bluuebunny/crossref_metadata_2025 huggingface dataset:
Primary Cutaneous Diffuse Large B-Cell Lymphoma-Leg Type Descriptors and Clinicopathologic Determinants of Survival: Analysis of a Pooled Database
Authors: Haddad Philip A , Amankwah Millicent
Published: December 2023

Background

Primary Cutaneous Diffuse Large B-cell Lymphoma-Leg Type (PCDLBCL-LT) is a rare but non-indolent subtype of B-cell lymphoma. While most of PCDLBCL-LT starts over the lower extremities, some cases may present at other cutaneous sites. The determinants of survival outcomes in this disease are not very well defined. Therefore, we conducted this pooled database analysis to identify the prognostic factors, clinicopathological characteristics, and therapeutic strategies that influence survival in this disease.

Methods

To study the demographic characteristics, molecular and immunohistochemical signatures, therapeutic interventions, survival, and prognostic factors, we compiled a pooled database of 122 cases that fit the diagnostic criteria for PCDLBCL-LT. Kaplan-Meier survival curves were constructed. Cox proportional hazards model and Log-rank tests were used to assess the influence of demographic and clinicopathologic factors on overall survival (OS) and disease-free survival (DFS).

Results

A total of 122 patients with confirmed PCDLBCL-LT were identified. The median age was 76. There was a male preponderance with M:F of 2.4. Seventy-three percent involved the extremities. The median duration of symptoms before diagnosis was 3.5 months. Involvement of lymph nodes, bone marrow, bone, and CNS occurred in 11%, 3%, 4%, and 3%, respectively. Constitutional symptoms were reported in 5%. The median OS and DFS of the whole group were 39 and 32 months, respectively. Patients younger than 70 had better median DFS (NR vs. 24 months, p=0.02) with a non-significant better median OS. Lymph node involvement (18 vs. 45 months, p=0.006) and stage T3 compared to T1/T2 (16 vs. 41 months, p=0.006) were associated with worse OS. Sex, constitutional symptoms, IHC phenotype, extra-lymphatic/extra-cutaneous organ involvement, and histologic cutaneous patterns did not impact OS. Compared to no treatment, chemotherapy, XRT+/-surgery, and stem cell transplant had numerically better OS without reaching statistical significance (5 vs. 39 vs. 41 vs. NR months, p=0.15). Patients who attained CR as their best response also had a superior median OS compared to responses less than CR and non-responders (61 vs. 23 vs. 11 months, p<0.0001).

Conclusion

This study presents updated clinicopathologic data from a large, pooled cohort of patients with PCDLBCL-LT. It identifies age, lymph node involvement, T stage, type of therapy, and quality of response to treatment as critical determinants of OS.
Complete Remission with Incomplete Count Recovery (CRi) Prior to sUCBT Is Associated with High Graft Failure in Acute Leukaemia Patients over 14 Years of Age
Authors: Wu Yue , Sun Guangyu , Tang Baolin , Song Kaidi , Zhu Xiaoyu
Published: December 2023

Recent studies have shown that measurable residual disease (MRD) has a definite impact on transplantation outcomes for acute leukaemia patients. However, the influence of complete remission with incomplete count recovery (CRi) prior to transplantation is rarely reported. Therefore, we retrospectively analysed 364 MRD-negative acute leukaemia patients who received single-unit unrelated cord blood transplantation (sUCBT). Among them, 90 patients were diagnosed with CRi. The cumulative incidence of neutrophil engraftment was lower for the CRi patients than for the CR patients. The cumulative incidences of platelet engraftment, 100-d non-relapse mortality (NRM), acute graft-versus-host disease(GVHD), chronic GVHD and the probabilities of 5-year overall survival, leukaemia-free survival and GVHD-free relapse-free survival were comparable. Among the patients older than 14 years (≥ 14), the CRi group was associated with decreased neutrophil and platelet engraftment compared to the CR patients (92.0% vs. 96.8%, 58.0% vs. 76.0%, P = 0.019, 0.018, respectively). Multivariate analysis of neutrophil engraftment in the patients ≥ 14 revealed that CRi,especially incomplete platelet recovery (CRp) prior to transplantation, were independent risk factors. Our study suggests that CRi is associated with an increased risk of graft failure for patients ≥ 14 after sUCBT, even after controlling for other risk factors.
Clinical Significance of Serum CD155 Levels in Acute Lymphoblastic Leukemia Patients
Authors: Azzazi Mohamed , Hegab Hany M , Said Rasha Magdy Mohamed , Ibrahim Nahed Moawad Ibrahim , Abdelfatah Rana G , Mostafa Mariam A
Published: December 2023

Background: Acute lymphoblastic leukemia (ALL) is a hematologic malignancy characterized

by poor outcomes in adults. Traditional diagnostic and prognostic markers take into account

clinical data but also rely heavily on expensive and invasive tests such as bone marrow studies

with cytogenetics. CD155 is an adhesion molecule that also modulates immune response in

malignancy. Previous studies have shown that serum CD155 (sCD155) levels are higher in

patients with malignancies, and have demonstrated a correlation between higher levels of

sCD155 and poor outcomes. This study investigated the diagnostic and prognostic value of

sCD155 in adult patients with acute lymphoblastic leukemia.

Methodology: 32 adult patients with acute lymphoblastic leukemia and 15 control patients were

enrolled in this study. Clinical and outcome data were collected from patients and a blood sample

from patients and controls was collected with ELISA testing for sCD155 levels.

Results: sCD155 was found to be significantly higher in patients than controls (p<0.05) and was

significantly associated with bone marrow aspirate blast count. It was not associated with other

clinical parameters including gender, age, initial CBC parameter counts, presence of

lymphadenopathy, presence of CNS infiltration, presence of Philadelphia chromosome, type of

ALL, or risk stratification of ALL besides being associated with hepatosplenomegaly. ROC curve

showed high sensitivity and specificity of sCD155 and Kaplan Meir curve showed a trend

towards worse outcomes in patients with high sCD155 but it was not statistically significant.

