bluuebunny/crossref_metadata_2025_split huggingface dataset:
Salvage chemotherapy with rituximab, oxaliplatin, cytosine arabinoside, and dexamethasone (ROAD) in patients with relapsed CD20+ aggressive B-cell lymphoma
Authors: Johnston P. B. , LaPlant B. , Kurtin P. , Habermann T. , Moore D. , Nabbout N. , Nikcevich D. , Rowland K. , Witzig T. 
Published: August 2020

8556 Background: In the original PARMA trial it was demonstrated that salvage chemotherapy with DHAP followed by autologous bone marrow transplant resulted in increased overall survival over salvage chemotherapy with DHAP alone in patients with aggressive lymphomas. The current study was designed to assess safety and feasibility of ROAD as a salvage chemotherapy regimen which could be administered as an inpatient or outpatient. Methods: Patients received immunochemotherapy on the following schedule: rituximab 375 mg/m2 weekly × 4, oxaliplatin 130 mg/m2 on day 2, Ara C 2000mg/m2 x 2 doses on day 2 and dexamethasone 40 mg on days 2–5, with OAD repeated at 3 week intervals (up to 6 cycles). Patients were considered for autologous stem cell transplantation after 2 cycles if eligible. Eligible histologies included diffuse large B cell lymphoma, mantle cell lymphoma and transformed lymphoma in first relapse. Results: 50 patients were accrued from Aug 2006 through Jul 2008: 5 patients were deemed ineligible after central pathology review. Baseline characteristics of eligible patients included median age 69 (range 23 - 77), 53% were male, 53% had advanced stage at relapse, LDH was elevated in 58% and all patients had an ECOG PS of 2 or less. Patients received a median of 2 cycles of therapy (range 1–6) with 39/45 receiving treatment in cycle 2, with 12 patients continuing beyond 2 cycles. 31 patients experienced grade III/IV hematologic toxicity and 22 patients had grade III/IV non-hematologic toxicity, primarily febrile neutropenia. One patient developed grade III nephrotoxicity due to disease progression. Twenty patients received their treatments exclusively as outpatients. 26 responses were seen in the 45 eligible patients (58%, 95% CI: 44–74%), with 20 responding patients proceeding to autologous SCT. Conclusions: ROAD is a safe and effective salvage chemotherapy regimen for relapsed aggressive lymphoma, including as a preparatory regimen prior to stem cell transplant. It appears to have similar response rates to R-DHAP in a similar patient population, but without the potential nephrotoxicity (data from prior published study from NCCTG). ROAD can be safely administered as an inpatient or outpatient. No significant financial relationships to disclose.
A phase I trial evaluating the safety and biological activity of iboctadekin (rhIL-18) in combination with rituximab in patients with CD20+ B-cell non-Hodgkin's lymphoma
Authors: Robertson M. J. , Kline J. , Bauman J. , Gardner O. , Jonak Z. , Koch K. M. , Murray S. C. , Weisenbach J. , Toso J. 
