Pub Date : 2024-09-04DOI: 10.1182/bloodadvances.2024012855
Dino Mehic, Stéphanie E Reitsma, Claire de Moreuil, Helmuth Haslacher, Maximilian Christian Koeller, Bas de Laat, Cihan Ay, Ingrid Pabinger, Alisa Wolberg, Johanna Gebhart
Bleeding disorder of unknown cause (BDUC) is a diagnosis of exclusion after evaluation of plasma coagulation and platelet function. The underlying mechanisms are unclear, but increased fibrinolysis and abnormal clot formation may play a role. All BDUC patients (n=375) from the Vienna bleeding biobank were analyzed in comparison to healthy controls (HC, n=100) in this case-control study. Plasmin generation (PG) parameters were analyzed using calibrated fluorescence detection in citrated-plasma samples. Turbidimetric plasma clot formation/ lysis of 293 (78%) BDUC patients and confocal microscopy of clots from representative BDUC patients (n=6) and HC (n=9) were assessed. Fibrinolytic factors were measured using commercially available ELISAs. In PG analysis, BDUC patients exhibited lower velocity and peak plasmin, but a higher endogenous plasmin potential compared to HC. Peak plasmin correlated with maximum clot absorbance, but not with clot lysis time. Clot absorbance is an indicator of clot fiber density. Confocal microscopy analysis revealed that BDUC patients' clots had a tendency towards thicker fibers, which negatively correlated with peak plasmin (r=-0.561, p=0.030). Peak plasmin correlated weakly with FXIII, but not with the other fibrinolytic factors (alpha2-antiplasmin, thrombin activatable fibrinolysis inhibitor or plasminogen activator inhibitor 1) or bleeding severity. A model comprising fibrinogen and parameters of PG yielded high predictive power in discriminating BDUC patients from HC during 5-fold stratified cross validation (80% of data, mean AUC: 0.847). The same model generalized well to unseen data (20% of data, AUC: 0.856). Overall, BDUC patients exhibited counterintuitively reduced peak plasmin, potentially related to altered clot structure.
{"title":"Plasmin Generation Analysis in Patients with Bleeding Disorder of Unknown Cause.","authors":"Dino Mehic, Stéphanie E Reitsma, Claire de Moreuil, Helmuth Haslacher, Maximilian Christian Koeller, Bas de Laat, Cihan Ay, Ingrid Pabinger, Alisa Wolberg, Johanna Gebhart","doi":"10.1182/bloodadvances.2024012855","DOIUrl":"https://doi.org/10.1182/bloodadvances.2024012855","url":null,"abstract":"<p><p>Bleeding disorder of unknown cause (BDUC) is a diagnosis of exclusion after evaluation of plasma coagulation and platelet function. The underlying mechanisms are unclear, but increased fibrinolysis and abnormal clot formation may play a role. All BDUC patients (n=375) from the Vienna bleeding biobank were analyzed in comparison to healthy controls (HC, n=100) in this case-control study. Plasmin generation (PG) parameters were analyzed using calibrated fluorescence detection in citrated-plasma samples. Turbidimetric plasma clot formation/ lysis of 293 (78%) BDUC patients and confocal microscopy of clots from representative BDUC patients (n=6) and HC (n=9) were assessed. Fibrinolytic factors were measured using commercially available ELISAs. In PG analysis, BDUC patients exhibited lower velocity and peak plasmin, but a higher endogenous plasmin potential compared to HC. Peak plasmin correlated with maximum clot absorbance, but not with clot lysis time. Clot absorbance is an indicator of clot fiber density. Confocal microscopy analysis revealed that BDUC patients' clots had a tendency towards thicker fibers, which negatively correlated with peak plasmin (r=-0.561, p=0.030). Peak plasmin correlated weakly with FXIII, but not with the other fibrinolytic factors (alpha2-antiplasmin, thrombin activatable fibrinolysis inhibitor or plasminogen activator inhibitor 1) or bleeding severity. A model comprising fibrinogen and parameters of PG yielded high predictive power in discriminating BDUC patients from HC during 5-fold stratified cross validation (80% of data, mean AUC: 0.847). The same model generalized well to unseen data (20% of data, AUC: 0.856). Overall, BDUC patients exhibited counterintuitively reduced peak plasmin, potentially related to altered clot structure.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142131888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-03DOI: 10.1182/bloodadvances.2023012077
Richard Burt, Aditi Dey, Ayse Akarca, Hermione Allen, Rodothea Amerikanou, Samantha Atkinson, David Auty, Jenny Chatzigerou, Emily Annie Cutler, Jose Afonso Guerra-Assuncao, Kristina Kirschner, Ruchi Kumari, Jiten Manji, Teresa Marafioti, Juma Ward, Adele K Fielding
Cancer associated fibroblasts (CAF) arising from bone marrow-derived mesenchymal stromal cells (MSC) are prominent in B-precursor acute lymphoblastic leukaemia (B-ALL). We have previously shown that CAF formation is triggered by exposure to reactive oxygen species-inducing chemotherapy and that CAF support chemoresistance by donating mitochondria to the cancer cells, through tunnelling nanotubes. In the present study, we show that exposure of MSC to ALL cell lines, patient-derived xenografts and primary cells or their conditioned media can also trigger CAF formation. Using bulk RNA sequencing in cell lines, we show that the MSC to CAF transition is accompanied by a robust interferon pathway response and we have validated this finding in primary cells. Using confocal microscopy and flow cytometry, we identify the take-up of leukaemia cell-derived mitochondrial dsRNA by MSC as a proximate trigger for the MSC to CAF transition. We show that inhibition of dsRNA formation in ALL cells by treatment with low-dose ethidium or the mitochondrial transcription inhibitor IMT1 or degradation of dsRNA in conditioned media by 100°C exposure ablates the ability of the ALL conditioned media to stimulate MSC to CAF transition. Our data reveal a novel and previously undescribed mechanism by which cancer cells induce a CAF phenotype in stromal cells, showing how B-ALL cells can directly induce the previously described niche-mediated protection within the bone marrow.
