bluuebunny/crossref_metadata_2025 huggingface dataset:
Intratumoral chemotherapy as an adjunct to endobronchial brachytherapy
Authors: Nader D. , Ketterl P. , Kelly D. , Flynn J. , Stark J. J. , Staren E. D. , Braun D. P.
Published: August 2020

7591

Background: NSCLC patients (pts) with clinically significant endobronchial obstruction have a poor prognosis and quality of life in both locally advanced and metastatic stages of disease. Radiation therapy (RTx) in conjunction with chemotherapy (CTx) improves survival compared to either modality alone but produces greater toxicity and morbidity. Significant clinical benefit with respect to disease management and quality of life could be realized with improved methods for controlling obstructing endobronchial lesions. The hypothesis for this study is that optimal clinical control of endobronchial lesions can be achieved by intratumoral injection of a drug with both clinical activity against NSCLC and synergy with RTx. Cisplatin (CPt), an active agent in NSCLC and a known radiosensitizer is an ideal drug for this objective. Thus, the goal of this exploratory study was to determine the clinical efficacy and tolerance to intratumoral CPt injection in combination with HDR brachytherapy (BTx) in NSCLC patients with obstructing endobronchial lesions. Methods: NSCLC pts (n=16) with > 75% endoluminal obstruction of a main or lobar airway were evaluated. Intratumoral CTx consisted of CPt (1 mg/ml; 0.5–2.0 ml/session) injected into the entire visible tumor through a flexible 21 gauge needle through the bronchoscope. BTx was given as 500 cGy/session at one cm diameter for 4 sessions concomitant with CTx. Results: All pts completed the entire 4 sessions of planned local therapy. There was complete resolution of injected lesions in 14/16 pts confirmed bronchoscopically and cytologically. In the other 2 pts, necrotic tissue occupying < 10 and 20% of the airway, cytologically negative for tumor was seen. There were no adverse events or complications related to bronchoscopy or local CTx. Conclusions: The results of this study demonstrate that intratumoral administration of CPt, as an adjunct to endobronchial BTx for the management of endobronchial obstructing lesions in patients with NSCLC is safe and effective. This approach offers the possibility of superior local tumor control while reducing toxicity to normal lung and esophagus as compared to conventional external beam radiation therapy modalities. Further studies evaluating the impact of this approach on survival and quality of life are warranted.

No significant financial relationships to disclose.
Vandetanib plus pemetrexed versus pemetrexed as second-line therapy in patients with advanced non-small cell lung cancer (NSCLC): A randomized, double-blind phase III trial (ZEAL)
Authors: De Boer R. , Arrieta Ó. , Gottfried M. , Blackhall F. H. , Raats J. , Yang C. H. , Langmuir P. , Milenkova T. , Read J. , Vansteenkiste J.
Published: August 2020

8010

Background: Vandetanib is a once-daily oral inhibitor of VEGFR, EGFR and RET signaling. A phase I trial of vandetanib + pemetrexed (pem) supported further investigation of this combination (de Boer et al, Ann Oncol 2008). Methods: The primary objective was to determine whether vandetanib 100 mg/day + pem 500 mg/m2 every 21 days (max 6 cycles) prolonged progression-free survival (PFS) vs placebo + pem. Overall survival (OS), objective response rate (ORR), time to deterioration of symptoms (TDS, by Lung Cancer Symptom Scale) and safety were secondary endpoints. Efficacy and safety were assessed in females as a co-primary analysis population. Eligibility criteria included stage IIIB/IV NSCLC, PS 0–2, and previous 1st-line therapy. Results: Between Jan 07-Mar 08, 534 patients (mean age 59 yrs; 38% female; 21% squamous histology; 8% brain metastases; stage IV 84%; PS 0/1/2: 41%/53%/6%) were randomized 1:1 to receive vandetanib + pem (n=256) or placebo + pem (n=278). Baseline characteristics were similar in both arms. Median duration of follow-up was 9.0 months, with 83% patients progressed and 50% deceased. There were positive trends seen for vandetanib + pem for both PFS (hazard ratio [HR] 0.86, 97.58% CI 0.69–1.06; P=0.108) and OS (HR 0.86, 97.54% CI 0.65–1.13; P=0.219); similar advantages were observed for females. There were statistically significant advantages for ORR (19.1% vs 7.9%, P<0.001) and TDS (HR 0.61, P=0.004). The adverse event profile was consistent with previous studies of vandetanib: rash (38% vs 26%), diarrhea (26% vs 18%) and hypertension (12% vs 3%) being more frequent in the vandetanib arm. There was evidence of reduced pem toxicity with the addition of vandetanib: anemia 8% vs 22%, nausea 29% vs 37%, vomiting 15% vs 22%, fatigue 37% vs 45%, and asthenia 11% vs 17%. The incidence of protocol-defined QTc prolongation was <1%. There was no increase in bleeding or thrombotic events in the vandetanib arm. Conclusions: The combination of vandetanib + pem demonstrated evidence of clinical benefit in patients with pretreated advanced NSCLC, although the study did not meet the primary endpoint of statistically significant PFS prolongation vs pem alone. Vandetanib + pem was generally well tolerated.