Published: August 2020

8566 Background: Iboctadekin (rhIL-18) is an immunostimulatory cytokine that has demonstrated anti-tumor activity in several preclinical models. When administered as monotherapy in phase I clinical studies, rhIL-18 was safe, well tolerated and induced potent biological responses (e.g. Th1 cytokine production and expression of activation markers on NK, CD8+ and CD4+ cells). These data affirm the endogenous role of IL-18 as a co-stimulatory cytokine and suggest that its optimal use would be in a combination with other immune modulators such as rituximab. Methods: Patients with CD20+ B cell non-Hodgkin's lymphoma are being given rituximab (375 mg/m2) IV weekly for 4 consecutive weeks in combination with ascending doses of intravenous rhIL-18 (1 to 100 mcg/kg in 6 cohorts of 3 patients each) IV weekly for 12 weeks to identify a dose that is safe and tolerable and gives a maximum biological effect. Eligible patients must have disease which progressed after standard therapy or for which there is no effective standard treatment. Assessments include safety/tolerability, pharmacokinetics, pharmacodynamics (serum cytokines, peripheral blood phenotypic markers and tumor biomarkers), immunogenicity and anti-tumor activity. Results: To date, thirteen subjects have been enrolled in the first four cohorts (1, 3, 10 and 20 mcg /kg of rhIL-18). The combination is well tolerated with a safety profile similar to that observed with rituximab or rhIL-18 monotherapy. The pharmacodynamic response is as expected with a dose-dependent decrease in circulating activated (CD69+) NK cells within 4 hours after completing the rhIL-18 infusion which rebound to pre-dose levels within 2–4 days. Using the International Working Group response criteria for lymphoma, two subjects had complete responses at 10 and 20 mcg/kg, one subject had a partial response at 10 mcg/kg and three subjects had stable disease at 1, 3 and 3 mcg/kg. Conclusions: These data show that the combination of rhIL-18 and rituximab is safe, well tolerated and induces potent biological activity. This study will define the dose level to be used in a future phase II trial evaluating this combination in patients with relapsed or refractory follicular lymphoma. [Table: see text]
Efficacy of the DAC inhibitor LBH589 in both rituximab-sensitive and rituximab-resistant lymphomas and effect on the antitumor activity of chemotherapy agents, monoclonal antibodies, and bortezomib
Authors: Maraj I. , Hernandez-Ilizaliturri F. J. , Chisti M. , Czuczman M. S. 
Published: August 2020

8576 Deacetylases (DACs) are enzymes that remove the acetyl groups from target proteins [histones (class I) and non-histones (class II)], leading to regulation of gene transcription and other cellular processes. LBH589 is a novel and potent DAC class I and II Inhibitor undergoing pre-clinical and clinical testing. In order to develop therapeutic options for refractory/resistant B-cell lymphomas we studied the effects of LBH589 in the anti-tumor activity of chemotherapy agents and monoclonal antibodies in a panel of rituximab-sensitive cell lines (RSCL), rituximab-resistant cell lines (RRCL), and in lymphoma cells isolated from patients with treatment-naïve or refractory/relapsed B-cell lymphomas by negative selection using magnetic beads. NHL cells lines were exposed to the following chemotherapy agents or monoclonal antibodies: CDDP, doxorubicin, vincristine, bortezomib or rituximab, veltuzumab, or isotype, alone or in combination with LBH589. In dose-sequence studies the treatment with LBH589 preceded or followed in vitro exposure to the chemotherapy agent or the monoclonal antibody by 24 hrs. Changes in mitochondrial potential were determined by alamar blue reduction using a kinetic assay. Patient-derived tumor cells were exposed to either LBH589, bortezomib or both. Changes in ATP content were determined by cell titer glow assay. RNA was isolated from NHL cell lines exposed to LBH859 and changes in gene expression of the Bcl-2 family members were determined by qualitative polymerase chain reaction (PCR). LBH589 was active as a single agent against RSCL, RRCL or patient-derived tumor cells. In addition, Bcl-XL gene down-regulation was observed following exposure to LBH859. Synergistic activity was observed by combining LBH589 and chemotherapy agents, bortezomib or either of the two anti-CD20 mAbs studied. The sequence of administration impacted the degree of antitumor activity observed. Our data suggests that LBH589 is active against various RSCL, RRCL and patient-derived tumor cells. Findings suggest that LBH589 added to systemic anti-CD20 and/or chemotherapy could result in a novel and potent treatment strategy against B-cell lymphomas. No significant financial relationships to disclose.
Prognostic significance of vascular endothelial growth factor (VEGF), VEGF receptors (VEGFR), and vascularity in diffuse large B-cell lymphoma treated with immunochemotherapy (R-CHOP)
Authors: Gratzinger D. , Advani R. , Zhao S. , Talreja N. , Tibshirani R. J. , Horning S. J. , Levy R. , Lossos I. S. , Gascoyne R. D. , Natkunam Y. 
