Pub Date : 2025-08-19DOI: 10.1016/j.bneo.2025.100161
Vijay Negi ∗ , Ryan Bertoli ∗ , Olivia Tuckey , Yuelin Jack Zhu , Robert L. Walker , Michael J. Difilippantonio , James H. Doroshow , Paul S. Meltzer , Peter D. Aplan
Abstract
5-Aza-4'-thio-2'-deoxycytidine (ATC) is an azanucleoside cytidine analog under investigation in preclinical studies for solid tumors as a promising DNA methyltransferase 1 (DNMT1) inhibitor. Repeated treatment with ATC has previously been shown to induce acute lymphoblastic leukemia (ALL) of both B-cell and T-cell origin in mice. Herein, RAG-1 deficient or “knockout” (KO) mice (B6.129S7-RAG-1tm1Mom/J) were treated with ATC to determine if ATC could be oncogenic in nonlymphoid cells. However, ATC treatment targeted early B progenitors and invariably led to B-lineage ALL, with a gene expression signature similar to human B-cell precursor (BCP)-ALL. Whole-exome sequencing revealed numerous single base substitutions of cytosine, primarily C>G transversions at CpG dinucleotides, within genes important for BCP-ALL. Bisulfite sequencing and treatment with a noncovalent DNMT1 inhibitor indicated that methylated cytosines were preferred targets for mutagenesis. This study reveals that ATC exposure leads to both DNMT1-dependent and -independent mutagenesis and provides a direct link between ATC exposure, a complex mutational signature, and malignant transformation.
{"title":"Azanucleoside treatment leads to B-cell precursor acute lymphoblastic leukemia","authors":"Vijay Negi ∗ , Ryan Bertoli ∗ , Olivia Tuckey , Yuelin Jack Zhu , Robert L. Walker , Michael J. Difilippantonio , James H. Doroshow , Paul S. Meltzer , Peter D. Aplan","doi":"10.1016/j.bneo.2025.100161","DOIUrl":"10.1016/j.bneo.2025.100161","url":null,"abstract":"<div><h3>Abstract</h3><div>5-Aza-4'-thio-2'-deoxycytidine (ATC) is an azanucleoside cytidine analog under investigation in preclinical studies for solid tumors as a promising DNA methyltransferase 1 (DNMT1) inhibitor. Repeated treatment with ATC has previously been shown to induce acute lymphoblastic leukemia (ALL) of both B-cell and T-cell origin in mice. Herein, RAG-1 deficient or “knockout” (KO) mice (B6.129S7-RAG-1tm1Mom/J) were treated with ATC to determine if ATC could be oncogenic in nonlymphoid cells. However, ATC treatment targeted early B progenitors and invariably led to B-lineage ALL, with a gene expression signature similar to human B-cell precursor (BCP)-ALL. Whole-exome sequencing revealed numerous single base substitutions of cytosine, primarily C>G transversions at CpG dinucleotides, within genes important for BCP-ALL. Bisulfite sequencing and treatment with a noncovalent DNMT1 inhibitor indicated that methylated cytosines were preferred targets for mutagenesis. This study reveals that ATC exposure leads to both DNMT1-dependent and -independent mutagenesis and provides a direct link between ATC exposure, a complex mutational signature, and malignant transformation.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"2 4","pages":"Article 100161"},"PeriodicalIF":0.0,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145324408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-19DOI: 10.1016/j.bneo.2025.100160
Evelyn H. Orlando ∗ , Patrick Gould ∗ , Brian Cuzzo , Maegan Ford , Yuxuan Chen , Alexander Sanjurjo , Saagar Jain , Benjamin May , Demetra Tsapepas , Rebecca J. Leeman-Neill , Govind Bhagat , Geoffrey K. Dube , Heather Morris , Selim Arcasoy , Farhana Latif , Ersilia M. DeFilippis , Mercedes Martinez , Gene Y. Im , Meaghan M. Phipps , Marcus R. Pereira , Jennifer E. Amengual †
Abstract
The association between Epstein-Barr virus (EBV) DNAemia after solid organ transplantation (SOT) and posttransplant lymphoproliferative disorder (PTLD) is well described. Published data support preemptive rituximab for EBV DNAemia after bone marrow transplant. However, there are inadequate data to support any specific preemptive strategy for DNAemia after SOT. The goal of this single-center retrospective cohort study was to explore the association between posttransplant rituximab and development of PTLD in SOT recipients with EBV DNAemia. This study included 1386 patients with EBV DNAemia after SOT at Columbia University Irving Medical Center from 2008 to 2023. There were 129 patients who received rituximab for various indications (eg, organ rejection, EBV DNAemia). Across all patients, 82 of 1386 (6%) developed PTLD and the 5-year PTLD-free survival rate was 95%. In multivariable analysis, posttransplant rituximab exposure for any indication was independently associated with a reduced rate of PTLD over time as a time-independent (hazard ratio [HR], 0.16; P = .011) but not time-dependent (HR, 0.25; P = .056) variable. When limiting the rituximab-exposed cohort to the 60 patients who received rituximab after documented EBV DNAemia, time-independent (HR, 0.25; P = .06) and time-dependent (HR, 0.43; P = .2) rituximab exposure were not associated with PTLD-free survival. Higher EBV peak viral load, high-risk organ transplant type, and high-risk EBV serostatus were independently associated with increased rates of PTLD. This retrospective study suggests that posttransplant rituximab may reduce the rate of PTLD in SOT recipients. Prospective, randomized studies are needed to more rigorously determine the benefit of preemptive rituximab for the prevention of PTLD in patients with EBV DNAemia.
