bluuebunny/crossref_metadata_2025_split huggingface dataset:
A pooled analysis of 1,144 patients with HIV-associated lymphoma: Assessment of lymphoma-, HIV-, and treatment-specific factors on clinical outcomes.
Authors: Barta Stefan K. , Xue Xiaonan , Tamari Roni , Lee Jeanette Y , Mounier Nicolas , Kaplan Lawrence D. , Ribera Josep-Maria , Spina Michele , Weiss Rudolf , Galicier Lionel , Boue Francois , Wilson Wyndham Hopkins , Wyen Christoph , Navarro Jose-Tomas , Dunleavy Kieron , Little Richard F. , Ratner Lee , Morgades Mireia , Garcia Olga , Sparano Joseph A. 
Published: March 2020

8005 Background: Non-Hodgkin Lymphoma (NHL) remains the most common malignancy in patients with HIV. Outcomes have significantly improved over the last decade, but there is no accepted consensus regarding the optimal initial therapeutic approach. Our objective was to assess the effects of clinical factors on response and survival. Methods: We performed a systematic review to search for prospective clinical phase II or III trials that assessed therapeutic interventions for HIV-associated NHL and assembled individual patient data from 16 trials published between 2000 and 2011 including 1144 patients (median N=62/trial, range 17-195). Treatment factors included type of chemotherapy (CHOP, N=642; EPOCH, N=178; CDE, N=191; intensive regimens, N=155) and rituximab use (N=542). Endpoints included complete response (CR), progression-free survival (PFS), and overall survival (OS). We used logistic regression and Cox proportional hazard models adjusted for age, sex, age-adjusted International Prognostic Index (IPI), baseline CD4 count, baseline HIV viral load, use of concurrent antiretroviral therapy, and histology. Odds ratios (OR) > 1 for CR denote improved CR, and hazard ratios (HR) < 1 indicate reduced risk of progression or death. Results: Among the lymphoma- and HIV-specific covariates evaluated, only a higher IPI score was associated with inferior CR rate, PFS and OS (p<0.001). Rituximab was associated with a higher CR rate (OR 1.75; p=0.017), better PFS (HR 0.39, p<0.001) and OS (HR 0.39, p<0.001); patients with a higher baseline CD4 count benefited more from rituximab (HR for OS 0.57 if baseline CD4 count ≥100/ul vs. <100/ul; p<0.001). For all histologies, initial therapy with the EPOCH regimen resulted in a better CR rate (OR 1.78, p=0.039), PFS (HR 0.61, p=0.032) and OS (HR 0.47, p<0.001) when compared to CHOP. Conclusions: In this pooled analysis including 1144 patients with HIV-associated NHL, the addition of rituximab to chemotherapy was associated with significantly improved CR rate, PFS, and OS, specifically for patients with a baseline CD4 count ≥100/uL. Treatment with infusional EPOCH was also more effective than CHOP.
R-CVP versus R-CHOP versus R-FM as first-line therapy for advanced-stage follicular lymphoma: Final results of FOLL05 trial from the Fondazione Italiana Linfomi (FIL).
