bluuebunny/crossref_metadata_2025 huggingface dataset:
Chemotherapy-induced neutropenia and treatment efficacy in advanced non-small cell lung cancer: An analysis of the Spanish Lung Cancer Group pharmacogenomic study of cisplatin and docetaxel combination (PLATAX)
Authors: Camps C. , De Las Peñas R. , López-Vivanco G. , Garde J. , Sanchez J. , Viñolas N. , García-Gómez R. , Barón S. , Terrasa J. , Pujol E.
Published: March 2020

7124

Background: Chemotherapy is the standard treatment for advanced non-small-cell lung cancer, and myelosuppression is a common side-effect. We aimed to assess whether haematological toxic effects could be a biological measure of drug activity and a marker of efficacy. Methods: We analysed data of 493 patients who received chemotherapy (cisplatin and docetaxel) within the pharmacogenomic, open-label, single-arm, multicentric PLATAX trial. Three subgroups of patients were considered: global population, patients who received at least three cycles of chemotherapy, and those who received at least six cycles. Neutropenia was categorised on the basis of worst WHO grade during chemotherapy: absent (grade 0), mild (grade 1–2), or severe (grade 3–4). Relative dose intensity was analysed for both drugs. The primary endpoint was overall survival. Results: Median overall survival was 9 months (8.2–9.7). Median relative dose intensity was 0.97 for cisplatin and docetaxel. 403 patients received at least three cycles of chemotherapy, and 255 received six or more. Neutropenia appeared in 172 patients (30.8%), 72 of them G3–4 (18.6%). Dose intensity was lower in patients who presented any grade of neutropenia versus those without neutropenia in the three analyzed subgroups, for both drugs (p < 0.05). Factors associated with higher risk of death were ECOG 1–2 (HR 1.8, p = 0.00) and female (HR 1.5, p = 0.02). There were no differences in overall survival between patients with G0 vs G1–2 vs G3–4 neutropenia (8.7 vs 11.6 vs 9.6 m, p = 0.41), however the risk of death was lower in patients with ECOG 0, that presented neutropenia (HR: 0.545, IC 95%: 0.31, 0.96; p = 0.034). Conclusions: Neutropenia during chemotherapy may be associated with increased survival of patients with advanced non-small cell lung cancer and ECOG 0. Its absence is not a result of underdosing. Prospective trials are needed to assess whether neutropenia could be a biological measure of drug activity and a marker of efficacy.

No significant financial relationships to disclose.
The effect of smoking history on survival outcome: An exploratory analysis of a phase III study of gemcitabine and cisplatin in patients with advanced non-small cell lung cancer (NSCLC)
Authors: Nguyen B. , Paul S. , Posther K. , Sandler A.
Published: March 2020

7141

Background: Exploratory analyses of data from phase II and phase III NSCLC studies of epidermal growth factor receptor (EGFR) inhibitors have shown that smoking history (specifically never smokers) is associated with positive clinical outcomes, indicating increased sensitivity to these agents. A phase III trial in chemonaïve patients (pts) with advanced NSCLC demonstrated that the regimen of gemcitabine-cisplatin is superior to cisplatin alone in terms of response rate, time to disease progression, and overall survival [JCO 2000;18:122–30]. We analyzed data from this trial to examine the effect of smoking history on survival outcome. Methods: All pts entered in the study were combined (524 pts) in a subgroup analysis conducted to evaluate the effect of smoking history (smokers vs non-smokers at baseline; number of never smokers unknown) on survival. In addition, 220 pts with a history of smoking were grouped by the total number of pack-years (pk-yrs) smoked (≤37.5 vs >37.5 pk-yrs), and each group was analyzed with regard to survival relative to the group’s median number of pk-yrs. Results: There was no significant difference in median survival time between smokers (n = 220) and non-smokers (n = 304) (8.5 vs 8.1 months, respectively; hazard ratio [HR]: 0.97 [95% CI: 0.81–1.17]; p-value = 0.739). Although the 112 pts who smoked ≤37.5 pk-yrs had a median of 22.5 pk-yrs and the 108 pts who smoked >37.5 pk-yrs had a median of 55.5 pk-yrs, there was no significant difference in median survival time between the groups (9.2 vs 8.5 months, respectively; HR: 1.00 [95% CI: 0.75–1.34]; p-value = 0.9897). Conclusions: In pts with advanced NSCLC, analyses of survival outcomes for chemotherapy with the combination of gemcitabine-cisplatin or cisplatin indicate that survival is independent of smoking history (smokers vs non-smokers at baseline), unlike targeted therapies, such as EGFR inhibitors for which smoking history (specifically never smokers) is a clinical predictor of the sensitivity of these agents and of survival.

[Table: see text]
Serial hypoxia imaging with 99mTc-HL91 SPECT to predict radiotherapy response in non-small cell lung cancer
Authors: Li J. , Li L. , Yu J. , Xing L. , Guo H. , Zhu H. , Sun X. , Yang G.
Published: March 2020

