bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I/II study of carfilzomib plus melphalan-prednisone (CMP) in elderly patients with de novo multiple myeloma.
Authors: Kolb Brigitte , Hulin Cyrille , Caillot Denis , Benboubker Lotfi , Tiab Mourad , Blin Nicolas , Leleu Xavier , Roussel Murielle , Attal Michel , Facon Thierry , Moreau Philippe 
Published: March 2020

8009 Background: Melphalan-prednisone + thalidomide (MPT) or bortezomib (MPV) are approved in frontline MM patients (pts) >65 years. Both regimens demonstrated significant benefit over MP alone in terms of PFS and OS but this benefit could be hampered by the risk of peripheral neuropathy (PN). Carfilzomib (Cfz) is a novel proteasome inhibitor that has demonstrated promising activity and favorable toxicity profile, with low rates of PN. This phase I/II study was designed to determine the maximum tolerated dose (MTD) of CMP, to assess safety and evaluate efficacy of this combination in newly diagnosed MM >65. Methods: In Phase I, Cfz was the only escalating agent starting at 20 mg/m2 (level 1) with maximal planned dose 36 mg/m2 (level 3), given IV on days 1, 2, 8, 9, 22, 23, 29, 30 for nine 42-day cycles. Oral melphalan 9 mg/m² and prednisone 60mg/m² were given on days 1 to 4, for all dose levels. Based on toxicity assessment, the study was amended to add dose level 4 (Cfz 45 mg/m2). MTD determination was based on occurrence of Dose limiting toxicities (DLTs) during the first cycle only. DLTs were defined as any grade 4 hematologic toxicity or preventing administration of 2 or more of the 8 Cfz doses of the first treatment cycle except grade 4 thrombocytopenia without bleeding or grade 4 neutropenia lasting ≤ 7 days; or grade ≥ 3 febrile neutropenia; or any other grade ≥ 3 nonhematologic toxicity. Results: As of January 20th 2012, 24 pts have been enrolled in the phase I: 6 pts at level 1 (Cfz 20), 6 at level 2 (Cfz 27), 6 at level 3 (Cfz 36), and 6 at level 4 (Cfz 45). There were 2 DLTs at level 4 (fever and hypotension not related to sepsis) and the MTD was considered to be 36 mg/m². Then, 16 additional pts were included in the phase II at level 3. Overall, 40 pts have been enrolled into the phase I/II study and 26 pts are evaluable for response. The ORR was 92% including 42% at least VGPR. These results compare favorably to those achieved with MPV, MPT, MPR or lenalidomide-dex (ORR 71, 76, 80 and 85%, respectively) in the same population. Conclusions: Frontline carfilzomib (36 mg/m2) + MP is a tolerable and very effective combination in elderly MM pts. Treatment is ongoing, with updated toxicity and efficacy data to be presented at the meeting.
Evidence for rituximab (R) underdosing in subpopulations of elderly patients with DLBC: Results of the RICOVER-60 study of the DSHNHL.
