bluuebunny/crossref_metadata_2025 huggingface dataset:
Limited Quality of Life Sacrifice for Optimizing Long-Term Survival: The Impact of p-Alg Compared to r-ATG in High-Risk Hematological Malignancy Patients Undergoing Matched Sibling Donor Transplantation
Authors: Cheng Qian , Yan Lingyan , Li Xin
Published: December 2024

Background: Disease relapse and graft-versus-host disease (GVHD) represent significant clinical challenges for high-risk hematological malignancies(HM) patients undergoing HLA-matched sibling donor transplantation (MDST). The inclusion of lymphocyte depleting antibodies significantly reduce the incidence of GVHD in MDST. However, the resulting T-cell depletion weakens the graft-versus-leukaemia (GVL) effect, potentially increasing the rate of disease relapse.How to balance the effect of GVHD and GVL remain unclear for high-risk HM patients receiving MDST. Here, we conducted a retrospective study to compare the efficacy of two lymphocyte depleting antibodies(r-ATG and p-ALG) as the GVHD prevention strategy.

Methods:A retrospective analysis was conducted on 48 patients with high-risk HM patients who underwent MSDT at our center from January 2019 to January 2024. Among them, 22 patients were in the p-ALG group (45mg/kg), and 26 patients were in the r-ATG group (3.5-4.5mg/kg). Data of GVHD, immune reconstitution, survival and recurrence after transplantation were analysed and compared between these two groups.

Results: Our results showed that p-ALG was more likely than r-ATG to induce chronic GVHD of moderate and prolonged duration, the p-ALG group had a higher 3-year cumulative incidence of chronic GVHD than the r-ATG group (64.4±12. 6% vs. 35.7±10.7%, p=0.063). However, there was no significant difference in total acute GVHD (aGVHD) (40.9±10.5% vs. 25.3±9%, p=0.209) and 3-year extensive cGVHD (25.5±11.4% vs. 9.3±6.4%, p=0.188) between the two groups. In terms of patient prognosis, the p-ALG group showed a higher 3-year overall survival rate compared to the r-ATG group (100% vs. 75.5%±8.8%, p=0.039). Although there was no statistically significant difference in the 3-year cumulative relapse rate (CIR) between the two groups, the p-ALG group showed a longer duration of disease remission after transplantation, with a lower 3-year cumulative incidence of post-MRD+ compared to the r-ATG group (4.5%±4.4% vs. 40.5%±11%, p=0.022).High-risk cytogenetic alterations were a significant factor associated with relapse, as 66.7% of patients who experienced a relapse had these high-risk alterations. Further stratified analysis showed that the risk of relapse was significantly increased in the high-risk genetic subgroup compared with the standard-risk group (OR=15.21, 95% CI [1.14-164.057], p=0.025). However, compared with r-ATG, the use of p-ALG has a protective effect in these high-risk patients (OR=0.33, 95% CI [0.002-0.563], p=0.019).

Conclusions: In comparison to r-ATG, the administration of p-ALG in high-risk HM patients receiving MDST is associated with an increased incidence of GVHD but results in a more favorable survival prognosis. We also found the potential superior benefits of p-ALG in MSDT particularly for HM patients with high-risk cytogenetic characteristics.
The Paradox of Platelet Activation and Impaired Function in Primary Myelofibrosis: In Vivo and Ex Vivo Platelet Function Study
Authors: Cacciola Emma , Cacciola Rossella Rosari , Allegra Alessandro , Leanza Rossana , Stagno Fabio , Vecchio Veronica
Published: December 2024

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by shortened survival. Thrombosis can be a risk factor associated with inferior survival. In PMF this risk factor is poorly studied. Clonal hematopoiesis and circulating free DNA (cfDNA) activate the platelets in PMF. It is reported that activated platelets recirculate as exhausted defective platelets with impaired function on ex vivo analysis. In PMF the studies on ex vivo platelet function are missing. Therefore, we studied P-selectin (CD62P) expression, as marker of in vivo platelet function, and the PFA (platelet function assay)-100, as marker of ex vivo platelet function. In addition, we measured the vWF ristocetin cofactor(vWF:Rco)/von Willebrand antigen (vWF:Ag) ratio. The study included 27 patients diagnosed with PMF according to WHO/ICC 2022 criteria. Patients were 46 years old (28-71 years). The mean duration of disease was 8 years (1-20 years). Nobody was on cytoreduction or antiplatelet. Nobody had thrombotic risk factors. Of 27patients, 21/27 were JAK2 mutated with variant allele frequency (VAF) of 50% and 6/27 CALR mutated with VAF of 51%. 19/27 were low- and 8/27 intermediate-1 risk IPSS. 30 healthy served as control. The mutations were conducted by ARMS-PCR gel electrophoresis. Cell blood counts (CBCs) were measured by automated analyzer. P-selectin was measured by flow cytometry and PFA-100 was measured on Collagen/ADP (CT-ADP) and Collagen/Epinephrine (CT/EPI) cartridges. vWF:Rco/vWF:Ag ratio was measured by latex immunoassay. CBCs were normal in all patients.All patients had hjgh P-selectin (45±3% vs 10±5%) and prolonged closure time (CT) of C/ADP (C/ADP, n.v. 68-121 s (144±20 s vs 90±10 s) and C/EPI (n.v. 84-160 s (241±20 s vs 95±15 s) (p<0.05). Interstingly, we found abnormal (<0.6) values of vWF:Rco/vWF:Ag ratio consistent with the prolonged CT. No difference there was with regards to the occurrence of JAK2 or CALR mutations. We speculate that PFA-100 might be a test of choice to show the hyperactivation of the patelets in PMF. Hence, could be suggested the primary prophylaxis with aspirin currently debated in PMF. Further studies are warranted and necessary.
Polatuzumab Vedotin-Based Regimens As Bridging Therapy before Chimeric Antigen Receptor T-Cell Therapy for Relapsed/Refractory Diffuse Large B Cell Lymphoma
Authors: Liu Xin-di , Cong Jia , Yang Jing , Wang Liang
Published: December 2024

