bluuebunny/crossref_metadata_2025_split huggingface dataset:
R-CHOP14 compared to R-CHOP21 in elderly patients with diffuse large B-cell lymphoma (DLBCL): Final analysis of the LNH03-6B GELA study.
Authors: Delarue Richard , Tilly Herve , Salles Gilles A. , Thieblemont Catherine , Mounier Nicolas , Molina Thierry Jo , Haioun Corinne , Bosly Andre 
Published: March 2020

8021 Background: In 2000, the GELA established a new standard for elderly patients with DLBCL, demonstrating survival advantage of R-CHOP21 over CHOP21. Based on RICOVER-60 results, the DSHNHL proposed R-CHOP14 as a standard. Comparison between both regimens is lacking. We report the results of the final analysis of the randomized phase III trial LNH03-6B, with a median follow-up of 56 months. Methods: Pts between 60 and 80 years old with DLBCL and aaIPI≥1 were eligible. They were randomized between R-CHOP14 and R-CHOP21 for 8 cycles. G-CSF prophylaxis was given according to physician decision. Primary objective was to evaluate the efficacy of R-CHOP14 compared to R-CHOP21 as measured by the EFS. Results: 602 pts were randomized, 600 were evaluable, 304 with R-CHOP14 and 296 with R-CHOP21. Median age was 70 years. Pts characteristics were similar between the two arms. Percentage of pts with baseline IPI3-5 was 72% in R-CHOP14 arm and 78% in R-CHOP21 arm. Median interval between 2 cycles was 14 d in R-CHOP14 arm and 21 d in R-CHOP21 arm. In R-CHOP14 arms, 89% of cycles were administered with G-CSF. Median dose-intensity for R-CHOP14 arm was 88% for cyclophosphamide and doxorubicin. There was no difference in median dose-intensity according to G-CSF administration at first cycle. Response rate (CR+CRu) was 71% in R-CHOP14 arm and 74% in R-CHOP21 arm (p=0.42). The 3-y EFS was 56% in R-CHOP14 arm and 60% in R-CHOP21 (HR 1.04; CI95% 0.82-1.31; p=0.79). Moreover, there is no difference between both arms regarding 3-y PFS (60% vs. 62%; HR 0.99; CI95% 0.78-1.26; p=0.90), DFS (72% vs. 67%; HR 0.80; CI95% 0.58-1.10; p=0.80) and OS (69% vs. 72%; HR 0.96; CI95% 0.73-1.26; p=0.75). Finally, percentage of patients with at least one serious adverse event (R-CHOP14: 51%; R-CHOP21: 47%) and rate of toxic death (4.6% and 4.7% respectively) were similar. Conclusions: Results of the final analysis of LNH03-6B demonstrate similar efficacy and safety profile between R-CHOP14 and R-CHOP21.
Long-term results of the phase II trial of the oral mTOR inhibitor everolimus (RAD001) in relapsed or refractory Waldenstrom macroglobulinemia.
Authors: Ghobrial Irene M. , Gertz Morie A. , LaPlant Betsy , Camoriano John Kelly , Hayman Suzanne R. , Lacy Martha , Chuma Stacey , Harris Brianna , Boswell Erica , Banwait Ranjit , Sheehy Patricia , Ansell Stephen Maxted , DeAngelo Daniel J , Dispenzieri Angela , Bergsagel Leif , Reeder Craig B. , Anderson Kenneth Carl , Richardson Paul Gerard Guy , Treon Steven P. , Witzig Thomas E. 
