bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ibrutinib dose modifications for management of cardiac adverse events in patients with B-cell malignancies: Pooled analysis of 10 clinical trials.
Authors: Stephens Deborah Marie , Brown Jennifer R. , Ma Shuo , Wang Michael , Moreno Carolina D. , Robak Tadeusz , Stevens Don A. , Li (Lee) Xin (Shane) , Saifan Chadi , Hsu Emily , Patel Sima , Burger Jan Andreas 
Published: June 2023

7538 Background: Continuous therapy with once-daily ibrutinib (Ibr) is associated with long-term PFS in pts with B-cell malignancies. Dose reduction is a potential AE management approach that may optimize treatment outcomes. We evaluated outcomes with dose reductions in Ibr-treated pts with cardiac AEs. Methods: Data were pooled for Ibr-treated pts from 10 studies of CLL (n=781), mantle cell lymphoma (MCL; n=250), marginal zone lymphoma (MZL; n=63) or Waldenström macroglobulinemia (WM; n=169). Cardiac AEs, initial and recurrent, were identified by preferred terms within the cardiac disorders system organ class. Recurrence was defined as an AE of same or worse grade, and was measured up to 30 days after last dose of ibrutinib or start of next-line therapy, whichever occurred earlier. Results: Overall, 234/1263 pts (19%) had cardiac AEs of any grade. Twelve pts were excluded from the analysis: 9 who had a dose reduction prior to a cardiac AE (0.7%) and 3 who had a fatal cardiac AE with no prior cardiac AE (0.2%). Of the remaining 222 pts with grade 1-4 cardiac AEs, 22 (10%) had Ibr dose reduction to 420 mg (n=3), 280 mg (n=10), or 140 mg (n=9) after a cardiac AE. These pts (n=22) tended to be older (≥75 y: 45% vs 29%), less heavily pretreated (≥1 prior therapy: 45% vs 73%), and with a lower Ibr discontinuation rate (23% vs 48%) than those without dose reduction (n=200). Recurrence of the same cardiac AEs at the same or worse severity was less frequent in pts with dose reductions, both overall (14% vs 18%) and as serious AEs (5% vs 10%). No pt died due to cardiac AE recurrence. Among pts with cardiac AEs who started with the 420 mg Ibr dose (177/222; excludes 45 patients with MCL or MZL who per label start with 560 mg dose), no cardiac AE recurred at same or worse severity in the subset with dose reductions (Table). PFS was not negatively impacted by dose reduction, both overall (n=22; median PFS not reached [NR], 24-mo PFS: 91%), and in those who started with the 420 mg dose (n=18; median PFS NR; 24-mo PFS, 94%). Conclusions: Dose reduction for cardiac AEs may enable pts to continue to benefit from long-term Ibr and mitigate the risk of cardiac AE recurrence or worsening. Clinical trial information: NCT01105247 , NCT01236391 , NCT01578707 , NCT01722487 , NCT01611090 . [Table: see text]
Depth of metabolic response at interim PET and survival outcomes among patients with primary refractory and early relapsing diffuse large B-cell lymphoma (DLBCL).
Authors: Bock Allison Marie , Mwangi Raphael , Ataei Fatemah , Thorpe Matthew , Maurer Matthew J. , Pritchett Joshua , Shreve Jacob Tyler , Paludo Jonas , Khurana Arushi , Cerhan James Robert , Witzig Thomas E. , Habermann Thomas Matthew , Wang Yucai , Young Jason R. , Nowakowski Grzegorz S. 