7143

Background: To evaluate the relationship between 99mTc-HL91 (99mTc labeled 4,9-diaza-3,3,10,10-tetramethyldodecan-2,11-dione dioxime) SPECT (single photon emission computed tomography) hypoxia imaging and the radiotherapy outcome and also to assess changes in tumor oxygenation during the course of treatment. Methods: 32 patients with pathologically proven non-small cell lung cancer received three-dimensional conformal radiotherapy were enrolled into the study. All patients were performed 99mTc-HL91 SPECT scanning at one or two days before radiotherapy. 18 patients were also performed during radiotherapy (30–40 Gy) and one or two days after radiotherapy. Anterior, posterior and lateral planar images were collected at 2 hours, 4 hours and 6 hours respectively after intravenous injection approximately 740MBq 99mTc-HL91. Regions of interest (ROIs) were drawn in the tumor and contralateral normal lung tissue and the radioactivity ratios of tumor to normal tissue (T/N) were calculated. Results: The relationship between T/N ratios at 4h images after injection which was shown as the best of three acquired images before radiotherapy and the response and over survival to radiotherapy were analyzed for all 32 patients. The results of 99mTc-HL91 imaging of 32 patients correlate well with radiotherapy response (P = 0.049) and also patient survival (P = 0.043). The average T/N value of 18 patients who receiving serial scanning was 1.57 ± 0.18, 1.44 ± 0.19 and 1.30 ± 0.14 respectively. There was significant statistic difference between these three groups (P = 0.000). Conclusions: HL91 SPECT imaging identified the hypoxia status and changes during radiotherapy in lung cancer. It was confirmed that hypoxia imaging with HL91 SPECT before treatment may predict radiotherapy response and patient survival. The relationship between T/N ratio and radiotherapy outcome in NSCLC

[Table: see text]

No significant financial relationships to disclose.
Evaluation of guilt, shame and depression in non-small cell lung cancer (NSCLC) relative to breast (BC) and prostate cancer (PC)
Authors: Schmidt N. K. , Else-Quest N. M. , Hammes L. , Eickhoff J. , Hyde J. , Schiller J. H.
Published: March 2020

7158

Background: Most NSCLC is related to smoking, and thus is potentially avoidable. Prior qualitative studies suggest that stigma from a self-induced illness results in feelings of guilt and shame in NSCLC patients (pts). This study is a prospective quantative study of guilt, shame and depression in NSCLC pts relative to BC and PC pts. Methods: Stage IV NSCLC, BC, and PC pts completed 3 surveys over 6 months (T1–3). The survey was a 20 minute questionnaire, including standardized tests of shame, guilt, and depression, as well as several investigator designed questions (IDQ) and demographic data. Goal enrollment is 94 NSCLC pts, 47 BC pts and 47 PC pts, with 80% power to detect a 0.75 point difference in the State Shame and Guilt Scale (SSGS, scores 1 to 5). Data for the first 159 pts with T1 and T2 data are presented. Means of the pooled results for the SSGS and IDQ were compared via analysis of variance; impact of cancer (CA) and gender were performed via regression analyses. Results: 92 NSCLC, 41 PC, and 26 BC patients have been enrolled. 55% of participants are male, mean age is 66 years (35–87), and 67% are married. There is a diverse range of incomes and education. IDQ were combined into a composite score, “self-blame” (reliable, internal consistency score 0.76). Results at T2 are presented in the table. Multiple regression analysis performed on women found that type of CA predicted depression, mediated by shame and guilt. Conclusions: NSCLC is associated with increased levels of guilt and shame leading to depression, relative to BC and PC. This disparity is particularly striking amongst women with NSCLC. Guilt, shame and depression may hamper a pt’s ability to advocate for themselves and may affect treatment outcomes. Further investigation is warranted as to whether a targeted intervention may improve levels of stigma amongst NSCLC pts. Funding provided by an American Medical Association Seed Grant.

[Table: see text]

No significant financial relationships to disclose.
Sorafenib combined with carboplatin/paclitaxel for advanced non-small cell lung cancer: A phase I subset analysis
Authors: Schiller J. H. , Flaherty K. T. , Redlinger M. , Binger K. , Eun J. , Petrenciuc O. , O’Dwyer P.
Published: March 2020

7194

Background: The EGFR is often overexpressed in advanced non-small-cell lung cancer (NSCLC) - a solid tumor associated with a poor prognosis. Oncogenic k-ras mutations and raised serum VEGF predict poor outcome in NSCLC. In vitro targets of sorafenib include Raf, which is downstream of EGFR and k-ras. Sorafenib also targets the VEGFR-2/-3 tyrosine kinases, involved in tumor angiogenesis. Preclinically, sorafenib targets the tumor and tumor endothelium to inhibit tumor growth. Methods: This subanalysis of a Phase I trial with a Phase II expansion in NSCLC was performed to evaluate the safety (adverse events graded by NCI-CTC 2.0) and preliminary anti-tumor activity (response by RECIST, PFS, TTP) of oral sorafenib combined with carboplatin/paclitaxel in 15 patients with advanced, progressive NSCLC. Carboplatin (AUC 6)/paclitaxel (225 mg/m2) was administered on Day 1, and sorafenib (100, 200, or 400 mg bid) on Days 2–18 of each 21-day treatment cycle. Results: Drug-related adverse events were reported by 73% (11/15) of patients, but were mostly grade 1–2 (53%) in severity; none was grade 4. The most common drug-related events at any grade were dermatologic (Hand-foot skin reaction [20%]; rash [60%]), and gastrointestinal (diarrhea [20%]; anorexia [13%]). There were no drug-related cardiovascular adverse events. Three patients reported grade 1–2 drug-related bleeding events (epistaxis n = 2; other n = 1). Of the 14 evaluable patients, four (29%) had a confirmed PR as best response, seven (50%) had SD, and three (21%) had PD. Therefore, the disease control rate (objective response plus SD) was 79%. Duration of response was 25 weeks. Median PFS was 34 weeks. Discussion: This sorafenib combination was well tolerated and showed promising preliminary anti-tumor activity in patients with advanced, progressive NSCLC.

