Ann-Kristin Schmälter, Myriam Labopin, Jurjen Versluis, Maria Pilar Gallego Hernanz, Matthias Eder, Peter von dem Borne, Gerard Socié, Patrice Chevallier, Edouard Forcade, Andreas Neubauer, Frédéric Baron, Ali Bazarbachi, Gesine Bug, Arnon Nagler, Christoph Schmid, Jordi Esteve, Mohamad Mohty, Fabio Ciceri
Acute myeloid leukemia (AML) with translocation t(8;16)(p11;p13) represents a rare entity that has been categorized as a disease-defining recurring cytogenetic abnormality with adverse risk in the 2022 European LeukemiaNet classification. This rating was mainly based on a retrospective analysis comprising patients from several large clinical trials, which, however, included only 21 patients treated with allogeneic stem cell transplantation (alloSCT). Therefore, the European Society for Blood and Marrow Transplantation performed a registry study on a larger cohort to evaluate the role of alloSCT in t(8;16) AML. Sixty transplant recipients with t(8;16) AML were identified. Two-year overall and leukemia-free survival (OS/LFS) was 43/39%. Patients transplanted in first complete remission (CR1, n = 44) achieved a 2-year OS/LFS of 48%/48%. Following alloSCT in CR1, the multivariable analysis identified a complex karyotype (CK) as a major risk factor for relapse (HR 4.17, p = .016), lower LFS (HR 3.38, p = .01), and lower OS (HR 3.08, p = .017). Two-year OS/LFS of patients with CK was 19%/19%, in contrast to 67%/67% in patients with t(8;16) outside a CK. Other factors for inferior outcomes were older age and secondary AML. In summary, alloSCT could mitigate the adverse risk of patients with t(8;16) AML not harboring a CK, particularly when performed in CR1.
急性髓性白血病（AML）t(8;16)(p11;p13)易位是一种罕见的疾病，在2022年欧洲白血病网络（European LeukemiaNet）的分类中被归类为具有不良风险的疾病定义复发性细胞遗传学异常。这一分类主要基于对几项大型临床试验患者的回顾性分析，但其中仅包括21名接受异基因干细胞移植（alloSCT）治疗的患者。因此，欧洲血液与骨髓移植学会（European Society for Blood and Marrow Transplantation）对更大规模的人群进行了登记研究，以评估异体干细胞移植在t(8;16)急性髓细胞性白血病中的作用。这项研究确定了 60 例 t(8;16) AML 移植受者。两年总生存率和无白血病生存率（OS/LFS）分别为43%和39%。首次完全缓解（CR1，n = 44）的移植患者的两年OS/LFS为48%/48%。CR1患者接受异体移植后，多变量分析发现复杂核型（CK）是导致复发（HR 4.17，p = .016）、较低LFS（HR 3.38，p = .01）和较低OS（HR 3.08，p = .017）的主要风险因素。CK患者的两年OS/LFS分别为19%/19%，而CK以外的t（8;16）患者的两年OS/LFS分别为67%/67%。导致不良预后的其他因素包括年龄偏大和继发性急性髓细胞性白血病。总之，allSCT可以减轻t(8;16)急性髓细胞性白血病患者不携带CK的不利风险，尤其是在CR1期进行allSCT时。
{"title":"The role of allogeneic stem cell transplantation in acute myeloid leukemia with translocation t(8;16)(p11;p13).","authors":"Ann-Kristin Schmälter, Myriam Labopin, Jurjen Versluis, Maria Pilar Gallego Hernanz, Matthias Eder, Peter von dem Borne, Gerard Socié, Patrice Chevallier, Edouard Forcade, Andreas Neubauer, Frédéric Baron, Ali Bazarbachi, Gesine Bug, Arnon Nagler, Christoph Schmid, Jordi Esteve, Mohamad Mohty, Fabio Ciceri","doi":"10.1002/ajh.27496","DOIUrl":"10.1002/ajh.27496","url":null,"abstract":"<p><p>Acute myeloid leukemia (AML) with translocation t(8;16)(p11;p13) represents a rare entity that has been categorized as a disease-defining recurring cytogenetic abnormality with adverse risk in the 2022 European LeukemiaNet classification. This rating was mainly based on a retrospective analysis comprising patients from several large clinical trials, which, however, included only 21 patients treated with allogeneic stem cell transplantation (alloSCT). Therefore, the European Society for Blood and Marrow Transplantation performed a registry study on a larger cohort to evaluate the role of alloSCT in t(8;16) AML. Sixty transplant recipients with t(8;16) AML were identified. Two-year overall and leukemia-free survival (OS/LFS) was 43/39%. Patients transplanted in first complete remission (CR1, n = 44) achieved a 2-year OS/LFS of 48%/48%. Following alloSCT in CR1, the multivariable analysis identified a complex karyotype (CK) as a major risk factor for relapse (HR 4.17, p = .016), lower LFS (HR 3.38, p = .01), and lower OS (HR 3.08, p = .017). Two-year OS/LFS of patients with CK was 19%/19%, in contrast to 67%/67% in patients with t(8;16) outside a CK. Other factors for inferior outcomes were older age and secondary AML. In summary, alloSCT could mitigate the adverse risk of patients with t(8;16) AML not harboring a CK, particularly when performed in CR1.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666907","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}
Christian Récher, Pierre-Yves Dumas, Emilie Bérard, Suzanne Tavitian, Thibaut Leguay, Jean Galtier, Camille Alric, Audrey Bidet, Eric Delabesse, Jean Baptiste Rieu, Jean-Philippe Vial, François Vergez, Isabelle Luquet, Emilie Klein, Anne-Charlotte de Grande, Audrey Sarry, Sven Zukunft, Uwe Platzbecker, Carsten Müller-Tidow, Claudia D Baldus, Martin Bornhäuser, Hubert Serve, Sarah Bertoli, Arnaud Pigneux, Christoph Röllig
According to current recommendations, older AML patients in first complete remission (CR) after induction chemotherapy should receive consolidation with intermediate-dose cytarabine (IDAC). However, no study has demonstrated the superiority of IDAC over other regimen. In this retrospective study, we compared the efficacy of mini-consolidations (idarubicin 8 mg/m2 day 1, cytarabine 50 mg/m2/12 h, day 1-5) and IDAC. Inclusion criteria were newly diagnosed AML, age > 60 years, first CR after induction and at least 1 cycle of consolidation. Of the 796 included patients, 322 patients received mini-consolidations and 474 patients received IDAC. Mini-consolidation patients were older, and more often, they had de novo AML and unfavorable risk. The rate of allogeneic transplantation was higher in the IDAC group. The median number of cycles was higher in the mini-consolidation group (4 vs. 2; p < .0001). Median relapse-free survival was 18 months with mini-consolidations and 12 months with IDAC (p = .0064). In multivariate analysis, the risk of relapse or death was significantly higher in the IDAC group (p = .004). Median OS was 36 versus 31 months with mini-consolidations or IDAC, respectively (p = .46). In multivariate analysis, the consolidation regimen had no significant influence on OS (p = .43). In older AML patients, post-remission therapy with mini-consolidations represents an alternative to IDAC.