摘要本文研究了实体器官移植（SOT）后eb病毒（EBV） dna血症与移植后淋巴细胞增生性疾病（PTLD）的关系。已发表的数据支持骨髓移植后EBV dna血症的抢先性利妥昔单抗治疗。然而，没有足够的数据来支持SOT后dna贫血的任何具体的先发制人策略。这项单中心回顾性队列研究的目的是探讨移植后利妥昔单抗与EBV dna血症SOT受者PTLD发展之间的关系。本研究纳入了哥伦比亚大学欧文医学中心2008年至2023年的1386例SOT后EBV dna血症患者。有129例患者接受了利妥昔单抗治疗各种适应症（如器官排斥、EBV dna血症）。在所有患者中，1386例中有82例（6%）发展为PTLD， 5年无PTLD生存率为95%。在多变量分析中，移植后任何适应症的利妥昔单抗暴露与随时间推移的PTLD发生率降低独立相关，这是一个与时间无关的变量（风险比[HR]， 0.16; P = 0.011），但与时间无关（风险比[HR]， 0.25; P = 0.056）。当将利妥昔单抗暴露队列限制在60例记录的EBV dna血症后接受利妥昔单抗治疗的患者时，时间无关（HR, 0.25; P = 0.06）和时间依赖（HR, 0.43; P = 0.2）的利妥昔单抗暴露与无ptld生存无关。较高的EBV峰值病毒载量、高危器官移植类型和高危EBV血清状态与PTLD发生率升高独立相关。这项回顾性研究表明，移植后利妥昔单抗可能降低SOT受者PTLD的发生率。需要前瞻性、随机研究来更严格地确定抢先性利妥昔单抗预防EBV dna血症患者PTLD的益处。
{"title":"Posttransplant rituximab exposure and risk of PTLD in solid organ transplant recipients with EBV DNAemia","authors":"Evelyn H. Orlando ∗ , Patrick Gould ∗ , Brian Cuzzo , Maegan Ford , Yuxuan Chen , Alexander Sanjurjo , Saagar Jain , Benjamin May , Demetra Tsapepas , Rebecca J. Leeman-Neill , Govind Bhagat , Geoffrey K. Dube , Heather Morris , Selim Arcasoy , Farhana Latif , Ersilia M. DeFilippis , Mercedes Martinez , Gene Y. Im , Meaghan M. Phipps , Marcus R. Pereira , Jennifer E. Amengual †","doi":"10.1016/j.bneo.2025.100160","DOIUrl":"10.1016/j.bneo.2025.100160","url":null,"abstract":"<div><h3>Abstract</h3><div>The association between Epstein-Barr virus (EBV) DNAemia after solid organ transplantation (SOT) and posttransplant lymphoproliferative disorder (PTLD) is well described. Published data support preemptive rituximab for EBV DNAemia after bone marrow transplant. However, there are inadequate data to support any specific preemptive strategy for DNAemia after SOT. The goal of this single-center retrospective cohort study was to explore the association between posttransplant rituximab and development of PTLD in SOT recipients with EBV DNAemia. This study included 1386 patients with EBV DNAemia after SOT at Columbia University Irving Medical Center from 2008 to 2023. There were 129 patients who received rituximab for various indications (eg, organ rejection, EBV DNAemia). Across all patients, 82 of 1386 (6%) developed PTLD and the 5-year PTLD-free survival rate was 95%. In multivariable analysis, posttransplant rituximab exposure for any indication was independently associated with a reduced rate of PTLD over time as a time-independent (hazard ratio [HR], 0.16; <em>P</em> = .011) but not time-dependent (HR, 0.25; <em>P</em> = .056) variable. When limiting the rituximab-exposed cohort to the 60 patients who received rituximab after documented EBV DNAemia, time-independent (HR, 0.25; <em>P</em> = .06) and time-dependent (HR, 0.43; <em>P</em> = .2) rituximab exposure were not associated with PTLD-free survival. Higher EBV peak viral load, high-risk organ transplant type, and high-risk EBV serostatus were independently associated with increased rates of PTLD. This retrospective study suggests that posttransplant rituximab may reduce the rate of PTLD in SOT recipients. Prospective, randomized studies are needed to more rigorously determine the benefit of preemptive rituximab for the prevention of PTLD in patients with EBV DNAemia.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"2 4","pages":"Article 100160"},"PeriodicalIF":0.0,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145266586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-06DOI: 10.1016/j.bneo.2025.100156
Sudipto Mukherjee , Weichuan Dong , Aaron T. Gerds , Hetty E. Carraway , Abhay Singh , Anjali S. Advani , Moaath K. Mustafa Ali , John C. Molina , Sophia Balderman , Akriti Jain , Paolo Caimi , Faiz Anwer , Mikkael A. Sekeres , Siran M. Koroukian
