Pub Date : 2024-09-01DOI: 10.1016/j.bneo.2024.100029
Emma Kroeze , Michelle M. Kleisman , Rico Hagelaar , Reno S. Bladergroen , Lennart A. Kester , Marijn A. Scheijde-Vermeulen , Freerk van Dijk , Jules P. P. Meijerink , Roland P. Kuiper ∗ , Jan L. C. Loeffen ∗
{"title":"T-cell lymphoblastic lymphoma compared with T-cell acute lymphoblastic leukemia: similar subtypes and different fusions","authors":"Emma Kroeze , Michelle M. Kleisman , Rico Hagelaar , Reno S. Bladergroen , Lennart A. Kester , Marijn A. Scheijde-Vermeulen , Freerk van Dijk , Jules P. P. Meijerink , Roland P. Kuiper ∗ , Jan L. C. Loeffen ∗","doi":"10.1016/j.bneo.2024.100029","DOIUrl":"10.1016/j.bneo.2024.100029","url":null,"abstract":"","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"1 3","pages":"Article 100029"},"PeriodicalIF":0.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2950328024000293/pdfft?md5=106dbe0b44388c3c2db4943f247d880b&pid=1-s2.0-S2950328024000293-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142095184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-28DOI: 10.1016/j.bneo.2024.100037
Sara H. Small , Ricardo E. Perez , Elspeth M. Beauchamp , Aneta H. Baran , Stephen D. Willis , Mariafausta Fischietti , Michael Schieber , Masha Kocherginsky , Diana Saleiro , Leonidas C. Platanias
Abstract
Chemoresistance represents an ongoing challenge in treating patients with acute myeloid leukemia (AML), and a better understanding of the resistance mechanisms can lead to the development of novel AML therapies. Here, we demonstrated that low expression of the DNA damage response gene Schlafen 11 (SLFN11) correlates with poor overall survival and worse prognosis in patients with AML. Moreover, we showed that SLFN11 plays an essential role in regulating chemotherapy sensitivity in AML. AML cells with suppressed levels of SLFN11 do not undergo apoptosis in response to cytarabine because of aberrant activation of the Ataxia telangiectasia and Rad3-related protein (ATR)/Checkpoint kinase 1 (Chk1) pathway, allowing for DNA damage repair, whereas sensitivity to cytarabine can be restored by inhibiting the ATR pathway. Importantly, SLFN11 knockout AML cells retain sensitivity to hypomethylating agents and the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax. Altogether, these results reveal SLFN11 as an important regulator and predictor of chemotherapy sensitivity in AML and suggest that targeting pathways suppressed by SLFN11 may offer potential combination therapies to enhance and optimize chemotherapy responses in AML.
摘要抗化疗是治疗急性髓性白血病（AML）患者的一个持续挑战，更好地了解抗化疗机制有助于开发新的AML疗法。在这里，我们证明了DNA损伤应答基因Schlafen 11（SLFN11）的低表达与急性髓性白血病患者的总生存率低和预后差相关。此外，我们还发现，SLFN11 在调节 AML 化疗敏感性方面起着至关重要的作用。由于共济失调毛细血管扩张症和 Rad3 相关蛋白（ATR）/检查点激酶 1（Chk1）通路的异常激活，SLFN11 水平受抑制的 AML 细胞不会对阿糖胞苷产生凋亡反应，从而进行 DNA 损伤修复，而对阿糖胞苷的敏感性可通过抑制 ATR 通路得到恢复。重要的是，SLFN11基因敲除的急性髓细胞保持了对低甲基化药物和B细胞淋巴瘤2（BCL-2）抑制剂venetoclax的敏感性。总之，这些结果揭示了 SLFN11 是急性髓细胞性白血病化疗敏感性的重要调节因子和预测因子，并表明针对 SLFN11 抑制的通路可能提供潜在的联合疗法，以增强和优化急性髓细胞性白血病的化疗反应。
{"title":"Targeting SLFN11-regulated pathways restores chemotherapy sensitivity in AML","authors":"Sara H. Small , Ricardo E. Perez , Elspeth M. Beauchamp , Aneta H. Baran , Stephen D. Willis , Mariafausta Fischietti , Michael Schieber , Masha Kocherginsky , Diana Saleiro , Leonidas C. Platanias","doi":"10.1016/j.bneo.2024.100037","DOIUrl":"10.1016/j.bneo.2024.100037","url":null,"abstract":"<div><h3>Abstract</h3><div>Chemoresistance represents an ongoing challenge in treating patients with acute myeloid leukemia (AML), and a better understanding of the resistance mechanisms can lead to the development of novel AML therapies. Here, we demonstrated that