根据目前的建议，诱导化疗后首次完全缓解（CR）的老年急性髓细胞白血病患者应接受中剂量阿糖胞苷（IDAC）巩固治疗。然而，还没有研究证明IDAC优于其他方案。在这项回顾性研究中，我们比较了迷你巩固疗法（伊达比星 8 毫克/平方米，第 1 天；阿糖胞苷 50 毫克/平方米/12 小时，第 1-5 天）和 IDAC 的疗效。纳入标准为新诊断的急性髓细胞性白血病，年龄大于 60 岁，诱导后首次 CR，至少巩固治疗一个周期。在纳入的796名患者中，322名患者接受了迷你巩固治疗，474名患者接受了IDAC治疗。接受迷你巩固治疗的患者年龄较大，且多为新发急性髓细胞性白血病患者，风险较低。IDAC组的异基因移植率更高。迷你合并组的周期中位数更高（4 vs. 2; p
{"title":"Mini-consolidations or intermediate-dose cytarabine for the post-remission therapy of AML patients over 60. A retrospective study from the DATAML and SAL registries.","authors":"Christian Récher, Pierre-Yves Dumas, Emilie Bérard, Suzanne Tavitian, Thibaut Leguay, Jean Galtier, Camille Alric, Audrey Bidet, Eric Delabesse, Jean Baptiste Rieu, Jean-Philippe Vial, François Vergez, Isabelle Luquet, Emilie Klein, Anne-Charlotte de Grande, Audrey Sarry, Sven Zukunft, Uwe Platzbecker, Carsten Müller-Tidow, Claudia D Baldus, Martin Bornhäuser, Hubert Serve, Sarah Bertoli, Arnaud Pigneux, Christoph Röllig","doi":"10.1002/ajh.27510","DOIUrl":"10.1002/ajh.27510","url":null,"abstract":"<p><p>According to current recommendations, older AML patients in first complete remission (CR) after induction chemotherapy should receive consolidation with intermediate-dose cytarabine (IDAC). However, no study has demonstrated the superiority of IDAC over other regimen. In this retrospective study, we compared the efficacy of mini-consolidations (idarubicin 8 mg/m<sup>2</sup> day 1, cytarabine 50 mg/m<sup>2</sup>/12 h, day 1-5) and IDAC. Inclusion criteria were newly diagnosed AML, age > 60 years, first CR after induction and at least 1 cycle of consolidation. Of the 796 included patients, 322 patients received mini-consolidations and 474 patients received IDAC. Mini-consolidation patients were older, and more often, they had de novo AML and unfavorable risk. The rate of allogeneic transplantation was higher in the IDAC group. The median number of cycles was higher in the mini-consolidation group (4 vs. 2; p < .0001). Median relapse-free survival was 18 months with mini-consolidations and 12 months with IDAC (p = .0064). In multivariate analysis, the risk of relapse or death was significantly higher in the IDAC group (p = .004). Median OS was 36 versus 31 months with mini-consolidations or IDAC, respectively (p = .46). In multivariate analysis, the consolidation regimen had no significant influence on OS (p = .43). In older AML patients, post-remission therapy with mini-consolidations represents an alternative to IDAC.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142646763","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}
Kristin Rathje, Nico Gagelmann, Anita Badbaran, Claudia Langebrake, Adrin Dadkhah, Johanna Richter, Radwan Massoud, Mathias Schäfersküpper, Franziska E. Marquard, Sofia Oechsler, Evgeny Klyuchnikov, Ina Rudolph, Silke Heidenreich, Christian Niederwieser, Catherina Lueck, Dietlinde Janson, Christine Wolschke, Boris Fehse, Francis Ayuk, Nicolaus Kröger
Despite the introduction of JAK inhibitors, allogeneic hematopoietic cell transplant remains the only potentially curative treatment for patients with myelofibrosis but has considerable treatment-related complications. Whether the incorporation of JAK inhibition into the transplant algorithm leads to improved outcomes is still unclear. Here, we analyzed different transplant platforms in myelofibrosis patients undergoing a first transplant, comparing immune profiles and outcomes of (1) 33 patients continuing JAK inhibition at start of conditioning until stable engraftment (PERI-group), (2) 38 patients receiving JAK inhibition prior to transplant until start of conditioning (PRE-group), and (3) 38 patients that had never received JAK inhibition (NON-group). Patients in the PERI-group showed significantly higher early B-cell recovery as well as significantly increased late recovery of gamma-delta T cells and NK cells. We observed excellent neutrophil and platelet engraftment (100% for both) in the PERI-group and no hematotoxic effects or increased rates of infections following peri-transplant JAK inhibition. Cumulative incidence of acute graft-versus-host disease (GvHD) grade II-IV at day 100 after transplant was 15% in the PERI-group versus 29% in the PRE-group versus 34% in the NON-group. Cumulative incidence of relapse at 1 year after transplant was 9% in the PERI-group compared with 16% in the PRE-group and 18% in the NON-group. In conclusion, peri-transplant JAK inhibition was feasible with promising engraftment and acute GvHD rates, though deserves further investigation.
