bluuebunny/crossref_metadata_2025 huggingface dataset:
Title:Revision of the Diagnostic Methods Used for the Detection of Pulmonary Embolism in Pregnant Women at the “Centre Hospitalier Universitaire De Sherbrooke”
Authors: Le Templier Genevieve
Published: December 2024

Introduction: We aim to describe the incidence of pulmonary embolism in pregnant patients in which this diagnosis was suspected in our hospital and to compare it with the 5% incidence found in medical literature. We also want to describe the use of serum D-dimer assay in our hospital and assess whether there has been an increase in its use over time for these patients, particularly since the appearance of the ARTEMIS study in March 2019.

Methods: We collected data from our local computerized clinical record for all pregnant patients aged 18 to 45 who underwent an investigation for pulmonary embolism between January 2015 and November 2019.

Results: Of the 186 of these patients, 4 (2.2%; 95% CI [0.84% - 5.40%]) were diagnosed with a confirmed pulmonary embolism. There was no statistically significant difference with the value of 5% found in the literature (p value at 0.07). Before March 2019, serum D-dimer was measured in 57.7% of pregnant patients in whom there was suspicion of pulmonary embolism. After March 2019, D-dimer was measured in 82.6% of these patients, representing a statistically significant increase in their use before and after March 2019, with a p-value of 0.02.

Conclusions: These results demonstrate that there is no statistically significant difference between the incidence of pulmonary embolism in pregnant women in which this diagnosis is suspected in our hospital and that found in medical literature. In recent years, some studies have shown that the serum D-dimer assay could be useful for the purpose of identifying pregnant patients who would benefit from imaging that could expose them to ionizing radiation, and indeed we have found an increase in the use of D-dimer in the diagnostic approach for pulmonary embolism in pregnant patients in our hospital after March 2019.
Outcome of Relapsed Childhood Acute Lymphoblastic Leukemia in Resource-Poor Country : Warrants the Need for Immunotherapy
Authors: Abu Shanap Mayada , Sultan Iyad
Published: December 2024

Introduction:

The overall survival (OS) rate for children with acute lymphoblastic leukemia (ALL) treated at King Hussein Cancer Center is approximately 80%, aligning with published results of the Total XV regimen.

Method:

From December 2003 until August 2023, children/adolescents (<18 years at diagnosis) with ALL in first and subsequent relapses were studied. Treatment of relapse consisted of reinduction regimens followed by intensive continuation therapy and hematopoietic stem cell transplantation (HSCT) in selected patients. The poor prognostic group (PPG) included patients who did not achieve remission after salvage chemotherapy and were referred to palliative care.

Results:

The study included 160 patients with a median age of 5 years (range: 0.4-19.8 years), followed for a median of 71 months (range: 4-248 months). Sites of relapse were: bone marrow (BM) in 64%(N=103) of the patients, combined relapse in 19 %( N=30) and isolated extra-medullary Relapse (IEM) relapse 17%(N=27). Complete remission (CR2) rates for all patients were 64% and vary according to time and site of relapse (100% for IEM, 56% for isolated BM/combined: 90% for late relapses, and 39% for early/very early relapses). The estimated 5-year-EFS and OS for the whole group were 30% and 40 %, respectively. Five-year-OS for patients with BM relapse was 29%, combined relapse 58%, and IEM 66%. Five-year-OS for patients with very early relapse was 12%, early relapse 36%, and late 74%.

Forty patients (39%) continued on chemotherapy after achieving CR2, and sixty-two patients (61%) underwent HSCT, with 60 (59%) alive in continuous complete remission (CCR) at last follow-up. All patients (N=58) in the PPG died of the disease.

In univariable analysis, worse OS was observed in patients <1 or≥10-years at diagnosis, those T-cell-immunophenotype, CNS 3 at diagnosis, BM and very early relapses. In multivariable analysis : age (p=0.02), site of Relapse( p=0.019) and time of relapse(p=0.009) were prognostic.

In univariable analysis, worse EFS was observed in patients <1 or≥10-years at diagnosis, T-cell-immunophenotype, CNS 3 at diagnosis, unfavorable cytogenetic at diagnosis, BM and very early relapses. In multivariable analysis Site of Relapse ( p=0.02)and time of relapse(p<0.001) were prognostic.

Conclusions

At our center, more than one-third of relapsed ALL patients were cured. However, survival rates are low in high-risk relapsed ALL (very early and isolated BM relapses). Conventional chemotherapy and adequate supportive care failed to salvage this high-risk group, indicating the need for immunotherapy as a bridge to allogeneic hematopoietic stem cell transplantation.
Leveraging Clonal Competition between Chip and Aggressive Malignant Clones As a Novel Therapeutic Approach
Authors: Guillermo Kiana Kalei , Huang Xin (Helen) , Heidmann Jianhong C , Fleischman Angela G.
Published: December 2024

Introduction:

Hematopoietic stem cells are in constant clonal competition, as a result variant clones resistant to inflammatory pressures emerge with aging resulting in clonal hematopoiesis. Multiple independent clones can coexist, and potentially come into equilibrium. However, with an acute leukemia a clone overtakes the system, thus inhibiting normal hematopoiesis. We sought to explore the possibility of leveraging the increased competitive ability of CHIP clones to dampen expansion of an aggressive malignant clone. As proof of principle, we tested whether introduction of Tet2-/- cells as competitors could dampen the expansion of MPLW515L cells, an aggressive MPN mouse model.

Methods:

We used a transduction-transformation model of MPL W515L as an aggressive MPN model. This mouse model usually results in death approximately 3-4 weeks post-transplant. Whole bone marrow from wild-type C57B/6 (CD45.1) mice was transduced with Green Fluorescent Protein (GFP) tagged retrovirus to induce expression of hMPLW515L. We transduced bone marrow with a low viral multiplicity of infection (MOI) resulting in approximately 1-5% GFP+ cells to extend survival beyond the expected 3-4 weeks post-transplant. The transduced bone marrow was mixed with unmanipulated whole bone marrow from either WT or Tet2-/- (both in CD45.1/2) to result in a 90%/10% mixture and transplanted into lethally irradiated CD45.2 mice. Peripheral blood counts, % GFP+ cells, and chimerism was followed biweekly. Surviving mice were sacrificed and analyzed at 5 months post-transplant.

