Blood advances最新文献

{"title":"Long-term safety and efficacy of fitusiran prophylaxis, and perioperative management, in people with hemophilia A or B.","authors":"Steven W Pipe, Toshko Lissitchkov, Pencho Georgiev, Sarah Mangles, Inga Hegemann, Alice Trinchero, Pratima Chowdary, Adam Forbes, Liqi Feng, Laurel A Menapace, Salim Kichou, Shauna Andersson, Marek Demissie, Margaret V Ragni","doi":"10.1182/bloodadvances.2024013900","DOIUrl":"10.1182/bloodadvances.2024013900","url":null,"abstract":"<p><strong>Abstract: </strong>Fitusiran is an investigational small interfering RNA therapeutic that targets antithrombin (AT) to rebalance hemostasis in people with hemophilia. Here, we present the results of a completed phase 2 open-label extension study, which evaluated the long-term safety and efficacy of fitusiran in participants with moderate or severe hemophilia A or B, with or without inhibitors. Male participants who had completed the phase 1 study (ClinicalTrials.gov identifier: NCT02035605) were enrolled. Participants received monthly subcutaneous fitusiran (50 or 80 mg) under the original dose regimen until a voluntary dosing pause in 2020, after which the AT-based dose regimen was introduced, targeting the recommended AT activity levels of 15% to 35%. Thirty-four participants (hemophilia A, n = 27; hemophilia B, n = 7) were enrolled in the phase 2 study and treated with fitusiran for a median exposure of 4.1 years. Adverse events reported on the original and the AT-based dose regimen were consistent with the identified risks of fitusiran. After implementation of the AT-based dose regimen, there were no thrombotic events, and a reduction in the incidence of elevated transaminases and biliary events was reported. The observed median annualized bleed rate (ABR) on the AT-based dose regimen (0.87) was comparable with the ABR under the original dose regimen (0.70). Furthermore, fitusiran prophylaxis was associated with improved health-related quality of life compared with baseline and provided successful hemostatic control during surgical procedures and invasive interventions. Overall, fitusiran was well tolerated, and effective bleeding control was maintained on an AT-based dose regimen. This trial was registered at www.clinicaltrials.gov as #NCT02554773.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":"1147-1158"},"PeriodicalIF":7.4,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11914172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142789613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of genomic biomarkers of disease progression and survival in primary CNS lymphoma.","authors":"Huimin Geng, Shirley Mo, Lingjing Chen, Aishwarya Ballapuram, Mazie Tsang, Ming Lu, Andreas M Rauschecker, Kwun Wah Wen, Walter Patrick Devine, David A Solomon, James L Rubenstein","doi":"10.1182/bloodadvances.2024014460","DOIUrl":"10.1182/bloodadvances.2024014460","url":null,"abstract":"<p><strong>Abstract: </strong>The determination of the genetic subtypes of primary central nervous system lymphoma (PCNSL) and their relationship to differential chemoimmunotherapeutic response has not been established. There is a particular need for genomic biomarkers that identify patients with newly diagnosed PCNSL at high risk of early progression and death. We applied targeted next-generation sequencing for detection of recurrent single-nucleotide variants, copy number alterations, and zygosity abnormalities in diagnostic specimens from 78 patients with PCNSL treated with a standard methotrexate-based regimen, to identify prognostically significant molecular subgroups. All patients received induction immunochemotherapy, and 44 proceeded to dose-intensive consolidation. Genomic aberrations at 4 loci were associated with 91% of lymphoma progression events and all 15 deaths: (1) chromosome 6p copy-neutral loss of heterozygosity (CN-LOH) or focal homozygous deletion (HD) at 6p21.3, and mutations of tumor suppressor genes (2) BTG1, (3) ETV6, and (4) TP53. Cox regression multivariate analysis demonstrated a high risk of progression in patients with aberrations at these loci. Genomic aberrations at these loci were also associated with significantly shorter survival. Lower expression of HLA-DR was associated with 6p CN-LOH/6p21.3 HD and inferior prognosis. These genomic aberrations identify a high-risk molecular subgroup that may inform risk stratification in PCNSL. Further elucidation of the mechanisms of therapeutic resistance associated with the high-risk genetic phenotype is requisite to facilitate precision medicine and progress in therapy.