Background:

Chimeric antigen receptor T-cell therapy (CAR-T) has achieved great success in treating relapsed/refractory diffuse large B cell lymphoma (R/R-DLBCL). It was reported that 7% of patients did not survive while awaiting the completion of CAR T cell manufacturing, which underlines the need for shortening CAR-T cell production times and the potential importance of bridging therapy. The goal of bridging therapy is to prevent rapid disease progression prior to CAR-T cell infusion. Commonly used bridging therapy includes immunotherapy, chemotherapy and/or targeted therapy, and radiotherapy. However, no standard-of-care bridging therapy has been defined yet for R/R-DLBCL. Polatuzumab vedotin (POLA) has been shown effective both in the first-line setting and as salvage therapy for DLBCL. In this retrospective study, we reported the efficacy and safety profiles of POLA -based regimens as bridging therapy before CD19/ CD22 Bispecific CAR-T cell therapy for R/R-DLBCL.

Methods:

21 patients with R/R-DLBCL enrolled in a prospective clinical trial of CD19/ CD22 Bispecific CAR-T cell therapy (NCT06081478) received POLA -based regimens as bridging therapy, and herein we only reported the efficacy and safety profiles of the bridging therapy retrospectively.

Results:

21 patients with R/R-DLBCL were included in this analysis. The median age was 57 (22-77) years old, and female to male ratio was 11:10. The median prior lines of therapy was three (2-6), and 11 patients were primary refractory to all lines of therapy, and 15 patients were refractory to the last line therapy before CAR-T cell therapy. 19 patients had advanced disease and IPI score >2. Commonly used regimens include: POLA+ Mitoxantrone Hydrochloride Liposome+dexamethasone (N=10), POLA+Obinutuzumab+BTK inhibitors (N=7), and POLA+other agents (N=4). All patients received one cycle bridging therapy, and 20 patients received subsequent CAR-T cell infusion. All patients were evaluated for efficacy of the bridging therapy before lymphodepleting conditioning therapy using PET-CT or CT scan. 15 patients (71.4%) responded to this POLA-based bridging therapy, among whom three patients (14.3%) got complete remission. Five patients got stable disease, but symptoms related to DLBCL got a little relieved. Concerning the safety profiles, five patients developed grade 3-4 bone marrow suppression (neutropenia or thrombocytopenia), and one patient infected with COVID-19 and got fever. All patients recovered to less than grade 2 adverse effects before lymphodepleting conditioning therapy.

Conclusions:

POLA-based regimens seemed to be effective and tolerable as bridging therapy before CAR-T cell therapy for R/R-DLBCL patients, and our findings need verification in large cohort studies.
A Pragmatic Monitoring Model for Non-Relapse Mortality Risk Based on Machine Learning in Patients Undergoing Allogeneic Hematopoietic Stem-Cell Transplantation
Authors: Shao Yang-Liu , Yang Jingjing , Li Xiaobo , Guan Di , Zhang Xiawei , Tong Wu , Song Zeliang , Wang Dao , Wei Zhijie , Wang Jingbo , Liu Xiangjun , He Yuelin , Dou Liping , Liu Daihong
Published: December 2024

Background：Prognostic biomarkers play a crucial role in assessing non-relapse mortality (NRM) following allogeneic hematopoietic stem cell transplantation (allo-HSCT).The concentrations of biomarkers fluctuate with the progression of complications and corresponding clinical interventions. However current predictive models are commonly built and applied based on biomarker concentrations measured at a single fixed time point, which may limit their predictive validity and utility for clinical applications.

Methods: A prospective, multicenter study (NCT04284904) involved 621 allo-HSCT patients from 7 Chinese transplant centers. Concentrations of biomarkers (ST2, REG3α, TNFR1, IL6, and IL8) were measured at day 7/14/28/60/90 post-HSCT; patients with acute GVHD were monitored at onset and weekly during the first treatment month.The time point of relative maximum concentration for each patient (MC) was determined based on the time at which the maximum metric was reached. A pragmatic monitoring model employing the relative maximum concentrations of ST2 and TNFR1 within three months post-transplantation was developed to forecast 6-month NRM in allo-HSCT patients: log10[-log10(1 - p)] = 1.4798(log10ST2) + 3.2733(log10TNFR1) - 21.632，where p = predicted probability of 6-month NRM.

Results：The 460 patients in the modeling cohort were randomly split into a training (n=310) and a test (n=150) set, with model validation performed on an independent cohort (n=159). In both the modeling and validation cohorts, the combination of ST2 and TNFR1 exhibited the highest AUC and C-index among the models (training set: 0.85, 0.80 ; test set: 0.85, 0.80; validation set: 0.95, 0.93).Patients were categorized into three risk groups based on model-derived thresholds: low risk (LR, ≤0.0567), moderate risk (MR, 0.0567-0.1309), and high risk (HR, ≥0.1309). The HR group experienced significantly higher 6-month NRM than the MR and LR groups in both the modeling cohort (40.62% vs. 13.11% vs. 1.57%, P < 0.001) and the validation cohort (47.37% vs. 9.76% vs. 0.00%; P < 0.001). Further, our investigation revealed that our predictive model effectively gauged NRM risk independently of HLA matching, recipient age, donor type, ATG-based GVHD prophylaxis, and other clinical considerations. Multivariate analysis identified model score as significant NRM predictors (P < 0.0001). The model consistently identified high-risk NRM patients throughout post-HSCT time points. The model effectively stratifies NRM risk in patients with or without acute GVHD.