由骨髓间充质基质细胞(MSC)产生的癌症相关成纤维细胞(CAF)在B-前体急性淋巴细胞白血病(B-ALL)中表现突出。我们以前的研究表明,接触活性氧诱导的化疗会触发 CAF 的形成,CAF 通过隧道式纳米管将线粒体捐赠给癌细胞,从而支持化疗抗性。在本研究中,我们发现间充质干细胞暴露于 ALL 细胞系、患者衍生的异种移植物和原代细胞或其条件培养基也会触发 CAF 的形成。通过对细胞系进行大量 RNA 测序,我们发现间充质干细胞向 CAF 的转变伴随着强大的干扰素通路反应,我们在原代细胞中也验证了这一发现。利用共聚焦显微镜和流式细胞术,我们确定间充质干细胞吸收白血病细胞衍生的线粒体dsRNA是间充质干细胞向CAF转变的近似触发因素。我们的研究表明,用低剂量乙硫胺或线粒体转录抑制剂 IMT1 处理 ALL 细胞,抑制其 dsRNA 的形成,或用 100°C 暴露降解条件培养基中的 dsRNA,可消除 ALL 条件培养基刺激间充质干细胞向 CAF 转化的能力。我们的数据揭示了癌细胞在基质细胞中诱导 CAF 表型的一种以前未曾描述过的新机制,显示了 B-ALL 细胞如何在骨髓中直接诱导以前描述过的龛介导的保护。
{"title":"Mitochondrial dsRNA from B-ALL cells stimulates mesenchymal stromal cells to become cancer associated fibroblasts.","authors":"Richard Burt, Aditi Dey, Ayse Akarca, Hermione Allen, Rodothea Amerikanou, Samantha Atkinson, David Auty, Jenny Chatzigerou, Emily Annie Cutler, Jose Afonso Guerra-Assuncao, Kristina Kirschner, Ruchi Kumari, Jiten Manji, Teresa Marafioti, Juma Ward, Adele K Fielding","doi":"10.1182/bloodadvances.2023012077","DOIUrl":"https://doi.org/10.1182/bloodadvances.2023012077","url":null,"abstract":"<p><p>Cancer associated fibroblasts (CAF) arising from bone marrow-derived mesenchymal stromal cells (MSC) are prominent in B-precursor acute lymphoblastic leukaemia (B-ALL). We have previously shown that CAF formation is triggered by exposure to reactive oxygen species-inducing chemotherapy and that CAF support chemoresistance by donating mitochondria to the cancer cells, through tunnelling nanotubes. In the present study, we show that exposure of MSC to ALL cell lines, patient-derived xenografts and primary cells or their conditioned media can also trigger CAF formation. Using bulk RNA sequencing in cell lines, we show that the MSC to CAF transition is accompanied by a robust interferon pathway response and we have validated this finding in primary cells. Using confocal microscopy and flow cytometry, we identify the take-up of leukaemia cell-derived mitochondrial dsRNA by MSC as a proximate trigger for the MSC to CAF transition. We show that inhibition of dsRNA formation in ALL cells by treatment with low-dose ethidium or the mitochondrial transcription inhibitor IMT1 or degradation of dsRNA in conditioned media by 100°C exposure ablates the ability of the ALL conditioned media to stimulate MSC to CAF transition. Our data reveal a novel and previously undescribed mechanism by which cancer cells induce a CAF phenotype in stromal cells, showing how B-ALL cells can directly induce the previously described niche-mediated protection within the bone marrow.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142124851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-03DOI: 10.1182/bloodadvances.2024013750
Vincenzo La Mura, Vincenzo Cardinale, Raimondo De Cristofaro, Adriano De Santis, Giovanni Di Minno, Luca Fabris, Fabio Marra, Filomena Morisco, Flora Peyvandi, Maurizio Pompili, Cristina Santoro, Ezio Zanon, Giancarlo Castaman
Adeno-associated virus (AAV)-based gene therapy (valoctocogene roxaparvovec) is an attractive treatment for hemophilia A. Careful clinical management is required to minimize the risk of hepatotoxicity, including assessment of baseline liver condition to determine treatment eligibility and monitoring liver function after gene therapy. This article describes recommendations (developed by a group of hemophilia experts) on hepatic function monitoring before and after gene therapy. To prevent harmful liver-related effects, gene therapy is contraindicated in patients with uncontrolled liver infections, autoimmune hepatitis, liver stiffness ≥8 kPa or cirrhosis. Before using gene therapy in patients with liver steatosis or other liver disorders, the risk of liver damage should be considered using a highly individualized approach. Treatment is not recommended in patients with abnormal liver enzymes, including alanine aminotransferase (ALT) at any level above the upper limit of normal (ULN). Therefore, pre-treatment assessment of liver health should include laboratory tests, abdominal ultrasound and liver stiffness measurements by transient elastography (TE). In the first year after therapy, ALT levels should be monitored 1-2 times/week to detect elevations ≥1.5 × ULN, which may require immunosuppressant therapy. Patients with ALT elevation should receive prednisone 60 mg/day for 2 weeks, followed by stepwise tapering when ALT returns to baseline. ALT monitoring should continue long-term (every 3-6 months), along with abdominal ultrasound (every 6 months) and TE (yearly) evaluations. When patients with good liver health are selected for treatment and closely monitored thereafter, ALT elevations can be promptly treated and are expected to resolve without long-term hepatic sequelae.
