Thijs C. J. Verheul, Nynke Gillemans, Kerstin Putzker, Rezin Majied, Tingyue Li, Memnia Vasiliou, Bert Eussen, Annelies de Klein, Wilfred F. J. van IJcken, Emile van den Akker, Marieke von Lindern, Joe Lewis, Ulrike Uhrig, Yukio Nakamura, Thamar van Dijk, Sjaak Philipsen
Reactivation of fetal hemoglobin expression alleviates the symptoms associated with β-globinopathies, severe hereditary diseases with significant global health implications due to their high morbidity and mortality rates. The symptoms emerge following the postnatal transition from fetal-to-adult hemoglobin expression. Extensive research has focused on inducing the expression of the fetal γ-globin subunit to reverse this switch and ameliorate these symptoms. Despite decades of research, only one compound, hydroxyurea, found its way to the clinic as an inducer of fetal hemoglobin. Unfortunately, its efficacy varies among patients, highlighting the need for more effective treatments. Erythroid cell lines have been instrumental in the pursuit of both pharmacological and genetic ways to reverse the postnatal hemoglobin switch. Here, we describe the first endogenously tagged fetal hemoglobin reporter cell line based on the adult erythroid progenitor cell line HUDEP2. Utilizing CRISPR-Cas9-mediated knock-in, a bioluminescent tag was integrated at the HBG1 gene. Subsequent extensive characterization confirmed that the resulting reporter cell line closely mirrors the HUDEP2 characteristics and that the cells report fetal hemoglobin induction with high sensitivity and specificity. This novel reporter cell line is therefore highly suitable for evaluating genetic and pharmacologic strategies to induce fetal hemoglobin. Furthermore, it provides an assay compatible with high-throughput drug screening, exemplified by the identification of a cluster of known fetal hemoglobin inducers in a pilot study. This new tool is made available to the research community, with the aspiration that it will accelerate the search for safer and more effective strategies to reverse the hemoglobin switch.
{"title":"A cellular reporter system to evaluate endogenous fetal hemoglobin induction and screen for therapeutic compounds","authors":"Thijs C. J. Verheul, Nynke Gillemans, Kerstin Putzker, Rezin Majied, Tingyue Li, Memnia Vasiliou, Bert Eussen, Annelies de Klein, Wilfred F. J. van IJcken, Emile van den Akker, Marieke von Lindern, Joe Lewis, Ulrike Uhrig, Yukio Nakamura, Thamar van Dijk, Sjaak Philipsen","doi":"10.1002/hem3.139","DOIUrl":"10.1002/hem3.139","url":null,"abstract":"<p>Reactivation of fetal hemoglobin expression alleviates the symptoms associated with β-globinopathies, severe hereditary diseases with significant global health implications due to their high morbidity and mortality rates. The symptoms emerge following the postnatal transition from fetal-to-adult hemoglobin expression. Extensive research has focused on inducing the expression of the fetal γ-globin subunit to reverse this switch and ameliorate these symptoms. Despite decades of research, only one compound, hydroxyurea, found its way to the clinic as an inducer of fetal hemoglobin. Unfortunately, its efficacy varies among patients, highlighting the need for more effective treatments. Erythroid cell lines have been instrumental in the pursuit of both pharmacological and genetic ways to reverse the postnatal hemoglobin switch. Here, we describe the first endogenously tagged fetal hemoglobin reporter cell line based on the adult erythroid progenitor cell line HUDEP2. Utilizing CRISPR-Cas9-mediated knock-in, a bioluminescent tag was integrated at the <i>HBG1</i> gene. Subsequent extensive characterization confirmed that the resulting reporter cell line closely mirrors the HUDEP2 characteristics and that the cells report fetal hemoglobin induction with high sensitivity and specificity. This novel reporter cell line is therefore highly suitable for evaluating genetic and pharmacologic strategies to induce fetal hemoglobin. Furthermore, it provides an assay compatible with high-throughput drug screening, exemplified by the identification of a cluster of known fetal hemoglobin inducers in a pilot study. This new tool is made available to the research community, with the aspiration that it will accelerate the search for safer and more effective strategies to reverse the hemoglobin switch.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 8","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11302795/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141897316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Andrew D. Zelenetz, Wojciech Jurczak, Vincent Ribrag, Kim Linton, Graham P. Collins, Javier L. Jiménez, Mark Bishton, Bhagirathbhai Dholaria, Andrea Mengarelli, Tycel J. Phillips, Nagendraprasad Sungala, Gerardo Musuraca, Oonagh Sheehy, Eric Van Den Neste, Mitsuhiko Odera, Lu Miao, Daniel P. Gold, Richard G. Ghalie, Pier L. Zinzani
In this global phase 2 study in patients with relapsed/refractory follicular lymphoma (FL), zandelisib was administered on intermittent dosing to mitigate immune-related adverse events and infections that have been reported with oral PI3Kδ inhibitors administered daily continuously. Eligible patients with measurable disease and progression after at least two prior therapies were administered zandelisib until disease progression or intolerability. The primary efficacy endpoint was objective response rate (ORR) and the key secondary efficacy endpoint was duration of response (DOR). We report on 121 patients with FL administered zandelisib on intermittent dosing after 8 weeks of daily dosing for tumor debulking. The median number of prior therapies was 3 (range, 2–8) and 45% of patients had refractory disease. The ORR was 73% (95% confidence interval [CI], 63.9–80.4), the complete response (CR) rate was 38% (95% CI, 29.3–47.3), and the median DOR was 16.4 months (95% CI, 9.5–not reached). With a median follow-up of 14.3 months (range, 1–30.5), the median progression-free survival was 11.6 months (95% CI, 8.3–not reached). Twenty-one patients (17%) discontinued therapy due to an adverse event. Grade 3–4 class-related toxicities included 6% diarrhea, 5% lung infections, 3% colitis (confirmed by biopsy or imaging), 3% rash, 2% AST elevation, and 1% non-infectious pneumonitis. Zandelisib achieved a high rate of durable responses in heavily pretreated patients with relapsed/refractory FL. The intermittent dosing resulted in a relatively low incidence of severe class-related toxicities, which supports the evaluation of zandelisib as a single agent and in combination with indolent B-cell malignancies.