Authors: Federico Massimo , Luminari Stefano , Dondi Alessandra , Sacchi Stefano , Franco Vito , Pileri Stefano , Lombardo Marco , Rossi Giuseppe , Arcaini Luca , Chisesi Teodoro , Petrini Mario , Galimberti Sara , Vitolo Umberto , Di Raimondo Francesco , Rigacci Luigi , Carella Angelo Michele , Angrilli Francesco , Freilone Roberto , Ferreri Andres , Brugiatelli Maura 
Published: March 2020

8006 Background: The optimal chemotherapy regimen for patients with advanced, active follicular lymphoma (FL) has not been established yet. We conducted a randomized trial comparing R-CVP with R-CHOP and R-FM. Methods: Previously untreated patients with advanced FL were randomly assigned to receive 8 doses of rituximab associated to 8 cycles of CVP, or 6 cycles of CHOP or FM (fludarabine 25 mg/m2 day 1-3, mitoxantrone 10 mg/m2 day 1). No maintenance therapy was allowed. The principal study end point was Time to Treatment Failure (TTF). Events in TTF were failure of induction therapy, progressive or relapse disease and death from any causes. In order to show a hazard ratio between each experimental arms and standard arm of 0.53 we planned to accrue 534 patients (178 per arm) with 4 years of accrual and 1 year of follow-up. Statistical tests were two-sided with an alpha error of 0.05, adjusted by Bonferroni for multiple arm comparison, and power of 90%. Results: Between March 2006 and September 2010, 534 patients were enrolled; 30 were subsequently excluded due to violation of inclusion criteria. Median patient age was 56 years (range 30-75), 63% of patients had stage IV disease, 37% had 3-5 FLIPI and 27% 3-5 FLIPI2 scores. At the end of induction treatment the overall response rate (CR+ PR) for the whole group was 91% (p=0.247). After a median follow-up of 34 months 208 events for TTF were recorded; 3-year TTF was 46%, 64% and 61% for patients treated with R-CVP, R-CHOP and R-FM respectively (R-CHOP vs R-CVP p=0.007; R-FM vs R-CVP p=0.021; R-FM vs R-CHOP p=0.969). The 3-year overall survival rate (OS) was 98%, 95% and 93% for R-CVP, R-CHOP and R-FM group, respectively (P=NS). Patients treated with R-FM had a higher rate of g III-IV neutropenia (64% vs 28% R-CVP, p<0.001; and vs 50% R-CHOP, p=0.015). During follow-up second malignancies were registered as late events in 23 patients (2%, 3% and 8% in R-CVP, R-CHOP and R-FM, respectively). Conclusions: This trial showed that R-CVP was associated with an inferior 3-year TTF and PFS compared with R-FM and R-CHOP. OS was similar among study arms but R-FM showed a higher rate of secondary tumors.
A phase I/II trial of cyclophosphamide, carfilzomib, thalidomide, and dexamethasone (CYCLONE) in patients with newly diagnosed multiple myeloma.
Authors: Mikhael Joseph , Reeder Craig B. , Libby Edward N. , Costa Luciano , Mayo Angela , Bergsagel P. Leif , Buadi Francis , Pirooz Nicholas , Lubben Jade Marie , Dueck Amylou C. , Stewart A. Keith 
Published: March 2020

8010 Background: Carfilzomib is a proteasome inhibitor that irreversibly binds its target with favorable toxicity profile that has shown significant activity in relapsed multiple myeloma (MM). Here we used carfilzomib as the center of a 4 drug induction regimen designed for MM patients pre stem cell transplant (SCT). Methods: We conducted a phase I safety run in 6 patients with no DLT observed before expanding to phase II. The phase II regimen is shown below. Treatment was for 4 cycles with expected SCT post induction. For the phase II portion of this trial, the primary endpoint is the proportion of patients who have ≥ very good partial response to treatment. All patients received herpes zoster prophylaxis and ASA daily. Results: Twenty seven patients were enrolled. Median age was 65 (range 27-74). ORR for evaluable patients (n=17) at phase II dosing is 100%: CR 35%, VGPR 48%, PR 18% after 4 cycles of CYCLONE. Grade 3 toxicity was reported in 52% of patients and 14% experienced a grade 4 toxicity. Grade 3/4 toxicities occurring in >5% of patients included fatigue, neutropenia, lymphopenia, thromboembolism, myopathy. Toxicities of any grade seen in >20% of patients included fatigue, constipation, lethargy, thrombocytopenia, somnolence, creatinine increased, malaise. Four patients (20%) developed grade 1 sensory neuropathy; no higher grade or painful neuropathy was evident. All patients are alive. All patients advancing to SCT successfully collected stem cells. One patient with t(4;14) disease who was not transplanted has progressed. 94% remain progression free. Conclusions: The 4 drug CYCLONE regimen has remarkable efficacy (83% ≥VGPR) and manageable toxicity in newly diagnosed patients with multiple myeloma. Especially notable was the low incidence of neuropathy and depth of response (CR 35%) after only 4 cycles. Given the relative lack of toxicity an extension of this regimen at higher doses of carfilzomib (20/45mg/m2) has been initiated. [Table: see text]
PANORAMA 2: A phase II study of panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory multiple myeloma.
