bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correlation of chemotherapy delivery and survival outcomes of follicular lymphoma in the immunchemotherapy era.
Authors: Wudhikarn Kitsada , Button Anna M , Smith Brian J. , Habermann Thomas Matthew , Thompson Carrie A. , Cerhan James Robert , Link Brian K. 
Published: March 2020

8563 Background: Optimal initial treatment of follicular lymphoma (FL) is unknown. Rituximab as monotherapy (R) or as a component of immunochemotherapy (R+Chemo) is established as effective and it is now reasonable to re-examine the role of chemotherapy dosing. We explored clinical features, systemic treatment and chemotherapy delivery with comparative effectiveness of delivered dose intensity (DDI) on outcomes. Methods: We reviewed the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource database along with medical records on newly diagnosed grade I-IIIa FL who received systemic therapy from 2002 to 2009. Presenting clinicopathologic factors, outcomes and systemic therapy details including doses of chemotherapy were collected. The event-free (EFS) and overall survival (OS) effects of systemic therapy and chemotherapy DDI were analyzed with multivariate Cox regression. Confounding effects of FLIPI, grade, stage, and age were considered in the analysis. Results: From 2002 to 2009, 631 newly diagnosed FL were enrolled. Median follow up duration was 52.7 months. We identified 322 grade I-IIIa FL treated with systemic therapy including 93 R and 229 R+Chemo. Age and stage were similarly distributed between the R and R+Chemo groups; however, patients in the R group had lower grade (p<0.01) and FLIPI (p=0.03). Multivariate analysis showed no significant differences in EFS (HR=1.24, p=0.28) or OS (HR=0.55, p=0.13) for R compared to R+Chemo. Among R-CVP or R-CHOP treated FL, DDI data were collected for 73 doxorubicin (dox) and 137 cyclophosphamide (cyc) patients. Eighty-five percent of patients received 90% or more pre-planned DDI. After controlling for confounding factors, higher cycDDI was associated with improved EFS (HR 0.55, P=0.04) and OS (HR 0.74, P=0.03). No significant OS or EFS effects of doxDDI were observed. Conclusions: Addition of chemotherapy to rituximab was not associated with a detectable difference in survival outcomes in grade I-IIIa FL at a median follow-up of 52.7 months. Among R+Chemo treated FL, chemotherapy was delivered completely in most patients and more completed delivery of cyclophosphamide was associated with improved EFS and OS.
A phase II study of gemcitabine, ifosfamide, and oxaliplatin (GIFOX) as upfront treatment for high-risk, non-anaplastic large cell, peripheral T-cell lymphomas.
Authors: Corazzelli Gaetano , Marcacci Gianpaolo , Frigeri Ferdinando , Capobianco Gaetana , Volzone Francesco , Becchimanzi Cristina , Donnarumma Daniela , Azzaro Rosa , De Filippi Rosaria , Russo Filippo , Pinto Antonio 
Published: March 2020

8564 Background: Patients (pts) with peripheral T/NK cell lymphomas (PTCL) and intermediate-high/high IPI risk have a 5-yr overall survival < 20%. Current chemotherapy is unsatisfactory while benefit of upfront autologous transplantation (ASCT) is limited by high pre-transplant progression rates and pts advanced age. We evaluated efficacy and stem cells (SCs)-mobilizing activity of a biweekly regimen of gemcitabine (G), ifosfamide (Ifo) and oxaliplatin (Ox) (GIFOX), as an upfront strategy ensuring fast cytoreduction and early ASCT access or an effective alternative to CHOP-like programs in transplant-inelegible pts. Methods: Six biweekly courses of GIFOX [G 1000 mg/m2 D1, Ox 130 mg/m2 D2, Ifo 5 g/m2 D2 as 24h infusion (fractionated over days 2-4 in pts>65 yrs), G-CSF DD 7-11] were planned for all pts, with SCs mobilization at course 3 in ASCT-eligible pts. Simon's minimax two-stage design was