Abstract
Compared with data from clinical trials, US population-level data show decreased effectiveness of hypomethylating agents (HMAs) in patients with myelodysplastic syndromes (MDS). We sought to identify factors associated with patterns of HMA use. In this retrospective cohort study, we identified 49 514 individuals aged ≥65 years with incident MDS during the years 2012 to 2013 using the 2011 to 2014 Medicare claims data set. We collected data on demographics, clinical characteristics, disease severity, and area-level socioeconomic measures. Multivariable logistic regression analysis was used to evaluate factors associated with receipt of HMA and duration of HMA therapy. A total of 7935 patients (16.1%) received HMAs. In adjusted analyses, the oldest age cohort (patients aged ≥85 years) had lower odds of receiving HMAs than their younger counterparts (aged 65-74 years; adjusted odds ratio [aOR], 0.41; 95% confidence interval [CI], 0.38-0.44). Females and Black patients had significantly lower odds than males and White patients to receive HMA (aOR, 0.81 [95% CI, 0.77-0.86] for females; aOR, 0.70 [95% CI, 0.62-0.8] for Blacks patients). In HMA recipients, factors associated with lower odds of receiving ≥4 cycles of HMAs included patients treated with decitabine (aOR, 0.7; 95% CI, 0.62-0.78), having 2 to 3 cytopenias (aOR, 0.69; 95% CI, 0.61-0.78), being nursing home residents (aOR, 0.64; 95% CI, 0.46-0.90), and having high frailty (aOR, 0.50; 95% CI, 0.34-0.75). We identified age-, sex-, and race-related disparities in receipt of HMAs, favoring younger, White males. The duration of therapy in HMA-treated patients in routine clinical practice showed wide divergence from recommended clinical guidelines.
{"title":"Disparities in real-world treatment patterns of hypomethylating agents among patients with MDS in the United States","authors":"Sudipto Mukherjee , Weichuan Dong , Aaron T. Gerds , Hetty E. Carraway , Abhay Singh , Anjali S. Advani , Moaath K. Mustafa Ali , John C. Molina , Sophia Balderman , Akriti Jain , Paolo Caimi , Faiz Anwer , Mikkael A. Sekeres , Siran M. Koroukian","doi":"10.1016/j.bneo.2025.100156","DOIUrl":"10.1016/j.bneo.2025.100156","url":null,"abstract":"<div><h3>Abstract</h3><div>Compared with data from clinical trials, US population-level data show decreased effectiveness of hypomethylating agents (HMAs) in patients with myelodysplastic syndromes (MDS). We sought to identify factors associated with patterns of HMA use. In this retrospective cohort study, we identified 49 514 individuals aged ≥65 years with incident MDS during the years 2012 to 2013 using the 2011 to 2014 Medicare claims data set. We collected data on demographics, clinical characteristics, disease severity, and area-level socioeconomic measures. Multivariable logistic regression analysis was used to evaluate factors associated with receipt of HMA and duration of HMA therapy. A total of 7935 patients (16.1%) received HMAs. In adjusted analyses, the oldest age cohort (patients aged ≥85 years) had lower odds of receiving HMAs than their younger counterparts (aged 65-74 years; adjusted odds ratio [aOR], 0.41; 95% confidence interval [CI], 0.38-0.44). Females and Black patients had significantly lower odds than males and White patients to receive HMA (aOR, 0.81 [95% CI, 0.77-0.86] for females; aOR, 0.70 [95% CI, 0.62-0.8] for Blacks patients). In HMA recipients, factors associated with lower odds of receiving ≥4 cycles of HMAs included patients treated with decitabine (aOR, 0.7; 95% CI, 0.62-0.78), having 2 to 3 cytopenias (aOR, 0.69; 95% CI, 0.61-0.78), being nursing home residents (aOR, 0.64; 95% CI, 0.46-0.90), and having high frailty (aOR, 0.50; 95% CI, 0.34-0.75). We identified age-, sex-, and race-related disparities in receipt of HMAs, favoring younger, White males. The duration of therapy in HMA-treated patients in routine clinical practice showed wide divergence from recommended clinical guidelines.