Authors: Pfreundschuh Michael , Mueller Carsten , Zeynalova Samira , Held Gerhard , Poeschel Viola , Zwick Carsten , Reiser Marcel , Lengfelder Eva , Steinhauer Hjalmar B. , Limmroth Christina , Schmitz Norbert , Murawski Niels ,   German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL)
Published: March 2020

8024 Background: Gender and weight independently influence R clearance and R serum elimination half life (Mueller et al., Blood 2012). To investigate whether the differences in R pharmacokinetics translate into different outcomes, we analyzed elderly patients (pts) with different R pharmacokinetics treated in the RICOVER-60 study. Methods: 1222 elderly pts. (61-80 y) were randomized to receive 6 or 8 cycles of CHOP-14 with or without R given on days 1, 15, 29, 43, 57, 71, 85, and 99. For this study, subgroup analyses were performed for pts with faster R clearance: elderly male (vs. female) pts and elderly weighty (upper quartile: >77kg) vs. slim (lower quartile: ≤60 kg) female pts. Results: Elderly females had a slower R clearance (8.21 ml/h vs. 12.68 ml/h; p=0.003) and a prolonged R half life compared to men (t1/2ß=30.7 vs. t1/2ß=24.7 d; p=0.003). Female pts had a higher 3-year PFS (68% vs. 61%; p=0.062) and OS (74% vs. 68% p=0.086). The differences in outcome were due to a greater outcome improvement by the addition of R in females: the difference in 3-year PFS between female and male pts was 5.1% (p=0.448) in pts. receiving CHOP-14 only and 7.7% (p=0.053) when R was added. In a multivariate analysis the relative risk for progression in male compared to female patients was not significantly elevated after CHOP-14 (1.1; p=0.348), but was significantly higher after R-CHOP-14 (1.6; p=0.004). With respect to weight, addition of R resulted in a significantly improved 3-year PFS (74% vs. 49%; p=0.006) in female pts with a body weight within the lower quartile (≤60 kg) who have an R serum half life of >38.1 days, while there was no improvement by the addition of R (72% vs. 71%; p=0.816) in female pts. with a body weight within the upper quartile (>77kg), who have a serum half life of <29.3 days. Conclusions: The reduced benefit of adding R to CHOP in elderly DLBCL pts. with a shorter rituximab serum half life (and hence lower serum levels) suggests that the respective subpopulations (males and weighty females) are underdosed when R is dosed 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 pts.
Outcome of elderly DLBCL patients with 6xCHOP-14 and 8 rituximab (R) applications given over an extended period (SMARTE-R-CHOP-14 trial of the DSHNHL).
Authors: Murawski Niels , Held Gerhard , Zeynalova Samira , Mueller Carsten , Poeschel Viola , Viardot Andreas , Haenel Mathias , Keller Ulrich , Reiser Marcel , Ziepert Marita , Schmitz Norbert , Pfreundschuh Michael ,   German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL)
Published: March 2020

8025 Background: 6xCHOP-14 with 8xR given over an extended period improved 3-year EFS (67% vs. 54%; p=0.030) and OS (80% vs. 67%, p=0.034) of poor-prognosis patients (IPI=3-5) in the SMARTE-R trial compared to the RICOVER-60 trial where patients received 8xR every 2 weeks. Because we had recently shown (Mueller et al., Blood 2012) that elderly male patients have a faster R clearance (12.68 ml/h vs. 8.21 ml/h; p=0.003) and shorter serum elimination half life (t1/2ß=24.7 vs. t1/2ß=30.7 days; p=0.003) than females, we analyzed whether these differences translated into different outcomes by comparing the results achieved by elderly female and male patients in the RICOVER-60 and SMARTE-R trials. Methods: In SMARTE-R, 189 evaluable elderly (61-80 y) pts. with DLBCL received 6 cycles of 2-weekly CHOP-14 combined with 8xR on days -4, -1, 10, 29, 57, 99, 155, and 239. The primary endpoint was event-free survival (EFS). 306 pts treated within the RICOVER-60 trial with 6xCHOP-14 + 8 R given on days 1, 15, 29, 43, 57, 71, 85 and 99 served as controls. Results: The 3-year EFS of 51 poor-prognosis male patients in SMARTE-R was 67% compared to 47% of 66 poor-prognosis male patients treated in RICOVER-60 (p=0.037); the respective figures were 71% vs. 53% (p=0.051) for PFS and 80% vs. 60% (p=0.027) for OS. In contrast, female poor-risk patients had only a small benefit from the extended rituximab exposure in SMARTE-R (n=48) compared to RICOVER-60 (n=57): 67% vs. 61% (p=0.354) for EFS; 71% vs. 67% (p=0.489) for PFS; and 80% vs. 76% (p=0.528) for OS. Conclusions: Elderly male patients with poor-prognosis DLBCL who have a faster R clearance and shorter R serum elimination half life than female patients, benefit significantly from the longer R exposure in SMARTE-R with a gain of 20% in 3-year OS, while the outcome of female patients was only slightly improved. Even though R maintenance has failed to demonstrate any benefit in the primary treatment of DLBCL to date, these results underline the importance of a minimum exposure time of R in order to exploit its full therapeutic potential in DLBCL. Supported by Deutsche Krebshilfe.