adopted with the primary and secondary endpoints of response rate (RR) and progression-free survival (PFS), respectively. Results: Thirty-four pts (median age 63 yrs, r 42-80) [PTCL, nos (n=16), AITL (n=7), extranodal NK/T-cell (n=5), SS (n=6)], with IPI score intermediate-high (62%) or high (38%) were accrued [stage IV: 71%; BM involvement: 38%; E-site >1: 47%; hi LDH: 71%; ECOG>1: 38%; B-symptoms: 44%]. A total of 172 courses was delivered (median 6, r 2-6). Only 5 pts received <4 courses, due to progression (n=4) or early death (n=1). Overall RR was 82% [95% CI, 66-92; 22 complete (CR) and 6 partial (PR) responses]. Twelve pts mobilized SCs (median CD34+ cells harvest: 4.36x106/kg) and 8 (7CRs,1PR) underwent ASCT, 6 to 13 weeks after the 6th course. Estimated 5-yr PFS was 48% (95%CI: 28-65); median PFS for non-transplanted pts was 15 mo.s. Estimated 4-yr disease-free survival was 58%. Relevant toxicities were G4 thrombocytopenia (13%), G4 anemia (23%), G3/G4 infection (29%/6%), G3 encephalopathy (6%). Conclusions: Response and survival rates of GIFOX in high-risk PTCL compared more than favorably to CHOP-based regimens. Effective cytoreduction and prompt access to ASCT were ensured, together with safe delivery of a full induction program to transplant-ineligible pts.
The role of radiotherapy and intrathecal CNS prophylaxis in extralymphatic craniofacial diffuse large B-cell lymphoma.
Authors: Murawski Niels , Zeynalova Samira , Held Gerhard , Ziepert Marita , Kempf Barbara , Viardot Andreas , Haenel Mathias , Witzens-Harig Mathias , Ruebe Christian , Fleckenstein Jochen , Zwick Carsten , Glass Bertram , Schmitz Norbert , Pfreundschuh Michael ,   German Non-Hodgkin Lymphoma Study Group (DSHNHL)
Published: March 2020

8566 Background: The role of radiotherapy and intrathecal prophylaxis in extralymphatic craniofacial involvement of aggressive B-cell lymphoma remains to be determined in the rituximab era. Methods: In a retrospective subgroup analysis of 9 consecutive prospective DSHNHL trials covering all DLBCL risk groups from 18 to 60 years of age, patients with and without craniofacial involvement were compared with respect to clinical presentation, event-free and overall survival. Results: 336 sites of extralymphatic craniofacial involvement were observed in 284/3840 (7.4%) patients (orbita: 30, paranasal sinuses: 90; main nasal cavity: 38, tongue: 26, remaining oral cavity: 99, salivary glands: 53). In a multivariable analysis adjusting for IPI risk factors the addition of rituximab improved EFS and OS in both patients with and without craniofacial involvement. The 141 responding patients who received radiotherapy to sites of craniofacial involvement had a similar 3-year event-free (79% vs 79%; p=0.835) and 3-year overall survival (88% vs. 85%; p=0.311) when compared with the 56 patients who did not receive radiotherapy. Without rituximab, the 2-year-rate of cumulative risk of CNS disease was increased in 205 patients with compared to 2586 patients without craniofacial involvement (4.2% vs. 2.8%; p=0.038), while this difference disappeared in patients who received CHOP(like) chemotherapy in combination with rituximab (1.7% in 77 patients with compared to 2.9% in 946 patients without craniofacial involvement; p=0.868). Of 85 patients with craniofacial involvement who received intrathecal prophylaxis with methotrexate, the 2-year-rate of cumulative risk of CNS disease was 4.3% compared to 2.3% in 189 patients who did not (p=0.995). Conclusions: Rituximab eliminates the increased risk for CNS disease in patients with craniofacial involvement. As a practical consequence intrathecal prophylaxis and radiotherapy to sites of craniofacial involvement should not be given any more.
Screening for coronary artery disease after mediastinal irradiation in Hodgkin lymphoma survivors.
