bluuebunny/crossref_metadata_2025 huggingface dataset:
NOMINATOR: Feasibility of genomic testing of rare cancers to match cancer to treatment.
Authors: Kee Damien , Kondrashova Olga , Ananda Sumitra , Brown Michael Paul , Cohen Paul Andrew , Dean Andrew , Desai Jayesh , Fellowes Andrew , Fox Stephen B. , Hadley Alison , Lindsay Dianne , Mileshkin Linda R. , O'Byrne Kenneth John , Prall Owen W.J. , Scott Hamish , Thomas David Morgan , Vines Richard , Waddell Nic , Papenfuss Anthony , Scott Clare L.
Published: May 2020

103

Background: Rare cancers (RCs) often lack proven treatments and consequently have poorer outcomes. Identification of molecular biomarkers can facilitate treatment selection and trials access for RC patients (pts) where histology-based trials are not feasible. We assessed the potential for next-generation sequencing (NGS) to impact RC care. Methods: Pts with a rare histology, poor-prognosis solid-tumor and no standard of care therapy underwent NGS genomic profiling of paired FFPE tumor and blood (PMCC comprehensive cancer panel; 391 genes). A virtual molecular tumour board (MTB) reviewed curated results regarding diagnosis, actionability (OncoKB) and treatment recommendations. Results: Between July 2017 and Nov 2019, 121 pt were prospectively enrolled across 4 Australian sites. 109 (91%) pts had a tumour with an incidence of < 1/100,000 person/years with 83 diverse RC histologies represented. 100 (83%) cases were successfully sequenced. The most commonly aberrant genes ( > 10%) were: TP53 (45%), CDKN2A/B, RB1, PTEN and NF1. 51 (51%) had at least one potentially actionable finding, with 27 matched to a clinically validated drug (OncoKB level 3 or better) [Table]. In 6 cases NGS resulted in a revised diagnosis (includes 4 with FDA approved therapy). Actionable germline mutations were detected in 3 individuals of which 2 were previously known. The majority of pts remain in follow-up, however, 8 died prior to or within 28 days of NGS result availability. Drug access remains a limitation with only 12 receiving therapy based on NGS/MTB guidance. Clinical trial information: ACTRN12616001000493 . Conclusions: NGS in RCs is feasible with potential impact in half of cases. Earlier testing and improved off-label/trial drug access is necessary to increase the likelihood that RC patients may benefit from molecularly guided therapy. [Table: see text]
A phase I dose escalation study evaluating the safety and tolerability of a novel anti-HER2 antibody-drug conjugate (PF-06804103) in patients with HER2-positive solid tumors.
Authors: Meric-Bernstam Funda , Calvo Emiliano , Moreno Victor , Chung Hyun Cheol , Park Yeon Hee , Bang Yung-Jue , Rosen Lee S. , Mita Monica M. , Garrido-Laguna Ignacio , Leung Abraham C.F. , Dube Harman , Zhong Wei , Chen Xiaoying , Dawaher Rula , Curigliano Giuseppe
Published: May 2020

1039

Background: PF-06804103 is an anti-HER2 immunoglobulin G1 antibody-drug conjugate (ADC), comprising an anti-HER2 monoclonal antibody conjugated with a cleavable linker to the cytotoxic agent Aur0101. PF-06804103 demonstrated strong activity in low to high HER2-expressing preclinical tumor models. In this study, the safety and tolerability of PF-06804103 was assessed in patients with advanced breast cancer (BC) or gastric cancer (GC). Methods: This multi-center, open-label, first-in-patient, phase I study (NCT03284723) has two parts: dose escalation (Part 1) and dose expansion (Part 2). In Part 1, groups of adult patients (pts) with HER2+ BC or HER2+ GC, who are resistant or intolerant to standard therapy or for which no standard therapy is available, received PF-06804103 intravenously once every 21 days (Q3W); dosage was escalated per cohort. Primary objectives were to evaluate the safety and tolerability of PF-06804103, characterize its dose-limiting toxicities (DLTs), and determine the recommended phase 2 dose. Response was assessed using RECIST v1.1. Objective response rate (ORR) was calculated for response-evaluable pts with target lesions at baseline and ≥1 post-baseline assessment (including unconfirmed responses). Results: A total of 35 pts (BC: n = 20; GC: n = 15) received PF-06804103 at escalating dose levels (0.15 mg/kg: n = 2; 0.5 mg/kg: n = 2; 1.2 mg/kg: n = 2; 2 mg/kg: n = 4; 3 mg/kg: n = 10; 4 mg/kg: n = 9; 5 mg/kg: n = 6). The median (range) number of prior therapies was 6 (3–18) and 3 (1–6) for BC and GC groups, respectively (all pts had prior HER2-targeted therapy). The 3 most common, drug-related adverse events (any grade) were alopecia (n = 17, 48.6%), fatigue (n = 15, 42.9%), and neuropathy (n = 9, 25.7%). DLTs (mostly grade 3) occurred in 3 pts and included arthralgia, neuropathy, myalgia, fatigue, and osteomuscular pain. Preliminary ORR in the patients treated with doses ≥3mg/kg was 52.4% (11/21). Conclusions: The PF-06804103 ADC demonstrated manageable toxicity and promising anti-tumor activity in this small, heavily pretreated study population. Clinical trial information: NCT03284723 .
Different response to ALK inhibitors in EML4-ALK positive mediastinal cancer of unknown primary.
Authors: Hu Chunhong , Zhao Lishu , Wu Fang
Published: May 2020