Interim analysis of the largest prospective trial to date in adult CD20-positive post-transplant lymphoproliferative disorder (PTLD): Introducing risk-stratified sequential treatment (RSST).
Authors: Trappe Ralf Ulrich , Dierickx Daan , Reinke Petra , Neuhaus Ruth , Morschhauser Franck , Zaucha Jan M. , Mollee Peter , Zimmermann Heiner , Dreyling Martin H. , Duehrsen Ulrich , Verhoef Gregor E.G. , Lehmkuhl Hans , Subklewe Marion , Huettmann Andreas , Tousseyn Thomas , Tarella Corrado , Leblond Veronique , Anagnostopoulos Ioannis , Riess Hanno , Choquet Sylvain ,   German PTLD Study Group and European PTLD Network
Published: March 2020

8030 Background: The prospective, multicenter international phase II PTLD-1 trial of sequential treatment (ST, 4 cycles of weekly rituximab followed by 4 cycles of CHOP-21 + G-CSF) in adult CD20-positive PTLD demonstrated excellent efficacy (90% overall response rate, ORR) and safety (11% treatment-related mortality, TRM). As the response to rituximab predicted overall survival (OS), the trial was amended in 2007 introducing risk-stratified sequential treatment (RSST) according to the response to rituximab (NCT00590447). Methods: Following rituximab on days 1, 8, 15 and 22, RSST consisted of 4 3-weekly courses of rituximab monotherapy for patients (pts) in complete remission (CR, low risk) while all others (high risk) received 4 cycles of R-CHOP-21 + G-CSF. Key exclusion criteria were CNS involvement, HIV infection, severe organ dysfunction not related to PTLD, and ECOG > 2. Primary endpoint was ORR. This is an analysis of the first 91 patients treated with RSST. Results: 79/91 pts had monomorphic, 12 polymorphic PTLD. 41/91 pts were kidney, 27 liver, 12 heart, 7 lung or heart+lung, 3 heart+kidney and 1 kidney+pancreas transplant recipients. Median age at diagnosis was 60 years (range 20-82). 73/91 pts had late PTLD and 39/85 PTLDs were EBV-associated. 1 pt died before initiation of treatment; 5 pts discontinued treatment after 4 cycles rituximab. TRM of RSST was 7/90 (8%) including 5 deaths with unknown remission status. ORR was thus 74/80 (93%, 95%CI: 84-97%; CR: 62/80 [78%]). 24/90 pts (27%) achieved CR with 4 cycles of rituximab. After a median follow up of >3 years, relapse rate in low risk pts was not increased by rituximab consolidation in RSST compared to CHOP consolidation in ST (3/23 vs. 5/14, p=0.104]). In patients in PD after rituximab, R-CHOP was more effective than CHOP in achieving CR (15/23 vs. 3/11, p=0.038). OS at 3 years was higher with RSST (70%, 95% CI: 60-82%) compared to ST (61%, 95%CI 49-72%) but this difference was not significant. Conclusions: With RSST 27% of pts were classified as low risk and achieved durable tumor control without chemotherapy while R-CHOP seems more efficient than CHOP in in high risk patients.
Impact of t (11;14) on the outcome of autologous hematopoietic cell transplantation (Auto-HCT) in multiple myeloma.