Authors: Alsina Melissa , Schlossman Robert L. , Weber Donna M. , Coutre Steven E. , Lonial Sagar , Gasparetto Cristina , Warsi Ghulam , Ondovik Michael S. , Mukhopadhyay Sutapa , Paley Carole S. , Richardson Paul Gerard Guy 
Published: March 2020

8012 Background: Patients (pts) with multiple myeloma (MM) refractory to bortezomib (BTZ) and an immunomodulatory drug have limited treatment options and a poor prognosis. In a phase I study of pts with relapsed or relapsed/refractory MM treated with panobinostat (PAN) + BTZ, clinical responses were observed overall and in pts with BTZ-refractory disease. We report results in PANORAMA 2, a trial in relapsed and BTZ-refractory pts. Methods: PANORAMA 2 is a single-arm, phase II study of PAN + BTZ + dexamethasone (Dex) in pts with relapsed and BTZ-refractory MM. Treatment phase 1 (TP1) consists of eight 3-week cycles of oral PAN + intravenous BTZ + oral Dex. Pts demonstrating clinical benefit enter treatment phase 2 (TP2) which consists of four 6-week cycles of PAN + BTZ + Dex. The primary endpoint is overall response (≥ partial response [PR]) in TP1. Results: Fifty-five pts with BTZ-refractory MM were enrolled with 10 pts ongoing and 28 in follow-up. The median age was 61 years (range 41-88 years). Pts were heavily pretreated: the median number of prior regimens was 4 (range 2-11), and most pts (64%) received prior autologous stem cell transplant. Twenty-seven (49%) and 36 (65%) pts had BTZ and Dex in their most recent prior line of therapy, respectively. Eighteen pts achieved ≥ PR for an overall response rate of 33% (1 near complete response and 17 PR), and 13 pts achieved MR for a clinical benefit rate of 56%. Three pts achieved a VGPR. Eighteen pts completed TP1 and entered TP2, and 2 have completed ≥ 12 cycles. Common adverse events (AEs) of any grade included thrombocytopenia (66%), fatigue (64%), diarrhea (62%), nausea (58%), dyspnea (40%), anemia (38%), decreased appetite (36%), and dizziness (36%). Common grade 3/4 AEs included thrombocytopenia (58%), fatigue (17%), anemia (15%), pneumonia (15%), neutropenia (13%), and diarrhea (13%). Only 1 pt (2%) experienced grade 3/4 peripheral neuropathy. Conclusions: PAN synergizes with BTZ in recapturing responses in heavily pretreated, BTZ-refractory MM pts. The combination of PAN and BTZ is a promising treatment for pts with BTZ-refractory MM that is generally well tolerated, with several pts receiving therapy long term.
Phase II, randomized, double blind, placebo-controlled study comparing siltuximab plus bortezomib versus bortezomib alone in pts with relapsed/refractory multiple myeloma.
Authors: Orlowski Robert Z. , Gercheva Liana , Williams Cathy , Sutherland Heather J , Robak Tadeusz , Masszi Tamás , Goranova-Marinova Vesselina , Dimopoulos Meletios A. , Cavenagh James D. , Spicka Ivan , Maiolino Angelo , Suvorov Alexander , Blade Joan , Samoilova Olga S , Van De Velde Helgi , Bandekar Rajesh , Kranenburg Britte , Xie Hong , Rossi Jean-Francois 
Published: March 2020

8018^ Background: Preclinical studies of siltuximab (S), a chimeric anti-IL-6 mAb, in combination with bortezomib (B) indicate an additive to synergistic effect in multiple myeloma (MM) cell lines. This randomized study evaluated the safety and efficacy of S+B compared with placebo (plc)+B in pts with relapsed/refractory MM after 1−3 prior tx lines, measurable disease but no prior B exposure. Methods: 286 pts were randomized 1:1 to S+B: B+plc. S 6 mg/kg or plc was given IV q2w. B 1.3 mg/m2 was given IV on d 1, 4, 8, 11, 22, 25, 29, 32 for a max of 4 of 42-d cycles and then reduced to q1w for 35-d cycles. B was stopped for pts with PD/intolerability, and high dose oral dexamethasone (dex) 40 mg could then be started qd on d 1−4, 9−12, 17−20 for a max of 4 of 28-d cycles and on d 1−4 of subsequent cycles until PD, while S/plc continued. Primary endpoint was PFS by EBMT criteria censored at the start of dex/subsequent tx. Secondary endpoints included overall