bluuebunny/crossref_metadata_2025_split huggingface dataset:
Update of Swatch Study: Selinxor Combined with Lenalidomide and Rituximab (R2) in Adults with Diffuse Large B Cell Lymphoma (DLBCL) and Indolent Non-Hodgkin's Lymphoma (iNHL)
Authors: Wang Li , Li Zhiming , Zhang Lina , Zhang Liling , Mei Jay , Zhao Wei Li 
Published: December 2023

Background：
Patients (pts) with relapsed/refractory (R/R) DLBCL and iNHL who are ineligible for, or relapse after, high-dose chemotherapy (HDC)/autologous stem cell transplantation (ASCT) have a poor prognosis and limited treatment options. Selinexor, a selective inhibitor of nuclear export has received accelerated approval by the U.S. Food and Drug Administration, for the treatment of adult patients with R/R DLBCL. Phase I/II study (NCT05265975), selinexor in combination with lenalidomide and rituximab (R2) for R/R DLBCL and iNHL, is ongoing. Phase I results were previously reported at ICML 2023 (Weili Zhao et al., ICML 2023, #658) and the recommended phase 2 dosing (RP2D) was determined.
Aims:
Here we update the preliminary results of SWATCH study.
Methods：
Additional 6 subjects will be recruited at this dose level 60mg to further confirm the safety and tolerability of RP2D. Eligible pts were treated with 6 cycles of rituximab (375mg/m2 on day 1), lenalidomide (25mg on d1-10) and selinexor (dose level: 60mg, on days 1, 8,15 of each 28-day cycle), followed by selinexor and lenalidomide maintenance until disease progression. Dose limiting toxicities (DLT) was defined as the occurrence of severe toxicities during the first cycle: grade 3 febrile neutropenia&gt; 5 days, grade 4 neutropenia or thrombocytopenia &gt;7 days, grade 3/4 thrombocytopenia with hemorrhage, or any grade 3 non-hematologic toxicity &gt;7 days.
Results:
From May 2022 to April 2023, 16 pts were enrolled and no DLT occurred. At baseline in these 16 pts, refractory to last line was 93.75% and primary refractory was 68.75%. Among 12 efficacy evaluable pts, 3 pts achieved complete response (CR), 5 pts achieved partial response (PR) and another 4 pts achieved progressive disease (PD). Most AEs were grade 1 or 2 and were reversible with supportive care or dose modification. At data cutoff (June 1, 2023), 7 pts were still receiving treatment and no pts came off study due to intolerability or AEs. Median PFS and median DOR were 11.2 months and not reached.
Conclusion：
Selinexor in combination with lenalidomide and rituximab showed encouraging preliminary efficacy and generally tolerable toxicity with an ORR of 66.7%, CR of 25% and median PFS 11.2 months in all evaluable dose level pts, and with an ORR of 80% and CR of 20% in evaluable selinexor 60mg dose (RP2D). This study is currently enrolling patients in the dose expansion group.
A Predictive Model Combining Clinical Characteristics and Nutritional Risk Factors for Overall Survival after Umbilical Cord Blood Transplantation
Authors: Tu Meijuan , Huang Aijie , Ning Lijuan , Tang Baolin , Zhang Chunli , Sun Guangyu , Wan Xiang , Song Kaidi , Yao Wen , Qiang Ping , Wu Yue , Zhu Xiaoyu 
Published: December 2023

Background: Umbilical cord blood transplantation (UCBT) is a curable therapy for hematological disease; however, the impact of nutritional status on UCBT outcomes remains controversial. To evaluate the joint effect of clinical characteristics and nutritional status on the prognosis of patients who underwent UCBT, we screened various factors to establish a predictive model of overall survival (OS) after UCBT.
Methods: We performed an integrated clinical characteristic and nutritional risk factor analysis and established a predictive model that could be used to identify UCBT recipients with poor OS.