Authors: Sasaki Koji , Lu Gary , Hosing Chitra , Popat Uday R. , Ahmed Sairah , Shah Nina , Bashir Qaiser , Dinh Yvonne , Orlowski Robert Z. , Champlin Richard E. , Qazilbash Muzaffar 
Published: March 2020

8040 Background: Approximately 15-20% of patients with multiple myeloma (MM) present with t(11;14)(q13;q32) involving IgH and CCND1-XT genes. In this study, we report the impact of the t(11;14) on the outcome of patients with MM. Methods: We performed a retrospective chart review on patients with MM who underwent high-dose chemotherapy followed by auto-HCT at the M.D. Anderson Cancer Center between 2/2000 and 8/2010, and had conventional cytogenetic (CC) or fluorescent in situ hybridization (FISH) results available before transplant. The primary objective was to compare the progression free survival (PFS) and overall survival (OS) of patients with t(11;14) to patients without chromosomal abnormalities. Results: CC or FISH studies were available for 1239 patients: 863 normal, 28 with t(11;14), 348 with other abnormalities. Concurrent high-risk abnormalities on CC or FISH were seen in 15/28 patients with t(11;14): del(13q) in 11 , del(17p) in 3, and t(14;16)(q32;q23) in 1. Induction treatment in patients with t(11;14) was: bortezomib + dexamethasone +/- thalidomide/lenalidomide : 15 (53%), thalidomide or lenalidomide + dexamethasone: 11 (39%), others 2 (8%); they received auto-HCT after a median of one line (1-7) of therapy. Median follow up in surviving patients was 39 months. There was no significant difference in median time from diagnosis to auto-HCT from diagnosis (6.9 vs. 7.7 months, p=1.0), disease status at auto HCT (>PR1: 82 vs. 76%, <PR1: 7 vs. 11%, relapsed 10 vs. 13%), complete remission (CR: 21% vs. 32%; p=0.30), very good partial remission (VGPR: 29% vs. 21%; p=0.23) or overall response (75% vs. 85%; p=0.18) between patients with t(11;14) and normal karyotype. Median PFS in patients with t(11;14) and normal karyotype was 15.7 months and 35.9 months, respectively (p=0.017). Median OS in patients with t(11;14) and normal karyotype was 51.4 months and 88.4 months, respectively (p=0.03). There was no difference in PFS (p=0.25) or OS (p=0.71) in patients with t(11;14), with or without other high-risk chromosomal abnormalities. Conclusions: In this large single center study with a long follow up, we demonstrated that t(11;14) in MM is associated with a shorter PFS and OS in the context of auto-HCT.
Biweekly regimen of nonpegylated liposomal doxorubicin with cyclophosphamide, vincristine, and prednisone plus rituximab (R-COMP-14) as primary treatment for diffuse large B-cell lymphoma (DLBCL): Long-term follow-up of a phase II study.
Authors: Herrero Joaquin , Gómez-Codina Jose , Provencio Mariano , Rueda Antonio , Sabin Pilar , Llanos Marta , Lobo Francisco , Vicente David , Garcia Arroyo Francisco Ramon ,   Grupo Oncologico para el estudio y Tratamiento de los Linfomas (GOTEL)
Published: March 2020

8062 Background: To evaluate the efficacy and toxicity of dose-dense biweekly schedule of (R-COMP-14) in patients newly diagnosed of agrressive diffuse B cell lymphomas (DLBCL). Methods: In this single-arm, open-label, multicenter trial, 60 pts were included between 2004 to 2008. Received rituximab (375 mg/m2) D1 + cyclophosphamide (750 mg/m2)D1 + vincristine (1.4 mg/m2; max. 2 mg)D1 + prednisone (100 mg/d D1 and D5) and non-pegylated liposomal doxorubicin (50 mg/m2) every two weeks. Response was assessed at cycle 3, and patients with complete or partial response received 5 additional courses. Granulocyte colony-stimulating factor (G-CSF). Pegfilgrastim was administered on day 2. The primary efficacy endpoint was (CR) and objective response rate (ORR). Survival follow-up data were updated. Results: 59 evaluable patients with a median age of 50 years (21-65) were analyzed. Clinical Characteristics: 22 Pts stage I-II (aaIPI≥1 (37%), 17 (29%) stage III, and 19 (32%) in stage IV. aaIPI=1 41(67%), aaIPI2/3= 18(33%).LVEF basal: 65,5[50-93]. Extra-nodal disease: 42%. B symptoms: 44.1%. The mean calculated dose intensities of cyclophosphamide, non-pegylated liposomal doxorubicin, vincristine and rituximab were 98,7%, 98,7%, 76,1% and 98,3% respectively. Among 60 eligible patients (96,7% completed six cycles and 74,4% completed all eight cycles. ORR was 81%, and CR rate of 54,2%. IC 95% [40,7-67,8]. The main toxicity was neutropenia Gr=III-IV/ and febrile neutropenia in 20% of patients. Neurotoxicity Gr=III-IV in 3,4%. No cardiac toxicity Gr: III-IV was reported. No toxic deaths. After a median follow-up of 25-64m(44m) the 5-year overall survival (OS), event-free survival, (EFS) and disease free survival (DFS) were 80%, 67%, and 77% respectively. Forty two patients (71%) had (<60 y) and med. OS(p=0,017) and med EFS(p=0,014) was 72,3% and 68,1 in aaIPI=1 and 50,4% and 33,8 in aaIPI>1. Conclusions: Dose dense R-COMP-14 is an effective regimen in patients with (DLBCL) comparable o R- CHOP-14. Good tolerability profile with no Gr: III-IV cardiac toxicity or reduction of LVEF.