尽管引入了JAK抑制剂，异基因造血细胞移植仍是骨髓纤维化患者唯一可能治愈的治疗方法，但治疗相关并发症也相当多。将JAK抑制剂纳入移植算法是否会改善治疗效果，目前仍不清楚。在此，我们对首次接受移植的骨髓纤维化患者的不同移植平台进行了分析，比较了（1）33 例患者在调理开始时继续使用 JAK 抑制剂直至稳定移植（PERI 组）；（2）38 例患者在移植前接受 JAK 抑制剂直至调理开始（PRE 组）；（3）38 例患者从未使用过 JAK 抑制剂（NON 组）的免疫概况和预后。PERI 组患者的早期 B 细胞恢复能力明显提高，后期γ-δ T 细胞和 NK 细胞恢复能力也明显提高。我们观察到，PERI 组患者的中性粒细胞和血小板移植效果极佳（均为 100%），而且在移植前抑制 JAK 后没有出现血液毒性反应或感染率升高。移植后第 100 天，急性移植物抗宿主病（GvHD）II-IV 级的累积发生率在 PERI 组为 15%，在 PRE 组为 29%，在 NON 组为 34%。移植后 1 年，PERI 组的累积复发率为 9%，而 PRE 组为 16%，NON 组为 18%。总之，移植前抑制 JAK 是可行的，其移植率和急性 GvHD 发生率都很乐观，但仍值得进一步研究。
{"title":"Clinical and Immune Effects of Peri-Transplantation JAK Inhibition for Myelofibrosis","authors":"Kristin Rathje, Nico Gagelmann, Anita Badbaran, Claudia Langebrake, Adrin Dadkhah, Johanna Richter, Radwan Massoud, Mathias Schäfersküpper, Franziska E. Marquard, Sofia Oechsler, Evgeny Klyuchnikov, Ina Rudolph, Silke Heidenreich, Christian Niederwieser, Catherina Lueck, Dietlinde Janson, Christine Wolschke, Boris Fehse, Francis Ayuk, Nicolaus Kröger","doi":"10.1002/ajh.27529","DOIUrl":"https://doi.org/10.1002/ajh.27529","url":null,"abstract":"Despite the introduction of JAK inhibitors, allogeneic hematopoietic cell transplant remains the only potentially curative treatment for patients with myelofibrosis but has considerable treatment-related complications. Whether the incorporation of JAK inhibition into the transplant algorithm leads to improved outcomes is still unclear. Here, we analyzed different transplant platforms in myelofibrosis patients undergoing a first transplant, comparing immune profiles and outcomes of (1) 33 patients continuing JAK inhibition at start of conditioning until stable engraftment (PERI-group), (2) 38 patients receiving JAK inhibition prior to transplant until start of conditioning (PRE-group), and (3) 38 patients that had never received JAK inhibition (NON-group). Patients in the PERI-group showed significantly higher early B-cell recovery as well as significantly increased late recovery of gamma-delta T cells and NK cells. We observed excellent neutrophil and platelet engraftment (100% for both) in the PERI-group and no hematotoxic effects or increased rates of infections following peri-transplant JAK inhibition. Cumulative incidence of acute graft-versus-host disease (GvHD) grade II-IV at day 100 after transplant was 15% in the PERI-group versus 29% in the PRE-group versus 34% in the NON-group. Cumulative incidence of relapse at 1 year after transplant was 9% in the PERI-group compared with 16% in the PRE-group and 18% in the NON-group. In conclusion, peri-transplant JAK inhibition was feasible with promising engraftment and acute GvHD rates, though deserves further investigation.","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"48 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643221","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}
Waseem Lone, Alyssa Bouska, Tyler A. Herek, Catalina Amador, Joo Song, Alexander M. Xu, Dylan Jochum, Issa Ismail Issa, Dennis D. Weisenburger, Xuan Zhang, Sharath Kumar Bhagavathi, Tayla B. Heavican‐Foral, Sunandini Sharma, Ab Rauf Shah, Abdul Rouf Mir, Aisha Ahmad Alkhinji, Dalia El‐Gamal, Bhavana J. Dave, Keenan Hartert, Jiayu Yu, Mallick Saumyaranjan, Timothy C. Greiner, Julie Vose, Timothy W. McKeithan, Kai Fu, Michael Green, Chengfeng Bi, Akil Merchant, Wing C. Chan, Javeed Iqbal
High‐grade B‐cell lymphoma not otherwise specified (HGBCL, NOS) has overlapping morphological and genetic features with diffuse large B‐cell lymphoma (DLBCL) and Burkitt lymphoma (BL), leading to uncertainty in its diagnosis and clinical management. Using functional genomic approaches, we previously characterized HGBCL and NOS, that demonstrate gene expression profiling (GEP), and genetic signatures similar to BL. Herein, we characterize distinct HGBCL, NOS, cohort (n = 55) in adults (n = 45) and in children (n = 10), and compared the GEP, genomic DNA copy number (CN), and mutational spectrum with de novo DLBCL (n = 85) and BL (n = 52). This subgroup, representing ~60% of HGBCL, NOS, lack gene‐expression signature of BL and double hit/dark zone lymphoma, but express DLBCL like signatures and are characterized by either GCB‐ or ABC‐like mRNA signatures and exhibit higher genomic complexity, similar to de novo DLBCL, and show alteration in genes regulating B‐cell activation (CD79B, MYD88, PRDM1, TBLIXR1, CARD11), epigenome (KMT2D, TET2) and cell cycle transition (TP53, ASPM). However, recurrent mutations in genes often mutated in BL (DDX3X, GNA13, CCND3), but rare in DLBCL, are also present in HGBCL‐NOS, highlighting genetic heterogeneity. Consistent with mutation spectrum, frequent genomic CN alterations in genes regulating B‐cell activation (del‐PRDM1, gain‐BCL6, ‐REL, ‐STAT3) and cell cycle regulators (del‐TP53, del‐CDKN2A, del‐RB1, gain‐CCND3) were observed. Pediatric cases showed GCB‐DLBCL‐like mRNA signatures, but also featured hallmark mutations of pediatric BL. Frequent oncogenic PIM1 mutations were present in adult HGBCL, NOS. In vitro analyses with pharmacologic or genetic inhibition of PIM1 expression triggered B‐cell activation and NF‐κB‐induced apoptosis, suggesting that PIM1 is a rational therapeutic target.