104

Background: With the development of next-generation sequencing (NGS) and precision medicine, targeted therapy especially molecule-driven therapy irrespective of tumor site may play an important role in cancer patients with druggable targets. Cancer of unknown primary (CUP) especially mediastinal CUP (MCUP) has poor prognosis with empirical chemotherapy but may harbor targetable genetic alterations. In the study, we evaluate the response to ALK inhibitors in ALK-positive MCUP. Methods: We queried the cancer database of the Second Xiangya hospitalfrom 2018.10 to 2019.12 for patients with ALK-positive cancers regardless of tumor site.Then we selected ALK-positive MCUP patients treated with ALK inhibitors, on which both NGS and programmed death-ligand 1 (PD-L1) testing were performed. Results: Forty-eightpatients with ALK-positive cancers were registered in the database. Two MCUP patients were found and showed different response. The first MCUP patient obtaining remarkable response to alectinib harbored ALK/TP53 co-mutation and TERT wild type accompanied by low PD-L1 expression, while the second one showing stable disease with crizotinib carried ALK/TP53/TERT co-mutation and high PD-L1 expression. Conclusions: We reveal for the first time that ALK inhibitors are applied to MCUP as first-line therapy and alectinib is firstly reported to treat MCUP patients. ALK inhibitor alectinib is expected to improve outcomes of patients with ALK-positive MCUP. NGS and PD-L1 testing should be recommended for MCUP to get more information about therapy and efficacy. [Table: see text]
SOPHIA analysis by chemotherapy (Ctx) choice: A phase III (P3) study of margetuximab (M) + Ctx versus trastuzumab (T) + Ctx in patients (pts) with pretreated HER2+ metastatic (met) breast cancer (MBC).
Authors: Escrivá Santiago , Im Seock-Ah , Cardoso Fatima , Cortes Javier , Curigliano Giuseppe , Gradishar William John , Pegram Mark D. , Wright Gail Lynn Shaw , Levy Christelle , De Laurentiis Michelino , Ferrero Jean-Marc , Bahadur Shakeela Wazeen , Kim Sung-Bae , Petráková Katarína , Riseberg David A. , Yardley Denise A. , Edlich Sutton , Hong Sam , Rock Edwin P. , Rugo Hope S.
Published: May 2020

1040

Background: Despite advances, pretreated HER2+ MBC remains incurable with ongoing need for new therapies. Investigational M has similar HER2 binding and antiproliferative effects as T. Relative to T, M Fc engineering increases binding affinity for both variants of activating Fc receptor (FcR) CD16A and decreases affinity for inhibitory FcR CD32B, coordinately activating innate and adaptive immunity. In a Phase 3 (P3) trial, M prolonged PFS over T (Table). Second interim OS results from Sept 2019 also favor M (hazard ratio [HR], 0.89; 95% CI 0.69–1.13; nominal P=0.326). Methods: SOPHIA (NCT02492711), an open-label P3 trial, enrolled pts with HER2+ MBC after pertuzumab and 1–3 lines of prior treatment (Tx) for MBC. Randomization was 1:1 to M (15 mg/kg IV q3w + Ctx) or T (6 [8 for loading dose] mg/kg IV q3w + Ctx), stratified by met sites (≤2, >2), lines of Tx for met disease (≤2, >2), and Ctx choice, including capecitabine (Cap), eribulin (Eri), gemcitabine (Gem), or vinorelbine (Vin). Primary endpoints were central blinded PFS and OS, assessed sequentially using the stratified log-rank test. Results: Investigator chemotherapy choices and results by chemotherapy are shown in the table. Subjects receiving Eri and Gem had the lowest PFS hazards ratios (HRs), favoring M over T, although no statistical significance of individual chemotherapy subgroups was seen. There was variable toxicity among Ctx subgroups, and fewer subjects receiving Cap had Ctx related Grade 3 or higher (>=Gr 3) AEs. In this unblinded study, more subjects on M than T in all subgroups discontinued Ctx while continuing study antibody. Conclusions: In combination with chemotherapy in pretreated HER2+ MBC, M improved PFS over T. Safety was manageable in all Ctx subgroups. Differences among HRs for chemotherapy subgroups may be driven by selection bias and/or sensitivity differences. Clinical trial information: NCT02492711 . [Table: see text]
Pyrotinib plus capecitabine for HER2-positive, trastuzumab-resistant metastatic breast cancer: A pooled analysis of three randomized controlled trials.
Authors: Jiang Zefei , Xu Binghe , Yan Min , Ouyang Quchang , Hu Xi-Chun , Li Wei , Feng Ji Feng , Zhang Qingyuan , Tong Zhongsheng , Yan Ping , Zhu Xiaoyu , Rong Shangyi , Zou Jianjun
Published: May 2020

1048

Background: Trastuzumab is the most widely used anti-HER2 agent in patients (pts) with HER2-positive breast cancer, both in (neo)adjuvant and metastatic settings; however, drug resistance is inevitable. This pooled study aimed to investigate the efficacy of pyrotinib plus capecitabine in pts with HER2-positive, trastuzumab-resistant relapsed or metastatic breast cancer. Methods: Data were derived from three randomized controlled trials, including a phase II (NCT02422199) and the PHOEBE phase III (NCT03080805) study comparing pyrotinib plus capecitabine vs lapatinib plus capecitabine and the PHENIX phase III (NCT02973737) study comparing pyrotinib plus capecitabine vs placebo plus capecitabine. Pts with trastuzumab-resistant disease were included in the analyses, including 39 pts who had relapsed within six months after adjuvant trastuzumab and 57 pts who had progressed within three months of trastuzumab treatment for metastatic disease. The pooled tumor response data (per blinded independent central review) were reported herein. Results: In the pooled analysis of all three studies, 63 pts received pyrotinib plus capecitabine. Among them, 28 (44.4%) pts had disease progression or died. The median progression free survival (PFS) was 12.4 months (95% CI, 6.9 to not reached). In total, 40 pts (63.5% [95% CI, 50.4% to 75.3%]) achieved objective response, and the estimated median duration of response (DoR) was 11.1 months (95% CI, 6.9 to not reached). In the pooled analysis involving the phase II and PHOEBE phase III, 43 pts were treated with pyrotinib plus capecitabine and 33 pts with lapatinib plus capecitabine. In total, 18 (41.9%) pts with pyrotinib plus capecitabine and 17 (51.5%) pts with lapatinib plus capecitabine had disease progression or died. The PFS tended to be prolonged with pyrotinib plus capecitabine vs lapatinib plus capecitabine (median, 12.4 months [95% CI, 6.9 to not reached] vs 6.9 months [95% CI, 5.5 to not reached]; hazard ratio, 0.62 [95% CI, 0.31 to 1.24]; p=0.0864). The objective response rate was 67.4% (95% CI, 51.5% to 80.9%) with pyrotinib plus capecitabine compared with 54.5% (95% CI, 36.4% to 71.9%) with lapatinib plus capecitabine. The estimated median DoR was 11.1 months [95% CI, 6.9 to not reached] vs not reached [95% CI, 4.2 months to not reached], respectively. Conclusions: Pyrotinib plus capecitabine showed favorable efficacy in pts with HER2-positive, trastuzumab-resistant relapsed or metastatic breast cancer. This combination could be a treatment option for this population.
Randomized phase II trial of MIBG versus MIBG/vincristine/irinotecan versus MIBG/vorinostat for relapsed/refractory neuroblastoma: A report from the New Approaches to Neuroblastoma Therapy Consortium.
Authors: DuBois Steven G. , Granger Meaghan , Groshen Susan G. , Tsao-Wei Denice , Shamirian Anasheh , Czarnecki Scarlett , Goodarzian Fariba , Berkovich Rachel , Shimada Hiroyuki , Mosse Yael P. , Shusterman Suzanne , Cohn Susan Lerner , Goldsmith Kelly C. , Weiss Brian D. , Yanik Gregory A. , Twist Clare , Irwin Meredith , Park Julie R. , Marachelian Araz , Matthay Katherine K.
Published: May 2020