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"2 4","pages":"Article 100156"},"PeriodicalIF":0.0,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145324409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Double-hit lymphoma (DHL), an aggressive B-cell lymphoma with a poor prognosis, harbors rearrangements of MYC and BCL2. The standard chemoimmunotherapy comprising R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) yields an unsatisfactory treatment response. Hypomethylating agents increase the susceptibility to malignant lymphoma via the restoration of tumor suppressor genes. Decitabine not only inhibits DNA methylation but also causes mitotic disruption, which leads to antileukemia effects through the covalent binding of DNA methyltransferase 1 to DNA. Previously, we developed an orally bioavailable prodrug of decitabine (OR-2100). Here, we investigated the efficacy and underlying mechanism of OR-2100 as a treatment for DHL. OR-2100 alone or in combination with key antilymphoma drugs, including doxorubicin and vincristine, suppressed the in vitro proliferation of DHL cell lines, particularly those with wild-type TP53. OR-2100 induced downregulation of CDCA8 and BIRC5 (baculoviral IAP [inhibitor of apoptosis] repeat–containing 5), the knockdown of which suppressed the proliferation of DHL cell lines. Both OR-2100 treatment and CDCA8 knockdown led to mitotic perturbation, suggesting that the disruption of mitosis may underlie the antitumor mechanism of OR-2100 given that the efficacy of OR-2100 was dependent on the TP53 status and that CDCA8 and BIRC5 are downstream targets of the E2F1 pathway. These findings suggest that the antitumor activity of OR-2100 may be mediated through inhibition of the E2F1 pathway. The combination of CHOP and OR-2100 reduced the tumor weight significantly in a xenograft mouse model without increased toxicities. The induction of mitotic perturbation might be a key antilymphoma mechanism for OR-2100, and the combination of OR-2100 and CHOP might be a promising treatment strategy for DHL.
摘要双重打击淋巴瘤（double -hit lymphoma， DHL）是一种预后不良的侵袭性b细胞淋巴瘤，含有MYC和BCL2的重排。标准的化学免疫疗法包括R-CHOP（利妥昔单抗加环磷酰胺、阿霉素、长春新碱和强的松）产生的治疗反应不令人满意。低甲基化药物通过恢复肿瘤抑制基因增加对恶性淋巴瘤的易感性。地西他滨不仅抑制DNA甲基化，而且引起有丝分裂中断，从而通过DNA甲基转移酶1与DNA的共价结合而产生抗白血病作用。在此之前，我们开发了一种口服生物可利用的前药地西他滨（OR-2100）。在这里，我们研究了OR-2100作为治疗DHL的疗效和潜在机制。or -2100单独或与关键抗淋巴瘤药物（包括阿霉素和长春新碱）联合使用可抑制DHL细胞系的体外增殖，尤其是野生型TP53细胞系。OR-2100诱导CDCA8和BIRC5（杆状病毒IAP [inhibitor of apoptosis] repeat-containing 5）的下调，其下调抑制了DHL细胞系的增殖。OR-2100治疗和CDCA8敲低均导致有丝分裂紊乱，鉴于OR-2100的疗效依赖于TP53状态，且CDCA8和BIRC5是E2F1通路的下游靶点，这表明有丝分裂的破坏可能是OR-2100抗肿瘤机制的基础。这些发现提示OR-2100的抗肿瘤活性可能是通过抑制E2F1通路介导的。在异种移植小鼠模型中，CHOP和OR-2100的联合使用显著降低了肿瘤重量，但没有增加毒性。诱导有丝分裂扰动可能是OR-2100的关键抗淋巴瘤机制，OR-2100与CHOP联合治疗可能是一种有希望的治疗DHL的策略。
