bluuebunny/crossref_metadata_2025 huggingface dataset:
A Systematic Review of Barriers and Enablers to Reproductive Care for Women with Cancer Identified Data Gaps in Best Practice
Authors: Sanil Parammal Shilpa , Anazodo Antoinette , Chadwick Verity , Rodgers Rachael , Dear Rachel , Hamad Nada
Published: December 2024

Background: Holistic care is becoming increasingly a priority in cancer treatment, including blood cancers, especially for women of reproductive potential (defined as women aged 15-49 years) who deal withunique challenges and circumstances. These challenges include fertility, sexual health, contraceptive counselling and use, and menstrual health. This is especially important in blood cancers because of their incidence during reproductive years.

Objective: This systematic review aimed to explore the barriers and enablers of healthcare providers taking thorough reproductive histories of women with reproductive potential.

Methods: Fifteen studies were included in this review, after searching PubMed, Embase, and CINAHL from 02 April 2024 to April 18, 2024, resulting in 565 articles. Searches were refined to include clinicians treating women with reproductive potential for cancer.

Results: Most studies focused on fertility history taking and counselling, and one study examined contraception in this population. The key barriers were categorized ashealthcare provider-related, patient-related, clinical/medical, organizational and accessibility-related. The most common barrier identified was healthcare providers' lack of knowledge around reproductive health in the context of cancer care, followed by consultation time limitations. The majority of the barriers can be traced back to personal beliefs and assumptions made by the healthcare provider regarding patient demographics and characteristics. Of the 15 studies, only three discussed enablers aiding clinicians in obtaining reproductive histories, including onsite obstetrics and gynecology services and standardized referral processes.

Conclusion: This review highlights an urgent need for the education of healthcare providers working in cancer care with patients of reproductive potential to ensure that reproductive health is not surpassed by the current cancer diagnosis. There is also a need for tangible guidelines regarding reproductive care for cancer patients, and for reproductive history and counselling to be mandatory in cancer care and ensure equitable access to holistic cancer care. Furthermore, there has to be increased research to understand the enablers to clinicians who are able to obtain thorough reproductive histories, which can form the basis for effective interventions to be put into place.
Predictive Model for Infection Risk in CAR-T Therapy Patients
Authors: An Ning , Li Chunrui , Luo Hui , Wang Xinran , Wang Di , Zhang Peiling , Mu Wei , Yu Qiuxia , Bao Yuhan , Gao Yang
Published: December 2024

Background:

Chimeric antigen receptor T-cell (CAR-T) therapy is a powerful treatment for hematologic malignancies, but it often leads to serious infections, a major cause of non-relapse mortality. These infections typically occur within the first 30 days post-therapy, a period also characterized by cytokine release syndrome (CRS). Early fever after CAR-T therapy can indicate either an infection or CRS, complicating diagnosis, especially in neutropenic patients. A predictive model is needed to accurately identify infections for prompt and effective management.

Methods:

This multicenter retrospective study involved three phases: model development, internal validation, and external validation. The internal cohort included 443 patients treated with CAR-T therapy at Tongji Hospital, Huazhong University of Science and Technology, from June 2016 to December 2023. The study excluded patients with pre-existing infections, fever unrelated to CRS or infection, incomplete data, or no fever within 30 days post-CAR-T therapy. An external validation cohort of 30 patients was recruited from three hospitals. Febrile events (temperature >38°C) within 30 days post-infusion were recorded, with daily assessments of blood counts and inflammation markers such as C-reactive protein (CRP), interleukin-6 (IL-6), and ferritin. Febrile episodes were classified as infection or CRS. A multivariate logistic regression model identified independent predictors of infection and established a scoring system.

Results:

Among the 443 patients, 514 febrile episodes were recorded, with 86% occurring during the first episode. Infections accounted for 21% of initial episodes, often co-occurring with CRS. The predictive model for infection during the first febrile episode included factors like pre-fever neutropenia (N), ferritin change (FCV) on the second day of fever, lymphocyte count (L), platelet count (Plt), IL-6 level, and CRP level. The model achieved an area under the curve (AUC) of 0.9, with 87% sensitivity and 81% specificity in the training set. The external validation cohort showed an AUC of 0.93, with sensitivity and specificity of 75% and 84%, respectively. The Hosmer-Lemeshow test confirmed a good model fit (P = 0.950), and decision curve analysis indicated a significant net benefit.

Conclusion:

This study developed and validated a robust risk assessment model for predicting infections within 30 days post-CAR-T therapy. The model, based on routine blood tests and febrile episodes, is practical for clinical use and offers high accuracy across different patient cohorts.
Treatment of Central Nervous System Viral Infections after Allo-HSCT with Intrathecal Donor Lymphocyte Infusion: Feasibility Analysis
Authors: Gui Ruirui , Li Zhen , Wang Juan , Zu Yingling , Zhang Wenli , Li Xudong , Li Wei , Lu Wenyi , Li Chao , Wang Xianjing , Zhou Jian
Published: December 2024