Authors: Daniëls Laurien Aletta , Krol Augustinus , de Graaf Michiel A , Scholte Arthur JHA , Putter Hein , van t Veer Mars B , de Roos Albert , Schalij Martin J , Creutzberg Carien L. 
Published: March 2020

8568 Background: Cardiovascular diseases are the most common non-malignant cause of death in Hodgkin Lymphoma (HL) survivors, especially those who had mediastinal irradiation as part of their treatment. We investigated the role of CT coronary angiography (CTA) as a screening tool for coronary artery disease (CAD) in asymptomatic HL survivors, related findings to stress testing and subsequent interventions. We also evaluated acceptance of screening. Methods: Patients were eligible if at least 10 years disease-free and treated with mediastinal radiotherapy. All patients were screened with ECG, stress testing and CTA. Primary endpoint was significant CAD (stenosis >50%) on CTA. A sample size of 50 patients would achieve ≥80% power to detect a difference of 13% (≥20% vs a population proportion of 7%) using a two-sided binominal test. Allowing for non-evaluable and false-positive scans, we considered CTA screening to be indicated for testing in a larger population if in ≥six patients revascularization would be necessary. Results: Fifty-two patients were included, 48 patients underwent CTA. Median age was 47 years, time since HL diagnosis 21 years. Most patients had no risk factors for CAD. There were 45 evaluable scans. Prevalence of significant CAD on CTA was found in 20% (N=9), and significantly increased compared to the 7% expected abnormalities (p=0.01, 95% CI 8.3-31.7%). In 5 of the 8 patients who underwent conventional angiography, significant CAD was confirmed, and revascularization performed. Two patients were started on medication. Stress testing was inaccurate for determining CAD: all participants were asymptomatic and 1 patient with significant CAD had signs of ischemia. Ninety percent of the participants were content with the screening offered in this study, regardless whether the CTA showed abnormalities or not. Conclusions: Prevalence of significant CAD among HL survivors is high. In our participants even the most severe and life-threatening CAD was not preceded by typical symptoms. In symptomatic cardiac patients revascularization improves survival. This might justify both screening by CTA and intervention in this asymptomatic population, but needs to be further evaluated in a larger cohort. Clinical trial information: NCT01271127.
A phase I dose-escalation trial of ublituximab (TG-1101), a novel anti-CD20 monoclonal antibody (mAb), for rituximab relapsed/refractory B-cell lymphoma patients.
Authors: Deng Changchun , Amengual Jennifer Effie , Schreeder Marshall T. , Clark-Garvey Sean , Patterson Molly , Miskin Hari , Sportelli Peter , O'Connor Owen A. 
Published: March 2020

8575 Background: Anti-CD20 therapy (rituximab or RTX) in treating patients (pts) with B-cell lymphomas has resulted in significant improvement in treatment response and clinical outcomes. Despite advances, pts continue to relapse from, or are refractory to, RTX-based regimens. Ublituximab (UTX) is a novel, chimeric mAb targeting a unique epitope on the CD20 antigen. UTX has been glycoengineered to enhance affinity for all variants of FcγRIIIa receptors, and therefore demonstrates greater ADCC activity than RTX (Le Garff-Tavernier, 2011). UTX displayed greater antitumor activity compared to RTX in NHL in vivo models and in low CD20 expressing tumors (ASH 2011). A phase I trial with UTX used as a single agent in pts with relapsed/refractory CLL reported a response rate of 45%. Herein we report on the phase I dose-escalation of UTX in pts with RTX relapsed/refractory B-cell lymphoma. Methods: Eligible pts have B-cell lymphoma relapsed or refractory to a RTX containing regimen. Pts are required to have measurable/evaluable disease, ECOG PS < 2 and no active hepatitis B/C. The phase I dose-escalation uses a sequential 3+3 design in dose cohorts of 450mg, 600mg and 900mg respectively. UTX is administered once weekly for 4 infusions followed by monthly maintenance therapy. PK and correlative PD data are being collected. Primary endpoint: Maximum Tolerated Dose (MTD) and Dose Limiting Toxicities (DLT). Efficacy is a secondary endpoint. Results: Nine pts (5 FL, 3 MZL, 1 MCL) have been enrolled (3 each cohort). Median age 63; 3/6 (M/F). Median prior Rx = 4 (2-6). RTX refractory (44%). 8/9 pts are evaluable for safety; no DLT’s observed and no Grade 3/4 AE’s to date. 7/9 pts have had at least one response assessment (8 wk scan), which includes: 1 CR (rituximab refractory MZL); 2 PR’s (1 MZL, 1 FL); 2 SD (FL) and 2 PD (1 transformed FL, 1 MCL). PK analysis is ongoing. Conclusions: UTX has been well tolerated to date with no G 3/4 AE’s with demonstrated early clinical activity at all doses. 7/9 patients continue to receive UTX treatment (range 1–25 wks). Enrollment in the 900mg expansion cohort is now open with an emphasis on RTX relapsed/refractory indolent or low CD20-expressing lymphomas. Clinical trial information: NCT01647971.