10500

Background: 131I-metaiodobenzylguanidine (MIBG) remains one of the most active agents for neuroblastoma. It is not clear if putative radiation sensitizers improve upon this activity. The primary aim of this trial was to identify the MIBG treatment regimen with highest response rate among: MIBG monotherapy (Arm A); MIBG/Vincristine/Irinotecan (Arm B); MIBG/Vorinostat (Arm C). The secondary aim was to compare toxicity across arms. Methods: We conducted a multicenter, randomized phase II trial. Patients 1-30 years with relapsed/refractory high-risk neuroblastoma were eligible with at least one MIBG-avid site and adequate autologous stem cells (ASCs). All patients received MIBG 18 mCi/kg on Day 1 and ASC on day 15. Patients on Arm A received only MIBG; patients on Arm B also received vincristine (2 mg/m2) IV on Day 0 and irinotecan (50 mg/m2) IV daily on Days 0-4; patients on Arm C also received vorinostat (180 mg/m2) orally once daily on days -1 to 12. The primary endpoint was response after one course according to NANT response criteria. The trial was designed as a pick-the-winner study with a maximum of 105 eligible and evaluable patients to ensure an 80% chance that the arm with highest response rate is selected, if that response rate is at least 15% higher than the other arms. Results: 114 patients enrolled. Three patients were ineligible and 6 eligible patients never received MIBG, leaving 105 eligible and evaluable patients (36 Arm A; 35 Arm B; and 34 Arm C; 55 boys; median age 6.5 years). 9 patients had received prior MIBG monotherapy, 65 prior irinotecan, and 7 prior vorinostat. After one course, the response rates (Partial Response or better) on Arms A, B, and C were 17% (95% CI 7-33%), 14% (5-31%), and 32% (18-51%). An additional 4, 4, and 7 patients met NANT Minor Response criteria [partial response in one disease category (e.g., bone marrow) and stable disease in other categories] on Arms A, B, and C, respectively. On Arms A, B, and C, rates of any grade 3+ non-hematologic toxicity were 19%, 49% and 32%; rates of grade 3+ diarrhea were 0%, 11%, 0%; and rates of grade 3+ febrile neutropenia were 6%, 11%, and 0%. Conclusions: The combination of vorinostat/MIBG had the highest response rate, with manageable toxicity. Vincristine and irinotecan do not improve the response rate to MIBG and are associated with increased toxicity. These data provide response rates for MIBG monotherapy in a contemporary patient population assessed with current response criteria. Clinical trial information: NCT02035137.
Segmental chromosome aberrations and clinical response impact outcome of inss stage III patients ≥18 months with unfavorable histology and without MYCN amplification: A Children’s Oncology Group (COG) report.
Authors: Pinto Navin R. , Naranjo Arlene , Hibbitts Emily , Ding Xiangming , Tibbetts Rachelle , Kennedy Rebekah , Pfau Ruthann , Hogarty Michael D. , Kreissman Susan G. , Irwin Meredith , Park Julie R. , Asgharzadeh Shahab
Published: May 2020

10502

Background: Patients with INSS stage III neuroblastoma represent a heterogeneous population with respect to disease presentation and prognosis and controversy exists regarding the most effective treatment algorithms. Patients ≥18 months of age with INSS Stage 3 tumors that are unfavorable histology (UH) and MYCN-non-amplified ( MYCN-NA) represent a small cohort of patients with an outcome intermediate of those with favorable histology tumors and MYCN amplified tumors. The presence of Segmental Chromosome Aberrations (SCA) may predict outcome; however, their impact specifically in this cohort of patients has not been reported. Methods: Eligible patients enrolled on therapeutic protocols A3973 (n=34), ANBL0532 (n=27), and biology protocol ANBL00B1 (n=101 with 29 treated on A3973/ANBL0532) with stage III disease, MYCN–NA, UH and age ≥18 months at diagnosis were analyzed. Copy number alterations and loss of heterozygosity (LOH) for relevant loci were scored for gains/losses by two independent reviewers. Results: The 5-year EFS/OS for children ≥18 months with stage III, MYCN–NA, UH disease treated on A3973 and ANBL0532 was 73.0±8.1%/87.9±5.9% and 61.4±10.2%/ 73.0±9.2%, respectively, with no statistical differences in EFS or OS between the two cohorts (p=0.1286 and p=0.2180, respectively). In the combined cohort of patients enrolled on A3973 and ANBL0532, statistically significant differences were found (p(s) <0.0001) in patients with CR/VGPR (n=39) and PR (n=13) having better outcomes than <PR (n=5) (5-year EFS: 74.0±7.6% vs. 75.0±12.5% vs. 0%; 5-year OS: 84.4±6.2% vs. 100% vs. 20.0±17.9%). Subjects with chromosome 11q loss/LOH had an inferior outcome in comparison to those without 11q loss/LOH (10-year EFS: 44.4+/-24.1% vs. 78.1+/-9.4%, p=0.01; 10-year OS: 62.4+/-15.9% vs. 85.9+/-7.8%, p=0.02)). Patients with 1p loss/LOH and 2p gain also showed trend towards worse event-free survival (p=0.086 and p=0.088, not statistically significant) but not in overall survival. Conclusions: High-risk therapy that included single myeloablative therapy led to an 81.6±5.3%5-year OS in patients ≥18 months with UH and MYCN–NA stage III neuroblastoma. Response to therapy is a powerful predictor of survival and the presence of chromosome 11q loss/LOH is also associated with inferior outcomes. These patients should continue to be treated on high-risk clinical trials.
CD19-targeted chimeric antigen receptor (CAR) T cells in CNS relapsed acute lymphoblastic leukemia (ALL).
Authors: Newman Haley , Barz Leahy Allison Emily , Li Yimei , Liu Hongyan , Myers Regina M , DiNofia Amanda M , Dolan Joseph Gregory , Callahan Colleen , Devine Kaitlin J , Wray Lisa , June Carl H. , Grupp Stephan A. , Rheingold Susan R. , Maude Shannon L.
Published: May 2020