Results:

There was early death from expansion of MPLW515L GFP+ cells within 3-4 weeks in 10% of both the WT and Tet2-/- competitor groups. However, of the surviving mice the percentage of GFP+ cells in the peripheral blood was consistently lower in the Tet2-/- competitor group compared to the WT competitor group (for example mean of 55% GFP+ in WT competitor group vs 23% at day 105 post-transplant). At five months post-transplant we sacrificed the cohort to assess the composition of MPLW515L cells in the hematopoietic stem and progenitor compartments. The percentage of GFP+ cells was higher in all cell populations assessed in the WT competitor group compared to the Tet2-/- competitor group. Moreover, spleen and liver weights were higher in the WT versus Tet2-/- competitor group.

Conclusions:

This work demonstrates proof of principle that clones with increased competitive ability and low malignant potential, such as Tet2-/- cells, can be used as a buffer for the expansion of highly aggressive clones. This concept of introduction of non-malignant competitor clones could be potentially be explored as a novel therapeutic approach in aggressive hematologic malignancies.
Parvovirus B19 Originates from Infected Hematopoietic Stem Cells Following Hematopoietic Stem Cell Transplantation
Authors: Pei Xuying , Huang Xiaojun , Liu Zhuojun , Fu Qiang , Zhao Xiaosu , Sun Yuqian
Published: December 2024

Background: Human parvovirus B19 (B19) can lead to severe refractory anemia, aplastic crisis, and systemic lethal syndromes due to persistent infection of erythroid progenitor cells after hematopoietic stem cell transplantation (HSCT), however, the causes of pancytopenia have not yet demonstrated. Previous studies on post-transplant B19 infection have mainly been case reports, leaving its clinical characteristics and pathogenesis largely unexplored.

Methods: We examined the clinical manifestations, risk factors, and prognosis of 136 adult patients infected with B19 at our institution from 2017 to 2023. A control group of 408 patients without B19 infection was selected using propensity score matching. Single cell full-length RNA sequence (scFAST-seq) of four B19-infected patients and four B19-negative patients after HSCT were adopted to profile B19-infected cell spectrum and functional characteristics. Polymerase chain reaction (PCR) were performed to validate scFAST-seq results.

Results: Our study revealed a 2.6% incidence of B19 DNA viremia after allo-HSCT, with a median onset of 94 days post-transplant. Severe anemia, granulocytopenia, and thrombocytopenia were observed in 69.1%, 80.9%, and 96.3% of B19-positive patients, respectively. Persistent B19 infection, defined as B19 DNAemia lasting for 28 days or more occurred in 48 patients, often accompanied by severe pancytopenia (97.9%) and organ complications (54.1%). Importantly, B19 infection significantly correlated with poorer transplant outcomes, evidenced by higher non-relapse mortality and lower overall survival at 1, 3, and 5 years compared to the control group. Based on scFAST-seq data, we found that in adition to erythroid-lineage cells, which are well-known targets of B19, this virus could infect a broad spectrum of the hematopoietic system, including giant bone marrow myeloid and lymphoid-lineage cells, and even hematopoietic stem cells (HSCs). Interestingly, the scFAST-seq data showed a dramatic decrease in hematopoietic stem cells in patients infected with B19, which suggest that B19 may impair the survival of HSCs, potentially leading to pancytopenia. Moreover, B19-infected HSCs exhibited a higher expression levels of differentiation pathways toward downstream lineages, which may suggest that B19 disease originates from the infected HSCs.

Conclusion: This study provides a comprehensive clinical overview of B19 infection following HSCT and indicates poorer transplant outcomes in patients with B19 infection. Importantly, our findings suggest that B19 can infect a broad spectrum of the hematopoietic system post-HSCT, potentially originating from infected hematopoietic stem cells in patients with persistent B19 infection.
Trends in Mortality Due to Hematologic Malignancies Among Patients Aged 25 and Older in the United States: Geographic and Metropolitan Area Disparities Insights from CDC Wonder Database
Authors: Durugu Satya R , Sinha Shrishti , Ali Hassan , Ahmed Faizan , Agrawal Shubham , Abboud Brian , Rojulpote Krishna V , Thirumaran Rajesh
Published: December 2024

Introduction

Hematologic malignancies represent a significant cause of mortality among adults aged 25 and older in the United States. This study examines geographic and metropolitan area disparities in mortality rates from 1999 to 2020.

Methods

A retrospective analysis of the CDC WONDER database was conducted to calculate age-adjusted mortality rates (AAMRs) per 100,000 persons. Trends were analyzed using Average Annual Percentage Change (AAPC) and Annual Percent Change (APC), stratified by geographical regions and metropolitan areas.

Results

From 1999 to 2020, hematologic malignancies caused 1,463,046 deaths among adults aged 25 and older. Geographic analysis revealed that all regions experienced a decrease in AAMR from 1999 to 2018, followed by slight, non-significant increase from 2018 to 2020. The Northeast showed a decrease from 36.72 to 26.38 (APC: -1.7256; 95% CI: -2.7731 to -0.2212; p = 0.0246), with a non-significant rise to 26.96 in 2020. The Midwest had similar trends, with the AAMR decreasing from 39.55 to 28.99 (APC: -1.6203; 95% CI: -1.7705 to -1.5059; p < 0.001) from 1999 to 2018, followed by a non-significant rise to 30.55 in 2020. The South saw a decrease from 35.96 to 26.41 (APC: -1.6129; 95% CI: -2.0725 to -1.4489; p < 0.001) from 1999 to 2018, with a non-significant rise to 27.17 in 2020. The West had a significant decrease from 35.85 to 25.82 (APC: -1.7130; 95% CI: -1.8933 to -1.6040; p < 0.001) from 1999 to 2018, followed by a non-significant rise to 26.45 in 2020. Metropolitan areas consistently had lower AAMRs compared to non-metropolitan areas, with the AAMR in metropolitan areas decreasing from 36.43 in 1999 to 27.19 in 2020, while non-metropolitan areas decreased from 37.77 in 1999 to 30.30 in 2020.