{"title":"Orally available decitabine prodrug OR-2100 induces mitotic perturbation for the treatment of double-hit lymphoma","authors":"Keisuke Kidoguchi , Hiroshi Ureshino , Yuta Yamamoto , Ryo Yanagiya , Yuki Kurahashi , Yuki Fukuda-Kurahasi , Yumeka Mine , Shigehisa Aoki , Kazutaka Nakashima , Hiroaki Miyoshi , Koichi Ohshima , Atsushi Kawaguchi , Shinya Kimura","doi":"10.1016/j.bneo.2025.100155","DOIUrl":"10.1016/j.bneo.2025.100155","url":null,"abstract":"<div><h3>Abstract</h3><div>Double-hit lymphoma (DHL), an aggressive B-cell lymphoma with a poor prognosis, harbors rearrangements of <em>MYC</em> and <em>BCL2</em>. The standard chemoimmunotherapy comprising R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) yields an unsatisfactory treatment response. Hypomethylating agents increase the susceptibility to malignant lymphoma via the restoration of tumor suppressor genes. Decitabine not only inhibits DNA methylation but also causes mitotic disruption, which leads to antileukemia effects through the covalent binding of DNA methyltransferase 1 to DNA. Previously, we developed an orally bioavailable prodrug of decitabine (OR-2100). Here, we investigated the efficacy and underlying mechanism of OR-2100 as a treatment for DHL. OR-2100 alone or in combination with key antilymphoma drugs, including doxorubicin and vincristine, suppressed the in vitro proliferation of DHL cell lines, particularly those with wild-type <em>TP53</em>. OR-2100 induced downregulation of <em>CDCA8</em> and <em>BIRC5</em> (baculoviral IAP [inhibitor of apoptosis] repeat–containing 5), the knockdown of which suppressed the proliferation of DHL cell lines. Both OR-2100 treatment and <em>CDCA8</em> knockdown led to mitotic perturbation, suggesting that the disruption of mitosis may underlie the antitumor mechanism of OR-2100 given that the efficacy of OR-2100 was dependent on the <em>TP53</em> status and that <em>CDCA8</em> and <em>BIRC5</em> are downstream targets of the E2F1 pathway. These findings suggest that the antitumor activity of OR-2100 may be mediated through inhibition of the E2F1 pathway. The combination of CHOP and OR-2100 reduced the tumor weight significantly in a xenograft mouse model without increased toxicities. The induction of mitotic perturbation might be a key antilymphoma mechanism for OR-2100, and the combination of OR-2100 and CHOP might be a promising treatment strategy for DHL.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"2 4","pages":"Article 100155"},"PeriodicalIF":0.0,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145220798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-04DOI: 10.1016/j.bneo.2025.100152
Curtis A. Lachowiez , B. Douglas Smith , Alexander Joseph Ambinder , Gary Binder , Anne Angiolillo , Ravi Potluri , Eros Papademetriou , Thomas W. LeBlanc
Abstract
Approximately 10% of patients with newly diagnosed acute myeloid leukemia (ND-AML) harbor the isocitrate dehydrogenase 1 gene mutation (mIDH1). In this real-world study evaluating ivosidenib (IVO) + hypomethylating agents (HMAs; n = 181) vs venetoclax (VEN) + HMAs (n = 99) in patients with mIDH1 ND-AML, those treated with IVO+HMA had higher rates of complete remission (CR; 42.5% vs 26.3%; P = .007), higher rates of composite CR + CR with incomplete platelet count recovery (63.0% vs 48.5%; P = .019), shorter median time to best response (3.3 vs 4.1 months; P = .006), and improved 6-month event-free survival (55.8% vs 38.4%; P = .006). Most patients treated with VEN received well under 28 days of VEN per cycle, likely due to anticipation of toxicity; outcomes with this short-schedule VEN were proportionately worse with fewer days of exposure per cycle. The between-group rate of grade ≥3 adverse events was similar within 30 days of treatment initiation, except for higher rates of febrile neutropenia for VEN+HMA vs IVO+HMA (8.1% vs 1.7%; P = .008). These findings support results from the phase 3 AGILE trial demonstrating IVO+HMA’s efficacy and favorable toxicity profile in patients with mIDH1 ND-AML. IVO + azacitidine should be considered as the preferred standard of care treatment regimen in this patient subgroup.
