bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I expansion trial of an oral TORC1/TORC2 inhibitor (CC-223) in diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM).
Authors: Goy Andre , Ribrag Vincent , Varga Andrea , Witzig Thomas E. , Ocio Enrique M. , Paz-Ares Luis G. , Mita Monica M. , Meyer Tim , Munster Pamela N. , Mahipal Amit , Delord Jean-Pierre , Arkenau Hendrik-Tobias , Gutierrez Martin , James Angela , Wong Lilly , Xu Shuichan , Wu Xiaoling , Carmichael James , Chopra Rajesh , Hege Kristen 
Published: March 2020

8522 Background: CC-223 is an ATP-competitive inhibitor of the mTOR kinase, including both TORC1 and TORC2 complexes. CC-223 was selected to address resistance of rapamycin analogues mediated by TORC2 activation. Methods: Following establishment of the MTD (reported at ASCO 2012), subjects with advanced DLBCL, MM and select solid tumors were enrolled in parallel expansion cohorts of up to 20 evaluable subjects. CC-223 was dosed at 45 mg once daily in 28 day cycles until disease progression. Results: As of 09 January, 2013, 35 subjects were enrolled including DLBCL (21) and MM (14). Results in solid tumor cohorts are reported separately. The most common (> 20%) related adverse events (all grades) were fatigue, hyperglycemia, rash, anorexia, nausea, vomiting and diarrhea. In addition, related serious adverse events included infection (2), pneumonitis (1), renal insufficiency (2), pancreatitis (1) and thrombocytopenia (1). CC-223 dose reduction was required in 9 subjects (27%), usually during cycle 1 or 2, and 4 additional subjects with DLBCL dropped out during cycle 1 due to toxicity. Systemic exposure was similar between the two tumor cohorts and was associated with inhibition of TORC1 (p4EBP1) and TORC2 (pAKT) biomarkers in blood cells. Reduction in glucose uptake (32 – 98% decrease) on PET imaging at day 15 was observed in 7/7 DLBCL subjects with results currently available. Three of 17 evaluable subjects with DLBCL had partial responses (PR) after 2 cycles; two with rapid and near complete regression (> 90%) of target lesions by CT and PET with PR confirmed and treatment ongoing at 6 and 8 cycles. Both had failed multiple prior treatment regimens (5 and 3, respectively), including autologous stem cell transplant (ASCT). No responses were observed in 10/14 evaluable subjects with MM although 2 subjects have prolonged stable disease (SD) with treatment ongoing at 12 and 14 cycles. Conclusions: Encouraging signals of biomarker and clinical activity were observed in DLBCL, including two near complete responses, which are ongoing. Due to dose reductions and interruptions, a starting dose of 30 mg QD is recommended for future studies. Clinical trial information: NCT01177397.
Pomalidomide plus low-dose dexamethasone (POM + LoDEX) versus high-dose dexamethasone (HiDEX) in relapsed/refractory multiple myeloma (RRMM): Impact of cytogenetics in MM-003.
Authors: Goldschmidt Hartmut , Dimopoulos Meletios A. , Weisel Katja C. , Moreau Philippe , Lacy Martha , Song Kevin W. , Delforge Michel , Karlin Lionel , Banos Anne , Rocafiguera Albert Oriol , Yu Xin , Sternas Lars , Jacques Christian , Zaki Mohamed H. , San-Miguel Jesùs F. 