Objective To investigate the efficacy and safety of intrathecal donor lymphocyte injection (IDLI) in the treatment of central nervous system virus infection after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods The clinical data of 32 patients with central nervous system virus infection after allo-HSCT treated with IDLI from May 2014 to February 2024 were retrospectively analyzed. Once the central nervous system virus infection was diagnosed, the patient or his family signed the IDLI treatment consent. The mononuclear cells were isolated from 10~20ml of peripheral blood of the original donor or a third immediate family member under strict aseptic conditions, then IDLI was performed once or twice a week, until the virus in cerebrospinal fluid turns negative by PCR and/or mNGS. Results In terms of donor lymphocyte origin, 27 cases were from the original donor and 5 were from a third immediate family member. A total of 125 times IDLI were given. The first IDLI was on day 97(40-1946) after allo-HSCT. The median number of cycles of IDLI was 3(1-12), median number of mononuclearcell in a single IDLI was 2.7 (1.25-3.18)×107, median duration of IDLI was 16 days (6-84). All 32 cases (100%) had an objective response, with best overall response of complete response in 21 (65.6%), partial response in 11(34.4%), median time to complete response was 17 days (8-77) after IDLI. A total of 12 (37.5%) patients died, none of the causes of death was CNS virus infection. Median follow-up was 201 days (2-3560), the 1-year overall survival rate was 60.1%, only 1 patient developed chronic graft-versus-host disease after the 12th IDLI treatment, and no immediate or long-term adverse reactions were observed in the other patients. Conclusion IDLI provides clinical benefit in patients with central nervous system virus infection after allo-HSCT, with high safety. These data represent a transformative and accessible treatment advance for patients with central nervous system virus infection after allo-HSCT with few treatment options.
Clinical Analysis of CAR-T Cell Therapy in Patients with Acute B-Lymphoblastic Leukemia and Central Nervous System Infiltration
Authors: Yan Hong , Li Biyi , Zheng Ruyue , Lin Yuehui , Deng Biping , Tong Chunrong , Wu Tong , Zhao Defeng
Published: December 2024

Background: Acute B-lymphoblastic leukemia (B-ALL) with central nervous system leukemia (CNSL) has traditionally been treated with whole-brain and spinal radiotherapy, combined with intrathecal chemotherapy, systemic chemotherapeutic drugs, and allogeneic hematopoietic stem cell transplantation for long-term survival. There are few reports of clinical cure and long-term survival in patients treated primarily with CAR-T therapy.

Objective: To observe the efficacy of CAR-T therapy in patients with B-ALL and CNSL.Methods and Results:A retrospective analysis was conducted on four cases of relapsed/refractory acute B-lymphoblastic leukemia (R/R B-ALL) with CNSL treated with CAR-T cell therapy at Beijing Boren Hospital from April 2018 to June 2023. Three patients were adult males, and one was a 6-year-old female, with a median age of 33.5 years (range: 6-48 years). Case 1 and 3 had PH+ B-ALL, case 2 had MEF2D-BCL9 fusion gene, and all three relapsed post-transplant. Case 4 relapsed during chemotherapy. Case 1 and 4 had isolated CNSL relapse (50%), case 3 had minimal residual disease (MRD) in bone marrow, and case 2 had hematologic relapse with bone marrow involvement and bilateral kidney and pancreatic infiltration. The clinical outcomes of single and sequential two-course CAR-T cell therapy were observed. The median follow-up for the four patients was 26 months (range: 18-64 months), with all achieving complete remission and a median remission duration of 25 months (range: 17-62 months). The overall survival rate at the end of follow-up was 100% (4/4). Case 1 had a sustained molecular remission for 62 months, case 2 for 21 months, case 3 for 32 months, and case 4 for 18 months. Case 1 experienced reversible ICANS, and the other three had CRS grades 0-1. The event-free survival (EFS) was greater than 18 months (100%), with one case reaching clinical cure criteria. The overall survival rate (OS) was 100%.

Conclusion:CAR-T cell therapy can be considered a primary treatment method for patients with B-ALL and CNSL. In this group of four patients, sustained remission was achieved without cranial radiotherapy or allogeneic hematopoietic stem cell transplantation, thus avoiding radiotherapy-related neurological damage, bone marrow suppression, and graft-versus-host disease (GVHD), improving overall patient quality of life.
CMV-Specific TCR-T Cells for the Treatment of CMV Reactivation after Allogeneic Hematopoietic Stem-Cell Transplantation
Authors: Tang Jingwen , Dou Liping , Liu Daihong
Published: December 2024

Cytomegalovirus (CMV) reactivation remains the leading cause of death after haploidentical stem cell transplantation (HSCT). Current therapies, including antiviral drugs and relay cell therapy using CMV-specific cytotoxic T lymphocytes (CTLs), have shown only limited benefit to patients, and T-cell receptor (TCR)-T-cell therapy offers a promising option for the treatment of CMV reactivation.

To evaluate the efficacy and safety of CMV-targeted T-cell receptor-engineered T (CMV-TCR-T) cell therapy as a first-line pre-emptive therapy ,we conducted a single-arm, open-label, phase I clinical trial for patients with CMV reactivation after HSCT. Ten patients with CMV reactivation after HSCT were adoptively transferred by one to three doses of HSCT donors-derived CMV-TCR-T cells. Meanwhile, 2 patients who had failed standard antiviral drugs used CMV-TCR-T cells as second-line therapy.

Eight of the first-line treatment patients responded within one month after infusion of CMV-TCR-T cells without administration of any antiviral drugs; the other two patients who initially did not respond to CMV-TCR-T cell therapy were given salvage ganciclovir and phosphonate, followed by rapid clearance of CMV. Second-line treatment patients were controlled with TCR-T cells after 2 weeks of ineffective use of antiviral drugs. CMV-TCR-T cells demonstrated overall robust expansion and persistence in peripheral blood after infusion. CMV-TCR-T cells were first detected in the peripheral blood of these patients 3-7 days after the initial CMV-TCR-T infusion, expanded rapidly and persisted for at least 1-4 months, providing long-term protection against CMV reactivation. In 2 patients, CMV-TCR-T cells began to expand even while anti-graft-versus-host disease reagents were still in use, further demonstrating the proliferative potential of CMV-TCR-T cells. No adverse events were observed except for grade 1 cytokine release syndrome in one patient and mild fever in two patients.