{"title":"High‐grade B‐cell lymphoma not otherwise specified, with diffuse large B‐cell lymphoma gene expression signatures: Genomic analysis and potential therapeutics","authors":"Waseem Lone, Alyssa Bouska, Tyler A. Herek, Catalina Amador, Joo Song, Alexander M. Xu, Dylan Jochum, Issa Ismail Issa, Dennis D. Weisenburger, Xuan Zhang, Sharath Kumar Bhagavathi, Tayla B. Heavican‐Foral, Sunandini Sharma, Ab Rauf Shah, Abdul Rouf Mir, Aisha Ahmad Alkhinji, Dalia El‐Gamal, Bhavana J. Dave, Keenan Hartert, Jiayu Yu, Mallick Saumyaranjan, Timothy C. Greiner, Julie Vose, Timothy W. McKeithan, Kai Fu, Michael Green, Chengfeng Bi, Akil Merchant, Wing C. Chan, Javeed Iqbal","doi":"10.1002/ajh.27513","DOIUrl":"https://doi.org/10.1002/ajh.27513","url":null,"abstract":"High‐grade B‐cell lymphoma not otherwise specified (HGBCL, NOS) has overlapping morphological and genetic features with diffuse large B‐cell lymphoma (DLBCL) and Burkitt lymphoma (BL), leading to uncertainty in its diagnosis and clinical management. Using functional genomic approaches, we previously characterized HGBCL and NOS, that demonstrate gene expression profiling (GEP), and genetic signatures similar to BL. Herein, we characterize distinct HGBCL, NOS, cohort (<jats:italic>n</jats:italic> = 55) in adults (<jats:italic>n</jats:italic> = 45) and in children (<jats:italic>n</jats:italic> = 10), and compared the GEP, genomic DNA copy number (CN), and mutational spectrum with <jats:italic>de novo</jats:italic> DLBCL (<jats:italic>n</jats:italic> = 85) and BL (<jats:italic>n</jats:italic> = 52). This subgroup, representing ~60% of HGBCL, NOS, lack gene‐expression signature of BL and double hit/dark zone lymphoma, but express DLBCL like signatures and are characterized by either GCB‐ or ABC‐like mRNA signatures and exhibit higher genomic complexity, similar to <jats:italic>de novo</jats:italic> DLBCL, and show alteration in genes regulating B‐cell activation (<jats:italic>CD79B</jats:italic>, <jats:italic>MYD88</jats:italic>, <jats:italic>PRDM1</jats:italic>, <jats:italic>TBLIXR1</jats:italic>, <jats:italic>CARD11</jats:italic>), epigenome (<jats:italic>KMT2D</jats:italic>, <jats:italic>TET2</jats:italic>) and cell cycle transition (<jats:italic>TP53</jats:italic>, <jats:italic>ASPM</jats:italic>). However, recurrent mutations in genes often mutated in BL (DDX3X, GNA13, CCND3), but rare in DLBCL, are also present in HGBCL‐NOS, highlighting genetic heterogeneity. Consistent with mutation spectrum, frequent genomic CN alterations in genes regulating B‐cell activation (del‐<jats:italic>PRDM1</jats:italic>, gain‐<jats:italic>BCL6</jats:italic>, ‐<jats:italic>REL</jats:italic>, ‐<jats:italic>STAT3</jats:italic>) and cell cycle regulators (del‐<jats:italic>TP53</jats:italic>, del‐<jats:italic>CDKN2A</jats:italic>, del‐<jats:italic>RB1</jats:italic>, gain‐<jats:italic>CCND3</jats:italic>) were observed. Pediatric cases showed GCB‐DLBCL‐like mRNA signatures, but also featured hallmark mutations of pediatric BL. Frequent oncogenic <jats:italic>PIM1</jats:italic> mutations were present in adult HGBCL, NOS. <jats:italic>In vitro</jats:italic> analyses with pharmacologic or genetic inhibition of <jats:italic>PIM1 expression</jats:italic> triggered B‐cell activation and NF‐κB‐induced apoptosis, suggesting that <jats:italic>PIM1</jats:italic> is a rational therapeutic target.","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"17 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142642568","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}
Hui Liu, Hui Xu, Peiru Chi, Zinan Feng, Xiaojun Xu, Danian Nie, Xudong Li, Xinquan Liang, Zhiping Fan, Na Xu, Fen Huang, Ren Lin, Zhixiang Wang, Hua Jin, Hongsheng Zhou, Xutao Guo, Dongjun Lin, Jing Sun, Qifa Liu, Li Xuan
Relapse is the major cause of treatment failure in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). This study aimed to evaluate the effect of a prophylactic tyrosine kinase inhibitor (TKI) strategy on relapse in this population. Patients were assigned to prophylactic or control groups based on measurable residual disease (MRD) pre-transplantation. The primary endpoint was the cumulative incidence of relapse. A total of 110 patients with Ph+ ALL undergoing allo-HSCT were enrolled in this prospective study. Thirty-eight patients with positive MRD pre-transplantation were included in the prophylactic group, and 72 with negative MRD pre-transplantation were included in the control group. The 4-year cumulative incidence of relapse was 25.3% (95% CI: 12.1%–41.0%) and 20.3% (11.6%–30.7%; HR = 1.272, 95% CI: 0.551–2.940, p = .549), and non-relapse mortality was 10.5% (3.3%–22.7%) and 9.7% (4.2%–17.9%; HR = 1.094, 95% CI: 0.320–3.738, p = .928) in the prophylactic and control groups. The 4-year overall survival was 71.8% (53.2%–84.1%) and 84.1% (72.9%–90.9%; HR = 1.746, 95% CI: 0.741–4.112, p = .196), and leukemia-free survival was 64.1% (45.8%–77.7%) and 70.0% (57.6%–79.4%; HR = 1.212, 95% CI: 0.607–2.421, p = .585) in the prophylactic and control groups. Our results suggest that prophylactic TKI post-HSCT in patients with positive MRD pre-transplantation can produce outcomes comparable to negative MRD pre-transplantation without TKI post-HSCT.