Published: June 2023

7543 Background: Total metabolic tumor volume (TMTV) and maximum standardized uptake value (SUVmax) may improve upon standard 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET-CT)-based assessment of advanced DLBCL during treatment. We report the association of TMTV and SUVmax changes at interim PET-CT (PET2) on survival outcomes in patients with primary refractory DLBCL (prDLBCL) and early relapsing DLBCL (erDLBCL). Methods: Adult patients with prDLBCL (less than a complete response (CR) or progression by the end of treatment (EOT)) or erDLBCL (CR at EOT with relapse within 12 months) between 2005 and 2019 at Mayo Clinic Rochester were included. The % change (Δ) from baseline to PET2 (after 2 cycles of 1L therapy) of TMTV and SUVmax were measured. A PET segmentation threshold of 1.5 liver mean SUV + two standard deviations with a minimum volume constraint of 0.5 mL was utilized (MIM Software, Inc., Cleveland OH, USA) with manual input as needed. Functional splines analysis determined SUVmax and TMTV threshold for analysis. Results: 131 patients had complete PET-CT data (N=79 prDLBCL, N=52 erDLBCL). Baseline median TMTV and SUVmax were 767.4 cm3 (range 0.9-6840.4) and 20.5 (2.0-52.6), respectively. At a median follow up of 77.6 months, 81 patients had died. 2-year OS rate was 53% (95% CI: 42-67) for patients with a PET2 ΔSUVmax decline ≥65% compared to 15% (95% CI: 7-29) for patients with a PET2 ΔSUVmax decline <65%(p<0.001). PrDLBCL had a 2-year OS rate of 48% (95% CI: 31-74) for a ΔSUVmax ≥65% compared to 7% (95% CI: 2-21) for a ΔSUVmax <65%(p<0.001), which captured 58% of prDLBCL patients (N=46). Two-year OS rate was 43% (95% CI: 34-54) for patients with a ΔTMTV ≥75% compared to 5% (95% CI: 1-35) for patients with ΔTMTV <75% (p<0.001). All patients with a ΔTMTV <75% had prDLBCL. PrDLBCL had a 2-year OS rate of 28% (95% CI: 18-44) for a ΔTMTV ≥75%. The outcomes for ΔSUVmax <65% and ΔTMTV <75% at PET2 remained significant in a cox regression model adjusted for IPI and bulky disease (>10cm)(Table). Conclusions: A ΔTMTV decline <75% or a ΔSUVmax decline <65% at PET2 identified an ultra-high-risk subgroup of DLBCL with particularly poor outcomes, that captured a high percentage of prDLBCL patients, and was significant after adjusting for IPI and bulky baseline disease. These patients may benefit from clinical trials evaluating alternative PET-adapted treatment strategies, but further evaluation among all patients with DLBCL is needed. [Table: see text]
Final three-year follow-up analysis of phase I/II study on tirabrutinib in patients with relapsed or refractory primary central nervous system lymphoma.
Authors: Asai Katsunori , Narita Yoshitaka , Nagane Motoo , Mishima Kazuhiko , Terui Yasuhito , Arakawa Yoshiki , Yonezawa Hajime , Fukuhara Noriko , Sugiyama Kazuhiko , Shinojima Naoki , Aoi Arata , Nishikawa Ryo 
Published: June 2023

7548 Background: Primary central nervous system lymphoma (PCNSL) is known as an uncommon and extremely aggressive type of non-Hodgkin lymphoma of brain tumors. Tirabrutinib (TIR), a second-generation oral Bruton’s tyrosine kinase inhibitor, was approved for the treatment of relapsed or refractory PCNSL (rrPCNSL) based on the results of phase I/II study in Japan (Trial registration: JapicCTI-173646) in 2020. Methods: In this study, 44 Japanese patients with rrPCNSL received TIR QD at doses of 320 mg (n = 20), 480 mg (n = 7), or 480 mg while fasting (480 mg fasted: n = 17). The International PCNSL Collaborative Group criteria were used to assess the primary endpoint, which was the overall response rate (ORR). We previously reported the interim results with 14.9 (range:1.4–27.7) months of median follow-up in 2020 (Mishima et al., the 25th Society for Neuro-Oncology 2020). The final analysis results with a three-year follow-up are reported here (data cutoff: April 27th, 2022). Results: For the entire population, the ORR was 63.6% with 36.4% of complete response, the median duration of response was 9.2 months, the median progression-free survival was 2.9 months, and the median overall survival was not reached (median follow-up: 37.1 months). The most frequent adverse events (AEs) were skin and subcutaneous tissue disorders and blood and lymphatic system disorders at any grade, including rash (36.4%) and neutropenia (27.3%), leukopenia (25.0%), lymphopenia (18.2%), and thrombocytopenia (11.4%). Grade ≥3 AEs were neutropenia (9.1%), leukopenia (9.1%), lymphopenia (6.8%), and erythema multiforme (6.8%). One patient with 480 mg had grade 5 AEs (Pneumocystis jirovecii pneumonia and Interstitial lung disease), while neither new grade 5 AEs nor new safety profiles were observed since the last data cutoff. As of the current data cutoff, 15 and 6 of 44 patients had been receiving TIR for more than one and three years, respectively, and 5 of the 6 patients continued receiving TIR, including 4 patients who were receiving 480 mg fasted. Conclusions: In conclusion, TIR showed long-lasting effectiveness in a subset of patients with a tolerable safety profile of rrPCNSL. Clinical trial information: JapicCTI-173646. [Table: see text]
Safety and efficacy profile of a very low dose of MC-1-50 for treatment of r/r NHL.