{"title":"Liver-related aspects of valoctocogene roxaparvovec gene therapy for hemophilia A: expert guidance for clinical practice.","authors":"Vincenzo La Mura, Vincenzo Cardinale, Raimondo De Cristofaro, Adriano De Santis, Giovanni Di Minno, Luca Fabris, Fabio Marra, Filomena Morisco, Flora Peyvandi, Maurizio Pompili, Cristina Santoro, Ezio Zanon, Giancarlo Castaman","doi":"10.1182/bloodadvances.2024013750","DOIUrl":"https://doi.org/10.1182/bloodadvances.2024013750","url":null,"abstract":"<p><p>Adeno-associated virus (AAV)-based gene therapy (valoctocogene roxaparvovec) is an attractive treatment for hemophilia A. Careful clinical management is required to minimize the risk of hepatotoxicity, including assessment of baseline liver condition to determine treatment eligibility and monitoring liver function after gene therapy. This article describes recommendations (developed by a group of hemophilia experts) on hepatic function monitoring before and after gene therapy. To prevent harmful liver-related effects, gene therapy is contraindicated in patients with uncontrolled liver infections, autoimmune hepatitis, liver stiffness ≥8 kPa or cirrhosis. Before using gene therapy in patients with liver steatosis or other liver disorders, the risk of liver damage should be considered using a highly individualized approach. Treatment is not recommended in patients with abnormal liver enzymes, including alanine aminotransferase (ALT) at any level above the upper limit of normal (ULN). Therefore, pre-treatment assessment of liver health should include laboratory tests, abdominal ultrasound and liver stiffness measurements by transient elastography (TE). In the first year after therapy, ALT levels should be monitored 1-2 times/week to detect elevations ≥1.5 × ULN, which may require immunosuppressant therapy. Patients with ALT elevation should receive prednisone 60 mg/day for 2 weeks, followed by stepwise tapering when ALT returns to baseline. ALT monitoring should continue long-term (every 3-6 months), along with abdominal ultrasound (every 6 months) and TE (yearly) evaluations. When patients with good liver health are selected for treatment and closely monitored thereafter, ALT elevations can be promptly treated and are expected to resolve without long-term hepatic sequelae.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142124850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-03DOI: 10.1182/bloodadvances.2024014273
Marcel Benkhoff, Karin Alde, Vincent Ehreiser, Jana Dahlmanns, Daniel Metzen, Jean M Haurand, Dragos Andrei Duse, Christian Jung, Malte Kelm, Tobias Petzold, Amin Polzin
Platelets are crucial in thrombus formation during ST-elevation myocardial infarction (STEMI). In addition, they also play an important role in post-ischemic thromboinflammation which is determined by the interplay between activated platelets and neutrophils. The latter form neutrophil extracellular traps (NETs) which are detectable in plasma as citrullinated histone H3 - DNA complexes. Prediction of risk of recurrent events is important in precision medicine. Therefore, we investigated if circulating thromboinflammatory markers predict clinical outcome after STEMI. We performed a prospective, multicentric, observational, all-comer study of STEMI patients (n=361). Thromboinflammation, measured as H3Cit-DNA complexes, was assessed on day one after presentation with STEMI as well as five days and six months after STEMI by ELISA. Twelve months clinical follow-up was conducted. Multivariate analysis was performed investigating which variables were independently associated with major adverse cardiac events (MACE). Patients were 64 ± 12 years old, 80 % male and 40 % had diabetes mellitus. Thromboinflammation was enhanced during index hospitalization as compared to six months follow-up (137.4 ± 100.0 µg/l vs. 53.7 ± 54.7 µg/l, p<0.001). Additionally, patients within the highest tertile of thromboinflammation at day one after STEMI showed worse outcome during follow-up (HR 2.57, CI 1.72-3.85, p<0.001). Receiver operating characteristics (ROC) analysis revealed a cut-off value of 219.3 µg/l. In multivariate logistic regression analysis, thromboinflammation was independently associated with outcome after STEMI. To sum it up, thromboinflammation is enhanced in STEMI. It identifies patients at high risk of MACE. Therefore, thromboinflammation might be a promising target and marker in precision medicine. Trial Registration Number: NCT03539133.