10511

Background: CNS relapse of B-ALL is difficult to treat after cranial radiation or multiple relapses. Durable remissions of relapsed/refractory (r/r) B-ALL have been seen with CD19 CAR T cells; however, most trials excluded patients with active CNS disease. As we observed CAR trafficking into the CSF, we hypothesized that CD19 CAR T cells could control CNS B-ALL. Methods: We identified children and young adults with r/r CNS B-ALL treated on 4 clinical trials of CD19 CAR T cells, CTL019 or CTL119. NCT01626495 and NCT02435849 excluded active CNS disease, while the former in an amendment as well as NCT02374333 and NCT02906371 permitted active CNS disease controlled on therapy. All trials permitted CNS disease that cleared and excluded bulky intracranial disease that did not improve. We analyzed outcomes (CR, RFS) and safety. Results: We identified 65 patients 1-29y (median 10y) with r/r CNS B-ALL (CNS+) of 182 treated with CTL019/CTL119. There were no differences in age, sex, history of SCT or neurologic comorbidities in the CNS+ and CNS- cohorts. CNS+ patients were more likely to be in ≥2nd relapse (74% vs 46%, p < 0.01), to have received cranial radiation (58% vs 11%, p < 0.01), to have detectable CNS disease (p = 0.02) and less bone marrow disease pre-infusion (p < 0.01). At 1 mo post infusion, 62 (95%) CNS+ and 110 (94%) CNS- patients were in CR; 1 in each cohort died of sequelae of CRS and was inevaluable for response. All patients with CNS disease detected pre-infusion cleared by mo 3, including 9 in the CNS+ cohort [5 CNS2 ( < 5 CSF WBC with blasts), 4 CNS3 ( > 5 CSF WBC with blasts or exam/imaging evidence)] and 8 in the CNS- cohort (isolated CNS2 status pre-infusion). There was no difference in RFS (p = 0.28) in the CNS+ and CNS- cohorts [24-mo RFS: 61% (95% CI 46-73%) and 60% (95% CI 48-70%)]. There were 4 CNS relapses in the CNS+ cohort, and 1 in the CNS- cohort. Encephalopathy rate and grade was similar in the CNS+ and CNS- cohorts (52% vs 40% any grade; 12% vs 11% grade 3/4; p = 0.41). There were no deaths due to neurotoxicity (NT) and no statistically significant differences in incidence or severity of any NT or CRS in the CNS+ and CNS- cohorts. Conclusions: The CD19 CAR T cell therapies CTL019/CTL119 are effective at clearing CNS disease and inducing durable remissions in children and young adults with r/r CNS B-ALL. CNS relapse rates are low ( < 3%). Most CD19 CAR T cell trials excluded patients with active CNS disease, primarily due to the risk of NT. We show that patients with r/r CNS B-ALL that is adequately controlled prior to infusion can be safely treated with CD19 CAR T cells, with no increased risk of NT. Clinical trial information: NCT01626495, NCT02435849, NCT02374333, NCT02906371.
Outcomes and toxicities in patients (pts) non-randomly assigned to immunotherapy Children’s Oncology Group (COG) ANBL0032.
Authors: Desai Ami Vijay , Gilman Andrew , Ozkaynak Mehmet Fevzi , Naranjo Arlene , London Wendy B , Tenney Sheena Cretella , Smith Malcolm , Seibel Nita , Shimada Hiroyuki , Matthay Katherine K. , Cohn Susan Lerner , Maris John M. , Bagatell Rochelle , Sondel Paul M. , Park Julie R. , Yu Alice L.
Published: May 2020