Authors: Li Shiqi , Yang Zhi , Liu Lin , Yuan Zhongtao , Zhang Yingzi , Luo Le , Zhang Lihua , Chen Yingnian , Zhang Qianzhen , Shen Junjie , Li Yunyan , Wang Linling , Wang Meiling , Zhu Wei , Huang Yufeng , Wang Youcheng , Dong Yancheng , Wang Sanbin , Qian Cheng 
Published: June 2023

7553 Background: CD19 chimeric antigen receptor (CAR) T cell therapy has shown promising efficacy in the r/r B-NHL. However, many patients fail to respond, or quickly relapse after the initial response. To improve efficacy, we established a novel PrimeCAR platform (PRIMCAR) that shortens the manufacture time to about 2 days and enriches more stem cell-like memory T (Tscm) cells in the product. The MC-1-50 CAR-T cells produced by the PRIMCAR platform have exhibited a promising efficacy for B-ALL (Shiqi Li, et al. J Clin Oncol 2022; 40 [suppl 16]. Abstract 7008). Here, we report the preliminary safety and efficacy data of MC-1-50 for r/r B-NHL. Methods: In this Phase I /II study (NCT04271410), MC-1-50 CAR T cells were manufactured by the PRIMCAR platform. T cells were infected with a lentiviral vector encoding a humanized CD19 specific scFv following 4-1BB and CD3ζ cytoplasmic domain. Patients (pts) received single-dose of MC-1-50 at dose ranged 0.5-5×105 CAR+/kg (Level 1, 0.5×105 CAR+/kg; Level 2, 3×105 CAR+/kg; Level 3, 5×105 CAR+/kg). Pts were pre-conditioned with fludarabine (25-30 mg/m2) and cyclophosphamide (200-300 mg/m2) daily for 3 days. Toxicity was graded by CTCAE, CRS and ICANS were graded by ASTCT criteria. Primary endpoints are the dose-limiting toxicities (DLTs) rate in the first 28 d and safety to determine a recommended Phase II dose (RP2D). Results: As of May 2022, thirteen pts with r/r B-NHL were infused with MC-1-50. Disease characteristics and outcomes are shown in the table. No DLTs were reported. 3 pts (23.08%) experienced CRS, including 2 (15.38%) at grade 1, and 1 (7.69%) at grade 2, no ≥ 3 CRS were observed, and no ICANS occurred. A preliminary dose-dependent response was observed. At dose Level 1 (DL1), none of the 3 patients showed a good response. At DL2, two patients showed PR response, and 3 of the 5 patients achieved CR response. At DL3, 5 of 5 patients achieved CR response. These patients with CR response did not experience a relapse during the followed-up (ranging from 5-18 months). CAR-T expansion was observed in all dose levels, although long-term persistence cannot be evaluated yet, 4 of 5 patients in DL2 and 3 of 5 patients in DL3 had detectable CAR expression by qPCR (≥50 copy/ ug DNA) in the 6-month follow-up. Conclusions: The PRIMCAR platform could produce CAR T cells quickly with a high percentage of Tscm. Treatment of r/r B-NHL at very low dose resulted in excellent safety profiles while exhibiting a high and durable efficacy. Clinical trial information: NCT04271410 . [Table: see text]
Evaluation of outcomes between rituximab-abbs and reference product rituximab in adult patients with newly diagnosed diffuse large B-cell lymphoma in a non-inferiority study.