Results : Four factors, including disease status, conditioning regimen, calf skinfold thickness and albumin level, were identified and used to develop a risk score for OS, which showed a positive predictive value of 84.0%. A high-risk score (≥2.225) was associated with inferior 3-year OS post-UCBT [67.5% (95% CI, 51.1%-79.4%), P=0.001]. Then, we built a nomogram based on the four factors that showed good discrimination with a C-index of 0.833 (95% CI, 0.743-0.922). Internal validation was performed by using the bootstrap method (corrected C-index:0.804). Multivariate analysis suggested that a high calf skinfold thickness (≥20.5mm) and a low albumin level (&lt;33.6g/L) conferred poor disease-free survival (DFS).
Conclusion: The predictive model combining clinical and nutritional factors could be used to predict OS in UCBT recipients, which may promote preemptive treatment.
Human Single Domain Antibody-Based CAR-T Cells Targeting BAFF-R Demonstrate Promising Preclinical Activity in B Cell Malignancies
Authors: Zhang Cuiling , Luo Qian , Wu Sungui , Xu Le , Wei Qiaoe , Zhang Yanying , Guan Chaoyang , Dong Xiaoqing , Tan Taochao , Chen Bing 
Published: December 2023

Background: B-cell activating factor-receptor (BAFF-R) is a potential B-cell specific target, highly expressed in B cell malignancies and regulates B cell proliferation and survival. Single-chain antibody-based CAR-T cells targeting BAFF-R (PMB101) has demonstrated antitumor effects against human B cell malignancies and can overcome CD19 antigen loss (Qin et al. Sci Transl Med. 2019;11(511)). However, CARs built on antigen-specific single chain antibody variable fragment (scFv) may have some immunological risks. Recently, single variable domain of heavy chain antibodies are becoming an alternative to scFv to construct CARs. To improve the function of BAFF-R CAR-T cells, we designed CARs with only a fully human heavy-chain variable domain.
Methods: A fully human antibody phage display library (IMARS, IASO Biotherapeutics) was used to select anti-BAFF-R clones using optimal protein/cell alternate panning. The enzyme-linked immunosorbent assay (ELISA) and flow cytometry were applied to evaluate the specificity of clones. The screened clones were grafted into a second-generation CAR with CD8α hinge, 4-1BB costimulatory and CD3ζ intracellular signaling domains to generate CAR-T cells. PMB101 and CAR-T cells constructed with VAY736 were used as positive controls. Non-transduced T cells from the same donor were used as a negative control.
Results: Four candidate clones including clone 1, 5, 77 and 80 were finally screened by in vitro functional evaluation, among which clone 5, 77 and 80 were variable domain heavy chain antibodies. The expression levels of the degranulation marker CD107a on CAR-T cells constructed with the four candidate clones were significantly upregulated after coculture with BAFF-R positive tumor cells, while BAFF-R negative tumor cells could not effectively activate CAR-T cells (data not shown). The four clones exhibited similar cytotoxicity in CAR-T cells compared with the PMB101 and VAY736 CAR-T cells using the luciferase-based cytotoxicity assay (data not shown). Xenografts were established in NPG mice following intravenous injection of 1 x 10 6 jeko-1 cells expressing the firefly luciferase gene on day - 5, and a single dose of 4 x 10 6 CAR T cells were infused IV on day 0. Compared to the other groups, no progressive tumor growth was discovered in mice treated with clone 5 CAR-T cells until day 49. Clone 5 CAR-T cells showed excellent in vivo antitumor activity to PMB101 and conferred long-term survival (data not shown).
Conclusion: We developed a novel BAFF-R CAR-T cell product structured on single-domain antibody. This product demonstrated promising preclinical activity, and it may provide an alternative choice for patients with B cell malignancies.