Conclusion: sCD155 remains a promising marker for diagnosis of ALL but further studies are

needed to confirm its prognostic value.
Health-Related Quality of Life (HRQL) in Cutaneous T-Cell Lymphoma: Psychological Burden and Influencing Factors from Mycosis Fungoides and Sézary Syndrome Patients in China
Authors: Hsu Tun-Ying , Sun Huiping , Li Zhiming , Huang Wenrong , Xie Linna , Yan Xiaojing , Zhao Haifeng , Kim Ki Hyon , Shi Yuankai
Published: December 2023

Introduction: Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes of cutaneous T-cell lymphomas (CTCL). However, beyond the clinical and economic burden, psychological burden from CTCL patients in China has not been reported and requires further evaluation.

Methods: The analysis used data from adults (≥18 years) clinically diagnosed with MF or SS, and have been receiving or have received disease-related treatment in the past year. MF patients with stage IA-IIA, patch or plaque phase were categorized into early stage, while stage IIB-IVA, tumor phase were late stage. All SS patients are late stage. HRQL data from the EQ-5D-5L, Skindex-29 and Functional Assessment of Cancer Therapy - General (FACT-G) were analysed at the item level and scored according to instrument guidelines. Multivariate analyses were used to identify factors associated with poor HRQL.

Results: Data were collected from a quantitative survey of 56 MF patients and 5 SS patients residing in 38 cities of 21 provinces across China: 56% were male, with a mean (SD) age of 39 (13) years (median was 38, ranged 19 to 74 years old). 51% were late stage. Based on emotional domain questions of Skindex-29, among all patients, 39% always or often worried about the disease progression, while 45% of late-stage patients were always and often worried. 36% of all patients often or always felt CTCL was annoying. Based on FACT-G, in physical well-being domain, 39% of all patients, and 48% of late-stage patients felt they were ill in “quite a bit” or “very much” scale, respectively. In social well-being domain, 35% of all, and 39% of early-stage patients felt “not at all” or only “a little bit” satisfied with their sex life. In emotional well-being domain, 38% of all patients were “not at all” or “a little bit” satisfied with their coping with the disease, while 36% of all patients “quite a bit” or “very much” worried about the condition getting worse. In the functional well-being domain, 29% of all patients felt they were “not at all” or “a little bit” able to work.

In multivariate analysis, regression on EQ-5D-5L score showed that younger patients were more likely to report severe anxiety and depression. Skindex-29 score showed that female patients worried more that the disease get more serious and causing scars on their skin.

Conclusions: In China, psychological burden with MF and SS, included anxiety, depression, worrying about disease progression, unable to work, and unsatisfied sex life. Younger patients and female patients reported greater psychological impact of the disease. Optimal medical management of MF and SS should address psychological impacts of the disease.
Hemolysis and Free Heme Impact Therapeutic Activity of Anti-CD20 Antibody
Authors: Dimitrov Jordan , Kanyavuz Alexia , Marey-Jarossay Annaelle , Lecerf Maxime
Published: December 2023

Hemolysis is a process of destruction of erythrocytes that can occur in different hereditary or acquired pathologies. It is accompanied by release of hemoglobin and heme, which both manifest potent pro-oxidative and pro-inflammatory activities. If released in large quantities hemoglobin and heme can directly contribute to systemic inflammation and tissue injury in hemolytic diseases. Moreover, it was demonstrated that heme binds to a significant fraction (ca. 10 %) of human antibodies (Abs) and this binding can result in considerable functional changes. Thus, heme-bound human IgG acquire reactivity towards a large set of unrelated proteins, including autoantigens. In a previous study we observed that 14 % of a repertoire of 117 clinical-stage therapeutic mAbs are able to bind heme and as a result they acquired autoreactivity and polyreactivity. Among these Abs some are specific for CD20 and used in lymphoma therapy (e.g. Rituximab). Importantly, therapeutic mAbs can be administered in patients with ongoing hemolysis. Thus, it is of critical importance to decipher molecular mechanism and functional consequences of interaction of heme with therapeutic mAbs and understand how the therapy of lymphoma can be affected by underling hemolysis and heme release.

The present study has the following objective: to elucidate the effect of heme on the therapeutic activity of anti-CD20 therapy in in vitro and in vivo models of B cell lymphoma. Effect of heme on anti-CD20 therapeutic Abs was assessed by i) binding assays - ELISA, western blot; protein microarrays; absorbance spectroscopy; surface plasmon resonance, and ii) molecular modeling. The impact of heme on functional and therapeutic activity of Rituximab was analyzed by i) site-directed mutagenesis; ii) flow cytometry; iv) in vitro and in vivo models of human B cell lymphoma.

Our data reveled molecular and functional details about the interaction of heme with Rituximab and other anti-CD20 Abs. Thus, we characterized the interaction of Abs with heme, and identified in case of Rituximab the putative binding site for heme that overlapped with antigen binding site. By using a protein array with >9800 human proteins, we identified the target proteins of heme-bound Rituximab. A mouse model of human B cell lymphoma revealed that the therapeutic activity of Rituximab was compromised following exposure to cell free heme under condition of acute intravascular hemolysis. Our study delineates that a fraction of currently used therapeutic mAbs show high sensitivity to heme and their therapeutic activity can be compromised under hemolytic conditions. This finding suggests that therapeutic interventions that reduce free heme and /or intravascular hemolysis should precede therapy with these Abs. Moreover, we identified sequence features of Abs that determine the sensitivity to heme. This finding can help to reduce sensitivity of heme of therapeutic Abs by protein engineering.
CRISPR-Based Gene-Editing Screens Revealed Modulators of Dexamethasone Sensitivity in Multiple Myeloma
Authors: Sobh Amin , Bonilla Emilie , Patel Alisha , Li Jianping , Dalal Mansi , Riva Alberto , Bennett Richard Lynn , Licht Jonathan D.
Published: December 2023

Background: Multiple myeloma (MM) is an incurable plasma cell malignancy that accounts for 10% of hematologic malignancies. Despite improved prognosis due to advances in treatment, most patients ultimately develop therapy resistance and relapse. The glucocorticoid dexamethasone is a potent anti-myeloma agent used in combination with proteasome inhibitors and Immunomodulatory drugs (IMIDs) as frontline treatment. Dexamethasone binds to the glucocorticoid receptor (GR), which induces apoptosis by driving an apoptotic transcriptional program. The mechanisms of Dexamethasone resistance in MM remain poorly understood.