Published: March 2020

8043 Background: The mammalian target of rapamycin (mTOR) signal pathway controls cell proliferation and survival. The trial's goal was to determine the anti-tumor activity and safety of single-agent everolimus (TORC1 inhibitor) in patients with relapsed/refractory Waldenstrom macroglobulinemia (WM). Methods: Eligible patients had measurable disease (IgM monoclonal protein >1000 mg/dL with >10% marrow involvement or nodal masses >2 cm), a platelet count ≥75,000 x 106/L, a neutrophil count ≥1,000 x 106/L. Patients received everolimus 10 mg PO daily. Tumor response was assessed after cycles 2 and 6 and then every 3 cycles until progression. Results: 60 pts were treated. The median age was 64 years (range, 43-85). The median number of prior therapies was 3 (range, 1-11). All but two patients (97%) had received prior rituximab based therapy and 64% of patients had received prior alkylator based therapies. The overall response rate (complete response CR+ partial response PR+ minimal response MR) was 73% (95% CI: 60-84%), with a PR of 50% and 23% MR. The median time to progression (TTP), progression-free survival (PFS), and overall survival (OS) for the entire study population is 28 months (mos), (95% CI: 18-not reached (NR)), 22 mos (95% CI: 12 0-NR), and 55 mos (95% CI: 55-NR), respectively. The estimated PFS at 12 and 24 months is 62% (95%CI: 51-75%), and 48% (95%CI: 37-63%), respectively. The 30 patients who achieved a PR responded after a median of 2 months (range, 1-26) of treatment. The median duration of response (DR) for these patients has not yet been reached and 19 of these patients remain in response after a median follow up of 31 months (range, 3-54). All but two patients had a decrease in their serum IgM. Grade 3 or higher related toxicities were observed in 67% of patients. The most common were hematological toxicities with cytopenias. Pulmonary toxicity occurred in 5% of patients. Dose reductions due to toxicity occurred in 63% of patients. Conclusions: Everolimus has high single-agent activity with an overall response rate of 73% and manageable toxicity in patients with relapsed WM, and offers a potential new therapeutic strategy for this patient population.
Survival outcomes in marginal zone lymphomas in the rituximab era: Analysis of the Surveillance, Epidemiology, and End Results (SEER) database.
Authors: Castillo Jorge J. , Olszewski Adam J. 
Published: March 2020

8045 Background: Despite prognostic models developed for marginal zone lymphoma (MZL), the impact of different characteristics and treatments on survival in the population is largely unknown. We studied survival of MZL patients included in the SEER database. Methods: Records of MZL adult cases diagnosed between 1989-2008 were studied using descriptive methods and analysis of overall (OS) and lymphoma-specific (LSS) survival based on Kaplan-Meier function, stratified log-rank tests and Cox proportional hazard models. Results: 13,957 patients with MZL were identified and classified as splenic (SMZL; n=1,111, 8%), nodal (NMZL; n=4,101, 29%) or extranodal MALT-type MZL (MALT; n=8,745, 63%). The median age was 68 years, 74% of patients were white and 55% were women. Median follow-up was 40 months. MALT was more common in non-Caucasians (p<10-27). B-symptoms were more common in SMZL (p<10-5). Both LSS and OS were significantly better for MALT (p<10-60) with no difference between SMZL and NZML (p=0.30). 10-year LSS estimates were 67% for SMZL, 67% for NMZL, 84% for MALT. There was evidence for improved LSS since 2000 in MALT (HR 0.69, 95% CI 0.59-0.82, p=0.0003) and NMZL (HR 0.64, 95% CI 0.54-0.77, p<10-5), but not for SMZL (HR 0.85, 95% CI 0.56-1.28, p=0.43). Similar results were found for OS. There were differences in survival in MALT subtypes depending on primary site (p<10-12; Table). Conclusions: In the rituximab era, survival has improved for MALT and NMZL, but not for SMZL, possibly due to disparate treatment paradigms. The prognosis of MALT is different depending on primary site of involvement. [Table: see text]
Effect of short-duration chemoimmunotherapy plus radioimmunotherapy on response rates in relapsed follicular lymphoma: A U.K. NCRI Lymphoma Group Study, CR UK/07/038.
