bluuebunny/crossref_metadata_2025_split huggingface dataset:
Different safety profiles of first-line bendamustine-rituximab (BR), R-CHOP, and R-CVP in an open-label, randomized study of indolent non-Hodgkin lymphoma (NHL) and mantle cell lymphoma (MCL): The BRIGHT study.
Authors: MacDonald David , van der Jagt Richard , Burke John M. , Kahl Brad S. , Wood Peter , Hawkins Tim E. , Hertzberg Mark , Kwan Yiu-Lam , Simpson David , Craig Michael , Kolibaba Kathryn S. , Issa Samar , Clementi Regina , Hallman Doreen M. , Munteanu Mihaela C. , Chen Ling , Flinn Ian 
Published: March 2020

8565 Background: The BRIGHT study demonstrated that first-line BR was non-inferior to R-CHOP/R-CVP in terms of complete remission rate in indolent NHL and MCL. This is the first detailed analysis of the safety and tolerability of the study regimens. Methods: Patients were preselected for R-CHOP or R-CVP, and then randomized to 6-8 cycles of BR (28-d cycle) or the preselected standard regimen (21-d cycles). BR dosing was bendamustine 90 mg/m2/d as a 30-min infusion on days 1 and 2 plus rituximab 375 mg/m2given before bendamustine on day 1. Colony stimulating factors (CSFs) and antiemetics were given per local standards. Results: In patients preselected for R-CHOP, 103 received BR and 98 R-CHOP. In patients preselected for R-CVP, 118 received BR and 116 R-CVP. For all regimens, ≥ 88% of patients received the planned 6 cycles. Main differences in adverse events (AEs), all grades, are shown in the Table. Incidence of grade 3/4 AEs was 69% for R-CHOP vs 56% BR, and 50% for R-CVP vs 56% BR. Grade 3/4 drug hypersensitivity, neuropathy, and rash were infrequent. Antiemetic use was similar between groups except use of aprepitant as an adjunct to 5-HT3 antagonists was higher with R-CHOP (23% [19% in cycle 1]) than BR (9% [2%]) or R-CVP (3% [2%]). CSF use was higher with R-CHOP (61%) than BR (29%) or R-CVP (27%). Analyses of event prevalence over the treatment period and by region will also be presented. Conclusions: BR, R-CHOP, and R-CVP have significantly distinct AE profiles. More nausea, vomiting, and hypersensitivity occurred with BR while more constipation, neuropathy, and alopecia occurred with RECHOP/R-CVP. Support: Teva BPP R&D, Inc. Clinical trial information: NCT00877006. [Table: see text]
Differential impact of sex in young and elderly patients with DLBC: Correlation with rituximab (R) pharmacokinetics.
Authors: Pfreundschuh Michael , Mueller Carsten , Zeynalova Samira , Held Gerhard , Poeschel Viola , Zwick Carsten , Rixecker Tanja , Schmitz Norbert , Murawski Niels ,   German Non-Hodgkin Lymphoma Study Group (DSHNHL)
Published: March 2020

8570 Background: Sex and weight independently influence R clearance in elderly DLBCL pts (Mueller et al., Blood 2012). Methods: We analyzed the impact of sex on R pharmacokinetics and outcome of 1,222 elderly pts of the RICOVER-60, 823 young (18 to 60 years) aaIPI=0,1 pts of the MInT, and 375 aaIPI=2,3 pts of the Mega-CHOEP trials. R pharmacokinetics was determined by ELISA in 33 young and 49 elderly patients. Population pharmacokinetic modeling was performed with nonlinear mixed-effect modeling software (NONMEM VI). Results: R clearance was independent of tumor mass (IPI), but weakly correlated (0.2, R2linear=0.045) with increasing age in male, and moderately inversely correlated (-0.5, R2linear=0.207) with age in female DLBCL patients, resulting in similar R clearances in young female and male patients (9.88 vs. 10.38 ml/h; p=0.238), but a significantly faster R clearance in elderly males compared to females (10.50 vs 8.25 ml/h; p=0.006). In the RICOVER-60 trial, elderly females had a higher 3-year PFS (68% vs. 61%) and OS (74% vs. 68%) than male pts. due to a greater outcome improvement by the addition of R in females. In a multivariable analysis adjusting for IPI, the hazard for progression in male compared to female pts. was not significantly increased after CHOP (HR=1.1; p=0.348), but was significantly higher after R-CHOP (OR=1.6; p=0.004). In contrast, young males treated in the MInT and Mega-CHOEP trials benefitted as much as females from the addition of rituximab, with a similar hazard for male pts. after CHOP and R-CHOP (HR=1.2) with no significant difference to female patients (HRPFS=1.2, p=0.552; HROS=1.0; p=0.898). Conclusions: While no differences in R clearance and benefit from rituximab were found in young female compared to male patients, the reduced benefit of adding R to CHOP in elderly male DLBCL pts. who have a shorter rituximab serum half life and hence lower serum levels suggests that this subpopulation is suboptimally dosed when R is given based on body surface area at 375 mg/m2. Ongoing studies of the DSHNHL investigate whether higher R doses for pts. with a shorter R serum half life can improve the outcome of the respective patients. Supported by Deutsche Krebshilfe and Roche.
Prognostic value of PET/CT scans on early chemo-cycle in diffuse large B-cell lymphoma: Prospective study.
Authors: Huang He , Lin Jia Tian , Guo Cheng-cheng , Shrestha Dr.Prem Raj , Liu Tingzhi , Tian Ying , Liang Chao Yong , Li Xue Ying , Zhang Mengping , Hong Huang Ming , Lin Tongyu 
Published: March 2020