大约10%的新诊断急性髓性白血病（ND-AML）患者携带异柠檬酸脱氢酶1基因突变（mIDH1）。在这个现实世界研究评估ivosidenib(伊)+ hypomethylating代理(HMAs; n = 181)、venetoclax (VEN) + HMAs (n = 99)患者mIDH1 ND-AML,那些接受伊+协会有更高的完全缓解率(CR; 42.5% vs 26.3%; P = .007),较高的复合CR + CR与不完整的血小板恢复(63.0% vs 48.5%; P = .019),更短的平均时间最好的回应(3.3 vs 4.1个月;P = .006),和改善生存6个月风平浪静(55.8% vs 38.4%; P = .006)。大多数接受VEN治疗的患者每个周期接受的VEN少于28天，可能是由于预期毒性；随着每个周期暴露天数的减少，这种短时间VEN的结果成比例地更差。在治疗开始的30天内，组间≥3级不良事件发生率相似，除了VEN+HMA与IVO+HMA的发热性中性粒细胞减少率更高（8.1% vs 1.7%; P = 0.008）。这些发现支持了3期AGILE试验的结果，表明IVO+HMA对mIDH1 ND-AML患者的疗效和良好的毒性特征。IVO +阿扎胞苷应被视为该患者亚组的首选标准护理治疗方案。
{"title":"Ivosidenib or venetoclax combined with hypomethylating agents in IDH1-mutated acute myeloid leukemia: a real-world study","authors":"Curtis A. Lachowiez , B. Douglas Smith , Alexander Joseph Ambinder , Gary Binder , Anne Angiolillo , Ravi Potluri , Eros Papademetriou , Thomas W. LeBlanc","doi":"10.1016/j.bneo.2025.100152","DOIUrl":"10.1016/j.bneo.2025.100152","url":null,"abstract":"<div><h3>Abstract</h3><div>Approximately 10% of patients with newly diagnosed acute myeloid leukemia (ND-AML) harbor the isocitrate dehydrogenase 1 gene mutation (m<em>IDH1</em>). In this real-world study evaluating ivosidenib (IVO) + hypomethylating agents (HMAs; n = 181) vs venetoclax (VEN) + HMAs (n = 99) in patients with m<em>IDH1</em> ND-AML, those treated with IVO+HMA had higher rates of complete remission (CR; 42.5% vs 26.3%; <em>P</em> = .007), higher rates of composite CR + CR with incomplete platelet count recovery (63.0% vs 48.5%; <em>P</em> = .019), shorter median time to best response (3.3 vs 4.1 months; <em>P</em> = .006), and improved 6-month event-free survival (55.8% vs 38.4%; <em>P</em> = .006). Most patients treated with VEN received well under 28 days of VEN per cycle, likely due to anticipation of toxicity; outcomes with this short-schedule VEN were proportionately worse with fewer days of exposure per cycle. The between-group rate of grade ≥3 adverse events was similar within 30 days of treatment initiation, except for higher rates of febrile neutropenia for VEN+HMA vs IVO+HMA (8.1% vs 1.7%; <em>P</em> = .008). These findings support results from the phase 3 AGILE trial demonstrating IVO+HMA’s efficacy and favorable toxicity profile in patients with m<em>IDH1</em> ND-AML. IVO + azacitidine should be considered as the preferred standard of care treatment regimen in this patient subgroup.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"2 4","pages":"Article 100152"},"PeriodicalIF":0.0,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145095526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-04DOI: 10.1016/j.bneo.2025.100150
June-Wha Rhee ∗ , Nicole Lamanna ∗ , Wassim Aldairy , Lipeng Chen , Jun Zhang , Dulce Ramirez , William B. White
Abstract
Hypertension is a common side effect of Bruton tyrosine kinase inhibitors (BTKis). The second-generation BTKi zanubrutinib has high BTK selectivity, which may minimize off-target effects. A phase 3 trial (ALPINE) demonstrated improved efficacy and safety of zanubrutinib vs ibrutinib in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). To better understand hypertension risk with zanubrutinib vs ibrutinib in ALPINE, this post hoc analysis evaluated hypertension development by measuring antihypertensive therapy initiation. Eligible adults with R/R CLL/SLL were randomized to zanubrutinib 160 mg twice-a-day or ibrutinib 420 mg daily until disease progression/unacceptable toxicity. Differences in treatment-emergent hypertension, antihypertensive therapy use and changes in blood pressure were evaluated. Of 648 patients (zanubrutinib, n = 324; ibrutinib, n = 324), nearly half used antihypertensive therapy at baseline (zanubrutinib, 48%; ibrutinib, 45%). With zanubrutinib vs ibrutinib, initiation of a new antihypertensive agent (28% vs 32%) or new antihypertensive class (24% vs 29%) were comparable. In patients without baseline antihypertensive therapy, 21% vs 29% with zanubrutinib vs ibrutinib, respectively, initiated new antihypertensive therapy. In all patients, time-to-initiation of a new antihypertensive class was longer with zanubrutinib vs ibrutinib; in those without baseline antihypertensive therapy, time-to-initiation of a new antihypertensive agent was also longer. Mean systolic blood pressure changes were lower with zanubrutinib vs ibrutinib. In conclusion, zanubrutinib was associated with longer time to initiation of antihypertensive therapy compared with ibrutinib in ALPINE. These findings could be of clinical importance when initiating BTKi therapy in patients with CLL/SLL. This trial was registered at www.ClinicalTrials.gov as #NCT03734016.