Median follow-up was 318 days. Six patients survived for more than 1 year and 2 patients died (2 in the first-line treatment group and 1 in the second-line treatment group).This study demonstrates the great potential of CMV infection after HSCT or other organ transplantation in terms of treatment and prevention.
Prognosis Prediction By Two Single Factors Could Predict the Survival of PCNSL Patients Received HD-MTX Therapy without HSCT
Authors: Renjie Bian , Qu Yi , Wu Danyang , Yu Jinxiang , Wang Xiaoxue , Wang Lei , He Juan , Wang Jun , Yan Xiaojing
Published: December 2024

Objective：Primary central nervous system lymphoma (PCNSL) is a rare subtype of extra-nodal non-Hodgkin lymphoma and and there is currently no defined standard treatment for newly diagnosed primary central nervous system lymphoma (PCNSL) except for the high-dose methotrexate (HD-MTX). Post-remission consolidation with autologous hematopoietic stem cell transplantation (auto-HSCT) was associated with the best survival outcome. However, not all the patients are available for auto-HSCT and PCNSL displays a wide variability in outcome. This study aimed to identify prognostic factors among individuals with PCNSL undergoing HD-MTX-based regimens without auto-HSCT.

Methods: This retrospective, single-center study included 93 patients diagnosed with PCNSL who underwent HD-MTX-based chemotherapy. Treatment options include: R-MT, R-M, R2-M or RMZ (R rituximab, M methotrexate, T temozolomide, R2 rituximab and lenalidomide, Z zanubrutinib). The dosage of HD-MTX was standardized at 3.5g/m2 (adjusted according to the patient's physical condition) and administered every 2-3 weeks per cycle. We collected the patients' clinical characteristics, imaging data, pathology data, treatment plan and follow-up data. Statistical analyses were conducted to identify independent predictors influencing PCNSL prognosis and to establish a prognostic scoring system.

Results: Univariate prognostic analysis of OS showed that male, KPS <70 or ECOG >1, deep brain tissue involvement, GCB phenotype, CD10-positive and Bcl-6-negative were poor prognostic factors for PCNSL. Besides, univariate prognostic analysis of PFS exhibited that males, KPS <70 or ECOG >1 and deep brain tissue involvement have a greater risk of disease progression. Cox multifactorial analysis identified shorter OS in males and Bcl-6-negative cases and shorter PFS in males. Consequently, male gender and Bcl-6 negativity were included in the predictive scoring system, each assigned a value of 1. The median OS was 10 months, 33 months, and not reached (NR) for low-risk, medium-risk and high-risk groups.

Conclusion: Gender disparity was observed in the prognosis of PCNSL patients who received HD-MTX, with males exhibiting worse outcomes in both OS and PFS compared to females. Bcl-6 negativity also correlated with shorter OS. When females with no BCL-6 expression, it generally predicts a worse prognosis.
Central Nervous System Involvement in Mantle Cell Lymphoma: Clinical Features, Prognostic Factors and Outcomes from Multi-Centers in China
Authors: Yang Ping , Li Chunyuan , Yang Yuan , Liu Shuozi , Zhang Weilong , Wang Jing , Chen Yingtong , Hao Xiaoyu , Jing Hongmei
Published: December 2024

Background: Central nervous system (CNS) involvement in mantle cell lymphoma (MCL) is uncommon, with the incidence of 3 to 5%. The median survival time was 3 to 6 months. Meanwhile, it is lower in Asia and previously mainly reported by case.

Patients and methods: We present the data on 16 patients with MCL who developed CNS involvement, from a database of 861 consecutively treated patients at 19 institutions.

Results: The crude incidence of CNS involvement in our cohort was 1.9%. In terms of clinical features, 25.0% patients were blastiod MCL, and 50% were high-risk group by MIPI score.46.7% were complex karyotypes. Eleven patients underwent second-generation sequencing, and the results showed the presence of high-risk gene mutations such as TP53 (3/11) NOTCH1 (3/11), ATM (3/11), KMT2D (2/11), CCND1 (2/11). One patient also had CDKN2A deletion and C-myc amplification. 43.8% of patients received high-dose cytarabine treatment, 50.0% received BTKi treatment, and 43.8% received BTKi+BCL-2i. The median treatment lines were 3 (1-6) lines. 75.0% of patients were early disease progression (POD24). The median time from diagnosis to central involvement is 22.0 (4-144) months. Six patients were treated with R-High-dose MTX , six cases were treated with R-BTKi ± other targeted drugs and three patients were treated with R-BTKi -high-dose MTX regimen, and one patient received local radiotherapy. CR and ORR were 12.5% and 31.3%, the median progression free survival after CNS involvement(PFS2) was 2.0 months and the median survival (OS2) was 7.0 months. Elevated levels of β 2-microglobulin, previous used BTKi, and SD/PD were poor prognostic factors for PFS2. In addition to the above factors, ECOG score ≥ 2 were inferior prognostic factors for OS2.

Conclusions: CNS involvement ,especially for patients who involved after BTKi treatment, the prognosis was extremely poor and there was a lack of effective treatment options.
Trends in the Renal Manifestations of Sickle Cell Disease over the Last 10 Years: A Nationwide Analysis
Authors: Solipuram Divya , Iqbal Rabia , Solipuram Swathi , Kumarasinghe Chathula , Kumar Suneet , Podrumar Alida I.
Published: December 2024

Background:

The rising number of adults with sickle cell disease (SCD) has underscored a notable increase in end-organ dysfunction like sickle cell hepatopathy, nephropathy and cardiomyopathy. No report to date has examined the trends in the renal manifestations of SCD

Aim:

To determine the morbidity and mortality associated with renal dysfunction in patients with and without SCD across a decade using national database

Methods:

We included all admissions with renal conditions to acute care hospitals across the United States from 2012 to 2021. Confounders were accounted for using multivariable regression analyses

Results:

Inpatient hospitalizations due to renal issues steadily increased from 1543031 to 2313787 from 2012 to 2021, among them 4070 had SCD in 2012 while 8529 had SCD in 2021. Incidence of renal issues in SCD reduced from 5217 per 100,000 to 4802 per 100,000 during this period. In-hospital mortality rates from renal issues increased from 3.6% to 4.9%[adjusted odds ratio- 1.06; CI 1.0-1.13; trend p 0.04] in those patients with SCD while it increased from 4.4% to 6.2%[adjusted odds ratio-1.05; CI 1.05-1.06; trend p 0.000] in those without SCD from 2012 to 2021. Renal transplantation rate was 1.47% and 1.09% for patients with and without SCD in 2012, that increased to 1.64% for patients with SCD while it decreased to 1.06% for patients without SCD in 2021. ESRD and dialysis rates reduced significantly from 56% to 39% in patients without SCD while in patients with SCD a higher rate of ESRD and dialysis with only a minor reduction in rates from 68% to 64% was noted from 2012 to 2021. Mean length of hospitalization was higher and showed an increasing trend from 2012 to 2021 for patients with [7.1 to 7.5d]and without SCD[6.4 to 7d] with a trend p value of 0.000. A similar increase in hospitalization charges from $75219 to $98152 in SCD vs $71369 to $96534 in those without SCD[trend p 0.000] was noted during the same period.

Conclusion:

Though there is slight reduction in incidence of renal issues in SCD over the last decade, in-hospital mortality significantly increased. SCD patients with renal issues had higher rates of ESRD, dialysis and transplantation compared to non-SCD patients with renal issues. A higher morbidity rates in terms of hospitalization charges and duration was also noted
Treatment Outcomes of BTK Inhibitors and Venetoclax with/without Anti-CD20 Monoclonal Antibody in Patients with Relapsed or Refractory Mantle Cell Lymphoma: A Real-World Experience
Authors: Yang Ping , Li Chunyuan , Liu Shuozi , Wang Jing , Chen Yingtong , Zhang Weilong , Jing Hongmei
Published: December 2024

Background: High-risk MCL patients with disease refractory/relapsed (R/R) lack effective treatment options and exhibit poor outcomes, posing challenges in management. The combination of BTK inhibitors (BTKi) and venetoclax obtained high complete remission (CR) and overall response rate (ORR) in clinical trials. The combination data for R/R MCL patients in the real-word is fewer. The aim of the study is to descibe the clinical characteristics and prognosis of BTKi combined venetoclax with or without anti-CD20 antibody in the R/R MCL patients of China.

Methods: A total of 49 patients treated with BTKi and venetoclax 200mg daily (Dual combination, n=17) or in combination with anti-CD20 monoclonal antibody (Triple combination, n=32) between June 2018 and February 2022 at our department were included in this retrospective analysis. All analyses were conducted using statistical language R (version 4.1.2). Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method.

Results: The median age was 62.0 years and the male-to-female ratio was 3.08:1.Patients had high-risk features including ki67≥30% (89.8%), blastoid/pleomorphic histology (36.7%), high-risk group of MCL International Prognostic Index (MIPI) (42.9%) complex karyotype (27.7%), TP53 mutations (71.4%), TP53 mutations combined with other high-risk gene mutations (57.1%) and 65.3% of progression of disease within 24 months (POD24). The basic clinical characteristics and cytogenetic features in the dual and triple combination were similar. The best ORR and CR were 67.4% and 53.1% in this study, and the 3-year PFS and OS were 37.5% and 50.8%, respectively. Except of TP53 mutations combined with other high-risk genes associating with worse OS, other high-risk factors including high-risk MIPI score, B/PMCL, Ki-67≥50%, POD24, and complex karyotype had the similar efficacy and prognosis to the low-risk. In the MA analysis, SD/PD after combination therapy was independent predictors for PFS and ECOG≥2, TP53 mutations with other high-risk genes mutation and SD/PD after combination treatment were the independent factors for poor OS. The most common adverse reactions were hematological toxicity and pulmonary infection. Finally, the most common death cause was disease progression (19/22) and 7 of them had secondary central nervous system involvement.

Conclusions: The combination of BTKi and venetoclax 200mg daily with or without CD20 antibody had a good efficacy for R/R MCL patients especially in early lines in our study.
Efficacy and Safety of CAR-T Therapy Targeting CLL1 in Patients with Extramedullary Diseases of Acute Myeloid Leukemia
Authors: Zhao Yifan , Bai Xue , Guo Shujing , Zhang Xiaomei , Zhao Mingfeng
Published: December 2024

O bjective

Approximately 10-20% of patients diagnosed with acute myeloid leukemia (AML) present with extramedullary diseases (EMDs), which exhibit a significantly distinct etiology, therapeutic response, and prognosis compared to AML patients without EMDs. The proportion of patients with EMDs further increases in those with refractory and relapsed AML. The objective of this study is to evaluate potential disparities in the efficacy and adverse effects of Chimeric Antigen Receptor T-cell therapy (CAR-T) therapy targeting CLL1 between patients with and without EMDs.

Methods

A total of 47 patients, including 20 patients with EMDs, were prospectively enrolled in this prospective study, which has obtained approval from the institutional review board of Tianjin First Center Hospital and has been duly registered with the China Clinical Trial Registration Center (Clinical Trial Number: ChiCTR2000041054). All patients underwent lymphodepletion chemotherapy with a 3-day regimen of fludarabine (25 mg/m2) and cyclophosphamide (300 mg/m2) prior to the infusion of CAR-T cells. Afterwards, we thoroughly evaluated the effectiveness and occurrence of side effects during the treatment process, while also comparing the differences in laboratory indicators between patients with and without EMDs.