Conclusion

This analysis reveals significant geographic and metropolitan area disparities in mortality rates due to hematologic malignancies among adults aged 25 and older in the U.S. Despite overall declines, there is a persistent higher mortality rate in non-metropolitan areas. Limited healthcare infrastructure, barriers to healthcare accessibility, and social determinants of health are suggested factors contributing to these results. This highlights the need for targeted public health interventions to address these disparities and improve outcomes in rural populations.
Reduced Incidence of Severe Hemorrhagic Cystitis in Prophylaxis Infusion of Mensenchymal Stromal Cells for Gvhd, a Secondary Endpoints in a Randomized,Multiple Center Clinical Tria
Authors: Yao Han , Wang Xiaoqi , Huang Ruihao , Feng Yimei , Deng Xiaojuan , Chen Ting , Zhu Lidan , Liu Jia , Liu Yuqing , Zhao Lu , Wang Lu , Zhang Cheng , Kong Peiyan , Gao Li , Gao Lei , Liu Qifa , Zhang Xiaohui , Zhang Xi
Published: December 2024

Aim:MSCs are being explored for their potential to prevent and treat graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) patients. A secondary endpoint was anaylzed in our multi-center prospective randomized controlled study (ChiCTR1900022292) aimed to evaluate the efficacy of MSC infusions in preventing hemorrhagic cystitis (HC), a common complication of allo-HSCT.

Methods:Based on the electronic data capture（EDC) ,clinical data, interleukin levels, and T lymphocyte subgroups were monitored to identify potential biomarkers and risk factors for predicting HC occurrence.

Results:A total of 192 patients were included in the analysis, of whom 36 (18.8%) developed HC. The results showed both a lower incidence of HC and severe HC in the MSCs group compared to the control group. Factors associated with severe HC included BK virus infection, older age, and slower platelet reconstitution(Table 1). Combination of these risk factors had an area under the curve (AUC) of 0.756 (95% CI: 0.586-0.851), with a specificity (1-specificity) of 0.688(Figure 1). Cytokine and T cell subset analysis revealed decreased levels of IL-4, TNF-α, and TNF-γ in patients with severe HC, as well as increases in CD3+ T cells, CD4/CD8 ratio, and CD19+ B cells.

Conclusions:This trial demonstrated the potential of MSCs to prevent severe HC in allo-HSCT patients. The identified biomarkers and risk factors may help predict and manage the development of HC in this population.

Key words:Hemorrhagic Cystitis,Mensenchymal Stromal Cells,Clinical Trial,prophylaxis
Trends in Mortality Due to Hematologic Malignancies Among Patients Aged 25 and Older in the United States: Annual Trends and Insights on Gender Disparities from the CDC Wonder Database
Authors: Durugu Satya R , Ali Hassan , Sinha Shrishti , Kalantri Shreyas , Ahmed Faizan , Abboud Brian , Rojulpote Krishna V , Thirumaran Rajesh
Published: December 2024

Introduction

Hematologic malignancies are a major cause of mortality among adults aged 25 and older in the United States. This study investigates annual trends and gender disparities in mortality rates from 1999 to 2020.

Methods

A retrospective analysis of the CDC WONDER database was conducted to calculate age-adjusted mortality rates (AAMRs) per 100,000 persons. Trends were assessed using Average Annual Percentage Change (AAPC) and Annual Percent Change (APC) stratified by year and gender.

Results

From 1999 to 2020, hematologic malignancies caused 1,463,046 deaths among adults aged 25 and older. The overall AAMR decreased from 37.30 in 1999 to 28.0 in 2020, with an AAPC of -1.3641 (95% CI: -1.5184 to -1.2762; p < 0.001). A significant decline occurred from 1999 to 2018 (APC: -1.6696; 95% CI: -1.7878 to -1.5890; p < 0.001), followed by a slight increase from 2018 to 2020 (APC: 1.5861; 95% CI: -0.7262 to 2.6695; p = 0.2151). Men exhibited higher AAMRs compared to women (40.6 vs. 23.7). Both genders saw a decrease in AAMR from 1999 to 2020 [Men: AAPC: -1.2398 (95% CI: -1.3859 to -1.1540; p < 0.001); Women: AAPC: -1.6315 (95% CI: -1.8334 to -1.5137; p < 0.001)]. For women, the AAMR decreased significantly from 29.50 in 1999 to 19.90 in 2019, followed by a minor rise to 20.80 in 2020. Similarly, for men the AAMR decreased from 48.60 in 1999 to 35.4 in 2019 and then increased to 37.40 by 2020.

Conclusion

This analysis highlights significant annual trends and gender disparities in mortality rates due to hematologic malignancies among adults aged 25 and older in the U.S. Despite an overall decline, Despite an overall decline, men demonstrated a higher mortality due to hematologic malignancies in comparison to women. Globally, men have higher incidence and death rates for leukemia, multiple myeloma (MM), non-Hodgkin lymphoma (NHL), and Hodgkin lymphoma (HL) compared to women. From 1990 to 2019, the male-to-female ratio for these cancers increased, suggesting the influence of hormonal, genetic, and environmental factors. Existing literature shows evidence for specific leukemia subtypes exhibiting higher mortality rates in men, with notable age groups having the highest death rates. This disparity underscores the need for further research to understand and address these gender differences in hematological malignancies.
Zanubrutinib Can Rapidly Improve Clinical Features Especially Anemia in Newly Diagnosed Waldenström Macroglobulinemia
Authors: An Ran , Zhang Sujiang , Wei Rong , Yan Zeying , Sun Haimin , Liu Zhiyin , Tian Jie , Wang Ying
Published: December 2024

Waldenström macroglobulinemia (WM) is a rare lymphoproliferative disease with an ambiguous clinical presentation. It is well established that bone marrow infiltration is a key component of the pathophysiology of WM, which most commonly presents as anemia. The phase III ASPEN study has already demonstrated the comparable efficacy and improved safety of zanubrutinib versus ibrutinib in patients with WM. Here, we presented a real-world study about zanubrutinib and WM in different center.