{"title":"The PI3Kδ inhibitor zandelisib on intermittent dosing in relapsed/refractory follicular lymphoma: Results from a global phase 2 study","authors":"Andrew D. Zelenetz, Wojciech Jurczak, Vincent Ribrag, Kim Linton, Graham P. Collins, Javier L. Jiménez, Mark Bishton, Bhagirathbhai Dholaria, Andrea Mengarelli, Tycel J. Phillips, Nagendraprasad Sungala, Gerardo Musuraca, Oonagh Sheehy, Eric Van Den Neste, Mitsuhiko Odera, Lu Miao, Daniel P. Gold, Richard G. Ghalie, Pier L. Zinzani","doi":"10.1002/hem3.138","DOIUrl":"10.1002/hem3.138","url":null,"abstract":"<p>In this global phase 2 study in patients with relapsed/refractory follicular lymphoma (FL), zandelisib was administered on intermittent dosing to mitigate immune-related adverse events and infections that have been reported with oral PI3Kδ inhibitors administered daily continuously. Eligible patients with measurable disease and progression after at least two prior therapies were administered zandelisib until disease progression or intolerability. The primary efficacy endpoint was objective response rate (ORR) and the key secondary efficacy endpoint was duration of response (DOR). We report on 121 patients with FL administered zandelisib on intermittent dosing after 8 weeks of daily dosing for tumor debulking. The median number of prior therapies was 3 (range, 2–8) and 45% of patients had refractory disease. The ORR was 73% (95% confidence interval [CI], 63.9–80.4), the complete response (CR) rate was 38% (95% CI, 29.3–47.3), and the median DOR was 16.4 months (95% CI, 9.5–not reached). With a median follow-up of 14.3 months (range, 1–30.5), the median progression-free survival was 11.6 months (95% CI, 8.3–not reached). Twenty-one patients (17%) discontinued therapy due to an adverse event. Grade 3–4 class-related toxicities included 6% diarrhea, 5% lung infections, 3% colitis (confirmed by biopsy or imaging), 3% rash, 2% AST elevation, and 1% non-infectious pneumonitis. Zandelisib achieved a high rate of durable responses in heavily pretreated patients with relapsed/refractory FL. The intermittent dosing resulted in a relatively low incidence of severe class-related toxicities, which supports the evaluation of zandelisib as a single agent and in combination with indolent B-cell malignancies.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 8","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11302793/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141897317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>Delayed hemolytic transfusion reaction (DHTR) is a severe and potentially fatal complication triggered by red blood cells (RBC) transfusions<span><sup>1</sup></span> in patients with sickle cell disease (SCD). Transfusions remain a major therapeutic intervention in the clinical management of anemia as well as both acute and chronic disease-related complications in SCD.<span><sup>1-3</sup></span> Typically, DHTR occurs days to weeks after a RBC transfusion due to the sudden destruction of both transfused and patients' RBCs, with a consequent drastic drop in hemoglobin (Hb), seriously threatening the life of SCD patients.<span><sup>4, 5</sup></span> During DHTR with hyperhemolysis, the release of free Hb and heme has deleterious impact on the vasculature, causing vasculo-toxicity and leading to vasculopathy due to intravascular oxidative stress, endothelial damage, increased expression of proadhesive, proinflammatory and chemotactic factors and reduced nitric oxide (NO) bioavailability. Upon RBC exposure, one or more alloantibodies are produced in SCD patients, which contribute to DHTR. In one-third of RBC transfused patients, complement activation—rather than alloantibodies production—plays a role in DHTR, both through the canonic pathway, whereby complement fixed antibody binds to RBCs, and the alternative pathway, whereby free heme-induced TLR4 signaling on endothelial cells activates the complement system.<span><sup>1</sup></span> Patients experience symptoms such as fever, pain, fatigue, mild jaundice or dark urine and a drastic Hb drop. The current treatment options for DHTRs are based on supportive care, erythropoiesis optimization, immunomodulatory treatments, including complement inhibition, steroids, intravenous immunoglobulin, and/or B cell depletion, and future transfusion avoidance, even if the latest may be not always feasible in some clinical conditions related to cardiac or respiratory failure.<span><sup>1, 3</sup></span></p><p>Among the therapeutic strategies proposed to overcome DHTR, carbon monoxide administration in the form of inhalation or carbon-monoxide-releasing molecules (CO-RMs) has shown promising results in preclinical studies.<span><sup>6</sup></span> A plethora of CORMs has been generated, structurally designed with a central transition metal such as iron, manganese, or cobalt, surrounded by CO as a ligand.<span><sup>6</sup></span> CO is a stable molecule that is continuously produced after the catabolism of heme by heme-oxygenases (HO), a family of enzymes with established anti-inflammatory and cytoprotective functions. Mechanistically, CO decreases the expression of proinflammatory and increases the expression of anti-inflammatory cytokines by activating the MKK3/p38β MAPK pathway and inducing PPARγ. In addition, it reduces TLR4 activation by inhibiting TLR4 trafficking, and its interaction with caveolin-1 at the plasma membrane. CO also serves as a bioactive signaling molecule acting as intracellular mediator in
{"title":"Improving CORM technology for the treatment of delayed hemolytic transfusion reaction","authors":"Michela Asperti, Francesca Vinchi","doi":"10.1002/hem3.140","DOIUrl":"10.1002/hem3.140","url":null,"abstract":"<p>Delayed hemolytic transfusion reaction (DHTR) is a severe and potentially fatal complication triggered by red blood cells (RBC) transfusions<span><sup>1</sup></span> in patients with sickle cell disease (SCD). Transfusions remain a major therapeutic intervention in the clinical management of anemia as well as both acute and chronic disease-related complications in SCD.<span><sup>1-3</sup></span> Typically, DHTR occurs days to weeks after a RBC transfusion due to the sudden destruction of both transfused and patients' RBCs, with a consequent drastic drop in hemoglobin (Hb), seriously threatening the life of SCD patients.<span><sup>4, 5</sup></span> During DHTR with hyperhemolysis, the release of free Hb and heme has deleterious impact on the vasculature, causing vasculo-toxicity and leading to vasculopathy due to intravascular oxidative stress, endothelial damage, increased expression of proadhesive, proinflammatory and chemotactic factors and reduced nitric oxide (NO) bioavailability. Upon RBC exposure, one or more alloantibodies are produced in SCD patients, which contribute to DHTR. In one-third of RBC transfused patients, complement activation—rather than alloantibodies production—plays a role in DHTR, both through the canonic pathway, whereby complement fixed antibody binds to RBCs, and the alternative pathway, whereby free heme-induced TLR4 signaling on endothelial cells activates the complement system.<span><sup>1</sup></span> Patients experience symptoms such as fever, pain, fatigue, mild jaundice or dark urine and a drastic Hb drop. The current treatment options for DHTRs are based on supportive care, erythropoiesis optimization, immunomodulatory treatments, including complement inhibition, steroids, intravenous immunoglobulin, and/or B cell depletion, and future transfusion avoidance, even if the latest may be not always feasible in some clinical conditions related to cardiac or respiratory failure.<span><sup>1, 3</sup></span></p><p>Among the therapeutic strategies proposed to overcome DHTR, carbon monoxide administration in the form of inhalation or carbon-monoxide-releasing molecules (CO-RMs) has shown promising results in preclinical studies.<span><sup>6</sup></span> A plethora of CORMs has been generated, structurally designed with a central transition metal such as iron, manganese, or cobalt, surrounded by CO as a ligand.<span><sup>6</sup></span> CO is a stable molecule that is continuously produced after the catabolism of heme by heme-oxygenases (HO), a family of enzymes with established anti-inflammatory and cytoprotective functions. Mechanistically, CO decreases the expression of proinflammatory and increases the expression of anti-inflammatory cytokines by activating the MKK3/p38β MAPK pathway and inducing PPARγ. In addition, it reduces TLR4 activation by inhibiting TLR4 trafficking, and its interaction with caveolin-1 at the plasma membrane. CO also serves as a bioactive signaling molecule acting as intracellular mediator in","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 8","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11299068/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ana Luísa Pereira, Serena Galli, César Nombela-Arrieta
Hematopoietic stem cells (HSCs) are the cornerstone of the hematopoietic system. HSCs sustain the continuous generation of mature blood derivatives while self-renewing to preserve a relatively constant pool of progenitors throughout life. Yet, long-term maintenance of functional HSCs exclusively takes place in association with their native tissue microenvironment of the bone marrow (BM). HSCs have been long proposed to reside in fixed and identifiable anatomical units found in the complex BM tissue landscape, which control their identity and fate in a deterministic manner. In the last decades, tremendous progress has been made in the dissection of the cellular and molecular fabric of the BM, the structural organization governing tissue function, and the plethora of interactions established by HSCs. Nonetheless, a holistic model of the mechanisms controlling HSC regulation in their niche is lacking to date. Here, we provide an overview of our current understanding of BM anatomy, HSC localization, and crosstalk within local cellular neighborhoods in murine and human tissues, and highlight fundamental open questions on how HSCs functionally integrate in the BM microenvironment.