Efficacy of ocaratuzumab (AME-133v) in relapsed follicular lymphoma patients refractory to prior rituximab.
Authors: Wayne Jennifer L. , Ganjoo Kristen N. , Pohlman Brad L. , De Vos Sven , Flinn Ian W. , Dang Nam H. , Mapara Markus Y. , Smith Mitchell R. , O'Reilly Adrienne M. , Marulappa Shashidhara Y. , Jain Vinay Kumar 
Published: March 2020

8081 Background: Ocaratzumab, previously known as AME-133v, is a humanized next-generation anti-CD20 monoclonal antibody. It has been optimized with a 13 to 20-fold increase in binding affinity to CD20 and improved binding to the low-affinity (F/F and F/V) polymorphisms of FcγRIIIa (CD16), which are thought to predict lower response rates and shorter duration of responses to rituximab. Methods: In a phase I dose escalation study in relapsed follicular lymphoma (FL) patients, ocaratuzumab was well-tolerated at doses up to 375 mg/m2 (Forero-Torres et al. CCR 2012). In a follow-on phase II trial, 44 patients with relapsed FL following prior rituximab and the low-affinity FcγRIIIa polymorphism (F-carriers) received 375 mg/m2 of ocaratuzumab weekly for 4 doses. In this study, overall response rate (ORR) was 36% and median progression free survival (PFS) was 91 weeks (Ganjoo et al. Haematologica 2011). Results: Amongst the 56 patients receiving 100 and 375 mg/m2 of ocaratuzumab, 8 patients had a previous time to progression of ≤ 180 days following their last rituximab treatment. These patients had a median of 2 prior rituximab treatments, (range 1-6 treatments), and median PFS following last treatment of 159 days. Five of the 8 patients showed a longer PFS after ocaratuzumab administration, compared with last rituximab treatment. All 5 patients expressed the homozygous low-affinity genotype of FcγRIIIa (F/F). At the time of study closure, 3 of the patients were still in remission (indicated by * in the table). Conclusions: This retrospective analysis suggests that ocaratuzumab may be non-cross-resistant to rituximab in patients with the low-affinity FcγRIIIa polymorphism. Prolonged PFS in selected patients following ocaratuzumab suggests that the increased binding affinity to CD16 and improved antibody-dependent cell-mediated cytotoxicity (ADCC) of this antibody is clinically relevant. As a single agent, ocaratuzumab may provide prolonged clinical benefit in relapsed FL patients and a clinical trial comparing ocaratuzumab to rituximab is in preparation. [Table: see text]
Effect of matrix metallopeptidase 13 (MMP13) on multiple myeloma (MM) cells, osteoclast (OCL) activity, and bone resorption.