A total of 30 newly diagnosed WM patients from Ruijin Hospital and Shanghai Tenth People's Hospital was included in this retrospective study. All patients received zanubrutinib as monotherapy. The median age of the 30 patients was 65 years（range 36-85 years）with 17 patients >65 years, the ratio of male to female was 1.5:1, and all patients met the indications for treatment. The majorities of patients (24/30, 80%) presented with non-specific symptoms such as fatigue, weight loss and fever. Additionally, three patients presented with significantly enlarged lymph nodes, 2 with bleeding and 1 with Reynolds phenomenon. According to IPSS, these patients can be categorized with high-risk (26.7%, 8/30), intermediate-risk (43.3%, 13/30) and low-risk (30%, 9/30). At the time of initial diagnosis, the median level of IgM was 20.3g/L (1.3-84.8g/L), while the median haemoglobin level was 95g/L (49-149g/L). In addition, MYD88 L265P mutation was detected in 81.5% (22/27) cases. All patients were treated with zanubrutinib as monotherapy, with a median time to first treatment (TTFT) of 3.3 months (range 0.4-28.1). The median duration of zanubrutinib therapy was 15.5 months (range 1.0-57.0). Zanubrutinib was well tolerated and no patients need to discontinue treatment. Further efficacy analysis demonstrated 24 patients showing strikingly improvement about hemoglobin levels and the median response time was 3.0 months (range 0.2-12 months). A significantly reduction of IgM level was also observed in 23 patients after 3 months treatment of zanubrutinib, with a median percentage reduction of 52% (50%-94%). We concluded that zanubrutinib can rapidly improve clinical features especially anemia in the treatment of newly diagnosed WM, which will largely boost confidence of clinicians as well as patients and finally be benefit to cure this disease.

Keywords:

Waldenström macroglobulinemia, Zanubrutinib, anemia
Pharmacological and Mechanism Study of a New RIPK1 Inhibitor Via Necroptosis to Treat Hemophagocytic Lymphohistiocytosis
Authors: Zhu Jinbing , Wang Jinjin , Zhao Ailin , Niu Ting
Published: December 2024

Background: Hemophagocytic lymphohistiocytosis (HLH) is a cytokine-release syndrome with high mortality, primarily treated with corticosteroids, though 30% of patients exhibit resistance. Necroptosis, a caspase-independent programmed cell death, is overly activated in autoimmune diseases, severe COVID-19, and SIRS, leading to sterile inflammation and cytokine storm. Receptor-interacting serine/threonine protein kinase 1 (RIPK1) regulates necroptosis, and inhibitors of RIPK1 show potential as treatments for inflammatory diseases, sepsis, cancer, and neurodegenerative diseases. In this study, we hypothesize that RIPK1 inhibitors can treat HLH by inhibiting necroptosis and sensitizing cells to corticosteroid-induced apoptosis.

Material and method: This study utilizes AI-assisted drug design and deep learning models based on conditionally recurrent neural networks for decentralized learning to develop a novel, highly selective, and potent RIPK1 inhibitor-SKLB-Z30. SKLB-Z30, with a new scaffold, demonstrates superior pharmacodynamics and safety compared to the reported RIPK1 inhibitor GSK2982772. We induced necroptosis in murine macrophage and T cell lines in vitro to explore the inhibitory effects of SKLB-Z30, both as monotherapy and in combination therapy. In secondary and primary murine models of HLH, we used SKLB-Z30 alone or with dexamethasone and preliminarily analyzed the mechanisms of action.

Result: This study successfully induced necroptosis in murine macrophages and T cells in vitro. PI/Hoechst results showed that SKLB-Z30 monotherapy inhibited necroptosis at low concentrations (10 nM), significantly outperforming GSK2982772. SKLB-Z30 dose-dependently inhibited the phosphorylation of key proteins (RIPK1, RIPK3, MLKL) in necroptotic macrophages and T cells. SKLB-Z30 also reduced TNFα and IL-6 levels in the supernatant of necroptotic cells in a concentration-dependent manner. In vivo, macrophage activation syndrome (MAS) and primary HLH animal models were successfully established. MAS and HLH mice exhibited significant anemia, thrombocytopenia, liver dysfunction, elevated body temperature, hepatosplenomegaly, increased ferritin, and bone marrow hemophagocytosis. Transcriptome sequencing revealed that the TNFα-RIPK1-RIPK3 signaling pathway was upregulated in model mice compared to normal mice. Immunohistochemistry showed significantly elevated p-RIPK1 and p-MLKL protein expression both in MAS and HLH mice. SKLB-Z30 monotherapy and combination therapy with dexamethasone significantly reduced liver and spleen size, improved anemia, increased platelet counts, reduced serum ferritin, and decreased levels of TNFα, IL-6, and other cytokines.

Conclusion: The novel RIPK1 inhibitor SKLB-Z30 demonstrated effective therapeutic action against HLH in both in vivo and in vitro experiments. RIPK1 inhibitors represent a promising new approach for the clinical treatment of HLH patients.
Sequential Pembrolizumab Followed By AVD in Advanced Hodgkin Lymphoma: A Retrospective Study from North India
Authors: Chand Rashmi ahmed , Naim Faran , Chand Rashmi , Quasimi Huma , Sharma Rahul , Kapoor Rajan , Kumar Rajiv , Gandhi Lorie , Surange Devyani , Shaikh Mohd Rizwan Mohamad Anwar
Published: December 2024

Background: Hodgkin lymphoma (HL) is one of the most curable forms of cancer, with high treatment success rates. Advances in treatment options, including chemotherapy, radiation therapy, and immunotherapy, have significantly improved the prognosis for patients with HL.