{"title":"Thromboinflammation is associated with clinical outcome after ST-elevation myocardial infarction.","authors":"Marcel Benkhoff, Karin Alde, Vincent Ehreiser, Jana Dahlmanns, Daniel Metzen, Jean M Haurand, Dragos Andrei Duse, Christian Jung, Malte Kelm, Tobias Petzold, Amin Polzin","doi":"10.1182/bloodadvances.2024014273","DOIUrl":"https://doi.org/10.1182/bloodadvances.2024014273","url":null,"abstract":"<p><p>Platelets are crucial in thrombus formation during ST-elevation myocardial infarction (STEMI). In addition, they also play an important role in post-ischemic thromboinflammation which is determined by the interplay between activated platelets and neutrophils. The latter form neutrophil extracellular traps (NETs) which are detectable in plasma as citrullinated histone H3 - DNA complexes. Prediction of risk of recurrent events is important in precision medicine. Therefore, we investigated if circulating thromboinflammatory markers predict clinical outcome after STEMI. We performed a prospective, multicentric, observational, all-comer study of STEMI patients (n=361). Thromboinflammation, measured as H3Cit-DNA complexes, was assessed on day one after presentation with STEMI as well as five days and six months after STEMI by ELISA. Twelve months clinical follow-up was conducted. Multivariate analysis was performed investigating which variables were independently associated with major adverse cardiac events (MACE). Patients were 64 ± 12 years old, 80 % male and 40 % had diabetes mellitus. Thromboinflammation was enhanced during index hospitalization as compared to six months follow-up (137.4 ± 100.0 µg/l vs. 53.7 ± 54.7 µg/l, p<0.001). Additionally, patients within the highest tertile of thromboinflammation at day one after STEMI showed worse outcome during follow-up (HR 2.57, CI 1.72-3.85, p<0.001). Receiver operating characteristics (ROC) analysis revealed a cut-off value of 219.3 µg/l. In multivariate logistic regression analysis, thromboinflammation was independently associated with outcome after STEMI. To sum it up, thromboinflammation is enhanced in STEMI. It identifies patients at high risk of MACE. Therefore, thromboinflammation might be a promising target and marker in precision medicine. Trial Registration Number: NCT03539133.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142124852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-03DOI: 10.1182/bloodadvances.2024014035
Emma Verner, Amanda Johnston, Nalini Pati, Eliza A Hawkes, Hui-Peng Lee, Tara Cochrane, Chan Y Cheah, Robin Filshie, Duncan Purtill, Hanlon Sia, Anoop Kumar Enjeti, Christina Brown, Nicholas Edward Murphy, Jennifer Curnow, Kenneth Lee, Maher K Gandhi, Mannu Walia, Belinda Butcher, Judith Trotman
The multicenter, prospective phase II Australasian Leukaemia and Lymphoma Group (ALLG) NHL29 trial (ACTRN12615000551594) was conducted to assess the addition of ibrutinib to R-mini-CHOP (IRiC) in patients aged ≥75 years with newly diagnosed Diffuse Large B-cell Lymphoma (DLBCL). Treatment consisted of six 21-day cycles of ibrutinib-R-mini-CHOP followed by two 21-day cycles of rituximab-ibrutinib. Co-primary endpoints were deliverability and 2-year overall survival (OS). All six cycles of R-mini-CHOP were completed in 63/79 patients (80%) with the median Average Relative Total Dose and Average Relative Dose Intensity for the entire regimen both 97% (IQR 82, 100; 88, 100). With a median follow-up of 35.5 months, the 2-year OS was 68% (95% CI, 55.6 - 77.4) with a 2-year PFS of 60.0% (95% CI, 47.7- 70.3). Median OS and PFS were 72 months (95% CI, 35 - not reached) and 40 months (95% CI, 20.4 - not reached) respectively. The overall response rate (ORR) was 76% (61/79 patients), with a complete response (CR) rate of 71% (56/79 patients). Deaths occurred in 34/79 patients (43%), including 17 from progressive disease and 5 treatment related. 67% patients experienced at least one serious adverse event. Most common adverse events were infections and diarrhea (majority grade 1-2). In both health-related quality of life measures, there was an improvement in functional and symptom scales, median health state classification score and median visual analogue scale in responders over time. In conclusion, this study showed that the addition of ibrutinib to R-mini-CHOP was both deliverable and efficacious in elderly DLBCL patients.