Conclusions: A pragmatic monitoring model for predicting NRM in allo-HSCT patients was established, showing potential for identifying high-risk individuals and improving personalized treatment.
Discovery of JNJ-89853413, a First-in-Class CD33xVδ2 T-Cell Engager for the Treatment of Acute Myeloid Leukemia
Authors: El Ashkar Sara , Kallal Lorena , Raman Kavita , Dash Ranjeet Prasad , Shah Nirav , Delbroek Lore , Kertész Lénárd , Van Acker Heleen , Junius Steffie , Cornelissen Ivo , Arumugam Surendar , Gerloff Lauren , Bradford Kathryn , Pietsch E. Christine , Luistro Leopoldo , Mattson Bethany , Guttke Christina , Safer Karim , Arts Janine , Patel Sonal , Philippar Ulrike
Published: December 2024

Targeted immunotherapy in acute myeloid leukemia (AML) remains a substantial clinical challenge due to the heterogenous nature of the AML cancer cells and the lack of AML-specific antigens. While several immunotherapies targeting CD33, including CAR-T and NK cell therapies, are being evaluated clinically, challenges have been experienced with immunotherapies targeting CD33 due to lack of tolerability. In addition, on-target off-tumor toxicities due to target expression on normal myeloid cells represent a major concern. Vδ2 T-cells represent a promising subset of T-cells to explore for novel and innovative cancer immunotherapy. They represent ~5% of the T-cell population in the peripheral blood of healthy donors and are prevalent in a broad set of cancers. Vδ2 T-cells are less affected by inhibition by immune check points on cancer cells and do not activate inhibitory Tregs, which may limit activity of CD3 bispecific T-cell engagers. In addition, differential expression of phosphoantigen-activated butyrophilins contributes to greater activity of Vδ2 T-cells against cancer cells over normal cells. Targeting CD33 (a well validated AML target that is expressed on ~90 % AML cells) with Vδ2 T-cell engagement could potentially provide advantages with regards to safety and efficacy compared to the existing therapies. We developed JNJ-89853413, a novel first-in-class human bispecific antibody comprising a CD33 arm paired with a high-affinity Vδ2 binder. JNJ-89853413 induced potent and selective T-cell mediated cytotoxicity on CD33+ cancer cells with specific activation of Vδ2 T-cells. Furthermore, JNJ-89853413 elicited dose-dependent cytotoxicity of primary AML blasts. In the presence of healthy donor PBMCs, JNJ-89853413 showed preferential cytotoxicity of co-cultured cancer cells with no cytotoxicity of healthy CD33-expressing monocytes or natural killer (NK) cells. JNJ-89853413 showed no impact on the colony forming potential of CD34+ hematopoietic stem and progenitors cells obtained from healthy donors in colony forming unit assays. In addition, JNJ-89853413 inhibited tumor growth of disseminated AML in in vivo regression xenograft models with expanded enriched Vδ2 T cells as effectors. Taken together, JNJ-89853413 represents a novel potential best- and first-in-class opportunity for AML immunotherapy that is progressing to clinical trials with a potential for cure and improved tolerability compared to existing treatments.
The Race Against Time: Rapid Dflc Response in C1D7 Predicts Complete Hematologic Response in Systemic AL Amyloidosis
Authors: Liu Yang , Bi Jingyi , Mai Ashley , Peng Nan , Wen Lei , Liu KaiYan , Lu Jin
Published: December 2024

Background: Daratumumab and bortezomib, the first-line regimens for AL amyloidosis, typically yield a complete hematologic response rate of nearly 60%. The median time to a hematologic response for the daratumumab based treatment is only 7-9 days. An early achievement of a complete hematologic response (CR) is particularly crucial in amyloidosis.

Methods: We retrospectively evaluated the relationship between dFLC (the difference between free light chain) reduction in C1D7 and complete hematologic response, organ response, and survival in newly diagnosed AL amyloidosis patients receiving daratumumab, bortezomib, and dexamethasone.

Results: The hematologic CR rate within six months for 48 patients was 66.7%. The median time to initial hematologic response among these patients was 7 days (range, 7-31), while the median time to achieve the best hematologic response was 2 months (range, 0.23-9). Using Receiver Operating Characteristic Curve (ROC) curve analysis, we predicted hematologic CR based on a dFLC reduction 7 days post-treatment (67.0% change, optimal sensitivity 87.5%, specificity 81.3%). We introduce the novel concept of “rapid hematologic dFLC response”, which is defined as a reduction in dFLC levels ≥ 67% after 7 days. The CR rate was 90.3% in rapid responders' groups while 23.5%in slow responders' group (P ＜0.01). After a median follow-up of 19 months (range: 0.3-57), cardiac and renal response achieved 72.0%, 62.8% in rapid responders' group while 43.8%, 40% in slow responders' group (P=0.104, P=0.025). The median major organ deterioration event-free survival (MOD-EFS) in rapid responders' group (not reached) was significantly superior than that in slow responders' group (19m, 95% CI: 1.785-23.14m, P=0.048).

Conclusion: Early dFLC reduction 7 days post-treatment indicates a high possibility of complete hematologic response and organ response. We propose a new concept of “the rapid hematologic dFLC response” in AL amyloidosis, based on treatment with daratumumab, bortezomib, and dexamethasone.
Interferon-Gamma Production By Dysplastic Cells Supports an Immune-Tolerant Bone Marrow Microenvironment in Myelodysplastic Syndrome Patients
Authors: Ciciarello Marilena , Girotti Francesca , Ocadlikova Darina , Zannoni Letizia , Ardizzoia Federica , Evangelisti Cecilia , Rossi Cesare , Cavo Michele , Curti Antonio
Published: December 2024

Background: Myelodysplastic syndromes (MDS) are a heterogeneous group of haematological malignancies with a poor prognosis and a risk of evolving into acute myeloid leukaemia (AML). Besides intrinsic cellular defects, extrinsic microenvironmental factors, particularly inflammatory signals in the bone marrow (BM), play a crucial role in MDS progression.