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":"1117-1131"},"PeriodicalIF":7.4,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11914178/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142614982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ubiquitous clot contraction blockers hit ubiquitin and more.","authors":"John W Weisel, Rustem I Litvinov","doi":"10.1182/bloodadvances.2024014973","DOIUrl":"10.1182/bloodadvances.2024014973","url":null,"abstract":"","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":"9 5","pages":"1092-1094"},"PeriodicalIF":7.4,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11938070/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lisocabtagene maraleucel for relapsed/refractory large B-cell lymphoma: a cell therapy consortium real-world analysis.","authors":"Peter A Riedell, Connor B Grady, Loretta J Nastoupil, Alejandro Luna, Nausheen Ahmed, Richard T Maziarz, Marie Hu, Jamie Brower, Wei-Ting Hwang, Stephen J Schuster, Andy I Chen, Olalekan O Oluwole, Veronika Bachanova, Joseph P McGurik, Miguel-Angel Perales, Michael R Bishop, David L Porter","doi":"10.1182/bloodadvances.2024014164","DOIUrl":"10.1182/bloodadvances.2024014164","url":null,"abstract":"<p><strong>Abstract: </strong>Lisocabtagene maraleucel (liso-cel) is an autologous CD19-directed chimeric antigen receptor T-cell therapy approved for the treatment of relapsed/refractory large B-cell lymphoma. We present a multicenter retrospective study evaluating safety, efficacy, and resource use of liso-cel in the standard-of-care setting. Patients received commercial liso-cel at 7 US medical centers, and patient selection, toxicity management, and disease assessment followed institutional practices. Among 101 patients who received infusion, the median age was 71 years (35% aged ≥75 years), 68% had a Charlson comorbidity index score of ≥3, and 10% had secondary central nervous system involvement. Median number of prior therapies was 3; and because of comorbidities, 33% would have been ineligible for the TRANSCEND study. Bridging therapy was used in 60% (43% received polatuzumab-based treatment). Any-grade cytokine-release syndrome occurred in 49% (3% grade ≥3) with any-grade immune effector cell-associated neurotoxicity syndrome occurring in 26% (10% grade ≥3). The overall response rate (ORR) to bridging therapy was 45%, with 18% achieving a complete response (CR). Following liso-cel infusion, the day 90 ORR was 66% (60% CR); and with a median follow-up of 15.5 months, 12-month progression-free survival (PFS) and overall survival (OS) were 55% and 68%, respectively. A normal lactate dehydrogenase level before lymphodepletion was associated with improved PFS and OS. These analyses confirm similar efficacy and safety of commercial liso-cel compared with pivotal trial results. Notably, these outcomes were achieved in patients predominantly of advanced age and with significant comorbidities. Results also likely reflect advancements in patient selection, toxicity management, and the use of novel bridging strategies.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":"1232-1241"},"PeriodicalIF":7.4,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827482","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}

{"title":"Genome-wide CRISPR/Cas9 screen identifies AraC-daunorubicin-etoposide response modulators associated with outcomes in pediatric AML.","authors":"Nam H K Nguyen, Roya Rafiee, Phani K Parcha, Abderrahmane Tagmount, Jeffrey Rubnitz, Raul Ribeiro, Xueyuan Cao, Stanley B Pounds, Christopher D Vulpe, Jatinder K Lamba","doi":"10.1182/bloodadvances.2024014157","DOIUrl":"10.1182/bloodadvances.2024014157","url":null,"abstract":"<p><strong>Abstract: </strong>Cytarabine, daunorubicin, and etoposide (ADE) have been the standard backbone of induction chemotherapy regimen for patients with pediatric acute myeloid leukemia (pAML) for >5 decades. However, chemoresistance is still a major concern, and a significant proportion of pAML becomes resistant to ADE treatment and relapse, leading to poor survival. Therefore, there is a considerable need to identify mechanisms mediating drug resistance for overcoming chemoresistance. Herein, we performed synthetic lethal CRISPR/Cas9 screens using the ADE components to identify response markers. We further integrated significant markers in 3 independent pAML clinical cohorts treated with only an ADE regimen to identify drug response biomarkers with prognostic significance. We were able to identify several mediators that represent clinically and biologically significant marker genes for ADE treatment, such as BCL2, CLIP2, and VAV3, which are resistant markers to ADE, with high expression associated with poor outcomes in pAML treated with ADE, and GRPEL1, HCFC1, and TAF10, which are sensitive markers to ADE, with high expression showing beneficial outcomes. Notably, BCL2, CLIP2, and VAV3 knockdowns in their expression in AML cell lines sensitized the cells more to the ADE components, suggesting that these modulators should be further studied as potential therapeutic targets to overcome chemoresistance.