Results

Among the 20 patients with EMDs and the 27 individuals without EMDs, complete remission was achieved by 65.00% and 81.48% of patients, respectively, resulting in long-term survival through subsequent hematopoietic stem cell transplantation. Although the overall survival, progression-free survival, and duration of remission period appeared to be shorter for patients with EMDs compared to those without EMDs, this difference did not reach statistical significance. The incidence rates of complications, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and hematological toxicities, were similar in both groups. Meanwhile, there were no significant differences observed in the levels of CAR-T cell proliferation and accompanying cytokines release between patients with and without EMDs.

Conclusion

The results of our study have demonstrated the efficacy of CLL1 CAR-T therapy in the treatment of AML patients with EMDs. Despite a high incidence of CRS, ICANS, and hematological side effects, most patients were effectively managed through systemic treatment and subsequent bridged HSCT. Therefore, we recommend CLL1 CAR-T therapy as an efficient and safe therapeutic option for AML patients, irrespective of the presence of EMDs.
Long-Term Efficacy and Safety of CD19-Specific CAR-T Cells Armed with IL-7 and CCL19 in Patients with Relapsed or Refractory Large B-Cell Lymphoma: A Multi-Center Prospective Study
Authors: Qian Wenbin , Liu Hui , Lei Wen , Wang Linqin , Chen Panpan
Published: December 2024

To further improve expansion, infiltration, persistence, and especially outcome, adjusting the Chimeric antigen receptor (CAR) structure to enhance antitumor efficiency is an important strategy. In this pattern, fourth-generation CAR-T, also named “armored CAR-T” or T cells redirected for universal cytokine killing (TRUCK), with the ability of expressing cytokines or chemokines, has been thoroughly evaluated in preclinical studies and clinical trials across various malignancies.

In our previous study, we developed a CD19-specific fourth-generation CAR-T expressing interleukin (IL)-7 and chemokine (C-C motif) ligand 19 (CCL19), named 7×19 CAR-T. In this long-term follow-up study of up to 5 years (NCT04833504), the 39 patients in the interim report were followed up for extended time.

Among these patients enrolled, the median age was 55 years (range, 29-73). Most of the patients (66.7%) had stage III or IV disease, 41% had an ECOG performance status score of 2 or 3, 64.1% had extranodal organ involvement, 51.3% had received at least three lines of previous therapies, 46.2% had received more than 10 times of prior treatment regimen, 51.3% had refractory disease, 7.7% experienced autologous stem cell transplantation (ASCT) and 46.2% had bulky disease defined as the presence of any mass with a single diameter over 7cm.

During a median follow-up of 63 months by reverse Kaplan-Meier method, 15 patients (38.5%) continued to survive at data cutoff. The median OS was 31 months, with an estimated 5-year OS of 43.6% (95% CI: 27.9 to 58.3%) among all patients and 64.6% among those achieving a CR. After excluding deaths unrelated to disease progression, the estimated disease-specific survival at 5 years reach 48.7% (95% CI: 32.4% to 63.2%). The median PFS was 13 months, with an estimated 5-year PFS of 30.8% (95% CI: 17.3% to 45.4%).

there was no significant difference between patients with or without bulky disease considering OS or PFS, which indicates that this armored CAR-T can to some extent overcome the adverse effect of bulky disease.

In summary, this updated 5-year analysis demonstrated the continued benefit of 7×19 CAR-T for in patients with Rel/Ref LBCL with satisfactory safety signals. The development of this study has laid a solid foundation for future frontline use or combined clinical research.
Clinical Outcomes for Patients with Triple Class Exposed Relapsed and Refractory Multiple Myeloma in Alberta, Canada
Authors: Jimenez-Zepeda Victor H. , Cheung Winson Y. , Mathew Stephen Mariet , Chan Henry
Published: December 2024

Background: Despite advances in treatment options, multiple myeloma (MM) remains generally incurable and most patients become relapsed or refractory to drug classes and require additional lines of therapy. Patients who are considered triple class exposed (TCE) (i.e., treated with three drug classes) may have limited treatment options and poor prognosis once they become relapsed/refractory MM (RRMM). There are limited published data available that examine real world treatment patterns and clinical outcomes in the TCE RRMM patient population. The purpose of this project was to explore Canadian-specific real-world treatment patterns and clinical outcomes in TCE RRMM patients in Canada. Methods: We leveraged multiple, population-based data sources from Alberta, Canada to identify TCE patients. The TCE cohort included individuals who have received a subsequent line of anti-myeloma treatment after prior exposure to a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and a monoclonal antibody (MAb), regardless of the sequence or combination used. Results: In total,1835 patients were evaluated. The TCE cohort included individuals who have received a subsequent line of anti-myeloma treatment after prior exposure to a PI, an IMiD, and a MAb, regardless of the sequence or combination used. 567 were consistent with the definition of TCE RRMM. Most patients with TCE MM were treated in the modern era (2020-present, 79%) and only 27% were >75 years old. 221 (39%) of TCE RRMM received a subsequent line of therapy. Median time to next therapy (TTNT) in the TCE RRMM was 18.1 months (8.4-13.3) and median TTNT and death was 10.1 months. Post TCE MM therapies will be presented in a Sankey diagram but as expected for the period of evaluation, no BCMA directed therapies were funded and publicly available for treatment of RRMM. Conclusion: The present study provides important insights into the treatment patterns and outcomes of patients with TCE RRMM. The advent of novel approaches such as CART's and bispecific is expected to address an unmet need in this growing population.
Cyclophosphamide Combined with Standard Immunosuppressive Therapy Improves Early Response Outcomes in Severe Aplastic Anemia
Authors: Pan Hong , Zhang Lele , Gao Zhen , Li Weiwang , Li Jianping , Nie Neng , Xiong Youzhen , Zhao Xin , Huang Jinbo , Zhao Jingyu , Yu Xiao , Kuang Zhexiang , Fang Liwei , Ge Meili , Yuan Weiping , Shi Jun
Published: December 2024

Background: Thrombopoietin receptor agonists combined with ALG/ATG and cyclosporine are the standard immunosuppressive therapy for severe aplastic anemia (SAA). However, early response rates remain suboptimal. Cyclophosphamide has shown efficacy in relapsed/ refractory AA. Therefore, we designed a clinical trial to evaluate cyclophosphamide combined with the standard immunosuppressive therapy as a first-line treatment for SAA and very severe aplastic anemia (VSAA) to improve early response rates.