Published: March 2020

8528 Background: RRMM patients (pts) who fail lenalidomide (LEN) and bortezomib (BORT) have poor prognosis. High-risk cytogenetics predict shorter survival. POM + LoDEX has demonstrated efficacy in pts with prior LEN and BORT and high-risk cytogenetics. MM-003 is an open-label, multicenter, phase III trial comparing POM + LoDEX vs. HiDEX in RRMM pts who failed LEN and BORT treatment (Tx) and have progressed on their last therapy. Methods: Pts must have been refractory to the last prior Tx (progressive disease [PD] during or within 60 days) and failed LEN and BORT after ≥ 2 consecutive cycles of each (alone or in combination). Randomization was 2:1 to POM 4 mg D1–21 + DEX 40 mg (20 mg for pts aged > 75 y) weekly; or DEX 40 mg (20 mg for pts aged > 75 y) D1–4, 9–12, and 17–20 (28-day cycles). Tx continued until PD or unacceptable adverse events (AEs). The primary endpoint was progression-free survival (PFS). Secondary endpoints included OS and AEs. This analysis examined pts meeting modified high-risk cytogenetic criteria—del(17p13) and/or t(4p16/14q32). Results: 302 pts received POM + LoDEX, and 153 pts received HiDEX. 225 and 107 pts, respectively, were evaluable for cytogenetics. Baseline characteristics were similar. Median PFS and OS were significantly longer with POM + LoDEX vs. HiDEX, regardless of cytogenetic risk (Table). The most common grade 3/4 AEs were neutropenia, anemia, and infection (Table). Discontinuation due to AE was low: 4% vs. 6% (high risk) and 10% vs. 4% (standard risk). Conclusions: Median PFS and OS were significantly longer with POM + LoDEX vs. HiDEX in pts with cytogenetically-defined high-risk disease, consistent with results from the intent-to-treat population. Tolerability was acceptable. POM + LoDEX should be considered a new Tx option in pts failing LEN and BORT. Clinical trial information: NCT01311687. [Table: see text]
Clinical response by baseline characteristics in patients (pts) with relapsed and bortezomib (BTZ)-refractory multiple myeloma treated with panobinostat (PAN), BTZ, and dexamethasone (DEX; PANORAMA 2).
Authors: Alsina Melissa , Richardson Paul Gerard Guy , Schlossman Robert L. , Weber Donna M. , Coutre Steven E. , Gasparetto Cristina , Mukhopadhyay Sutapa , Ondovik Michael S. , Khan Mahmudul H , Paley Carole S. , Lonial Sagar 
Published: March 2020

8531 Background: In PANORAMA 2, PAN + BTZ + DEX recaptured responses in heavily pretreated pts with BTZ-refractory MM; overall response rate (ORR), clinical benefit rate (CBR), and progression-free survival (PFS) were 34.5%, 52.7%, and 5.4 months, respectively. Here, we evaluate clinical response per baseline characteristics. Methods: Response was based on European Group of Blood and Marrow Transplantation 1998 criteria. High-risk cytogenetics was defined as del(17p), t(4;14), or t(14;16). Quality of life (QoL) was measured with Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) v4.0 scale. Results: Response rate trended higher in pts whose prior BTZ therapy was not their last line of therapy (Table). Although no trend in response rate was noted, PFS appeared longer in pts progressing within 60 days of their last BTZ-containing regimen than in those progressing on their last BTZ-containing regimen. In the 14 pts with high-risk cytogenetics, ORR was 42.9% and CBR was 71.4%. The mean FACT/GOG-Ntx subscale did not exhibit a clinically meaningful change from baseline (mean ± standard deviation [SD], 114.2 ± 21.1; n = 41) to cycle 9 day 1 (day 169; 104.2 ± 15.4; n = 16) as determined by 50% SD threshold for minimally important difference. Other QoL parameters were similarly unchanged. Conclusions: PAN + BTZ + DEX demonstrated activity regardless of baseline demographics in heavily pretreated pts with BTZ-refractory MM. Clinical trial information: NCT01083602. [Table: see text]
Pomalidomide (POM) with or without low-dose dexamethasone (LoDEX) in patients (Pts) with relapsed and refractory multiple myeloma (RRMM): MM-002 phase II age subgroup analysis.