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":"1078-1091"},"PeriodicalIF":7.4,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11914169/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"α-Actinin-1 deficiency in megakaryocytes causes low platelet count, platelet dysfunction, and mitochondrial impairment.","authors":"Xiangjie Lin, Hanchen Gao, Min Xin, Jian Huang, Xia Li, Yutong Zhou, Keyu Lv, Xin Huang, Jinghan Wang, Yulan Zhou, Dawei Cui, Chao Fang, Lanlan Wu, Xiaofeng Shi, Zhixin Ma, Yu Qian, Hongyan Tong, Jing Dai, Jie Jin, Jiansong Huang","doi":"10.1182/bloodadvances.2024014805","DOIUrl":"10.1182/bloodadvances.2024014805","url":null,"abstract":"<p><strong>Abstract: </strong>Cytoskeletal remodeling and mitochondrial bioenergetics play important roles in thrombocytopoiesis and platelet function. Recently, α-actinin-1 mutations have been reported in patients with congenital macrothrombocytopenia. However, the role and underlying mechanism of α-actinin-1 in thrombocytopoiesis and platelet function remain elusive. Using megakaryocyte (MK)-specific α-actinin-1 knockout (KO; PF4-Actn1-/-) mice, we demonstrated that PF4-Actn1-/- mice exhibited reduced platelet counts. The decreased platelet number in PF4-Actn1-/- mice was due to defects in thrombocytopoiesis. Hematoxylin and eosin staining and flow cytometry revealed a decrease in the number of MKs in the bone marrow of PF4-Actn1-/- mice. The absence of α-actinin-1 increased the proportion of 2 N-4 N MKs and decreased the proportion of 8 N-32 N MKs. Colony-forming unit-MK colony formation, the ratio of proplatelet formation-bearing MKs, and MK migration in response to stromal cell-derived factor-1 signaling were inhibited in PF4-Actn1-/- mice. Platelet spreading, clot retraction, aggregation, integrin αIIbβ3 activation, and CD62P exposure in response to various agonists were decreased in PF4-Actn1-/- platelets. Notably, PF4-Actn1-/- platelets inhibited calcium mobilization, reactive oxygen species (ROS) generation, and actin polymerization in response to collagen and thrombin. Furthermore, the PF4-Actn1-/- mice exhibited impaired hemostasis and thrombosis. Mechanistically, proteomic analysis of low-ploidy (2-4 N) and high-ploidy (≥8 N) PF4-Actn1-/- MKs revealed that α-actinin-1 deletion reduced platelet activation and mitochondrial function. PF4-Actn1-/- platelets and Actn1 KO 293T cells exhibited reduced mitochondrial membrane potential, mitochondrial ROS generation, mitochondrial calcium mobilization, and mitochondrial bioenergetics. Overall, in this study, we report that mice with α-actinin-1 deficiency in MKs exhibit low platelet count and impaired platelet function, thrombosis, and mitochondrial bioenergetics.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":"1185-1201"},"PeriodicalIF":7.4,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11925533/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hematopoietic cell transplant compared with standard care in adolescents and young adults with sickle cell disease.","authors":"Mark C Walters, Mary Eapen, Yiwen Liu, Fuad El Rassi, Edmund K Waller, John E Levine, John J Strouse, Joseph H Antin, Suhag H Parikh, Nitya Bakshi, Carlton Dampier, Jennifer J Jaroscak, Shayla Bergmann, Trisha Wong, Vamsi Kota, Betty Pace, Lazaros J Lekakis, Premal Lulla, Robert S Nickel, Kimberly A Kasow, Uday Popat, Wally Smith, Lolie Yu, Nancy DiFronzo, Nancy Geller, Naynesh Kamani, Elizabeth S Klings, Kathryn Hassell, Adam Mendizabal, Keith Sullivan, Donna Neuberg, Lakshmanan Krishnamurti","doi":"10.1182/bloodadvances.2024013926","DOIUrl":"10.1182/bloodadvances.2024013926","url":null,"abstract":"<p><strong>Abstract: </strong>Disease-modifying therapies are standard of care (SOC) for sickle cell disease (SCD), but hematopoietic cell transplantation (HCT) has curative potential. We compared outcomes prospectively through 2 years after biologic assignment to a donor or no donor (SOC) arm based on the availability of an HLA-matched sibling or unrelated donor (BMT CTN 1503). A donor search was commenced after eligibility confirmation. The primary end point was a comparison of survival between the treatment arms 2 years after biologic assignment. Power