Safety Profile in Patients with Chronic Lymphocytic Leukemia Undergoing Treatment with 1st and 2nd Generation Bruton Tyrosine Kinase Inhibitors: Multicentric Real-World Experience
Authors: Lopez Garcia Alberto , Garcia Alfonso , Macia Ester , Morillo Daniel , Miranda Carolina , Bermejo Laura , Yuste Maria , Llamas Sillero Maria Pilar , Cordoba Raul 
Published: December 2023

INTRODUCTION
Chronic lymphocytic leukemia (CLL) is the most frequent leukemia, being more frequent in older adults.
Bruton's tyrosinkinase inhibitors (BTKi) have revolutionized the treatment, displacing immunochemotherapy treatment in all patient profiles.
The selectivity profile in the action of these drugs means that the toxicity of first and second generation BTKi is different, resulting in higher rates of atrial fibrillation and arterial hypertension, mainly in patients treated in the second line or later, while maintaining their efficacy.
Real-life studies are needed to be able to demonstrate the effects in first-line treatment in a more heterogeneous patient profile, without the strict exclusion and inclusion criteria used in clinical trials.
METHODS
An observational, retrospective, multicenter, retrospective study was performed. Patients with in treatment with Ibrutinib or Acalabrutinib in first line or later were included. Demographic data, comorbidity, cytogenetic and mutational disease data, adverse effect profile, comprehensive geriatric assessment (if applicable) and treatment response evaluation data are collected.
RESULTS
A total of 91 patients were included with a median age of 73.22 years SD 11.06. Fifty-three (58.2%) were male. Fifty-three (58.2%) were treated in frontline, 31.9% (29) in second line and 9.9% (9) in subsequent lines.
Acalabrutinib was used in 25 (27.5%) patients and Ibrutinib in 66 (72.5%). Patient characteristics are shown in Table 1.
Differences were revealed between these two BTKis in terms of line of treatment, with the majority being treated first (P=0.006) and Rai stage, with Rai II predominating (P=0.014). No differences were found between the two BTKis according to the rest of the characteristics.
In terms of toxicity, 14 (15.4%) of patients treated with Ibrutinib developed arterial hypertension, compared to no patients in the Acalabrutinib arm (p=0.009).
With respect to the development of cardiac toxicity, 19 (20.9%) patients suffered some cardiotoxic event, 3 (3.3%) in patients on acalabrutinb and 16 (17.6%) on ibrutinib, with no significant differences found between the two drugs (p=0.2). No significant differences were found with respect to other toxicities (hematologic, digestive, bleeding and infections). Table 2
No differences were found in terms of progression-free survival or overall survival.
CONCLUSIONS
The iBTKs have changed the treatment of CLL, although the second-generation iBTKs have a safer cardiovascular profile and are just as effective in our cohort, even in the frontline.
Abbv-101, a Highly Potent and Selective Clinical Stage Bruton Tyrosine Kinase Degrader for the Treatment of B-Cell Malignancies
Authors: Pan Chin , Gururaja Tarikere L , Li Haiyan , Nguyen Henry , Zhai Yongjiao , Xie Xiaoping , Ding Rong-Xian , Mathew Rebecca , Hoh Hana Y , Jia Zhaozhong J , Liu Bo , Shu Cassandra , Assaily Wissam , Lam Lloyd T , Riehm Jacob J , Stevenson Claudina , Will Christine , Innocenti Federico , Rivkin Alexey 
Published: December 2023

Bruton tyrosine kinase (BTK), a clinically validated target for various B-cell malignancies, plays a critical role in regulating cell growth, adhesion and homing to key lymphoid tissues that provide a microenvironment favorable to cancer cells. Despite the success of approved covalent BTK inhibitors in diseases such as CLL, most patients do not achieve complete response with monotherapy and eventually relapse, often via the emergence of the BTK-C481S mutation. Additionally, covalent BTK inhibitors have not shown sufficient differentiation from standard-of-care (SoC) in B-cell malignancies such as diffuse large B cell lymphoma (DLBCL) to warrant approval to date. To address these unmet needs, a next-generation orally bioavailable BTK degrader ABBV-101 has been developed. Unlike BTK inhibitors that solely bind to and impede the catalytic domain of BTK, ABBV-101 eliminates the protein in a highly selective fashion. This degradation mechanism targets both the catalytic and scaffolding functions of BTK, and thus may enable deeper and more durable responses in patients with B-cell malignancies.