10523

Background: Immunotherapy with the anti-GD2 antibody dinutuximab plus sargramostim (GM-CSF), aldesleukin (IL-2) and isotretinoin following consolidation therapy improved outcome for high-risk neuroblastoma (HRNBL) pts enrolled on COG ANBL0032. Randomization was halted in 2009; subsequent pts were non-randomly assigned to immunotherapy. Toxicities and survival were evaluated. Methods: HRNBL pts < 31 years old with a pre-autologous stem cell transplant (ASCT) response of ≥ partial response (PR) were eligible. Demographics, INSS stage, tumor biology, 1993 INRC pre-ASCT response and toxicities were summarized using descriptive statistics. Five-year (yr) EFS and OS from time of study enrollment were estimated. Results: From 2009-2015, 1,183 pts were non-randomly assigned to immunotherapy. 96.7% (n = 1,144) were ≥18 months old and 83.1% (n = 765/921) had stage 4 disease. 45.1% (n = 363/805) of tumors with known biology were MYCN amplified, 94.5% (n = 749/793) had unfavorable histology, and 54.9% (n = 397/723) were diploid. Pre-ASCT, 352 (29.8%) pts had complete response (CR), 418 (35.3%) had very good partial response (VGPR), and 413 (34.9%) had PR. 1,042 (88.1%) pts underwent a single and 141 (11.9%) underwent tandem ASCT. For the entire cohort, 5-yr EFS was 61.1±1.9% and 5-yr OS was 71.9±1.7%. 5-yr EFS and OS for pts ≥18 months of age with stage 4 disease (n = 746) were 58.4±2.3% and 71.0±2.1%. 5-yr EFS and OS were 82.3±4.8% and 86.7±4.2% among pts with stage 3 disease (n = 110). EFS but not OS was superior for those with a CR/VGPR pre-ASCT vs. PR (5-yr EFS: 64.2±2.2% vs. 55.4±3.2%, p = 0.0133; OS: 72.7±2.1% vs. 70.5±2.9%, p = 0.3811). There was a trend toward improved OS for those treated with tandem vs. single transplant (5-yr EFS: 65.9±4.3% vs. 60.4±2.1%, p = 0.1282; OS: 76.5±3.8% vs. 71.2±1.9%, p = 0.0704). Grade ≥3 toxicities ( > 10% of pts) during GM-CSF and IL-2-containing cycles, respectively, included pain (15.6/11.4%), fever (15.1/32.7%), anemia (18.9/21.7%), thrombocytopenia (13.9/17.4%), lymphopenia (12.3/16.0%), and hypokalemia (13.3/25.2%). Additional Grade ≥3 toxicities ( > 10% of pts) included hypoxia (10.1%) during GM-CSF-containing cycles, and anaphylaxis (12.0%), neutropenia (16.1%), hyponatremia (16.5%), and hypotension (13.8%) during IL-2-containing cycles. Conclusions: In this large cohort of HRNBL pts treated with immunotherapy, 5-yr EFS was 61.1%. Superior EFS was observed for pts with stage 3 disease and for those with CR/VGPR pre-ASCT. IL-2-containing cycles were associated with increased toxicity. Clinical trial information: NCT00026312.
Outcome in patients with refractory high-risk neuroblastoma.
Authors: Siddiqui Amir Bari , Oppong Akosua , Yuan Cindy , Gao Guimin , Bagatell Rochelle , Berg Katherine , Sokol Elizabeth , MacQuarrie Kyle , Pinto Navin R. , Gollapudi Anurekha , Mody Rajen , Wolfe Ian , Shusterman Suzanne , Foster Jennifer , Smith Valeria , Cohn Susan Lerner , Desai Ami Vijay
Published: May 2020

10537

Background: Outcome for high-risk neuroblastoma (HRNBL) patients (pts) with refractory disease at end of induction (EOI) is poor. The impact of therapies such as I-131-MIBG or irinotecan/temozolomide/dinutuximab (I/T/DIN) prior to autologous stem cell transplant (ASCT) on outcome is unknown. Methods: A multi-center, retrospective study of HRNBL pts diagnosed between 2008-2018 with refractory disease at EOI was conducted. Demographics, tumor biology, treatment response, and outcomes were abstracted. 3-year (yr) EFS and OS from time of diagnosis were estimated by the Kaplan-Meier method. Results: 3-yr EFS and OS were 54% and 79% for the 136 pts analyzed. 91 pts received no additional therapy prior to ASCT (Cohort 1); 32 pts received post-induction therapy prior to ASCT (Cohort 2); and 13 pts did not undergo ASCT (Cohort 3). The prevalence of metastatic disease in Cohort 1, 2, and 3 was 65%, 97%, and 85%. 3-yr EFS and OS were not statistically different between Cohort 1 (3-yr EFS and OS; 62% and 81%) and Cohort 2 [3-yr EFS and OS; 49% (p = 0.48) and 82% (p = 0.19)]. Outcome for Cohort 3 pts was significantly worse than Cohort 1 [3-yr EFS: 15% vs. 62% (p < .001); and 3-yr OS: 48% vs. 81% (p = 0.003)] and Cohort 2 [3-yr EFS: 15% vs. 49% (p < .001); and 3-yr OS 48% vs. 82% (p = 0.035)]. For Cohort 2 pts with metastatic disease, post-induction therapy included I/T/DIN (n = 12), MIBG (n = 16), MIBG plus I/T/DIN (n = 1), and other (n = 2). Metastatic disease response was observed in 10/12 (83%) pts who received I/T/DIN and 9/16 (56%) who received MIBG. MIBG plus I/T/DIN (n = 1) or MIBG with chemotherapy (n = 1) also induced response. Among the 21 pts with metastatic disease response, 3-yr EFS and OS were 69% and 94%; significantly better than Cohort 2 patients who did not respond to post-induction therapy [3-yr EFS and OS: 11% (p = 0.016) and 66% (p = 0.2)]. 6 Cohort 2 pts achieved a complete response (CR) in metastatic sites following I/T/DIN (n = 5) or MIBG (n = 1), and all are alive without relapse with median follow-up of 3.4 years (range 2.7-8.1). The single Cohort 3 patient who achieved a metastatic CR with I/T/DIN and did not undergo ASCT remains disease-free 2.4 years from diagnosis. Conclusions: Patient characteristics differed in the 3 Cohorts, reflecting the influence of refractory disease on treatment decisions. For Cohort 2 pts, outcome was better for those with metastatic disease at EOI who responded to post-induction therapy compared to those who did not. Pts who achieved a metastatic CR of refractory disease had excellent survival. Prospective studies testing the efficacy of I/T/DIN in pts with refractory metastatic disease at EOI are warranted.
Rhabdomyosarcoma of the female genital tract: Long-term outcome and association with DICER1 variation.
Authors: Kebudi Rejin , Bay Buyukkapu Sema , Gorgun Omer , Dural Ozlem , Onder Semen , Bilgic Bilge , Yilmaz Ismail , Iribas Ayca , Arndt Carola A. S. , Harris Anne , Field Amanda , Schultz Kris Ann Pinekenstein , Hill Ashley , Darendeliler Emin
Published: May 2020

