bluuebunny/crossref_metadata_2025_split huggingface dataset:
Weekly dosing of the investigational oral proteasome inhibitor MLN9708 in patients (pts) with relapsed/refractory multiple myeloma (MM): A phase I study.
Authors: Kumar Shaji , Bensinger William , Reeder Craig B. , Zimmerman Todd M. , Berenson James R. , Liu Guohui , Berg Deborah , Gupta Neeraj , Di Bacco Alessandra , Hui Ai-Min , Niesvizky Ruben 
Published: March 2020

8034 Background: Phase 1 studies are evaluating IV and oral dosing of the reversible proteasome inhibitor MLN9708 in multiple tumor types. We report the safety, MTD, pharmacokinetics (PK), pharmacodynamics, and preliminary responses with weekly oral MLN9708 in pts with relapsed/refractory MM (NCT00963820). Methods: Pts aged ≥18 yrs received MLN9708 on d 1, 8, and 15 of 28-d cycles. In the dose-escalation phase, pts required ≥2 prior therapies (including bortezomib, thalidomide/lenalidomide, and corticosteroids). At the MTD, pts were to be enrolled to relapsed and refractory (RR), bortezomib-relapsed (VR), proteasome inhibitor (PI) naïve, and carfilzomib (CZ) expansion cohorts. Results: 36 pts have been enrolled to date (data cut-off: Dec 1, 2011), 32 in the dose-escalation phase (0.24–3.95 mg/m2) and 8 to expansion cohorts (2 RR, 5 VR, 1 PI naïve; RR and VR cohorts each include 2 pts from MTD dose-escalation cohort). Median age was 64.5 yrs (range 40–79), 53% were male, and median number of prior lines of therapy was 3.5 (range 1-13), including 92%, 92%, 56%, and 8% who had prior bortezomib, lenalidomide, thalidomide, and carfilzomib, respectively. Pts have received a median of 2 cycles (range 1–11); 5 pts remain on treatment. Among 24 DLT-evaluable pts, 3 DLTs were seen: 2 at 3.95 mg/m2 (1 grade 3 rash, 1 grade 3 GI AEs) and 1 at 2.97 mg/m2 (grade 3 GI AEs). The MTD was determined as 2.97 mg/m2. Overall, 69% of pts had drug-related AEs, and 28% had related grade ≥3 AEs, including thrombocytopenia (17%), diarrhea (11%), nausea, neutropenia, and fatigue (each 8%). Only 3 (8%) pts had drug-related peripheral neuropathy (PN; no grade ≥3). 2 pts discontinued due to AEs. In 18 response-evaluable pts, 1 had a VGPR at 3.95 mg/m2, 1 had a PR at 2.97 mg/m2, and 8 have achieved SD durable for up to 9.5 mos. PK analyses showed linear plasma PK (0.8–3.95 mg/m2), Tmax of 0.5-2 hr, and terminal half-life of 7 d for MLN2238 (biologically active hydrolysis product). There was a trend for a dose-dependent increase in whole blood 20S proteasome inhibition. Conclusions: Current data suggest weekly oral MLN9708 is generally well tolerated with infrequent PN, and shows early signs of antitumor activity.
Early determination of treatment sensitivity in HIV-related Hodgkin lymphoma by FDG-PET/CT after two cycles of ABVD chemotherapy: A European Cooperative Study Group on AIDS and Tumors (GECAT) study.