Authors: Fu Jing , Li Shirong , Feng Rentian , Jin Mei Hua , Sabeh Farideh , Weiss Stephen , Lentzsch Suzanne 
Published: March 2020

8099 Background: MM cells produce OCL-activating factors that induce excessive bone resorption resulting in lytic lesions. The role of MMPs in invasion/progression of solid tumors is well-known, but its function in MM has not been well elucidated. Our group has shown that MMP13 is highly expressed in primary MM cells and in sera of MM patients. Levels of MMP13 significantly correlate with the extent of bone disease. MMP13 is induced by IL-6 via AP-1 activation in MM cells and enhances fusion of OCL precursors resulting in excessive bone resorption. OCL formation using MNCs of mmp-13-/- mice resulted in a fusion defect, significantly decreased OCL size and activity, which could be reversed by exogenous MMP13 (ASH 2009, IMW 2011). Methods: Methods will be presented in the Results section. Results: RT-PCR and western blotting revealed that IL-6 treatment of MM cells induced MMP13 transcription (30-fold) and secretion (>1000-fold). Protein expression of the AP-1 members c-Jun and c-Fos was induced by IL-6, which correlated with MMP13 upregulation. Our data further indicate that the catalytic activity of MMP13 is not required to enhance OCL formation and bone resorption. To prove this, we generated the MMP13 activity-dead mutation MMP13-E223A construct by site-directed mutagenesis PCR-based cloning. The mutated protein was overexpressed in HEK293 cells and purified from the supernatant to confirm whether loss of catalytic activity blocks MMP13 function. To further investigate the in vivo role of MMP13 in MM bone disease, MMP13 expression was knocked down (KD) in murine 5TGM1-MM cells by pKLO. 1 puro lentiviral infection containing sh-RNA targeting mouse MMP13 sequence. MMP13-KD 5TGM1-MM cells or WT-5TGM1-MM cells were intratibially injected into RAG2-/- mice. Development of lytic bone lesions are monitored by micro-QCT and data will be available at the time of presentation. Conclusions: Our data suggest that MMP13, secreted by MM cells, plays a critical role in the development of lytic lesions. Targeting MMP13 represents a promising approach to treat or to prevent bone disease in MM.
Patterns of nonhematologic malignancies in a population of African American veterans with monoclonal gammopathy of unknown significance (MGUS).
Authors: Ghanem Hady , Namburi Swathi , Rivera Gabriel , Amdur Richard , Schechter Geraldine P. 
Published: March 2020

8103 Background: Monoclonal Gammopathy of Unknown Significance (MGUS) is characterized by the presence of a monoclonal immunoglobulin in the serum or the urine with no evidence of hematologic malignancy. A possible relationship between MGUS and increased incidence of NHM has been suggested in Caucasian populations. However, data in African Americans with MGUS are lacking. Methods: Non-MGUS controls were selected randomly from patients who did not have a paraprotein detected on electrophoresis (NMGUS) and were matched 2-to-1 to MGUS cases. Descriptive statistics and comparisons are presented to compare MGUS and NMGUS groups. Results: 492 male patients with MGUS patients were matched with 984 male NMGUS patients. 451 patients had abnormal serum protein studies (91.6%) and 40 had light chain disease (8.4%). Median age at diagnosis of MGUS was 68 years (28-81). 144 MGUS patients (29.2%) and 296 NMGUS patients (30%) had 1 or more NHM. The median age of diagnosis of 1st NHM was 70 (25-94) in the MGUS group and 68.4 in the NMGUS group (34.5-94.4). 19 MGUS patients (3.8%) and 27 NMGUS patients had 2 different types of NHM (2.7%). 1 MGUS patient (0.2%) and 3 NMGUS patients (0.3%) had 3 NHM. 57 patients had MGUS before NHM (11.5%) and 69 patients were diagnosed with MGUS after the diagnosis of NHM (14%), and median differences between diagnosis of MGUS and 1st NHM were 4 years (1-12 years) and 5 years (1-38 years) respectively. Types of NHM were comparable, and prostate cancer was the most prevalent NHM in both groups (15% of MGUS patients and 17% of NMGUS patients). Median time of follow up was 49.3 months for MGUS patients and 35.2 months for NMGUS patients 140 of the MGUS patients (28.4%) and 214 non-MGUS patients (21.75%) had died at data cut-off. Conclusions: Based on these observational data, prevalence and types of NHM appear to be comparable in MGUS and NMGUS African American patients. All cause mortality appears to be higher for NHM patients if they had MGUS. This pattern will need to be verified prospectively in a larger group of patients.