{"title":"Bone marrow niches for hematopoietic stem cells","authors":"Ana Luísa Pereira, Serena Galli, César Nombela-Arrieta","doi":"10.1002/hem3.133","DOIUrl":"10.1002/hem3.133","url":null,"abstract":"<p>Hematopoietic stem cells (HSCs) are the cornerstone of the hematopoietic system. HSCs sustain the continuous generation of mature blood derivatives while self-renewing to preserve a relatively constant pool of progenitors throughout life. Yet, long-term maintenance of functional HSCs exclusively takes place in association with their native tissue microenvironment of the bone marrow (BM). HSCs have been long proposed to reside in fixed and identifiable anatomical units found in the complex BM tissue landscape, which control their identity and fate in a deterministic manner. In the last decades, tremendous progress has been made in the dissection of the cellular and molecular fabric of the BM, the structural organization governing tissue function, and the plethora of interactions established by HSCs. Nonetheless, a holistic model of the mechanisms controlling HSC regulation in their niche is lacking to date. Here, we provide an overview of our current understanding of BM anatomy, HSC localization, and crosstalk within local cellular neighborhoods in murine and human tissues, and highlight fundamental open questions on how HSCs functionally integrate in the BM microenvironment.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 8","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11289431/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141859567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Anna M. Aalbers, Paul L. A. van Daele, Virgil A. S. H. Dalm, Peter J. M. Valk, Marc H. G. P. Raaijmakers
<p>VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is an inflammatory syndrome caused by acquired mutations in the gene encoding ubiquitin like modifier activating enzyme 1 (<i>UBA1</i>) that is often fatal.<span><sup>1, 2</sup></span> Allogeneic hematopoietic stem cell transplantation is currently considered the only curative treatment modality.<span><sup>3-6</sup></span> We were the first to report eradication of virtually all <i>UBA1</i>-mutated cells by the hypomethylating agent azacitidine, reflected in clinical and genetic remissions,<span><sup>7</sup></span> a finding confirmed in a recent phase II clinical trial.<span><sup>8</sup></span></p><p>Here, we report persistent, long-term (11–84 months) genetic and clinical remissions in VEXAS patients responding to treatment with the hypomethylating agent azacitidine, after cessation of therapy. The data indicate that azacitidine treatment may be an attractive alternative to stem cell transplant for disease eradication in VEXAS syndrome patients and reveal long-term clonal stability of <i>UBA1</i>-mutated cells under homeostatic and inflammatory conditions.</p><p>Since its first description in December 2020,<span><sup>1</sup></span> a <i>UBA1</i> variant-confirmed diagnosis of VEXAS syndrome was made in 11 patients at our institution until February 2024 (all male, median age at diagnosis 67 years, range 57–77 years). <i>UBA1</i> mutation detection and panel-based sequencing in these patients was performed as previously reported<span><sup>7</sup></span> and as described in the Supporting Information Methods section. Of these 11 patients, eight have been exposed to azacitidine (administered at a dose of 75 mg/m<sup>2</sup> subcutaneously once daily for 7 days in a 4-weekly schedule). Of the three patients that were not exposed to azacitidine, two patients were treated with corticosteroids and deceased due to infectious complications, and one patient was considered not a candidate for azacitidine treatment due to psychosocial circumstances. In two patients, azacitidine was used as a last resort on an in-house basis, after failure of multiple other lines of treatment, at the time that patients were critically ill (WHO performance status 4) due to VEXAS-related (respiratory) pathology. Both patients died shortly after administration of the first cycle of azacitidine with clinically active disease, and before genetic assessment of response after the first cycle. Six patients received multiple cycles of azacitidine (range, 3–8 cycles) on an out-patient basis with genetic monitoring of disease response. The characteristics of these six patients are listed in Table 1. Patients 1 and 2 carried a concurrent <i>DNMT3A</i> mutation at diagnosis with a variant allele frequency (VAF) of 59% and 30%, respectively, and patient 3 carried a <i>TET2</i> mutation with a VAF of 4%. In patients 4, 5, and 6 no other mutations were detected by panel-based sequencing. Three of these six patients have bee
{"title":"Long-term genetic and clinical remissions after cessation of azacitidine treatment in patients with VEXAS syndrome","authors":"Anna M. Aalbers, Paul L. A. van Daele, Virgil A. S. H. Dalm, Peter J. M. Valk, Marc H. G. P. Raaijmakers","doi":"10.1002/hem3.129","DOIUrl":"10.1002/hem3.129","url":null,"abstract":"<p>VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is an inflammatory syndrome caused by acquired mutations in the gene encoding ubiquitin like modifier activating enzyme 1 (<i>UBA1</i>) that is often fatal.<span><sup>1, 2</sup></span> Allogeneic hematopoietic stem cell transplantation is currently considered the only curative treatment modality.<span><sup>3-6</sup></span> We were the first to report eradication of virtually all <i>UBA1</i>-mutated cells by the hypomethylating agent azacitidine, reflected in clinical and genetic remissions,<span><sup>7</sup></span> a finding confirmed in a recent phase II clinical trial.<span><sup>8</sup></span></p><p>Here, we report persistent, long-term (11–84 months) genetic and clinical remissions in VEXAS patients responding to treatment with the hypomethylating agent azacitidine, after cessation of therapy. The data indicate that azacitidine treatment may be an attractive alternative to stem cell transplant for disease eradication in VEXAS syndrome patients and reveal long-term clonal stability of <i>UBA1</i>-mutated cells under homeostatic and inflammatory conditions.