Authors: Jagannath Sundar , Hofmeister Craig C. , Baz Rachid C. , Siegel David Samuel DiCapua , Vij Ravi , Chen Christine , Lonial Sagar , Anderson Kenneth Carl , Chen Min , Zaki Mohamed H. , Richardson Paul Gerard Guy 
Published: March 2020

8532 Background: POM demonstrated clinical efficacy and favorable tolerability in RRMM pts previously treated with lenalidomide (LEN) and bortezomib (BORT), in the randomized, multicenter, open label MM-002 phase II trial. This analysis evaluated whether the efficacy and tolerability of POM+LoDEX treatment is consistent across age subgroups. Methods: Pts with RRMM who had received ≥ 2 prior therapies, including LEN and BORT, and were refractory to their last regimen were randomized to either POM+LoDEX (POM 4 mg/day, days 1–21 of a 28-day cycle; LoDEX 40 mg/week) or POM alone. End points included progression-free survival (PFS), response rate (based on EBMT criteria), response duration, and safety. A post-hoc analysis based on age (≤ 65 vs. > 65 yrs) was conducted. Results: A total of 221 pts with a mean age of 64 yrs (range 34–88) were randomized to POM+LoDEX (n = 113) or POM (n = 108). The efficacy outcomes and the most common treatment emergent grade 3/4 adverse events (AEs) for the age subgroups according to treatment arm are presented in the Table. Conclusions: Regardless of age (≤ 65 vs. > 65 yrs), POM with or without LoDEX was effective and generally well tolerated in heavily pretreated RRMM pts who had already received LEN and BORT. POM with or without LoDEX represents a new clinical option for pts previously treated with numerous lines of therapy. Updated data will be presented at the meeting. Clinical trial information: NCT00833833. [Table: see text]
Combined analysis of single-agent lenalidomide in relapsed/refractory mantle cell lymphoma.
Authors: Witzig Thomas E. , Vose Julie , Zinzani Pier Luigi , Habermann Thomas Matthew , Tuscano Joseph M. , Sinha Rajni , Williams Michael E. , Drach Johannes W. , Ramchandren Rod , Kalayoglu Besisik Sevgi , Zhang Lei , Cicero Sherri , Fu Tommy , Goy Andre 
Published: March 2020

8533 Background: Mantle cell lymphoma (MCL) is an aggressive form of non-Hodgkin lymphoma (NHL) with poor prognosis. The immunomodulatory agent lenalidomide shows consistent activity with tolerable safety in multiple phase II studies of relapsed/refractory aggressive NHL (NHL-002 and NHL-003) and MCL post-bortezomib (MCL-001). This pooled analysis further examined the efficacy and safety of single-agent lenalidomide in patients with relapsed/refractory MCL. Methods: Single-agent lenalidomide was given 25 mg/d PO on days 1-21 of 28-day cycles as tolerated for 52 weeks (NHL-002) or until disease progression (NHL-003 and MCL-001). All MCL patients received ≥1 prior treatment, including bortezomib in MCL-001. Efficacy data were examined by independent central review for MCL-001 and NHL-003 and by investigators for NHL-002. Results: 206 patients with relapsed/refractory MCL were studied. The median age was 67 y (range 33-84; 63% ≥65 y), 91% stage III/IV disease and 51% had received ≥4 prior regimens (76% prior bortezomib). Overall response rate (ORR) with lenalidomide was 32% (10% CR/CRu), with a median time to response of 2.1 months and median duration of response (DOR) of 16.6 months (not yet reached in patients with CR/CRu; Table). Kaplan-Meier estimates for median PFS and OS were 5.4 and 23.9 months, respectively. Mean daily dose of lenalidomide was 21 mg. Grade 3/4 AEs included neutropenia (44%), thrombocytopenia (29%), anemia (11%), and fatigue (7%). Other any-grade AEs included tumor flare reaction (7%), venous thromboembolic events (7%), and invasive second primary malignancies (3%). Conclusions: Lenalidomide produced rapid and durable responses in patients with relapsed/refractory MCL, and exhibited a predictable safety profile among 3 phase II studies of lenalidomide in heavily pretreated patients, including prior treatment with bortezomib. Clinical trial information: MCL-001: NCT00737529; NHL-002: NCT00179660; NHL-003: NCT00413036. [Table: see text]
Treatment outcome with the combination of carfilzomib, lenalidomide, and low-dose dexamethasone (CRd) for newly diagnosed multiple myeloma (NDMM) after extended follow-up.