10538

Background: Rhabdomyosarcoma (RMS) of the female genital tract is rare, accounting for 3.5% of cases of rhabdomyosarcomas. Germline DICER1 mutations are associated with predisposition to pleuropulmonary blastoma and other tumors including sarcomas. Recently DICER1-associated RMS of the uterus/ovary has ben reported.. The aim of this study is to evaluate demographic characteristics, molecular pathogenesis, treatment and long term outcome of female genital tract rhabdomyosarcoma. Methods: Files of children with RMS of the female genital tract diagnosed at the Istanbul University, Oncology Institute during 1990-2019 were reviewed. Molecular genetic sequencing was performed by polymerase chain reaction amplification of genomic DNA extracted from the formalin-fixed, paraffin embedded tumors, followed by Sanger sequencing. Genetic testing for DICER1 variants of the proband and family members was performed if DICER1 mutation was detected in the tumor of the proband. Results: Of 210 RMS cases, 11 arose from the female genital tract. The median age at diagnosis was 52 months (10 months-15 years). Primary sites were vaginal (n = 5), uterus (n = 4), and ovary(n = 2). Presenting symptoms included vaginal mass (n = 6), vaginal bleeding (n = 5), and abdominal pain (n = 3). Four had group 1, five group 3, two group 2 disease and all received chemotherapy (vincristine, actinomycinD + cyclophosphamide).Three received radiotherapy; three underwent hysterectomy. DICER1 mutation was detected in tumor tissue in three patients:[ c.5113G > A (p.E1705K); c.5428G > T (p.D1810Y); c.1870C > T (p.Arg624Ter)] Genetic testing revealed germline DICER1 pathogenic variation in two patients and their family members, one of whom had cystic nephroma in infancy and history of Wilms tumor in an uncle. They were referred for surveillance for the DICER1 related diseases. A patient with metachronous bilateral ovarian RMS died. Two are married, one has children. The 5 year survival for RMS of the female genital tract was 85.7 % at a median follow-up of 34 (4-298) months. Conclusions: Rhabdomyosarcoma of the female genital tract is associated with a favorable prognosis, however some individuals undergo aggressive local therapies. Individuals with RMS of the female genital tract should be tested for DICER1 pathogenic variation. The detection of a DICER1 mutation in an individual or family members is important to facilitate surveillance for related tumors, so that they may be detected at the earliest possible stage, potentially increasing survival and decreasing risks of late effects.
The role of autologous stem-cell transplantation in high-risk neuroblastoma consolidated by anti-GD2 immunotherapy: Results of 2 consecutive studies in a single referral institution.
Authors: Mora Jaume , Castañeda Alicia , Flores Miguel Angel , Santa-María Vicente , Garraus Moira , Gorostegui Maite , Simao Margarida , Perez-Jaume Sara , Mañe Salvador
Published: May 2020

10539

Background: Treatment of high-risk NB within the major international cooperative groups (COG and SIOP) comprise intensive induction, consolidation with high dose chemotherapy and autologous stem cell rescue (ASCR) followed by anti-GD2 immunotherapy and isotretinoin as maintenance therapy. In the COG studies dinutuximab and cytokines (GM-CSF and IL-2) were used to treat patients in complete remission (CR) after ASCR whereas SIOPEN studies used dinutuximab-beta plus/minus IL-2 and included patients with responsive (no progression 109 days after ASCR) but refractory (skeletal metaiodobenzylguanidine positivity with three or fewer areas of abnormal uptake). Methods: Since December 2014, HR-NB patients referred to HSJD were eligible for consolidation with anti-GD2/GM-CSF immunotherapy in 2 consecutive studies (dinutuximab for EudraCT 2013-004864-69 and naxitamab for 017-001829-40) and naxitamab/GM-CSF compassionate use (CU) with or without prior ASCR. Patients were enrolled in 1st CR or with primary refractory bone/bone marrow (B/BM) disease. We accrued a study population of two groups whose consolidative therapy, aside from ASCR, was similar: anti-GD2 (dinutuximab or naxitamab) antibodies + GM-CSF and local radiotherapy. This is a retrospective analysis of their event-free survival (EFS) and overall survival (OS) calculated from study entry. Results: From Dec 14 til Dec 19, 67 study patients were treated with the COG (dinutuximab + GM-CSF+ IL-2 + RA) regimen (n = 21) in the HSJD-HRNB-Ch14.18 study or with Naxitamab and GM-CSF in the Ymabs study 201 (n = 12) or CU (n = 34). 23 patients were treated with primary refractory disease in the B/BM, and 44 in 1st CR. The 67 study patients included 13 (19%) treated following single ASCR and 54 following induction chemotherapy and surgery. Median follow-up for all surviving patients is 16.2 months. Two-year rates for ASCR and non-ASCR patients were, respectively: EFS 64% vs. 54% (p = 0.28), and OS 66.7% vs. 84% (p = 0.8). For the 44 pts in 1st CR, 2-year rates for ASCR and non-ASCR patients were, respectively: EFS 65% vs. 58% (p = 0.48), and OS 71% vs. 85% (p = 0.63). Conclusions: In this retrospective, single center study, ASCR did not provide survival benefit when anti-GD2 + GM-CSF based immunotherapy was used for consolidation after dose-intensive conventional chemotherapy.
A phase I study of simvastatin in combination with topotecan and cyclophosphamide in pediatric patients with relapsed and/or refractory solid and CNS tumors.
Authors: Cash Thomas , Jonus Hunter C. , Tsvetkova Maya , Beumer Jan Hendrik , Lee Jasmine Y , Henry Curtis , Aguilera Dolly , Harvey R. Donald , Goldsmith Kelly C.
Published: May 2020