Authors: Mounier Nicolas , Bower Mark , Spina Michele , Besson Caroline , Schiantarelli Clara , Re Alessandro , Bonnet Fabrice , Hentrich Marcus , Wyen Christoph , Van Den Neste Eric , Vandoni Irene , Tirelli Umberto , Borsatti Eugenio 
Published: March 2020

8046 Background: The high prognostic value of FDG-PET/CT performed after 2 cycles of chemotherapy for HIV negative Hodgkin lymphoma (HL) is well known. However, experience with PET in HIV-related HL needs to be further studied as nodal FDG uptake can be observed in various opportunistic infections and AIDS-related conditions. Methods: A total of 45 consecutive HL patients (pts) were enrolled in 10 centers from the GECAT. There were 42 males and 3 females. Median age was 46 yo, range [26;64]. Median CD4 count was 391/mm3, range [33;1191]. Viral load was negative in 38 pts (84%) and uncontrolled in 5 pts (11%). Forthy three pts (96%) received concomitant HAART. HL was staged III-IV in 25 pts. International Prognostic Index scored 3-5 in 24 pts. All PET studies were performed after 2 ABVD cycles. They were scored, blinded to treatment outcome, according to the 5-point Deauville visual scale. It was considered as negative when scored 1-3 (i.e tumor FDG uptake less or equal than liver uptake) and positive when scored 4-5 (i.e. more than liver uptake or new lesions). Chemotherapy was not modified : 4-8 cycles of ABVD, as initially planned. Results: Overall, 35 pts (78%) achieved a CR after the end of treatment. Three pts received Involved Field Radiation Therapy. At a median follow-up of 18 months, 3 pts relapsed and 2 of them died from HL. The 2 yr OS and PFS were estimated at 94 and 90%, respectively. PET after 2 cycles of ABVD was negative in 40 pts (89%) and positive in 5 pts (11%). Patients with negative PET had a significantly better outcome than those with positive PET in term of 2 yr PFS (94% vs 60%, P=0.005), and 2 yr OS (100% vs 60%, P=0.0002). The negative predictive value was estimated at 97% and specificity at 93%. All patients who were PET-negative after the 2nd cycle stayed PET-negative after the 4th cycle and entered a durable CR. Conclusions: This largest study in HIV-positive HL showed that interim PET could play a central role in driving risk-tailored treatment. In further studies, de-escalation strategies should be tested for patients responding after 2 cycles of ABVD and those not reponding should be managed with intensive salvage strategies.
Final results of phase I/II trial of vorinostat in combination with cyclophosphamide, etoposide, prednisone, and rituximab (R-CVEP) for elderly patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).
Authors: Straus David J. , Hamlin Paul A. , Matasar Matthew J. , Palomba Maria Lia , Drullinsky Pamela , Zelenetz Andrew David , Gerecitano John F. , Noy Ariela , Hamilton Audrey M. , Wegner Brett , Zhang Zhigang , Elstrom Rebecca L. , Cella David 
Published: March 2020

8054 Background: Standard treatment of relapsed/refractory DLBCL in elderly patients who are not candidates for autologous stem cell transplantation (auSCT) has not been established. Cyclophosphamide (C), etoposide (E), prednisone (P) and procarbazine (CEPP) has been used by many clinicians based on limited data (Blood 76: 1293-98, 1990). Vorinostat (V) is a histone deacetylase inhibitor that is approved for relapsed cutaneous T-cell lymphoma and has activity in B-cell lymphomas. This trial defined the maximum tolerated dose (MTD) of V added to standard therapy and determined the response rate of this combination. Methods: Patients ≥age 60 with relapsed/refractory DLBCL not candidates for auSCT were enrolled on R-CVEP (R 375mg/m2 IV, d1; C 600mg/m2 d1 and 8, E 70mg/m2 IV d1, 140mg/m2 d2 and 3; V PO and Pred 60mg/m2 PO d1-10) every 28 days for 6 cycles. In the phase I component V was administered at doses of 300mg/d or 400mg/d for 10 days. The phase I was a 3 + 3 design and the phase II a two stage design requiring 8/20 complete responses (CR) for expansion. Assessment of response utilized end-of-treatment positron emission tomography (PET) (JCO 25: 579-86, 2007). Quality of life (QOL) was measured with the FACT-Lym v.4. Results: 27 pts. were enrolled. 1 died before treatment. For 26 pts: median age 76 yrs. (69-88), 14 females and 12 males, baseline PS (ECOG) 1 (0-2). Median follow-up for survivors: 9.2 mo. Phase I: 6 pts. at 300mg/d (no dose-limiting toxicity-DLT), 6 pts. at 400mg/d (2 grade 3 neutropenia = DLT). MTD 300mg/d x 10d. For 20 pts. at V 300mg/m2 (6 phase I + 14 phase II): 2 off study for toxicity, 1 withdrew consent, 6 CR (30%), 5 partial response (PR) (25%), 6 progressed (30%). Phenotypic overall responses (OR): germinal center (GC) 4/8 (2 CR), non-GC 6/10 (3 CR), transformed CLL 1/2 (1 CR). Median progression-free survival: 10 mo. QOL results will be presented. Conclusions: OR rate for V added to conventional chemotherapy and R was 55% (CR 30%, PR 25%) in relapsed/refractory DLBCL in elderly pts. not candidates for auSCT. This could provide a baseline for comparison with future clinical trials in this understudied population.