Authors: Jakubowiak Andrzej J. , Dytfeld Dominik , Griffith Kent A. , Jasielec Jagoda , McDonnell Kathryn , Lebovic Daniel , Vesole David H , Jagannath Sundar , Chottiner Elaine G. , Anderson Tara B. , Detweiler-Short Kristen , Stockerl-Goldstein Keith , Ahmed Asra Z. , Jobkar Terri L. , Durecki Diane E. , Mietzel Melissa A , Couriel Daniel R. , Vij Ravi , Kaminski Mark Stefan 
Published: March 2020

8543 Background: We previously reported results from a phase 1/2 trial of CRd in NDMM (NCT01029054), demonstrating a high rate (42%) of stringent complete response (sCR) and overall favorable efficacy /safety after a median of 12 cycles of treatment (tx) and a median follow-up of 13 mo (Jakubowiak et al Blood, 2012). Here we report updated results after extended tx and additional 12 mo of follow-up. Methods: Patients (pts) received 28-day (d) cycles of carfilzomib (CFZ) 20–36 mg/m2 IV (d1, 2, 8, 9, 15, 16), lenalidomide (LEN) 25 mg PO (d1–21), and dexamethasone 40/20 mg PO wkly (cycles 1–4/5–8). For cycles 8–24, CRd was given with a modified CFZ schedule (d1, 2, 15, 16) and then LEN alone after cycle 24. Stem cell transplant was an option after cycle 4. Response was assessed by IMWG plus nCR. Results: As of Nov 2012, 53 pts had received a median of 22 CRd cycles (range 2–24); 7 pts opted for transplant; 24 continued LEN maintenance for median 8 mo (range 1–10). Median follow-up was 25 mo (range 5–37). With extended tx, the CR rate was 64%; sCR improved from 42% to 53%, ≥nCR from 62% to 72%, and ≥VGPR from 81% to 87% (follow-up 13 vs 25 mo); ≥PR remained at 98%. Immunophenotypic CR (IMWG) was achieved in 22/26 evaluated pts. Of pts in sCR, 25% had high-risk cytogenetics per IMWG. In pts who did not proceed to transplant (n=46), the sCR was 59%, CR 70%, ≥nCR 78%, ≥VGPR 91%, and ≥PR 100%. Over the course of tx, depth of response improved. Median time to ≥VGPR was 4 cycles (range 2–17), ≥nCR 4.5 cycles (range 2–15), and sCR 10 cycles (range 4–30); 2 pts converted to sCR during LEN maintenance. At 2 years, the estimated PFS rate was 94% and OS was 98%; for pts with sCR, rates were 96% and 100%, respectively. Adverse event types, rates, and dose modifications during extended tx were comparable with those previously reported. There was 1 death off study due to disease progression. Conclusions: Extended follow-up showed that depth of response continued to improve over the course of prolonged CRd tx, resulting in exceptional CR, sCR, and PFS. Extended tx continued to be well tolerated. The results compare favorably with historical studies in both transplant and non-transplant NDMM. Clinical trial information: NCT01029054.
Comparative outcomes of splenectomy and rituximab-based chemotherapy in elderly patients with splenic marginal zone lymphoma.
Authors: Olszewski Adam J. 
Published: March 2020

8549 Background: Despite advances in diagnosis and therapy, over 50% of patients with splenic marginal zone lymphoma (SMZL) undergo splenectomy. The objective of this retrospective study was to compare outcomes in SMZL patients undergoing surgery or rituximab-containing chemoimmunotherapy (RCIT) based on the Surveillance, Epidemiology, and End Results-Medicare linked database. Methods: Records of 521 SMZL patients diagnosed between 2000 and 2007 were extracted, excluding cases with incomplete Medicare coverage. Two treatment arms were defined by receipt of RCIT or splenectomy within 2 years of diagnosis. Factors confounding treatment selection or prognosis were balanced in both arms using a propensity score. The primary endpoint was lymphoma-related death, estimated using competing risk models, with overall survival (OS) and toxicities as secondary endpoints. Results: Of the 341 eligible patients (median age, 77 years), 67 (20%) were untreated, while 169 (50%) underwent splenectomy and 97 (28%) chemotherapy (64% single-agent rituximab) at median 1.4 months from diagnosis. Stage IE, treatment in a teaching hospital and good performance status were associated with a preference for splenectomy. There was no evidence of significantly different risk of lymphoma-related death after treatment with RCIT rather than surgery (hazard ratio, HR, 1.10, 95%CI 0.56-2.18, P=0.78). There was an excess of early mortality after splenectomy (7% within 90 days) but more later events with RCIT (OS at 3 years 69% vs. 67%, respectively). More patients required chemotherapy after surgery (38%) than vice versa (14%, P<0.001). Nursing home admissions were more common after splenectomy (22%, P=0.03). There were more inpatient hospitalizations after multidrug RCIT (P=0.003), but not after rituximab alone (P=0.65). Conclusions: Although SMZL is considered indolent, most elderly patients required treatment soon after diagnosis in this population-based study. Survival outcomes were similar after either RCIT or splenectomy. Complications of surgery or combination chemotherapy are significant, suggesting rituximab alone as a more suitable option in elderly patients.