</p><p>Since its first description in December 2020,<span><sup>1</sup></span> a <i>UBA1</i> variant-confirmed diagnosis of VEXAS syndrome was made in 11 patients at our institution until February 2024 (all male, median age at diagnosis 67 years, range 57–77 years). <i>UBA1</i> mutation detection and panel-based sequencing in these patients was performed as previously reported<span><sup>7</sup></span> and as described in the Supporting Information Methods section. Of these 11 patients, eight have been exposed to azacitidine (administered at a dose of 75 mg/m<sup>2</sup> subcutaneously once daily for 7 days in a 4-weekly schedule). Of the three patients that were not exposed to azacitidine, two patients were treated with corticosteroids and deceased due to infectious complications, and one patient was considered not a candidate for azacitidine treatment due to psychosocial circumstances. In two patients, azacitidine was used as a last resort on an in-house basis, after failure of multiple other lines of treatment, at the time that patients were critically ill (WHO performance status 4) due to VEXAS-related (respiratory) pathology. Both patients died shortly after administration of the first cycle of azacitidine with clinically active disease, and before genetic assessment of response after the first cycle. Six patients received multiple cycles of azacitidine (range, 3–8 cycles) on an out-patient basis with genetic monitoring of disease response. The characteristics of these six patients are listed in Table 1. Patients 1 and 2 carried a concurrent <i>DNMT3A</i> mutation at diagnosis with a variant allele frequency (VAF) of 59% and 30%, respectively, and patient 3 carried a <i>TET2</i> mutation with a VAF of 4%. In patients 4, 5, and 6 no other mutations were detected by panel-based sequencing. Three of these six patients have bee","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 8","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11287193/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>The survival rates for pediatric patients with primary refractory or high-risk relapsed B-cell acute lymphoblastic leukemia (r/r B-ALL), treated with chemotherapy-based protocols and followed by allogeneic hematopoietic cell transplantation (HCT), range from 15% to 30%.<span><sup>1</sup></span> These outcomes are even more unfavorable in countries with evolving healthcare insurance systems due to treatment-related mortality and financial toxicity.<span><sup>2</sup></span> The long-term event-free survival for such high-risk relapse of B-ALL is dependent on achieving minimal residual disease (MRD) negativity prior to HCT.<span><sup>3</sup></span></p><p>In the past decade, there have been significant advancements in targeted antibody-based immunotherapies for managing r/r B-ALL.<span><sup>4-11</sup></span> Blinatumomab (Blina) is a T-cell engager that provides an antileukemic effect by targeting cytotoxic T cells to CD19-expressing cancer cells. Several studies have revealed the excellent efficacy of Blina in low-burden disease.<span><sup>4-8</sup></span> However, recipients of Blina with high tumor burden have low response rates and are at risk of severe cytokine release syndrome (CRS).<span><sup>9</sup></span> Whereas, Inotuzumab ozogamicin (InO) targets CD22, which is conjugated to calicheamicin, a potent cytotoxic agent and works well even for high-burden disease with response rates as high as 80%.<span><sup>10, 11</sup></span></p><p>To optimize the use of these novel immunotherapies in r/r B-cell ALL, we designed a disease-burden-adapted protocol of InO followed by Blina for high-burden (minimal residual disease (MRD) > 5%) CD22+ CD19+ disease and Blina only for low-burden (MRD ≤ 5%) CD19+ disease.</p><p>This is a retrospective analysis of 39 patients with r/r B-cell ALL patients aged 1–18 years treated in three centers from January 2018 to August 2023. Patients were treated with a chemotherapy-based protocol from January 2018 to April 2021 and on a disease-burden-adapted immunotherapy protocol from May 2021 to August 2023.</p><p>End-of-induction (EOI) MRD of >5% with high-risk cytogenetics or age >16 years and all patients with end-of-consolidation (EOC) MRD > 0.1% irrespective of age or cytogenetics were considered primary refractory. Very early relapse (<18 months from diagnosis; marrow or isolated extramedullary), early relapse (18–36 months from diagnosis or until 6 months off therapy; marrow or isolated extramedullary), and late relapse (≥36 months from diagnosis or >6 months off therapy; marrow or isolated extramedullary) with postrelapse induction MRD of ≥0.1% and second relapse with any level of disease were considered as high-risk.</p><p>A fractionated dose of InO as 1.8 mg/m<sup>2</sup> per course was administered intravenously over 1 h on Days 1, 8, and 15 of 28-day cycle as previously described.<span><sup>10, 11</sup></span> Blina was given as a 28-day continuous intravenous infusion. The first 7 days of the f
{"title":"Disease-burden-adapted immunotherapy protocol for primary refractory or high-risk relapsed pediatric acute lymphoblastic leukemia","authors":"Sanaa Khan, Krishnan VP, Yamini Krishnan, Gazel Sainulabdin, Somdipa Pal, Rincy Mathews, Darshan Kataria, Kunal Sehgal, Purva Kanvinde, Lashkari Harshaprasad, Minnie Bodhanwala, Bharat Agarwal, Ambreen Pandrowala, Prashant Hiwarkar","doi":"10.1002/hem3.111","DOIUrl":"10.1002/hem3.111","url":null,"abstract":"<p>The survival rates for pediatric patients with primary refractory or high-risk relapsed B-cell acute lymphoblastic leukemia (r/r B-ALL), treated with chemotherapy-based protocols and followed by allogeneic hematopoietic cell transplantation (HCT), range from 15% to 30%.<span><sup>1</sup></span> These outcomes are even more unfavorable in countries with evolving healthcare insurance systems due to treatment-related mortality and financial toxicity.<span><sup>2</sup></span> The long-term event-free survival for such high-risk relapse of B-ALL is dependent on achieving minimal residual disease (MRD) negativity prior to HCT.<span><sup>3</sup></span></p><p>In the past decade, there have been significant advancements in targeted antibody-based immunotherapies for managing r/r B-ALL.<span><sup>4-11</sup></span> Blinatumomab (Blina) is a T-cell engager that provides an antileukemic effect by targeting cytotoxic T cells to CD19-expressing cancer cells. Several studies have revealed the excellent efficacy of Blina in low-burden disease.<span><sup>4-8</sup></span> However, recipients of Blina with high tumor burden have low response rates and are at risk of severe cytokine release syndrome (CRS).<span><sup>9</sup></span> Whereas, Inotuzumab ozogamicin (InO) targets CD22, which is conjugated to calicheamicin, a potent cytotoxic agent and works well even for high-burden disease with response rates as high as 80%.<span><sup>10, 11</sup></span></p><p>To optimize the use of these novel immunotherapies in r/r B-cell ALL, we designed a disease-burden-adapted protocol of InO followed by Blina for high-burden (minimal residual disease (MRD) > 5%) CD22+ CD19+ disease and Blina only for low-burden (MRD ≤ 5%) CD19+ disease.</p><p>This is a retrospective analysis of 39 patients with r/r B-cell ALL patients aged 1–18 years treated in three centers from January 2018 to August 2023. Patients were treated with a chemotherapy-based protocol from January 2018 to April 2021 and on a disease-burden-adapted immunotherapy protocol from May 2021 to August 2023.