low expression of the DNA damage response gene Schlafen 11 (<em>SLFN11</em>) correlates with poor overall survival and worse prognosis in patients with AML. Moreover, we showed that SLFN11 plays an essential role in regulating chemotherapy sensitivity in AML. AML cells with suppressed levels of SLFN11 do not undergo apoptosis in response to cytarabine because of aberrant activation of the Ataxia telangiectasia and Rad3-related protein (ATR)/Checkpoint kinase 1 (Chk1) pathway, allowing for DNA damage repair, whereas sensitivity to cytarabine can be restored by inhibiting the ATR pathway. Importantly, <em>SLFN11</em> knockout AML cells retain sensitivity to hypomethylating agents and the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax. Altogether, these results reveal <em>SLFN11</em> as an important regulator and predictor of chemotherapy sensitivity in AML and suggest that targeting pathways suppressed by SLFN11 may offer potential combination therapies to enhance and optimize chemotherapy responses in AML.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"1 4","pages":"Article 100037"},"PeriodicalIF":0.0,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142573254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-28DOI: 10.1016/j.bneo.2024.100039
Jinjun Cheng , Rachel Mariani , Jyotinder Nain Punia , Marimar de la Cruz Bonilla , Pichayut Nithagon , Metin Ozdemirli , Wen Shuai , Larry Wang , Oussama Abla , Shunyou Gong
{"title":"Clinical and pathological features of pediatric peripheral T-cell lymphoma after solid organ transplantation","authors":"Jinjun Cheng , Rachel Mariani , Jyotinder Nain Punia , Marimar de la Cruz Bonilla , Pichayut Nithagon , Metin Ozdemirli , Wen Shuai , Larry Wang , Oussama Abla , Shunyou Gong","doi":"10.1016/j.bneo.2024.100039","DOIUrl":"10.1016/j.bneo.2024.100039","url":null,"abstract":"","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"1 4","pages":"Article 100039"},"PeriodicalIF":0.0,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142319509","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-28DOI: 10.1016/j.bneo.2024.100038
Kuo-Kai Chin ∗ , Yannis Valtis ∗ , Andriy Derkach , Meira Yisraeli Salman , Leora Boussi , Jenna Ciervo , Mark B. Geyer , Jae H. Park , Martin S. Tallman , Jacob L. Glass , Aaron D. Goldberg , Eytan M. Stein
Abstract
The combination of a hypomethylating agent (HMA) and venetoclax (VEN) is approved for adults aged >75 years with newly diagnosed acute myeloid leukemia (AML) as well as those ineligible for intensive chemotherapy (IC). HMA/VEN is increasingly substituted for IC in adults with AML aged <75 years, particularly in those with adverse cytogenetic and molecular features. When patients fail to respond or relapse after HMA/VEN, the utility of salvage IC is largely unknown. We performed a retrospective single-institution study and identified 46 patients who received IC after HMA/VEN, including 24 patients who received HMA/VEN as their first treatment for AML. This population had complete remission (CR)/CR with incomplete count recovery (CRi)/morphologic leukemia-free state rate of 37%, CR/CRi rate of 28%, and a median overall survival (mOS) of 7.2 months (95% confidence interval, 5.0-10.3). Patients who relapsed after an initial response to HMA/VEN and subsequently received IC were more likely to achieve a CR/CRi than those refractory to HMA/VEN (50% vs 19%; P = .04), although there was no statistically significant difference in survival (mOS, 8.8 vs 5.4 months; P = .64). Age >65 years predicted poorer survival (mOS, 4.3 vs 10.6 months; P < .001). IC after HMA/VEN should be further studied and chosen with caution.