Authors: Illidge Timothy M , Bates Andrew T. , Davies Andrew John , Pettengell Ruth , Andrews Barry , Dent Louise , Hampson Grace , Zivanovic Maureen , Gallop-Evans Eve , Radford John A. , Johnson Peter W. M. ,   UK NCRI Lymphoma Group
Published: March 2020

8056 Background: Radioimmunotherapy (RIT) and rituximab (R) maintenance have been investigated after chemotherapy (CT) or R-CT in first line treatment of follicular lymphoma (FL), but less is known about the efficacy of RIT after R-CT in relapsed FL. This phase II study was conducted to examine efficacy and safety of abbreviated R-CT followed by 90Y Ibritumomab tiuxetan in patients with recurrent FL. Methods: Patients (pts) had FL, at 1st or 2nd relapse after response to R-CT or CT alone. All had WHO/ECOG performance status ≤2, and adequate bone marrow (BM), kidney, liver and cardiac function. BM involvement by lymphoma had to be <25% prior to infusion of 90Y Ibritumomab tiuxetan, but could be higher at study entry. Pts received 3 cycles of either R-CHOP or R-CVP, followed by 90Y Ibritumomab tiuxetan (15MBq/Kg, maximum 1200 MBq). No maintenance R was given. Results: 52 pts were enrolled from 6/2008 to 7/2010. Median age was 62 years (range 31-87). 46% had high FLIPI score at entry, 31% intermediate. 80% were at 1st recurrence. Median duration of best prior remission was 27.7 months. 65% pts had previously received R and 25% doxorubicin. 71% pts had R-CHOP and 29% R-CVP, prior to RIT. Overall response rate (ORR) after 3 cycles R-CT was 94% (CR/CRu 10%) and after RIT ORR 96% (CR/CRu 28%). Grade 3/4 thrombocytopenia occurred in 58% pts (median duration 16 days): 3/52 pts after R-CT and 27/52 after RIT. Grade 3/4 neutropenia occurred in 62% pts: 15/52 pts after R-CT and 27/52 after RIT. 5 pts had a total 8 grade 3 infections, only 1 attributable to RIT. 6 pts required platelets and 4 red cell transfusions. 1 pt developed myelodysplasia 10 months after 90Y Ibritumomab tiuxetan, but no other second malignancy was recorded. PFS was 31.4 months (95% CI 15.8 - not reached). There was no difference in PFS according to FLIPI score at entry or reinduction CT (R-CHOP vs R-CVP). Pts with CR/CRu following RIT showed a trend to improved PFS compared to those with PR (12 month PFS 90% versus 63%, p=0.06). Conclusions: Abbreviated R-CT and consolidation with 90Y Ibritumomab tiuxetan is an option for pts with recurrent FL, with responses of comparable duration to those seen after a full course R-CHOP.
Efficacy and safety of bexarotene combined with psoralen/ultraviolet A light (PUVA) compared to PUVA treatment alone in stage IB-IIa mycosis fungoides (MF): Final results from EORTC cutaneous lymphoma task force (CLTF) phase III clinical trial 21011.
Authors: Whittaker Sean , Ortiz-Romero Pablo L. , Dummer Reinhard , Ranki Annamari , Hasan Baktiar , Meulemans Bart , Gellrich Sylke , Knobler Robert , Stadler Rudolf , Shash Emad 
Published: March 2020

8076 Background: Skin-directed treatment with methoxsalen (PUVA) is the current treatment standard in stage IB-IIA MF. A combination of PUVA and bexarotene might be of additional clinical benefit for MF stage I/II patients (pts). Methods: EORTC 21011 was a randomised, open label phase III study comparing combined bexarotene and PUVA versus PUVA alone in pts with stage IB and IIA MF. Study primary endpoint was response (complete clinical + partial response, CCR+PR) rate; secondary endpoints: cumulative dose of UVA and number of PUVA sessions necessary to achieve a CCR, duration of CCR, time to relapse, safety and percentage of drop-outs. Results: The study recruited stage IB/IIA MF pts and was prematurely closed due to low accrual after 93/145 required pts (65%) were randomized; 45 to PUVA, 48 to PUVA+bexarotene. Median number of PUVA weeks were 12 (1-17) in PUVA vs. 10.5 (1-16) in combination arm. Total