</p><p>End-of-induction (EOI) MRD of >5% with high-risk cytogenetics or age >16 years and all patients with end-of-consolidation (EOC) MRD > 0.1% irrespective of age or cytogenetics were considered primary refractory. Very early relapse (<18 months from diagnosis; marrow or isolated extramedullary), early relapse (18–36 months from diagnosis or until 6 months off therapy; marrow or isolated extramedullary), and late relapse (≥36 months from diagnosis or >6 months off therapy; marrow or isolated extramedullary) with postrelapse induction MRD of ≥0.1% and second relapse with any level of disease were considered as high-risk.</p><p>A fractionated dose of InO as 1.8 mg/m<sup>2</sup> per course was administered intravenously over 1 h on Days 1, 8, and 15 of 28-day cycle as previously described.<span><sup>10, 11</sup></span> Blina was given as a 28-day continuous intravenous infusion. The first 7 days of the f","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 8","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11284769/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Axel André, Lydia Montes, Damien Roos-Weil, Laurent Frenzel, Marguerite Vignon, Thomas Chalopin, Pierre-Edouard Debureaux, Alexis Talbot, Agathe Farge, Fabrice Jardin, Karim Belhadj, Bruno Royer, Jean-Pierre Marolleau, Bertrand Arnulf, Pierre Morel, Stéphanie Harel
A second autologous stem-cell transplantation (ASCT2) is considered for relapsed multiple myeloma (RMM) patients showing prolonged response after a first ASCT. However, given breakthrough treatments like anti-CD38 and immunotherapy, its role remains debated. We conducted a real-life study in 10 French centers (1996–2017) involving 267 RMM patients receiving ASCT2. The median age was 61 years, with 49% females. Most patients received melphalan 200 mg/m² before ASCT2, with low early mortality (1%). Very good partial response or better (VGPR+) rate post ASCT2 was 78%. Post ASCT2, 48% received consolidation therapy and 40% maintenance therapy. Median event-free survival (EFS) after ASCT2 was 2.6 years (95% confidence interval [CI]: 2.3–2.8), and 2-year EFS estimate was 63% (95% CI: 57–70). Median overall survival (OS) was 8.1 years (95% CI: 5.9–NA), and 2-year OS estimate was 92% (95% CI: 88–95). Multivariate analysis revealed that VGPR+ status and maintenance therapy post ASCT2 were associated with better EFS (hazard ratio [HR]: 0.6; 95% CI: 0.3–0.9, p = 0.012 and HR: 0.4; 95% CI: 0.3–0.6, p < 0.001, respectively) and OS (HR: 0.4; 95% CI: 0.2–0.9, p = 0.017 and HR: 0.2; 95% CI: 0.1–0.4, p < 0.001, respectively), while male sex correlated with poorer outcomes for EFS (HR: 2.5; 95% CI: 1.7–3.7, p < 0.001) and OS (HR: 2.7; 95% CI: 1.4–4.9, p = 0.002). Overall, ASCT2 appeared efficient with low toxicity in RMM. Maintenance therapy was associated with extended EFS and OS, particularly in patients with VGPR+ status post ASCT2. These findings underscore ASCT2's potential in RMM when coupled with maintenance therapy in selected patients.
{"title":"Impact of second autologous stem-cell transplantation at relapsed multiple myeloma: A French multicentric real-life study","authors":"Axel André, Lydia Montes, Damien Roos-Weil, Laurent Frenzel, Marguerite Vignon, Thomas Chalopin, Pierre-Edouard Debureaux, Alexis Talbot, Agathe Farge, Fabrice Jardin, Karim Belhadj, Bruno Royer, Jean-Pierre Marolleau, Bertrand Arnulf, Pierre Morel, Stéphanie Harel","doi":"10.1002/hem3.106","DOIUrl":"10.1002/hem3.106","url":null,"abstract":"<p>A second autologous stem-cell transplantation (ASCT2) is considered for relapsed multiple myeloma (RMM) patients showing prolonged response after a first ASCT. However, given breakthrough treatments like anti-CD38 and immunotherapy, its role remains debated. We conducted a real-life study in 10 French centers (1996–2017) involving 267 RMM patients receiving ASCT2. The median age was 61 years, with 49% females. Most patients received melphalan 200 mg/m² before ASCT2, with low early mortality (1%). Very good partial response or better (VGPR+) rate post ASCT2 was 78%. Post ASCT2, 48% received consolidation therapy and 40% maintenance therapy. Median event-free survival (EFS) after ASCT2 was 2.6 years (95% confidence interval [CI]: 2.3–2.8), and 2-year EFS estimate was 63% (95% CI: 57–70). Median overall survival (OS) was 8.1 years (95% CI: 5.9–NA), and 2-year OS estimate was 92% (95% CI: 88–95). Multivariate analysis revealed that VGPR+ status and maintenance therapy post ASCT2 were associated with better EFS (hazard ratio [HR]: 0.6; 95% CI: 0.3–0.9, <i>p</i> = 0.012 and HR: 0.4; 95% CI: 0.3–0.6, <i>p</i> < 0.001, respectively) and OS (HR: 0.4; 95% CI: 0.2–0.9, <i>p</i> = 0.017 and HR: 0.2; 95% CI: 0.1–0.4, <i>p</i> < 0.001, respectively), while male sex correlated with poorer outcomes for EFS (HR: 2.5; 95% CI: 1.7–3.7, <i>p</i> < 0.001) and OS (HR: 2.7; 95% CI: 1.4–4.9, <i>p</i> = 0.002). Overall, ASCT2 appeared efficient with low toxicity in RMM. Maintenance therapy was associated with extended EFS and OS, particularly in patients with VGPR+ status post ASCT2. These findings underscore ASCT2's potential in RMM when coupled with maintenance therapy in selected patients.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 8","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285034/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Christos Varelas, Efthymia Vlachaki, Philippos Klonizakis, Despoina Pantelidou, Fani Minti, Michael Diamantidis, Nikolaos Sabanis, Evdoxia Koravou, Ioanna Christodoulou, Despina Papadopoulou, Stamatia Theodoridou, Tasoula Touloumenidou, Apostolia Papalexandri, Ioanna Sakellari, Sofia Vakalopoulou, Vasilis Perifanis, George Vassilopoulos, Ioannis Mitroulis, Eleni Gavriilaki