Effect of phosphotidylinositol 3-kinase-delta inhibitor idelalisib (GS-1101) on signaling in primary non-Hodgkin lymphoma cells: Correlative studies from NCT01306643.
Authors: Arita Adriana , Hanlon Katherine , Chkourko Halina , Lannutti Brian Joseph , Johnson David Michael , Gabrilove Janice Lynn , Scigliano Eileen , Parekh Samir S. , Brody Joshua 
Published: March 2020

8579 Background: Studies of GS-1101, an oral phosphatidylinositol 3-kinase (PI3K)d-specific inhibitor, in heavily pre-treated patients with indolent-non-Hodgkin's lymphomas (iNHL) have shown marked clinical activity [Kahl BS, et al., Blood 2010]. We have shown that GS-1101 blocks both constitutive and inducible signaling events proximally downstream of PI3K [Lannutti BJ, et al., Blood 2011]. We hypothesized that flow-cytometric interrogation of PI3Kd-inhibition in iNHL samples might demonstrate signaling differences between patients that can be correlated with clinical outcomes. Methods: Single-cell suspensions of biopsy specimens from patients were incubated with or without GS-1101, B-cell receptor stimulated and stained with lineage markers and phospho-specific antibodies targeting signaling nodes proximally (e.g. pAkt S473) or distally (e.g. pS6 S235/6) downstream, or "parallel" to (e.g. pErk1/2) described PI3K pathways. Results: Healthy and iNHL B cells demonstrated complete or near-complete inhibition of PI3K proximal downstream signaling by GS-1101. PI3K distal downstream signaling was completely inhibited by GS-1101 in healthy B cells. The degree inhibition of distal downstream signaling was variable between iNHL patients. iNHL showed marked variability in the degree of PI3K distal downstream signaling amongst tumor cells within the same sample, suggesting an admixture of "PI3K-dependent“ and "PI3K-independent" tumor cells. We also observe variable PI3K-independence amongst other NHL histologies such as mantle cell lymphoma. Additionally, combining inhibition of PI3K with that of other signaling nodes shows additive distal downstream effects. Conclusions: We demonstrate that GS-1101 blocked both constitutive and invoked signaling proximally downstream of PI3K in primary iNHL cells. By correlating clinical outcomes in the ongoing study with signaling readouts between patients we may develop predictive rules for response. Ongoing studies will focus on studying the change in intratumoral cell subsets which develop in vivo as patients progress on PI3Kd inhibitor therapy.
Effect of a novel agent, SL-401, targeting interleukin-3 (IL-3)-receptor on plasmacytoid dendritic cell (pDC)-induced myeloma cell growth and drug resistance.