Authors: Nguyen Vivian , Wong Helen , Mok Timothy , Cushing Merta , Lam Michael , Ho Stephanie Lai-Ting , Law Lisa Y. , Aziz Ashraf R. , Niu Fang , Hui Rita L. 
Published: June 2023

7556 Background: Rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the standard of care for diffuse large b-cell lymphoma (DLBCL). However, adding rituximab has increased treatment costs. Thus, development of biosimilars help provide more affordable care. Though rituximab-abbs was studied primarily in the follicular lymphoma population, in 2018 the FDA approved this drug as the first biosimilar for all indications of the reference product based on extrapolation. However, there are no clinical trials studying the effectiveness and safety of rituximab-abbs in DLBCL in the U.S. Methods: This is a data-only, non-inferiority study to compare two-year overall survival (OS) and the incidence of serious adverse events (AEs) between rituximab-abbs and its reference product (RP) as R-CHOP among adult patients with newly diagnosed DLBCL, with an index date from December 1, 2018-December 31, 2020. Non-inferiority will have a margin set to the upper limit of 5% for serious AEs, and a lower limit of 5% for OS. To assess for safety, we are following up on AEs until end of patient’s Kaiser Permanente (KP) membership, death, six months after last rituximab dose, or December 2022 for all AEs except infusion reactions. For infusion reactions only, the follow up is 1 day. To assess for efficacy, we are following up on OS until end of patient’s KP membership, death, December 2022, or two years. Results: 535 patients were enrolled; 240 patients received RP rituximab and 295 patients received rituximab-abbs. The median time of follow up was 730 days, or 2 years (range in days, 2.0-730). Complete response was similar in the RP rituximab group and the rituximab-abbs group (70.4% vs. 77.3% respectively, p = 0.07). Additionally, partial response was also similar among the two products (19.2% vs. 16.9%, p = 0.51). The Kaplan-Meier two-year survival curve was also similar between the two products (p = 0.52), demonstrating no difference. Further statistical analysis confirmed the non-inferiority of the biosimilar products for survival. Infusion reaction adverse events (13.8% vs. 11.2%, p = 0.37) and non-infusion adverse events (68.3% vs. 71.2%, p = 0.47) were also similar in the two groups, with a survival curve demonstrating no difference between the two products and data analysis meeting the non-inferiority criteria. Conclusions: Rituximab and rituximab-abbs are non-inferior to each other in both efficacy and safety. Long term follow up would be needed to confirm these results.
Impact of neighborhood deprivation on disability free survival in patients with aggressive B cell non-Hodgkin lymphoma.