{"title":"Ibrutinib plus rituximab and mini-CHOP in very elderly patients with newly diagnosed DLBCL: A phase II ALLG study.","authors":"Emma Verner, Amanda Johnston, Nalini Pati, Eliza A Hawkes, Hui-Peng Lee, Tara Cochrane, Chan Y Cheah, Robin Filshie, Duncan Purtill, Hanlon Sia, Anoop Kumar Enjeti, Christina Brown, Nicholas Edward Murphy, Jennifer Curnow, Kenneth Lee, Maher K Gandhi, Mannu Walia, Belinda Butcher, Judith Trotman","doi":"10.1182/bloodadvances.2024014035","DOIUrl":"https://doi.org/10.1182/bloodadvances.2024014035","url":null,"abstract":"<p><p>The multicenter, prospective phase II Australasian Leukaemia and Lymphoma Group (ALLG) NHL29 trial (ACTRN12615000551594) was conducted to assess the addition of ibrutinib to R-mini-CHOP (IRiC) in patients aged ≥75 years with newly diagnosed Diffuse Large B-cell Lymphoma (DLBCL). Treatment consisted of six 21-day cycles of ibrutinib-R-mini-CHOP followed by two 21-day cycles of rituximab-ibrutinib. Co-primary endpoints were deliverability and 2-year overall survival (OS). All six cycles of R-mini-CHOP were completed in 63/79 patients (80%) with the median Average Relative Total Dose and Average Relative Dose Intensity for the entire regimen both 97% (IQR 82, 100; 88, 100). With a median follow-up of 35.5 months, the 2-year OS was 68% (95% CI, 55.6 - 77.4) with a 2-year PFS of 60.0% (95% CI, 47.7- 70.3). Median OS and PFS were 72 months (95% CI, 35 - not reached) and 40 months (95% CI, 20.4 - not reached) respectively. The overall response rate (ORR) was 76% (61/79 patients), with a complete response (CR) rate of 71% (56/79 patients). Deaths occurred in 34/79 patients (43%), including 17 from progressive disease and 5 treatment related. 67% patients experienced at least one serious adverse event. Most common adverse events were infections and diarrhea (majority grade 1-2). In both health-related quality of life measures, there was an improvement in functional and symptom scales, median health state classification score and median visual analogue scale in responders over time. In conclusion, this study showed that the addition of ibrutinib to R-mini-CHOP was both deliverable and efficacious in elderly DLBCL patients.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142124849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-30DOI: 10.1182/bloodadvances.2024013277
Amitkumar Mehta, Leslie Popplewell, Graham P Collins, Sonali M Smith, Ian W Flinn, Nancy L Bartlett, Nilanjan Ghosh, Gal Hacohen-Kleiman, Yanan Huo, Linda Su-Feher, Camille Renard, Ranjana H Advani, Mark Roschewski
Relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL) is generally considered incurable with current treatment options. Previous phase 1b/2 results showed combining the anti-cluster-of-differentiation (CD) 47 activity of magrolimab with the anti-CD20 activity of rituximab (M+R) has antitumor activity against R/R iNHL. Here, we report 3-year follow-up data from this phase 1b/2 study (NCT02953509) assessing long-term safety and efficacy of M+R in R/R iNHL. After magrolimab priming, 4 groups of phase 1b M+R patients received 10-45 mg/kg magrolimab maintenance doses with 375 mg/m2 rituximab. Phase 2 explored 30 and 45 mg/kg magrolimab. Primary endpoints were treatment-emergent adverse events (TEAEs) and objective response rate (ORR). Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Exploratory analysis included assessment of circulating tumor DNA, biomarkers of magrolimab tumor penetration, and drug target expression. Of 46 patients treated in phase 1b/2, 42 had follicular lymphoma and 4 had marginal zone lymphoma. All patients experienced ≥1 any-grade TEAE, and 44 reported ≥1 treatment-related TEAE. No additional toxicities were reported during long-term follow-up, and there were no treatment-related deaths. Median follow-up was 36.7 (range, 1.2-62.3) months. The ORR was 52.2%, with 30.4% achieving a complete response. The median DOR was 15.9 (95% CI, 5.6-not estimable) months. The median time-to-response was 1.8 (range, 1.6-5.5) months; median PFS and OS were 7.4 (95% CI, 4.8-13.0) months and not reached, respectively. These results demonstrate the long-term safety and efficacy of M+R in patients with iNHL and support further exploration of CD47-based treatment combinations.