摘要低甲基化药物（HMA）和 Venetoclax（VEN）的联合用药已被批准用于年龄为 75 岁的新诊断急性髓性白血病（AML）成人患者以及不符合强化化疗（IC）条件的患者。在 75 岁的成人急性髓细胞白血病患者中，HMA/VEN 越来越多地取代 IC，尤其是那些细胞遗传学和分子特征不良的患者。当患者接受HMA/VEN治疗后无反应或复发时，挽救性IC的效用在很大程度上还不得而知。我们进行了一项单机构回顾性研究，确定了 46 名在 HMA/VEN 后接受 IC 治疗的患者，其中包括 24 名首次接受 HMA/VEN 治疗的急性髓细胞性白血病患者。这些患者的完全缓解（CR）/CR伴不完全计数恢复（CRi）/无形态白血病状态率为37%，CR/CRi率为28%，中位总生存期（mOS）为7.2个月（95%置信区间，5.0-10.3）。与HMA/VEN难治性患者相比，HMA/VEN初始反应后复发并随后接受IC治疗的患者更有可能获得CR/CRi（50% vs 19%；P = .04），但生存期（mOS，8.8个月 vs 5.4个月；P = .64）没有显著统计学差异。65岁的患者生存率较低（mOS，4.3 个月 vs 10.6 个月；P = .001）。应进一步研究 HMA/VEN 后的 IC，并谨慎选择。
{"title":"Intensive chemotherapy after hypomethylating agent and venetoclax in adult acute myeloid leukemia","authors":"Kuo-Kai Chin ∗ , Yannis Valtis ∗ , Andriy Derkach , Meira Yisraeli Salman , Leora Boussi , Jenna Ciervo , Mark B. Geyer , Jae H. Park , Martin S. Tallman , Jacob L. Glass , Aaron D. Goldberg , Eytan M. Stein","doi":"10.1016/j.bneo.2024.100038","DOIUrl":"10.1016/j.bneo.2024.100038","url":null,"abstract":"<div><h3>Abstract</h3><div>The combination of a hypomethylating agent (HMA) and venetoclax (VEN) is approved for adults aged >75 years with newly diagnosed acute myeloid leukemia (AML) as well as those ineligible for intensive chemotherapy (IC). HMA/VEN is increasingly substituted for IC in adults with AML aged <75 years, particularly in those with adverse cytogenetic and molecular features. When patients fail to respond or relapse after HMA/VEN, the utility of salvage IC is largely unknown. We performed a retrospective single-institution study and identified 46 patients who received IC after HMA/VEN, including 24 patients who received HMA/VEN as their first treatment for AML. This population had complete remission (CR)/CR with incomplete count recovery (CRi)/morphologic leukemia-free state rate of 37%, CR/CRi rate of 28%, and a median overall survival (mOS) of 7.2 months (95% confidence interval, 5.0-10.3). Patients who relapsed after an initial response to HMA/VEN and subsequently received IC were more likely to achieve a CR/CRi than those refractory to HMA/VEN (50% vs 19%; <em>P</em> = .04), although there was no statistically significant difference in survival (mOS, 8.8 vs 5.4 months; <em>P</em> = .64). Age >65 years predicted poorer survival (mOS, 4.3 vs 10.6 months; <em>P</em> < .001). IC after HMA/VEN should be further studied and chosen with caution.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"1 4","pages":"Article 100038"},"PeriodicalIF":0.0,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-28DOI: 10.1016/j.bneo.2024.100036
Elizabeth A. Brem , Kevin Shieh , Dennis Juarez , Roberta Buono , Deepa Jeyakumar , Susan O’Brien , Thomas H. Taylor , David A. Fruman
{"title":"A phase 1 study adding pitavastatin to venetoclax therapy in AML and CLL/SLL: a mechanism-based drug repurposing strategy","authors":"Elizabeth A. Brem , Kevin Shieh , Dennis Juarez , Roberta Buono , Deepa Jeyakumar , Susan O’Brien , Thomas H. Taylor , David A. Fruman","doi":"10.1016/j.bneo.2024.100036","DOIUrl":"10.1016/j.bneo.2024.100036","url":null,"abstract":"","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"1 4","pages":"Article 100036"},"PeriodicalIF":0.0,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142423516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-28DOI: 10.1016/j.bneo.2024.100035
Robert J. Kreitman , Lacey James , Julie Feurtado , Holly Eager , Olena Sierra Ortiz , Mory Gould , Isaac Shpilman , Hong Zhou , Peter D. Burbelo , Jeffrey I. Cohen , Hao-Wei Wang , Constance M. Yuan , Evgeny Arons
Abstract
Patients with the B-cell malignancy hairy cell leukemia (HCL) and the poorer-prognosis variant HCLv often receive anti-CD20 monoclonal antibodies (mAbs), which kill normal B cells, impairing humoral immunity. We measured COVID-19 antibodies after doses of COVID-19 vaccine in patients with HCL (n = 415) and HCLv (n = 32). After the second COVID-19 vaccine dose, spike antibody level most strongly correlated with normal B-cell levels (r = 0.365, P < .0001), followed by CD4+ T-cell count (r = 0.244, P = .0002), and was less related to immunoglobulin G level (r = 0.101, P = .14). Spike antibody also correlated with normal B cells after the third to fifth vaccine doses and with CD4+ count after the third dose. Normal B-cells were undetectable in 87% of patients within 6 months after the last dose of anti-CD20 mAb and were lower than in patients at 6 to 12 months (P = .0003), which, in turn, were lower than at 12 to 18 months (P = .0002). Infection with COVID-19 became more common after use of the third vaccine dose; spike antibody levels were higher in patients with prior infection (positive vs negative nucleocapsid antibodies; P < .0001). Spike antibodies decreased faster after ibrutinib or anti-CD20 mAb. We conclude that decreased levels of normal B cells in patients with HCL/HCLv, due to disease and/or anti-CD20 therapy, are associated with lower COVID-19 vaccination efficiency and such patients may not respond well to vaccines. The associated studies were registered at www.ClinicalTrials.gov as #NCT01087333 (HCL/HCLv) and #NCT04362865 (COVID-19).