Published: August 2020

8581 Background: Diffuse large B cell lymphoma (DLBCL) cells coexpress VEGF, VEGFR1 and VEGFR2. In patients (pts) treated with CHOP chemotherapy alone, VEGFR1 predicted improved overall survival (OS) while microvessel density (MVD) predicted poorer OS; VEGF and VEGFR2 were not predictive (Lab Invest. 2008;88:38). We now assess these factors in pts treated with R-CHOP. Methods: 162 pts with de novo DLBCL treated with R-CHOP and median followup of 44 months were evaluated retrospectively with immunohistochemistry on tissue microarrays. Scoring: VEGF, VEGFR1, VEGFR2, and phosphoVEGFR2 (pVEGFR2) in lymphoma cells (categorical variable) <5%, none; 5–30%, weak; >30%, strong. MVD (continuous variable): average CD34+ microvessels/4 hpf. Statistics: univariate Cox proportional hazards regression, and multivariate Cox regression for testing independence from the International Prognostic Index (IPI) for two endpoints, OS and progression-free survival (PFS). Pearson chi-square testing for independence of variables. Results: VEGF and MVD did not correlate with OS or PFS. Pts with higher VEGFR2 (53%) had poorer OS but not PFS independent of the IPI (z=3.15, p=0.0016; 2 yr OS 100%/84%/76%). Pts with any pVEGFR2 (13%) had worse PFS independent of IPI (z=1.98, p=0.048) and a trend toward poor OS (p=0.056). VEGFR1 did not correlate with OS or PFS in the group as a whole. Since VEGFR1 and VEGFR2 expression correlate strongly (Χ2=56, p =9.8E-12) opposing associations with outcome could be masked. On subset analysis the 39% of pts with weak VEGFR2 had better OS with higher VEGFR1 (z=-1.64, p=0.016; 2 yr OS 68%/85%/92%). Conclusions: In contrast to our prior observations in CHOP treated pts, in DLBCL treated with R-CHOP MVD was not prognostically significant. The association of VEGFR1 with better OS was previously seen with CHOP alone, whereas the correlation of VEGFR2 and phosphorylated VEGFR2 with poorer OS was only seen with R-CHOP. Independent confirmation will be important, especially because multiple comparisons were made with 5 predictors and 2 endpoints tested. It is possible that VEGFR1 and VEGFR2 oppose each other functionally; future studies are indicated to address the mechanism of this effect. No significant financial relationships to disclose.
EPOCH-F: A salvage regimen for multiple myeloma prior to reduced intensity allogenic hematopoietic stem cell transplantation
Authors: Jamshed S. , Fowler D. , Neelapu S. , Dean R. M. , Steinberg S. M. , Snow K. , Odom J. , Gress R. E. , Bishop M. 