In AML, we demonstrated that leukemic cells produced interferon (IFN)γ, allowing us to stratify them in INFGhigh and IFNGlow samples. Higher IFNγ levels remodelled the BM microenvironment, favouring the indoleamine 2,3-dioxygenase (IDO)1-dependent induction of immunosuppressive Tregs associated with increased engraftment of leukemic cells in a mouse model. Furthermore, AML samples with increased IFNγ production showed downregulated expression of HLA class II genes, including CIITA (Class II major histocompatibility complex transactivator). Since leukemic cells with high CIITA methylation are resistant to HLA-dependent IFNγ up-regulation, CIITA methylation/HLA-downregulation could represent a further IFNγ-dependent mechanism of immune suppression. This study aims to explore Tregs induction and HLA down-regulation as putative IFNγ-dependent mechanisms of tolerance and immune escape in MDS, eventually favouring AML progression.

Methods: We used quantitative real-time PCR and flow cytometry to characterize BM-derived MDS samples (N=22) at diagnosis.

Results: MDS samples showed varying IFNγ levels, generally higher than in AML samples. MDS samples had more IFNγ-positive cells in the BM than IFNGlow AML samples, with dysplastic cells being the primary source of IFNγ, although CD3+, CD8+ T cells, and NK cells also contributed. Interestingly, we found a positive correlation between IFNγ and IDO1 expression at both mRNA and protein levels, suggesting an immune-tolerant microenvironment in MDS similar to AML.

Next, MDS samples had a higher percentage of total Tregs than healthy donors and IFNGlow AML samples but lower than INFGhigh AML samples. Treg levels varied with MDS prognostic risk. MDS samples also exhibited different levels and patterns of HLA class II gene expression correlated with IFNγ, with some MDS samples holding an IFNγ-inducible HLA class II gene expression and others with a not-inducible HLA class II gene expression, suggesting a correlation with CIITA methylation grade.

Summary/Conclusions:

This study shows that IFNγ production by MDS cells remodels the BM landscape toward IDO1 upregulation, Treg induction and modulation of HLA class II gene expression, supporting the immune-tolerant role of inflammation, which is emerging as a critical aspect in AML prognosis and outcome and could be implied in MDS risk stratification and progression in AML.
The Combination of the Novel Trifunctional BCMA NK Cell Engager SAR445514 with IMiDs and Celmods Enhances Cytotoxicity Against Multiple Myeloma Cells As Compared to Single Agents
Authors: Tang Alexandre , Zaghi Elisa , Perlat Elodie , Boisrobert-D'heilly Virginie , Van de Velde Helgi , Desjonqueres Alexandre , Fantin Valeria , Chiron Marielle , Virone-Oddos Angela
Published: December 2024

Introduction:

SAR445514 (SAR'514) is a trifunctional anti-BCMA NK Cell Engager (NKCE), currently in a phase 1/2 trial in patients with relapsed/refractory (R/R) multiple myeloma (MM) (NCT05839626). SAR'514 acts by targeting BCMA antigen expressed on MM cells and by co-engaging NKp46 and CD16a activating receptors on NK cells, facilitating the formation of an immunological synapse between NK and BCMA-positive tumor cells. This leads to NK cell activation, degranulation and tumor cell killing. The anti-tumor activity of SAR'514 in preclinical models has been previously described (Tang et al. “The novel trifunctional anti-BCMA NK cell engager SAR'514 has potent in-vitro, in-vivo and ex-vivo anti-myeloma effect through dual NK cell engagement” American Association for Cancer Research 2023). Herein, we further document SAR'514 in vitro anti-myeloma effects in combination with pomalidomide (IMiD), iberdomide and mezigdomide (CELMoDs), which have established or emerging therapeutic roles in MM.

Methods:

The cytotoxic activity of SAR'514 was evaluated in vitro as a single agent alongside pomalidomide, iberdomide or mezigdomide and also as a combination with each of these IMiD/CELMoDs against the fluorescent BCMA-positive H929-RFP MM cells, in the presence of healthy donor NK cells at an effector to target ratio set at 1:2 during 4 days by live-cell imaging analysis (Incucyte system).

Results:

SAR'514 and the different IMiD/CELMoDs demonstrated potent MM cell killing in a concentration-dependent manner as single agents against H929 cells as compared to an isotype control that does not bind to BCMA. When SAR'514 was combined with either pomalidomide, iberdomide or mezigdomide, a higher cytotoxic activity was observed as compared to single agent pomalidomide (p=0.1197) and significantly higher as compared to single agent iberdomide (p=0.0035) or mezigdomide (p=0.0026). SAR'514 shows the highest potency in combination with mezigdomide.

Conclusion:

In summary, these results demonstrate that the combinations of SAR'514 with pomalidomide IMiD or iberdomide and mezigdomide CELMoDs potentiate MM tumor cell killing in vitro and provide consistent support for the evaluation of this combination in patients with multiple myeloma.
Shock Index As a Predictor of Earlier Risk of Vaso-Occlusive Crisis in Trauma Patients with Sickle Cell Disease
Authors: Parchuri Ektha , Ashraf Rida , Owais Aqsa , Lapping-Carr Gabrielle , Brown Joshua B
Published: December 2024

Objectives: Clinical implications and management of traumatic injury in individuals with sickle cell disease (SCD) are poorly understood. Trauma exposure may increase post-injury vaso-occlusion, potentially causing secondary complications. The shock index (SI), calculated as the heart rate divided by systolic blood pressure at emergency department (ED) admission, represents the degree of shock after injury. Values of the SI >0.9 are associated with the need for massive transfusion, emergency surgery, and increased mortality in the setting of trauma. We evaluate the shock index (SI) as a predictive tool for prognosis, examining its association with vaso-occlusive events (VOE) in trauma patients with SCD.