Association of prior rituximab exposure among patients undergoing autologous stem cell transplantation for relapsed/refractory diffuse large B-cell lymphoma with inferior outcomes in males compared with females.
Authors: Lazaryan Aleksandr , Copelan Edward Alan , Bejanyan Nelli , Dean Robert M. , Sobecks Ronald M. , Hill Brian Thomas , Pohlman Brad L. , Kalaycio Matt E. , Bolwell Brian James , Sweetenham John W. 
Published: March 2020

8055 Background: The combination of rituximab with CHOP remains the standard upfront therapy of patients (pts) with advanced diffuse large B-cell lymphoma (DLBCL). Gender disparity in survival of pts with DLBCL appears to be significantly modified by the use of rituximab in both upfront (Ngo, 2008; Pfreundschuh, 2009; Riihijarvi, 2010) and post-transplant maintenance (CORAL trial) settings. The presence of interaction between gender and prior rituximab exposure remains unknown in pts with relapsed/refractory DLBCL undergoing autologous stem cell transplantation (ASCT). Methods: We conducted a retrospective cohort study of 320 consecutive pts who underwent ASCT for relapsed/refractory DLBCL at our center from 01/1998 to 12/2010. Relapse-free survival (RFS) and overall survival (OS) were estimated by Kaplan-Meier method and by Cox proportional hazards regression analysis in SAS 9.1 (Cary, NC). Results: Among all pts (median age=54 yrs (IQR, 45-61); 92% Caucasians) 210 (66%) were males and 110 (34%) were females. 85 pts (27%) received more than two prior chemotherapy regimens. 174 pts (55%) had pre-ASCT exposure to rituximab as a part of induction or salvage regimens. Preparative regimen for ASCT uniformly consisted of Bu/Cy/VP-16. In the stratified univariate analysis of pts treated with rituximab prior to the ASCT, male pts had inferior RFS (p=0.02; hazard ratio [HR]=1.86, 95% CI, 1.09-3.18) and OS (p=0.03; HR=1.94, 95% CI, 1.05-3.58). In pts who did not receive rituximab prior to the ASCT, no difference in RFS or OS according to gender was observed (all p>0.4). Gender disparity among rituximab recipients was even more evident for both RFS (p=0.004; HR=2.22, 95% CI, 1.28-3.83) and OS (p=0.005; HR=2.42, 95% CI, 1.3-4.5) in the multivariable analyses controlling for age at transplant, number of prior chemotherapies, and pre-ASCT disease response. Conclusions: Our data support an emerging concern that male patients with DLBCL have inferior outcomes when treated with rituximab. The present study has extended this observation to pts with relapsed/refractory DLBCL treated with ASCT.
Characteristics and outcomes of extranodal NK/t-cell lymphoma (ENKL): A North American (NA) multi-institutional experience.