Published: August 2020

8592 Background: Variation in baseline host immune status contributes to inconsistent donor engraftment and may impede maximal graft-versus-myeloma effects after reduced intensity allogenic hematopoietic stem cell transplantation (RIHSCT) for advanced multiple myeloma (MM). As no specific salvage regimen has been designed for MM patients being considered for RIHSCT, we evaluated EPOCH-F a novel salvage regimen designed to provide disease control and immune depletion. Methods: EPOCH-F is an infusional chemotherapeutic regimen consisting of etoposide, vincristine and adriamycin, with prednisone, cyclophosphamide and fludarabine given in 21 day cycles prior to RIHSCT. Targeting a CD4+ T cell count, 22 pts were treated <5 cycles of EPOCH-F. Pts proceeded to RIHSCT after adequate lymphodepletion or if there was disease progression during EPOCH-F, regardless of CD4 count. Results: Median age was 53 years (range 36–65); median time from initial therapy to transplant was 12 months (range 2–168). Median number of prior therapies was 2 (range 1–8), 63% had chemotherapy sensitive disease and 68% had received a novel agent. Pts received a median of 3 cycles (range 1–5), with manageable toxicities, mostly hematologic. Grade IV Neutropenia was seen in 77% of the administered cycles with only 6 episodes of neutropenic fever. Median lymphocyte count decreased from 1423/μL (range 335–2788) to 519/μL (range 102–1420); CD4 count decreased from 320/μL (range 130–1366) to 115/μL (30–309). In 21 evaluable pts, the ≥PR rate to EPOCH-F was 22% with 13% CR/nCR. 68% had SD and only 1 pt progressed. 20 pts underwent RIHSCT from HLA matched sibling. Median Day 100 chimerism was 100% (range 60–100, mean 95). 70% of patients achieved ≥VGPR and CR/nCR was seen in 40%. Acute GVHD (grade II-IV) was seen in 47% and chronic GVHD (grade III-IV) was seen in 52% of the pts. TRM at 100 days was 5% and 30% at 60 months. Median overall survival of patients after RIHSCT was 46.1 months. Conclusions: EPOCH-F is an active regimen which provides pre-transplantation lympho-depletion, disease control and allows consistent engraftment in multiple myeloma patients undergoing RIHSCT. No significant financial relationships to disclose.
Phase II study of aflibercept (VEGF trap) in recurrent inoperable stage III or stage IV melanoma of cutaneous or ocular origin
Authors: Tarhini A. A. , Christensen S. , Frankel P. , Margolin K. , Ruel C. , Shipe-Spotloe J. , DeMark M. , Kirkwood J. M. 
Published: August 2020

9028 Background: Aflibercept is a fusion protein combining the Fc portion of human IgG1with the extracellular ligand-binding domains of human VEGFR1 and VEGFR2, acting as a high-affinity soluble VEGF receptor and potent angiogenesis inhibitor. Methods: Phase II study of aflibercept in patients with inoperable stage III or IV melanoma who had received no prior chemotherapy or hormonal therapy. A 2-stage design was adopted focusing upon response rate (RECIST) and 4-month PFS rate. First stage accrual of 21 patients was specified, while final accrual of 41 is planned, with adequate response/4 month PFSR. Aflibercept was given at 4 mg/kg IV every 2 weeks. Response was assessed every 8 weeks. Results: Twenty seven patients (16 male, 11 female), age 23–83 (median 58) have been enrolled to date. All had AJCC stage IV melanoma (3M1a, 3M1b, 21M1c). Karnofsky PS: 100 (13), 90 (11) or 80 (3). Nine patients had primary ocular melanoma, 16 cutaneous and 2 unknown primary site. A total of 160 cycles have been administered (median 4; range 1–18). Grade 3/4 toxicities included cerebral ischemia (1 patient; 4%), confusion (1; 4%), thrombocytopenia (1; 4%), hypertension (7; 26%), hypotension (1; 4%), left ventricular diastolic dysfunction (1; 4%), fatigue (1; 4%), proteinuria (4; 15%), extraocular muscle paresis (1; 4%), renal failure (1; 4%), back pain (1; 4%), headache (1; 4%). Interim analysis was conducted after the first 21 patients (stage 1). Eight (1 M1a, 1M1b, 6M1c; 4 ocular, 3 cutaneous, 1 unknown primary) of the first 21 patients had at least 4 months of PFS (10 out of 27; 2 additional patients with cutaneous melanoma had SD: 1M1a and 1M1c). One patient (23rd; cutaneous, M1c) had a confirmed complete remission. Four patients were taken off study prior to response evaluation for toxicity (3) or treatment refusal (1). One patient is currently disease free who was not evaluable for response (previous surgery and radiofrequency ablation of measurable disease site). Eleven patients had progression. Conclusions: Aflibercept can be administered with acceptable toxicity, and exhibits promising antitumor efficacy against advanced melanoma. This study continues second stage accrual with anticipated closure before June 2009. [Table: see text]
A phase I/II study of CR011-vcMMAE, an antibody-drug conjugate (ADC) targeting glycoprotein NMB (GPNMB) in patients (pts) with advanced melanoma
Authors: Hwu P. , Sznol M. , Pavlick A. , Kluger H. , Kim K. B. , Boasberg P. , Sanders D. , Simantov R. , Crowley E. , Hamid O. 