In preclinical studies, the BTK degrader ABBV-101 has shown potent in vitro and in vivo efficacy in BCR pathway-dependent leukemia/lymphoma models, including covalent BTK inhibitor resistant BTK-C481S systemic mouse CLL and human DLBCL models. ABBV-101 degrades BTK-WT and BTK-C481S with similar sub-nanomolar potency in the human DLBCL cell line TMD8 which translates to potent cellular growth inhibition. In addition to the BTK-C481S mutation, ABBV-101 demonstrates similar potent activity against novel BTK mutations associated with resistance to reversible BTK inhibitors in the clinic, an emerging unmet need. ABBV-101 induces complete tumor regression in the BTK-C481S TMD8 DLBCL xenograft model. A spontaneous mouse CLL model carrying BTK-C481S mutation was developed through crossing BTK-C481S knock-in mice with the Emu-TCL1 transgenic mice in the C57BL/6 background. ABBV-101 completely inhibits BTK-C481S Emu-TCL1 CLL burden increase in the blood compartment and reduces CLL burden in the spleen and lymph nodes, whereas covalent BTK inhibitors show no activity. Further, ABBV-101 induces complete tumor regressions in multiple non-GCB DLBCL PDX models, demonstrating deeper and more durable response than covalent and reversible inhibitors. Combination with a BCL-2 inhibitor enhances the efficacy of ABBV-101 in CLL and DLBCL models. Kinome and global proteomics profiling showed ABBV-101 to be highly selective, a designed feature that may enable favorable tolerability in patients. ABBV-101 is currently in phase 1 clinical trial for a variety of B-cell malignancies. ClinicalTrials.gov identifier: NCT05753501
Underrepresentation of Older Adults in Clinical Trials of Chimeric Antigen Receptor (CAR) T-Cell Therapy for Hematologic Malignancies: An FDA Analysis
Authors: Seam Pamela , Mahat Upendra , Bouchkouj Najat , Sharma Poornima , Peredo-Pinto Helka , Elmacken Mona , Kaushal Megha , Jia Yuxia , Wang Shu , Xu Zhiheng , Kasamon Yvette , Kanaparu Bindu , Richardson Nicholas , Gormley Nicole 
Published: December 2023

Background: As the population ages, the prevalence of hematologic malignancies in older adults will continue to increase. Older adults, especially older than 75 years, are routinely underrepresented in clinical trials evaluating hematologic malignancies, largely due to access and logistics, comorbidities, toxicity concerns, and eligibility restrictions. Given the recent approvals of multiple CAR T-cell therapies for patients with hematologic malignancies, we evaluated the rates of enrollment of older adults (age ≥ 65 years) in registrational trials of CAR T-cell therapies submitted to the U.S. Food and Drug Administration (FDA).
Methods: We conducted a pooled analysis of the registrational trials submitted to the FDA between 2017 and 2021 that supported approvals of autologous CAR T-cell therapies in patients with hematologic malignancies. Datasets submitted with the biologic license applications were pooled and analyzed descriptively for demographics, disease characteristics, and efficacy outcomes. Patients between the ages of 65 and 74 and age 75 and above were analyzed separately.
Results: Thirteen registrational trials evaluating six CAR T-cell products in 1,319 patients with hematologic malignancies were submitted to FDA. The median age at enrollment was 60 years (range: 3 to 86). In total, 7% (88) of patients were 75 years and older, 28% (366) were between the ages of 65 and 74 years, and 66% (865) were under the age of 65 years. The hematologic malignancies included large B-cell lymphoma (59%), multiple myeloma (15%), follicular lymphoma (13%), B-cell acute lymphoblastic leukemia (9%), and mantle cell lymphoma (5%). Response rates by age group and histology are shown in Table 1 and Table 2.