[Table: see text]
Prognostic role of promoter hypermethylation of death-associated protein (DAP) kinase and p16 genes in early-stage non-small cell lung cancer
Authors: Lu C. , Wistuba I. , Zhou X. , Bekele B. N. , Putnam J. B. , Correa A. , Mao L.
Published: March 2020

7216

Background: Promoter hypermethylation is an epigenetic mechanism of gene silencing commonly observed in malignancies. Prior studies suggest that hypermethylation of DAP kinase and p16, genes involved in apoptosis and cell cycle regulation, respectively, are associated with poorer survival in NSCLC patients. In this study we investigate the prognostic role of DAP kinase and p16 promoter hypermethylation in a large cohort of early-stage NSCLC patients. Methods: Pathologic stage I and II NSCLC patients who underwent complete surgical resection between 1/97 and 12/01 at our institution and did not receive adjuvant therapy were identified. Formalin-fixed, paraffin-embedded tissue blocks were retrieved, and p16 and DAP kinase promoter methylation status was determined by methylation specific PCR. Two-sided statistical analyses were performed to determine associations between methylation status, clinicopathologic characteristics, and survival. Results: DAP kinase and p16 methylation status was observed in 36.3% (97 of 267) and 36.4% (95 of 261) cases, respectively. Subject characteristics: 55% female, 77% former/current smokers, 81% stage I, 19% stage II, 61% adenocarcinoma, 29% squamous carcinoma, 63% performance status (PS) 0, 37% PS 1,93% < 5% weight loss. Recurrent NSCLC and death occurred in 21.3% and 38% of cases, respectively. No significant associations were observed between DAP kinase methylation status and subject characteristics. P16 methylation was associated with moderate/high grade (p = 0.03). A higher frequency of p16 methylation was observed in ever vs never smokers (39% vs 28%, p = 0.17). Preliminary analyses do not demonstrate significant associations between methylation status and overall survival (p16 p = 0.13; DAP kinase p = 0.56) or disease-free survival (p16 p = 0.36; DAP kinase p = 0.71). Conclusions: In this relatively large cohort of early-stage NSCLC patients, we did not detect significant associations between p16 and DAP kinase promoter methylation and clinical outcome. Further subset analyses stratified by gender and histology will be performed. The prognostic role of these biomarkers in NSCLC remains unclear.

No significant financial relationships to disclose.
Differential canonical pathways derived from microarrays using RNA from paraffin-embedded non-small cell lung cancer tissue
Authors: Joshi M. M. , Petersen R. P. , Conlon D. H. , Tanaka K. , Shimizu D. , Kuramochi H. , Williams M. , Danenberg P. V. , Danenberg K. D. , Harpole D. H.
Published: March 2020

7226

Background: Several molecular targets have been approved for use in patients with non-small cell lung cancer (NSCLC) and several hundred are in various phases of investigation. However, the efficacy of these targets range from 5–15% of the overall population of NSCLC patients. Therefore, the challenge remains to appropriately match the most active target with the individual patient. Our goal was to investigate a novel strategy for identifying active pathways from formalin-fixed, paraffin-embedded (FFPE) NSCLC samples. Methods: Ten 5 um sections of FFPE tumor were collected from 66 NSCLC patients consisting of equal numbers of long- (+5-year) and short-term (<2 year cancer death) survivors. Sixty samples were microdissected (6 samples contained no tumor tissue) and RNA was extracted using a proprietary procedure of Response Genetics, Inc. Amplification and labeling of RNA were done using the Affymetrix two cycle amplification kit. Resulting cRNA was hybridized to the U133 plus 2.0 GeneChip. A differentially expressed gene list between long and short survivors was determined. These data were also analyzed for differential canonical pathways using Ingenuity Pathway Analysis. Results: We identified the differential pathways indicated by the unique gene signatures between early stage patients surviving <2 yrs and >2 yrs for both adenocarcinomas and squamous cell carcinomas. Adenocarcinoma pathways that differed between short- and long-term survivors were: G2M DNA damage checkpoint, EGF, estrogen receptor, hypoxia, VEGF, PDGF, IL-6 JAK/Stat and neurotrophin/Trk signaling. In contrast, for squamous cell carcinomas the main differing pathways were: Wnt/b-catenin signaling and retinol metabolism. Conclusions: We have demonstrated the feasibility of generating differential canonical pathways from FFPE NSCLC specimens which may serve as a tool to guide selection of molecular targets for the individual patient. In addition, these pathways may be a rational method for selecting the correct subset of patients most likely to respond to agents being investigated in early phase clinical trials. These data require validation in a larger prospective study.

[Table: see text]
Single-agent bortezomib in previously untreated multiple myeloma (MM): Results of a phase II multicenter study
Authors: Anderson K. , Richardson P. , Chanan-Khan A. , Schlossman R. , Munshi N. , Oaklander A. , Heffner L. , Hassoun H. , Avigan D. , Amato A.
Published: March 2020

7504

Background: Bortezomib is effective in relapsed and/or refractory MM. This trial evaluated its efficacy and safety as monotherapy in previously untreated MM. Methods: Pts with untreated, symptomatic MM were eligible, with pts receiving concomitant steroids, platelet count < 30 × 109/L, or grade > 2 peripheral neuropathy [PN] excluded. Endpoints included response rate (RR) [Bladé criteria], time to progression, safety, incidence/severity of PN, and effect of dose modifications on PN. Pts received bortezomib 1.3 mg/m2 (d1, 4, 8, 11 every 21d) for 8 cycles. Comprehensive neurologic evaluation including electrophysiologic testing [NCS] and skin biopsy was performed in a subset of pts (n = 34). Results: Sixty-six pts (47% with stage III MM) were treated and 60 pts are evaluable for response, with an overall RR of 38% (CR 10%, PR 28%). PN was reported in 55% (36/65) pts (23 grade 1, 12 grade 2). One pt with grade 3 PN was discontinued. Other common treatment-associated adverse events reported to date include grade 1–2 fatigue in 21% (6/29), and rash in 17% (5/29) pts. Preliminary analysis shows PN improved or resolved in 75% (6/8 pts, with available follow-up data) with dose reduction. At baseline, small-fiber neuropathy (SFN) was seen in 52% (17/33) and large fiber axonal neuropathy (LFN) occurred in 9% (3/34) pts by NCS. SFN worsened in 41% (7/17) pts with baseline SFN. After completion of treatment, new SFN was seen in 33% (8/24) pts and LFN in 17% (4/24) pts by NCS. Conclusion: Single agent bortezomib is active in newly diagnosed MM pts (CR 10%), has manageable toxicity and offers a steroid-sparing approach. Underlying SFN appears more common in MM than previously appreciated and can also develop during bortezomib therapy, with symptomatic PN improving with dose modification.