Authors: Chauhan Dharminder , Ray Arghya , Brooks Christopher , Rowinsky Eric K. , Anderson Kenneth Carl 
Published: March 2020

8582 Background: Multiple myeloma (MM) remains incurable despite novel therapies, highlighting the need for further identification of factors mediating disease progression and drug resistance. The bone marrow (BM) microenvironment confers growth, survival, and drug resistance in MM cells. Our recent study utilized in vitro and in vivo MM xenograft models to show that plasmacytoid dendritic cells (pDCs) were significantly increased in MM BM and promote MM growth (Chauhan et al., Cancer Cell 2009, 16:309). Importantly, we found increased IL-3 levels upon pDC-MM interaction, which in turn, trigger MM cell growth and pDCs survival. IL-3R is highly expressed on pDCs. We utilized SL-401, a novel biologic conjugate that targets IL-3R, to examine whether abrogation of IL-3–IL-3R signaling axis affects pDC-MM interaction and its tumor promoting sequelae. Methods: MM cell lines, patient MM cells, and pDCs from healthy donors or MM patients were utilized to study the anti-MM activity of SL-401. MM cells and pDCs were cultured alone or together in the presence or absence of SL-401, followed by analysis of cell growth or viability. Results: SL-401 significantly decreased the viability of pDCs at low concentrations (IC50: 0.83 ng/ml; P < 0.005, n = 3). SL-401 also decreased the viability of MM cells at clinically achievable doses. Co-culture of pDCs with MM cells induced growth of MM cell lines; and importantly, low doses (0.8 ng/ml) of SL-401 blocked MM cell growth-promoting activity of pDCs. MM patient-derived pDCs induced growth of MM cell lines and primary MM cells as well; conversely, SL-401 inhibited pDC-triggered MM cell growth (P < 0.005, n= 5). Tumor cells from 3 of the 5 patients were from patients whose disease was progressing while on bortezomib, dexamethasone, and lenalidomide therapies. In agreement with these results, SL-401 blocked pDC-induced growth of dexamethasone-resistant MM cell lines. Conclusions: Our study therefore provides the basis for directly targeting pDCs or blocking the pDC-MM interaction, as well as targeting MM, in novel therapeutic strategies with SL-401 to enhance MM cytotoxicity, overcome drug-resistance, and improve patient outcome.
Quality of life (QOL) improvements for pomalidomide plus low-dose dexamethasone (POM + LoDEX) in relapsed and refractory multiple myeloma (RRMM) patients (pts) enrolled in MM-003.
Authors: Song Kevin W. , Dimopoulos Meletios A. , Weisel Katja C. , Moreau Philippe , Lacy Martha , Delforge Michel , Karlin Lionel , Goldschmidt Hartmut , Banos Anne , Rocafiguera Albert Oriol , Hudgens Stacie , Yu Zhinuan , Sternas Lars , Jacques Christian , Zaki Mohamed H. , San-Miguel Jesùs F. 
Published: March 2020

8583 Background: Poor prognosis and therapy exhaustion have been associated with reduced QOL in RRMM. In MM-003, a randomized, multicenter, open-label phase 3 trial, POM + LoDEX (n = 302) significantly improved progression-free and overall survival vs. high-dose dexamethasone (HiDEX; n = 153) in pts who failed lenalidomide (LEN) and bortezomib (BORT) and progressed on their last therapy. This analysis evaluated QOL changes in these pts. Methods: To assess pt-reported outcomes, cross-sectional and longitudinal analyses were performed. Minimal important differences for 5 clinically relevant EORTC QLQ-C30 domains (Global Health Status, Physical Functioning, Fatigue, Emotional Functioning, and Pain) were calculated as meaningful change thresholds (1 standard error of measurement) from baseline through cycle (C) 5. Time to QOL worsening was compared between arms using the Kaplan-Meier method. Results: Favorable trends were observed for POM + LoDEX vs. HiDEX in each of the 5 relevant domains. The cross-sectional analysis indicated statistically or marginally significant (P < .10) differences favoring POM + LoDEX in Global Health Status (C2, 4), Physical Function (C2, 3, 4), Emotional Function (C2, 3, 4), and Fatigue (C2) scores. Longitudinal comparisons between arms confirmed the significance of score changes for Global Health Status (C2; P = .01), Physical Functioning (C3 and 4; P = .018 and .028, respectively), Emotional Functioning (C3; P = .018), and Fatigue (C5; P = .008) for POM + LoDEX vs. HiDEX. HiDEX pts exhibited clinically meaningful worsening in Global Health Status and Physical Functioning scores vs. POM + LoDEX by C2 (P = .04) and C3 (P = .02), respectively. POM + LoDEX extended median time to meaningful worsening vs. HiDEX for Global Health Status (114 vs. 85 days, P = .05), Physical Functioning (174 vs. 106 days; P = .09), Fatigue (113 vs. 60 days; P = .02), Emotional Functioning (190 vs. 124 days; P = .04), and Pain (147 vs. 113 days; P = .2). Conclusions: In heavily pretreated pts who failed LEN and BORT, POM + LoDEX resulted in better clinical outcomes as well as improvement in clinically relevant QOL measurements over the course of treatment. Clinical trial information: NCT01311687.