Methods: In this retrospective cohort study, medical records of adult patients with SCD with an emergency department (ED) visit for traumatic injury from 2000-2022 were reviewed. The primary exposure was the SI. Our primary outcome was time-to-VOE. Cox regression determined the association between time-to-VOE and SI, adjusting for demographic data (age, gender), mechanism of injury, trauma team activation (TTA), hemoglobin and hematocrit at time of admission.

Results: Records of 356 adult SCD patients were reviewed; 54 patients had an ED visit for traumatic injury with measures for SI, hemoglobin, and hematocrit at time of admission. The cohort had a mean age of 31.83 years with male predominance (66.1%). Mean hemoglobin, hematocrit, and SI at admission were 10.80, 31.79, and 0.71 respectively. Mean time-to-VOE was 3.52 days. Cox proportional hazards model revealed that SI (HR = 14.63 (95% CI: 1.40-152.70), P = 0.025) particularly at a critical threshold of 0.79, and TTA (HR = 0.37, P = 0.03), were significantly associated with increased hazard of earlier time-to-VOE. Injury hematocrit and hemoglobin, SCD genotype, age, and gender did not exhibit statistically significant associations with time-to-VOE.

Conclusion: Patients with SCD with a higher SI value are expected to have a significantly earlier time-to-VOE than patients with lower SI, especially at a critical threshold above 0.79. Our results are consistent with prior data supporting the need for trauma team activation to provide critical interventions in patients with SCD following trauma. Future research may refine risk assessment models to anticipate disease-specific complications and allow tailored interventions in sickle cell patients following trauma.
Auto-HSCT Vs CAR-T Cell Therapy for Paients with Relapsed/Refractory DLBCL in Partial Remission with Deauville Score of 4 or 5 after Salvage Chemotherapy
Authors: Chen Siyuan , Wang Li , Xu Pengpeng , Cheng Shu , Tang Wei , Wu Wen , Ji Mengmeng , Zheng Zhong , Yan Zixun , Sheng Lingshuang , Shen Yige , Zhao Weili
Published: December 2024

Introduction: For patients with diffuse large B-cell lymphoma (DLBCL) who achieve partial remission (PR) after salvage chemotherapy, the comparative difference in efficacy between autologous stem cell transplantation (auto-HSCT) and chimeric antigen receptor T-cell (CAR-T) therapy remains unclear. The aim of this study is to evaluate the relative efficacy of auto-HSCT vs CAR-T cell therapy in the retrospective cohort of patients with relapsed/refractory DLBCL who achieve partial remission (PR) with Deauville Score of 4 or 5 after salvage chemotherapy, and to provide evidence for treatment options of this population.

Methods: In a single center retrospective cohort, 35 adult patients (age≥18 years) with relapsed/refractory DLBCL who received auto-HSCT (2021-2024, n=16) or CAR-T cell therapy (2018-2024, n=19) in PR status with Deauville Score of 4 or 5 by positron emission tomography/computed tomography (PET/CT) after second-line or higher salvage chemotherapy were identified. Relevant clinical factors were assessed and there were no significant differences between the two groups at baseline.

Results: The median follow-up time was 16.1 months (range 0.8-67.8). Of the 16 patients who received auto-HSCT, three experienced disease progression but none died, while in the CAR-T therapy group, five experienced disease progression and three of them died ultimately. There were no significant differences in progression-free survival (PFS) (P=0.588) and overall survival (OS) (P=0.106) between patients in the auto-HSCT group and the CAR-T cell therapy group (2-year PFS: 84.6% vs 65.8%; 2-year OS: 100.0% vs 80.2%). Either in the univariable analysis or in the multivariable regression analysis, Deauville Score and the choice of treatment with auto-HSCT or CAR-T cell therapy was not associated with PFS and OS.

Conclusions: In our study cohort, for relapsed/refractory DLBCL that reached PR after salvage therapy, similar PFS and OS were observed in both cohorts of the auto-HSCT and CAR-T cell therapy, regardless of Deauville score of 4 or 5. Although not statistically different, there was a trend toward better OS in the auto-HSCT group. Considering the cost of CAR-T cell therapy product preparation and the clinical risks associated with cytokine release syndrome (CRS), our results suggest the continued clinical significance of auto-HSCT for the treatment of this group of patients by demonstrating real-world outcomes.
A Single Mutation in the SENP1 Region Regulates the Excessive Erythropoiesis in the Andes
Authors: Azad Priti , Akbari Ali , Zhou Dan , Poulsen Orit , Mali Prashant , Bafna Vineet , Haddad Gabriel
Published: December 2024

Background: Approximately 20% of individuals living in Peruvian mountains suffer from debilitating Monge's disease or Chronic Mountain Sickness (CMS). They manifest the disease in adulthood and often die because of excessive erythropoiesis (EE) (Hematocrit of >65%, averaging 72%, mostly occurring in males), an extreme phenotype that often leads to myocardial infarction or stroke. The uniqueness of this Andean population is even more significant when we realize that there are individuals who live side by side at the same altitude as those with CMS but do not suffer from the same extreme phenotype (non-CMS). We have shown a critical role of SENP1 (a gene we obtained from differential SNP analysis throughout whole genomes) in regulating EE response in the highlanders. In order to understand the mechanism(s)that upregulates SENP1 levels in CMS, we applied bioinformatics approaches and CRISPR/Cas9-mediated genomic editing to decipher causal SNPs in the SENP1 region.

Methods: We performed Whole Genome Analysis and applied bioinformatics methods iSAFE (integrated Selection of Allele Favored by Evolution) and CADD (Combined Annotation Dependent Depletion) Score to identify causal SNPs in the selected region of SENP1 gene that could lead to the pathology. We further utilized an in-vitro human iPS-derived model system and CRISPR approach to switch alleles and study their functional role in regulating the EE response.