[Table: see text]
Dose-escalated CHOP plus etoposide (Hi-CHOEP) is not superior to base-line CHOEP in young good-prognosis patients with aggressive lymphoma: Results of a randomized DSHNHL trial
Authors: Pfreundschuh M. G. , Zeynalova S. , Duehrsen U. , Pflueger K. , Vrieling T. , Berdel W. E. , Mergenthaler H. , Einsele H. , Bentz M. , Schmitz N. , Loeffler M.
Published: March 2020

7513

Background: The addition of etoposide to CHOP (CHOEP) resulted in improved outcome of young patients with good-prognosis aggressive lymphoma (NHL-B1 trial; Blood 2004, 104:626). In order to improve results further, the maximal dose-escalated version of CHOEP-21 tolerable without stem cell support in a preceding dose-escalation study (Hi-CHOEP: C: 1400 mg/m2, H: 65 mg/m2, O: 2 mg, E: 175 mg/m2 × 3, P: 100 mg × 5) was compared to baseline CHOEP-21 in a randomized trial. Methods: Intention-to-treat-analysis comparing CHOEP-21 (n = 194) with Hi-CHOEP (n = 195) in 389 young (18–60 years) patients with good-prognosis (aaIPI = 0,1) aggressive lymphoma. Results: Despite excellent adherence to the protocol (median relative dose of myelosuppressive drugs CHOEP-21: 98%; Hi-CHOEP: 93%), CR/CRu (78.4% vs. 79.5%; p = 0.783), and progressions (12.4% vs. 9.7%; p = 0.409) were not significantly different. After 37 months median observation, there was no difference in the primary endpoint time to treatment failure (64% vs. 68%; p = 0.639) nor overall survival (83% vs. 86%; p = 0.849). Neither low-risk nor low-intermediate risk patients profited from Hi-CHOEP. In a multivariate analysis, elevated LDH and advanced stage (III&IV) were confirmed as independent risk factors for TTF and survival. Hi-CHOEP was considerably more toxic than CHOEP-21 (grade 3 & 4 leukocytopenia 100% vs. 87.2%, p < 0.001, thrombocytopenia 80.8% vs. 9.6%, p < 0.001; infections 19.7% vs. 5.4%, p ≤ 0.001; therapy associated deaths 2.6% vs. 0%). Conclusions: Due to its equal efficacy and lower toxicity, CHOEP-21 is to be preferred over dose-escalated Hi-CHOEP. Our results indicate that dose escalation (in contrast to dose-densification and/or addition of rituximab) does not hold promise for young good-prognosis patients with aggressive lymphoma. Supported by Deutsche Krebshilfe.

[Table: see text]
Effect on survival of treatment associated deep vein thrombosis in newly diagnosed multiple myeloma patients
Authors: Zangari M. , Barlogie B. , Cavallo F. , Anaissie E. , Hollmig K. , Manns A. , Karri S. , Mohiuddin A. , Pineda-Roman M. , Bolejack V. , Tricot G.
Published: March 2020

7549

Background: Cancer patients experiencing thromboembolic disease have a poor prognosis. We report the effect on survival of treatment-associated DVT in myeloma patients. Methods: 668 newly diagnosed patients with progressive or symptomatic MM were enrolled in our Total Therapy 2 study, which included induction phase with VAD, DCEP, CAD and DCEP followed by high dose chemotherapy and tandem transplants. Patients were randomly assigned to receive Thalidomide or not during the whole treatment. Both arms otherwise received identical chemotherapy. Patients were followed and when clinically indicated underwent radiological studies to confirm a suspected DVT. If present, they were treated with low-molecular weight heparin followed by warfarin. Results: With a median follow up of 47 months a total of 158 patients experienced DVT; the median age was 57 years, 59% were male, 24% were IgA, 197 patients (30%) had abnormal cytogenetics (CA) including 100 patients with deletion of chromosome 13. The baseline characteristics were balanced between patients with and without DVT, with the exception of female gender, which was more prominent in the non DVT group (32% vs 46%, p = .018) on thalidomide, whereas CRP ≥ 8 mg/dl (57% vs 33%, p = .001), and IL6 > 9 pg/ml (47% vs 14%, p < .001) were more frequently observed in the DVT group on no thalidomide. Within each arm of the trial no significant differences in prognostic factors for survival (chromosomal abnormalities, low albumin level, β2-microglobulin, CRP) were seen. DVT status did not affect EFS (p = .3) or OS (p = .3) for the entire group, but a statistically longer EFS (p = .03) was observed in patients who developed a thromboembolic episode in the non thalidomide arm. No effect on survival (EFS p = .3; OS p = .95) was seen in the thalidomide arm. Conclusions: Development of DVT in newly diagnosed myeloma patients treated with chemotherapy ± thalidomide, does not affect overall survival. Patients not exposed to thalidomide who developed thrombosis during chemotherapy had significantly longer EFS. Our observation supports a survival benefit associated with anticoagulation therapy in cancer patients.