response rate (ORR), OS, and safety before dex. Results: 142 and 144 pts received S+B and B+plc, respectively. Baseline demographics and disease characteristics were well balanced across S+B and B+plc, except for age (median 64 vs. 61 yrs) and myeloma type (IgG 65 vs. 71%, IgA 27 vs. 20%). Median tx duration was 5.1 mo in both grps. Median PFS was 8.1 mo in S+B and 7.6 mo in B+plc (HR 0.869, p = 0.345). ORR (CR+PR) was 55% in pts on S+B and 47% on B+plc (p = 0.213); CR rates were 11 and 7% (p = 0.342), respectively. With 24.5 mo median follow up, median OS was 30.8 mo for S+B and 36.9 mo for B+plc (HR 1.353 for S+B, p = 0.103). Fewer pts on S+B than B+plc moved to dex (23 vs. 31%) and had subsequent SCT (5 vs. 11%). Gr ≥3 AEs occurred in 91% on S+B and 74% on B+plc. Common gr ≥3 AEs in S+B were neutropenia (49%), thrombocytopenia (48%), leukopenia (14%). SAEs occurred in 29% on S+B and 24% on B+plc. Death occurred within 30 d of last study agent administration pre-dex in 8% on S+B and 5% on B+plc. Conclusions: The combination of S+B had higher response rates but did not prolong survival compared with B+plc. A negative survival trend heavily influenced by differences in dex and SCT rescue was noted. S+B appears to be generally well tolerated but had a higher incidence of hematologic AEs.
A multicenter phase II study of bendamustine with rituximab in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).
Authors: Ogura Michinori , Ando Kiyoshi , Niitsu Nozomi , Kim Seok Jin , Ohmachi Ken , Takahashi Naoki , Uchida Toshiki , Takahashi Naoto , Uike Naokuni , Eom Hyeon Seok , Chae Yee Soo , Terauchi Takashi , Tateishi Ukihide , Tatsumi Mitsuaki , Kim Won Seog , Suh Cheolwon , Tobinai Kensei ,   Japanese and Korean Bendamustine Lymphoma Study Group
Published: March 2020

8023 Background: Effective salvage therapies are needed in patients (pts) with relapsed/refractory DLBCL after R-CHOP. Therapy with bendamustine plus rituximab (B-R) was well tolerated and effective in the preceding phase I study in relapsed/refractory aggressive B-cell non-Hodgkin lymphoma, including DLBCL. This phase II study assessed the efficacy and safety of B-R in pts with relapsed/refractory DLBCL. Methods: Pts with histologically confirmed DLBCL (excluding transformed disease) and 1-3 prior therapies received rituximab 375 mg/m2 IV on day 1 and bendamustine 120 mg/m2 IV on days 2 and 3 of each 21-day cycle, for up to 6 cycles. Recovery of neutrophil count to ≥1,000/mm3 and platelet count to ≥75,000/mm3 were required prior to the start of each cycle; treatment delays >2 weeks resulted in discontinuation. The primary endpoint was overall response rate (ORR); secondary endpoints included complete response (CR) rate, progression-free survival (PFS), and safety. Results: A total of 63 pts were enrolled; data from 59 pts were available. Median age was 67 (range, 36-75) years with 37 pts over 65 years. The majority of pts (64.4%) had 1 prior therapy; 57 pts (96.6%) were previously treated with rituximab-containing combination chemotherapy and 8 (13.6%) had prior auto-PBSCT. Pts received a median of 4 (range, 1-6) treatment cycles. Sixteen (27.1%) pts completed 6 treatment cycles; most common reasons for early discontinuation were disease progression (n=15) and failure to meet criteria to start the next cycle (n=13). Among 59 pts evaluable for response, ORR was 62.7% with a 37.3% CR rate. The median PFS was 200 days (95% CI, 109-410). Most common grade 3/4 adverse events (AEs) included CD4 lymphocytes decreased (66.1%), neutropenia (54.2%), and thrombocytopenia (10.2%). Four (6.8%) pts discontinued due to serious AEs (cytomegalovirus infection, infection, pneumonia, and pneumonia/respiratory failure). Conclusions: B-R demonstrated promising activity in pts with relapsed/refractory DLBCL. Toxicity was primarily hematologic and generally manageable. These results suggest that B-R is a promising salvage regimen for pts with relapsed/refractory DLBCL after R-CHOP.