UVA doses were 107J/cm2 (1.4-489.9) in PUVA vs. 101.7J/cm2 (0.2-529.9) in combination arm. Few grade 3-4 toxicities were observed in both arms (liver enzyme elevation, neutropenia, anemia, increased cholesterol, photosensitivity, pruritus, rash, hypertriglyceridemia). Best overall response (CCR/PR) rate was 71.1% (33/45) for PUVA alone and 77.1% (37/48) for combination arm (p-value=0.57). The median of duration of response was 9.6 for PUVA vs 5.8 months for combination arm (p value=0.33). CCR was seen in 25 pts, 10 in PUVA (CCR 24%) and 15 in combination therapy (CCR 33%) (pvalue=0.45). Similarily, a lower UVA dose was required to achieve a CCR in the combination arm (median of 55.8 J/cm2) compared to the PUVA arm (median of 117.58 J/cm2) (p value=0.5). Conclusions: No significant difference in response rate was observed in this study. There was a trend towards fewer PUVA sessions and lower UVA dose to achieve CCR in the PUVA/bexarotene combination arm (median of 27.5 vs. 22,p-value = 0.11) but this did not achieve statistical significance due to insufficient power. The safety profile was acceptable, as there were only few grade 3-4 toxicities observed in both arms.
Dual-point FDG-PET: A novel scanning technique in Hodgkin lymphoma with bulky disease.
Authors: Gallamini Andrea , Bianchi Andrea , Borra Anna , Zaucha Jan M. , Malkowski Bogdan , Thyss Antoine , Mounier Nicolas , Razzouk-Cadet Micheline , Darcourt Jacques , Zwarthoed Colette , Chauvie Stephane , Biggi Alberto 
Published: March 2020

8077 Background: Interim 18F-FDG-PET (iPET) is the most important prognosticator in advanced-stage ABVD-treated Hodgkin Lymphoma (HL), but in early stage w/ or w/o bulky lesion a low PPV of iPET was reported. Dual-point PET scan (2P-PET) has been used to discriminate unspecific inflammatory from neoplastic FDG uptake. At the Tx end, with a single FDG-avid mass (SFAM), the specificity of PET in Tx response evaluation was sub-optimal. We report here preliminary results from a cohort of HL patients (p) presenting with bulky lesions, scanned with 2P-PET with the aim to increase specificity and PPV. Methods: From 12.2008 till 01.2012 24 HL bulky p from Italian, French and Polish centers underwent 2P-PET at baseline (2P-PET-0), after 2 ABVD (2P-PET-2) and at Tx end (2P-PET-end). 2P-PET scanning technique consisted in 2 consecutive image acquisitions +60’ (EaS) and +120’(LaS) after single, standard-dose FDG injection. Tx was ABVD (x4 or x6) ± consolidation RxT. No Tx change was done based on iPET results. Scans were reviewed by 2 expert readers in a consensus session. Standardized-Uptake Value (SUV)MAX was calculated both in EaS and LaS using Volume of Interest Regions (VOIs) in sites of residual FDG uptake already recorded in PET-0. ΔSUVMAX and FDG retention index (RI) were calculated from SUVs in the same VOIs of both scans. Results: In 24 p (1 stage I,12 II, 4 III, 7 IV), 34 2P-PET were done.10 p underwent 2P-PET-0: in 10/10 SUVMAX increased from EaS to LaS (ΔSUVMAX 1-4.3). 15 p had a 2P-PET-2: 12 with a mean-follow-up of 18.36 months were evaluable, 3 too short ( +1, +5, +6 months). 7/12 p showed a RI reduction of 55% (200-14): all are in continuous CR (CCR). 5/12 p. showed a 20% (11-26) RI increase: all progressed +1 to +9 months after Tx end. Overall 3/12 cases (1 false +, 2 false- with a Deauville score 4 and 2,3 respectively) were correctly classified after 2P-PET. 9 p with a SFAM had a 2P-PET-end: in the 5/9 with an increased RI of 23% (9-43) a biopsy proved HL relapse. In 4/9 a reduced RI of -29% (9-45) was found: in 2 biopsy disclosed presence of residual thymic along with inflammatory tissue and 2 were in CCR +2 to+8 after Tx end. Conclusions: DSUV Max increased at baseline and in all relapsing patients, and decreased in patients in CCR. The PPV and a PNV of 2P-PET were 100%.