[Table: see text]
MO19390 (SAiL): Safety and efficacy of first-line bevacizumab (Bv)-based therapy in advanced non-small cell lung cancer (NSCLC)
Authors: Crino L. , Mezger J. , Griesinger F. , Zhou C. , Reck M. M.
Published: August 2020

8043

Background: MO19390 (SAiL) is a single-arm, multicenter, international trial evaluating the safety and efficacy of first-line Bv in combination with a range of chemotherapy regimens in over 2,000 patients (pts). Methods: Primary endpoint was safety; secondary endpoints included time to disease progression (TTP) and overall survival (OS). Pts with untreated locally advanced, metastatic or recurrent non-squamous NSCLC (ECOG PS 0–2) received Bv (7.5 or 15mg/kg) with standard chemotherapy for up to six cycles, then non-progressors proceeded to receive Bv until disease progression. Results: This analysis (data cut-off July 2008) was based on 2,008 pts with a median age of 59. Pts (%) were: male 60.1; stage IIIB/IV 19.5/80.5 (no data 3 pts); adenocarcinoma/large cell/other 85.8/7.1/7.1; ECOG PS 0/1/2 38.1/56.1/5.8. Pts received a median of 6 Bv cycles and 4 chemotherapy cycles. 26.7% of pts experienced grade ≥3 serious adverse events (SAEs); 8.3% of pts experienced grade ≥3 SAEs related to Bv. Adverse events (AEs) of special interest (all grades) included bleeding (27.6%), hypertension (19.3%), proteinuria (14.6%), thromboembolism (8.6%), CHF (2.9%) and GI perforation (1.2%). The incidence of AEs of special interest (all grades) was comparable across the various types of chemotherapy regimens: carboplatin doublets (50.6%)/cisplatin doublets (49.9%)/non-platinum doublets (41.7%)/monotherapy (37.5%). No new safety signals were reported. Trial data were not deemed mature enough to provide efficacy results. Conclusions: SAiL confirms that Bv-based therapy has a well-established and manageable safety profile. Clinical outcomes obtained in this real-life population are consistent with those seen in the pivotal trials of bevacizumab (Avastin) in NSCLC (E4599 and AVAiL), and compare favorably with historical data. Updated efficacy results for 2,147 pts will be presented, based upon an additional 5 months’ follow-up.

[Table: see text]
Docetaxel plus carboplatin with or without levofloxacin prophylaxis in elderly patients (pts) with advanced non-small cell lung cancer (NSCLC): The APRONTA trial
Authors: Schuette W. , Nagel S. , von Weikersthal L. Fischer , Pabst S. , Schumann C. , Salm T. , Roscher K. , Dickgreber N.
Published: August 2020

8047

Background: Elderly pts receiving chemotherapy are more likely to have febrile neutropenia and infection than younger pts. Prophylactic fluoroquinolone during chemotherapy reduces the rate of infection and hospitalization vs placebo. The effect of prophylactic treatment with the fluoroquinolone, levofloxacin, on infection rates and survival during docetaxel plus carboplatin therapy was assessed in elderly pts with advanced NSCLC. Methods: In this randomized, double-blind, placebo-controlled Phase III study, eligible pts were aged ≥65 years with previously untreated, histologically/cytologically proven stage IIIB/IV NSCLC, and normal cardiac, renal, hepatic, and hematologic function. Active infection or antibiotics 72 hours before inclusion was not permitted. A planned sample size of 192 pts was considered sufficient for analysis. Pts were randomized to docetaxel (75 mg/m2 IV, Day 1) plus carboplatin (AUC 6 IV, Day 1) q3w, plus placebo or levofloxacin (500 mg po, once daily) on Days 5–11. Primary endpoint was grade 3/4 infection rate or systemic antibiotic therapy of grade 1/2 infection rate. Secondary endpoints were progression free-survival and overall survival. Between-group comparisons were performed using Fisher's exact test. Results: 192 pts (median age 70 years; ECOG PS 0/1/2 in 36%/55%/9%) were randomized to docetaxel plus carboplatin and levofloxacin (n=99) or placebo (n=93); 5 pts received no treatment and were excluded from the ITT population. Rate of grade 3/4 infection was 27.5% (95% CI: 19.3–39.0%) with levofloxacin vs 36.7% (95% CI: 27.1–48.0%) with placebo. Median progression-free survival (PFS) for patients in the levofloxacin arm was 165 days compared with 121 days in the placebo arm (p=0.22). Median overall survival was comparable between groups (307 vs 314 days, respectively; p=0.28). Conclusions: Levofloxacin prophylaxis reduces the rate of grade 3/4 infection compared with placebo.

[Table: see text]
Phase II study of amrubicin (AMR) in patients (pts) with non-small cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy: WJTOG0401
Authors: Hayashi H. , Kaneda H. , Okamoto I. , Miyazaki M. , Kudoh S. , Sawa T. , Takeda K. , Negoro S. , Iwamoto Y. , Nakagawa K.
Published: August 2020

8059

Background: AMR is a totally synthetic 9-aminoanthracycline and a novel topoisomerase II inhibitor. AMR has shown promising clinical activity for advanced NSCLC as well as SCLC. This trial was conducted to evaluate the efficacy and safety of AMR for pts with NSCLC previously treated with platinum-based chemotherapy. Methods: Eligible pts had a performance status 0 to 1, previous treatment with one platinum-based chemotherapy for advanced NSCLC, and adequate organ function. Pts received AMR 40 mg/m2 intravenously on days 1–3 every 3 weeks. The primary endpoint was the objective response rate, which determined the sample size based on an optimal two-stage design. With the target activity level of 18% and the lowest response rate of interest set at 5%, 60 eligible patients were required with a 90% power to accept the hypothesis and a 5% significance level to reject the hypothesis. Results: Sixty-one pts (median age, 63 years; range 51–74 years) were enrolled. The median treatment cycles were 2 (range, 1–15). No complete responses and 7 partial responses were observed, giving an overall response rate of 11.5% (95% CI, 4.7–22.2%). Twenty patients (32.8%) had stable disease and 34 patients (55.7%) had progressive disease as the best response. The overall disease control rate (complete response + partial response + stable disease) was thus 44.3% (95% CI, 31.5–57.6%). The median overall survival and 1-year survival rate were 8.5 months and 32.0%, respectively. Grade 3/4 hematological toxicities were neutropenia (82%), anemia (27.9%) and thrombocytopenia (24.6%). Grade 3/4 non-hematological toxicities were anorexia (9.8%), febrile neutropenia (29.5%) and pneumonitis (1.6%). No treatment-related death and cardiac toxicity were observed. Conclusions: AMR exhibits significant activity with manageable toxicities as second-line therapy for advanced NSCLC.