{"title":"A prophylactic tyrosine kinase inhibitor strategy based on measurable residual disease pre-transplantation for Ph+ acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation: A prospective multicenter cohort study","authors":"Hui Liu, Hui Xu, Peiru Chi, Zinan Feng, Xiaojun Xu, Danian Nie, Xudong Li, Xinquan Liang, Zhiping Fan, Na Xu, Fen Huang, Ren Lin, Zhixiang Wang, Hua Jin, Hongsheng Zhou, Xutao Guo, Dongjun Lin, Jing Sun, Qifa Liu, Li Xuan","doi":"10.1002/ajh.27516","DOIUrl":"https://doi.org/10.1002/ajh.27516","url":null,"abstract":"Relapse is the major cause of treatment failure in Philadelphia chromosome-positive (Ph<sup>+</sup>) acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). This study aimed to evaluate the effect of a prophylactic tyrosine kinase inhibitor (TKI) strategy on relapse in this population. Patients were assigned to prophylactic or control groups based on measurable residual disease (MRD) pre-transplantation. The primary endpoint was the cumulative incidence of relapse. A total of 110 patients with Ph<sup>+</sup> ALL undergoing allo-HSCT were enrolled in this prospective study. Thirty-eight patients with positive MRD pre-transplantation were included in the prophylactic group, and 72 with negative MRD pre-transplantation were included in the control group. The 4-year cumulative incidence of relapse was 25.3% (95% CI: 12.1%–41.0%) and 20.3% (11.6%–30.7%; HR = 1.272, 95% CI: 0.551–2.940, <i>p</i> = .549), and non-relapse mortality was 10.5% (3.3%–22.7%) and 9.7% (4.2%–17.9%; HR = 1.094, 95% CI: 0.320–3.738, <i>p</i> = .928) in the prophylactic and control groups. The 4-year overall survival was 71.8% (53.2%–84.1%) and 84.1% (72.9%–90.9%; HR = 1.746, 95% CI: 0.741–4.112, <i>p</i> = .196), and leukemia-free survival was 64.1% (45.8%–77.7%) and 70.0% (57.6%–79.4%; HR = 1.212, 95% CI: 0.607–2.421, <i>p</i> = .585) in the prophylactic and control groups. Our results suggest that prophylactic TKI post-HSCT in patients with positive MRD pre-transplantation can produce outcomes comparable to negative MRD pre-transplantation without TKI post-HSCT.","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"76 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643229","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}
Aintzane Zabaleta, Noemi Puig, Maria-Teresa Cedena, Aina Oliver-Caldes, José J. Perez, Cristina Moreno, Luis-Esteban Tamariz-Amador, Paula Rodriguez-Otero, Felipe Prosper, Veronica Gonzalez-Calle, Lucía López-Corral, Beatriz Rey-Búa, Borja Puertas, Fátima Mirás, José María Sánchez-Pina, Nieves López-Muñoz, Manel Juan, E. Azucena González-Navarro, Álvaro Urbano, Carlos Fernández de Larrea, Joan Blade, Juan-José Lahuerta, Joaquín Martinez-Lopez, Maria-Victoria Mateos, Jesús F. San Miguel, Bruno Paiva
The impact of measurable residual disease (MRD) in relapse/refractory multiple myeloma (RRMM) patients treated with T-cell redirecting immunotherapy is uncertain. We analyzed MRD dynamics using next-generation flow in 201 patients treated in clinical trials with chimeric antigen receptor (CAR) T cells and T-cell engagers (TCE). Achieving MRD negativity at 10−6 was associated with 89% reduction in the risk of progression and/or death. Survival outcomes were improved in patients with sustained versus transient MRD negativity and were dismal in those who remained MRD positive. The intent-to-treat MRD negative rates were higher in patients treated with CAR T cells versus TCE. However, among patients achieving MRD negativity, there were no differences in survival outcomes when stratified according to treatment with CAR T cells versus TCE. In multivariate analysis including the number of prior lines of treatment, International Staging System, cytogenetic risk, extramedullary disease and type of T-cell redirecting immunotherapy, only the complete remission (CR) and MRD statuses showed independent prognostic value for progression-free and overall survival. In conclusion, our study shows that deep and sustained MRD negative CR is the most relevant prognostic factor and should be considered as the treatment endpoint in RRMM patients treated with CAR T cells and TCE.
在接受T细胞重定向免疫疗法治疗的复发/难治性多发性骨髓瘤（RRMM）患者中，可测量残留疾病（MRD）的影响尚不确定。我们利用新一代流式细胞术分析了在嵌合抗原受体（CAR）T细胞和T细胞吞噬体（TCE）临床试验中接受治疗的201名患者的MRD动态。MRD阴性率达到10-6与病情进展和/或死亡风险降低89%相关。MRD持续阴性与短暂阴性相比，患者的生存状况有所改善，而MRD持续阳性的患者生存状况则不容乐观。接受 CAR T 细胞治疗的患者的意向治疗 MRD 阴性率高于接受 TCE 治疗的患者。然而，在获得 MRD 阴性的患者中，根据 CAR T 细胞治疗与 TCE 治疗进行分层后，生存结果并无差异。在包括既往治疗次数、国际分期系统、细胞遗传学风险、髓外疾病和T细胞重定向免疫疗法类型在内的多变量分析中，只有完全缓解（CR）和MRD状态对无进展生存期和总生存期具有独立的预后价值。总之，我们的研究表明，深度和持续的MRD阴性CR是最相关的预后因素，应被视为接受CAR T细胞和TCE治疗的RRMM患者的治疗终点。
{"title":"Clinical significance of complete remission and measurable residual disease in relapsed/refractory multiple myeloma patients treated with T-cell redirecting immunotherapy","authors":"Aintzane Zabaleta, Noemi Puig, Maria-Teresa Cedena, Aina Oliver-Caldes, José J. Perez, Cristina Moreno, Luis-Esteban Tamariz-Amador, Paula Rodriguez-Otero, Felipe Prosper, Veronica Gonzalez-Calle, Lucía López-Corral, Beatriz Rey-Búa, Borja Puertas, Fátima Mirás, José María Sánchez-Pina, Nieves López-Muñoz, Manel Juan, E. Azucena González-Navarro, Álvaro Urbano, Carlos Fernández de Larrea, Joan Blade, Juan-José Lahuerta, Joaquín Martinez-Lopez, Maria-Victoria Mateos, Jesús F. San Miguel, Bruno Paiva","doi":"10.1002/ajh.27526","DOIUrl":"https://doi.org/10.1002/ajh.27526","url":null,"abstract":"The impact of measurable residual disease (MRD) in relapse/refractory multiple myeloma (RRMM) patients treated with T-cell redirecting immunotherapy is uncertain. We analyzed MRD dynamics using next-generation flow in 201 patients treated in clinical trials with chimeric antigen receptor (CAR) T cells and T-cell engagers (TCE). Achieving MRD negativity at 10<sup>−6</sup> was associated with 89% reduction in the risk of progression and/or death. Survival outcomes were improved in patients with sustained versus transient MRD negativity and were dismal in those who remained MRD positive. The intent-to-treat MRD negative rates were higher in patients treated with CAR T cells versus TCE. However, among patients achieving MRD negativity, there were no differences in survival outcomes when stratified according to treatment with CAR T cells versus TCE. In multivariate analysis including the number of prior lines of treatment, International Staging System, cytogenetic risk, extramedullary disease and type of T-cell redirecting immunotherapy, only the complete remission (CR) and MRD statuses showed independent prognostic value for progression-free and overall survival. In conclusion, our study shows that deep and sustained MRD negative CR is the most relevant prognostic factor and should be considered as the treatment endpoint in RRMM patients treated with CAR T cells and TCE.","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"76 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643222","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}
Hajer Oun, Kirsteen Harper, Mike Leach, Barbara J. Bain
A 76-year-old man with a history of chronic obstructive pulmonary disease with lung fibrosis, type 2 diabetes mellitus, and chronic kidney disease underwent computed tomography imaging of the chest due to increasing dyspnea. The bones appeared sclerotic, and a bone scan showed diffuse tracer uptake throughout the axial and appendicular skeleton. The prostate showed no features of malignancy on magnetic resonance imaging and prostate-specific antigen was 6.6 μg/L (normal range (NR) 0–5). Serum tryptase levels were mildly elevated at 16 μg/L (NR 2–14) on two occasions. Biochemical investigations showed vitamin D < 14 nmol/L (NR > 50), alkaline phosphatase 665 U/L (NR 30–130), parathyroid hormone 52.8 pmol/L (NR 1.6–7.5), calcium 2.43 mmol/L (NR 2.2–2.6) and phosphate 1.07 mmol/L (NR 0.8–1.5), in keeping with hyperparathyroidism secondary to vitamin D deficiency and chronic kidney disease (creatinine 169 μmol/L and estimated glomerular filtration rate 34 mL/min).