Methods: This study was a single-arm, prospective, phase II clinical trial using a Simon two-stage design. The primary endpoint was the overall response rate (ORR) at 3 months. Newly diagnosed SAA/VSAA patients received a combination treatment as follows: porcine ALG at 25 mg/kg/day from days 1 to 5, cyclosporine at 3-5 mg/kg/day continuously, herombopag at 15 mg/day starting from day 1 and continued for 6 months, cyclophosphamide at 20 mg/kg/day on days 29-30 and days 43-44.

Results: Among the 36 patients evaluable for the primary endpoint, the 3-month ORR was 66.7% (24/36), with a complete response (CR) rate of 8.3% (3/36) and a superior remission rate of 22.2% (8/36). 28 patients were evaluable for the 6-month efficacy, the ORR at 6 months was 75% (21/28), with a CR rate of 28.6% (8/28) and a superior remission rate of 64.3% (18/28). The most common adverse events after cyclophosphamide were grade 1-2 gastrointestinal reactions (100%) and grade 3-4 neutropenia (66.7%), with a median duration of 6 days (range: 4-33 days). The infection rate within 3 months was 58.3% (21/36). The mortality rate within 3 months was 0%.

Conclusion: Cyclophosphamide in combination with standard immunosuppressive therapy as first-line treatment shows good safety and efficacy, with two-thirds of patients achieving a response and becoming transfusion-independent within 3 months.
Prognostic Significance of POD24 and Monoclonal Paraproteinemia in Extranodal MZL
Authors: Wang Lingli , Gao Jinjie , Wan Wei , Dong Fei , Wang Jing , Zhang Weilong , Yang Ping , Ma Lan , Zhao Wei , Wang Jijun , Jing Hongmei
Published: December 2024

Marginal zone lymphoma (MZL) is a relatively uncommon subtype of non-Hodgkin's lymphoma, which can be categorized into three types: splenic MZL, nodal MZL (NMZL), and extranodal MZL (EMZL) of mucosa-associated lymphoid tissue (MALT). Extranodal MZL originates from extranodal organs and presents with diverse clinical manifestations depending on the affected organ. This retrospective study reviewed 104 patients who were diagnosed and treated for EMZL at the Department of Hematology in Peking University Third Hospital from 2014 to 2023, and had undergone at least one cycle treatment and evaluation. The median follow-up duration was 36 months. Among these patients, 48.1% were male, with a median age of 60 years. The stomach was the most frequently involved organ, followed by the lung and colon. The overall survival at 3-year and 5-year for the entire cohort were found to be 93.4% and 89.6%, respectively, while the progression-free survivals were determined as 78.2% and 58.3%. Survival analysis revealed that presence of B symptoms as well as progression of disease within 24 months (POD24) significantly influenced patient prognosis. Further investigation demonstrated the association between detectable monoclonal immunoglobulin protein (M protein) levels during disease onset in relation to tumor burden among patients. A total of 32 patients underwent next-generation sequencing analysis of tumor tissue; KEGG enrichment analysis showed that mutated genes primarily enriched pathways such as “PD-L1 expression and PD-1 checkpoint pathway in cancer,” “Jak-STAT signaling pathway”，and “Th1and Th2 cell differentiation.”
Leptin Receptor+ Stromal Cells Create a Perisinusoidal Niche for Thrombopoiesis in the Bone Marrow By Synthesizing Cxcl14
Authors: Xue Yuanyuan , Merchant Salma , Reyes Amanda , Luo Maowu , Morrison Sean J.
Published: December 2024

Leptin Receptor expressing (LepR+) mesenchymal stromal cells are a critical source of multiple growth factors in the bone marrow that promote the maintenance of hematopoietic stem cells and early hematopoietic progenitors as well as the regeneration of hematopoietic and vascular cells. Here, we show that LepR+ cells promote thrombopoiesis in the bone marrow by synthesizing the chemokine Cxcl14. We systematically examined the Cxcl14 expression pattern by single cell RNA sequencing and using Cxcl14dsRed knock-in mice. We found that Cxcl14 was mainly expressed in the bone marrow by perisinusoidal LepR+ cells. HSC frequency and function were not significantly affected when Cxcl14 was conditionally deleted from LepR+ cells; however, blood platelet counts decreased in Lepr-cre; Cxcl14 fl/flmice. Megakaryocytes from Lepr-cre; Cxcl14fl/fl bone marrow exhibited defective cytoplasmic maturation and proplatelet release based on deep imaging of the bone marrow. Lipidomic analysis showed Cxcl14 deletion reduced polyunsaturated fatty acids (PUFA) in triglycerides in megakaryocytes. RNA sequencing and western blot analysis showed that genes related to exogenous lipid uptake were downregulated in CD42+ megakaryocytes from Lepr-cre; Cxcl14fl/fl mice. In vivo, the lower platelet counts in Lepr-cre; Cxcl14fl/fl mice were rescued through a high PUFA diet. Our results suggest that Cxcl14 signaling can enhance lipid uptake through lipid transporters to promote megakaryocyte maturation. Moreover, recombinant mouse Cxcl14 protein increased the formation of colonies by megakaryocyte progenitors (CFU-Mk) in culture and accelerated the formation of proplatelets. LepR+ cells thus create a perisinusoidal niche for thrombopoiesis by synthesizing Cxcl14.
Preclinical Efficacy of Decoy-Resistant IL-18 in Hematological Malignancies
Authors: Lindquist Jeffrey N , Qin Kai , Liu Jeffrey M , Ring Aaron M , Uppal Hirdesh
Published: December 2024