{"title":"Magrolimab Plus Rituximab in Relapsed/Refractory Indolent Non-Hodgkin Lymphoma: Phase 1/2 Trial 3-Year Follow-up.","authors":"Amitkumar Mehta, Leslie Popplewell, Graham P Collins, Sonali M Smith, Ian W Flinn, Nancy L Bartlett, Nilanjan Ghosh, Gal Hacohen-Kleiman, Yanan Huo, Linda Su-Feher, Camille Renard, Ranjana H Advani, Mark Roschewski","doi":"10.1182/bloodadvances.2024013277","DOIUrl":"https://doi.org/10.1182/bloodadvances.2024013277","url":null,"abstract":"<p><p>Relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL) is generally considered incurable with current treatment options. Previous phase 1b/2 results showed combining the anti-cluster-of-differentiation (CD) 47 activity of magrolimab with the anti-CD20 activity of rituximab (M+R) has antitumor activity against R/R iNHL. Here, we report 3-year follow-up data from this phase 1b/2 study (NCT02953509) assessing long-term safety and efficacy of M+R in R/R iNHL. After magrolimab priming, 4 groups of phase 1b M+R patients received 10-45 mg/kg magrolimab maintenance doses with 375 mg/m2 rituximab. Phase 2 explored 30 and 45 mg/kg magrolimab. Primary endpoints were treatment-emergent adverse events (TEAEs) and objective response rate (ORR). Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Exploratory analysis included assessment of circulating tumor DNA, biomarkers of magrolimab tumor penetration, and drug target expression. Of 46 patients treated in phase 1b/2, 42 had follicular lymphoma and 4 had marginal zone lymphoma. All patients experienced ≥1 any-grade TEAE, and 44 reported ≥1 treatment-related TEAE. No additional toxicities were reported during long-term follow-up, and there were no treatment-related deaths. Median follow-up was 36.7 (range, 1.2-62.3) months. The ORR was 52.2%, with 30.4% achieving a complete response. The median DOR was 15.9 (95% CI, 5.6-not estimable) months. The median time-to-response was 1.8 (range, 1.6-5.5) months; median PFS and OS were 7.4 (95% CI, 4.8-13.0) months and not reached, respectively. These results demonstrate the long-term safety and efficacy of M+R in patients with iNHL and support further exploration of CD47-based treatment combinations.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-30DOI: 10.1182/bloodadvances.2024012599
Nektarios Kostopoulos, Francesca Costabile, Elisavet Krimitza, Silvia Beghi, Denisa Goia, Renzo Perales-Linares, George Thyfronitis, Michael J LaRiviere, Elise A Chong, Stephen J Schuster, Amit Maity, Constantinos Koumenis, John P Plastaras, Andrea Facciabene
Chimeric antigen receptor (CAR) T cell therapy targeting CD19 (CART-19) represents a significant advance in the treatment of patients with relapsed or refractory CD19-positive B-cell lymphomas. However, a significant portion of patients either relapse or fail to respond. Moreover, many patients have symptomatic disease, requiring bridging radiation therapy (RT) during the period of CAR-T cells manufacturing. To investigate the impact of 1-2 fractions of low-dose RT on CART-19 treatment response, we developed a mouse model using A20 lymphoma cells for CART-19 therapy. We found that low dose fractionated RT had a positive effect on generating abscopal systemic antitumor responses beyond the irradiated site. The combination of RT with CART-19 therapy resulted in additive effects on tumor growth in irradiated masses. Notably, a significant additional increase in antitumor effect was observed in non-irradiated tumors. Mechanistically, our results validate activation of the cGAS/STING pathway, tumor-associated antigen (TAA) cross-priming, and elicitation of epitope spreading. Collectively, our findings suggest that RT may serve as an optimal priming and bridging modality for CAR-T cell therapy overcoming treatment resistance and improving clinical outcomes in patients with CD19-positive hematologic malignancies.
{"title":"Local Radiation Enhances Systemic CAR T Cell Efficacy by Augmenting Antigen Cross-Presentation and T-cell Infiltration.","authors":"Nektarios Kostopoulos, Francesca Costabile, Elisavet Krimitza, Silvia Beghi, Denisa Goia, Renzo Perales-Linares, George Thyfronitis, Michael J LaRiviere, Elise A Chong, Stephen J Schuster, Amit Maity, Constantinos Koumenis, John P Plastaras, Andrea Facciabene","doi":"10.1182/bloodadvances.2024012599","DOIUrl":"https://doi.org/10.1182/bloodadvances.2024012599","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR) T cell therapy targeting CD19 (CART-19) represents a significant advance in the treatment of patients with relapsed or refractory CD19-positive B-cell lymphomas. However, a significant portion of patients either relapse or fail to respond. Moreover, many patients have symptomatic disease, requiring bridging radiation therapy (RT) during the period of CAR-T cells manufacturing. To investigate the impact of 1-2 fractions of low-dose RT on CART-19 treatment response, we developed a mouse model using A20 lymphoma cells for CART-19 therapy. We found that low dose fractionated RT had a positive effect on generating abscopal systemic antitumor responses beyond the irradiated site. The combination of RT with CART-19 therapy resulted in additive effects on tumor growth in irradiated masses. Notably, a significant additional increase in antitumor effect was observed in non-irradiated tumors. Mechanistically, our results validate activation of the cGAS/STING pathway, tumor-associated antigen (TAA) cross-priming, and elicitation of epitope spreading. Collectively, our findings suggest that RT may serve as an optimal priming and bridging modality for CAR-T cell therapy overcoming treatment resistance and improving clinical outcomes in patients with CD19-positive hematologic malignancies.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-30DOI: 10.1182/bloodadvances.2024013152