Aim: To define cellular processes that modulate dexamethasone sensitivity in MM.

Methods: We performed loss-of-function CRISPR screens in the t(4;14), NSD2 overexpressing, MM cell lines KMS11 and LP1 using the genome-wide Brunello sgRNA library.

Results: The screens identified genes whose loss altered MM cell sensitivity to dexamethasone, most being cell type-specific suggesting heterogeneity in mechanisms influencing dexamethasone cytotoxicity across MM patients. In KMS11 cells, disruption of the IL10/JAK/STAT signaling pathway and glycosaminoglycans/heparan sulfate synthesis pathway increases sensitivity to dexamethasone. By contrast, loss of chromatin remodeling factors including the polycomb group member EPC1 and the SWI/SNF complex components BRD7 and BRD9, altered dexamethasone response exclusively in LP1 cells. Perturbations resulting in dexamethasone resistance in both cell lines include the GR and its co-chaperone PTGES3 in addition to members of the NFKB inhibitor family (NFKBIA, NFKBIB). By contrast, disruption of the druggable GR co-chaperone FKBP5 or the histone deacetylase HDAC8 increased sensitivity to dexamethasone. In addition, the GID/CTLH E3 ubiquitin ligase complex was also identified as a general determinant of dexamethasone resistance in MM cells as disruption of several constituents of this complex resulted in increased dexamethasone sensitivity in both cell lines. The mechanism by which the GID/CTLH complex confers dexamethasone tolerance in MM cells is currently under investigation.

Conclusions: Multiple cellular processes contribute to modulating the cytotoxic effect of dexamethasone in MM. Such processes often regulate expression, stability, or localization of the GR. NFKB signaling and the GID/CTLH E3 ubiquitin ligase activity are key determinants of dexamethasone resistance. Targeting these processes can increase the therapeutic effect of dexamethasone in MM.
Prognostic Factors in Hospitalized Patients with HIV-Associated Burkitt's Lymphoma - Real World Data Analysis
Authors: Pichardo Rayli , Ramo Aula , Abu Omar Yazan , Dabak Vrushali S.
Published: December 2023

Introduction

Burkitt Lymphoma (BL) is a highly aggressive and rare B-cell non-Hodgkin Lymphoma, characterized by translocation and dysregulation of the MYC gene. BL comes in three distinct forms: endemic, sporadic, and immunodeficiency related, which is most commonly secondary to HIV. Despite improvements in antiretroviral therapy (ART), the reported incidence of BL has remained stable over time. BL is a highly curable disease in patients able to tolerate aggressive therapies. However, little is known about real-world outcomes in United States patients with HIV- related BL. Our study highlights multiple factors associated with inpatient mortality and morbidity.

Methods

The National Inpatient Sample database was queried from October 2015 to December 2020.

Adults aged >= 18 with a primary diagnosis of BL were identified and stratified into those with and without HIV. Complications included were queried using ICD codes most found in the secondary diagnosis variables. Baseline characteristics, inpatient complications, and outcomes were compared using chi-squared and Wilcoxon rank-sum tests. Logistic regression analysis was performed to assess the risk of death before and after adjusting for multiple risk factors.

Results

We found 3,650 admissions with a primary diagnosis of BL, 400 (11%) of whom had HIV. Patients with HIV were younger, 49% were younger than 40 years old as compared to 29% in patients with no HIV. There was a higher percentage of black patients 115 (29%), and most had Medicaid 170 (44%), there was no difference between income, hospital bed size or geographical region. Interestingly, in multivariable analysis, there were no significant differences in length of stay, race, or mortality between patients with and without HIV. The factors associated with mortality in HIV patients included acute renal failure OR 11.4 (1.22 to 107) and Sepsis OR 38.6 (1.62 to 921)

Conclusion

BL is an increasingly important disease in HIV-infected patients given that the incidence remains high despite advances in ART. This nationwide data analysis demonstrates the demographic characteristics of patients with HIV-associated BL in the US and the encouraging findings that outcomes are not significantly different between patients with and without HIV. Yet our study demonstrates the disproportionate distribution of HIV-BL in females and black patients. Further studies are needed to examine gender and racial disparities.
A Real-World Pharmacovigilance Analysis of Chemotherapy-Related Myelodysplastic Syndrome and Acute Myeloid Leukemia
Authors: Goyal Shriya , Gaddam Shiva Jashwanth , Grewal Udhayvir , Ramadas Poornima
Published: December 2023

Background

Myelodysplastic syndrome (MDS) and Acute Myeloid Leukemia (AML) are well-known complications of traditional chemotherapy used to treat different solid and hematological malignancies. It is also reported with some newer drugs (eg. PARP inhibitors). We sought to analyze the real-world data of different chemotherapeutic drugs causing MDS/AML

Methods

From the FDA Adverse Events Report System (FAERS) public dashboard, we obtained the data on all the events reported as MDS and AML. Data was available for the years 1970 - 2023, and the events were analyzed for different drugs.