Methods: We performed a retrospective study of 15 HL patients, including adolescents and elderly, treated at two tertiary centers in north India between 2023 and 2024. The treatment regimen consisted of the sequential administration of Pembrolizumab with Adriamycin, Vinblastine, and Dacarbazine (AVD). Pembrolizumab (IV, 200 mg) was administered every 21 days starting on cycle 1, day 1, followed by interim assessment with PET-CT. Patients who achieved partial or complete metabolic response were subsequently given six cycles of AVD (doxorubicin [IV, 25 mg/m2], vinblastine [IV, 6 mg/m2], and dacarbazine [IV, 375 mg/m2]).

Results: This study includes patients with a median age of 43 years, spanning from 16 to 74 years. The cohort comprises 66.7% males and 33.3% females. All patients were advanced stage (stage III or IV). The distribution of the International Prognostic Score (IPS) is as follows: 46.7% with scores of 0-1, 20% with a score of 2, 13.3% with a score of 3, and 20% with a score of ≥4. B symptoms are present in 46.7% of the patients. After three cycles pembrolizumab immunotherapy, the observed responses are: 46.6% with a complete response, 40.0% with a partial response, 6% with progressive disease, and 6% resulting in death. Following the administration of six AVD cycles of Pembrolizumab 14 patients are evaluable as 1 is still on treatment, the complete metabolic response is 78.5%, with 14.2 % showing refractory disease.

Conclusion: Sequential pembrolizumab followed by AVD is a promising first-line treatment for advanced-stage Hodgkin's lymphoma, but it doesn't always result in a fairytale outcome for every patient. Here, for the first time, we demonstrate that sequential Pembrolizumab-AVD therapy has shown a refractory response in 14.2 % patients, whereas it has achieved 100% complete response rates in studies conducted worldwide. This suggests potential regional differences in treatment efficacy or patient response. Further studies are needed to explore the underlying reasons and to optimize therapeutic strategies for Hodgkin Lymphoma in diverse populations.
Safety and Efficacy of Iruplinalkib for Patients with Relapsed or Refractory (r/r) ALK+ Lymphoma: A Phase II Trial
Authors: Wang Yue , Wei Fang , Wang Wanli , Zhao Linjun , Chen Jie , Song Yuqin , Zhu Jun , Liu Weiping
Published: December 2024

Background：

Anaplastic lymphoma kinase-positive (ALK+) lymphoma includes ALK+ anaplastic large cell lymphoma (ALCL) and ALK+ large B cell lymphoma (LBCL). ALK is a receptor tyrosine kinase in the insulin receptor superfamily. ALK inhibitor such as crizotinib exhibited significant effectiveness in relapsed or refractory (r/r) ALK+ lymphoma. Iruplinalkib, a highly selective oral ALK and c-ros oncogene 1 (ROS1) tyrosine kinase inhibitor (TKI), has shown promising anti-tumor activity with a manageable safety profile in r/r ALK+ non-small cell lung cancer. Herein, we reported the efficacy and safety of iruplinalkib for r/r ALK+ lymphoma.

Aims:

To evaluate the efficacy and safety of iruplinalkib in patients with r/r ALK+ lymphoma.

Methods:

This prospective stage II study enrolled patients aged 18-65 years with histologically confirmed r/r ALK+ lymphoma, including the r/r ALK+ ALCL and ALK+ LBCL. The primary endpoint were overall response rate (ORR), and the secondary endpoints included complete response rate (CRR) , progression-free survival(PFS) and safety.

Results:

As of the database cutoff on July 30, 2024, 6 patients were enrolled. The median age was 39 years (range, 23-70). Three patients (50.0%) were male. Five (83.3%) patients were diagnosed with ALK+ ALCL, 1 patient (16.7%) had ALK+ LBCL. The median line of prior chemotherapy was 1 (range, 1-2).

Among 5 patients with evaluable response, the ORR was 80% with a CRR of 20.0%.One patient with ALK+ ALCL achieved complete remission, 2 with ALK+ ALCL and 1 with ALK+LBCL achieved partial remission，and 1 with ALK+ ALCL achieved stable disease. The median PFS was 2.5 months (range, 0.9-6.0 months). Serious adverse events (SAEs) were not observed in all patients. No treatment discontinuation or death due to treatment-related adverse events (TRAEs) was reported.

Summary/Conclusion:

Iruplinalkib demonstrated a tolerable safety and a good efficacy in r/r ALK+ lymphoma patients.

Keywords:Anaplastic lymphoma kinase; Iruplinalkib; Lymphoma; Therapeutics; Prognosis
DNA Methylation in Juvenile Myelomonocytic Leukemia and Its Clinical Significance
Authors: Liu Chenmeng , Wang Xingchen , Chen Yunlong , Wan Yang , An Wenbin , Ren Yuanyuan , Liu Fang , Guo Ye , Yang Wenyu , Zhu Xiaofan
Published: December 2024

Juvenile myelomonocytic leukemia (JMML) is a rare myelodysplastic/myeloproliferative neoplasm that develops during infancy and early childhood. Aberrant DNA methylation constitutes an independent risk factor in JMML .

A total of 41 newly diagnosed JMML were enrolled in this study, including 31 males and 11 females from Dec 2013 to Dec 2023 at our single center. Quantification of DNA methylation was performed using an Illumina Infinium MethylationEPIC Beadchip platform (Illumina). Unsupervised hierarchical clustering of the most variable CpG sites across all JMML samples classified three clusters, low methylation (LM), intermediate methylation (IM), and high methylation (HM).