Authors: Maeda Lauren Shizue , Geiger Jessica L. , Savage Kerry J. , Rose Jim , Pinter-Brown Lauren C. , Lunning Matthew Alexander , Abramson Jeremy S. , Bartlett Nancy , Vose Julie , Drape Jacqueline , Muffly Lori S. , McMillan Alex , Evens Andrew M. , Smith Sonali M. , Horwitz Steven M. , Ansell Stephen Maxted , Advani Ranjana 
Published: March 2020

8060 Background: ENKL is a rare and aggressive subtype of peripheral T-cell lymphoma. Due to its geographic predilection there is a paucity of data on clinical experiences from non-Asian countries. The purpose of this study was to analyze characteristics and outcomes of patients (pts) with ENKL identified from major academic centers in NA. Methods: Pts with newly diagnosed CD56+ ENKL were retrospectively identified. Analyses included disease characteristics, ethnicity, therapy, and outcomes. Results: 115 pts (63.5% Caucasian, 20% Asian, 16.5% other) were identified across 10 centers diagnosed between 5/1990-5/2011 (Era 1: pre-2000, n=16; Era 2: 2000-2005, n=45; Era 3: post-2005, n=54). Median age was 52 years (19-88). 75 (65%) had stage I/II disease and were treated with combined modality therapy (CMT) n=48, chemotherapy (CT) n=14 or radiotherapy (RT) n=14. 40 pts had stage III/IV disease and were treated with CT (n=23), CMT (n=12) or RT (n=5). CT regimens used alone or in CMT were either anthracycline-based (n=68) or other (n=29). 63% of stage I/II pts and 40% with stage III/IV achieved complete remission (CR). 30 pts underwent a stem cell transplant (SCT); 14 in first CR and 16 at progression/relapse (autologous, n=21; allogeneic, n=9). Pts with stage I/II disease had a better progression-free survival (PFS) and overall survival (OS) compared with stage III/IV (12 vs 5.2 months (p=0.003) and 41.5 vs 8.9 months (p<0.0001), respectively). For all stages, treatment with CMT compared with CT or RT alone was also associated with better PFS and OS, 18.0 vs 3.9 months (p<0.0001), and 41.5 vs 10.2 months (p=0.002) respectively. Non-anthracycline-based regimens were associated with better PFS (p=0.001) and OS (p=0.045). No survival differences were seen between Asian and non-Asian pts. Conclusions: This series represents one of the largest experiences of ENKL in NA. Our data are consistent with Asian studies in: 1) majority of pts present with early stage disease; 2) overall poor outcome; 3) superiority of CMT and non-anthracycline regimens. Advances in understanding biology and international collaborative efforts are required to improve outcome in this rare entity.
Progression-free survival for subsequent relapses in patients with peripheral T-cell lymphoma (PTCL).
Authors: Horwitz Steven M. , Delarue Richard , Lunning Matthew Alexander , Vose Julie , Coiffier Bertrand 
Published: March 2020

8063 Background: In B-cell lymphoma, overall response (ORR) is lower and progression free survival (PFS) is often shorter with each subsequent progression. However, this has not been described for PTCL. Methods: We undertook a retrospective analysis in two U.S. centers (MSKCC and UNMC) and in GELA studies. All data for PTCL were reviewed to collect data for each line of therapy: treatment, response, PFS, date of next treatment, and survival. When date of progression could not be defined we calculated PFS as the time to next treatment. Pts who did not progress, died during first line, or were untreated at progression 1 were excluded. Data were collected for 4 lines of treatment, front line and 3 progressions. Results: 254 pts were identified. 205 were analyzed (49 excluded for missing data): GELA 116, MSKCC 51, and UNMC 37. Diagnoses were PTCL NOS in 34% and 60%, AITL in 49% and 35%, ALCL Alk- in 3% and 5%, and others in 15% and 18% for GELA and US centers respectively. 67% were male, median age was 51 vs 58 y. Advanced stage was more frequent in GELA (79% vs. 56% for US); baseline IPI was ≥2 in 90% vs 71%. Multidrug regimens were given in 99% and 80% for front line, 67% and 66% for 2nd line, 61% and 50% for 3rd line, 53% and 54% for 4th line, for GELA and US. Significantly fewer pts received each subsequent line of therapy with 205 pts receiving 2nd line, 96 pts 3rd line and 38 pts 4th line. No pt ≥65 y received 4th line treatment. Responses and PFS are listed in the table. Conclusions: For pts with PTCL, similar to B-cell lymphomas, ORR and PFS decrease with each line of therapy. When evaluating the activity of therapies in relapsed PTCL, line of therapy is a consideration and this series provides a benchmark for comparison. Based on this dataset, it is possible that better responses will be seen as new agents are moved into earlier treatment paradigms. [Table: see text]
Dose- and time-intensified ABVD without radiotherapy (RT) for advanced-stage Hodgkin lymphoma (HL) with mediastinal bulky disease (MBD).