Results

A total of 24,565 events of MDS and AML were reported to the FAERS database between 1970 and 2023. 11,045 (44.97%) occurred in males, 9,803 (39.91%) in females, and 3,714 (15.12%) events had no sex specified. Most of them were severe AEs, and 11,486 (46.7%) of them were fatal. Among all the different chemotherapeutic drugs, the highest number of reports were related to Cyclophosphamide - 3,735 events (15.20%), followed by Lenalidomide - 3,028 events (12.33%) and Etoposide - 2,017 events (8.21%) (Table 1). When individually analyzed, MDS and AML accounted for 3.1% of all AEs related to Cyclophosphamide, compared to 0.9% for Lenalidomide AEs, and 4.2% for Etoposide AEs (Table 2).

Conclusions

Based on this retrospective analysis, we found that cyclophosphamide was the most common drug associated with MDS/AML reported to the FAERS, followed by Lenalidomide and Etoposide. However, MDS/AML was a more common AE with Etoposide, than with Cyclophosphamide or Lenalidomide. Considering the fatality rates of these events, a comprehensive risk-benefit and possible alternative therapy discussion must be held with the patients prior to treatment planning.
The Prognostic Value of Dynamic Change of NK-Cell Counts in Diffuse Large B-Cell Lymphoma Treated with R-CHOP
Authors: Huan Chen , Zheng Zhongxin , Wei Yongqiang , Guo Xutao , Wei Qi , Feng Ru , Wei Xiaolei
Published: December 2023

Key words: Diffuse large B-cell lymphoma, Natural killer cell count, prognosis.

Introduction

Natural killer (NK) cell counts at diagnosis have been reported to be associated with poor outcomes, but the dynamic change and prognostic value of NK cell counts after treatment in diffuse large B-cell lymphoma (DLBCL)remain unknown.

NK cell count was test by flow cytometry at diagnosis, interim and the end of treatment. Receiver operating characteristic (ROC) curve was used to determine the best cutoff value for survival analysis. Overall survival (OS) and progression-free survival (PFS) were analyzed by the method of Kaplan-Meier and Cox proportional hazard regression model.

A total of 175 DLBCL patients were analyzed and 45 of them were divided into the low NK cell counts with the cut-off value was 94.5/ul. Patients with low NK cell counts were associated with B symptoms (p < 0.001), high LDH (p=0.002), advanced stage (p < 0.001) and high IPI scores (p=0.001). Survival analysis showed patients with low NK cell counts at diagnosis showed more inferior OS and PFS than those with high NK cell counts (p < 0.001 and p < 0.001). There were 60 patients showed low NK cell counts at the interim, consist of 31patients with low and 29 with high NK cell counts at diagnosis and 65 patients had low NK cell counts at the end of the treatment, consist of 31patients with low and 34 with high NK cell counts at diagnosis. But NK cell count at the interim or end of treatment had no impact on the PFS (p = 0.415 and p = 0.011) and OS (p = 0.537 and p = 0.836) of DLBCL patients. Multivariable analysis revealed that NK cell counts was an independent prognostic factor OS [relative risk (RR);95% confidence interval (CI),0.157-0.984, p = 0.046] and PFS (RR,0.335;95%CI,0.191-0.588, p < 0.001） in all DLBCL patients independent of IPI.

In conclusion, low NK cell counts at diagnosis is a simple and effective adverse prognostic factor in DLBCL patients treated with R-CHOP. However, the NK cell counts at the interim and the end of the treatment showed no impact on outcome.
High IL-10 Expression Is Associated with Poor Prognosis in Primary Gastrointestinal Lymphoma
Authors: Wang Lingli , Ma Lan , Gao Jinjie , Wan Wei , Yang Ping , Zhu Mingxia , Dong Fei , Jing Hongmei
Published: December 2023

Background：Primary gastrointestinal lymphoma（PGIL）is defined as the primary malignant lymphoma of the gastrointestinal tract. The long-term prognosis and life quality of PGIL patients are influenced due to gastrointestinal complications. Cytokines have a close immunological relationship with lymphocytes, however, the relationship with serum cytokines and PGIL prognosis is still unknown.

Method：We conducted a retrospective analysis of 165 PGIL patients referred to Department of Hematology of Peking university third hospital over a 10-year period between 2012-2022，and serum cytokine detection was performed on 85 patients' peripheral blood. Serum cytokine（IL-2,IL-4,IL-6,IL-9,IL-10,TNF-a）were quantified using flow cytometer. Median follow-up time was 29 months, and 1-year progression-free survival(PFS) of total PGIL patients was 84.1%, and 3-year PFS was 67.9%.The 1-year overall survival（OS）was 90.9%,and 3-year OS was 89.2%.

Results：The median age of PGIL patients was 57-year-old, and 58.8% of them were male. The two most common pathological types were diffuse large B-Cell lymphoma (40.0%) and mucosa-associated lymphoid tissue(30.6%).Our results also showed that IL-4 level was higher in surviving PGIL patients, while IL-10 level was higher in deceased PGIL patients. There was no statistically significant difference in other serum cytokines(IL-2,IL-6,IL-9, TNF-a) between surviving and deceased PGIL patients. Survival analysis showed that the OS of patients in the low IL-10 level group was lower than that in the high IL-10 group（P=0.03）

Conclusion：High IL-10 expression is associated with poor prognosis in primary gastrointestinal lymphoma
Safety and Efficacy of Autologous HSCT in Nine Patients with AIDS-Related Non-Hodgkin Lymphoma
Authors: Liu Jun , Zhou Yixing , Liang Shunsi , Zeng Chensi , Zhang Lingqian , Huang Dehong , Xiao Chunyan , Yang Tao , Li Jieping , Nan Yingyu , Li Qiying , Xiang Ying , Liu Yao
Published: December 2023

Background：In recent years, with the application of HIV combined with resistance retroviral therapy, the number of AIDS-NHL patients has gradually increased, surpassing Kaposi's sarcoma and becoming the first AIDS-related tumor. The prognosis of AIDS-NHL patients is worse than that of ordinary NHL patients, and more powerful treatment is needed. To analyze the safety and efficacy of 9 AIDS-related non-Hodgkin lymphoma (AIDS-related non-Hodgkin lymphoma, AIDS-NHL) treated with autologous hematopoietic stem cell transplantation (auto-hematopoietic stem cell transplantation, ASCT).