Interleukin-18 (IL18) is a proinflammatory cytokine that modulates both innate and adaptive immune responses. Historically, wild-type recombinant IL-18 has shown limited anti-tumor efficacy in preclinical models and clinical trials, likely due to upregulation of IL-18 binding protein (IL-18BP), a negative regulator of IL-18 signaling. Accordingly, Decoy-Resistant IL-18 (DR-18), an engineered IL-18 cytokine capable of interacting with the IL-18 receptor but resistant to IL-18BP inhibition, has demonstrated enhanced therapeutic potential in mouse solid tumor models, both as a single agent and in combination with anti-PD-1 [Zhou T, et al. Nature. 2020;583(7817):609-614.], and in leukemia following allogeneic bone marrow transplantation (alloBMT) [Minnie SA et al. Sci Immunol. 2022;7(76):eabo3420]. Here we evaluated murine DR-18 in a diverse set of mouse hematological tumor models, including in combination with conventional chemotoxic and immunotherapeutic agents. mDR-18's effect on survival was assessed and the immune cells required for mDR-18 activity were identified by depletion studies.

Results: Treatment with mDR-18 elicited strong efficacy as a single agent and showed combination activity across diverse syngeneic mouse models of hematological tumors. mDR-18 demonstrated robust single agent activity in tumor growth inhibition for subcutaneously implanted A20 B-cell lymphoma (95%), C1498 Acute myeloid leukemia (85%), and MPC-11 Plasma cell myeloma (50%). Combination treatment of mDR-18 with Aza+Vento chemotherapy increased treatment efficacy in C1498 (95%). mDR18 also showed increased survival as a single agent that was enhanced in combination with Aza+Vento. To ascertain the immune cells required for this activity of mDR-18, animals with C1498 tumors were treated with mDR-18 while depleting either CD4+, CD8+, NK1.1+, or both CD4+ & CD8+ cells from the mice. The activity of mDR-18 was abrogated in CD8+ and CD4+/CD8+ cell depleted animals. Examining the role of mDR-18 in combination with Blinatumomab, a CD3-CD19 bi-specific T-Cell engager, demonstrated greater tumor growth inhibition and a more durable response than monotherapy with either agent.

Conclusion: These studies extend the efficacy of DR-18 therapy in hematologic malignancies and demonstrate the potential benefit of combining DR-18 with additional agents beyond anti-PD-1, including chemotherapy and T cell engagers. These findings strengthen the rationale for expanding the use of the Phase I human DR-18 cytokine (ST-067, NCT04787042 & NCT06492707) in combination therapies for patients with hematological tumors.
YM155 Exerts Anti-Myeloma Effects Via Myc/BBC3 Signaling Pathway in Vitro
Authors: Jin Xianghong , Zhang Fujing , He Huiwen , Li Ziping , Zhuang Junling
Published: December 2024

Background: Our previous studies have demonstrated a strong link between Myc rearrangement (Myc-R) and poor prognosis in newly diagnosed multiple myeloma (NDMM). The survivin inhibitor YM155, a novel small molecule, is currently under clinical investigation for aggressive B-cell lymphomas with Myc translocation. However, its effects on myeloma cells remain unclear.

Objectives: This study aims to explore the anti-myeloma mechanisms of YM155 in vitro through cell-based experiments.

Methods: In vitro, six MM cell lines (AMO-1, MM.1S, RPMI-8226, NCI-H929, U266, and KMS-11) were treated with YM155 to determine the IC50 using the CCK8 assay. Cell apoptosis was assessed by flow cytometry. RNA sequencing was conducted on MM.1S and RPMI-8226 cells to identify relevant regulatory pathways. Protein-protein interaction and transcription factor target prediction analyses were performed to predict interactions between proteins and the binding sites of Myc and its target genes. The identified regulatory pathways were validated using qPCR and Western blot (WB).

Results: The IC50 of YM155 in various MM cell lines ranged from 2.5 to 15 nM, which was similar to that of bortezomib. YM155 demonstrated a time- and dose-dependent inhibition of cell viability and induced apoptosis, significantly downregulating Myc expression at mRNA and protein levels. The combination of YM155 and bortezomib showed superior cytotoxicity compared to either agent alone, suggesting a synergistic effect. RNA sequencing indicated that Myc expression was suppressed and P53 signaling pathway was activated after YM155 treatment. This was confirmed by RT-qPCR and WB, which showed activation of pro-apoptotic protein BBC3 and inhibition of anti-apoptotic protein BCL2. JASPAR bioinformatic analysis predicted that Myc might inhibit BBC3 expression by binding its promoter region, thereby activating P53 pathway. Additionally, the IC50 of YM155 in bortezomib-resistant cells was 10.56 nM, similar to that in naïve cells.

Conclusion: YM155 exhibits in vitro anti-myeloma activity in a dose- and time-dependent manner and has a synergistic anti-tumor effect with bortezomib, reversing resistance to some extent. YM155 exerts its anti-myeloma effects by inhibiting Myc and upregulating BBC3 expression, which activates the P53 pathway. This provides its potential role for the treatment of high-risk/relapsed refractory MM.