摘要B细胞恶性肿瘤毛细胞白血病（HCL）和预后较差的变异型HCLv患者经常接受抗CD20单克隆抗体（mAbs）治疗，这种抗体会杀死正常B细胞，损害体液免疫。我们在HCL（415人）和HCLv（32人）患者注射COVID-19疫苗后测量了COVID-19抗体。第二剂 COVID-19 疫苗接种后，尖峰抗体水平与正常 B 细胞水平的相关性最强（r = 0.365，P < .0001），其次是 CD4+ T 细胞计数（r = 0.244，P = .0002），与免疫球蛋白 G 水平的相关性较小（r = 0.101，P = .14）。尖峰抗体还与第三至第五剂疫苗接种后的正常 B 细胞以及第三剂疫苗接种后的 CD4+ 细胞计数相关。87%的患者在最后一剂抗CD20 mAb后6个月内检测不到正常B细胞，低于6至12个月时的水平（P = .0003），而后者又低于12至18个月时的水平（P = .0002）。使用第三剂疫苗后，COVID-19 感染变得更加常见；之前感染过的患者的尖峰抗体水平更高（核头抗体阳性与阴性；P < .0001）。使用伊布替尼或抗 CD20 mAb 后，尖峰抗体下降更快。我们的结论是，由于疾病和/或抗CD20治疗，HCL/HCLv患者正常B细胞水平下降与COVID-19疫苗接种效率降低有关，这类患者可能对疫苗反应不佳。相关研究已在 www.ClinicalTrials.gov 注册，注册号为 #NCT01087333（HCL/HCLv）和 #NCT04362865（COVID-19）。
{"title":"COVID-19 vaccination in patients with classic and variant hairy cell leukemia","authors":"Robert J. Kreitman , Lacey James , Julie Feurtado , Holly Eager , Olena Sierra Ortiz , Mory Gould , Isaac Shpilman , Hong Zhou , Peter D. Burbelo , Jeffrey I. Cohen , Hao-Wei Wang , Constance M. Yuan , Evgeny Arons","doi":"10.1016/j.bneo.2024.100035","DOIUrl":"10.1016/j.bneo.2024.100035","url":null,"abstract":"<div><h3>Abstract</h3><div>Patients with the B-cell malignancy hairy cell leukemia (HCL) and the poorer-prognosis variant HCLv often receive anti-CD20 monoclonal antibodies (mAbs), which kill normal B cells, impairing humoral immunity. We measured COVID-19 antibodies after doses of COVID-19 vaccine in patients with HCL (n = 415) and HCLv (n = 32). After the second COVID-19 vaccine dose, spike antibody level most strongly correlated with normal B-cell levels (r = 0.365, <em>P</em> < .0001), followed by CD4<sup>+</sup> T-cell count (r = 0.244, <em>P</em> = .0002), and was less related to immunoglobulin G level (r = 0.101, <em>P</em> = .14). Spike antibody also correlated with normal B cells after the third to fifth vaccine doses and with CD4<sup>+</sup> count after the third dose. Normal B-cells were undetectable in 87% of patients within 6 months after the last dose of anti-CD20 mAb and were lower than in patients at 6 to 12 months (<em>P</em> = .0003), which, in turn, were lower than at 12 to 18 months (<em>P</em> = .0002). Infection with COVID-19 became more common after use of the third vaccine dose; spike antibody levels were higher in patients with prior infection (positive vs negative nucleocapsid antibodies; <em>P</em> < .0001). Spike antibodies decreased faster after ibrutinib or anti-CD20 mAb. We conclude that decreased levels of normal B cells in patients with HCL/HCLv, due to disease and/or anti-CD20 therapy, are associated with lower COVID-19 vaccination efficiency and such patients may not respond well to vaccines. The associated studies were registered at <span><span>www.ClinicalTrials.gov</span><svg><path></path></svg></span> as #NCT01087333 (HCL/HCLv) and #NCT04362865 (COVID-19).</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"1 4","pages":"Article 100035"},"PeriodicalIF":0.0,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-31DOI: 10.1016/j.bneo.2024.100031
Paola Ghione , Kurt S. Bantilan , Erel Joffe , M. Lia Palomba , Ariela Noy , Philip Caron , Paul Hamlin , Anita Kumar , Matthew Matasar , Colette Owens , Alison Moskowitz , Lorenzo Falchi , David Straus , Steven Horwitz , Gilles Salles , Ahmet Dogan ∗ , Andrew D. Zelenetz ∗