高血压是布鲁顿酪氨酸激酶抑制剂（BTKis）的常见副作用。第二代BTKi zanubrutinib具有较高的BTK选择性，可以最大限度地减少脱靶效应。一项3期试验（ALPINE）表明，zanubrutinib与ibrutinib在复发/难治性（R/R）慢性淋巴细胞白血病(CLL)/小淋巴细胞淋巴瘤（SLL）患者中的疗效和安全性有所提高。为了更好地了解扎鲁替尼与伊鲁替尼在ALPINE患者中的高血压风险，本事后分析通过测量抗高血压治疗的开始来评估高血压的发展。符合条件的成年R/R CLL/SLL患者随机接受扎鲁替尼160 mg /天2次或伊鲁替尼420 mg /天，直到疾病进展/不可接受的毒性。评估两组在治疗突发性高血压、抗高血压治疗使用和血压变化方面的差异。在648例患者（zanubrutinib, n = 324; ibrutinib, n = 324）中，近一半在基线时使用降压治疗（zanubrutinib, 48%; ibrutinib, 45%）。扎鲁替尼与伊鲁替尼，开始使用新的抗高血压药物（28% vs 32%）或开始使用新的抗高血压药物（24% vs 29%）具有可比性。在没有基线抗高血压治疗的患者中，分别有21%和29%的扎鲁替尼和伊鲁替尼开始了新的抗高血压治疗。在所有患者中，扎鲁替尼比伊鲁替尼开始新的抗高血压药物类别所需的时间更长；在没有基线抗高血压治疗的患者中，开始使用新的抗高血压药物的时间也更长。与依鲁替尼相比，扎鲁替尼组的平均收缩压变化更低。总之，与依鲁替尼相比，扎鲁替尼与ALPINE患者开始抗高血压治疗的时间更长相关。这些发现可能对CLL/SLL患者启动BTKi治疗具有临床重要性。该试验在www.ClinicalTrials.gov注册为#NCT03734016。
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Pub Date : 2025-08-04DOI: 10.1016/j.bneo.2025.100149
Karla C. Fischer , Veronique Litalien , Sarah T. Diepstraten , Michelle Jahja , Fiona C. Brown , Gemma L. Kelly , Andrew H. Wei , Suzanne Cory
Abstract
Deregulated expression of the transcription factor c-MYC is well established as a primary driver of diverse tumor types. In this study, for the first time to our knowledge, we show that mouse and human myeloid leukemias provoked by oncogenic mixed lineage leukemia (MLL) fusion proteins are dependent on the MYC family member MNT (MAX network transcriptional repressor), which is highly expressed in these AMLs. To investigate the role of MNT, we generated Mnt-deletable murine MLL::AF9 acute myeloid leukemias (AMLs), using the well-studied hemopoietic reconstitution model. Mnt deletion provoked the apoptosis of MLL::AF9 AML cells in vitro and increased apoptosis elicited by the BH3 (BCL-2 homology region 3) mimetic drugs S63845 (MCL-1 (Myeloid cell leukemia-1) specific), ABT-199/Venetoclax (BCL-2 (B-cell lymphoma-2) specific), and A-1331852 (BCL-XL (B-cell lymphoma-extra large) specific). Remarkably, by inducing Mnt deletion in vivo in transplanted MLL::AF9 AMLs, we significantly extended the survival of transplant recipients (P < .0001), 50% of which became leukemia free. Using inducible CRISPR/Cas9, we also showed that 3 of 4 human AML cell lines were more potently killed in vitro by BH3 mimetic drugs after MNT deletion. Of note, inducing MNT deletion in a human MLL-rearranged AML cell line transplanted into NSG (NOD SCID Gamma) mice debulked established leukemia and significantly extended the survival of transplant recipients. Taken together with previous studies that demonstrated a critical role for MNT in the development and sustained expansion of B and T lymphomas, our results suggest that a small molecule inhibiting MNT function may be a valuable therapeutic agent for myeloid and lymphoid malignancies.