A multicenter phase II study of vorinostat in patients (pts) with relapsed or refractory indolent B-cell non-Hodgkin lymphoma (B-NHL) or mantle cell lymphoma (MCL).
Authors: Ando Kiyoshi , Ogura Michinori , Suzuki Tatsuya , Ishizawa Kenichi , Oh Sung Yong , Kim Won Seog , Tanaka Yoshinobu , Shimamoto Takashi , Tobinai Kensei 
Published: March 2020

8029 Background: Most pts with indolent B-NHL relapse even after rituximab-containing chemotherapy. Vorinostat is an orally active histone deacetylase (HDAC) inhibitor, and is under investigation as monotherapy or in combination regimens in various hematologic malignancies. It has been reported that the histone acetyltransferase genes (EP300 and CREBBP) are frequently mutated in NHL, suggesting the potential usefulness of HDAC inhibitors in its treatment. Methods: We conducted a phase 2 study to investigate the efficacy, safety and tolerability of vorinostat in pts with indolent B-NHL or MCL with the overall response rate (ORR) against follicular lymphoma (FL) as the primary endpoint. The primary hypothesis was to demonstrate the efficacy in FL pts as measured by the ORR. Assuming the true ORR with vorinostat of 50% and without vorinostat of less than 25%, 39 pts will provide 90% power to demonstrate an ORR>25%. Vorinostat was administered at the dose of 200 mg BID for 14 consecutive days in a 21-day cycle. The ORR and PFS were determined by an independent review panel in the Full Analysis Set (FAS) population. Results: A total of 56 pts with a median age of 60 years (range: 33 - 75) were enrolled, and 50 of them (39 with FL, 11 with other subtypes of indolent B-NHL or MCL) were included in the FAS population. The number of prior therapeutic regimens was 2 (range: 1 - 4) and 41 pts have previously received rituximab-based regimens.. The percentages of pts with FLIPI at low risk, intermediate risk and high risk were 41%, 39%, and 21%, respectively. The ORR in 39 pts with FL was 49% (95% CI: 32, 65), and the pre-specified statistical success criterion was met. The median PFS in 39 pts with FL was 17.5 months (range: 2, 22+), especially the median PFS in 19 responders with FL has not yet been reached. The major toxicities were hematologic and gastrointestinal ones, which were reversible and manageable. Grade 3/4 infection was observed in 2%. Conclusions: This phase 2 study demonstrated that oral vorinostat is an agent with sustained antitumor activity in pts with relapsed or refractory indolent B-NHL, with acceptable safety profiles, warranting further investigations.
Phase Ib trial of AVL-292, a covalent inhibitor of Bruton's tyrosine kinase (Btk), in chronic lymphocytic leukemia (CLL) and B-non-Hodgkin lymphoma (B-NHL).
Authors: Brown Jennifer R. , Sharman Jeff Porter , Harb Wael A. , Kelly Kevin R. , Schreeder Marshall T. , Sweetenham John W. , Barr Paul M. , Foran James M. , Gabrilove Janice Lynn , Kipps Thomas J. , Ma Shuo , O'Brien Susan Mary , Evans Erica , Lounsbury Heather , Silver Bruce A. , Singh Juswinder , Stiede Kathryn , Westlin William , Witowski Steven , Mahadevan Daruka 
Published: March 2020

8032 Background: Btk supports activation, survival, and proliferation of malignant B cells in CLL and B-NHL. AVL-292 is an oral, potent (IC50 < 0.5nM), selective small molecule covalent inhibitor of Btk. Methods: Patients (pts) with previously treated CLL or B-NHL were administered AVL-292 in escalating cohorts of 125, 250, or 400 mg po QD using a 3+3 design in continuous 28 day cycles until progressive disease (PD) or toxicity. Key objectives were safety, DLT, MTD, PK, and Btk occupancy. Plasma AVL-292 levels were assessed by LC-MS-MS. Btk occupancy by AVL-292 was assessed by covalent probe assay in peripheral blood mononuclear cells. Results: 12 pts have enrolled (3 each at 125 and 250 mg and 6 at 400 mg: 5M/7F; median age 68 years, range 45-79; median 2.5 prior