence of chronic conditions (grade 1-5) between survivors and controls and to calculate prevalence ratio (PR) and 95% confidence intervals (CI). Mean cumulative count (treating death as a competing risk) of chronic conditions by age was used to estimate cumulative burden with imputation of outcomes for non-clinically assessed survivors. Results: The median age at diagnosis was 0.9 (range: 0.0-14.4) and the median age at follow-up was 31.9 (range: 20.2-54.6) years for clinically assessed survivors. Median age of controls was 34.7 (range: 18.3-70.2). Treatment consisted of chemotherapy (75%), radiation (23%) and surgery (91%). Survivors were more likely than controls to have hearing loss (31.4% vs. 2.9%, PR = 10.7, 95% CI = 5.2-22.0), cardiomyopathy (8.8% vs. 0.7%, PR = 11.9, 95% CI = 2.7-52.5), hypothyroidism (10.9% vs. 5.2%, PR = 2.1, 95% CI = 1.1-4.3) or neurological disorders (56.9% vs. 32.4%, PR = 1.8, 95% CI = 1.4-2.2). At 35 years of age, the cumulative incidence of survivors experiencing at least one grade 3-5 condition was 67.3% (95% CI = 58.3-76.0%). By age 35 survivors experienced, on average, 8.5 (95% CI = 7.6-9.3) grade 1-5 and 2.4 (95% CI = 2.0-2.8) grade 3-5 conditions per 100 survivors, which was higher than the burden of grade 1-5 (3.3 [95%CI = 2.9-3.7]) and grade 3-5 (0.9 [95%CI = 0.7-1.0]) conditions identified among controls. Conclusions: Two-thirds of survivors are affected by severe or life-threatening health conditions. Continued follow-up, screening and intervention provide opportunities to optimize health.
Infection related late mortality in survivors of childhood cancer with asplenia or radiation-induced hyposplenism: A report from the Childhood Cancer Survivor Study.
Authors: Weil Brent , Madenci Arin L , Liu Qi , Gibson Todd M. , Yasui Yutaka , Neglia Joseph Philip , Leisenring Wendy M. , Howell Rebecca M. , Tonorezos Emily S. , Friedman Danielle Novetsky , Tinkle Christopher , Diller Lisa , Armstrong Gregory T. , Oeffinger Kevin C. , Weldon Christopher Bertero
Published: September 2018

10563

Background: Asplenia or hyposplenism can develop in survivors of childhood cancer following splenectomy or radiotherapy exposure to the left upper quadrant of the abdomen (LUQ). Knowledge regarding long-term infection related outcomes for these survivors is limited. Methods: Infection related late mortality (sepsis, meningitis or pneumonia) was evaluated in 20,805 5-year survivors (diagnosed <21 years of age from 1970-1999, median follow-up 26 years, range 5-44) using cumulative incidence and Poisson regression models to calculate adjusted relative risk (RR) and 95% confidence intervals (CI). Average LUQ radiation was calculated as a surrogate for splenic radiation. Results: Treatment included splenectomy for 1328 survivors (6%). An additional 10,295 (49%) were exposed to LUQ radiotherapy without splenectomy. The cumulative incidence of infection related late mortality was 1.4% (95%CI: 0.7%-2.2%) at 35 years after splenectomy and 0.6% (95%CI: 0.4%-0.8%) after LUQ radiotherapy, with a total of 78 deaths attributable to infectious causes (25 sepsis, 1 meningitis, 52 pneumonia). Splenectomy (RR=8.4, p<0.001) and increasing LUQ radiotherapy dose (p<0.001) were independently associated with infection related late mortality (Table). Conclusions: Splenectomy and LUQ radiotherapy increased risk for infection related late mortality. While infectious mortality increased with increasing LUQ radiation dose, even lower dose exposure (<10Gy) increased risk substantially. Accordingly, cancer survivors exposed to LUQ radiotherapy should be considered at risk for functional asplenia and managed similarly to asplenic individuals with respect to vaccinations and febrile illnesses. [Table: see text]
Hepatic injury after treatment for childhood cancer: A report from the St. Jude Lifetime Cohort study.
Authors: Green Daniel M. , Wang Mingjuan , Krasin Matthew J. , Srivastava Deokumar , Relling Mary V. , Howell Carrie R , Ness Kirsten K. , Kaste Sue C. , Greene William , Fernandez-Pineda Israel , Pui Ching-Hon , Jeha Sima , Bishop Michael William , Furman Wayne Lee , Robison Leslie L. , Hudson Melissa M.
Published: September 2018