Abstract
The prognostic relevance of CD5 expression in marginal zone lymphoma (MZL) remains poorly characterized. We aimed to compare baseline characteristics and outcomes of patients with CD5+ MZL and CD5– historical matched controls. We hypothesized that patients with CD5+ MZL may have similarities to other CD5– expressing B-cell lymphomas, which may be informative when considering alternative therapeutic approaches for this MZL subgroup. We retrospectively analyzed 64 patients with CD5+ MZL and 137 CD5– MZL controls matched on age at diagnosis and sex. The CD5+ and CD5– cases did not differ in terms of mucosa assiociated lymphoid tissue (MALT)–lymphoma International Prognostic Index or incidence of nodal involvement. Bone marrow involvement was significantly more frequent in CD5+ patients than in CD5– patients (67.5% vs 47.2%; P = .048). Mutated immunoglobulin heavy chain variable region gene was more common in CD5+ patients (80.0%) than CD5– patients (64.0%), but this association was not significant (P = .327). Overall survival was calculated until death from any cause, disease-specific survival until lymphoma-related death, and time from diagnosis to first treatment was calculated either considering all interventions or only systemic treatments. None of these outcomes were associated with CD5 expression.
摘要CD5表达在边缘区淋巴瘤（MZL）中的预后相关性仍不十分明确。我们旨在比较CD5+ MZL患者和CD5-历史匹配对照的基线特征和预后。我们假设 CD5+ MZL 患者可能与其他 CD5 表达的 B 细胞淋巴瘤有相似之处，这在考虑针对这一 MZL 亚群的替代治疗方法时可能具有参考价值。我们对 64 例 CD5+ MZL 患者和 137 例 CD5- MZL 对照组进行了回顾性分析。CD5+和CD5-病例在粘膜相关淋巴组织（MALT）-淋巴瘤国际预后指数或结节受累发生率方面没有差异。CD5+患者骨髓受累的发生率明显高于CD5-患者（67.5% vs 47.2%; P = .048）。免疫球蛋白重链可变区基因突变在CD5+患者（80.0%）中比CD5-患者（64.0%）更常见，但这种关联并不显著（P = .327）。总生存期计算至任何原因死亡为止，疾病特异性生存期计算至淋巴瘤相关死亡为止，从诊断到首次治疗的时间计算考虑了所有干预措施或仅考虑了系统治疗。这些结果均与 CD5 表达无关。
{"title":"CD5 expression in marginal zone lymphoma does not predict inferior outcome and has similarities to indolent lymphomas","authors":"Paola Ghione , Kurt S. Bantilan , Erel Joffe , M. Lia Palomba , Ariela Noy , Philip Caron , Paul Hamlin , Anita Kumar , Matthew Matasar , Colette Owens , Alison Moskowitz , Lorenzo Falchi , David Straus , Steven Horwitz , Gilles Salles , Ahmet Dogan ∗ , Andrew D. Zelenetz ∗","doi":"10.1016/j.bneo.2024.100031","DOIUrl":"10.1016/j.bneo.2024.100031","url":null,"abstract":"<div><h3>Abstract</h3><div>The prognostic relevance of CD5 expression in marginal zone lymphoma (MZL) remains poorly characterized. We aimed to compare baseline characteristics and outcomes of patients with CD5<sup>+</sup> MZL and CD5<sup>–</sup> historical matched controls. We hypothesized that patients with CD5<sup>+</sup> MZL may have similarities to other CD5<sup>–</sup> expressing B-cell lymphomas, which may be informative when considering alternative therapeutic approaches for this MZL subgroup. We retrospectively analyzed 64 patients with CD5<sup>+</sup> MZL and 137 CD5<sup>–</sup> MZL controls matched on age at diagnosis and sex. The CD5<sup>+</sup> and CD5<sup>–</sup> cases did not differ in terms of mucosa assiociated lymphoid tissue (MALT)–lymphoma International Prognostic Index or incidence