Methods: 9 patients with AIDS-NHL were prospectively treated for their safety and efficacy.

Results: The male to female ratio of 9 AIDS-NHL patients was 8:1, and the median age was 38 years. The pathology types were 4 DLBCL, 2 PBL, 1 BL, 1 HGBL and 1 HL, including 3 patients with refractory relapse (1 each of DLBCL, HGBL and PBL). Except for three patients with refractory relapse, the remaining six patients underwent first-line autologous HSCT. One PBL stage was in stage I low-risk group and the remaining patients were in stage III - IV high-risk group. Before transplantation, one patient was progressive, one patient was in partial remission, and the other patients achieved complete remission after chemotherapy. All patients underwent autologous HSC mobilization using PEG-G-CSF, with all CD34 + cell numbers> 210 ^ 6 / Kg. Transplantation pretreatment was performed with the BeEAM protocol, with a median time to granulocyte engraftment of 11 days and a median time to platelet engraftment of 14 days, with no transplant-related death. Two patients who did not achieve CR before transplantation all died due to disease progression within 3 months after transplantation, and the remaining patients remained in complete disease remission through follow-up until February 28,2023.

Conclusion: AIDS-NHL patients are aggressive and have a poor prognosis, and active treatment is needed to improve their long-term survival. Our center prospectively performed autologous HSCT in nine patients with AIDS-NHL, and the results showed that the time of granulocyte and platelet engraftment was consistent with that of ordinary NHL patients, with no transplant-related death and was well tolerated. Failure to achieve complete remission before transplantation may be one of the adverse factors for the early death of patients.
The Addition of Lenalidomide to R-CHOP Is Effective for Prevention of CNS Relapse in High-Risk Patients with Diffuse Large B-Cell Lymphoma
Authors: Wei Xiaolei , Guo Xutao , Wei Qi , Xiong Dan , Zhang Peng , Zhang Zewen , Wei Yongqiang , Feng Ru
Published: December 2023

Central nervous system (CNS) relapse is an uncommon but devastating event in patients in diffuse large B-cell lymphoma (DLBCL). Although several prophylaxis attempts including intrathecal methotrexate and intravenous high-dose methotrexate were conducted to reduce the CNS relapse rate, the optimal management remained uncertain. Herein, we performed an open-label, multicenter trial to explore the efficacy and safety of the combination of lenalidomide and R-CHOP (R2-CHOP) for preventing the CNS relapse in the high-risk diffuse large B cell lymphoma.

Eligible patients were aged 18-80 years, newly diagnosed DLBCL and high risk for CNS recurrence: CNS-IPI:4-6 or involvement of testicular, kidneys or adrenal glands. Lenalidomide orally 25 mg per day was administered on days 1 through 10 of each cycle and delivered concomitantly with standard dose R-CHOP-21 regimen. All patients received aspirin 100mg per day prophylaxis throughout. The primary endpoint was 2-year central nervous system relapse rates. The secondary endpoint were 2-year overall survival, progression-free survival, and treatment-emergent adverse events. This trial is registered with ClinicalTrials.gov, number NCT04544059.

A total of 56 DLBCL patients with high-risk for CNS relapse were included in this study. The median age of the patients in this study was 57 years old (range 26-77） and 47.8% patients were female. 88.9% patients had a CNS-IPI score ≥4 and the left patients may be involved with testicular, kidneys or adrenal glands. With a median follow up of 20 months,45patients finished planned cycles of R2-CHOP treatment and only 2（4.4%） patient developed CNS relapse. The 2-year progression-free survival and overall survival were 77.8% and 79.7%, respectively.

In summary, lenalidomide with R-CHOP is effective for prevention of CNS relapse in high-risk patients with diffuse large B-cell lymphoma.

Keywords:

Diffuse large B-cell lymphoma, central nervous system relapse, lenalidomide.
Risk Factors for Positive Posttransplantation Measurable Residual Disease in Patients with Acute Lymphoblastic Leukemia
Authors: Wang Yuewen , Fu Guomei , Xu Lanping , Wang Yu , Cheng Yi-Fei , Zhang Yuanyuan , Zhang Xiaohui , Liu Yanrong , Liu Kaiyan , Huang Xiao-Jun , Chang Ying-Jun
Published: December 2023

Background: The level of MRD before and after transplantation is related to inferior transplant outcomes, and post-hematopoietic stem cell transplantation measurable residual disease (post-HSCT MRD) has higher prognostic value in determining risk than pre-HSCT MRD. However, no work has been devoted to the risk factors for positive post-HSCT MRD in patients with ALL. This study evaluated the risk factors for post-HSCT MRD positivity in patients with acute lymphoblastic leukemia (ALL) who underwent allogeneic HSCT (allo-HSCT).

Methods: A total of 1683 ALL patients were enrolled. Cox proportional hazard regression models were built for time-to-event outcomes. Multivariate analysis was performed to determine independent influencing factors from the univariate analysis.

Results: Both in total patients and in T-ALL or B-ALL, pediatric or adult, HLA-matched sibling donor transplantation or haploidentical HSCT subgroups, positive pre-HSCT MRD was a risk factor for post-HSCT MRD positivity ( P < 0.001 for all). Disease status was also a risk factor for post-HSCT MRD positivity in all patients and in the B-ALL, pediatric, or haploidentical SCT subgroups ( P =0.003; P=0.035; P =0.003, respectively). A risk score for post-HSCT MRD positivity was developed using the variables pre-HSCT MRD and disease status. The cumulative incidence of post-HSCT MRD positivity was 12.3%, 25.1%, and 38.8% for subjects with scores of 0, 1, and 2-3, respectively ( P<0.001). Multivariate analysis confirmed the association of the risk score with the cumulative incidence of post-HSCT MRD positivity and relapse as well as LFS and OS.