The median age of patients is 34 months (range: 3-144 months). All patients were followed up until 1 June 2024. The median follow-up time was 23months (range: 2-96 months). The median level of HbF was 14.65% (1.2%-76.1%). The median blast percentage in BM, as measured by flow cytometry, was 2.18% (0-11%). Among the samples analyzed, 8 were classified into the LM subgroup, 16 exhibited IM, and 17 showed HM. In the methylation analysis, a total of 15 patients had both peripheral blood and bone marrow samples sent for testing. Interestingly, both sample types from the same patient exhibited consistent results. The methylation level of one case transitioned from LM to HM during relapse. 34.1% of children carried PTPN11 mutation. Patients with PTPN11 mutations tended to be classified into HM(P=0.02). In univariate analysis, children with PTPN11 mutations had a lower probability of overall survival (OS) (84%±7% vs 42%±13%, P<0.001). Patients in HM subgroup were more likely to have a higher blast percentage in BM (4.39% vs 1.2%, P=0.003) and higher level of HbF (49.9% vs 3.1%, P=0.003) at diagnosis compared to those not. Among children who did not undergo HSCT, those in the HM subgroup exhibited a poorer OS compared to those in the IM and LM subgroups (P=0.06). The 2-year OS for children in the HM subgroup was 65%. HSCT significantly improved the OS of children within the HM (89%±10% vs 25%±15%, P=0.002).

Overall, Patients in the HM subgroup exhibited poor overall survival.HSCT can significantly improve the OS of patients in HM subgroup. Peripheral blood and bone marrow samples from the same patients exhibited consistent patterns of methylation grouping.
The Thrombosis in Patients with Lower Limb Injuries Requiring Immobilisation Study . (TILLIRI study)
Authors: O'Keeffe Denis , O'Halloran Thomas , Ni Ainle Fionnuala , Bassa Bibi , Watts Michael , Egan Siobhan
Published: December 2024

Background: Patients requiring temporary lower limb immobilisation after injury have an increased venous thromboembolism (VTE) risk. The extent of this risk in published studies varies. The TRiP(cast) model (Thrombosis Risk Prediction following cast immobilization) quantifies VTE risk using clinical risk factors. Delineating low from high VTE risk patients is challenging in the clinical setting.

Aims: To determine the 90-day incidence of symptomatic VTE following temporary lower limb immobilisation after injury in an undifferentiated patient population. To prospectively collect data on VTE risk factors, including those incorporated in the TRiP(cast) model, to retrospectively calculate TRiP(cast) scores.

Methods: TILLIRI is a prospective multicentre cohort study including 10 sites within the Irish Network for VTE Research (INViTE). Patients ≥ 18 years with an immobilised injured lower limb following injury were included. Twenty-one clinical variables were collected at presentation. Thromboprophylaxis was prescribed according to clinical gestalt. Patients were followed up at 90-days to determine if a VTE occurred.

Results: Between November 2018 and February 2023, 1243 patients were recruited. Follow up was complete for 1200 patients. 43 patients (3.5%) were lost to follow up. 44 (3.6%) patients and 126 (10%) patients were prescribed an anticoagulant and aspirin respectively. VTE incidence at 90-day follow-up was 7/1222 (0.57%; CI 0.15%-0.99%). TRiP(cast) scores were calculated for 1177/1222 patients. 846 patients (71.9%) had a TRiP(cast) Score < 7, received no prophylaxis and had no VTE.

Conclusion: TILLIRI indicates a low incidence of VTE in an undifferentiated patient population following lower limb immobilization with low rates of anticoagulation and aspirin use. The proportion of patients with low TRiP(cast) scores and no symptomatic VTE rate suggests that thromboprophylaxis may potentially be avoided in patients with a TRiP(cast) score < 7, with a low risk of VTE at 90 days. Future studies examining targeted strategies to identify low-risk patients can help safely avoid unnecessary anticoagulation.
Challenges in Interpreting Avws Screening in Polycythemia Vera: Correlations with Clinical and Laboratory Features
Authors: Weihermann Viktoria , Melo Raphael B. , Kayano Alexandre , Silva Camila Alves , Rocha Tania Rubia , Silva Wellington F. , Rocha Vanderson , Seguro Fernanda Salles
Published: December 2024

Background: The risk of thrombotic and hemorrhagic complications frequently coexists in myeloproliferative neoplasms (MPN), partly due to the occurrence of acquired von Willebrand syndrome (AVWS), particularly in essential thrombocythemia. However, the value of screening for AVWS in other MPNs is not so clear. Additionally, it is unknown whether laboratory-diagnosed AVWS correlates with clinical manifestations. Therefore, we aimed to investigate the connection between specific clinical and laboratory features and AVWS, and to determine if AVWS was associated with bleeding in our polycythemia vera (PV) cohort.

Methods: This is a cross-sectional study involving adult PV patients followed at Hospital das Clínicas of the Faculty of Medicine, University of São Paulo, Brazil. Screening for AVWS was conducted using von Willebrand factor antigen (VWF Ag) and activity levels measured by the ristocetin cofactor assay (RCO). AVWS was defined as a VWF:RCo/Ag ratio < 0.6. Additionally, we collected data on thrombotic and bleeding complications.

Results: We evaluated 46 of 597 patients (54% male, median age 62.5 years) diagnosed with polycythemia vera who were screened for AVWS from 2012 until 2023. In only three patients, the tests were ordered immediately after a bleeding event. At the moment of the screening, the median blood counts were: hematocrit 43% (IQR 38-51), leukocytes 11.7 x 109/L (8.0-16.8), platelets 572 x 109/L (IQR 307-952). Median VWF antigen was 146% (range 64-464), median VWF:RCo was 58% (range 1-159) and median function/antigen ratio (VWF:RCo/Ag) was 0.42 (range 0.01-0.78). Thirty-six patients (78%) had a screening test (VWF:RCO / Ag < 0.6) positive for AVWS, and this parameter was correlated to thrombosis (p=0.03), but not to bleeding (p=0.58).