10541

Background: HMG-CoA reductase inhibitors (statins) can inhibit IL-6-mediated STAT3 activation, a critical pathway in pediatric CNS and solid tumors. Statins also inhibit tumor proliferation, angiogenesis, and restore apoptosis in preclinical pediatric solid tumor models. We therefore conducted a phase 1 trial of simvastatin in combination with topotecan and cyclophosphamide in children with relapsed/refractory (r/r) solid and CNS tumors. Methods: Eligible patients were 1-29 years of age with a r/r solid or CNS tumor. Simvastatin was administered orally twice daily on days 1-21, with topotecan 0.75 mg/m2/dose IV and cyclophosphamide 250 mg/m2/dose IV on days 1-5. Four dose levels (DLs) were planned: 140, 180, 225, 290 mg/m2/dose. A 3+3 design was used to determine the maximum tolerated dose (MTD). Pharmacokinetic and pharmacodynamic analyses were performed. Results: The median (range) age of 14 eligible patients was 11.5 years (1 - 23). Diagnoses included neuroblastoma (N = 4), sarcoma (N = 7), and one each of malignant rhabdoid tumor of kidney, medulloblastoma, and Wilms tumor. Eleven DLT-evaluable patients received a median of 4 cycles (range: 1-6). There were 3 cycle 1 DLTs, grade 3 diarrhea and grade 4 creatine phosphokinase (CPK) increased at DL 1, and grade 4 CPK increased at DL 0 (100 mg/m2/dose). Grade 3/4 treatment-related cycle 1 adverse events occurring in ≥ 10% patients were neutropenia (100%), leukopenia (100%), thrombocytopenia (91%), lymphopenia (91%), anemia (55%), febrile neutropenia (55%) and CPK increased (18%). Best overall response was partial response in 1 patient and stable disease in four. Simvastatin and simvastatin acid Cmax (geomean 82.5 and 12.6 ng/mL) and AUC0-6 (geomean 82.5 and 12.6 ng•h/mL) were comparable with reported pediatric literature values (Cmax 3.5 and 0.4-2.1 ng/mL; AUC0-8 10.7 and 3.8 ng•h/mL) after correction for the higher doses (3.77 vs 0.16 mg/kg) used in our study. Patient peripheral blood mononuclear cells showed maximum phospho-(p)STAT3 inhibition on Day 5, with recurrence by Day 21 despite continued simvastatin dosing. Plasma IL6 levels showed sustained IL6 inhibition with decrease to normal values by Day 21 in all patients, indicating potential on target effects. Conclusions: For this first-in-pediatrics trial of statins as anti-cancer therapy, the MTD of simvastatin with chemotherapy was 100 mg/m2/dose. This combination was well-tolerated with predominantly hematologic toxicity and predictable DLTs related to simvastatin. Clinical trial information: NCT02390843.
Emotional distress, stress, and cardiovascular health in adult survivors of childhood cancer.
Authors: Lubas Margaret M. , Wang Mingjuan , Jefferies John L. , Ness Kirsten K. , Ehrhardt Matthew J. , Krull Kevin R. , Mulrooney Daniel A. , Srivastava Deo Kumar , Robison Leslie L. , Hudson Melissa M. , Armstrong Gregory T. , Brinkman Tara M.
Published: May 2020

10547

Background: The contribution of emotional distress and stress to cardiac health in adult survivors of childhood cancer has not been reported, despite evidence of causal associations in the general population. Methods: Comprehensive medical assessments and standardized measures of depression, anxiety, post-traumatic stress disorder, and perceived stress were performed on 3,267 survivors in the St. Jude Lifetime Cohort (median[range] 29.9[18.0-64.5] years of age; 7.7[0-24.8] years at diagnosis; 49% female). Physical outcomes included hypertension, diabetes, dyslipidemia, cardiomyopathy, dysrhythmia (grades 2-4 per the NCI CTCAE criteria), myocardial infarction (grades 3-4), and metabolic syndrome (yes/no). Multivariable generalized linear models examined associations between these outcomes with any distress/stress, adjusted for demographics, cumulative anthracycline dose and thoracic radiation, physical activity, BMI, smoking, and alcohol intake. Unadjusted longitudinal associations between distress/stress and new onset cardiac conditions were examined among survivors who completed repeat medical assessment(s) (n = 1748; median follow-up = 3.9 years). New onset conditions were defined as a change from grade 0-1 at baseline to ≥ grade 2 at follow-up. Results: Survivor reported distress/stress (29% overall) was more prevalent in those with hypertension (28.2% vs 19.5%, P< 0.001), dyslipidemia (16.4% vs. 11.3%, P< 0.001), diabetes (9.4% vs. 6.9%, P= 0.02), and metabolic syndrome (32.2% vs. 23.2%, P< 0.001), but not among dysrhythmia, cardiomyopathy, and myocardial infarction. In separate multivariable models, distress/stress was associated with hypertension (RR = 1.24, 95% CI 1.07-1.43), dyslipidemia (RR = 1.29, 95% CI 1.03-1.61), and metabolic syndrome (RR = 1.35, 95% CI 1.17-1.54). Baseline distress/stress was associated with new onset hypertension (OR = 1.33, 95% CI 0.94-2.01), dyslipidemia (OR = 1.37, 95% CI 0.94-1.87), and dysrhythmia (OR = 2.78, 95% CI 1.12-6.91). Conclusions: Emotional distress/stress is associated with adverse cardiovascular health and may serve as an intervention target for improving cardiac health outcomes among survivors of childhood cancer.
Peripheral motor and sensory neuropathy in survivors of childhood central nervous system (CNS) tumors in the St. Jude Lifetime (SJLIFE) cohort.
Authors: Rodwin Rozalyn L , Lu Lu , Srivastava Deo Kumar , Brinkman Tara M. , Krull Kevin R. , Armstrong Gregory T. , Khan Raja B. , Phillips Nicholas S. , Merchant Thomas E. , Gajjar Amar J. , Robison Leslie L. , Hudson Melissa M. , Kadan-Lottick Nina S. , Ness Kirsten K.
Published: May 2020

10549

Background: Survivors of CNS tumors are at risk for peripheral motor and sensory neuropathy. Chemotherapy’s contribution to peripheral neuropathy has not been well studied in this population. We aimed to estimate the prevalence of peripheral neuropathy, and determine its association with tumor characteristics and treatment exposures. Methods: Within the SJLIFE cohort, survivors of CNS tumors (n = 363, median [range] age 24 [18-53] years, 43.3% female) ≥10 years from diagnosis and ≥ 18 years at evaluation completed in-person assessments for peripheral motor and sensory neuropathy (defined as abnormal motor or sensory subscales of the Modified Total Neuropathy Score). For comparison, matched community controls (n = 445, median [range] age 34 [18-70] years, 55.7% female) underwent the same assessment. Prevalence of ≥ grade 2 motor or sensory neuropathy was estimated by a modified Common Terminology Criteria for Adverse Events. Multivariable analyses adjusting for age, sex and race were used to identify associated disease and treatment characteristics. Results: Overall, 11.0% of survivors of CNS tumors versus 0.9% of controls had ≥grade 2 motor neuropathy (p < 0.001), and 15.7% of survivors of CNS tumors versus 2.3% of controls had ≥grade 2 sensory neuropathy (p < 0.001). Prevalence of motor and sensory neuropathy varied by diagnosis (Table). Vinca alkaloid exposure (OR 3.5, 95% CI 1.7-7.0) and infratentorial tumor location (OR 2.5, 95% CI 1.1-5.4, reference supratentorial location) were independent risk factors for sensory neuropathy. Infratentorial tumor location was also associated with an increased risk of motor neuropathy (OR 2.4, 95% CI 1.2-4.8). History of radiation and surgery were not significant independent risk factors for motor or sensory neuropathy. Conclusions: Prevalence of peripheral motor and sensory neuropathy was significantly higher in survivors of CNS tumors than in matched community controls. Survivors of CNS tumors would benefit from increased surveillance to identify and treat peripheral neuropathy, especially in those who received vinca alkaloids or had infratentorial tumors. [Table: see text]
Clinical and genetic risk factors for radiation-associated ototoxicity: A report from the childhood cancer survivor study and the St. Jude Lifetime Cohort.
Authors: Trendowski Matthew R. , Baedke Jessica , Sapkota Yadav , El Charif Omar , Wheeler Heather E. , Leisenring Wendy M. , Robison Leslie L. , Hudson Melissa M. , Morton Lindsay M. , Oeffinger Kevin C. , Travis Lois B. , Howell Rebecca M. , Yasui Yutaka , Armstrong Gregory T. , Bhatia Smita , Dolan M. Eileen
Published: May 2020