8573 Background: To evaluate the prognostic value of positron emission tomography/computed tomography (PET/CT) scan on early chemo-cycle in newly-diagnosed diffuse large B cell lymphoma (DLBCL) patients. Also to distinguish the variation in outcome of early-responder (ER), late-responder (LR) and non-responder (NR). Methods: Newly diagnosed 149 DLBCL patients were treated with R-CHOP regimen for 2-8 cycles (mean: 5.49 cycles) in our center (Feb 2008–Jan 2013). The median age at diagnosis was 47 years (range, 17-80 years); 78 males (52.35%) and 71 females (47.65%); 63 stage I-II (42.3%) and 86 stage III-IV (57.7%); 45 B symptoms (30.2%); 90 IPI 1-2 scores (60.4%) and 59 IPI 3-5 scores (39.6%). All the patients with bulky disease, extranodal invasions and residual disease underwent baseline PET/CT scan and repeated after every 2 chemo-cycles. Results: After 2 subsequent cycles, the PET/CT evaluation showed complete remission (CR) in 82/149 (early-responder, 55.03%), and non-CR in 67/149 (44.97%) patients. Among 67 non-CR patients, 39 achieved CR (late-responder), 21 partial remission (PR), 3 stable disease (SD) and 4 progressive diseases (PD) (non-responder). After a follow-up of median 618 days (range 45-1816 days), the 1st and 2nd year progression-free survival (PFS) rate in NR were significantly different from ER (61.3% vs 92.6% , 52.5% vs 86.6%, p < 0.001) and LR (61.3% vs 91.6%, 52.5% vs 75.9%, p=0.023), and no significant differences were found between ER and LR (p=0.329). The 1st and 2nd year overall survival (OS) were 98.5%, 91.9% in ER; 97.3%, 97.3% in LR and 89.8%, 60.0% in NR respectively with significant differences between NR and ER (p=0.005), between NR and LR (p=0.008), but there was no statistically significant difference between ER and LR (p=0.558). The 1st and 2nd year disease free survival (DFS) rate did not differ between ER and LR (92.6% vs 84.6%, 86.9% vs 76.7%, p=0.250). Conclusions: The PET/CT findings in early chemo-cycle response might predict PFS advantage, but the difference of DFS and OS between ER and LR were not so obvious, and NR showed poor prognosis according to our current data. Clinical trial information: CTR-TRC-11001687.
Long-term safety and efficacy of pomalidomide (POM) with or without low-dose dexamethasone (LoDEX) in relapsed and refractory multiple myeloma (RRMM) patients enrolled in the MM-002 phase II trial.
Authors: Siegel David Samuel DiCapua , Richardson Paul Gerard Guy , Vij Ravi , Hofmeister Craig C. , Baz Rachid C. , Jagannath Sundar , Chen Christine , Lonial Sagar , Jakubowiak Andrzej J. , Bahlis Nizar J. , Song Kevin W. , Belch Andrew , Raje Noopur S. , Shustik Chaim , Lentzsch Suzanne , Chen Min , Zaki Mohamed H. , Anderson Kenneth Carl 
Published: March 2020