Keywords: Multiple myeloma, high-risk, YM155, Myc inhibitor, drug resistance
αIIbβ3-Dependent Platelet Procoagulant Activity Promotes Pulmonary Arterial Thrombosis Triggered By Blood-Borne Tissue Factor
Authors: Tashbook Sarah E. , Kaminski Tomasz W. , Sundd Prithu , Brzoska Tomasz
Published: December 2024

Rationale. In situ pulmonary arterial thrombosis (PAT), in the absence of concomitant deep vein thrombosis, is a life-threatening complication linked to several settings, including chronic obstructive pulmonary disease, asthma, sickle cell disease, emergency and elective surgeries, and viral infections. The occurrence of thrombotic complications in these conditions is correlated with elevated concentrations and activity of blood-borne tissue factor (TF). While TF is a primary initiator of blood coagulation, activated platelets accelerate coagulation by externalizing anionic phospholipids, such as phosphatidylserine (PS), and providing a catalytic surface for the assembly of coagulation enzyme complexes. In vitro experiments demonstrate that anionic phospholipids regulate TF-initiated coagulation; however, there is a lack of in vivo data on whether or how platelets contribute to the blood-borne TF-dependent in situ PAT.

Methods. We employed state-of-the-art quantitative fluorescence intravital lung microscopy (qFILM) to investigate PAT development in C57BL/6 (WT) mice following intravascular (IV) TF administration. We examined the impact of coagulation inhibition with heparin, platelet αIIbβ3 inhibition using eptifibatide, and phosphatidylserine (PS) blocking with annexin A5 (ANX) on circulating TF-induced PAT in WT mice. Fluorochrome-conjugated anti-mouse CD49b antibody, anti-mouse fibrin antibody, and dextran were administered IV for in vivo staining and visualization of platelets, fibrin, and blood vessels, respectively. Additionally, a modified prothrombin time assay (mPTA) was used to investigate the effect of platelet procoagulant activity on mouse platelet-rich plasma (PRP) clotting.

Results. TF triggered dose-dependent PAT in mice in vivo, which involved the development of platelet-rich thrombi in the junctions of pulmonary arterioles and capillaries, resulting in transient ischemia in the arteriole and the downstream capillary tree. The PAT, triggered by IV TF, was entirely abrogated by IV administration of heparin, eptifibatide, and ANX. In addition, the mPTA study confirmed that modification of platelet procoagulant activity by αIIbβ3 inhibition significantly extended clotting times in WT mouse PRP samples.

Conclusions. Our findings strongly suggest that circulating TF may contribute to the development of in situ PAT. We demonstrate that TF's action is dependent on platelet αIIbβ3 signaling, which promotes platelet procoagulant activity, accelerates coagulation and leads to PAT. Both our models have potential applications in investigating the molecular determinants of PAT associated with various pulmonary disorders, and in evaluating the efficacy of new antithrombotic drugs.
The Efficacy and Safety of Selinexor Plus Ruxolitinib Regimen in Ruxolitinib-Resistant Myelofibrosis: A Retrospective Study
Authors: Wen Ziyu , Zhou Xuan , Lin Bingyu , Liu Xiaoli , Wang Qiang , Xu Na
Published: December 2024

B ackgroundMyelofibrosis (MF) includes two types: primary MF (PMF) and post-polycythemia vera (PPV) and post-essential thrombocythemia (PET) MF, also known as secondary MF (SMF). Perturbation of the JAK/STAT signaling pathway is the hallmark of MF. Despite the meaningful improvements JAK inhibitors provide in managing splenomegaly and symptoms, they do not significantly impact disease progression. Consequently, issues such as treatment failure, poor efficacy, leukemia progression, and safety concerns persist in managing MF, particularly in patients who respond poorly or are intolerant to the JAK inhibitor ruxolitinib (RUX). In recent years,Combination therapy with different mechanisms has emerged as a new approach to improve prognosis post-ruxolitinib. Selinexor (SEL), an oral XPO1 inhibitor, may inhibit MF through various pathways. The 2024 CSCO Guidelines for hematological malignancies recommend SEL as first-line treatment for PMF. Cell experiments have confirmed that selinexor has the potential to overcome JAK resistance. A parallel cohort phase 2 study reported that 71.42% of RUX-intolerant/resistant MF patients receiving the SEL plus RUX regimen had reduced spleen volume, and 38.09% achieved spleen response. Here, we report on the efficacy and safety of SEL combined with RUX in RUX-resistant MF patients in a retrospective study.

Method This is a retrospective single-center study aimed at evaluating the efficacy and safety of SEL combined with RUX regimen in RUX-resistant MF patients. The study included 21 MF patients with a poor response to RUX: 12 with PMF, 4 with post-PV MF, and 5 with post-ET MF. Patients received SEL at 20 mg, 40 mg, or 60 mg QW plus RUX (dosage determined by the investigator).

Result The median age is 56 (range, 37-71) years and the median duration of previous RUX treatment is 11.3 (6-39) months. 47.6% of patients had peripheral blood blasts of 1-9%. 16 (76.2%) patients harbored JAK2 mutations, 2 (9.5%) patients CALR mutations and 1 (5%) patient MPL mutations. All patients had splenomegaly, and 8 (38.1%) were transfusion-dependent. According to the DIPSS risk score, 11 patients (52.4%) were classified as high-risk, 5 (23.8%) as intermediate-2 risk, and 5 (23.8%) as unknown risk. Spleen size reduced in 16 (76.2%) patients with a median response time of 2.3 (1-3) months. Three patients underwent bridging to transplantation and are currently surviving with good recovery. Peripheral blood blasts decreased in 10 (47.6%) patients after one month of treatment. The most common adverse events during treatment were gastrointestinal reactions and cytopenias.

Conclusion The combination of SEL and RUX showed promising efficacy and manageable safety profile in RUX-resistant patients with myelofibrosis.

Keyword Selinexor; ruxolitinib; ruxolitinib-resistant; myelofibrosis