<p>Sickle cell disease (SCD) results from mutations in the β-globin gene, producing abnormal hemoglobin S (HbS) and leading to complications causing significant morbidity and mortality.<span><sup>1</sup></span> One of the hallmark consequences of SCD is the occurrence of vaso-occlusive crises (VOCs), which arise from the interplay of factors in the disease's pathophysiology, involving abnormal hemoglobin polymerization, inflammation, endothelial dysfunction, and activation of the immune system, culminating in the painful obstruction of blood vessels by sickled red blood cells, that tend to obstruct blood vessels, leading to reduced blood flow and oxygen supply. This vicious cycle of ischemia followed by reperfusion constitutes the ischemia-reperfusion model.<span><sup>2</sup></span></p><p>The complement system, a complex defense mechanism, is implicated in various diseases through unregulated activation.<span><sup>3</sup></span> However, diagnostic challenges hinder patient selection for complement inhibition.<span><sup>4</sup></span> Preliminary data from our group using novel assays indicate complement activation even at a steady state in a limited patient population.<span><sup>5</sup></span></p><p>Limited information exists on additional markers in the complement activation and endothelial dysfunction cycle in SCD. Neutrophil extracellular traps (NETs), indicative of thromboinflammation, are elevated in SCD patients, even during steady state.<span><sup>6</sup></span> ADAMTS13 (A Disintegrin and Metalloproteinase with Thrombospondin motifs), studied for its role in SCD vasculopathy, shows conflicting results as a potential biomarker.<span><sup>7, 8</sup></span> Genetic variants and autoantibodies leading to unregulated complement activation are implicated in the pathogenesis of various human diseases.<span><sup>9</sup></span></p><p>Despite the lack of specific biomarkers or targeted treatments for crises, our hypothesis posits the presence of complement activation and thromboinflammation in SCD, particularly during complications, with distinct yet unexplored clinical or genetic features in these patients.</p><p>Our study's methods regarding patient population, observation period, functional assays, and genetic, bioinformatic, and statistical analysis are demonstrated in supplementary materials. Our study included 81 adult SCD patients who are treated in different Hemoglobinopathies Units across Northern Greece. Their median age was 41 years, and 50 were female (61.7%). As expected in our population, the majority had the S/beta genotype (62), while 19 patients had the S/S genotype. Twenty-three presented SCD complications during the observation period (17 vaso-occlusive crises and six proteinuria/nephropathy) and were studied during this complication. Importantly, none of the patients that presented with renal damage, was on deferasirox, or other iron chelation therapy. The remaining 58 patients were studied at the end of the observation period.
{"title":"Prospective study of complement activation and thromboinflammation within sickle cell disease and its complications","authors":"Christos Varelas, Efthymia Vlachaki, Philippos Klonizakis, Despoina Pantelidou, Fani Minti, Michael Diamantidis, Nikolaos Sabanis, Evdoxia Koravou, Ioanna Christodoulou, Despina Papadopoulou, Stamatia Theodoridou, Tasoula Touloumenidou, Apostolia Papalexandri, Ioanna Sakellari, Sofia Vakalopoulou, Vasilis Perifanis, George Vassilopoulos, Ioannis Mitroulis, Eleni Gavriilaki","doi":"10.1002/hem3.135","DOIUrl":"10.1002/hem3.135","url":null,"abstract":"<p>Sickle cell disease (SCD) results from mutations in the β-globin gene, producing abnormal hemoglobin S (HbS) and leading to complications causing significant morbidity and mortality.<span><sup>1</sup></span> One of the hallmark consequences of SCD is the occurrence of vaso-occlusive crises (VOCs), which arise from the interplay of factors in the disease's pathophysiology, involving abnormal hemoglobin polymerization, inflammation, endothelial dysfunction, and activation of the immune system, culminating in the painful obstruction of blood vessels by sickled red blood cells, that tend to obstruct blood vessels, leading to reduced blood flow and oxygen supply. This vicious cycle of ischemia followed by reperfusion constitutes the ischemia-reperfusion model.<span><sup>2</sup></span></p><p>The complement system, a complex defense mechanism, is implicated in various diseases through unregulated activation.<span><sup>3</sup></span> However, diagnostic challenges hinder patient selection for complement inhibition.<span><sup>4</sup></span> Preliminary data from our group using novel assays indicate complement activation even at a steady state in a limited patient population.<span><sup>5</sup></span></p><p>Limited information exists on additional markers in the complement activation and endothelial dysfunction cycle in SCD. Neutrophil extracellular traps (NETs), indicative of thromboinflammation, are elevated in SCD patients, even during steady state.<span><sup>6</sup></span> ADAMTS13 (A Disintegrin and Metalloproteinase with Thrombospondin motifs), studied for its role in SCD vasculopathy, shows conflicting results as a potential biomarker.<span><sup>7, 8</sup></span> Genetic variants and autoantibodies leading to unregulated complement activation are implicated in the pathogenesis of various human diseases.<span><sup>9</sup></span></p><p>Despite the lack of specific biomarkers or targeted treatments for crises, our hypothesis posits the presence of complement activation and thromboinflammation in SCD, particularly during complications, with distinct yet unexplored clinical or genetic features in these patients.</p><p>Our study's methods regarding patient population, observation period, functional assays, and genetic, bioinformatic, and statistical analysis are demonstrated in supplementary materials. Our study included 81 adult SCD patients who are treated in different Hemoglobinopathies Units across Northern Greece. Their median age was 41 years, and 50 were female (61.7%). As expected in our population, the majority had the S/beta genotype (62), while 19 patients had the S/S genotype. Twenty-three presented SCD complications during the observation period (17 vaso-occlusive crises and six proteinuria/nephropathy) and were studied during this complication. Importantly, none of the patients that presented with renal damage, was on deferasirox, or other iron chelation therapy. The remaining 58 patients were studied at the end of the observation period.","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 7","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11270009/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141758402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) are two BCMA-directed CAR T-cells approved for the treatment of relapsed or refractory multiple myeloma. Similar to CD19-directed CAR T-cells, acute adverse events may occur after BCMA-directed CAR T-cells, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). However, a new type of neurotoxicity has been recently reported in patients treated with BCMA-directed CAR T-cells, the so-called movement and neurocognitive toxicity (MNT). Common features include late onset of Parkinson-like symptoms such as tremor, bradykinesia, and neurocognitive disorder. Only 10 cases of MNT occurring after BCMA-directed CAR T-cells have been reported so far (Table 1). The symptoms appeared with a median time of 36 days (range, 14–914 days). Interestingly, all cases occurred in male patients and after cilta-cel except for one patient who had been treated with ide-cel.