There were 12 bleeding events (26% of the cohort) and neither VWF antigen, VWF:RCo, hematocrit, leukocyte count, platelet count or risk group could be associated with these events. It was observed that VWF antigen was higher with higher platelet counts (p=0.02). A reduced function/antigen ratio (VWF:RCo/Ag) showed a significant association with leukocytosis and thrombocytosis, but not with hematocrit above normal range.

In nine patients, the AVWS screening tests were done on at least two occasions. We observed that the level of VWF:RCo increases when the patients achieve the target hematocrit level below 45%.However, the VWF:RCo/VWF ratio improved only when the platelets levels lowered after cytoreduction.

Conclusions: Most of the patients in our cohort (78%) had a positive screening for AVWS by the VWF:RCO / Ag ratio criteria. However, we did not show a correlation with bleeding events or blood count parameters. Despite the significant number of bleeding events, establishing the diagnosis of AVWS or a correlation with bleeding events is a challenge for patients with PV.
Prospective Study of Avapritinib in Patients with Relapsed/Refractory or MRD-Positive Core-Binding Factor Acute Myeloid Leukemia with KIT Mutations
Authors: Dou Xueqing , Chen Suning , Wu Depei
Published: December 2024

Core-binding factor acute myeloid leukemia (CBF-AML), which includes the recurrent genetic abnormalities RUNX1::RUNX1T1 and CBFβ::MYH11 fusions, is generally associated with a favorable prognosis. However, KIT gene mutations are a common co-occurring event in CBF-AML, and the presence of KIT mutations is associated with a poorer prognosis in these patients. Avapritinib is a tyrosine kinase inhibitor that was developed to specifically target mutations in the KIT and PDGFRA genes. While avapritinib has been approved for the treatment of gastrointestinal stromal tumors (GIST) with PDGFRA mutations and advanced systemic mastocytosis, its efficacy and safety in CBF-AML with KIT mutations have not been extensively investigated.

In this study, we evaluated the efficacy and safety of avapritinib in patients with relapsed/refractory or measurable residual disease (MRD)-positive CBF-AML harboring RUNX1::RUNX1T1 or CBFβ::MYH11 fusions. A total of 40 patients, including 24 males and 16 females, with a median age of 41 years (range, 13-77), were enrolled from two big medical centers in China. The majority of patients (33/40, 82.5%) had RUNX1::RUNX1T1 fusions, while the remaining 17.5% (7/40) had CBFβ::MYH11 fusions. In these patients, 23 (57.5%) had KIT N822 mutations, 5 (12.5%) had KIT N822 mutations, 8 (20%) had complex KIT mutations, and 4 (10%) patients had other KIT mutations. Thirteen patients had relapsed/refractory AML, and the other 27 had a positive molecular MRD of fusion genes after two consolidation treatment at least. All of the patients received avapritinib monotherapy at a dose of 100mg daily (in combination with azole antibiotics) or 200mg daily orally, with or without in combination with chemotherapy.

In the 13 relapsed/refractory AML patients, 6 had a good response to avapritinib, achieving an overall response rate（ORR) of 46.2%. Five of the 6 responding patients then underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) and achieved molecular MRD-negative remission, although one patient subsequently died of pulmonary infection. Among the 27 patients with positive molecular MRD, 19 (70.4%) demonstrated a good response to avapritinib, with a reduction in molecular MRD level of at least 1 log, and 11 (40.7%) achieved molecular MRD negativity.The most common adverse event (AE) was hematological toxicity, and other AEs included facial edema, gastrointestinal reactions, rash, QT interval prolongation, and hair depigmentation.

In general, the study results suggest that avapritinib demonstrated good efficacy and safety in patients with CBF-AML harboring KIT gene mutations. These findings may support expanding the indications for this therapy in the treatment of AML.
Clinical Characteristics and Risk Factors of Chronic Kidney Disease Among Patients with Myeloproliferative Neoplasms
Authors: Gao Zicheng , Zhou Xuan , Wang Qiang , Xu Dan , Liu Xiaoli , Xu Na , Liu Qifa
Published: December 2024

Abstract:

Background: Classical BCR::ABL-negative myeloproliferative neoplasms (MPN), which mainly include essential thrombocytopenia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF), characterized by the overproduction of mature myeloid blood cell lineages and commonly complicate with thrombosis. Recently, reports of MPN related kidney dysfunction especially chronic kidney disease gradually gained attention. However, the clinical characteristics of CKD in MPN patients is still unclear.

Aim: The aim of this study was to investigate the clinical characteristics and risk factors of complicated with CKD in patients with MPN.

Methods: We retrospectively analyzed the clinical characteristics and genetic characteristics of MPN patients who visited Nanfang hospital regularly from June 2008 to December 2023. The predictors of complicated with CKD and over survival (OS) were analyzed by logistic regression or Cox proportional hazards model.

Result: A total of 1373 patients were included, 15.4% of whom had CKD. 1216 clonal hematopoiesis of indeterminate potential (CHIP) related mutations were detected.78.6% of patients had at least one CHIP-related mutation. Patients with CHIP-related mutations were more likely to be older, with 24% being ≥ 65 years of age compared with 7.2% in non-CHIP-related mutation (P < 0.001), and also had fewer CALR mutations (8.1% vs. 27.6%, p < 0.001), and a higher incidence of cardiovascular events, hypertension, diabetes and CKD (25.3% vs. 11.3%, P<0.001; 10.6% vs. 5.8%, P = 0.014; 13% vs. 8.5%, P = 0.040; 17.3% vs. 8.5%, P < 0.001).The multivariate logistic analysis indicated that age ≥65 years old (HR:0.95, 95% CI, 0.94-0.97, p < 0.001), mutation in TET2 (HR:6.54, 95% CI, 2.88-14.88, p < 0.001)、ASXL1 (HR: 2.29, 95% CI, 1.00-5.24,p = 0.049), complicated with cardiovascular events (HR:90.82, 95% CI, 48.62-169.65, p < 0.001), hypertension (HR: 3.42, 95% CI, 1.94-6.03, p < 0.001) and diabetes (HR: 2.16, 95% CI, 1.31-3.54, p = 0.002) are risk factors for CKD in MPN. The multivariable COX analysis revealed that age ≥ 65 years old (HR: 1.88, 95% CI, 1.20 - 2.96, P = 0.006), diagnosed PMF (HR: 11.23, 95% CI, 6.36 - 19.82, P < 0.001), complicated with CKD (HR: 3.48, 95% CI, 2.15 - 5.64, P < 0.001) were the unfavorable predictors of OS, while female (HR: 0.50, 95% CI, 0.34 - 0.75, P < 0.001) was the favorable factors.