Results: By applying iSAFE and CADD score we were able to shortlist 7 causal SNPs: rs10783232, rs7959755, rs17122612, rs72644843, rs11609399, rs11613781 and rs60629297. Among them, rs7959755 and rs10783232 were the top ranked (Rank 1 and 2) SNPs. We successfully generated and validated A to G switch in the rs10783232 in the non-CMS cells using CRISPR. We further tested the impact of this switch on function of the allele and observed a significant increase in SENP1 mRNA levels (p<0.05) as well doubling of BFU-e colonies (p<0.05) in the non-CMS cells as compared to the control non-CMS cells. We also tested the effect of allele switch (G to A) for the lower ranked (Rank 44) SNP rs11613781 and did not observe a significant effect on SENP1 levels or BFU colony formation.

Conclusion: These results demonstrate that rs10783232 plays a critical role in regulating SENP1 mRNA levels under hypoxia as well as the EE in the Andean highlanders.
Dynamic Changes in Proteostasis Network Activity Influence Hematopoietic Stem Cell Ontogeny and Human Umbilical Cord Blood Fitness
Authors: Yu Helena , Signer Robert
Published: December 2024

Hematopoietic stem cells (HSCs) establish hematopoiesis and maintain regeneration of blood and immune cells to meet shifting demands for blood cell production during development and throughout life. The protein homeostasis (proteostasis) network is uniquely configured in adult HSCs to preserve stem cell fitness and longevity. However, the regulation of proteostasis in developing HSCs is largely unexplored. Here, we comprehensively analyzed proteostasis network activity throughout fetal and neonatal development. Fetal HSCs exhibited up to 7-fold higher protein synthesis rates than their adult counterparts but contained similarly low amounts of unfolded and misfolded proteins as adult HSCs, which depend on unusually low protein synthesis rates to preserve proteome quality. Surprisingly, this was not accomplished through enhanced protein degradation as fetal and adult HSCs exhibited similarly low protein degradation activity. However, we found that fetal HSCs preferentially activated Heat shock factor 1 (Hsf1), a key proteostasis sensor and master regulator of the heat shock response, and preferentially expressed multiple Hsf1 target genes. Conditional deletion of Hsf1 in the developing hematopoietic system resulted in compensatory suppression of protein synthesis and aberrant expansion of fetal liver HSCs but had no effect when deleted in young adult HSCs. These data indicate that fetal and adult HSCs utilize distinct mechanisms to preserve proteostasis.

Strikingly, as part of these studies, we discovered that HSCs exhibit a dramatic spike in unfolded protein abundance at birth. This raised the question of whether proteostasis disruption limits the efficacy and regenerative potential of human umbilical cord blood-derived hematopoietic stem and progenitor cells, which are collected immediately after birth. To test this, we fractionated umbilical cord blood-derived CD34+ cells based on unfolded protein content and assessed their function. CD34+ cells with low unfolded protein content had up to 9-fold higher colony-forming efficiency than CD34+ cells with high unfolded protein. Furthermore, CD34+ cells with high unfolded protein content exhibited diminished reconstituting activity in xenotransplantation assays in vivo.

These findings indicate that the HSC proteostasis network undergoes dynamic changes throughout ontogeny and that HSCs depend on distinct age-specific mechanisms to maintain proteostasis throughout life. Stratifying CD34+ cells by variations in proteostasis identifies populations with varied fitness and engraftment potential. As a result, uncovering distinct proteostasis dependencies could offer a unique window for uncovering new therapeutic avenues for enhancing HSC fitness that leverage developmental stage-specific proteostasis programs and reveal proteostasis-based biomarkers as predictors of stem cell quality and transplantation outcomes.
Epigenomic Biomarkers for Treatment Resistance & Lineage Switching Potential in Acute Leukemia
Authors: Eiken Alexandria P , Burmeister Liala , Janssens Derek , Triche Timothy J
Published: December 2024

Acute lymphoblastic leukemia (ALL) is the most common childhood leukemia, and modern induction protocols secure remission in up to 98% of pediatric cases. But relapse rates are high, and late effects are common among survivors. Infant ALL, particularly KMT2A rearranged (KMT2Ar) disease, has poor long-term survival (about 50%) despite decades of treatment optimization.

KMT2A was originally named MLL, for Mixed Lineage Leukemia. Lineage switching via loss of transcriptional and antigenic programs defines an ultra-high-risk group of KMT2Ar ALL. Lineage specific immunotherapy in frontline ALL treatment has fueled increasing reports of lineage switching, spurring a search for markers predictive of switch potential. Relapses of ALL, such as acute myeloid leukemia (AML) or mixed-phenotype leukemia (MPAL), are almost uniformly refractory. Even among primary MPAL patients, KMT2Ar cases have notably unfavorable outcomes.

Menin inhibitors (MENi) target key vulnerabilities of KMT2Ar leukemia. Clinical reports of rapidly developing MENi resistance, often associated with lineage switching, have spawned a search for markers of resistance potential. However, a subset of KMT2Ar AML patients with monocytic features responds durably to CD33-targeted immunotherapy and chemotherapy. This suggests that myeloid transformation potential alone is insufficient to predict treatment outcome. We reasoned that epigenomic profiling of ALL, AML, and MPAL patient samples, before and after lineage switching and MENi resistance, could inform a search for treatment-relevant biomarkers.

In a cohort of 37 KMT2Ar cases profiled via AutoCUT&Tag, we identified an excess of the histone acetylation reader ENL at non-canonical AML-specific targets among lineage-switching ALL cases. ENL was significantly enriched at these sites in patient samples before lineage switching but absent in B-ALL cases that did not switch lineages. Previous work in a small cohort of adult MPAL cases showed significantly better outcomes in (mostly fusion-negative) cases whose AML-like or ALL-like DNA methylation signatures matched the target of therapy.