Bone marrow trephine biopsy sections showed areas of active bone resorption by multinucleate osteoclasts forming recesses known as Howship's lacunae (top and bottom left, all histological images hematoxylin and eosin, ×50 objective). In other areas, lamellar bone was being actively laid down by rows of osteoblasts (top center). There was patchy fibrosis at sites of previous bone resorption (bottom center). Notably, there were osteoclasts also visible in the marrow aspirate (top and bottom right, May–Grünwald–Giemsa, ×100 objective). There was no abnormal mast cell population.
These features are typical of hyperparathyroidism where osteoclasts strive to release calcium whilst osteoblasts attempt to repair the trabecular damage. This active bone remodeling with the associated trabecular changes generates the sclerotic radiological appearance of the affected bones. Osteoblasts and osteoclasts normally work together in bone repair, remodeling, and growth but this process is exaggerated under the influence of increased parathyroid hormone whether primary, due to a parathyroid adenoma, or secondary, as a result of vitamin D deficiency or chronic kidney disease. The recognition of the features of bone disorders with associated bone marrow fibrosis is important so that they are not confused with myeloproliferative neoplasms.
{"title":"Hyperparathyroidism and the Hematologist","authors":"Hajer Oun, Kirsteen Harper, Mike Leach, Barbara J. Bain","doi":"10.1002/ajh.27527","DOIUrl":"https://doi.org/10.1002/ajh.27527","url":null,"abstract":"<div>\u0000<figure>\u0000<div><picture>\u0000<source media=\"(min-width: 1650px)\" srcset=\"/cms/asset/b04baa4a-6e9e-4b9c-9c1d-6db3d8f072e6/ajh27527-gra-0001-m.jpg\"/><img alt=\"image\" data-lg-src=\"/cms/asset/b04baa4a-6e9e-4b9c-9c1d-6db3d8f072e6/ajh27527-gra-0001-m.jpg\" loading=\"lazy\" src=\"/cms/asset/596227e9-704e-4d09-a9bc-5ecba0f0acec/ajh27527-gra-0001-m.png\" title=\"image\"/></picture><p></p>\u0000</div>\u0000</figure>\u0000</div>\u0000<p>A 76-year-old man with a history of chronic obstructive pulmonary disease with lung fibrosis, type 2 diabetes mellitus, and chronic kidney disease underwent computed tomography imaging of the chest due to increasing dyspnea. The bones appeared sclerotic, and a bone scan showed diffuse tracer uptake throughout the axial and appendicular skeleton. The prostate showed no features of malignancy on magnetic resonance imaging and prostate-specific antigen was 6.6 μg/L (normal range (NR) 0–5). Serum tryptase levels were mildly elevated at 16 μg/L (NR 2–14) on two occasions. Biochemical investigations showed vitamin D < 14 nmol/L (NR > 50), alkaline phosphatase 665 U/L (NR 30–130), parathyroid hormone 52.8 pmol/L (NR 1.6–7.5), calcium 2.43 mmol/L (NR 2.2–2.6) and phosphate 1.07 mmol/L (NR 0.8–1.5), in keeping with hyperparathyroidism secondary to vitamin D deficiency and chronic kidney disease (creatinine 169 μmol/L and estimated glomerular filtration rate 34 mL/min).</p>\u0000<p>Bone marrow trephine biopsy sections showed areas of active bone resorption by multinucleate osteoclasts forming recesses known as Howship's lacunae (top and bottom left, all histological images hematoxylin and eosin, ×50 objective). In other areas, lamellar bone was being actively laid down by rows of osteoblasts (top center). There was patchy fibrosis at sites of previous bone resorption (bottom center). Notably, there were osteoclasts also visible in the marrow aspirate (top and bottom right, May–Grünwald–Giemsa, ×100 objective). There was no abnormal mast cell population.</p>\u0000<p>These features are typical of hyperparathyroidism where osteoclasts strive to release calcium whilst osteoblasts attempt to repair the trabecular damage. This active bone remodeling with the associated trabecular changes generates the sclerotic radiological appearance of the affected bones. Osteoblasts and osteoclasts normally work together in bone repair, remodeling, and growth but this process is exaggerated under the influence of increased parathyroid hormone whether primary, due to a parathyroid adenoma, or secondary, as a result of vitamin D deficiency or chronic kidney disease. The recognition of the features of bone disorders with associated bone marrow fibrosis is important so that they are not confused with myeloproliferative neoplasms.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"19 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599906","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}
Enrico Costa, Russell E. Ware, Léon Tshilolo, Julie Makani, Hubert G. M. Leufkens, Lucio Luzzatto
<h2>1 BACKGROUND</h2> <p>Globalization of clinical trials, defined operationally as conduct in the international arena, has grown over the past few decades. The pharmaceutical industry is expanding its activities not only in High-Income countries but also in Low- and Middle-Income countries (LMICs).<span><sup>1</sup></span></p> <p>For pharmaceutical companies, this shift can be associated with several benefits: a larger pool of potential participants, faster enrollment in trials, and substantial cost savings.<span><sup>1</sup></span> At the same time, there may be advantages also for LMICs in terms of capacity building, gaining experience, and access to innovation.<span><sup>2</sup></span></p> <p>Drug development and access to medicines in LMICs is certainly a challenge for patients with sickle cell disease (SCD), a condition that is most highly prevalent in malaria-endemic countries in the global South, but that, through the tragedy of the transatlantic slave trade and subsequent migrations, is also prominent in the global North.<span><sup>3</sup></span></p> <p>The prevalence of SCD outside Africa has accelerated the development of new medicinal products, enhanced by a conducive regulatory framework. The orphan drug legislation in the United States (US) and the European Union (EU) have provided pharmaceutical developers with special incentives (e.g., periods of market exclusivity) to counterbalance the limited market size. In addition, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have implemented special pathways to expedite the review and approval of treatments for serious and life-threatening diseases. Accordingly, in both the US and the EU, treatments for SCD can be approved based on surrogate endpoints or more flexible evidence.