Conclusion: Our single-center data indicates that MPN patients have a 15.4% incidence rate of complicated with CKD. Age ≥65 years old, mutation in TET2, ASXL1, complicated with cardiovascular events, hypertension and diabetes are independent risk factors for CKD in MPN patients. Diagnosed PMF, male, complicated with CKD were the unfavorable factors for OS.

Keywords: Myeloproliferative neoplasms; Chronic kidney disease; Clonal hematopoiesis; Clonal hematopoiesis of indeterminate potential
Mastl Is a New Therapeutic Target for Acute Myeloid Leukemia
Authors: Chen Fangli , Liu Ligen , Chen Huijie , Wu Yicheng , Wang Yuanqin , Fu Zhen , Zhang Tinghua , Jiang Xuewei , Lu Yingting , Zhao Limin , Li Jutang , Yang Li
Published: December 2024

Recently, the approval of several new generation of targeted therapeutic agents greatly improved the prognosis of Acute myeloid leukemia (AML). Despite of these undeniable progresses, many patients still lack effective therapies. Moreover, resistance to the targeted agents represent major clinical challenges. Therefore, there is an unmet need to discover new therapeutic targets and overcome the resistance. In this study, our strategy is to discover a specific kinase, which can be served as monotherapy and also overcoming resistance to current venetoclax-based therapies.

Through high-throughput screening of a custom kinase inhibitor library of 500 compounds and re-analyzing genome-wide CRISPR/Cas9 screen data sets, we identified Microtubule Associated Serine/Threonine Kinase Like (MASTL) as a potential novel target for AML treatment. Public data and our in house data showed MASTL expression was significantly higher in AML patients than healthy subjects. RNAi and pharmacologic inhibition of MASTL reduced cell viability and colony formation in THP-1 and OCI-AML3 cells. MASTL knock down and MASTL inhibitor significantly reduced tumor growth in THP-1 derived subcutaneous tumor model and prolonged survival in xenograft NCG mouse model. Mechanistically, MASTL knock down induced downregulation of Survivin and upregulation of Puma in THP-1 cells. Transcriptome analysis showed MASTL suppression was associated with several signaling pathways including Rap1, Toll-like receptor, MAPK, TNF signaling pathway. Importantly, MASTL knock down dramatically suppressed the expression of S100A8 and S100A9, which is known to be involved in venetoclax resistance in AML. Both genetic and pharmacologic inhibition of MASTL reversed venetoclax resistance in venetoclax resistant cell lines. The combination of venetoclax and MASTL inhibitor significantly reduced tumor growth than each monotherapy in vivo.

In conclusion, our data suggest that MASTL inhibition is a promising strategy for AML treatment. Moreover, MASTL inhibition potentiates venetoclax response and overcome venetoclax resistance in AML.
Inhibiting CCR7-Regulated Cellular Senescence Enhances the Killing Ability of CD19 CAR-T Cells Against Aggressive B-Cell Lymphoma Cells
Authors: Wang Jiyu , Li Jinlan , Huang Keke , An Furun , Wang Huiping , Tao Qianshan , Zhai Zhimin
Published: December 2024

Resistance and relapse are the main challenges currently faced in the treatment of B-cell non-Hodgkin lymphoma (B-NHL) patients with CD19 Chimeric antigen receptor (CAR) T-cell therapy therapy. Therapy-induced senescence (TIS) is one of the most important mechanisms of tumor resistance. In this study, we utilized single-cell transcriptome sequencing to analyze therapy-induced lymphoma cells, revealing a distinct group of TIS characterized by memory B cell subpopulations exhibiting strong positive expression of CCR7, which is significantly elevated in TIS subpopulation compared to normal proliferating and autonomously senescent lymphoma cell subpopulations. Further analysis using immunohistochemistry, flow cytometry, and ELISA showed that CCR7 expression and serum CCL21 levels were significantly increased in patients with aggressive B-NHL who failed CAR-T therapy. Moreover, abnormally high CCR7 expression was associated with poor prognosis in B-NHL patients. In vitro, further co-culture of aggressive B-NHL cells pre-treated with the CCR7 blocking antibody CAP-100 and CD19 CAR-T cells revealed that inhibiting CCR7 could significantly suppress B-NHL cell senescence and markedly enhance the ability of CD19 CAR-T cells to kill lymphoma cells. Mechanistically, senescent B-NHL cells exhibited typical stemness characteristics in terms of immunophenotype and biological functions, including the up-regulation of stemness molecular markers, stronger colony-forming abilities, and increased invasive and migratory capabilities. Inhibiting CCL21/CCR7 signaling can block the ARHGAP18/NFKBIA pathway, reversing the enhanced stemness characteristics of B-NHL-TIS, and thereby enhancing the cytotoxicity of CD19 CAR-T cells. In summary, TIS promotes stem cell characteristics in B-NHL cells through activation of the CCR7/ARHGAP18/IKBα signaling pathway. Targeting CCR7/ARHGAP18 may overcome the intrinsic resistance of senescent B-NHL cells to CD19 CAR-T cell killing by inhibiting the acquisition and maintenance of stemness.