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The impact of brain metastases on overall survival (OS) in National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) clinical trials (CT) in advanced non-small cell lung cancer (NSCLC)
Authors: Bradbury P. A. , Twumasi-Ankrah P. , Ding K. , Leighl N. B. , Goss G. D. , Laurie S. , Shepherd F. A. , Seymour L.
Published: August 2020

8075

Background: NSCLC patients (pts) with brain metastases (BMet) commonly are excluded from participating in clinical trials (CTs), based on perceptions of inferior outcomes. We evaluated the validity of this exclusion criterion, by investigating the OS of stage IV NSCLC pts with (BMet) and without (non-BMet) a prior history of BMet recruited to NCIC CTG CTs. Methods: This pooled analysis utilized data from BR.18 (paclitaxel/ carboplatin [PC] ± MMPI [BMS275291]), BR.21 (erlotinib vs. placebo), BR.24 (PC± VEGFR TKI [AZD2171]). Each trial permitted entry of pts with neurologically stable BMet, provided they had been treated and off corticosteroids (BR.24), or either treated or not but without corticosteroids (BR.18), or on a stable corticosteroid dose (BR.21). The primary end-point of these analyses was OS, evaluated in the pooled pt cohorts stratified by treatment arm, and in each trial individually. Results: Of 1,349 stage IV pts, 131 had a history of BMet. Of these, 103 (78%) pts had cranial radiation prior to randomization and 15 (11%) prior craniotomy. The median age of the BMet cohort was 56yrs vs. 61yrs for non-BMet cohort. There was no difference in baseline PS (BMet: PS 0–1 vs. 2 vs. 3 =74% vs. 21% vs.5%; non-BMet: 81% vs. 16% vs. 4%, p=0.16), weight loss (p=0.73) or hemoglobin (p=0.80) between the two cohorts. Female gender (41% vs. 33%, p=0.04) and adenocarcinoma (66% vs. 51%, p=0.005) was more common in the BMet cohort. There was no OS difference between the BMet and non-BMet cohort in the pooled analysis, stratified by trial (HR 1.05, 95%CI 0.85–1.28, stratified log-rank p=0.67), or in multivariate analysis adjusted for baseline covariates (AHR 1.12, 95%CI 0.91–1.37, p=0.31). There was also no OS difference between BMet and non-BMet pts when evaluated in each individual trial separately. Conclusions: Pts with a prior history of BMet have a similar OS to those pts without BMet in NSCLC in NCIC CTG CTs. In neurologically stable pts, BMet, should not be an exclusion criterion, while discontinuation or stable dose of corticosteroids appears a reasonable eligibility requirement.

No significant financial relationships to disclose.
Prognostic factors in patients enrolled in clinical trials of second-line chemotherapy for advanced non-small cell lung cancer (aNSCLC): A pooled analysis of 11 randomized trials
Authors: Di Maio M. , Camps C. , Smit E. F. , Schuette W. , Georgoulias V. , Takeda K. , Quoix E. , Wachters F. M. , Gebbia V. , Gridelli C.
Published: August 2020

8082

Background: Prognostic factors for newly diagnosed aNSCLC have been extensively studied, but less information is available on factors associated with outcome of 2nd-line treatment. Better knowledge of prognostic factors could be helpful to better select patients for further chemotherapy after failure of 1st-line treatment. Methods: The analysis is based on individual patient data collected for 2 meta-analyses on 2nd-line treatment of aNSCLC, one comparing weekly vs every 3 week docetaxel (Di Maio, J Clin Oncol 2007; 25:1377), and one comparing single-agent vs doublet chemotherapy (Di Maio, J Clin Oncol in press). Primary endpoint was overall survival (OS). All analyses were stratified by trial. Results: Out of 11 trials, 2 trials were excluded due to missing information on baseline characteristics considered in multivariate analysis. Of the other 9 trials (1239 pts), 1197 pts (97%) had complete information: 78%/22% males / females, 83%/17% younger / older than 70, 28%/59%/13% Performance Status (PS) 0 / 1 / 2, 18%/82% stage IIIB / IV, 32%/47%/21% squamous / adenocarcinoma / other histology. 84% were pretreated with platin and 44% had obtained objective response (OR) to 1st line treatment. With 956 deaths, median OS was 7.4 months. At multivariate analysis, prognosis was significantly influenced by gender (worse in males vs females, Hazard Ratio [HR] 1.23 [95%CI 1.04–1.45], p=0.01), by PS (worse in PS1 vs PS0, HR 1.36 [1.16–1.59], p=0.0001 and in PS2 vs PS0, HR 3.01 [2.41–3.76], p<0.00001), by tumor histology (better in adenocarcinoma vs squamous, HR 0.85 [0.73–0.99], p=0.04 and worse in other histology vs squamous, HR 1.27 [1.05–1.52], p=0.01), by stage (worse in stage IV vs IIIB, HR 1.28 [1.07–1.53], p=0.007), by type of previous treatment (worse for pts pretreated with platin vs pts not pretreated with platin, HR 1.49 [1.14–1.93], p=0.003), and worse for pts not obtaining OR vs pts obtaining OR during 1st line (HR 1.25 [1.10–1.44], p=0.001). Conclusions: In addition to patient-related (gender, PS) or tumor-related factors (histology, stage), prognosis of pts eligible for 2nd line treatment of aNSCLC is significantly conditioned by previous use of platin and response to 1st line treatment.