Simon Renders, Maud Ngoya, Herve Finel, Marie-Thérèse Rubio, William M Townsend, Roland Schroers, Urban Novak, Nicolaas Schaap, Mahmoud Aljurf, Grzegorz Helbig, Matthew Collin, Guido Kobbe, Huynh Anne, José Antonio Antonio Pérez-Simón, Adrian Bloor, Hervé Ghesquieres, Anna Sureda, Norbert Schmitz, Bertram Glass, Peter Dreger
Although broadly employed, consolidative autologous hematopoietic stem cell transplantation (autoHCT) for relapsed/refractory (r/r) T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) has never been specifically investigated. Here we have analyzed outcomes of autoHCT for THRLBCL compared to diffuse large cell B-cell lymphoma not otherwise specified (DLBCL). Eligible for this retrospective registry study were adult patients with r/r THRLBCL and DLBCL, respectively, who underwent a first autoHCT in a salvage-sensitive disease status as assessed by PET-CT between 2016 and 2021 and were registered with the European Society for Blood and Marrow Transplantation (EBMT) database. Primary endpoint was progression-free survival (PFS) 2 years after transplantation. Two-hundred-one patients with THRLBCL and 5,543 with DLBCL were included. There were no significant differences in terms of disease status at HCT, pretreatment lines, and interval from diagnosis to transplant between the cohorts, but patients with THRBCL were significantly younger, contained a higher proportion of men, and had a better performance status. Compared to DLBCL, THRLBCL was associated with significantly better 2-year PFS (78% vs. 59%; p<0.001) and overall survival (OS; 81% vs. 74%; p=0.02) because of a significantly lower 2-year relapse incidence (RI; 16% vs. 35%; p<0.001). On multivariate analysis, favorable relapse risk (hazard ratio (HR) 0.46, 95%CI 0.31-0.7) and PFS (HR 0.58, 95%CI 0.41-0.82) of patients with THRLBCL remained significant, while OS benefits (HR 0.78, 95%CI 0.54-1.12) did not. These results were validated in a propensity-score matched analysis. These data prove autoHCT as an effective treatment option for salvage-sensitive r/r THRLBCL.
虽然自体造血干细胞移植(autoHCT)已被广泛应用于治疗复发/难治性(r/r)T细胞/组织细胞丰富的大B细胞淋巴瘤(THRLBCL),但从未进行过专门的研究。在此,我们分析了自体血细胞移植治疗THRLBCL与非特异性弥漫大细胞B细胞淋巴瘤(DLBCL)的疗效比较。有资格参与这项回顾性登记研究的患者分别是r/r THRLBCL和DLBCL成人患者,他们在2016年至2021年期间接受了首次自体HCT,经PET-CT评估处于挽救敏感疾病状态,并在欧洲血液和骨髓移植学会(EBMT)数据库中进行了登记。主要终点是移植后两年的无进展生存期(PFS)。共纳入了211名THRLBCL患者和5543名DLBCL患者。两组患者在接受造血干细胞移植时的疾病状态、预处理线以及从诊断到移植的间隔时间方面没有明显差异,但THRBCL患者明显更年轻,男性比例更高,表现状态更好。与DLBCL相比,THRLBCL的2年PFS明显更好(78% vs. 59%; p
{"title":"Autologous stem cell transplantation in T-cell/histiocyte-rich large B-cell lymphoma: EBMT Lymphoma Working Party study.","authors":"Simon Renders, Maud Ngoya, Herve Finel, Marie-Thérèse Rubio, William M Townsend, Roland Schroers, Urban Novak, Nicolaas Schaap, Mahmoud Aljurf, Grzegorz Helbig, Matthew Collin, Guido Kobbe, Huynh Anne, José Antonio Antonio Pérez-Simón, Adrian Bloor, Hervé Ghesquieres, Anna Sureda, Norbert Schmitz, Bertram Glass, Peter Dreger","doi":"10.1182/bloodadvances.2024013152","DOIUrl":"https://doi.org/10.1182/bloodadvances.2024013152","url":null,"abstract":"<p><p>Although broadly employed, consolidative autologous hematopoietic stem cell transplantation (autoHCT) for relapsed/refractory (r/r) T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) has never been specifically investigated. Here we have analyzed outcomes of autoHCT for THRLBCL compared to diffuse large cell B-cell lymphoma not otherwise specified (DLBCL). Eligible for this retrospective registry study were adult patients with r/r THRLBCL and DLBCL, respectively, who underwent a first autoHCT in a salvage-sensitive disease status as assessed by PET-CT between 2016 and 2021 and were registered with the European Society for Blood and Marrow Transplantation (EBMT) database. Primary endpoint was progression-free survival (PFS) 2 years after transplantation. Two-hundred-one patients with THRLBCL and 5,543 with DLBCL were included. There were no significant differences in terms of disease status at HCT, pretreatment lines, and interval from diagnosis to transplant between the cohorts, but patients with THRBCL were significantly younger, contained a higher proportion of men, and had a better performance status. Compared to DLBCL, THRLBCL was associated with significantly better 2-year PFS (78% vs. 59%; p<0.001) and overall survival (OS; 81% vs. 74%; p=0.02) because of a significantly lower 2-year relapse incidence (RI; 16% vs. 35%; p<0.001). On multivariate analysis, favorable relapse risk (hazard ratio (HR) 0.46, 95%CI 0.31-0.7) and PFS (HR 0.58, 95%CI 0.41-0.82) of patients with THRLBCL remained significant, while OS benefits (HR 0.78, 95%CI 0.54-1.12) did not. These results were validated in a propensity-score matched analysis. These data prove autoHCT as an effective treatment option for salvage-sensitive r/r THRLBCL.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-30DOI: 10.1182/bloodadvances.2024013743