The incorporation of rituximab (R) and liposomal doxorubicin (LD) into CODOX-m/IVAC for untreated Burkitt lymphoma (BL): Final results of a prospective multicenter phase II study.
Authors: Evens Andrew M. , Carson Kenneth Robert , Nabhan Chadi , Islam Nahida , Jovanovic Borko , Barr Paul M. , Caimi Paolo Fabrizio , Gallot Lillia , Gregory Stephanie A. , Gordon Leo I. 
Published: March 2020

8080 Background: Two-year survival rates remain <65-70% for adult BL. Further, there is a paucity of data examining the addition of R with CODOX-M/IVAC. Methods: 25 patients (pts) with classic BL enrolled onto this phase II study (3/07-4/11). Pts were classified as low risk (LR) or high risk (HR); LR received 3 CODOX-M, while HR had 4 alternating CODOX-M/IVAC (Mead et al, Blood 2008). LD (40 mg/m2) was used in lieu of doxorubicin, while intravenous R (500 mg/m2) was given days 0 + 8 of CODOX-M and days 0 + 6 of IVAC cycles. Ejection fraction (EF) was assessed at baseline, s/p 2 cycles and completion. Results: Median age was 44 years (yrs) (23-70). There were 20 HR and 5 LR pts; 3 HR and 1 LR pt were HIV+. 15% of HR pts had + CNS disease. In addition, 35% of HR pts had bulk >10 cm and 40% had bone marrow involvement. 24/25 pts were evaluable for toxicity and response. Therapy was completed at a median of 13 weeks (11-20) for HR pts and 10 weeks for LR (9-12). Myelosuppression (62% grade 4 thrombocytopenia, 4% grade 4 anemia) and mucositis (33% grade 3, 13% grade 4) appeared comparable with prior CODOX-M/IVAC data. Other grade 3 toxicities were infection (38%), neutropenic fever (29%), transaminitis (33%), diarrhea (8%), creatinine (8%), seizure (4%), vomiting (4%). Notably, there was no grade 3 or 4 neuropathy. Two grade 2 and three grade 3 cardiac events occurred (all depressed EF, no clinical CHF). Two of the three grade 3 cardiac events occurred in pts age >65 yrs. Among all pts, the median change in EF at baseline vs study end was -2% (-22% to +11%). The overall response rate (modified Cheson with FDG-PET) after 2 cycles was 100% with a 67% complete remission rate. At a median follow-up of 2.3 yrs, 2-year PFS and OS rates for all pts were 86% and 86%, respectively (LR 2-yr PFS and OS: both 100%; HR 2-yr PFS and OS: both 82%). Furthermore, 2-yr PFS and OS for HR, HIV-negative BL were 91% and 91%, respectively (disease-specific survival: 100%). Conclusions: The integration of R and LD into CODOX-M/IVAC for adult BL is feasible and associated with similar tolerability compared with prior reports. Moreover, this regimen was associated with excellent survival rates, especially for HIV-negative BL.
Disruption of the eIF4F translation initiation complex as a determinant of diffuse large B-cell lymphoma responsiveness to enzastaurin (LY317615.HCl) and its primary metabolite (LY326020).