MM-008 trial: Pharmacokinetics (PK) and tolerability of pomalidomide plus low-dose dexamethasone (POM plus LoDEX) in relapsed/refractory multiple myeloma (RRMM) patients with renal impairment (RI).
Authors: Matous Jeffrey , Siegel David Samuel DiCapua , Duong Hien Kim , Kasserra Claudia , Sternas Lars , Jacques Christian , Klesczewski Kenneth , Zaki Mohamed H. , Shah Jatin J. 
Published: March 2020

8585^ Background: POM + LoDEX has shown significant clinical activity in RRMM pts including those refractory to lenalidomide and bortezomib. Renal impairment is a common comorbidity for MM pts, occurring in > 40%. POM is extensively metabolized with less than 5% renally eliminated as parent drug. Thus, renal function may not substantively affect parent drug exposure. Previous POM trials excluded pts with severe renal impairment. MM-008 is a phase 1, multicenter, open-label study designed to assess the PK and safety of POM + LoDEX in RRMM pts and normal or impaired renal function. Methods: RRMM pts (≥ 1 prior therapy [Tx]) with creatinine clearance (CrCl) ≥ 60 ml/min (cohort A) or severe renal impairment (CrCl < 30 ml/min [cohort B]) not requiring dialysis were included. Cohort A received POM 4 mg and cohort B received POM 2 mg or 4 mg D1-21/28-day cycle following a standard 3 + 3 dose-escalation design. Both cohorts received DEX 40 mg (20 mg for pts aged > 75 y) D1, 8, 15, and 22. Cohort C will assess pts with severe renal impairment (CrCl < 30 ml/min) requiring dialysis (up to 14 pts planned). Pts were not permitted to enroll in more than 1 cohort. G-CSF was not permitted in cycle 1. Tx continued until progressive disease or unacceptable toxicity. Results: As of Feb 5, 2013, 11 pts have been treated (8 pts in cohort A; 3 pts in cohort B at 2 mg). Age ranged from 46-71 y (cohort A) and 57-64 (cohort B). 5 pts were aged > 65 y in cohort A (aged 66, 69 [n = 3], and 71 y); none in cohort B. 7 pts in cohort A have received > 1 cycle of Tx; 5 pts have received ≥ 3 cycles. One pt in cohort B has received > 3 cycles. All 3 pts in cohort B have completed 1 full cycle of Tx with no dose-limiting toxicities reported. Dose escalation is planned. The most common grade 3/4 adverse events (AEs) in cohort A were neutropenia (n = 3) and pneumonia (n = 2). No grade 3/4 AEs have been observed for pts in cohort B to date. POM dose reduction due to AE occurred in 2 pts (both in cohort A), all pts remain on study. PK and updated AE data will be presented at the meeting. Conclusions: MM-008 is an ongoing trial evaluating PK and safety in pts with renal impairment. Early tolerability data are encouraging. Clinical trial information: NCT01575925.