<span><sup>4</sup></span></p> <p>To assess the trends and impact of globalization on the development of SCD drugs, we analyzed data from industry-sponsored studies initiated in the time interval from 1 January 1990 through 30 June 2024 (see Appendix S1). In the study period, a total of 79 pharmaceutical active substances were tested in 156 clinical trials.</p> <p>Overall, 56.4% of enrolling centers were in North America, 20.5% in Europe, 7.9% in Africa, 5.7% in Latin America, 9.1% in Asia and Middle East, and 0.4% in Australia. Temporal trends from the early 2000s to the last 5 years showed a relative decrease of enrolling centers in North America from 63.1% to 44.0%, and in Europe from 28.5% to 22.2%. By contrast, in African centers there was an increase from 0.5% to 13.2%, in Latin America from 1.1% to 9.0%, and in Asia and the Middle East from 5.7% to 11.4%. The number of Australian centers remained low over time.</p> <p>Similar trends were mirrored in the drug development phases: for instance, enrolling centers in Africa increased from 2.8% in Phase 1 trials to 4.2% in Phase 2, and to 10.6% in Phase 3 and 11.9% in Phase 4 trials. Similar increases were observed in Latin America
{"title":"Globalization in clinical drug development for sickle cell disease","authors":"Enrico Costa, Russell E. Ware, Léon Tshilolo, Julie Makani, Hubert G. M. Leufkens, Lucio Luzzatto","doi":"10.1002/ajh.27525","DOIUrl":"https://doi.org/10.1002/ajh.27525","url":null,"abstract":"<h2>1 BACKGROUND</h2>\u0000<p>Globalization of clinical trials, defined operationally as conduct in the international arena, has grown over the past few decades. The pharmaceutical industry is expanding its activities not only in High-Income countries but also in Low- and Middle-Income countries (LMICs).<span><sup>1</sup></span></p>\u0000<p>For pharmaceutical companies, this shift can be associated with several benefits: a larger pool of potential participants, faster enrollment in trials, and substantial cost savings.<span><sup>1</sup></span> At the same time, there may be advantages also for LMICs in terms of capacity building, gaining experience, and access to innovation.<span><sup>2</sup></span></p>\u0000<p>Drug development and access to medicines in LMICs is certainly a challenge for patients with sickle cell disease (SCD), a condition that is most highly prevalent in malaria-endemic countries in the global South, but that, through the tragedy of the transatlantic slave trade and subsequent migrations, is also prominent in the global North.<span><sup>3</sup></span></p>\u0000<p>The prevalence of SCD outside Africa has accelerated the development of new medicinal products, enhanced by a conducive regulatory framework. The orphan drug legislation in the United States (US) and the European Union (EU) have provided pharmaceutical developers with special incentives (e.g., periods of market exclusivity) to counterbalance the limited market size. In addition, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have implemented special pathways to expedite the review and approval of treatments for serious and life-threatening diseases. Accordingly, in both the US and the EU, treatments for SCD can be approved based on surrogate endpoints or more flexible evidence.<span><sup>4</sup></span></p>\u0000<p>To assess the trends and impact of globalization on the development of SCD drugs, we analyzed data from industry-sponsored studies initiated in the time interval from 1 January 1990 through 30 June 2024 (see Appendix S1). In the study period, a total of 79 pharmaceutical active substances were tested in 156 clinical trials.</p>\u0000<p>Overall, 56.4% of enrolling centers were in North America, 20.5% in Europe, 7.9% in Africa, 5.7% in Latin America, 9.1% in Asia and Middle East, and 0.4% in Australia. Temporal trends from the early 2000s to the last 5 years showed a relative decrease of enrolling centers in North America from 63.1% to 44.0%, and in Europe from 28.5% to 22.2%. By contrast, in African centers there was an increase from 0.5% to 13.2%, in Latin America from 1.1% to 9.0%, and in Asia and the Middle East from 5.7% to 11.4%. The number of Australian centers remained low over time.</p>\u0000<p>Similar trends were mirrored in the drug development phases: for instance, enrolling centers in Africa increased from 2.8% in Phase 1 trials to 4.2% in Phase 2, and to 10.6% in Phase 3 and 11.9% in Phase 4 trials. Similar increases were observed in Latin America","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"32 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599907","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}
Jing Luo, Jiaojiao Zhang, Ligen Liu, Rong Wei, Yonghua Yao, Min Xu, Jumei Shi, Jianmin Yang, Jian Hou, Jin Wang, Jian-Qing Mi
{"title":"Efficacy and safety of zanubrutinib monotherapy for chronic lymphocytic leukemia/small lymphocytic lymphoma: A multicenter, real-world study in China.","authors":"Jing Luo, Jiaojiao Zhang, Ligen Liu, Rong Wei, Yonghua Yao, Min Xu, Jumei Shi, Jianmin Yang, Jian Hou, Jin Wang, Jian-Qing Mi","doi":"10.1002/ajh.27519","DOIUrl":"https://doi.org/10.1002/ajh.27519","url":null,"abstract":"","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567748","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}
Courtney D. DiNardo, Keith W. Pratz, Panayiotis Panayiotidis, Xudong Wei, Vladimir Vorobyev, Árpád Illés, Inho Kim, Vladimir Ivanov, Grace Ku, Catherine L. Miller, Meng Zhang, Fernando Tatsch, Jalaja Potluri, Xenia Schmidt, Christian Récher