No significant financial relationships to disclose.
Comparison of progression-free survival (PFS) and tumor response as endpoints for predicting overall survival (OS) in untreated extensive-stage small cell lung cancer (ED-SCLC): Findings based on North Central Cancer Treatment Group (NCCTG) trials
Authors: Foster N. R. , Qi Y. , Krook J. E. , Kugler J. W. , Kuross S. A. , Jett J. R. , Molina J. R. , Schild S. E. , Adjei A. A. , Mandrekar S. J.
Published: August 2020

8085

Background: Historically, tumor response has been the primary endpoint in phase II (P2) trials in ED-SCLC. We investigated the suitability of alternate PFS based endpoints to predict OS as early evidence of efficacy in the P2 setting. Methods: Individual patient (pt) data from 942 pts from 11 previously untreated ED-SCLC P2 and phase III (P3) platinum- or paclitaxel-based treatment trials were pooled. Best response (BR), response confirmed (RC), objective status at 16 weeks (RR16), and PFS rate at 5 and 6 months were considered. Percent agreement (PA) and kappa (k) for PFS5, PFS6, BR, RC, and RR16 with OS at 12 months (OS12) was calculated on a per-pt basis and predictive utility was assessed using the area under the receiver operating characteristic (A- ROC) curve in logistic models. Cox models were used to assess the prognostic impact of the endpoints on subsequent survival, using landmark analysis. Results: The median OS and PFS were 9.6 m and 5.5 m, respectively. PFS5 and PFS6 had the highest PA, k, and A-ROC values, and were predictive of subsequent survival in the landmark analysis (p <0.0001; c-statistics ≥ 0.60). While RR16 and BR were significantly associated with subsequent survival (p<0.0001, c-statistics of 0.61 and 0.57, respectively) the PA, k, and A-ROC values were lower. Conclusions: PFS rate at 5 and 6 months is more predictive of 12-month OS and subsequent survival than tumor response in untreated ED-SCLC. PFS based endpoints should be routinely used as primary endpoints in P2 trials within ED-SCLC.

[Table: see text]

No significant financial relationships to disclose.
Safety and efficacy of YM155 in diffuse large B-cell lymphoma (DLBCL)
Authors: Cheson B. D. , Vose J. M. , Bartlett N. L. , Lopez A. , Van der Jagt R. H. , Tolcher A. W. , Weisenburger D. D. , Seiz A. L. , Shamsili S. , Keating A. T.
Published: August 2020

8502

Background: Survivin is a member of the inhibitor of apoptosis proteins (IAPs) family which is responsible for preservation of cell viability and regulation of mitosis in tumor cells. YM155, a survivin suppressant, has exhibited anti-tumor activity in solid tumors and non-Hodgkins lymphoma (NHL), including DLBCL patients enrolled in Phase I and Phase II monotherapy studies. Methods: Two studies enrolled 43 DLBCL patients; a Phase I study enrolled patients with solid tumors and NHL (n=1 relapsing DLBCL and n=1 refractory DLBCL), and a Phase II study enrolled refractory DLBCL patients (n=41). YM155 was administered at 4.8 mg/m2/day (Phase I) and at 5 mg/m2/day (Phase II) as a 168-hour continuous infusion in a 21 day cycle. Patients could continue to receive YM155 until disease progression or unacceptable toxicity. Results: Data are presented for the first 27 patients (Phase I and Phase II) who have completed therapy. Median age was 61 (23–80) years and 63% were male. Three patients (11%) had partial responses (PR) confirmed by independent review using Cheson criteria (N=2; 1999 criteria and N=1; 2007 updated criteria). All responders received 2 prior regimens. Two responders were refractory to their last regimen and one had relapsed approximately 2 years after stem cell transplant (SCT). One patient responded after 2 cycles, completed 5 total cycles and proceeded to SCT (disease-free > 3.7 years post SCT). A second patient responded after 3 cycles, completed 7 total cycles and proceeded to SCT in OCT08. The third patient responded after 12 cycles and received 26 total cycles (1.5 years) before disease progression. The most common (>4%), treatment-related grade 3/4 adverse events included anemia (16.0%) and neutropenia, fatigue, hemoglobin decrease and deep vein thrombosis (8.0% each). Conclusions: YM155 is well tolerated and has modest single-agent, anti-tumor activity in relapsed/refractory DLBCL patients. Because of single-agent activity and preliminary data showing synergism when YM155 is combined with other agents additional clinical studies are being planned.

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Long-lasting responses after four doses of rituximab in Waldenström's macroglobulinemia: Clinical value of minor responses: A follow-up of the Eastern Cooperative Oncology Group E3A98 trial
Authors: Gertz M. A. , Abonour R. , Heffner L. T. , Greipp P. R. , Uno H. , Rajkumar S. V.
Published: August 2020

8513

Background: Waldenström's macroglobulinemia is a low-grade lymphoplasmacytic lymphoma that is responsive to rituximab. Uniform response criteria define an objective response as a 50% reduction in the IgM level, and a minor response as a 25% reduction in IgM level. No publications in the literature exist that justify the use of the minor response. Clinicians who treat patients that achieve a minor response are left uncertain as to whether the response is adequate and patients should be monitored for progression or whether they should be considered therapy failures and crossover to an alternate chemotherapy regimen in an effort to achieve a deeper response. Methods: 69 patients, 34 previously untreated, and 35 previously treated (but rituximab naive) were included. All patients were treated with a single four-week course of rituximab 375 mg/m2 and were monitored with no further therapy until progression. Results: There were 19 objective and 17 minor responses out of 69 eligible patients (52.2%). Response rate and progression-free survival (26.6 mo) were similar whether patients were previously untreated or previously treated. Previously treated rituximab-naïve and previously untreated patients had, five-year survivals of 48% and 85%, respectively. There was no difference in overall or progression free survival between patients who achieved an objective response when compared to those who achieved a minor response. There was no difference between objective and minor responders by age, time from diagnosis to treatment in the treated group, bone marrow lymphoplasmacytes, hemoglobin level, creatinine, IgM level, or M-spike. The pre-treatment level of IgM did not predict overall survival, progression-free survival, time to progression, or response rate (All p>0.05). This lack of significance was found whether IgM was assessed as a continuous or discrete variable. Conclusions: These results reconfirm rituximab's efficacy as a single-agent for the treatment of Waldenström's macroglobulinemia, and patients who have a 25–50% reduction in their IgM protein derive significant clinical benefits that are durable and appear to not have an impact on overall survival.