Authors: Burkart Madelyn , Demetriou Nicholas , Sunderraj Ashwin , Ma Shou , Winter Jane N. , Gordon Leo I. , Moreira Jonathan , Karmali Reem , Roy Ishan 
Published: June 2023

7564 Background: Advancements in treatment over the last decade have greatly improved survival in B cell non-Hodgkin’s lymphoma (NHL), yet not all patients (pts) benefit the same. Non-Hispanic Black (NHB), uninsured and lower socioeconomic status pts continue to suffer worse survival. However, the impact of neighborhood deprivation on disability has not been explored. We aimed to assess the association between neighborhood deprivation and disability free survival (DFS) in NHL pts. Methods: 258 aggressive NHL pts treated between 2005-2020 were included. Pts without documented follow up were excluded. Race/ethnicity was categorized as non-Hispanic white (NHW), Hispanic, NHB and other. Primary outcomes included progression free survival (PFS), overall survival (OS) and DFS. DFS was defined as time to needing any rehabilitative, home-health or skilled nursing services immediately following induction therapy, indicating disability and lack of functional independence. Neighborhood deprivation was assigned using the national Area Deprivation Index (ADI), a validated measure classifying neighborhood adversity. Pts were categorized into high (67-99), intermediate (34-66) or low (1-33) ADI scores, with least disadvantaged designated by lower scores. Kaplan-Meier analyses were used to compare PFS, OS and DFS. Results: Demographic data is shown in the table; 45% were female, 65% were NHW, 10% were NHB, 8% were Hispanic and 10% were other. Median age at diagnosis was 57 years. There was no difference in PFS or OS between racial/ethnic groups (p=0.91 and p=0.23 respectively). Payor source influenced both PFS and OS (p<0.001 and p<0.001 respectively), with self-pay associated with worse PFS and OS. Neighborhood deprivation based on ADI did not influence PFS (p=0.33) or OS (p=0.76). High ADI score was associated with worse DFS compared to lower ADI scores (p=0.03). ADI score differed significantly based on race/ethnicity (p<0.0001), with more NHB pts residing in areas of high ADI scores (40% vs 5% NHW vs 10% Hispanic). There was no association between ADI score and a pt’s ECOG performance status, IPI score or albumin at diagnosis (p=0.87, p=0.78 and p=0.59 respectively). Conclusions: NHL pts with higher neighborhood adversity experience more disability after treatment despite similar survival. Further work is needed to better understand how neighborhood factors are contributing to disability before community-level strategies for improvement can be developed. [Table: see text]
Final analysis of the phase IB part of the LOC-R01 trial, a non-comparative randomized phase IB/II study of escalating doses of lenalidomide and ibrutinib in association with R-MPV for patients with a newly diagnosed primary central nervous system lymphoma (PCNSL).
Authors: Alcantara Marion , Chevrier Marion , Jardin Fabrice , Schmitt Anna , Houillier Caroline , Oberic Lucie , Chinot Olivier L. , Morschhauser Franck , Peyrade Frederic , Houot Roch , Foulon Christine , Chauvin Estelle , Ghesquieres Herve , Soussain Carole 
Published: June 2023

7566 Background: Results of conventional induction chemotherapies in PCNSL need to be improved. Ibrutinib, a BTK inhibitor, and lenalidomide, an immunomodulatory drug, have shown promising results in the relapse setting, supporting to further assess their combination with standard high-dose methotrexate-based chemotherapy. Methods: Patients (pts) with newly diagnosed PCNSL, aged 18 to 60, were randomized to receive four 28-day cycles of either ibrutinib or lenalidomide in combination with R-MPV (rituximab, methotrexate, procarbazine, vincristine and prednisone) in a 3+3 design for ibrutinib 420/560/280 mg (D3 to D14 and D17 to D28) and lenalidomide 20 mg D1 to 14/20 mg D1 to 21/15 mg D1 to 21. Responder pts then received a consolidation with R-Cytarabine and an intensive chemotherapy with autologous stem cell transplantation. The objective of the phase IB study was to define the recommended phase II dose (RP2D) based on the dose-limiting toxicity (DLT) occurring during the first induction cycle. We present the results of the phase IB, including the toxicities that occurred throughout induction therapy. Results: 26 pts (median age 52) were randomized, 13 in each treatment group. Four DLTs (/21 evaluable pts) have been observed: grade 5 aspergillosis and pneumocystosis (N=1, ibrutinib 560 mg and concurrent high-dose corticosteroids without prophylaxis), grade 4 catheter-related infection > 7 days (N=1, lenalidomide 20 mg D1-14) and grade 3 increased alanine aminotransferase > 7 days (N=1, lenalidomide 20 mg D1-14 and N=1, lenalidomide 15 mg D1-21). RP2D of ibrutinib and lenalidomide were 560 mg (D3-14 and D17-28) and 15 mg (D1-21) respectively, in combination with R-MPV. One Lyell’s syndrome was reported as a serious adverse event (AE) at cycle 2 in the lenalidomide arm. Grade ≥3 treatment-related AEs occurring in ≥2 pts at any time during induction treatment are detailed in the table. After 4 induction cycles, 3/11 evaluable pts had CR/CRu and 7/11 had partial response (PR) in the ibrutinib group. In the lenalidomide arm, 6/10 evaluable pts had CR/CRu and 4/10 had PR. Survivals will be presented. Conclusions: Targeted induction immunochemotherapy with ibrutinib or lenalidomide and R-MPV is feasible for newly diagnosed PCNSL and shows promising response rates. Adverse events should be monitored carefully. The phase II part of the study is ongoing and opened to patients up to 65 years old. Clinical trial information: NCT04446962 . [Table: see text]
Unveiling the prognostic significance of BCL6+/CD10+ mantle cell lymphoma: A systematic analysis.