[Table: see text]
Point mutation of C-terminal region of CD20 molecule predicts rituximab-induced complement-dependent cytotoxicity and clinical response to rituximab in non-Hodgkin’s lymphoma
Authors: Terui Y. , Mishima Y. , Mishima Y. , Yokoyama M. , Hatake K. , Sugimura N. , Kojima K. , Sakurai T. , Takeuchi K.
Published: March 2020

7563

Background: Although rituximab is commonly used as induction and maintenance therapy for malignant lymphoma, some patients become refractory to treatment and the mechanism of resistance is unclear. The aim of this study was to investigate the relationship between CD20 mutations and rituximab resistance. Methods: To investigate whether CD20 mutations affect response to rituximab, fresh CD19+ lymphoma cells were isolated from the lymph nodes, or bone marrow of 68 patients with NHL. The cells were subsequently sorted by flow cytometry. RNA was prepared from the isolated cells and RT-PCR was performed. The PCR products were sequenced, subcloned into an expression vector pTARGET, transfected into K562 cells. CD20 expression was examined by flow cytometry and laser scanning confocal microscopy. Results: In all 68 patients, overall response rate (CR+CRu+PR) to rituximab was 91.2% (62/68), but t four cases became PD after PR. DNA sequence analysis revealed that point mutations were mostly observed in three CD20 domains - extracellular/cytoplasmic domains, the third transmembrane domain and the C-terminal cytoplasmic domain. Two cases had point mutations in extracellular/cytoplasmic domains, one patient had point mutations in the transmembrane domain, four cases showed point mutations in the C-terminal cytoplasmic domain and six cases had non-specific CD20 mutations, which did not affect CD20 expression. 56 patients showed no mutations of CD20 gene. CD20 expression was very weak in patients with point mutations in the C-terminal cytoplasmic domain, whereas expression was increased in patients with point mutations in the transmembrane domain. Conclusions: Point mutations in CD20 may cause rituximab resistance and identification of CD20 mutations upon diagnosis may help to predict a patient’s response to rituximab.

No significant financial relationships to disclose.
Comparative trial of BBR 2778 (pixantrone) + rituximab vs single agent rituximab in the treatment of relapsed/refractory indolent non-Hodgkin’s lymphoma (NHL)
Authors: Santoro A. , Voglova J. , Gabrail N. , Ciuleanu T. , Liberati M. , Hancock B. W. , Stromatt S. , Caballero D.
Published: March 2020

7578

Background: BBR 2778 is a novel aza-anthracenedione that shows structural similarities to the anthracyclines, demonstrates single agent activity in patients with NHL, and does not exhibit cardiotoxic effects in animal models. This phase III open-label study was designed to compare the efficacy and tolerability of combination rituximab and BBR 2778, with that of single agent rituximab, in patients (pts) with relapsed or refractory indolent NHL. Methods: Pts were randomly assigned to receive both rituximab and BBR 2778 (experimental arm), or rituximab alone (control arm). In the experimental arm, pts received 375 mg/m2 rituximab IV on days 1 and 8 of cycles 1 and 2 only, and 90 mg/m2 BBR 2778 IV on days 2 and 8 of cycle 1, and on days 1 and 8 of all subsequent cycles. Pts could receive six 21-day cycles of BBR 2778. In the control arm, pts received 375 mg/m2 rituximab IV on days 1, 8 and 15 of cycle 1 and day 1 of cycle 2 only. Disease response was assessed every other cycle according to International Workshop to Standardize Response Criteria for NHL. Toxicities were assessed throughout the study using NCI-CTC criteria. Study was closed early due to poor enrollment. Results: 38 pts (20 experimental, 18 control) were enrolled. Mean age was 66 and 59 years in the experimental and control arm, respectively. Most patients were males and most had ECOG performance status 0 or 1. Efficacy is summarized in the table. Response rate (75 vs 33%) and time to progression (13.2 vs 8.1 months) were better in the BBR 2778 arm. Only pts in the experimental arm had study drug related serious adverse events (2 febrile neutropenia, 1 pneumonia, 1 neutropenia) and adverse events resulting in withdrawal (6 vs 0). Conclusions: Combination of BBR 2778 and rituximab is superior to rituximab alone with regard to time to progression and overall response rate. BBR 2778 combined with rituximab appeared to be a generally well tolerated regimen in patients with relapsed/refractory indolent NHL.

[Table: see text]

[Table: see text]
Clinical characteristics and prognostic factors in diffuse large B-cell lymphoma with bone marrow involvement
Authors: Lee K. , Yi J. , Choi I. , Kim J. , Kim D. , Lee J. , Heo D. , Bang Y. , Cho H. , Kim N.
Published: March 2020

7588

Background: Although several studies have been reported about non-Hodgkin’s lymphomas (NHL) with bone marrow (BM) involvement, most of them have not performed immunophenotypic studies and contained heterogeneous NHL histologies. Until now, only a few studies with small sample sizes have been reported about clinical characteristics and prognostic factors in diffuse large B-cell lymphoma (DLBCL) with BM involvement. Methods: Between January 1993 and March 2004, 486 patients were diagnosed with DLBCL. Among 84 DLBCL patients who had BM involvement at initial diagnosis, 9 were not ineligible because of the lack of clinical data or unavailability of BM specimen. So, clinical factors and patterns of BM involvement of 75 patients were analyzed in this study. Results: At initial diagnosis, the median age was 57 years (range: 25∼79). In addition to BM, lymph nodes (76%), spleen (23%), Waldeyer’s ring (19%), gastrointestinal tract (16%), lung/pleura (15%), bone (15%), central nervous system (9%), nasal cavity (8%) and liver (7%) were also involved. Among 75 patients, 67 patients received anthracycline-containing chemotherapy; 4 patients received non-anthracycline-containing chemotherapy and 4 could not receive systemic chemotherapy because of combined medical conditions. The median survival was 32.3 months (5-year overall survival [OS]: 38%). In univariate analysis for prognostic factors, high-intermediate or high international prognostic index (IPI), B-symptoms, leucopenia, anemia, thrombocytopenia, pattern of BM involvement (interstitial or diffuse pattern), > 10% replacement of BM area by lymphoma cells, > 10% of large cell infiltration in BM-involved area by lymphoma at initial diagnosis were associated with poor OS (p < 0.05). Multivariate analysis indicated that > 10% replacement of BM area by lymphoma cells (p < 0.001), peripheral thrombocytopenia (p = 0.001) and high-intermediate or high IPI (p = 0.042) were independent predictors of poor OS. Conclusions: To our knowledge, this is the largest study about DLBCL patients with BM involvement. The BM areas involved by lymphoma cells, peripheral thrombocytopenia and IPI at initial diagnosis are independent prognostic factors in these patients.