No significant financial relationships to disclose.
In vivo activity of rituximab-CpG oligodeoxynucleotide conjugate against rituximab-resistant human CD20+ B-cell lymphoma
Authors: Timmerman J. , Betting D. , Yamada R. , Hurvitz S. , Steward K. , Said J. , van Rooijen N. , Kafi K.
Published: August 2020

8529

Background: The anti-CD20 monoclonal antibody rituximab (R) is a mainstay in the treatment of B cell non-Hodgkin's lymphoma (NHL), exerting anti-tumor effects via antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity, and apoptosis induction. Toll-like receptor 9 agonist CpG oligodeoxynucleotides (CpG) are potent activators of ADCC and T cell immunity, and have been studied for anti-NHL effects when administered by systemic or intratumoral routes. We sought to optimize the delivery of CpG to sites of NHL to improve R efficacy. Methods: We utilized an aggressive syngeneic human CD20-expressing murine B cell lymphoma (38C13-huCD20) to study the in vivo augmentation of R efficacy by CpG. Established tumors in immunocompetent mice were treated with R plus CpG given systemically, intratumorally, or chemically linked to antibody using maleimide-sulfhydryl chemistry (D. Betting et al, J. Immunol. 2008; 181: 4131). Results: 5- to 7-day established tumors were completely resistant to single agent R. Combining intratumoral, but not systemic administration of CpG with R resulted in tumor eradication from up to 42% of mice (p < 0.0003 vs. R alone, CpG alone, R + systemic CpG). Mechanistic studies indicated that both natural killer cells and complement participated in the cure of tumors by intratumoral CpG + R, by increasing tumor cell sensitivity to complement and ADCC lysis, and by augmenting the cytotoxicity of ADCC effectors. To overcome the need for repeated direct intratumoral injections and allow precise targeting of CpG to tumor cells, we chemically linked CpG to R using a cleavable linker. A single i.v. injection of this R-CpG conjugate achieved eradication of established tumors from 100% of mice. In contrast, equivalent doses of unlinked i.v. R + CpG, CpG alone, or R alone cured only 8% of mice. Thus, combining CpG with R was most effective using direct conjugation to the antibody. Conclusions: In conclusion, enhancement of R efficacy required sustained intratumoral delivery of CpG to maximize anti-tumor responses. R-CpG conjugate efficiently eradicated an established B cell lymphoma that is fully resistant to single-agent R. Clinical testing of anti-CD20-CpG conjugates against B cell NHL is thus warranted.

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First results of long-term rituximab maintenance treatment in follicular lymphoma: Safety analysis of the randomized phase III trial SAKK 35/03
Authors: Taverna C. J. , Bassi S. , Hitz F. , Mingrone W. , Pabst T. , Cevreska L. , del Giglio A. , Vorobiof D. A. , Simcock M. , Ghielmini M.
Published: August 2020

8534

Background: Rituximab maintenance has been shown to be effective in patients with follicular lymphoma. The optimal duration of maintenance remains unknown. Methods: We prospectively registered 270 patients with untreated, chemotherapy resistant or relapsed follicular lymphoma. All patients received rituximab induction consisting of 4 weekly doses (375 mg/m2). Responding patients (PR and CR) were randomized to a short maintenance consisting of four doses of rituximab (375 mg/m2) every two months (arm A) or prolonged maintenance consisting of rituximab every two months for a maximum of five years or until progression or unacceptable toxicity (arm B). Primary endpoint was event-free survival. Here we present the safety analysis. Results: From October 2004 to November 2007 165 patients were randomized, 82 in arm A and 83 in arm B. The median follow up is 22.7 months. A total of 442 hematological and non-hematological adverse events were observed, 27 of grade 3 and 6 of grade 4. Five subsequent cancers and 9 grade 3 and 4 infections were reported. Grade 3 and 4 neutropenia occurred in 5 patients, decreased levels of IgG were observed in 19 patients. Four grade 3 infections occurred after 2 years of maintenance. In arm B, maintenance was stopped due to unacceptable toxicity (fever) in 1 patient after 18 months and due to subsequent breast cancer in 1 patient after 20 months. One patient died 4 months after randomization because of ileus and consecutive peritonitis; considered to be unrelated to therapy. Twenty-nine patients are on maintenance for two or more years of which 6 patients are on for three or more years. In this analysis, median duration of the prolonged maintenance is 23.7 months. Conclusions: Rituximab maintenance beyond two years is feasible. We do not have evidence for increased toxicity after 2 years of maintenance. However, close follow up of patients under prolonged rituximab maintenance is necessary. The trial has been closed for accrual but there are still patients on treatment.

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Phase II trial of combination of bortezomib and rituximab in relapsed and/or refractory Waldenstrom macroglobulinemia
Authors: Ghobrial I. M. , Matous J. , Padmanabhan S. , Badros A. , Chuma S. , Leduc R. , Rourke M. , Kunsman J. , Harris B. , Warren D. , Richardson P.
Published: August 2020

8535

Background: This phase II study aimed to determine safety and activity of weekly bortezomib in combination with rituximab in patients with relapsed/refractory Waldenstrom macroglobulinemia (WM). Methods: Patients who had at least one previous therapy for WM and who had relapsed or refractory disease were eligible. NCI CTCAE v3.0 was used for toxicity assessment. All patients received bortezomib IV weekly at 1.6mg/m2 on days 1, 8, 15, q 28 days × 6 cycles, and rituximab 375 mg/m2 at days 1, 8, 15, 22, on cycles 1 and 4. Results: 37 pts (26 men and 11 women, median age 62 years, range 42 - 73) have been treated to date. The median number of lines of prior treatment was 3 (range 1 - 5). All patients had received prior rituximab and 5 pts received prior bortezomib. The median IgM at baseline was 3540 mg/dL (range 700-10,800). The median follow up is 12 months (range 5 - 26 months). Thirty-five pts are evaluable for response. Complete remission and near complete remission occurred in 2 (6%), partial remission in 17 (48%), and minimal response in 10 (29%). Progressive disease occurred in 1 (3%) and stable disease occurred in 5 (14%). Most patients achieved response rapidly within 3 months of therapy (2–7 months). Rituximab flare occurred only in 6 patients (20%). At 24 months of follow up, 8/35 pts have shown relapsed disease. The median time to progression and duration of response has not been reached. Patients tolerated therapy well without significant toxicities: grade 3 peripheral neuropathy occurred in only 2 pts. Grade 1 and 2 neuropathy occurred in 10 pts (26%). Other grade 3 and 4 toxicities included neutropenia in 5 patients, and anemia and thrombocytopenia in 4 patients. Grade 5 pneumonia and viral infection occurred in 1 patient who was within the first cycle of therapy and did not receive herpes zoster prophylaxis. Attributable toxicities otherwise proved manageable with appropriate supportive care and the combination was generally well tolerated. Conclusions: The combination of weekly bortezomib and rituximab has been well tolerated and demonstrates encouraging activity, with CR+ PR + MR in 83% of evaluable patients with relapsed WM. No significant peripheral neuropathy has been observed to date with this regimen.