Authors: Castillo Dan Ran , Park Daniel , Jeon Won Jin , Chong Esther G , Joung Bowon Floyd , Moon Jin Hyun Floyd , Pham Bryan , Lee Jae , Siddiqui Zeeshan , Nguyen Anthony Loc , Zhang Ke Kurt , Cao Huynh Le 
Published: June 2023

7572 Background: Mantle cell lymphoma (MCL) is heterogenetic B-cell neoplasm that characterized by the presence of the IgH/CCND1 translocation. The significance of CD10 expression in MCL is not fully understood. The co-expression of CD10 and BCL6 in MCL is rare requiring further investigation to determine its clinical significance. This meta-analysis aims to examine the relationship between MCL variants and their cellular behaviors and clinical outcomes. Methods: A search of the GDC and dbGaP database was conducted using the PICOS model and PRISMA guidelines to retrieve survival data. Overall survival (OS) data was pooled from multiple studies and analyzed using the R programming package survival and a log-rank test was performed to compare OS. Mean differences between BCL6+ vs. BCL6- for individual studies were calculated and combined to minimize batch effects. Summary statistics across studies were obtained by averaging mean differences and pooling individual standard deviations. The correlation between CD10 and BCL6 was tested using Fisher's exact test, with a significance level of 0.05. Results: The analysis included a total of 537 patients (425 males and 112 females), with a median age at diagnosis of 69 years in CD10+ MCL and 61.5 years in CD10- MCL. Out of the 537 patients, 70 were CD10+ positive, and BCL6 positivity had an odds ratio of 5.11 [95% CI [2.49, 10.46]; p = 0.0000286) for CD10 positivity compared to CD10 negativity. The subgroup analysis revealed a higher frequency of blastoid/pleomorphic/small variants in BCL6+/CD10+ MCL. BCL6 positivity was associated with worse OS, independent of CD10 expression (median OS of 14 months in BCL6+ MCL vs. 43 months in BCL6- MCL; p = 0.01). The co-expression of BCL6 and CD10 was associated with a shorter median OS (22 months in BCL6+CD10+ vs. 55 months in BCL6-CD10+, p = 0.01) and significantly higher mitotic index (Ki67%) compared to BCL6-/CD10+ MCL (mean Ki67% of 63.13 ± 19.45% vs. 45 ± 21.69%, p < 0.01). The forest plot analysis showed that BCL6 expression was correlated with a significantly higher Ki67% (difference of 24.29; p = 0.0094). Conclusions: Our meta-analysis found that BCL6 expression correlates with CD10 positivity in MCL variants and has a negative impact on prognosis, independent of CD10 expression. Higher Ki67% levels in BCL6+ MCL compared to BCL6- MCL support the prognostic value of the BCL6+ immunophenotype in MCL variants. Prognostic scoring systems adjusted for BCL6 expression should be incorporated into MCL management. Targeted therapies against BCL6 may offer potential treatment options for MCL subtypes. [Table: see text]