10567

Background: We assessed hepatic injury (HI) in a large cohort of childhood cancer survivors (CCS). Methods: We measured aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in 2751 SJLIFE CCS ( > 10 years (yrs) post-diagnosis, age ≥18 yrs), and graded using the Common Terminology Criteria for Adverse Events (CTCAE) v 4.03. Multivariable log binomial regression was used to estimate associations between demographic and clinical factors and grades 1–4 ALT and AST. Variables with a p < 0.1 were examined in multivariable models. Results: 1339 (48.7%) CCS were female. 2271 (82.6%) were non-Hispanic white (NHW). Median age at diagnosis - 7.4 yrs, median age at evaluation - 31.4 yrs, and median time from diagnosis to evaluation - 23.2 yrs. 177 (6.4%) had grades 1-4 AST (grade 1 = 164, grade 2 = 9, grade 3 = 4), and 421 (15.3%) had grades 1-4 ALT (grade 1 = 394, grade 2 = 18, grade 3 = 8). The multivariable results are shown in the table below. Conclusions: Male gender, obesity, hepatitis C virus infection, and treatment with busulfan are risk factors for increased AST and ALT. V10 is an additional risk factor for increased ALT. These results may guide future treatment designs and lifestyle interventions. [Table: see text]
Prevalence of attention-deficit/hyperactivity disorder in pediatric brain tumor survivors.
Authors: Shabason Emily Kauvar , Brodsky Cole , Baran Julie , Hobbie Wendy , Minturn Jane E. , Blum Nathan , Hocking Matthew
Published: September 2018

10572

Background: Pediatric brain tumor survivors (PBTS) often have neurodevelopmental late effects, including attention and concentration deficits, which may impact cognitive and academic functioning. Such symptoms are also seen in attention-deficit/hyperactivity disorder (ADHD), which affects ~5-8% of children and adolescents. This study examined the prevalence of ADHD diagnosis and ADHD medication use in PBTS and identified higher risk subsets of patients. Methods: A retrospective chart review was completed of PBTS (n = 106), diagnosed from 1999-2013, who were at least 2 years from the end of tumor-directed therapy (surgery, chemotherapy and/or radiation therapy) and without a multi-system genetic disorder or severe developmental delay prior to brain tumor diagnosis. Subjects were already screened for or enrolled in 3 other studies of PBTS late effects. Statistical analysis involved chi-squared analysis. Results: Among the 106 patients, 55.7% were male, with an average age at time of brain tumor diagnosis of 5.9 years (0-12.2 years). The most common tumor types were glioma (51.9% with 47.2% low grade, 4.7% high grade), medulloblastoma (13.2%) and ependymoma (11.3%), with 50% of tumors supratentorial, 46.2% infratentorial and 3.8% either extending or multifocal across the tentorium. Of the patients, 42.5% received radiation therapy, 38.7% chemotherapy and 86.8% surgery. Nineteen patients (17.9%) had ADHD diagnoses, and 20 (18.9%) had been on ADHD medications. Clinical factors associated with an ADHD diagnosis were supratentorial vs. infratentorial tumors (28.3% vs. 6.1%, p = 0.013), no radiation therapy vs. radiation therapy (27.9% vs. 4.4%, p = 0.002) and no chemotherapy vs. chemotherapy (24.6% vs. 7.3%, p = 0.024). ADHD diagnosis was not associated with age of brain tumor diagnosis or surgical treatment. Conclusions: Our study suggests that PBTS have over twice the ADHD prevalence as the general population, most notably in patients with supratentorial tumors or without a history of radiation therapy or chemotherapy. The results suggest that a closer look at this population is warranted and that select patients may benefit from behavioral or pharmacologic ADHD treatments to optimize functioning.