No significant financial relationships to disclose.
Phase I trial of subcutaneous (SQ) alemtuzumab (A) and CHOP in T-cell lymphoma: Preliminary results
Authors: Porcu P. , Baiocchi R. A. , Lee J. , Lin T. S. , Blum K. , Grady T. , Grever M. R. , Byrd J. C.
Published: March 2020

7594

Background: T-cell lymphomas are highly chemoresistant. Cure rates with combination chemotherapy do not exceed 25–30%. We showed that A, a humanized IgG1 targeting the CD52 antigen expressed on most human leukocytes, is cytotoxic for malignant T-cells in vitro and in vivo, regardless of p53 mutational status (Blood 106, 3380, 2005). Thus, we initiated a Phase I study with A and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) in T-cell lymphoma. Methods: Accrual goal: 15–18 patients (pts) with untreated (u) or relapsed (r) peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL), excluding ALK-1-positive anaplastic large cell lymphoma. Primary objective: maximal tolerated dose (MTD). All pts receive single agent SQ A loading (3, 10, 30 mg) over 5 days, followed by one SQ A dose with each CHOP every 21 days for a total of 8 cycles. A dose levels: 3, 10, 20 and 30 mg. All pts receive valacyclovir and trimethoprim-sulfamethoxasole, plus G-CSF and erythropoietin according to guidelines. Results: Eight of the nine enrolled pts on cohort 1 (A=3 mg) and cohort 2 (A=10 mg) are evaluable for toxicity (uPTCL= 4, rPTCL=1, rCTCL=3). All pts completed single agent A loading on time and tolerated well further SQ A. No cycle was delayed due to myelosuppression. There were no opportunistic infections or neutropenic fevers. Four pts completed all planned therapy. Three pts did not complete therapy due to progression (2) or toxicity (1). One pt remains on study after 4 cycles. There were no Grade 4 adverse events (AEs). Grade 3 AEs included fatigue (1), anemia (1), dyspnea (1) and emesis (1). Cohort 1 was expanded due asymptomatic cytomegalovirus [CMV] reactivation requiring hospitalization for thrice daily foscarnet, thus resulting in Grade 3 AE. Protocol was amended and subsequent asymptomatic CMV reactivations (2) were treated with oral valganciclovir. No symptomatic CMV reactivation occurred. Conclusions: At current dose levels, SQ A can be easily and safely administered with CHOP chemotherapy and growth factor support, without excessive myelosuppression or infectious AEs. Asymptomatic CMV reactivation can be managed with oral valganciclovir. Further A dose escalation is in progress.

[Table: see text]
Dactinomycin (A) and vincristine (V) with or without cyclophosphamide (C) and radiation therapy (RT) for newly diagnosed patients with low-risk embryonal/botryoid rhabdomyosarcoma (RMS). An IRS-V report from the Soft Tissue Sarcoma Committee of the Children’s Oncology Group (STS COG)
Authors: Walterhouse D. O. , Meza J. L. , Raney R. B. , Anderson J. , Wiener E. S. , Donaldson S. S. , Qualman S. J. , Meyer W.
Published: March 2020

9001

Background: The STS COG defines patients with low-risk RMS as those with localized tumors of embryonal histology that occur in favorable sites or occur in unfavorable sites and are grossly resected. Intergroup Rhabdomyosarcoma Studies (IRS)-III (1984–1991) and -IV (1991–1997) found that these patients had a 5-year failure-free survival (FFS) of 83% and an overall survival of 95%. Methods: Two subsets were identified for the IRS-V low-risk RMS study (D9602) (1997–2004) based on the hypothesis that they required different treatment intensities to achieve similar excellent outcomes. Patients assigned to Subset A (Stage [Sg] 1 Group [Gp] I/IIA, Sg 1 Gp III orbit, Sg 2 Gp I) received VA (cumulative doses over 1 year of treatment: V: 54 mg/m2, A: 24 mg/kg) ± local RT. Patients assigned to Subset B (Sg 2 Gp IIB/C, Sg 1 Gp III non-orbit, Sg 2 Gp II, Sg 3 Gp I/II) received VA + C (C: 28.6 g/m2) ± RT. The RT dose was reduced to 36 Gy (instead of 41.4 Gy on IRS-IV) for Gp IIA patients and to 45 Gy (instead of 50.4 or 59.4 Gy on IRS-IV) for Gp III orbit patients. The primary endpoint was FFS. Results: Estimated 3-yr FFS was 89% (95% CI 84%, 93%) for Subset A (n=263) and 89% (95% CI 77%, 95%) for Subset B (n=79). Median follow-up was 2.9 years. Estimated 3-yr FFS was 80% (95% CI 64%, 89%; n=59) for patients with Sg 1 Gp IIA disease and 88% (95% CI 77%, 94%; n=76) for Gp III orbit disease. Conclusions: There is not evidence to suggest that outcome for these patients differs from outcomes observed in similar patients treated on IRS-III and IRS-IV.