Conclusion: Our results indicated that positive pre-MRD and disease status were two independent risk factors for post-HSCT MRD positivity in patients with ALL who underwent allogeneic HSCT.
High Frequency Mutant Genes and Prognosis Value of HIV-Related Diffuse Large B-Cell Lymphoma
Authors: Peng Yu , Ran Longrong , Zhao Mingyu , Yang Zailin , Liu Yao
Published: December 2023

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype in AIDS-related lymphoma (ARL) in HIV-infected patients, and the probability of DLBCL in HIV-infected patients is up to 17 times higher than that of the healthy population. However, the genetic mutation profile of HIV-associated DLBCL is still controversial, and the gene regulatory mechanism of HIV infection leading to the high incidence of DLBCL is still unclear.

Methods: A total of 12 HIV-positiveDLBCL and 39 HIV-negativeDLBCL patients who treated in Chongqing University Cancer Hospital from March 2022 to October 2022 were enrolled. Tumor tissue samples were selected to detect by second-generation sequencing technology, and gene heat mapping was used to analyze the high-frequency mutant genes in HIV-positive lymphoma patients, comparing the differences mutant genes between HIV-positive and HIV-negative DLBCL patients. The specific mutant genes in HIV-positive DLBCL were screened, and Kaplan-Meier estimate the impact of specific gene changes on disease prognosis in analyze DLBCL lymphoma.

Results Compared with HIV-negative DLBCL patients, 12 patients with HIV-positive DLBCL were mostly male (91.7%), and the disease subtype was mostly germinal center B-cell like(GCB) subtype (75%). HIV-positive DLBCL patients were associated with EBV infection, elevated LDH, increased proportion of CD4 + cells < 200 (cell/ul), and more aggressive. The gene heat mapping results showed that TP53, TBL1XR1 and KMT2D had higher mutations in HIV-positive DLBCL and HIV-negative DLBCL patients. Compared with HIV-positive DLBCL, HIV-negative DLBCL patients were more likely to have gene mutations such as IGLL5, KMT2C, CD79B, BTG1, HIST1H1E, TNFRSF14, B2M. Compared with HIV-negative DLBCL patients, HIV-positive DLBCL patients detected more complex gene mutation sites, and were more common to have gene mutations including TP53, LRP1B, MYC, NOTCH2, SPEN, EP300, SOCS1, TYK2, ARID1A, GNA13, MAP2K1. Among those gene mutations, LRP1B, MYC, TYK2 have a higher probability in HIV-positive DLBCL patients (P<0.05). Compared with HIV-negative DLBCL patients, HIV-positive DLBCL patients have a worse prognosis by Kaplan-Meier analysis, and patients with LRP1B, MYC, TYK2 mutations had a longer time to achieve complete remission.

Conclusion HIV-positive DLBCL patients are more prone to gene mutations, and the mutant genes are more complex and diverse. LRP1B, MYC and TYK2 gene mutations may play an important role in the occurrence and development of HIV-positive DLBCL and affect the prognosis of patients.

Keyword HIV; lymphoma; genetic mutation; prognosis
Transplant Associated Thrombotic Microangiopathy: Acomprehensive Review and Local Experience
Authors: Benkhadra Maria , Gulied Amaal , Mohamed Mohamed Saeed , Mudawi Deena , Gaziev Javid , Al-Khabori Murtadha , Yassin Mohamed A
Published: December 2023

Introduction

Thrombotic Microangiopathy (TMA) is a rare, life-threatening severe condition characterized by microangiopathic hemolytic anemia, thrombocytopenia and microthrombi in the walls of small blood vessels leading to ischemic organ dysfunction. Transplant-associated TMA (TA-TMA) can occur as a complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). The mechanism of TA-TMA is not fully understood, and conventional treatment options are based on targeting the identified risk factors and hypothesized pathophysiology. This review aimed to compile the information to date about TA-TMA and possible treatment strategies and report successful cases at the National Center for Cancer Care and Research (NCCCR).

Methods

Scientific databases were scoped for reviews on TA-TMA, its pathophysiology, risk factors and therapeutic strategies. Results were compiled to formulate an understanding of TA-TMA. Local cases of TA-TMA at NCCCR were also reported.

Results

TA-TMA pathophysiology and risk factors are described in Figure 1 and Table 1, respectively. Due to the complexity of the patient cases under investigation, TA-TMA diagnosis is clinical. Proposed diagnostic criteria include anemia, thrombocytopenia, elevated LDH, presence of schistocytes, hypertension, proteinuria, and elevated sC5b-9. Therapeutic approaches start the management of modifiable risk factors such as withdrawal or decreasing the dosage of calcineurin inhibitors (CNIs), control of hypertension and AKI, treatment of active infections and management of graft versus host disease (GvHD). Therapeutic plasma exchange (TPE) may benefit some patients who are positive for factor H autoantibodies. eculizumab, a humanized antibody against complement protein, can be highly effective in patients with TA-TMA. It is recommended for patients with high-risk features such as elevated sC5b-9 and proteinuria and can also be used for patients with organ damage or disseminated disease. Other available treatment options include rituximab and defibrotide. Other therapeutic agents are under clinical trials such as ravulizumab (C5 inhibitor), nomacopan (C5 and leukotriene B4 inhibitor) and narsoplimab (mannan-binding lectin-associated serine protease-2 [MASP-2] inhibitor). Four cases were diagnosed with TA-TMA at NCCCR between September 2017 and February 2023, as described in Figure 2. All cases recovered; however, the challenge remains in the choice of therapy. Thus far, the choice is to individualize therapy according to comorbidities, severity of clinical presentation and availability of the treatment options.