8588 Background: MM-002 is a randomized, open-label, multicenter phase II trial evaluating the safety and efficacy of POM with or without LoDEX in advanced RRMM pts. Methods: Pts who had received ≥ 2 prior therapies, including lenalidomide (LEN) and bortezomib (BORT), and were refractory to their last treatment were randomized to POM+LoDEX (POM 4 mg/day, days 1–21 of a 28-day cycle; LoDEX 40 mg/week) or POM alone. End points included progression-free survival (PFS), response rate (according to EBMT criteria and investigator assessment), response duration, overall survival (OS), and safety. The efficacy outcomes are based on the intent-to-treat population (POM+LoDEX, n = 113; POM, n = 108). Results: The median number of prior therapies in each group was 5 (range 1–13). In the POM+LoDEX arm, 30 (27%) pts had high-risk cytogenetics, including del(17p13) and/or t(4p16/14q32). The overall response rate (≥ partial response) was 34% and 15% with POM+LoDEX and POM, respectively, with a median duration of 8.3 (95% CI: 5.8–10.1) and 8.8 (95% CI: 5.5–11.4) mos, respectively. At least minimal response was observed in 45% and 31% of pts, respectively. Median PFS was 4.6 (95% CI: 3.6–5.5) and 2.6 (95% CI: 1.9–2.8) mos with POM+LoDEX and POM, respectively, with a median follow-up of 16.0 and 12.2 mos. Median OS was 16.5 (95% CI: 12.4–18.5) and 13.6 (95% CI: 9.6–18.1) mos, respectively. The most common treatment emergent Gr 3/4 adverse events (AEs) reported in the safety population (n = 219) were neutropenia (44%), anemia (23%), thrombocytopenia (21%), and pneumonia (18%); there were no reports of Gr 3/4 peripheral neuropathy. The incidence of deep-vein thrombosis was low (2%). AEs were managed through dose reductions or interruptions, and supportive care with G-CSF (52%), RBC transfusions (47%), and platelet transfusions (17%). Discontinuations due to AEs were 10%. Conclusions: POM with or without LoDEX is clinically effective and generally well tolerated in RRMM pts who have received multiple prior treatments, including LEN and BORT. AEs were predictable and manageable. Updated data will be presented at the meeting. Clinical trial information: NCT00833833.
Longitudinal whole body MRI (wbMRI) in monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma.
Authors: Merz Maximilian , Wagner-Gund Barbara , Neben Kai , Ho Anthony D. , Goldschmidt Hartmut , Hillengass Jens 
Published: March 2020

8590 Background: The detection of bone marrow focal lesions (FLs) by MRI at the initial work up has prognostic significance in multiple myeloma (MM), smoldering MM as well as MGUS. Currently, there are no data available on the predictive relevance of new FLs or FLs increasing in size in longitudinally performed wbMRIs for the follow-up of sMM and MGUS. Methods: We retrospectively analyzed 87 patients (sMM n=65; MGUS n=22) that received at least 2 (up to 5) wbMRIs for follow-up. The date of progression into MM requiring systemic therapy was defined as event for the analysis of progression free survival (PFS). Radiological progressive disease (rPD) was defined as the appearance of novel FLs or increase in size of preexisting FLs. Kaplan-Meier plots of PFS for patients with rPD and patients without rPD were analyzed using the log-rank test for significant differences. Results: Median follow-up was 61 months (9.8-101) with a median time between follow-up wbMRIs of 15.8 months (1-73). Progression from sMM/MGUS into MM was found in 28 patients (sMM 40%; MGUS 9%). Using wbMRI, rPD was found in 21 patients (sMM 32%; MGUS 0%). Of all patients, 76% (n=16) with rPD and 16% (n= 9) without rPD progressed into MM during the observation period. Analysis of Kaplan Meyer plots for PFS revealed a highly significant shorter PFS for patients with rPD (32 months) compared to patients with radiological stable disease in wbMRI (PFS not reached; p<0.0001). New appearance or progression of diffuse bone marrow infiltration was not associated with a shorter PFS (not reached; p>0.05). Conclusions: In our study, the appearance of novel FLs or progression of preexisting FLs was highly predictive for progression from sMM into MM requiring systemic treatment. We conclude that wbMRI is effective for the longitudinal follow-up of patients with sMM and MGUS and identifies a group of patients at risk for progression into MM.
Promotion of human multiple myeloma cell growth in vitro and bone marrow invasion in vivo by Notch receptors and the CXCR4/SDF1 axis.
Authors: Chiriva-Internati Maurizio , Mirandola Leonardo , Lazzari Elisa , Colombo Michela , Lancellotti Marialuigia , Cobos Everardo , Yu Yuefei , Figueroa Jose A. , Saadeh Charles , Wade Raymond , Zepeda Kristopher , Mer Jesse , Konala Venu , Radhi Saba , Aulakh Amardeep , Jenkins Marjorie , Jumper Cynthia A. , Alalawi Raed , Chiaramonte Raffaella 
Published: March 2020