To investigate whether this observation could extend to KMT2Ar cases and inform MENi resistance, we analyzed DNA methylation across correlated blocks of CpG loci overlapping ENL binding sites in 1599 pediatric and adult ALL, AML, MPAL, and normal bone marrow samples. We found significant differences in DNA methylation between cases with favorable and unfavorable outcomes, particularly in KMT2Ar cases with lineage alterations at relapse, and these differences were more pronounced at noncanonical (lineage-switch-related) AML associated peaks. Our results illustrate the feasibility of rapid epigenomic profiling in high-risk acute leukemia for clinical trial optimization and improvement of outcomes in KMT2Ar cases.
Eltrombopag Plus G-CSF for Peripheral Blood Stem Cell Mobilization: Interim Analysis of a Single Arm, Phase 2 Trial
Authors: Yu Ta-Chuan , Huang Tai-Chung , Wu Shang-Ju
Published: December 2024

Background

Autologous hematopoietic stem cell transplantation (auto-HSCT) is the standard treatment for relapsed/refractory lymphoma. However, 9% of patients in the plerixafor era could still not obtain adequate peripheral blood stem cells (PBSC) for auto-HSCT. Thrombopoietin (TPO) receptor agonists have been shown to stimulate stem cell proliferation. This study aimed to address whether add-on eltrombopag could improve the successful rate of autologous PBSC harvest.

Methods & Materials

In this phase 2, single-arm IIT, East-Asian patients with lymphomas scheduled to receive ESHAP chemo-mobilization for PBSC harvest are enrolled. Subjects receive eltrombopag at a dose of 75 mg daily from day 6 of ESHAP until the end of PBSC harvest. The primary endpoint is the proportion of patients obtaining more than 2.0 x 106/kg CD34+ cells on the first apheresis day. Based on Simon's two-stage design, an interim analysis was performed when 13 patients received the intervention. A total of 46 patients will be enrolled for final analysis.

Results

The interim analysis completed in May 2024, is reported here. The median age was 55 (range 22-72); DLBCL is the most common diagnosis (n=7). Twelve patients (92.3%) obtained more than 2.0 x 106/kg CD34+ cells on the first apheresis day with the add-on eltrombopag. The median CD34+ cells obtained at the first apheresis was 9.34 x 106/kg. Both results were significantly higher than those derived from the historical control data. No significant eltrombopag-related side effect was observed.

Conclusions

This interim analysis showed that adding eltrombopag to stem cell mobilization is safe and can potentially increase the amount of harvested PBSC. The efficacy and safety will be verified in the final analyses.
Bacterial (Non-Clostridium Difficile) and Parasitic Stool Studies Have Limited Utility in Pediatric Hematopoietic Stem Cell Transplant Patients
Authors: Nagy Matthew , Wychera Chiara , Schemm Jeffrey , Brewster Ryan , Duncan Christine
Published: December 2024

Background: Diarrhea is a common complication among pediatric hematopoietic stem cell transplantation (HCT) recipients. Although the majority of cases are secondary to graft versus host disease (GVHD), stool microbiological studies are often performed to evaluate an underlying infectious etiology. The aim of this study was to assess the frequency and utility of stool studies in children who have undergone HCT.

Methods: Demographics, clinical characteristics, and results for bacterial (Shigella, Salmonella enterica, Yersinia enterocolitica, Enterohemorrhagic Escherichia coli (SSYCE), and Clostridium Difficile), viral (Rotavirus, Cytomegalovirus, Norovirus, and Adenovirus), and parasitic (ova & parasite examination, of all patients who underwent HCT at a large, academic, freestanding children's hospital and affiliate cancer center and were admitted to the hospital for more than one day between Jan 2006 and Dec 2023 were obtained. Statistical analysis conducted included t-tests, chi-square and linear regression.

Findings: Overall, 1381 HCT recipients (9.2 ± 6.6 years) were included. Altogether, 6509 stool studies were obtained among 741 (54%) patients. Those with stool studies sent were more likely to have undergone an allogeneic transplant (63% vs 72%, p<0.001). Of those with allogeneic transplant, those with stool studies sent had higher incidence of GVHD, both acute (27% vs 17%, p=0.001) and chronic (23% vs. 11%, p<0.001). SSYCE studies were sent on 363 (26%, 2252 studies) patients with one (0.04%) positive result for Yersinia enterocolitica. Clostridium Difficile was sent on 706 (51%, 2055 studies) patients, with 156 positive results (7.6%). Stool ova and parasite was sent on 143 (10%, 242 studies) patients, with two positive results of Giardia lamblia (0.8%), however, in both instances the studies prior to HCT showed positivity for the same parasite . Viral studies were sent on 638 (46%, 1960 studies) patients, with 107 positive studies (5.5%) Over the years, there was a significant increase in studies sent for yersinia (p = 0.013) and adenovirus (p=0.007), and decrease for rotavirus (p=0.011) and clostridium difficile (p<0.001).

Interpretation: We identified a negligible rate of positivity for SSYCE and parasitic stool studies, despite the use of these tests in more than a quarter of all HCT patients admitted in the prior 8 years. Given the overall low diagnostic value, we argue that routine use of these studies in post-HCT pediatrics patients should be avoided, barring specific clinical circumstances, which would also serve to avoid unnecessary testing costs.
The Disparity of Circulating Immune Cell Subsets and Inflammatory Status between HIV-Positive and HIV-Negative Patients with Lymphoma
Authors: Xiao Qing , Quan Xi , Chen Shuang , Wang Chaoyu , Jun Li , Zhang Xiaomei , Yang Zailin , Liu Yao
Published: December 2024

Background:

Differences in circulating immune cell subsets and inflammatory status, and their impact on prognosis in HIV+ lymphoma patients compared to HIV-negative lymphoma patients are not fully understood.