Authors: Graff Jeremy Richard , McNulty Ann M , Dumstorf Chad A , Parsons Stephen H , Konicek Bruce W , Hall Chad A 
Published: March 2020

8082 Background: Enzastaurin (enza) is in ph 3 registration trials for DLBCL patients at high risk of relapse following R-CHOP therapy. In a phase 2 DLBCL study, 4 of 55 treated patients were progression- free after prolonged, continuous oral enza therapy with 3 of these 4 confirmed as complete responders (Robertson et al., JCO, 2007). The molecular mechanism for this differential response is unclear. Methods: In clinical trials, Enza yields 2-4 µM total circulating drug, comprised of ~50% enza, ~50% primary metabolite, LY326020. We therefore evaluated the sensitivity of a DLBCL cell panel representing both Activated B Cell (ABC) and Germinal Center (GC) subtypes to enza and LY326020. Gene expression analyses, western blotting to explore intracellular signaling and mRNA cap analogue co-capture assays were used to identify the critical effectors of drug sensitivity. Results: For the first time, we show the profound biological activity of LY326020, the primary metabolite that accounts for ~ 50% of circulating drug in patients. Like Enza, though more potently, LY326020 inhibits PKC and PI3K-AKT-TOR pathway signaling and robustly induces apoptosis in both ABC and GC DLBCL cells. In both sensitive and resistant cells, enza and LY326020 reduced phosphorylation of numerous proteins in the PI3K-AKT-TOR pathway (e.g. pGSK3βser9) in a dose and time-dependent manner. However, only sensitive DLBCL cells showed reduced 4EBP1ser65 phosphorylation. Accordingly, we show a dose and time-dependent increase in 4EBP1: eIF4E binding. This increase is most pronounced by LY326020. Moreover, cells selected for resistance to enza show reduced 4EBP1 expression and cells lacking 4EBP1 are insensitive to the pro-apoptotic effects of enza and LY326020. Conclusions: These data demonstrate that sensitivity of DLBCL to both enza and LY326020 is critically dependent upon 4EBP1 modulation and subsequent disruption of the eIF4F translation complex. Moreover, these data are the first to show the potent biologic activity of LY326020, the primary metabolite of enza that accounts for ~50% of total circulating drug in patients and in preclinical models.
Hematologic safety data from four phase II studies of single-agent carfilzomib in relapsed and/or refractory multiple myeloma
Authors: Nooka Ajay K. , Badros Ashraf Z. , Patel Priti , McCulloch Leanne , Lonial Sagar , Kaufman Jonathan L. 
Published: March 2020

8086 Background: Carfilzomib (CFZ) is a next-generation proteasome inhibitor that is currently being evaluated in patients (pts) with multiple myeloma (MM). Given that the majority of pts with MM exhibit either disease- or therapy-related myelosuppression sometime in the course of their disease, detailed evaluation of treatment-emergent hematologic safety data with CFZ is of significant interest. In the following analysis, we report the hematologic safety profile for single-agent CFZ from 526 pts treated in four phase 2 studies. Methods: Pts treated with CFZ in trials 003-A0, 003-A1, 004, and 005 were included in the analysis. Pts with preexisting hematologic abnormalities of Grade (G) 0–2 (G0–3 for 005) were eligible to enroll. CFZ was dosed in all studies on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle (C). Doses were 20 mg/m2 in C1 for all studies escalating to 27 mg/m2 in C2 per individual protocol, except 005 (15 mg/m2 in C1, 20 mg/m2 in C2, and 27 mg/m2 in C3). Incidence, frequency, and severity of thrombocytopenia, lymphopenia, neutropenia, and anemia were analyzed in terms of adverse events (AEs) of interest. Laboratory data were analyzed for trends over time. Results: See table below for summary of hematologic events. In general, platelet counts trended down, reached a nadir by Day 8 of a 28-day treatment cycle, and normalized before the start of next cycle. There was no evidence of cumulative thrombocytopenia or clinically significant episodes of bleeding associated with thrombocytopenia. Febrile neutropenia was reported in 1% of pts. No mortality due to hematologic events was reported. Conclusions: Hematologic AEs, although common with CFZ treatment, were infrequently dose limiting. Clinically significant G3/4 cytopenias were both infrequent and transient. In summary, the hematological safety profile of CFZ was similar to or better than currently approved MM therapies, providing further evidence of its acceptable safety profile in heavily pretreated MM pts. Summary of hematologic events. [Table: see text]