[Table: see text]
PX-171–004, a multicenter phase II study of carfilzomib (CFZ) in patients with relapsed myeloma: An efficacy update
Authors: Vij R. , Wang M. , Orlowski R. , Stewart A. K. , Jagannath S. , Kukreti V. , Le M. H. , Kunkel L. , Siegel D.
Published: August 2020

8537

Background: Carfilzomib (CFZ) is a proteasome inhibitor, active against hematologic malignancies. Preclinically, CFZ overcomes bortezomib (BTZ) resistance in multiple tumors, including myeloma (MM). PX-171–004 is an ongoing Phase II study evaluating safety and efficacy of CFZ in MM patients with relapsed disease after 1–3 prior therapies. Overall Response Rate (ORR) of 35.5% for all subjects was previously reported (ASH 2008); updated data are now available. Methods: Patients were divided into two cohorts: BTZ-naïve and BTZ-exposed. CFZ 20 mg/m2 was administered Days 1, 2, 8, 9, 15 and 16 in a 28-day cycle, for up to 12 cycles. Dexamethasone 4 mg po was administered prior to each dose in Cycle 1. The primary endpoint was ORR, defined as Partial Response (PR) or better. Secondary endpoints included Duration Of Response (DOR) and Time To Progression (TTP). Results: 31 patients were enrolled; 14 (45%) BTZ-naïve and 17 (55%) BTZ-exposed. Of the BTZ-exposed cohort, 2 subjects received BTZ exclusively as a single agent, 6 had BTZ in a chemotherapy combination, and 9 received BTZ in a transplant regime. Overall, 23 (74%) subjects had > 1 prior therapy and 27 (87%) received transplant. In BTZ-naïve patients, CFZ achieved an ORR of 57%; median DOR of 8.6 mos (range >1.9 to >9.7 mos). To date, 7 patients (50%) remain progression free and 3 patients have completed 12 cycles. The median follow-up was 10 mos and the median TTP has not been reached. For the BTZ- exposed group, CFZ achieved an ORR of 18%; median DOR not yet reached (>8.5 mos) (range >1 d to >8.5 mos). 7 patients (41%) are progression free and 3 patients have completed 12 cycles. Median follow-up and TTP were 9.2 and 8.9 mos, respectively. Conclusions: These preliminary results demonstrate that single-agent CFZ is tolerable for at least 1 yr and achieves sustained responses in relapsed MM. Prior BTZ mono/combination therapy does not preclude durable response with CFZ. These data support continuing evaluation of CFZ in the treatment of relapsed MM.

[Table: see text]

[Table: see text]
Autologous and allogeneic transplantation for aggressive T-cell lymphomas: A single institution experience
Authors: Lansigan F. , Cooper D. , Seropian S. , Foss F.
Published: August 2020

8558

Aggressive T-cell lymphomas (ATCL) represent 10–15% of non-Hodgkin lymphoma and have a worse prognosis than aggressive B-cell lymphomas. Both autologous (Auto) and allogeneic (Allo) stem cell transplantation have been used as consolidation in first remission and at relapse, but the role of transplantation has not been clearly defined. There were 24 Auto and 18 Allo between 8/1997 and 12/2007. The Allo group consisted of 4 PTCLu, 3 angioimmunoblastic(AITL), 2 panniculitis-like, 2 cutaneous(CTCL) with large cell transformation, 2 NK-cell, 2 anaplastic large cell(ALCL), 1 hepatosplenic, 1 enteropathic, and 1 refractory CTCL. The Auto group consisted of 6 PTCLu, 12 ALCL (5 Alk+, 5 Alk-, 2 Alk unk), 4 AITL, 1 CTCL with transformation, and 1 T-lymphoblastic lymphoma. The median age was 51y(Allo) and 52y(Auto). Median prior therapies were 3(Allo) and 1(Auto). There were 14 matched- and 4 matched-unrelated Allo transplants; 7 were ablative and 11 were reduced-intensity. Median time from diagnosis to Allo or Auto was 18 and 8mo, respectively. Median follow-up was 29mo (Allo) and 24mo (Auto). The day 100 TRM was 11%(Allo) and 4%(Auto) respectively. The relapse mortality was 11%(Allo) and 33%(Auto). The non-relapse mortality was 33%(Allo) and 8%(Auto). The 1- and 2-year overall survival(OS) rates were similar within the Allo and Auto groups (78% vs 74%, and 67% vs 60% respectively). The 1- and 2-year progression-free survival (PFS) for the Allo vs Auto groups were 68% vs 52%, and 53% vs 45%, respectively (p=0.28). Within the Auto group, 14(58%) were transplanted in first complete remission(CR1), and 10(42%) in CR2, beyond CR2, or PR. Patients in CR1 had significantly better PFS (57 vs 17mo, p=0.007) and OS (76 vs 29mo, p=0.004) than those in CR2, beyond CR2, or PR. Allo patients with prior Auto(6) had a poorer OS than patients with no prior Auto(12), 32 vs 60mo, respectively, but the results were not statistically significant, p=0.15. One Allo was transplanted in CR1 and is still alive at 33mo. We conclude that outcomes for Auto are best in CR1. For patients with resistant or relapsed disease, Allo should be strongly considered rather than Auto. These results also suggest that a prospective randomized trial comparing Auto and Allo for ATCL in first remission is warranted.