8591 Background: Multiple myeloma (MM) originates from post-germinal center B cells, and is caused by malignant plasma cells accumulating in the bone marrow. Interactions of MM cells with the bone marrow stroma promote tumor growth, migration and drug resistance. The chemokine receptor CXCR4 and its ligand SDF1 are critical regulators of this process. MM cells frequently hyper-express CXCR4 and respond to SDF1,2 enhancing MM cell infiltration, proliferation and osteolysis. Notch receptors similarly promote MM cell growth, drug resistance and the associated osteolytic process. We hypothesized that the CXCR4/SDF1 axis mediates the effects of Notch signals in MM. Methods: We used real-time PCR, flow-cytometry, E.L.I.S.A. and chemotaxis assay to explore the effects of CXCR4 in cultured human MM cell lines after Notch inhibition or over-stimulation. Additionally, we validated our findings in a NOD/SCID murine model xenografted with human MM cells. Results: Our results show that Notch blocking reduced CXCR4 and SDF1 expression by MM cells. Further, Notch activation was required for MM cell chemotactic and proliferative response to SDF1 in vitro. We then investigated the outcome of anti-Notch treatment on human MM cells bone invasion in NOD/SCID mice. Interfering with Notch activity dramatically reduced xenografted MM cell ability to infiltrate the bone marrow, ultimately resulting in diminished tumor burden. Notably, such effect was associated with a decrease of CXCR4 expression. Conclusions: This was the first time that Notch receptors were reported to regulate the CXCR4/SDF1 axis and bone marrow invasion in human MM. These findings indicate that specific Notch-tailored therapies may effectively hamper CXCR4-mediated bone infiltration and associated lesions, and are expected to significantly improve treatment outcome and survival.
Early versus late treatment for smoldering (asymptomatic) multiple myeloma: A systematic review.
Authors: Alahamdi Mubarak Salem , Tay Jason 
Published: March 2020

8593 Background: Expectant management remains the current standard of care for patients with smoldering multiple myeloma (SMM). Recent appreciation of "high risk" smoldering myeloma and the advent of novel therapeutic agents may allow one to better tailor the timing of therapeutic interventions. Herein, we performed a systematic review of the literature, summarizing the available randomized controlled trial (RCT) evidence for treatment of SMM. Methods: Our systematic search strategy includes MEDLINE, EMBASE, Cochrane Database, and relevant bibliographies where the following search concepts were used: RCT, SMM as defined as per the IMW Criteria, and treatment. Two reviewers independently extracted data on study design, population, sample size, treatment, clinical outcomes, and trial quality, were any discrepancies were discussed and resolved. Results: We identified 7 RCTs (2 articles and 5 abstracts) representing 869 patients. Six articles compared early versus deferred treatment for SMM; 2 studies compared early Melphalan plus Prednisone (MP) versus deferred MP. 3 studies compared bisphosphonates versus abstention while one study compared lenalidomide with dexamethasone to therapeutic abstention. Further, one study compared thalidomide with zoledronate to zoledronate alone. The median age is 66. Four studies received a Jadad score of 3 while three studies received a score of 2. Allocation concealment was described in four studies. Risk of disease progression was lower in patients receiving therapy compared to abstention OR 0.5(0.38-0.68). The events that demonstrate disease progression were not clearly defined. Further, the use of combination therapy compared to a single intervention decreased the risk of progression OR 0.23(0.11-0.51). No difference in OS was noted in patients receiving therapy compared to abstention OR 0.95(0.57-1.57). Conclusions: Early treatment of SMM compared with abstention decreases the risk of disease progression. However, OS was not improved by earlier intervention. High risk SMM may benefit from early intervention. The optimal intervention(s) remains to be defined, and further studies are warranted in this understudied population.
Phase I study of TH-302, an investigational hypoxia-targeted drug, and dexamethasone in patients with relapsed/refractory multiple myeloma.
Authors: Ghobrial Irene M. , Laubach Jacob , Armand Philippe , Boswell Erica , Hanlon Courtney , Chuma Stacey , Chu Esther Dawn , Handisides Damian , Kroll Stew , Hickingbottom Barbara , Anderson Kenneth Carl , Richardson Paul Gerard Guy 
Published: March 2020