Narendranath Epperla, Ying Huang, Amanda F Cashen, John L Vaughn, Walter Hanel, Talha Badar, Stefan K Barta, Paolo F Caimi, Tarsheen K Sethi, Nishitha Reddy, Reem Karmali, Celeste Bello, Julio C Chavez, Shalin K Kothari, Francisco J Hernandez-Ilizaliturri, Jakub Svoboda, Frederick Lansigan, Martha J Glenn, Jonathon B Cohen, Caryn Sorge, Beth Christian, Alex F Herrera, Mehdi Hamadani, Luciano J Costa, Ana C Xavier
There are limited data assessing the risk scores for primary treatment failure (PTF) classical Hodgkin lymphoma (cHL, PTF-cHL) undergoing autologous hematopoietic cell transplantation (auto-HCT). ECLIPSE is a multicenter retrospective cohort of patients with PTF- cHL (15 years or older) diagnosed on or after Jan 1, 2005, at 15 US medical centers. PTF was defined as one of the following patterns of failure: [1] progressive disease by imaging during or within 6 weeks of completion of frontline chemotherapy (primary progression [PP]); [2] partial response (PR) or stable disease (SD) by imaging after completion of frontline treatment (PR/SD); [3] progression of disease by imaging (and confirmed by biopsy) within 12 months of frontline therapy completion after prior documentation of complete response (CR, early relapse [ER]). A total of 478 patients were included in the analysis. Among these, 217 (45%) were PP, 86 (18%) were PR/SD, and 175 (37%) were ER. The 6-month and 1-year cumulative incidence of non-relapse mortality following auto-HCT was 0.9% and 1.1%, respectively. The median PFS and OS following auto-HCT were 4.33 years and 10.09 years, respectively. While those not in CR at the time of auto-HCT was associated with inferior PFS and OS, advanced age and those diagnosed before 2011 were associated with inferior OS. This study showcases the safety and long-term efficacy of auto-HCT, even in patients with high risk disease who are traditionally considered chemo-refractory and will serve as a benchmark for the ongoing transplant vs no transplant trials.
{"title":"Evaluation of prognostic factors for high-risk classical Hodgkin lymphoma undergoing autologous transplantation.","authors":"Narendranath Epperla, Ying Huang, Amanda F Cashen, John L Vaughn, Walter Hanel, Talha Badar, Stefan K Barta, Paolo F Caimi, Tarsheen K Sethi, Nishitha Reddy, Reem Karmali, Celeste Bello, Julio C Chavez, Shalin K Kothari, Francisco J Hernandez-Ilizaliturri, Jakub Svoboda, Frederick Lansigan, Martha J Glenn, Jonathon B Cohen, Caryn Sorge, Beth Christian, Alex F Herrera, Mehdi Hamadani, Luciano J Costa, Ana C Xavier","doi":"10.1182/bloodadvances.2024013743","DOIUrl":"https://doi.org/10.1182/bloodadvances.2024013743","url":null,"abstract":"<p><p>There are limited data assessing the risk scores for primary treatment failure (PTF) classical Hodgkin lymphoma (cHL, PTF-cHL) undergoing autologous hematopoietic cell transplantation (auto-HCT). ECLIPSE is a multicenter retrospective cohort of patients with PTF- cHL (15 years or older) diagnosed on or after Jan 1, 2005, at 15 US medical centers. PTF was defined as one of the following patterns of failure: [1] progressive disease by imaging during or within 6 weeks of completion of frontline chemotherapy (primary progression [PP]); [2] partial response (PR) or stable disease (SD) by imaging after completion of frontline treatment (PR/SD); [3] progression of disease by imaging (and confirmed by biopsy) within 12 months of frontline therapy completion after prior documentation of complete response (CR, early relapse [ER]). A total of 478 patients were included in the analysis. Among these, 217 (45%) were PP, 86 (18%) were PR/SD, and 175 (37%) were ER. The 6-month and 1-year cumulative incidence of non-relapse mortality following auto-HCT was 0.9% and 1.1%, respectively. The median PFS and OS following auto-HCT were 4.33 years and 10.09 years, respectively. While those not in CR at the time of auto-HCT was associated with inferior PFS and OS, advanced age and those diagnosed before 2011 were associated with inferior OS. This study showcases the safety and long-term efficacy of auto-HCT, even in patients with high risk disease who are traditionally considered chemo-refractory and will serve as a benchmark for the ongoing transplant vs no transplant trials.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-29DOI: 10.1182/bloodadvances.2024013670
Sophie Paczesny, Iztok Hozo, Benjamin Djulbegovic
{"title":"Biomarker-derived Fast-and-frugal decision tree for preemption of Veno-occlusive Disease/Sinusoidal obstructive syndrome.","authors":"Sophie Paczesny, Iztok Hozo, Benjamin Djulbegovic","doi":"10.1182/bloodadvances.2024013670","DOIUrl":"https://doi.org/10.1182/bloodadvances.2024013670","url":null,"abstract":"","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}