Published: August 2020

9032 Background: GPNMB is expressed on melanoma cells and represents a potential target for ADCs. CR011-vcMMAE is a fully-human monoclonal antibody to GPNMB conjugated to the tubulin inhibitor monomethylauristatin E (MMAE). Dose limiting toxicity in Phase I (n=32) was rash; tumor shrinkage including one partial response (PR) was observed. We now report Phase II data at the maximum tolerated dose of 1.88 mg/kg iv q3w. Methods: Eligible pts had unresectable stage III or stage IV melanoma and had received no more than 1 prior cytotoxic regimen but any number of other therapies. Pts received CR011-vcMMAE until disease progression (PD) or intolerable toxicity. The primary endpoint was overall response (ORR) by RECIST using a minimax two-stage design (p0=0.5; p1=0.2, α=β=0.1) with 18 patients in the first stage and a total of 32 pts. Secondary endpoints included progression free survival (PFS) and duration of response. Results: 36 pts (median age 67 years [range 37–79]; 94% stage IV; 68% M1c) were treated for a median of 2.4 months (m)(range 0.5–7.5m). 18 pts discontinued (14 PD, 2 consent, 1 adverse event [AE], 1 stable disease [SD]) and 18 pts were ongoing. The study met the criteria for advancement to the second stage; 4 PRs (1 unconfirmed) and 19 SD (range 1.7–7.5 mo) have been observed; final ORR is pending. The unconfirmed PR was in a pt with 96% tumor reduction and PD 6 weeks later. Median PFS was 4m. The most common AEs were rash (81%), fatigue (72%), alopecia (63%) and pruritus (56%). The most common grade 3/4 AEs were neutropenia (22%) and rash (19%). Grade 2 or higher rash was associated with longer PFS. Conclusions: CR011-vcMMAE is active and well-tolerated in heavily pretreated pts with advanced melanoma. Rash may be a useful biomarker for activity. More frequent dosing is being explored. [Table: see text]
Association between immune-related adverse events (irAEs) and disease control or overall survival in patients (pts) with advanced melanoma treated with 10 mg/kg ipilimumab in three phase II clinical trials
Authors: Lutzky J. , Wolchok J. , Hamid O. , Lebbe C. , Pehamberger H. , Linette G. , de Pril V. , Ibrahim R. , Hoos A. , O'Day S. 