Conclusion

TA-TMA remains a significant clinical challenge for transplant physicians, and more research is needed to improve our understanding of its pathogenesis, diagnosis, and management, particularly in guiding the choice of therapy.
Lenalidomide and Dexamethasone for Patients with Rosai-Dorfman Disease: A Single Arm, Single Center, Prospective Phase 2 Study
Authors: Chang Long , He Lin , Li Jian , Zhou Daobin , Cao Xinxin , Gao Wen
Published: December 2023

Background

Rosai-Dorfman disease (RDD) is a rare heterogeneous histiocytic disorder. Because of the rarity of RDD and a lack of prospective randomized trials, the treatment strategy for RDD is mostly based on retrospective study. Previous studies showed thalidomide or lenalidomide was effective in recurrent/refractory RDD with skin involvement.

Aims

This study was designed to evaluate the efficacy and safety of lenalidomide and dexamethasone (RD) for Rosai-Dorfman Disease.

Methods

This phase 2, prospective, single-center study enrolled 13 newly diagnosed and 9 recurrent patients with RDD from June 2021 to August 2022 (NCT 04924647). The RD regimen was lenalidomide 25mg d1-21 and dexamethasone 20-40mg d1,8,15,22 for a cycle and 12 cycles in total. The primary endpoint was event-free survival (EFS). Events were defined as a poor response to RD, reactivation after RD therapy or death from any cause. The secondary endpoint was overall response rate (ORR) and overall survival (OS).

Results

The median age was 44 years (range 21-71 years). Fifteen patients were male (68.2%). All the patients were extranodal RDD (2 unifocal, 3 single-system multifocal and 17 multisystem). The most common organ involved was bones (45.5%) and subcutaneous tissue (45.5%), followed by sinus (37.5%). Four patients (18.2%) had central nervous system (CNS) involvement. MAPK pathway alterations were found in 6/15 (20.0%) of the patients. All patients received at least six courses of RD regimen therapy, with median 12 (6-12) courses. Overall, 18 patients (81.8%) completed protocol treatment, and 4 patients (18.2%) went off protocol (3 patients' decision, 1 poor response). The overall response rate was 86.4% (19/22), including 7 patients (31.8%) achieving complete remission and 12 patients (54.5%) achieving partial remission. After a median follow-up of 22 months (range 8-24 months), 3 patients (13.6%) relapsed. No patients died or lost follow-up. The estimated 2-year EFS and OS was 67.8% and 100.0%, respectively. To evaluate the prognostic factors of EFS using univariate analysis, we found that patients with CNS, respiratory system, multi-system involvement and MAPK pathway gene mutations had similar outcomes. No patients had grade 3-4 adverse effects. 8 patients (36.4%) had grade 1 gastrointestinal complications (vomiting, nausea and diarrhea). 6 patients (27.3%) experienced anemia, neutropenia or thrombocytopenia. Only 1 patient (5.6%) had grade 2 neutropenia. 5 patients (22.7%) experienced rash and 5 patients (22.7%) experienced fatigue with grade 1 events. All complications improved with supportive treatment.

Conclusion

Lenalidomide and dexamethasone regimen is an efficient and safe regimen for newly diagnosed and recurrent RDD.
Gene Regulatory Networks Controlling Sinusoidal Hematopoietic Niche Function
Authors: Li Wantong , Faisal Muhammad , Oyman Konur , Blaser Bradley Wayne
Published: December 2023

The bone marrow sinusoidal vascular niche is important for HSC engraftment and regeneration of hematopoiesis after transplantation, but the epigenetic factors that control these biological functions are undefined. Here, we show that sinusoidal hematopoietic niche functions are controlled by gene regulatory networks (GRNs), involving transcription factors (TFs) that bind to enhancers to regulate corresponding target genes.

To characterize sinusoidal niche specific transcriptional and chromatin accessibility states, we performed multimodal single nuclei RNA and ATAC-seq analysis on unsorted zebrafish embryos. We identified 4 niche clusters, including mesenchymal stem cells, fibroblasts, osteoblasts and sinusoidal endothelial cells. Differential RNA transcriptome analysis confirmed the identity of each niche cluster with canonical gene markers for each niche cluster. To examine differential transcriptional accessibility in zebrafish niche clusters, we aggregated co-accessible regions in cells from these clusters. Each cluster demonstrated a unique chromatin accessibility profile with differentially accessible regions. Differential motif activity based on chromatin accessibility analysis further exhibited unique TF motifs activity in sinusoidal endothelial cells.

To identify potential regulatory TFs in sinusoidal vascular niche, we predicted TFs based on the TF binding sites accessibility and TF expression. Thus, we identified 3 specific expressed and enriched TFs for sinusoidal vascular niche, including Fli1 (Friend leukemia integration 1), Mef2a (Myocyte enhancer factor 2A) and Mef2c. Next, to investigate genomic regulatory regions that interact with TFs, in which control the transcription of their target genes, we performed random forests and regression trees machine learning methods to infer GRNs. We observed multiple active GRNs in sinusoidal vascular niche, which were predicted to essential for regulating hematopoietic niche development and HSC maintenance, including klf12, egfl7, ebf3 and ldb2.