No significant financial relationships to disclose.
A phase II trial of gemcitabine, ifosfamide, dexamethasone, and oxaliplatin (GIDOX) for patients with refractory or relapsed non-Hodgkin's lymphoma
Authors: Park B. , Kim W. , Eom H. , Kim J. , Oh S. , Suh C.
Published: August 2020

8559

Background: Gemcitabine combined with cisplatin has been known as an effective regimen for lymphoma treatment in salvage setting. However, this regimen has the modest response with severe nephrotoxcity and neurotoxicity, especially to heavily treated patients. We investigated the response rate and toxicity of gemcitabine, ifosfamide, dexamethasone, and oxaliplatin (GIDOx) for recurrent or refractory aggressive B-cell non-Hodgkin lymphoma (NHL), looking for the more effective and less toxic therapy. Methods: Patients with recurrent or refractory diffuse large B-cell NHL or mantle cell lymphoma, measurable disease, and more than one previous chemotherapy regimen were eligible. Treatment consisted of gemcitabine 1000 mg/m2 intravenously (i.v.) on Days 1 and 8, ifosfamide 2000 mg/m2 i.v. on Day 1, dexamethasone 40 mg orally on Days 1–4, and oxaliplatin 130mg/m2 i.v. on Day 2, every 21 days. The primary end point was a response after three cycles. Patients could then proceed to stem cell transplantation (SCT) or receive up to six treatment cycles. Results: Twenty-seven eligible patients were evaluable for toxicity and response. The median age of the patients was 54 years (range, 18–75 years) and most had diffuse large-cell lymphoma. After 3 cycles, there were 4 complete responses (CR; 15%) and 10 partial responses (PR; 37%). There was an overall response rate (RR) of 52%. The RR after completion of all protocol chemotherapy including SCT was 44% (10 CR, 2 PR). In total 88 cycles of GIDOx, grade 3 and 4 neutropenia occurred in 33% and 16% of cycles, respectively. Grade 3 and 4 thrombocytopenia occurred in 14% and 16% of cycles, respectively. Tow patients (2%) experienced febrile neutropenia. Seven patients (26%) proceeded to SCT. Conclusions: GIDOx is an active salvage regimen in aggressive B-cell NHL and can be administered with acceptable toxicity.

No significant financial relationships to disclose.
Efficacy of lenalidomide oral monotherapy in relapsed or refractory indolent non-Hodgkin's lymphoma: Final results of NHL-001
Authors: Witzig T. E. , Wiernik P. H. , Moore T. , Reeder C. , Cole C. , Justice G. , Kaplan H. , Voralia M. , Pietronigro D. , Vose J. M.
Published: August 2020

8560

Background: Lenalidomide has shown activity in a wide range of hematological malignancies. We conducted a phase II trial of single-agent lenalidomide in indolent non-Hodgkin's lymphoma (NHL). Methods: Patients with relapsed or refractory indolent NHL were eligible, with no limit on the number of previous therapies. Oral lenalidomide 25 mg was self-administered once-daily on days 1–21 of every 28-day cycle for up to 52 weeks as tolerated, or until disease progression. The primary endpoint was overall response rate (ORR), with secondary endpoints of response duration, progression-free survival (PFS), and safety. Results: Forty-three patients were enrolled and were evaluable for response and safety. Patients had received a median of 3 prior systemic therapies (1–17) and half of all patients were refractory to their last therapy. The ORR was 23% (10/43), including a complete response (CR) or unconfirmed CR (CRu) rate of 7%. The median time to first response was 3.6 months (1.7–4.2) and the median time to CR or CRu was 4.2 months (1.9–11.1). Twenty-seven percent (6/22) of patients with follicular lymphoma grade 1 or 2, and 22% (4/18) of patients with small lymphocytic lymphoma responded to therapy. The median duration of response has not reached, but is longer than 16.5 months with 7 of 10 responses ongoing at 15–28 months. Median PFS was 4.4 months (2.5–10.4). Adverse events were consistent with the known safety profile of lenalidomide and manageable; the most common grade 3 or 4 adverse events were neutropenia (30% and 16%, respectively) and thrombocytopenia (14% and 5%, respectively). Conclusions: Oral lenalidomide monotherapy produces durable responses with manageable side effects in relapsed or refractory indolent NHL and warrants further investigation in the treatment of indolent NHL.

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Vorinostat in combination with bexarotene in advanced cutaneous T-cell lymphoma: A phase I study
Authors: Dummer R. , Hymes K. , Sterry W. , Steinhoff M. , Assaf C. , Kerl H. , Ahern J. , Rizvi S. , Ricker J. L. , Whittaker S.
Published: August 2020

8572

Background: Vorinostat, a histone deacetylase inhibitor, is registered for the treatment of advanced cutaneous T-cell lymphoma (CTCL) in the US. Preclinical studies suggest that vorinostat may enhance the activity of chemotherapeutic or biological anticancer agents in a variety of cancers. This Phase I, multicenter, open-label study systematically evaluated vorinostat combined with the retinoid bexarotene in patients (pts) with advanced CTCL. Methods: Eligible pts were aged ≥18 years with stage ≥IB progressive, persistent, or recurrent CTCL refractory to ≥1 systemic therapy. Primary objective was to determine the maximum tolerated dose (MTD). Phase Ia Part I: dose escalation of vorinostat (200–400 mg/day) and bexarotene (150–300 mg/m2/day); Part II: fixed vorinostat dose (400 mg/day) with bexarotene dose escalation (150–450 mg/day). Cycles were repeated every 28 days for ≤6 cycles. Clinical activity and safety of the combination was also assessed. Results: 23 pts received ≥1 dose of study medication. Three pts in dose level (DL) 2 experienced dose-limiting toxicities (DLTs) ( Table ). No DLTs were observed in the first cycle of DL 2a and 2b. The MTD (Part I) was vorinostat 200 mg/day plus bexarotene 300 mg/m2/day. The Part II MTD was not reached as the study was discontinued early due to low enrollment; no DLTs were observed at DL 6 or 7. The most common drug-related adverse events (DRAEs) were hypothyroidism (35%), fatigue (30%), and hypertriglyceridemia (30%). No Grade 4 or 5 DRAEs were reported and 4 pts had serious DRAEs (Grade ≤3). Eighteen pts have discontinued: 5 due to AEs, 5 due to progressive disease, and 8 withdrew consent. Of 22 pts evaluable for efficacy, 4 (18%) had an objective response, and 7 (32%) derived clinical benefit (pruritis relief). Conclusions: These preliminary data suggest that the vorinostat/bexarotene combination is feasible in pts with advanced CTCL; however, the dosage of either drug must be reduced to avoid unacceptable side effects.