Dose-dense R-CHOP (administered every 2 weeks) with sargramostim in patients with newly diagnosed diffuse large B-cell lymphoma.
Authors: Chaudhary Preeti , Groshen Susan G. , Tsao-Wei Denice D , Siddiqi Imran , Duddalwar Vinay , Berman Nancy , Duran Christine , Wang Teh-Chun , Tulpule Anil 
Published: March 2020

8554 Background: R-CHOP administered every 3 weeks is standard of care for the treatment of diffuse large B-cell lymphoma (DLBCL). There are conflicting reports regarding the superiority of dose dense (DD) regimen (R-CHOP administered every 2 weeks), compared to the standard R-CHOP regimen. In a Phase II study, the tolerability and efficacy of DD-RCHOP+Sargramostim was evaluated. Methods: All patients received intravenous rituximab, 375 mg/m2; cyclophosphamide, 750 mg/m2; doxorubicin, 50 mg/m2 and vincristine, 1.4 mg/m2 on day 1; prednisone 100 mg orally on days 1-5 and sargramostim 250 mg/m2subcutaneously on days 3-13. Chemotherapy cycles were repeated every 2 weeks. Results: We studied50 newly diagnosed, previously untreated DLBCL patients (median age 54.1 years, range 21.4-80.3 years). Stage III and IV disease was noted in 12 (24%) and 29 (58%) patients, respectively. Baseline characteristics included the following: high-intermediate or high-risk IPI score (n=38, 76%), extranodal involvement (n=32, 64%), bone marrow infiltration (n=5, 10%), B-symptoms (n=23, 46%), median LDH level (272, range 118-3797) and good baseline performance status (n=45, 90%). The median follow up from the start of treatment was 12.7 months (range 0.1-41.4 months). Among the 46 patients evaluated for response, complete response (CR) or unconfirmed CR (CRu) was observed in 36 (78%) patients, partial response (PR) or an unconfirmed PR in 9(20%) patients and 1 patient had stable disease. The probability of overall survival (OS) at 18 months was 0.84. The probability of disease free survival in complete responders at 9 months was 0.89. Neutropenia was the most common hematological toxicity and accounted for delays in 40 (20%) treatment cycles. There were no episodes of fever/sepsis in the 33 patients (66%) with grade 3 or 4 neutropenia. IgG, IgA and IgM levels decreased during therapy and returned to normal in 2-4 months post therapy. No opportunistic infections were reported. Conclusions: The administrationof DD-RCHOP+Sargramostim regimen is safe, tolerable and effective in patients with newly diagnosed DLBCL. However, neutropenic episodes were significant, accounting in many cases for treatment delays.
Certification and role of local pathologists for diffuse large B-cell lymphoma (DLBCL) subtyping and eligibility determination in the phase II PYRAMID study.