10550

Background: Cranial radiation therapy (CRT) for pediatric cancer often results in ototoxicity in the form of hearing loss and tinnitus. We sought to identify clinical determinants and genetic risk factors for ototoxicity among adult survivors of pediatric cancer treated with cranial radiation. Methods: Relationships between age at last observation, sex, cumulative CRT dose and self-reported ototoxicity were evaluated for hearing loss and tinnitus among 1,991 (tinnitus) and 2,198 (hearing loss) survivors in the Childhood Cancer Survivor Study who received CRT. Logistic regression evaluated associations with non-genetic risk factors and comorbidities as well as SNP dosages in GWAS of CRT-related tinnitus (cases: 146; controls: 1,845) and hearing loss (cases: 270; controls: 1,928). Results: Males were more likely to report CRT-related tinnitus (9.4% vs. 5.4%; p = 5.81x10−4) and hearing loss (14.0% vs. 10.7%; p = 0.02) than females after adjusting for dose and age at last observation. Survivors with tinnitus or hearing loss were more likely to experience persistent dizziness or vertigo (tinnitus: p < 2.00x10−16; hearing loss: p = 6.35x10−9), take antidepressants (tinnitus: p = 0.02; hearing loss: p = 0.01) and report poorer overall health (tinnitus: p = 9.40x10−7; hearing loss: p = 1.30x10−6) compared to survivors without tinnitus or hearing loss after age-adjustment. GWAS of CRT-related tinnitus revealed a prominent signal in chromosome 1 led by rs203248 (p = 1.50x10−9), while GWAS of CRT-related hearing loss identified rs332013 (p = 5.79x10−7) in chromosome 8 and rs67522722 (p = 7.78x10−7) in chromosome 6 as approaching genome-wide significance. Replication analysis in an independent cohort of pediatric cancer survivors (SJLIFE) indicated that rs67522722, intronic to ATXN1, a gene associated with the neurodegenerative disorder spinocerebellar ataxia type 1, was significantly associated with CRT-related hearing loss (p = 0.03). Enrichment analysis and LD score regression with previous GWAS results of cisplatin-related hearing loss and tinnitus in testicular cancer survivors showed no detectable enrichment in genetic architecture with CRT-related hearing loss and tinnitus, respectively. Conclusions: Radiation-associated ototoxicity was associated with sex, several neuro-otological symptoms, increased antidepressant use and poorer self-reported health. GWAS of CRT-related hearing loss identified rs67522722 that was replicated in an independent cohort of pediatric cancer survivors.
Treatment intensity and risk of chronic health conditions and late mortality among long-term survivors of Wilms tumor: A report from the Childhood Cancer Survivor Study.
Authors: Weil Brent R , Green Daniel M. , Murphy Andrew J , Liu Qi , Howell Rebecca M. , Weldon Christopher Bertero , Mullen Elizabeth Anne , Madenci Arin L , Leisenring Wendy M. , Neglia Joseph Philip , Oeffinger Kevin C. , Termuhlen Amanda M. , Mostoufi-Moab Sogol , Levine Jennifer , Krull Kevin R. , Yasui Yutaka , Robison Leslie L. , Armstrong Gregory T. , Chow Eric Jessen , Armenian Saro
Published: May 2020

10553

Background: Refinement in risk stratification has led to intensification of therapy for Wilms tumor (WT) patients with adverse prognostic factors. Chronic health conditions (CHCs) including cardiac conditions, subsequent malignant neoplasms (SMNs), and late mortality are known risks for WT survivors, however the impact of specific treatment regimens on these outcomes is largely unknown. Methods: Late mortality (all-cause and non-recurrence death > 5 years from diagnosis), SMNs, and severity-graded CHCs (2 = moderate, 3 = severe, 4 = life-threatening, 5 = fatal) were assessed in 5-year WT survivors in the Childhood Cancer Survivor Study diagnosed from 1970-99. Survivors were categorized according to therapy received (Table). Cumulative incidence of mortality and standard mortality ratios (SMR) were estimated. Piecewise exponential models estimated rate ratios (RR) with 95% confidence intervals (CI). Results: Among 1507 survivors (median age at follow-up 26 yrs; range 6-55), 35-year cumulative incidence of all-cause mortality was 7.9% (SMR 2.9, CI 2.3-3.6) and 5.1% (SMR 1.9, CI 1.4-2.4) for non-recurrence mortality. RRs for developing any grade 2-5 CHC, grade 3-5 SMN, and grade 2-5 cardiac CHCs were higher for survivors compared to sibling controls (2.0, CI 1.8-2.3; 7.4, CI 5.0-10.8; 2.6, CI 2.2-3.1, respectively). Compared with VA and no RT, RR for non-recurrence late mortality and CHCs among survivors were higher for VAD + any RT, and for ≥ 4 drugs + any RT (Table). Conclusions: Administering increased-intensity therapy for WT is associated with increased late health consequences and non-recurrence late mortality, necessitating strategies to monitor and improve long-term health among survivors. [Table: see text]