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Analysis of prognostic factors in patients with adult T-cell leukemia/lymphoma
Authors: Beltran B. E. , Morales D. , Quiñones P. , Salas R. , Castillo J.
Published: August 2020

8575

Background: Adult T-cell leukemia/lymphoma (ATLL) is associated with human T-cell lymphotropic virus type-I (HTLV-1) described in Southern Japan, Europe, Caribbean and South America. Risk-stratification tools for ATLL have not been adequately evaluated. This study attempts to define prognostic factors for patients with ATLL. Methods: A total of 102 cases from our Institution were collected between January 1997 and September 2008. Diagnosis was based on clinical history and histological findings consistent with ATLL and either positive HTLV-1 serology or evidence of HTLV-1 integration. Survival curves were estimated using the Kaplan-Meier method. Univariate and multivariate analyses were evaluated using log-rank and Cox regression tests, respectively. Results: Median age was 61 years with a female:male ratio of 1.15:1. Clinical types were acute (n=45), lymphomatous (n=43), cutaneous (n=10), smoldering (n=3) and chronic (n=1). Median OS for acute, lymphomatous, smoldering and cutaneous subtype were 2, 11, 17 and 39 months, respectively (log-rank 28.5, p<0.00001). In the univariate analysis, presence of B symptoms, ECOG performance status 2, clinical stage II or higher, elevated LDH level and bone marrow (BM) involvement were independent factors for survival with p<0.05. The IPI score was available in 92 patients; 13 (14%), 12 (13%), 29 (32%) and 38 (41%) patients were low, low-intermediate, high-intermediate and high-risk, respectively. Median OS by IPI risk group was 40, 13, 6 and 2 months, respectively (p<0.005). The prognostic index for T-cell lymphoma (PIT) score was determined in 80 patients; 20 (25%), 17 (21%), 33 (41%) and 10 (13%) patients had scores of 0–1, 2, 3 and 4, respectively. Median OS by PIT risk group was 19, 5, 3 and 2 months, respectively (p<0.005). In multivariate analysis, BM involvement and elevated LDH were significant for survival. Conclusions: This retrospective series represents the largest Latin-American experience on ATLL, which is a heterogeneous disease with distinct clinical features and outcomes. The IPI ant PIT scores, used for risk-stratification of aggressive B-cell and peripheral T-cell lymphomas, respectively, appear as good prognostic indicators for ATLL as well. Further research is needed to better risk-stratify this unique lymphoma.

No significant financial relationships to disclose.
Bortezomib plus modified R-CHOP as initial therapy for indolent B-cell lymphomas: Phase I results
Authors: Flowers C. , Sinha R. , Kaufman J. , Shenoy P. , Lewis C. , Bumpers K. , Rogatko A.
Published: August 2020

8577

Background: Adding rituximab (R) to chemotherapy improves survival for patients (pts) with follicular lymphoma (FL) and other indolent non-Hodgkin lymphomas (NHL), but not all pts respond. Bortezomib (B) + RCHOP has a high complete response (CR) rate, but higher doses of B with standard vincristine produced severe neuropathy. We developed a phase I/II trial to test if adding B to RCHOP with modified vincristine dosing can be well-tolerated and yield a high CR rate. Methods: Untreated pts with indolent NHL and indications for treatment based on GELF criteria or FLIPI ≥3 received R 375mg/m2, cyclophosphamide 750mg/m2, doxorubicin 50mg/m2, vincristine 1.4mg/m2 (capped at 1.5mg) on day 1, B 1.0- 1.6mg/m2 days 1 and 8, and prednisone 100mg days 1–5 for 6–8 cycles. The maximum tolerated dose (MTD) was defined as the regimen at which <30% grade ≥3 non-hematological or grade ≥4 hematological toxicity (>14 days) occurs. Dose escalation used the Escalation with Overdose Control Bayesian method with upper bound (θ=0.3). This facilitated MTD finding with fewer pts given prior data on B+RCHOP. Functional Assessment of Cancer Therapy (FACT) Neurotoxicity (11-item; 4 point scale), EMG, nerve conduction velocity and epidermal nerve fiber density measures were taken at baseline and after cycle 4. Results: 11 pts with FL (n=6) or other indolent NHL enrolled in phase I. Median age was 59 years (range 29–69). 6 pts (55%) had stage IV disease; 8 (64%) had FLIPI ≥2. Pts received RCHOP + B at 1.0 mg/m2 (n=1), 1.3 mg/m2 (n= 6) or 1.6 mg/m2 (n= 4) and together completed 67 cycles. Treatment was well tolerated. Neuropathy occurred in 4 pts (36%), with 2 grade 1, 1 grade 2 and 1 grade 3 toxicity ( Table ). Grade 4 neutropenia occurred in 4 pts (36%), but none >14 days. Overall response rate was 100% with 5/8 finished pts (63%) achieving CR. 3 continue on treatment. Mean FACT Neurotoxicity after cycle 4 remained < 1 for all items. Conclusions: Adding bortezomib to RCHOP produces limited toxicity when vincristine is capped at 1.5 mg. Phase II will explore the efficacy of this regimen.

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[Table: see text]