Finally, we examined whether these putative gene regulatory networks were conserved across species and tissue types. We used same approach (single-cell multiome sequencing) on E4-HUVEC cells, a transduced human umbilical vein endothelial cells (HUVEC) with the adenovirus E4ORF1 gene, which was a well-defined model of the human sinusoidal vascular niche. We likewise observed regulatory networks in HUVEC cells. As in zebrafish, GRNs in human sinusoidal cluster consisted of FLI1 and MEF2 family, regulatory regions and their target genes. Our findings reveal that unique sinusoidal vascular niche specific gene regulatory networks, including TFs, regulatory regions and target genes indicate the treatments targeting GRNs may help to facilitate reprogramming of sinusoidal endothelial niche to support HSC homing and regeneration after transplantation.
Cytarabine Plus Etoposideis+Peg-Rhg-CSF Is More Effective Than Cyclophosphamide + G-CSF As a Stem Cell Mobilization Regimen in Poorly Mobilized MM and Lymphoma
Authors: Cheng Yixuan , Chen Dong , Pei Renzhi , Du Xiaohong , Li Chen , Zhuang Xianxu , Li Fenglin , Ye Peipei , Lu Ying
Published: December 2023

There are several methods for hematopoietic stem cell (HSC) mobilization in lymphoma and multiple myeloma (MM)，of which Cyclophosphamide(Cy) plus granulocyte-colony stimulating factor(G-CSF)is a commonly used HSC mobilization regimen,but this regimen often fails to collect a sufficient number of stem cells, especially for poorly mobilized patients.However,previous studies have shown that the mobilization effect of cytarabine plus etoposide and G-CSF seems to have a higher mobilization efficacy. The purpose of this study is to retrospectively compare the mobilization effects of using cytarabine ，etoposide plus polyethylene glycol recombinant human granulocyte stimulating factor(PEG-rhG-CSF)(EAP) and Cy+G-CSF in proven poor mobilizer or predicted poor mobilizer of MM or lymphoma. A total of 43 patients were mobilized by EAP regimen and the 44 patients by Cy+G-CSF, including 56 patients with MM and 31 patients with lymphoma.Both groups were comparable. The target yield of 2× 10 6 CD34 + cells/kg was achieved in 90.7% (EAP) and 70.7% (Cy) of patients(P=0.003) by 1.3 and 1.6 apheresis (means).By single apheresis in 76.7% (EAP) and 29.5% (Cy) of patients achieve the ideal yield of 5× 10 6 CD34 + cells/kg .EAP mobilization resulted in higher peak concentration of CD34+ cells in blood in the first apheresis (median 59.4 vs 9.5/µL, p＜0.001)and second apheresis(median 23.2 vs 8.5/µL, p=0.001)compared to Cy mobilization. The median time of antibiotic administration in EAP mobilization was shorter than that in Cy mobilization (median 1.2 vs 3.1/d, p=0.041). The toxicity is different,the median time of agranulocytosis (median 1.2 vs 3.1/d, p=0 .003) after EAP mobilization were shorter than those after Cy，however, the median time for thrombocytopenia gr.4 (median 0.5 vs 0.2/d, p=0.001) was longer in the EAP group. In view of these results, we conclude that mobilization with EAP is excellent mobilization regimen with acceptable toxicity and could be considered in MM and lymphoma patients with factors of poor mobilization.
Safety and Efficacy of a-319 (a CD3xCD19 T cell engager) in Patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma
Authors: Liu Wei Ping , Jiang Bo , Shuang Yue Rong , Zhao Xing , Zhong Xuan Fan , Tan Ying , Yu Guo Jian , Xue Sheng Jie , Shen Wu Zhong , Tu Gui Yun , Yang Zheng , Chen Han Yang , Xu Jason , Liu Shui , Yan Xiao Qiang Qiang , Zhu Jun , Song Yu Qin
Published: December 2023

Background: A-319 is a CD19 x CD3 bispecific T cell engager to treat B-cell non-Hodgkin Lymphoma (B-NHL). A-319 contains a scFV domain derived from SP34 CD3 antibody and a CD19 binding domain in a Fab format without Fc. A-319 has the same mechanism of action as that of blinatumomab, and may benefit B-NHL patients. We report the phase I study results of A-319 in patients with relapsed/refractory B-NHL.

Methods: The current study is a multi-center, open-label, dose-escalation phase I clinical study. The primary endpoint was to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of A-319. The secondary endpoints were to evaluate the pharmacokinetics (PK) and efficacy.

During dose escalation stage, one treatment cycle contains one week of A-319 priming doses and three weeks of treatment doses. During priming doses, A-319 was administered three times per week (day 1, day 3 and day 5) at dose level of 0.05 ug/kg/day by 24 hr IV infusion. Dose escalation started at week two at dose level of 0.05, 0.15, 0.3, 0.6, 1.2, 1.8 and 2.4 ug/kg/day, respectively, by 6 hr IV infusion three times per week. The study was registered at ClinicalTrials.gov (NCT04056975).

Results: A total of 21 B-NHL patients (CD19+) were treated with A-319 for at least 1 cycle. Eighteen (85.7%) patients experienced adverse events and 12 (57.1%) patients experienced treatment-related adverse events (TRAEs). The most common TRAE was cytokine release syndrome (CRS, 23.8%, n=5), followed by fever (66.7%, n=14) and decreased immunoglobulin (23.8%, n=5). Most of the reported adverse events were CTCAE Grade I-II. Five patients experienced CRS (Grade I-II, n=5；≥Grade III, n=0). Six patients experienced immune effector cell-associated neurotoxicity syndrome (Grade I-II, n=6；Grade III, n=2). The serious adverse events were reported in 3 patients, which included lung infection (Grade III, n=1), interstitial pneumonia (Grade I, n=1), and pulmonary embolism (Grade III, n=1). There was no reported DLT. No fatal cases were reported during treatment. The preliminary pharmacokinetic (PK) results showed that A-319 has linear PK properties with an estimated T 1/2 of 6-10 hrs. Preliminary responses were reported that one patient achieved complete remission (CR), 3 achieved partial remission (PR), and 7 achieved stable disease (SD) after one cycle of treatment. In the 5 th cohort (at the dose level of 1.2 ug/kg/day), one patient with diffuse large B cell lymphoma (DLBCL) achieved CR, one with follicular lymphoma (FL) achieved PR and on with DLBCL achieved SD.

Conclusions: A-319 was well tolerated in relapsed/refractory B-NHL. A-319 at the dose level of 1.2 ug/kg/day showed encouraging disease control and warranted further clinical investigation.