8602 Background: TH-302 is an investigational 2-nitroimidazole prodrug of the DNA alkylator Br-IPM designed to be selectively activated in hypoxia. In multiple myeloma (MM) mouse models, diseased animals demonstrate a marked expansion of areas of hypoxia in the bone marrow. TH-302 exhibited anti-tumor activity against MM in vitro and in vivo and synergism was seen when combined with bortezomib (Hu et al, Blood 2010; Chesi et al, Blood 2012). Based on these findings, a phase I/II study of TH-302 plus dexamethasone (dex) was initiated for patients (pts) with relapsed/refractory MM. Methods: Eligible pts in the study (NCT01522872) had ECOG PS ≤ 2, receipt of at least two prior therapies, and acceptable hepatorenal function and hematologic status. A standard 3+3 dose escalation design was used with a fixed oral 40 mg dose of dex and 40% dose increments of TH-302. TH-302 was administered IV with dex on days 1, 4, 8, and 11 of a 21-day cycle. The objectives were to determine DLTs and the MTD; assess the safety, tolerability and preliminary clinical activity of TH-302 plus dex; and study the relationship between hypoxia within the bone marrow and response to TH-302. Results: Eleven pts have been treated: 7M/4F with a median age 61 years (range: 53 – 86) and 6 prior therapies (range: 3 – 10). All received both bortezomib and lenalidomide/thalidomide containing regimens. TH-302 was dosed at 240 (n=5), 340 (n=4), and 480 (n=2) mg/m² for a median of 5 cycles. No DLTs were reported at 240 or 340 mg/m². Two pts treated at 480 mg/m² had DLTs of grade 3 mucositis, exceeding the definition of MTD. A dose expansion is thus ongoing at 340 mg/m2. Two patients had SAEs related to TH-302 (pneumonia). Five pts continue on study after a median of 7 cycles (range: 2–11). Nine pts have had efficacy evaluations: 2 pts with partial responses, 2 pts with minimal responses, and 5 pts with stable disease, for an overall response rate (of MR or better) of 44%. Conclusions: TH-302 can be administered at 340 mg/m2 biweekly + dex, with dose limiting mucositis seen at higher doses. Initial clinical activity has been noted with an ORR of 44% in heavily pretreated MM pts who are relapsed/refractory to both bortezomib and lenalidomide. Clinical trial information: NCT01522872.
Implications of rapidity of response to initial therapy in multiple myeloma.
Authors: Ghimire Krishna Bilas , Rajkumar Vincent , Dispenzieri Angela , Lacy Martha , Gertz Morie , Buadi Francis , Dingli David , Hayman Suzanne R. , Leung Nelson , Russell Stephen , Lust John Anthony , Zeldenrust Steven R. , Lin Yi , Kapoor Prashant , McCurdy Arleigh Robertson , Kyle Robert A. , Kumar Shaji 
Published: March 2020

8606 Background: The rapidity of response to initial therapy in multiple myeloma (MM) depends on a variety of factors. There is limited data on its implications on long term outcomes in patients (pts) with newly diagnosed MM. Methods: We retrospectively examined the outcomes in a cohort of 454 pts with newly diagnosed MM between Jan 2000- Dec 2011 undergoing induction therapy. Results: The median age at diagnosis was 66 yrs (29-92). Pts had measurable serum M-spike (>= 1 g/dL), dFLC (>=10 mg/dl) or 24 hour urinary M protein excretion (UrM; >=200 mg) in 70, 63 and 39% respectively. We first examined the relationship between the response to first cycle of therapy and overall survival (OS). We divided pts into quartiles based on their % reduction in the serum M spike, dFLC or UrM. The median OS (Table) was poorest for pts with the least reduction of serum M protein (P<0.001) and of dFLC. The cutoffs for Q1 was 25, 40and 40% decrease for serum M spike, dFLC and 24 hr UrM respectively. Among various baseline characteristics only higher age was predictive of a poor (Q1) response. Given the trend toward worse OS among the Q 4 group (maximum decrease in serum M spike), we examined the relationship to cytogenetic risk. Among 232 pts with FISH data available, proportion of pts with high-risk disease was 27, 12, 22 and 31% respectively in quartiles 1 - 4). In a multivariate analysis, quartile 1 and 4 of serum M-protein response and the high-risk FISH were independent risk factors associated inferior OS. Conclusions: Both shallow and very deep response to therapy in cycle 1 is a strong indicator of eventual disease outcome and should be considered as marker of high-risk disease, likely through different mechanisms. For the shallow responders, prospective trials should assess if a change in therapeutic management will alter the outcome of these pts. The rapid deep responders also appear represent a different high-risk biology, emphasizing the fact that pts with high-risk disease often have excellent initial responses, but poor long term outcomes. [Table: see text]