Published: August 2020

9034 Background: The monoclonal antibody ipilimumab targets cytotoxic T-lymphocyte antigen-4. The most common AEs associated with ipilimumab are irAEs, and both antitumor and irAE responses likely reflect its immune-mediated mechanism of action. In this report, a potential association between disease control (DC) or overall survival (OS) and irAEs in patients (pts) with advanced melanoma treated with 10 mg/kg ipilimumab in 3 Phase II clinical trials was explored. Methods: Across 3 Phase II studies (CA184008, 022, and 007), ipilimumab (10 mg/kg) was given every 3 weeks (Q3W) x 4 (induction); eligible pts could continue to receive ipilimumab Q12W starting at week (wk) 24 (maintenance). In study 022, pts were randomized to 0.3, 3, and 10 mg/kg groups, whereas study 008 was a single-arm trial of ipilimumab 10 mg/kg. In study 007, ipilimumab 10 mg/kg was administered either with placebo or daily prophylactic budesonide. Disease control (CR/PR/SD) was evaluated using modified World Health Organization (mWHO) and immune- related response criteria (Hodi FS, et al. J Clin Oncol 26: 2008 (May 20 suppl; abstr 3008). Association between DC and grade 0/1 vs. grade ≥2 irAEs was examined (studies 007, 008, and 022). Association between OS and irAEs which developed within 12 wks of ipilimumab treatment was also explored using landmark analyses from Day 81 (studies 008 and 022). Results: Across the 3 phase II studies, the rate of DC by mWHO in pts with grade 0/1 irAEs was 20–24% and in pts with grade ≥2 irAEs was 34–43%. The number of pts with DC was higher among those who experienced an irAE compared with those who did not, but DC was not statistically significantly associated with grade 0/1 vs grade ≥2 irAEs. For pts who lived up to Day 81 in studies 008 and 022, median OS (95% CI) from Day 81 was 14.8 mo (10.0–21.7) for any irAE and 8.21 mo (5.29–13.7) for no irAE within 12 weeks; median OS was 13.6 mo (5.78-NR) for any grade ≥2 irAE and 11.3 mo (7.95–15.8) for no grade ≥2 irAE within 12 weeks. Conclusions: DC and survival benefits with ipilimumab are observed among pts that develop an irAE and among pts that do not develop an irAE. Thus, pts who do not experience an irAE may still demonstrate clinical benefit with ipilimumab. [Table: see text]
Dendritic cell vaccination in melanoma patients: Update and subgroup analysis of clinical response to post-vaccine treatment
Authors: Ridolfi L. , Fiammenghi L. , Petrini M. , Granato A. M. , Ancarani V. , Pancisi E. , Valmorri L. , Riccobon A. , Ridolfi R. 
Published: August 2020

9042 Background: Dendritic cells (DCs) play a crucial role in the interplay between innate and adaptive immune response towards cancer. The combination of immunotherapies with standard treatments for cancer could represent a further chance for advanced melanoma patients. In the literature, higher response rates than those normally obtained have been reported after second-line chemotherapy in patients with non small cell lung cancer pre-treated with vaccines and in patients with follicular B-cell lymphoma vaccinated with an anti-idiotype vaccine whilst in remission. On the basis of this data, we reviewed and updated the clinical results of our dendritic cell based vaccine clinical trial in stage IV melanoma patients. Methods: From December 2002 to 2007, 24 pre-treated metastatic melanoma patients were vaccinated with mature DCs (mDCs) pulsed with autologous tumor lysate (ATL) and keyhole limpet hemocyanin (KLH) followed by a 5-day treatment with low-dose subcutaneous Interleukin-2. Results: We observed 2 complete response (CR), 2 mixed response (MR), 5 partial response (PR), 4 stable disease (SD) and 11 progressive disease (PD) (overall response (OS) 37.5%; clinical benefit 54.1%). All 13 responders had delayed-type hypersensitivity (DTH) positivity to KLH, of whom 10 also showed positivity to the lysate. Eleven (45.8%) of the 24 patients underwent further lines of treatment (5 chemotherapy [CT], 3 surgery [S], 4 biotherapy, 2 radiotherapy [RT] and 4 biochemotherapy [BioCT]) after stopping vaccination (8 due to progression and 3, in SD, because all of their lysate had been used). Of these 11 patients, 2 obtained CR (1 RT, 1 S), 5 PR (3 BioCT, 2 S) for an OR of 63.6%, 1 SD (BioCT) and 3 showed PD as the best response to subsequent therapies, with a median OS of 30 months (range 16–52). Of the 3 SD patients who were forced to stop vaccine treatment, 1 had CR following RT and 2 progressed. Conclusions: Metastatic melanoma responds poorly to standard therapy, in particular after first-line treatment. Vaccination could enhance clinical response to subsequent third- or fourth-line therapies, thus prolonging overall survival. No significant financial relationships to disclose.