calculations required 60 participants in the donor arm and 140 in the no donor arm to determine if early transplant-related mortality might be balanced by disease-related mortality over a longer period of follow-up. Secondary objectives were a comparison of the changes in SCD-related events, functional outcomes, and organ function. The data were analyzed according to the intent-to-treat principle. A total of 113 participants were enrolled with 28 in the donor arm and 85 in the no donor arm. The 2-year probabilities of survival were 89% and 93%, in the donor vs no donor arms. Vaso-occlusive pain (VOC) was less frequent in the donor arm in the second year after biologic assignment (P < .001). Based on PROMIS-57 surveys, there was a decrease in fatigue (P = .003) and an increase in the ability to participate in social roles and activities (P = .003) in the donor arm 2 years after biologic assignment. Differences in other secondary outcomes did not reach statistical significance. Barriers to accrual prevented an objective comparison of survival. Assignment to the donor arm led to improvements in VOC, fatigue, and social function. This trial was registered at www.clinicaltrials.gov as #NCT02766465.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":"955-965"},"PeriodicalIF":7.4,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11907447/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unbiased high-throughput screening of drug-repurposing libraries identifies small-molecule inhibitors of clot retraction.","authors":"Lorena Buitrago, Miriam-Rose Menezes, Chloe Larson, Jihong Li, Thomas Kartika, Priyam Banerjee, Fraser Glickman, Barry Coller","doi":"10.1182/bloodadvances.2024013810","DOIUrl":"10.1182/bloodadvances.2024013810","url":null,"abstract":"<p><strong>Abstract: </strong>Platelet clot retraction, the ultimate phase of platelet thrombus formation, is critical for clot stabilization. It requires functional αIIbβ3 receptors, fibrin, and the integrated actions of the actin-myosin contractile and cytoskeletal systems. Disturbances in clot retraction have been associated with both bleeding and thrombosis. We recently demonstrated that platelets treated with the αIIbβ3 antagonist peptide Arg-Gly-Asp-Trp, which eliminates fibrinogen-mediated platelet aggregation, are still able to retract clots. We have exploited this observation to develop an unbiased, functional high-throughput assay to identify small-molecule inhibitors of fibrin-mediated clot retraction adapted for a 384-well plate format. We tested 9710 compounds from drug-repurposing libraries (DRLs). These libraries contain compounds that are either US Food and Drug Administration approved or have undergone preclinical/clinical development. We identified 27 compounds from the Library of Pharmacologically Active Compounds library as inhibitors of clot retraction, of which 14 are known inhibitors of platelet function. From the DRLs, we identified 135 compounds (1.6% hit rate). After extensive curation, these compounds were categorized based on the activity of their reported target. Multiple kinase and phosphodiesterase inhibitors with known antiplatelet effects were identified, along with multiple deubiquitination and receptor inhibitors, as well as compounds that have not previously been reported to have antiplatelet activity. Studies of 1 of the deubiquitination inhibitors (degrasyn) suggest that its effects are downstream of thrombin-induced platelet-fibrinogen interactions and thus may permit the separation of platelet thrombin-induced aggregation-mediated events from clot retraction. Additional studies of the identified compounds may lead to novel mechanisms of inhibiting thrombosis.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":"1049-1068"},"PeriodicalIF":7.4,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11909436/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142388163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ibrutinib for therapy of steroid-refractory chronic graft-versus-host disease: a multicenter real-world analysis.","authors":"Joseph Pidala, Jongphil Kim, Denise Kalos, Corey Cutler, Zachariah DeFilipp, Mary E D Flowers, Betty K Hamilton, Kuo-Kai Chin, Marcello Rotta, Najla El Jurdi, Mehdi Hamadani, Gulrayz Ahmed, Carrie Kitko, Doris Ponce, Anthony Sung, Helen Tang, Nosha Farhadfar, Eneida Nemecek, Iskra Pusic, Muna Qayed, Hemalatha Rangarajan, William Hogan, Aaron Etra, Samantha Jaglowski","doi":"10.1182/bloodadvances.2024014374","DOIUrl":"10.1182/bloodadvances.2024014374","url":null,"abstract":"<p><strong>Abstract: </strong>To examine the activity of ibrutinib in