Authors: Corazzelli Gaetano , Russo Filippo , Frigeri Ferdinando , Volzone Francesco , Capobianco Gaetana , Arcamone Manuela , Morelli Emanuela , Becchimanzi Cristina , Marcacci Giampaolo , De Filippi Rosaria , Saggese Mariangela , Pinto Antonio 
Published: March 2020

8066 Background: The role of consolidation RT on MBD after upfront chemotheraphy for advanced HL is debated, also given the supradditive iatrogenic risk. We present the results achieved in the subset of patients (pts) with MBD (max width > 1/3 of thoracic diameter) accrued in a phase II study of an intensified ABVD program without RT. Methods: The current analysis derives from the final evaluation of our trial for advanced HL (stage IIXB-IV) conducted from 06/2004 to 03/2010 (Russo et al, ASH 2009 abst 715). Pts were scheduled to 6 cycles of a ‘time-densified’ ABVD (3-week intercycle, drugs on days 1 and 11) with the first 4 cycles being also ‘dose-intensified’: doxorubicin (ADM) 35 mg/m2, days 1 and 11 and G-CSF on days 6-8 and 17-19. Results: Of 82 accrued pts, 39 had BMD at presentation. Median age was 29yrs (r 16-58); male 46%; stage IIB 48%, III 8%, IV 43%; B-sympt 87%, E-disease 53%; IP Score ≥3 51%. All pts completed the intensified program. Median actual dose intensities for ADM, bleomycin, vinblastine and dacarbazine were 23.12, 6.69, 3.96 and 245 mg/week, respectively; the increase over conventional ABVD was 85% for ADM and averaged 32% for the other agents. PET2 negativity was achieved in 36/39 (92%; 95% CI 79-98), complete responses (CR) in 37/39 [94%; 95% CI 82-99]. At a median f.u. of 54 mo.s (r 20-91) all pts are alive with an event-free survival of 89% (95% CI, 80-98). Events were: <CR (n=1, CS IVB), progression (n=1, CS IIIA), relapse [n=2; at 10 (CS IVA ) and 15 (CS IIB) months after treatment]; all these pts had isolated mediastinal recurrence. CTCAE v3.0 toxicity: Grade (G) 2 nail changes (31%), G2-G3 hemorrhoids (12%-3%), G3 infection (13%) and constipation (5%), G3-G4 stomatitis (7%-2%). No acute or delayed G3-G4 cardiac events, nor G3-G4 decline in pulmonary function (FEV1, DLCO,FEF25-75) were seen. Conclusions: Intensified ABVD can achieve PET2 negativity in a very high proportion of pts with MBD and ensure a long-term disease-free status even without RT. While results need confirmation on a randomized basis, the low mediastinal failure rate seems in line with recent suggestions that RT could be omitted in MBD when CR is achieved upon intensified chemotheraphy.
Phase I trial of fenretinide (4-HPR) intravenous emulsion in hematologic malignancies: A California Cancer Consortium study (PhI-42).