Authors: Said Jonathan W. , Reeves James Andrew , Flinn Ian , Tulpule Anil , Robles Robert Leon , Flowers Christopher , DiBella Nicholas J. , Kolibaba Kathryn S. , Venugopal Parameswaran , Kolevska Tatjana , De Vos Sven , Jaye David L. , Esseltine Dixie , Mulligan George , Corvez Maria Margarita , Eckardt John R. , Brockman Bryan , Chico Isagani M. , Leonard John , Kussick Steven 
Published: March 2020

8559 Background: The role of local pathologists in promoting patient (pt) accrual and evaluating eligibility criteria involving a complicated immunohistochemical (IHC) algorithm has rarely been investigated. The phase II PYRAMID trial (NCT00931918) is assessing R-CHOP ± bortezomib for newly diagnosed pts with non-germinal-center B-cell (non-GCB) subtype DLBCL. In this trial, local pathologists were encouraged to perform DLBCL subtyping at the point of biopsy, identify suitable pts for the trial, and facilitate accrual. Methods: Determination of GCB vs non-GCB subtype is per the Hans method, an algorithm based on IHC for CD10, BCL-6, and IRF4/MUM1. In stage 1, pathologists demonstrated IHC subtyping proficiency by evaluating a tissue microarray (TMA) of 12 DLBCL cases; those with ≥80% of samples in agreement with central lab results were certified for determining trial eligibility. In stage 2, to broaden participation, pathologist certification occurred via teleconference outlining trial eligibility criteria, tissue subtyping requirements, and determining pathologists’ experience with the Hans method. Results: 182 pathologists have been certified for local subtyping, 50 via TMA and 132 by teleconference. 66/88 active study sites have ≥1 certified pathologist. Only 1 of the 10 top enrolling sites lacks a certified pathologist. 52% (84/162) of pts have been enrolled based on local pathologist subtyping prior to central lab confirmation. Discordance with central lab results occurred in 9/84 cases (11%). Enrollment rates pre- and post-local pathologist certification were 0.053 and 0.096 pts/site/month; an improvement of 81%. Trial accrual correlates with the presence of a certified local pathologist (p=0.0026). The rate of ineligible GCB cases sent for central lab testing was lower from sites with a certified pathologist (23% [69/299 cases] vs 38% [40/106 cases] for sites without). Conclusions: Engagement of local pathologists in trials requiring pathology selection can significantly improve accrual. This study demonstrates the effectiveness of various training modalities in improving selection by local pathologists using a complex IHC algorithm. Clinical trial information: NCT00931918.
Y90-ibritumomab tiuxetan (Y90-IT) and high-dose melphalan as conditioning regimen before autologous stem cell transplantation (ASCT) for elderly patients with lymphoma in relapse or resistant to chemotherapy: A feasibility trial (SAKK 37/05).
Authors: Voegeli Michele , Rondeau Stephanie , Berardi Simona , Lerch Erika , Wannesson Luciano , Pabst Thomas , Rentschler Jochen , Bargetzi Mario , Jost Lorenz M. , Ketterer Nicolas , Bischof Delaloye Angelika , Ghielmini Michele E. G. 
Published: March 2020

8560 Background: Standard conditioning regimens for ASCT are often not tolerated by elderly patients. Single agent high-dose melphalan has been shown to be safe and active in elderly patients with multiple myeloma. Y90-IT is a well-tolerated lymphoma treatment and feasible in the transplantation setting. We therefore investigated this combination of high-dose melphalan and Y90-IT as a conditioning regimen for elderly patients. Methods: Patients ≥65 years with relapsed or chemotherapy resistant CD20-positive lymphoma in PR or CR after salvage chemotherapy could be enrolled prior to stem cell mobilization. Myeloablation regimen consisted of standard dose Y90-IT followed by melphalan at escalating doses (100, 140, 170 and 200mg/m2, with a 3+3 phase I design) and by ASCT. The primary objective was to identify the MTD of melphalan in combination with standard dose Y90-IT (as defined < 1 DLT in 3 patients); secondary endpoints were toxicity and CR rate 100 days after transplantation. Results: Between 2006-2012 twenty patients were included. Median age was 72 years (range 66-77). One patient was considered retrospectively ineligible and was evaluable for toxicity but not for DLT. Thirteen patients received the treatment and were transplanted. Eleven patients were evaluable for DLT. No DLT occurred. Non-hematological grade 3 or higher treatment related adverse events were: infection (n=6, including 2 cases of febrile neutropenia), diarrhea (n=3), mucositis, anorexia, viral hepatitis, hypokalemia, dehydration and multi-organ failure (n=1). Seven patients did not start treatment because of mobilization failure (n=3), progressive disease (n=2), worsening of cardiac failure (n=1) and grade 3 dyspnea (n=1). Seven patients achieved a CR/CRu and 2 patients were stable 100 days after transplantation. Conclusions: The combination ofstandard dose Y90-IT and high dose melphalan (200mg/m2) is a safe and feasible conditioning regimen before ASCT for patients ≥65 years. The results show promising activity. Clinical trial information: NCT00392691.