Conclusions: Older adults, particularly those aged 75 years or older, were underrepresented in the trials supporting FDA approval of CAR T-cell therapies considering the predominant hematologic malignancies included in this pooled analysis and the median age of diagnosis of these diseases in the U.S. population. Although clinically meaningful efficacy was achieved across age groups and diseases, more data are needed to determine the impact of age on efficacy outcomes in specific malignancies. In this analysis, data were limited among patients 75 years and older in all histologies except large B cell lymphoma. Work to evaluate the impact of age on safety and tolerability outcomes is ongoing. To improve accrual, greater efforts to understand and reduce barriers to clinical trial enrollment for older adults are needed, especially given the expanding use of CAR T-cell therapies and their toxicity profiles.
BCMA-Directed CAR-T Cell Therapy Is Associated with a Higher Risk of Infections: A Systematic Review and Meta-Analysis
Authors: Bindal Poorva , Banegas Marcela , Paredes Rodrigo , Jose Hernandez Maria , Aggarwal Pushan , Arnason Jon E. , Alonso Carolyn 
Published: December 2023

Background:
Chimeric antigen receptor (CAR) T-cell therapy is a rapidly evolving immunotherapy for hematological malignancies. With increasing access to this modality, there is an urgent need for a comprehensive understanding of infectious complications to optimize prophylaxis and improve clinical outcomes. We conducted a systematic review and meta-analysis to assess the incidence and characteristics of infectious complications in adult patients receiving CAR T-cell therapy.
Methods:
The study was registered on PROSPERO and we searched 5 electronic databases from inception to 2022. Each author independently screened titles, reviewed full texts to identify eligible studies and extracted data from included studies using Covidence, a data extraction tool for conduction of standard systematic reviews. A random effects model was used, and proportions were used as a measure of outcome. We assessed heterogeneity using I^2 statistic. Risk of bias assessments were conducted using the RoB 2.0 for RCTs and ROBINS I tool for non-RCTs.
Results:
Our search identified 12,441 studies of which 363 underwent full-text review (Figure 1). 33 studies were eligible for inclusion in the analysis and enrolled a total of 2866 patients. The pooled incidence of an infectious event in adult patients after CAR T-cell therapy was 38% (95%CI 0.31, 0.46; p&lt;0.01; I2 = 98%]. No significant difference was noted in the incidence among studies with a longer follow up duration compared to studies with follow up of £ 30 days [40% (95% CI 0.30-0.50) vs 32% (95% CI 0.24-0.40), p=0.20 respectively]. BCMA-directed CAR T-cell therapies used for management of multiple myeloma had a significantly higher incidence of infectious complications compared to CD19 targeted agents, 64% (95% CI 0.53-0.74, I2 = 65%) versus 39% (95% CI 0.30-0.49; I2 = 98%; p &lt;0.01) respectively, Figure 2. Clostridium difficile and Escherichia coli were the most common pathogens causing bacterial infections, while cytomegalovirus was the most commonly identified viral pathogen affecting these patients.
Conclusion:
In this study, BCMA-directed CAR T-cell therapies were associated with a significantly higher risk of infectious complications. The results of this study can guide the development of strategies to prevent and manage infectious complications in this patient population.
Role of Nutrition Support in Improving Outcomes in Allogeneic Stem Cell Transplant Patients
Authors: Al Bawaliz Anas , Sidhu Jasdeep Singh , Cecil Abigail , Gunaratnam Bakeerathan , Emmons Robert V.B. , Chao Ju-Hsien , Yasin Hassaan , Hegazi Mohamed 
Published: December 2023

Introduction: Allogeneic hematopoietic stem cell transplant (Allo-SCT) can be associated with several complications related to the cytotoxic conditioning regimen, infections associated with immune suppression, and GVHD. Malnutrition amongst Allo-SCT patients has been reported to be an independent negative prognostic factor. It may be evident on presentation or develop as a sequela of decreased appetite, mucositis, and digestive GVHD. Whether supportive nutrition (enteral feeding or total parenteral nutrition (TPN)) contributes to favorable transplant outcomes is yet to be determined.