<span><sup>4</sup></span> MNT has been associated with high expansion and persistence of circulating CAR T-cells, cerebrospinal fluid infiltration by CAR T-cells, and no clear response to levodopa. Autopsy report from a patient who died shortly after presenting with MNT showed a T-cell infiltrate in the periventricular region of the basal ganglia as well as BCMA expression in the basal ganglia, suggesting an on-target off-tumor toxicity.<span><sup>1</sup></span> BCMA expression was also found on basal ganglia cells of healthy subjects.<span><sup>1</sup></span> Potential risk factors of MNT include high tumor burden at baseline before the start of lymphodepletion, grade ≥2 CRS, occurrence of ICANS, high CAR T-cell expansion, and prolonged persistence.<span><sup>1</sup></span> Management of this new and rare toxicity remains poorly defined. Corticosteroids, systemic chemotherapy, anakinra, intrathecal injections of cytarabine and steroids, IV Ig, and plasmaspharesis have been tested without clear benefit. Most patients experience mild or no improvement of their symptoms. In some patients, symptoms worsen and may lead to death.</p><p>Here, we report the case of two female patients who developed parkinsonism after ide-cel infusion.</p><p>Patient 1 is a 74-year-old woman who had been diagnosed with monoclonal gammopathy of unknown significance in 2003, which progressed to multiple myeloma in 2009. Before undergoing CAR T-cell therapy, she had received 11 prior lines of therapy including chemotherapy, IMIDs, proteasome inhibitors, daratumumab, and lastly talquetamab, a CD3/GPRC5D bispecific antibody. She was offered CAR T-cell therapy after developing lytic bone lesions while being treated with talquetamab. She received bridging therapy with Selinexor, which allowed partial metabolic response. After ide-cel infusion, she developed grade 1 CRS on Day 2 and no ICANS. She did not require treatment with tocilizumab nor dexamethasone. She was discharged on Day 10 postinfusion.</p><p>I
{"title":"Parkinson-like neurotoxicity in female patients treated with idecabtagene-vicleucel","authors":"Audrey Couturier, Martine Escoffre, Frédérique Leh, Anne-Sophie Villoteau, Xavier Palard, Florence Le Jeune, Olivier Decaux, Thierry Lamy, Roch Houot","doi":"10.1002/hem3.131","DOIUrl":"10.1002/hem3.131","url":null,"abstract":"<p>Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) are two BCMA-directed CAR T-cells approved for the treatment of relapsed or refractory multiple myeloma. Similar to CD19-directed CAR T-cells, acute adverse events may occur after BCMA-directed CAR T-cells, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). However, a new type of neurotoxicity has been recently reported in patients treated with BCMA-directed CAR T-cells, the so-called movement and neurocognitive toxicity (MNT). Common features include late onset of Parkinson-like symptoms such as tremor, bradykinesia, and neurocognitive disorder. Only 10 cases of MNT occurring after BCMA-directed CAR T-cells have been reported so far (Table 1). The symptoms appeared with a median time of 36 days (range, 14–914 days). Interestingly, all cases occurred in male patients and after cilta-cel except for one patient who had been treated with ide-cel.<span><sup>4</sup></span> MNT has been associated with high expansion and persistence of circulating CAR T-cells, cerebrospinal fluid infiltration by CAR T-cells, and no clear response to levodopa. Autopsy report from a patient who died shortly after presenting with MNT showed a T-cell infiltrate in the periventricular region of the basal ganglia as well as BCMA expression in the basal ganglia, suggesting an on-target off-tumor toxicity.<span><sup>1</sup></span> BCMA expression was also found on basal ganglia cells of healthy subjects.<span><sup>1</sup></span> Potential risk factors of MNT include high tumor burden at baseline before the start of lymphodepletion, grade ≥2 CRS, occurrence of ICANS, high CAR T-cell expansion, and prolonged persistence.<span><sup>1</sup></span> Management of this new and rare toxicity remains poorly defined. Corticosteroids, systemic chemotherapy, anakinra, intrathecal injections of cytarabine and steroids, IV Ig, and plasmaspharesis have been tested without clear benefit. Most patients experience mild or no improvement of their symptoms. In some patients, symptoms worsen and may lead to death.</p><p>Here, we report the case of two female patients who developed parkinsonism after ide-cel infusion.</p><p>Patient 1 is a 74-year-old woman who had been diagnosed with monoclonal gammopathy of unknown significance in 2003, which progressed to multiple myeloma in 2009. Before undergoing CAR T-cell therapy, she had received 11 prior lines of therapy including chemotherapy, IMIDs, proteasome inhibitors, daratumumab, and lastly talquetamab, a CD3/GPRC5D bispecific antibody. She was offered CAR T-cell therapy after developing lytic bone lesions while being treated with talquetamab. She received bridging therapy with Selinexor, which allowed partial metabolic response. After ide-cel infusion, she developed grade 1 CRS on Day 2 and no ICANS. She did not require treatment with tocilizumab nor dexamethasone. She was discharged on Day 10 postinfusion.</p><p>I","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 7","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11270580/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141763973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Charlotte L. B. M. Korst, Kaz Groen, Patricia W. C. Bosman, Fleur van der Valk, Christie P. M. Verkleij, Sandy Kruyswijk, Maaike E. M. de Ruijter, Dianne M. Heijink, Maria T. Kuipers, Sonja Zweegman, Niels W. C. J. van de Donk
<p>Teclistamab, a T-cell redirecting bispecific antibody (BsAb) targeting B-cell maturation antigen (BCMA), has marked activity in heavily pretreated multiple myeloma (MM) patients (overall response rate: 63.0%; at least very good partial response [≥VGPR]: 59.4%; median progression-free survival [PFS]: 11.3 months).<span><sup>1, 2</sup></span> Teclistamab treatment induces T-cell activation and production of proinflammatory cytokines such as interleukin-6 (IL-6).<span><sup>3</sup></span> This increase in cytokines frequently results in a systemic inflammatory response syndrome (cytokine-release syndrome [CRS]), characterized by fever, and in more severe cases also hypotension and hypoxia.<span><sup>1, 2, 4, 5</sup></span> CRS mitigation strategies include step-up dosing and premedication with steroids and antihistamines. The incidence of CRS in teclistamab-treated patients was 72.1% (grade 2: 21.2%; grade ≥3: 0.6%) with most CRS events occurring during step-up dosing.<span><sup>1, 2, 4</sup></span> Recurrent CRS occurred in 33.3% of the patients.