No significant financial relationships to disclose.
131I-Metaiodobenzylguanidine (131I-MIBG) double infusion with autologous stem cell transplant for neuroblastoma: A New Approaches to Neuroblastoma Therapy (NANT) study
Authors: Matthay K. K. , Quach A. , Huberty J. , Franc B. , Groshen S. , Shusterman S. , Veatch J. , Brophy P. , Yanik G. , Maris J.
Published: March 2020

9011

Background: 131I-MIBG provides targeted radiotherapy with >30% response in refractory neuroblastoma, but the activity infused is limited by radiation safety and hematologic toxicity. The goal was to determine the maximum tolerated dose of 131I-MIBG in two consecutive infusions at a 2-week interval, supported by autologous stem cell transplant (ASCT) 2 weeks after the second dose. Methods: The 131I-MIBG was escalated in a 3+3 Phase I trial design, with levels calculated by total red marrow radiation index (RMI) from the double infusion. The first infusion of 131I-MIBG was 12, 15, 18 and 21 mCi/kg for levels 1, 2, 3 and 4 respectively. Using detailed dosimetry, the second infusion was adjusted to achieve the target RMI, except at Level 4, where the second infusion was capped at 21 mCi/kg. Results: Twenty-one patients were enrolled at Level 1–4, with 18 evaluable for toxicity. Median age at enrollment was 7 years, all were heavily pretreated, including 12 with prior high dose therapy and ASCT, and 12 patients had bone marrow tumor. Cumulative 131I-MIBG given to achieve the target RMI ranged from 18 mci/kg to 49 mCi/kg. RMI delivered per mCi of MIBG decreased in 15/19 patients by mean of 0.21 cGy/mCi with the second infusion. Hematologic toxicity was acceptable, with median time to ANC>500 after ASCT of 13 (4–27) days. Platelet transfusion was required in 15/18 patients, with median time to platelet independence of 18 (6–47) days after ASCT. There were no non-hematologic toxicities above grade 2 attributed to therapy, though 9 patients had grade 1–2 elevations of transaminase, and 1 had grade 2 hypothyroidism. Responses in 17 evaluable patients included 1 PR, 4 MR, 6 SD, and 6 PD. Eleven patients are alive at median of 361 days (46–483); 5 died of PD and 1 of unrelated toxicity. Conclusion: The lack of toxicity with this approach allowed dramatic dose intensification of 131I-MIBG, with minimal toxicity and the possibility of improved response.

[Table: see text]

No significant financial relationships to disclose.
A phase I study of bevacizumab in children with refractory solid tumors: A Children’s Oncology Group study
Authors: Glade Bender J. L. , Adamson P. C. , Baruchel S. , Shaked Y. , Chen H. X. , Reid J. M. , Ingle A. M. , Blaney S. M. , Kandel J. J. , Yamashiro D. J.
Published: March 2020

9017

Background: Bevacizumab is a humanized monoclonal antibody targeting the vascular endothelial growth factor (VEGF-A) that has demonstrated significant growth inhibition in several pre-clinical models of pediatric solid tumors. However, the agent has never been tested in pediatric patients. Methods: A phase I dose escalation study in children with refractory solid tumors was conducted to define the dose limiting toxicities (DLTs), and to determine the pharmacokinetics (PK) and recommended phase II dose of bevacizumab administered by IV infusion every 2 weeks in 28-day cycles. Cohorts were enrolled at dose levels of 5, 10, and 15 mg/kg; the final dose level was expanded to include at least 3 children <6 years of age. Serial blood samples were collected for PK, plasma VEGF concentration, and circulating mature and progenitor endothelial cells (CECs/CEPs). Results: 20 patients (10 male), median age 13 yrs (range 1–21), were enrolled at dose levels 5 (n=3), 10 (n=3), and 15 (n=14) mg/kg. 18 patients were fully evaluable for toxicity (one withdrew consent prior to treatment and the second was removed for rapid disease progression). A total of 67 cycles were administered with a median of 3 per patient (range 1–16). Treatment was well tolerated and no DLTs were observed. Only one grade 3 toxicity, lymphopenia, was attributed to drug. Non-dose limiting, grade 1–2 toxicities included infusional reaction (n=3), rash (n=3), mucositis (n=2), and proteinuria (n=3). There was no hypertension, hemorrhage or thrombosis reported. There were no partial or complete responses; 3 pts with Ewings and 2 pts with soft tissue sarcoma had disease stabilization for > 3 months. The serum exposure to bevacizumab as measured by AUC appeared to increase in proportion to dose. The median clearance of bevacizumab was 4.1 ml/day/kg (range 3.2–15.9), and the median T1/2 was 11.8 days (range 3.9–14.6). In some patients, a rapid rate of rise in plasma VEGF, increase in mature CECs or decrease in CEPs was observed. Conclusion: Bevacizumab at doses up to 15mg/kg every two weeks is well tolerated in children with solid tumors.

No significant financial relationships to disclose.
Randomized trial and pharmacokinetic study of pegfilgrastim vs. filgrastim in children and young adults with newly diagnosed sarcoma treated with dose intensive chemotherapy
Authors: Fox E. , Jayaprakash N. , Widemann B. C. , Hawkins D. , Dagher R. , Mansky P. , Mackall C. , Helman L. J. , Steinberg S. , Balis F. M.
Published: March 2020