therapies, range 1-10) including 8 CLL (2 with 17p-, 2 with 11q22-, 2 with both 17p-/11q22-; 2 mutated IGHV, 5 unmutated IGHV, 1 missing) and 4 B-NHL (1 diffuse large B cell lymphoma (DLBCL); 1 follicular (FL); 2 marginal zone (MZL)). Median time on treatment is 65 days, range 28-158. Ten of 12 pts continue on treatment: 1 pt (DLBCL) discontinued for PD after 1 cycle and 1 pt (FL) for DLT (Gr 4 plts; 400 mg QD). No other DLTs or grade 4 adverse events (AEs) have occurred and MTD has not been reached. Most frequent AEs reported include transient diarrhea, rash/skin infection, URI, nausea, and fatigue. Gr 3 AEs include 1 atrial fibrillation (not drug related) and 1 ANC low (probably drug related). To date, 8 of 8 CLL patients have stable disease (SD) with median 28% decrease from baseline lymph node measurement (range 3-40% decrease). Six of 8 pts with CLL experienced increased ALC in cycle 1: median increase 89.5% (range 50-212%). Two of 4 NHL pts have SD (both MZL), 1 PD (DLBCL), and 1 not evaluable due to DLT (FL). Full Btk occupancy was achieved with dose levels ≥ 250 mg. Multiple dose PK exposure (AUClast) was linear with no accumulation from Day 1 to 15. Conclusions: AVL-292 was well tolerated from 125-400 mg po QD and early efficacy analysis in CLL and B-NHL shows 10/11 efficacy evaluable pts with SD. Full Btk occupancy was achieved with ≥ 250 mg QD and PK was predictable with no accumulation. Dose escalation is ongoing and MTD cohort expansion is planned.
Response rates to single-agent carfilzomib in patients refractory or intolerant to both bortezomib and immunomodulators in trial PX-171-003-A1.
Authors: Siegel David Samuel DiCapua , Martin Thomas , Singhal Seema , Wang Michael , Vij Ravi , Jakubowiak Andrzej J. , Jagannath Sundar , Lonial Sagar , Kukreti Vishal , Bahlis Nizar J. , Alsina Melissa , Chanan-Khan Asher Alban Akmal , Buadi Francis , Reu Frederic J. , Somlo George , Kunkel Lori A. , Rajangam Kanya , Chang Yu-Lin , Orlowski Robert Z. , Stewart A. Keith ,   Myeloma Research Consortium (MMRC)
Published: March 2020

8035 Background: Patients (pts) with relapsed and refractory multiple myeloma (RR MM) who are refractory or intolerant to both bortezomib (BTZ) and immunomodulators (IMiDs; thalidomide [Thal] or lenalidomide [Len]) (ie, “double-refractory/intolerant”), have few therapeutic options and a poor prognosis. Carfilzomib (CFZ), a next generation proteasome inhibitor (PI), has shown durable single-agent activity in clinical studies including 003-A1, an open-label, single-arm phase 2b trial in RR MM. The present analysis describes clinical activity in pts from 003-A1 with double-refractory/intolerant disease and in other groups of clinical interest including pts with disease refractory to all 5 approved classes of anti-MM tx (alkylators, anthracyclines, corticosteroids, IMiDs, and PIs) in clinical use (“refractory to all approved tx”). Methods: Pts from 003-A1 with double-refractory/intolerant disease were analyzed, as were pts with disease refractory to all approved tx. CFZ was given on days 1, 2, 8, 9, 15, 16 of 28-day cycles (C), (20 mg/m2 in C1; 27 mg/m2 in C2–12). Primary endpoint was overall response rate (ORR). Secondary endpoints included duration of response (DOR), overall survival, and safety. Results: The study ORR was 22.9% with median DOR of 7.8 mo (N=266). 228 pts (86%) with double-refractory/intolerant disease had ORRs of 20.6% and a median DOR of 7.4 mo. Conclusions: Single-agent CFZ demonstrated clinically meaningful, durable responses in pts with double-refractory/intolerant MM or disease refractory to all 5 approved classes of tx. The ORRs across groups of clinical interest were generally consistent with results for the entire study population. These results are notable for a next-generation PI and demonstrate the activity of single-agent CFZ in pts with advanced stage MM. [Table: see text]