<span><sup>4</sup></span> Patients are generally hospitalized for the administration of the step-up doses and first full dose to adequately monitor for early signs and symptoms of CRS (median hospital stay in a real-world setting: 10 days).<span><sup>1, 6</sup></span> Treatment of CRS with steroids or the IL-6 receptor-blocking antibody tocilizumab is effective with rapid resolution of symptoms.<span><sup>3, 4</sup></span> Patients who received tocilizumab for their first CRS event were less likely to experience a subsequent CRS event compared to those who did not receive tocilizumab (20.0% vs. 62.2%).<span><sup>4</sup></span> A single dose of tocilizumab blocks the IL-6 receptor for approximately 10 days and covers the full step-up dosing period.<span><sup>7</sup></span> Based on these data, we aimed to evaluate the efficacy of tocilizumab administered prior to the first step-up dose to prevent the development of CRS following the initiation of teclistamab therapy in 29 patients treated in our hospital.</p><p>Teclistamab was administered according to the approved schedule with two step-up doses (0.06 and 0.3 mg/kg) followed by the full dose of 1.5 mg/kg every week (48–72 h between step-up doses and the first full dose). In patients undergoing hemodialysis, teclistamab was given directly after hemodialysis sessions. Prophylactic tocilizumab (8 mg/kg intravenously [IV]; maximum dose of 800 mg) was administered 1 h prior to the first step-up dose. Patients also received 16 mg dexamethasone, 2 mg clemastine, and 1000 mg acetaminophen 1 h prior to both step-up doses and the first full dose. All patients received herpes zoster (valacyclovir) and <i>Pneumocystis jirovecii</i> pneumonia prophylaxis (co-trimoxazole, or pentamidine in case of co-trimoxazole allergy). Granulocyte colony-stimulating factor was considered in cases of grade ≥3 neutropenia, and IgG replacement was given in cases with polyclonal IgG <
此外，预防性托珠单抗有可能减少类固醇在CRS治疗中的使用，而类固醇与开始BsAb治疗后较高的感染性并发症风险有关15。我们的数据还支持进一步评估预防性托珠单抗，以实现门诊患者安全使用替卡单抗，这有可能减少医疗资源的使用并改善患者的生活质量。此外，这项分析的样本量太小，无法就预测托珠单抗预防后 CRS 的疾病或患者相关因素得出明确结论。然而，我们的结果和另一项研究12 的结果表明，尽管使用了托珠单抗预防治疗，但循环浆细胞的高频率可能与≥2 级 CRS 相关。需要对更多患者进行新的研究，以评估哪些基线特征可预测接受托西珠单抗预防治疗的患者的 CRS。此外，在 MajesTEC-1 的关键队列中，有一部分患者没有发生 CRS，4 这表明，在预防性使用托珠单抗的策略中，我们也让原本不需要使用托珠单抗的患者接触到了托珠单抗。遗憾的是，目前还无法可靠地确定哪些患者会发生 CRS。4 总之，在加大剂量 1 之前使用预防性托珠单抗明显降低了 CRS 的发生频率，而且不影响疗效。虽然递增剂量通常在住院环境中进行，但我们也证明了预防性使用托西珠单抗的低CRS率可能会提高门诊特克司他单抗递增剂量的安全性和可行性，同时降低入院治疗CRS的风险。Charlotte L. B. M. Korst、Kaz Groen、Patricia W. C. Bosman、Fleur van der Valk、Christie P. M. Verkleij、Sandy Kruyswijk、Maaike E. M. de Ruijter、Dianne M. Heijink、Maria T. Kuipers、Sonja Zweegman和Niels W. C. J. van de Donk招募患者、提供数据并解释数据。Charlotte L. B. M. Korst 和 Niels W. C. J. van de Donk 设计并进行了统计分析。Niels W. C. J. van de Donk 起草了手稿的第一版，所有作者均可获得研究中报告的所有数据，并修改和批准了手稿的最终版本。Sonja Zweegman 曾获得 Celgene、武田和杨森的研究资助，并在杨森、武田、BMS、Oncopeptides 和赛诺菲的顾问委员会任职，所有报酬均由该机构支付。Niels W. C. J. van de Donk 获得了杨森制药、AMGEN、Celgene、诺华、Cellectis 和 BMS 的研究资助，并在杨森制药、AMGEN、Celgene、BMS、武田、默克、罗氏、诺华、拜耳、Adaptive、辉瑞、艾伯维和赛维耶的顾问委员会任职，所有这些机构均向其支付报酬。其余作者声明没有利益冲突。泰克司他单抗同情使用计划和MajesTEC-1研究得到了杨森制药公司的支持。
{"title":"Prophylactic tocilizumab reduces the incidence of cytokine release syndrome in relapsed/refractory myeloma patients treated with teclistamab: Implications for outpatient step-up dosing","authors":"Charlotte L. B. M. Korst, Kaz Groen, Patricia W. C. Bosman, Fleur van der Valk, Christie P. M. Verkleij, Sandy Kruyswijk, Maaike E. M. de Ruijter, Dianne M. Heijink, Maria T. Kuipers, Sonja Zweegman, Niels W. C. J. van de Donk","doi":"10.1002/hem3.132","DOIUrl":"10.1002/hem3.132","url":null,"abstract":"<p>Teclistamab, a T-cell redirecting bispecific antibody (BsAb) targeting B-cell maturation antigen (BCMA), has marked activity in heavily pretreated multiple myeloma (MM) patients (overall response rate: 63.0%; at least very good partial response [≥VGPR]: 59.4%; median progression-free survival [PFS]: 11.3 months).<span><sup>1, 2</sup></span> Teclistamab treatment induces T-cell activation and production of proinflammatory cytokines such as interleukin-6 (IL-6).<span><sup>3</sup></span> This increase in cytokines frequently results in a systemic inflammatory response syndrome (cytokine-release syndrome [CRS]), characterized by fever, and in more severe cases also hypotension and hypoxia.<span><sup>1, 2, 4, 5</sup></span> CRS mitigation strategies include step-up dosing and premedication with steroids and antihistamines. The incidence of CRS in teclistamab-treated patients was 72.1% (grade 2: 21.2%; grade ≥3: 0.6%) with most CRS events occurring during step-up dosing.<span><sup>1, 2, 4</sup></span> Recurrent CRS occurred in 33.3% of the patients.<span><sup>4</sup></span> Patients are generally hospitalized for the administration of the step-up doses and first full dose to adequately monitor for early signs and symptoms of CRS (median hospital stay in a real-world setting: 10 days).<span><sup>1, 6</sup></span> Treatment of CRS with steroids or the IL-6 receptor-blocking antibody tocilizumab is effective with rapid resolution of symptoms.<span><sup>3, 4</sup></span> Patients who received tocilizumab for their first CRS event were less likely to experience a subsequent CRS event compared to those who did not receive tocilizumab (20.0% vs. 62.2%).<span><sup>4</sup></span> A single dose of tocilizumab blocks the IL-6 receptor for approximately 10 days and covers the full step-up dosing period.<span><sup>7</sup></span> Based on these data, we aimed to evaluate the efficacy of tocilizumab administered prior to the first step-up dose to prevent the development of CRS following the initiation of teclistamab therapy in 29 patients treated in our hospital.</p><p>Teclistamab was administered according to the approved schedule with two step-up doses (0.06 and 0.3 mg/kg) followed by the full dose of 1.5 mg/kg every week (48–72 h between step-up doses and the first full dose). In patients undergoing hemodialysis, teclistamab was given directly after hemodialysis sessions. Prophylactic tocilizumab (8 mg/kg intravenously [IV]; maximum dose of 800 mg) was administered 1 h prior to the first step-up dose. Patients also received 16 mg dexamethasone, 2 mg clemastine, and 1000 mg acetaminophen 1 h prior to both step-up doses and the first full dose. All patients received herpes zoster (valacyclovir) and <i>Pneumocystis jirovecii</i> pneumonia prophylaxis (co-trimoxazole, or pentamidine in case of co-trimoxazole allergy). Granulocyte colony-stimulating factor was considered in cases of grade ≥3 neutropenia, and IgG replacement was given in cases with polyclonal IgG <","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 7","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11266829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141758401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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