9020

Background: Daily subcutaneous (SC) filgrastim reduces the duration of severe neutropenia in children receiving dose intensive chemotherapy. A single SC dose of pegfilgrastim may be as efficacious. Methods: We conducted a randomized, non-inferiority trial comparing neutrophil recovery, tolerability, and pharmacokinetics of pegfilgrastim (100 mcg/kg SC once/cycle) to filgrastim (5 mcg/kg SC daily until post nadir ANC >10,000) in children and young adults with newly diagnosed sarcoma treated with vincristine, doxorubicin, and cyclophosphamide (VDC) for cycles 1, 2, 5, 9, 11, 13 alternating with etoposide and ifosfamide (IE) for cycles 3, 4, 6–8, 10, 12, 14. Local control with radiation or surgery was initiated after cycle 5. Serum GCSF concentrations were monitored during cycle 1 and measured by ELISA. Complete blood counts were monitored thrice weekly during cycles 1–4. Cycle duration was collected for all cycles. Results: Accrual has been completed. 34 patients (median age 19 y, range 3–25 y) were enrolled, 28 have completed 4 cycles, and 26 have completed therapy. Growth factor associated toxicity included reversible transaminase elevation and arthralgias and was similar on the 2 treatment arms. For filgrastim (n=13) the median (range) GCSF Cmax was 12 ng/mL (4–16 ng/mL), Css was 7 ng/mL (2–9 ng/mL) and Tmax was 6 h (4–8 h). For pegfilgrastim (n=13), the median (range) GCSF Cmax was 69 ng/mL (11–235 ng/mL), Css was 43 ng/mL (7–151 ng/mL) and Tmax was 28 h (4–168 h). Median (range) neutrophil recovery and cycle duration are presented in the table. Conclusion: Pegfilgrastim was well tolerated. Peak and steady state serum GCSF concentrations were higher in patients receiving pegfilgrastim but more variable. The number of days of severe neutropenia and the cycle duration with single dose pegfilgrastim appear to be at least equivalent to daily filgrastim.

[Table: see text]

No significant financial relationships to disclose.
Results of randomized study on dexrazoxane administration in children with de novo acute leukemia
Authors: De Berranger E. , Vaksmann G. , Thebaud-Leculee E. , Wyckaert I. , Mazingue F. , Francart C. , Dalle J. , Nelken B.
Published: March 2020

9037

Background: Anthracyclins and anthracenediones represent major drugs for both AML and ALL. Among other mechanisms, these drugs induce free radical production responsible of cardiac toxicity. It appeared very important to protect cardiomyocytes. Dexrazoxane (DZ) was developed in this goal. In adult patients, its efficiency was demonstrated both to protect heart and to respect anticancer therapy. We conducted a prospective single bind randomized study using DZ in pediatric acute leukemia. Methods: From Dec 00 to Sept 03, 16 patients (pts) were enrolled for receiving or not DZ (1g for 50mg of doxorubicin equivalent dose) with chemotherapy. Cardiac function was evaluated by echocardiogram before induction and after each chemotherapy course of either EORTC 58951 (arm VHR) or LAME01 trials and each year after treatment completion. The cardiologist operator did not know if child received DZ or not. The cumulative equivalent doxorubicin doses were 310 and 450mg/m2 for EORTC 58951 and LAME01, respectively. The primary end-point was cardiac function evolution. The secondary end points were OS, EFS and the respect of therapy schedule. Results: 16 pts (9M/7F, 11AML/5ALL), median age 8.5y (2.4 - 16.1) were enrolled. 5 AML and 3 ALL pts received DZ. Median f-up was 28.5 months (10–47). Mean left ventricular shortening fractions were 39 and 35% in pts without DZ and 40 and 39% in pts with DZ before chemotherapy and 1 year after diagnosis, respectively. Mean wall stress values were 50 and 50g/cm2 for patients without DZ and 39 and 38g/cm2 for pts with DZ. All these values were comparable. 12 pts were alive, 6 in each arm. 1 pt relapsed in DZ arm and 3 in the other arm. 2 pts died of disease and 2 from infection equally dispatched in the 2 arms. Mean time between successive chemotherapy courses was identical in different groups. 2 patients given DZ presented severe hepatic toxicity (≥grade 3 of WHO classification) followed by quick and spontaneous regression. None other toxicity > grade 1 were observed. Conclusions: DZ may be used safely in children receiving anthracycline. No difference in OS and DFS appear in our study. Median follow-up was probably too short for distinguishing any cardiac alteration, and patient number was low.

No significant financial relationships to disclose.
Fertility preservation in children newly diagnosed with cancer: Existing standards of practice in Australia and New Zealand
Authors: Heath J. A. , Stern C. J.
Published: March 2020

9047

Background: Over the past two decades, rapid advances have occurred in both the successful treatment of childhood cancers and reproductive medicine. We sought to establish the current level of clinical practice for sperm, oocyte and gonadal tissue collection and storage in children newly diagnosed with cancer in Australia and New Zealand (ANZ). Methods: A cross-sectional survey of all pediatric oncology services in ANZ was performed. Comparisons to recently published North American practices and to current recommendations for best practice were also made. Results: Of the 13 centers invited to participate, 12 (92%) completed the survey. All centers had offered sperm conservation, but only ten (83%) had offered oocyte/ovarian tissue conservation. Available methods of gamete collection and storage were not consistent. Two centers were using GnRH agonists as fertility protection in post-pubertal females. Forty-two per cent had offered fertility conservation to males and females prior to completion of sexual development. All centers were more likely to offer sperm conservation than oocyte conservation for any given disease. The most common diseases for which conservation was offered were lymphomas and sarcomas. The anticipated cumulative dose at which centers elected to offer fertility preservation varied widely, both for the alkylator cyclophosphamide (1g/m2 to 10g/m2) and for abdominal/pelvic irradiation (any to 12 Gy) and spinal irradiation (any to 18Gy). Fertility counseling was offered in a variety of settings by 82% of centers. Despite 92% of centers agreeing that fertility preservation guidelines would be helpful, only two (17%) had any in place. Overall, there was greater uptake and consistency of utilization of fertility services in ANZ when compared with published North American data. Conclusions: There are inconsistencies regarding the indications for and methods of gamete conservation in pediatric oncology centers throughout ANZ. Unresolved medical, legal and ethical issues suggest the development of guidelines and a voluntary code of practice would be helpful.

No significant financial relationships to disclose.