Aims:

We analyzed the expression of circulating immune cell subsets and inflammatory status in newly diagnosed HIV+ lymphoma patients and HIV- lymphoma patients in our department, and we also analyzed the influence of circulating immune cell subsets and inflammatory status on the prognosis of lymphoma.

Methods:

The study subjects enrolled 99 patients with newly diagnosed lymphoma from July 2022 to December 2023 at the Department of Hematology-Oncology of Chongqing University Cancer Hospital, including 33 patients with HIV+ lymphoma and 66 patients with HIV- lymphoma matched by sex and age. The clinical information of these patients was collected, and the peripheral blood lymphocyte subsets, expression of granzyme, perforin and inflammatory status were detected at the time of new diagnosis. Meanwhile, the curative effect and survival of the patients were followed up. Then, the differences of lymphocyte subsets and other indicators between the two groups were analyzed, and the relationship between the lymphocyte subsets and the complete response (CR) rate after four courses of chemotherapy was analyzed, and the relationship between the lymphocyte subsets and other clinical characteristics of patients was analyzed.

Results:

There were no significant differences in gender, age, or bone marrow invasion at initial diagnosis between HIV+ lymphoma patients and HIV- lymphoma patients. The CR rate of HIV+ lymphoma patients after 4 courses of chemotherapy was lower than that of HIV- lymphoma patients. In terms of lymphocyte subsets, compared with HIV- lymphoma group, the total number of lymphocytes, the proportions and counts of CD4+ T lymphocytes, and the CD4/CD8 ratio in HIV+ lymphoma group were lower；the proportions and counts of CD8+ T lymphocytes were higher in HIV+ lymphoma. HIV+ lymphoma patients had lower NK cell counts, lower double-negative T (DNT) lymphocyte counts, and lower Treg cell counts. With regard to inflammatory factors, the expressions of interleukin-2 receptor (IL-2R) and interleukin-6 (IL-6) were higher in HIV-positive lymphoma patients than in HIV-negative lymphoma patients.

Conclusion:

In summary, our study showed that compared to HIV- lymphoma patients, HIV+ lymphoma patients had lower CR rates after four courses of chemotherapy, and their counts of CD4+ T lymphocytes, NK cells, DNT cells and Treg cells in peripheral blood were all decreased to varying degrees, and CD4/CD8 ratios were also lower, but CD8+ T lymphocyte counts increased significantly. In addition, HIV+ lymphoma patients had elevated levels of some inflammatory factors, suggesting a higher inflammatory status in vivo.
Efficacy and Safety of Carfilzomib-Based Regiments for the Treatment of Relapsed or Refractory Multiple Myeloma: Single-Center Real-Word Data
Authors: Zhao Weiwei , Liu Juan , Chen Liyan , Wang Lianjie , Xue Yanming , Tian Yaoyao , Liu Yao , Dong Xiushuai , Chang Yuying , Chen Xi , Yu Liqian , Zhang Xiaomin , Jin Yinglan , Song Yan , Han Biqing , Yao Dandan , Wang Wei
Published: December 2024

Introduction:

Carfilzomib has been approved for the treatment of relapsed or refractory multiple myeloma (RRMM) in China1 and become a new trend for the treatment of RRMM in clinical practice. In this study, we retrospectively analyzed the clinical data of 60 RRMM patients in real world to investigate the clinical efficacy and safety of carfilzomib-based therapies, with a view to further optimizing the treatment of RRMM.

Methods:

we retrospectively collected and analyzed clinical data of 60 RRMM patients treated with carfilzomib based chemotherapy regimens in the Hematology Department of the Second Affiliated Hospital of Harbin Medical University from January 2023 to June 2024. The efficacy was evaluated at the end of each cycle of treatment, and the adverse effects were recorded in detail during the treatment process. The primary endpoint is Overall Response Rate (ORR), while the secondary endpoints are Overall Survival (OS) and Progress Free Survival (PFS) according to 2016 IMWG criteria.

Results:

Sixty RRMM were available for efficacy and safety assessment. Carfilzomib based therapies includes KRd (carfilzomib, lenalidomide and dexamethasone; 8 cases), KCd (carfilzomib, cyclophosphamide, and dexamethasone; 10 cases), DKd (carfilzomib, daratumumab, and dexamethasone; 8 cases), KPd(carfilzomib, pomalidomide, and dexamethasone; 8 cases), KBd (carfilzomib, bendamustine, cyclophosphamide, and dexamethasone; 4 cases), KDD(carfilzomib, dexamethasone and liposomal doxorubicin; 4 cases) and Kd (carfilzomib and dexamethasone; 20 cases). The median number of cycles was 4 (2-9). The ORR was 83.3%(50/60) of which 6 (10.0%) complete response (CR) in 6 cases, 10 (16.7%) very good partial response (VGPR) , and 34 (56.7%) partial response (PR). Patients of older than 60 years old, R-ISS stage III, high-risk cytogenetic abnormalities, and previous ≥3 lines of therapy account for 60%, 73.3%, 63.3%, and 26.7% respectively. The ORR was significantly lower in patients who previously had received third-line and higher treatment (50%) than in those who had received first- and second-line treatment(95.5%, p＜0.05). Median PFS was 8 months and the data of OS was unmature. The most common hematological and non-hematological adverse effects were thrombocytopenia (50.0%) and upper respiratory tract infection (30%) respectively which were resolved or relieved in vast majority of patients after symptomatic treatment without affecting the course of treatment.

Conclusion:

The efficacy of carfilzomib-based regimens in RRMM is promising and adverse effects are manageable.

References：

1.Carfilzomib (Kyprolis®) label.