Authors: Mohrbacher Ann , Kang Min H , Yang Allen S. , Groshen Susan G. , Vergara Lori , Gutierrez Martin , Murgo Anthony J. , Kummar Shivaani , Quick Donald , Reynolds C. Patrick , Newman Edward M. , Maurer Barry 
Published: March 2020

8073 Background: Fenretinide (4-HPR) is a cytotoxic retinoid with broad anticancer activity in preclinical studies. Due to limited bioavailability of a capsule formulation an intravenous intralipid-like emulsion formulation (4-HPR ILE) was developed to increase systemic exposures. Methods: 4-HPR was administered as a continuous intravenous infusion for 120 hrs every 21 days. Systemic toxicities, responses, and pharmacokinetics were assessed. Accelerated Simon design proceeded until moderate or dose-limiting toxicities (DLT) were scored on Course 1. Doses were 80 mg/m2/day to 1810 mg/m2/day. Patients with asymptomatic hypertriglyceridemia were scored separately. All patients were heavily pretreated. Results: Toxicity-evaluable patients = 25. At 1810 mg/m2/day, two patients experienced DLT hypertriglyceridemia, one with transient Grade 2 pancreatitis; at 1280 mg/m2/day (8 pts), two had asymptomatic Grade 4 hypertriglyceridemia, one experienced DLT pleural effusions; at 905 mg/m2/day (6 pts) 2 experienced asymptomatic Grade 4 hypertriglyceridemia; All 5 pts at 640 mg/m2/day tolerated treatment. Pharmacokinetics showed a dose-to-plasma level relationship with mean steady-state 4-HPR levels of ~mid-20’s μM (640 mg/m2); ~mid-30’s μM (905 mg/m2/day); and ~mid-50’s μM (1280 mg/m2). Responses to date include a 64% CR+PR+SD response rate (36% CR+PR response rate) in 11 relapsed T-cell lymphomas which included histone deacetylase inhibitor-refractory patients, and a PRu response in a NHL B-cell lymphoma. Reversible hypertriglyceridemia related to the intralipid vehicle accounted for 6/7 DLTs. Conclusions: MTD = 1280 mg/m2/day x 5 days, every three weeks. 4-HPR ILE was safely administered and obtained 4-HPR plasma levels 6 -7 times higher than previously obtained using oral capsules. Durable complete responses were observed in T-cell lymphomas from 905 – 1810 mg/m2/day. An expanded cohort is accruing to a dosing schedule modified to decrease asymptomatic hypertriglyceridemia of 600 mg/m2 on Day 1 (to allow for induction of serum lipases) followed by 1200 mg/m2 Days 2-5. Supported by NCI U01 CA062505 and CPRIT RP10072.
Costimulatory molecule profiles and NK cell recovery after autologous hematopoietic cell transplantation (HCT) in multiple myeloma (MM) patients.
Authors: Htut Myo , Gallez-Hawkins Ghislaine , Palmer Joycelynne , Liu Xueli , Spielberger Ricardo Tomas , Parker Pablo Miguel , Farol Len , Franck Anne , Li Xiuli , Jeannet Laëtitia , Reburiano Eunicia , Jimenez Valerie , Duarte Lupe , Sahebi Firoozeh , Karanes Chatchada , Forman Stephen J. , Krishnan Amrita Y. , Zaia John 
Published: March 2020

8089 Background: Increased immune responses post autologous HCT may be of benefit in long term disease control. Responses may be mediated by NK cell function and possibly other alternate pathways, including costimulatory molecule pathways. This pilot study assesses the expression of inhibitory (PD-1 and CTLA-4) and stimulatory (OX-40, ICOS, 4-1BB, and CD28) molecules on NK cells after auto-HCT in MM patients and evaluates the effect of lenalidomide treatment on these pathways. Methods: 17 patients with MM undergoing HCT, median age 56.7 years (36 – 67), were included in the study. Peripheral blood samples were taken 3 days prior to HCT and 14, 30, 60, 90, 180 days after HCT. At d180 post-HCT, 13/17 patients were receiving lenalidomide with d91 as median start date. NK cells and their costimulatory molecules were evaluated by flowcytometry using 2 six color panels of antibodies. One way ANOVA test and Kruskal-Wallis test (non-parametric) were applied to analyze the data using the Graphpad Software. Results: See table below. NK cell number was highest (median: 26% of total lymphocytes) at d14 (p: < 0.0001) compared to pre and post HCT levels. At d180, TNF-R OX40 expression was significantly increased in ≤PR group (n=5) (median: 9.5% of NK cells) compared to ≥VGPR (n=12) (0.8%; p=0.0084). In addition, NK cell number was higher in the lenalidomide group (n=13) (median: 15.15 % of total lymphocytes) compared to the no lenalidomide group (n=4) (6.74%; p=0.0108) at d180 post HCT. Significantly lower level of CTLA-4 expression was also found in the lenalidomide group (0.33% vs. 2.54%; p=0.0362). Conclusions: We observed NK cell recovery to baseline values at 60 days after HCT. At d180 post-HCT, OX-40 expression in NK cells was higher in ≤PR group than ≥VGPR group. Lenalidomide treatment was associated with higher NK cells number and decreased expression of CTLA-4. This observation could be a possible marker of enhanced host NK cell immune response against MM. Future clinical trials will explore therapies that increase NK cell responses. [Table: see text]