<p>Based on results from the randomized, placebo-controlled phase 3 VIALE-A (NCT02993523) and VIALE-C (NCT03069352) trials,<span><sup>1-4</sup></span> venetoclax in combination with hypomethylating agents or low-dose cytarabine (LDAC) has become standard of care in patients with newly diagnosed acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. Cytopenias are common adverse events with venetoclax and are primarily managed with protocol-mandated dose modifications, including dose interruptions and cycle delays.<span><sup>2, 5</sup></span> Neutropenia and febrile neutropenia may be mitigated with granulocyte-colony stimulating factor (G-CSF)<span><sup>4, 6</sup></span>; however, limited evidence exists on G-CSF use and impact on safety and efficacy in patients receiving low-intensity therapies. The present analysis assessed outcomes by G-CSF use post-remission (i.e., following blast clearance) among patients with newly diagnosed, intensive-chemotherapy–ineligible AML who received venetoclax-azacitidine or venetoclax-LDAC in the VIALE-A and VIALE-C trials, respectively.</p> <p>VIALE-A and VIALE-C study designs have been previously described.<span><sup>1, 3</sup></span> Both trials enrolled patients aged ≥18 years with newly diagnosed AML who were ineligible for induction chemotherapy (aged ≥75 years or with comorbid conditions precluding intensive chemotherapy treatment). In VIALE-A, patients received venetoclax-azacitidine or placebo-azacitidine; in VIALE-C, patients received venetoclax-LDAC or placebo-LDAC. Both trial protocols allowed G-CSF use with administration for cytopenia management as per institutional practice. In this exploratory post hoc analysis, patients treated with venetoclax combinations who had achieved a best response of complete remission (CR)/CR with incomplete hematologic recovery (CRi) were assessed for outcomes by G-CSF use, including overall survival (OS), duration of CR/CRi (DOR), and safety. G-CSF use was analyzed from the time of remission achievement (post-remission), defined as blast clearance (<5% bone marrow blasts) for this analysis. Clinical data cutoff was December 1, 2021 for VIALE-A and February 15, 2021 for VIALE-C.<span><sup>2, 3</sup></span> The analysis populations included patients who achieved best response of CR/CRi, unless otherwise specified.<span><sup>1, 3</sup></span> Data presentation is descriptive in nature, and formal statistical comparisons were not performed due to the post hoc nature of this analysis. Additional details are in the Data S1.</p> <p>Approximately half of patients treated with venetoclax combinations in VIALE-A and VIALE-C received G-CSF post-remission. In VIALE-A, 50% (95/191) of CR/CRi responders in the venetoclax-azacitidine arm and 26% (11/42) in the placebo-azacitidine arm received G-CSF post-remission (Tables S1 and S2). In VIALE-C, 46% (32/69) of CR/CRi responders in the venetoclax-LDAC arm and 22% (2/9) in the placebo-LDAC arm received G-CSF post
{"title":"The impact of post-remission granulocyte colony-stimulating factor use in the phase 3 studies of venetoclax combination treatments in patients with newly diagnosed acute myeloid leukemia","authors":"Courtney D. DiNardo, Keith W. Pratz, Panayiotis Panayiotidis, Xudong Wei, Vladimir Vorobyev, Árpád Illés, Inho Kim, Vladimir Ivanov, Grace Ku, Catherine L. Miller, Meng Zhang, Fernando Tatsch, Jalaja Potluri, Xenia Schmidt, Christian Récher","doi":"10.1002/ajh.27515","DOIUrl":"https://doi.org/10.1002/ajh.27515","url":null,"abstract":"<p>Based on results from the randomized, placebo-controlled phase 3 VIALE-A (NCT02993523) and VIALE-C (NCT03069352) trials,<span><sup>1-4</sup></span> venetoclax in combination with hypomethylating agents or low-dose cytarabine (LDAC) has become standard of care in patients with newly diagnosed acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. Cytopenias are common adverse events with venetoclax and are primarily managed with protocol-mandated dose modifications, including dose interruptions and cycle delays.<span><sup>2, 5</sup></span> Neutropenia and febrile neutropenia may be mitigated with granulocyte-colony stimulating factor (G-CSF)<span><sup>4, 6</sup></span>; however, limited evidence exists on G-CSF use and impact on safety and efficacy in patients receiving low-intensity therapies. The present analysis assessed outcomes by G-CSF use post-remission (i.e., following blast clearance) among patients with newly diagnosed, intensive-chemotherapy–ineligible AML who received venetoclax-azacitidine or venetoclax-LDAC in the VIALE-A and VIALE-C trials, respectively.</p>\u0000<p>VIALE-A and VIALE-C study designs have been previously described.<span><sup>1, 3</sup></span> Both trials enrolled patients aged ≥18 years with newly diagnosed AML who were ineligible for induction chemotherapy (aged ≥75 years or with comorbid conditions precluding intensive chemotherapy treatment). In VIALE-A, patients received venetoclax-azacitidine or placebo-azacitidine; in VIALE-C, patients received venetoclax-LDAC or placebo-LDAC. Both trial protocols allowed G-CSF use with administration for cytopenia management as per institutional practice. In this exploratory post hoc analysis, patients treated with venetoclax combinations who had achieved a best response of complete remission (CR)/CR with incomplete hematologic recovery (CRi) were assessed for outcomes by G-CSF use, including overall survival (OS), duration of CR/CRi (DOR), and safety. G-CSF use was analyzed from the time of remission achievement (post-remission), defined as blast clearance (<5% bone marrow blasts) for this analysis. Clinical data cutoff was December 1, 2021 for VIALE-A and February 15, 2021 for VIALE-C.<span><sup>2, 3</sup></span> The analysis populations included patients who achieved best response of CR/CRi, unless otherwise specified.<span><sup>1, 3</sup></span> Data presentation is descriptive in nature, and formal statistical comparisons were not performed due to the post hoc nature of this analysis. Additional details are in the Data S1.</p>\u0000<p>Approximately half of patients treated with venetoclax combinations in VIALE-A and VIALE-C received G-CSF post-remission. In VIALE-A, 50% (95/191) of CR/CRi responders in the venetoclax-azacitidine arm and 26% (11/42) in the placebo-azacitidine arm received G-CSF post-remission (Tables S1 and S2). In VIALE-C, 46% (32/69) of CR/CRi responders in the venetoclax-LDAC arm and 22% (2/9) in the placebo-LDAC arm received G-CSF post","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"213 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142563290","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}
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