steroid-refractory chronic graft-versus-host disease (SR-cGVHD) after the US Food and Drug Administration approval, we conducted a multicenter retrospective study. Data were standardly collected (N = 270 from 19 centers). Involved organs included skin (75%), eye (61%), mouth (54%), joint/fascia (47%), gastrointestinal (GI) (26%), lung (27%), liver (19%), genital (7%), and others (4.4%). The National Institutes of Health (NIH) severity was mild in 5.7%, moderate 42%, and severe 53%. Thirty-nine percent had overlap subtype. Karnofsky performance status (KPS) was ≥80% in 72%. The median prednisone was 0.21 mg/kg (0-2.27). Ibrutinib was started at a median of 18.2 months after cGVHD onset and in earlier lines of therapy (second line, 26%; third, 30%; fourth, 21%; fifth, 9.6%; sixth, 10%; seventh or higher, 1.2%). Among evaluable patients, the 6-month NIH overall response rate (ORR; complete response [CR]/partial response [PR]) was 45% (PR 42%; CR 3%). The median duration of response was 15 months (range, 1-46). Liver involvement had association with 6-month ORR (multivariate [MVA] odds ratio, 5.49; 95% confidence interval [CI], 2.3-14.2; P < .001). The best overall response was 56%, with most (86%) achieving by 1 to 3 months. With a median follow-up for survivors of 30.5 months, failure-free survival (FFS) was 59% (53%-65%) at 6 months and 41% (36%-48%) at 12 months. On MVA, increased age (hazard ratio [HR], 1.01; 95% CI, 1.0-1.02; P = .033), higher baseline prednisone (HR, 1.92; 95% CI, 1.09-3.38; P = .032), and lung involvement (HR, 1.58; 95% CI, 1.1-2.28; P = .016) had worse FFS. Ibrutinib discontinuation was most commonly due to progressive cGVHD (44%) or toxicity (42%). These data support that ibrutinib has activity in SR-cGVHD, provide new insight into factors associated with response and FFS, and demonstrate the toxicity profile associated with discontinuation.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":"1040-1048"},"PeriodicalIF":7.4,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11909441/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elotuzumab in combination with pomalidomide, bortezomib, and dexamethasone in relapsed and refractory multiple myeloma.","authors":"Andrew J Yee, Jacob P Laubach, Erica L Campagnaro, Brea C Lipe, Omar Nadeem, Robb S Friedman, Craig E Cole, Elizabeth K O'Donnell, Giada Bianchi, Andrew R Branagan, Robert L Schlossman, Samantha J Shapiro, Cynthia C Harrington, Jill N Burke, Marilyn T Gammon, Kathleen J Lively, Cassandra A Reimonn, Danielle X Andrade, Robert Redd, Jens G Lohr, Kenneth C Anderson, Paul G Richardson, Noopur S Raje","doi":"10.1182/bloodadvances.2024014717","DOIUrl":"10.1182/bloodadvances.2024014717","url":null,"abstract":"<p><strong>Abstract: </strong>Elotuzumab is a monoclonal antibody targeting signaling lymphocyte activation molecule F7 on plasma and natural killer cells, which enhances the activity of lenalidomide, pomalidomide, and bortezomib in multiple myeloma (MM). The OPTIMISMM study showed improved outcomes with the combination of pomalidomide, bortezomib, and dexamethasone (PVd) in relapsed/refractory MM. Therefore, we studied adding elotuzumab to PVd (elo-PVd) in relapsed/refractory MM in a multicenter phase 2 trial. The primary objective was to determine the overall response rate (ORR). Patients with relapsed/refractory disease and ≥1 prior line of treatment (including lenalidomide and a proteasome inhibitor) were eligible. For each 28-day cycle, elotuzumab was weekly for the first 2 cycles and then every other week; pomalidomide on days 1 to 21; bortezomib on days 1, 8, and 15; and dexamethasone weekly. The trial enrolled 48 patients with a median 3 prior lines (range, 1-9). Prior therapies included pomalidomide (33%), daratumumab (25%), and isatuximab (4%). The ORR was 56.3%, and the median progression-free survival (PFS) was 10 months. In patients with 1 prior line of therapy, ORR was 73.7%; median PFS was 23.4 months. Common grade ≥3 adverse events were neutropenia (33%); infections, any (33%); lung infection (27%); hypophosphatemia (19%); and thrombocytopenia (15%). Elo-PVd is, to our knowledge, one of the first trials of a quadruplet regimen in relapsed/refractory MM incorporating a monoclonal antibody to show efficacy across diverse prior treatments, including triple-class exposed patients with prior anti-CD38 monoclonal antibody. This trial was registered at ClinicalTrials.gov as #NCT02718833.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":"1163-1170"},"PeriodicalIF":7.4,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11925518/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}