{"title":"MNT: a new target for AML","authors":"Karla C. Fischer , Veronique Litalien , Sarah T. Diepstraten , Michelle Jahja , Fiona C. Brown , Gemma L. Kelly , Andrew H. Wei , Suzanne Cory","doi":"10.1016/j.bneo.2025.100149","DOIUrl":"10.1016/j.bneo.2025.100149","url":null,"abstract":"<div><h3>Abstract</h3><div>Deregulated expression of the transcription factor c-MYC is well established as a primary driver of diverse tumor types. In this study, for the first time to our knowledge, we show that mouse and human myeloid leukemias provoked by oncogenic mixed lineage leukemia (MLL) fusion proteins are dependent on the MYC family member MNT (MAX network transcriptional repressor), which is highly expressed in these AMLs. To investigate the role of MNT, we generated <em>Mnt-</em>deletable murine <em>MLL::AF9</em> acute myeloid leukemias (AMLs), using the well-studied hemopoietic reconstitution model. <em>Mnt</em> deletion provoked the apoptosis of <em>MLL::AF9</em> AML cells in vitro and increased apoptosis elicited by the BH3 (BCL-2 homology region 3) mimetic drugs S63845 (MCL-1 (Myeloid cell leukemia-1) specific), ABT-199/Venetoclax (BCL-2 (B-cell lymphoma-2) specific), and A-1331852 (BCL-X<sub>L</sub> (B-cell lymphoma-extra large) specific). Remarkably, by inducing <em>Mnt</em> deletion in vivo in transplanted <em>MLL::AF9</em> AMLs, we significantly extended the survival of transplant recipients (<em>P</em> < .0001), 50% of which became leukemia free. Using inducible CRISPR/Cas9, we also showed that 3 of 4 human AML cell lines were more potently killed in vitro by BH3 mimetic drugs after <em>MNT</em> deletion. Of note, inducing <em>MNT</em> deletion in a human <em>MLL-</em>rearranged AML cell line transplanted into NSG (NOD SCID Gamma) mice debulked established leukemia and significantly extended the survival of transplant recipients. Taken together with previous studies that demonstrated a critical role for MNT in the development and sustained expansion of B and T lymphomas, our results suggest that a small molecule inhibiting MNT function may be a valuable therapeutic agent for myeloid and lymphoid malignancies.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"2 4","pages":"Article 100149"},"PeriodicalIF":0.0,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145266416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bendamustine is one of the primary chemotherapeutic agents for the treatment of B-cell lymphomas, whereas its toxicity to T cells is associated with a high rate of infectious complications and a potential negative impact on subsequent immunotherapies. Bendamustine has previously been reported to be a potent in vitro inhibitor of HOIP, the catalytic subunit of the linear ubiquitin chain assembly complex (LUBAC). Because LUBAC functions as a checkpoint for tumor necrosis factor receptor superfamily (TNFRSF)–induced cell death, we hypothesized that bendamustine may have specific activity on the CD40 or BAFF-R signaling in B-cell lymphomas. In a cell culture assay, we found that bendamustine not only suppressed CD40L- and BAFF-driven NF-κB signaling in B-cell lymphomas but also induced higher cell death in the presence of these signals, a phenomenon not typical of other chemotherapeutic agents. Bendamustine resistance was shown to be driven by knockout of TRAF3, a mediator of CD40 and BAFF-R signaling. Importantly, the toxic effect of bendamustine on T cells was also found to be associated with another TNFRSF molecule, OX40. Pretreatment with an antibody blocking OX40-OX40L signaling attenuated bendamustine-induced T-cell depletion in mice, whereas preserving the cytotoxic effect of bendamustine on transplanted B-cell lymphoma. In conclusion, both the antilymphoma effect and the T-lymphopenia induced by bendamustine are associated with TNFRSF signaling, and the T-cell toxicity can be separately controlled by blocking OX40 signaling before bendamustine administration.
{"title":"Bendamustine switches TNF receptor superfamily signal from a survival to a death signal in B-cell lymphomas","authors":"Kensuke Nakao , Hiroshi Arima , Yui Arakawa , Tomoyasu Jo , Yujuan Guo , Iroha Morita , Tomohiro Taya , Toshio Kitawaki , Akifumi Takaori-Kondo , Momoko Nishikori","doi":"10.1016/j.bneo.2025.100157","DOIUrl":"10.1016/j.bneo.2025.100157","url":null,"abstract":"<div><h3>Abstract</h3><div>Bendamustine is one of the primary chemotherapeutic agents for the treatment of B-cell lymphomas, whereas its toxicity to T cells is associated with a high rate of infectious complications and a potential negative impact on subsequent immunotherapies. Bendamustine has previously been reported to be a potent in vitro inhibitor of HOIP, the catalytic subunit of the linear ubiquitin chain assembly complex (LUBAC). Because LUBAC functions as a checkpoint for tumor necrosis factor receptor superfamily (TNFRSF)–induced cell death, we hypothesized that bendamustine may have specific activity on the CD40 or BAFF-R signaling in B-cell lymphomas. In a cell culture assay, we found that bendamustine not only suppressed CD40L- and BAFF-driven NF-κB signaling in B-cell lymphomas but also induced higher cell death in the presence of these signals, a phenomenon not typical of other chemotherapeutic agents. Bendamustine resistance was shown to be driven by knockout of TRAF3, a mediator of CD40 and BAFF-R signaling. Importantly, the toxic effect of bendamustine on T cells was also found to be associated with another TNFRSF molecule, OX40. Pretreatment with an antibody blocking OX40-OX40L signaling attenuated bendamustine-induced T-cell depletion in mice, whereas preserving the cytotoxic effect of bendamustine on transplanted B-cell lymphoma. In conclusion, both the antilymphoma effect and the T-lymphopenia induced by bendamustine are associated with TNFRSF signaling, and the T-cell toxicity can be separately controlled by blocking OX40 signaling before bendamustine administration.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"2 4","pages":"Article 100157"},"PeriodicalIF":0.0,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145266587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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