Methods: We conducted a retrospective single-center study that evaluated patients who underwent Allo-SCT from Jan 2018 through Sept 2021. A chart review was conducted, and relevant data was collected. Primary outcomes were the impact of nutrition support (enteral feeding, TPN or both) among malnourished patients during the first 100 days post-transplant (T+100) on mortality and the composite outcome of acute GVHD incidence, infection rate, and days to engraftment. A higher composite score indicated worse outcomes. GVHD grading was based on the CIBMTR grading system (I-IV). The data was analyzed using Chi-Square and two-sample t-test.
Results: A total of 70 Allo-SCT patients were identified. Of them, 42 (60%) were diagnosed with malnutrition, of which 23 (55%) received nutrition support. The mortality rate in patients who required nutrition support was significantly higher compared to those who did not receive nutrition support (83% (19/23) vs 11% (2/19)) with an odds ratio of 40 for this association (CI 6.5-248.9, p-value &lt; 0.0001). The composite outcome was statistically higher amongst patients requiring nutrition support (mean 2.0, median score 1.8, SD 0.6) compared to those who did not need nutritional support (mean 1.6, median score 1.5, SD 0.4). These differences were found to be statistically significant using the Satterthwaite method (p-value 0.0218).
Conclusion: Based on this data, we found that a reactive approach of nutrition support in the setting of malnutrition had no benefit on mortality and our pre-defined composite outcome during the first 100 days of allogeneic stem cell transplantation. This is fuel for conducting a prospective study using a preemptive enteral feeding approach to prevent the development of malnutrition and related complications.
Responses to Combination Chemotherapy with MAPK Pathway Inhibition in Relapsed and Refractory LCH
Authors: Karri Vivekanudeep , El-Mallawany Nader Kim , Lin Howard , Abhyankar Harshal A , Agrusa Jennifer Elise , Velazquez Jessica , Eckstein Olive S. , Gulati Nitya , Allen Carl E , McClain Kenneth L. 
Published: December 2023

MAPK pathway inhibition (MAPKi) is associated with high response rates in patients with Langerhans cell histiocytosis (LCH), but monotherapy may not be curative and efficacy in LCH-associated neurodegeneration (LCH-ND) is not known. Based on upregulation of Bcl-xL by MAPK activation, we hypothesize that MAPKi may render LCH cells more sensitive to chemotherapy-induced cytotoxicity.
We assessed the safety and efficacy of combination therapy in 10 patients with refractory systemic disease and LCH-ND. Records of patients treated with combination therapy at Texas Children's Hospital from October 2018 to July 2023 were reviewed for clinical responses as well as peripheral blood/tissue BRAFV600E mutation status, ataxia rating scores, and toxicity.
The median age at the start of combination therapy was 6.82 years (range, 0.48-20.45 years) with a median of 4 treatments prior to this therapy regimen (range, 1-14). Almost all Clofarabine was administered outpatient (typical starting dose 25 mg/m2/day x 5 days). MAPK inhibitors included BRAFV600E inhibitors (50%) and MEK inhibitors (50%). Overall response was 8/10 (80%), with 5/5 (100%) objective response rate (ORR) for systemic disease. Further, 5/6 (83%) demonstrated reduced or extinguished peripheral BRAFV600E+ fraction by the end of combination therapy. Ataxia rating scores were improved in 2/3 (67%) individuals with clinical neurodegeneration. Common toxicities during treatment included fever, skin rash, arthralgia, and cytopenia.
Combining therapy was well-tolerated and associated with clinical and molecular improvement in most patients with highly refractory systemic LCH and LCH-ND. Further prospective multi-center trials are required to optimize this approach, determine potential for combination therapy to achieve cure, and compare risks and benefits to chemotherapy or MAPK inhibitor monotherapy.