of nodal involvement. Bone marrow involvement was significantly more frequent in CD5<sup>+</sup> patients than in CD5<sup>–</sup> patients (67.5% vs 47.2%; <em>P</em> = .048). Mutated immunoglobulin heavy chain variable region gene was more common in CD5<sup>+</sup> patients (80.0%) than CD5<sup>–</sup> patients (64.0%), but this association was not significant (<em>P</em> = .327). Overall survival was calculated until death from any cause, disease-specific survival until lymphoma-related death, and time from diagnosis to first treatment was calculated either considering all interventions or only systemic treatments. None of these outcomes were associated with CD5 expression.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"1 4","pages":"Article 100031"},"PeriodicalIF":0.0,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142423599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-31DOI: 10.1016/j.bneo.2024.100032
Ella Troy , Joseph Caporale , Yasemin Sezgin , Marcelo S. F. Pereira , Gregory Behbehani , Justin Lyberger , Dean A. Lee ∗ , Meisam Naeimi Kararoudi ∗
Abstract
CD38 is a metabolically active enzyme broadly expressed on the surface of normal and malignant hematologic cells. It has been targeted clinically with anti-CD38 monoclonal antibodies (mAbs), for which efficacy may be limited by natural killer (NK)–cell fratricide. Isatuximab is an anti-CD38 mAb that uniquely inhibits CD38 metabolic activity. Here, we used CRISPR/adeno-associated virus (AAV) to generate fratricide–resistant and metabolically–enhanced CD38KO/CD38-chimeric antigen receptor (CAR) NK cells using 2 isatuximab-based CD38 single-chain variable fragments (scFvs; reversing heavy and light chain orientation) on the same CD8α/4-1BB/CD3ζ base, and we demonstrate their activity against a range of CD38+ hematologic malignancies (acute myeloid leukemia, multiple myeloma, Burkitt lymphoma, and T-cell leukemia/lymphoma). The cytotoxicity of the CAR NK cells was enhanced by upregulating CD38 expression on the malignant targets with all-trans retinoic acid (ATRA). By generating CD38KO/CD38-CAR T cells using the same engineering approach, we show that the CAR NK cells had higher cytotoxicity than CAR T cells against all hematologic tumor targets. Additionally, AAVS1KO/CD38-CAR NK cells were capable of targeting CD38 without experiencing fratricide and have a similar enhanced metabolic activity via the inhibitory activity of the cis-acting isatuximab-based scFv. Finally, we report fratricide-resistant CD38-CAR NK cells with enhanced metabolism and cytotoxicity toward CD38+ hematologic malignancies, further increased by combination treatment with ATRA.
摘要CD38是一种代谢活性酶，广泛表达于正常和恶性血液细胞表面。临床上，抗 CD38 单克隆抗体（mAbs）一直以其为靶点，但其疗效可能会受到自然杀伤（NK）细胞自相残杀的限制。伊沙妥昔单抗是一种抗 CD38 mAb，它能独特地抑制 CD38 的代谢活性。在这里，我们使用 CRISPR/腺相关病毒（AAV）生成了抗自相残杀和代谢增强的 CD38KO/CD38-嵌合抗原受体（CAR）NK 细胞，其中使用了 2 种基于伊沙妥昔单抗的 CD38 单链可变片段（scFvs；我们证明了它们对一系列 CD38+ 血液恶性肿瘤（急性髓性白血病、多发性骨髓瘤、伯基特淋巴瘤和 T 细胞白血病/淋巴瘤）的活性。）通过全反式维甲酸（ATRA）上调恶性肿瘤靶点的 CD38 表达，增强了 CAR NK 细胞的细胞毒性。通过使用相同的工程方法生成 CD38KO/CD38-CAR T 细胞，我们发现 CAR NK 细胞比 CAR T 细胞对所有血液肿瘤靶点都具有更高的细胞毒性。此外，AAVS1KO/CD38-CAR NK 细胞能够靶向 CD38，而不会发生自相残杀，并且通过顺式作用的伊沙妥昔单抗 scFv 的抑制活性增强了类似的代谢活性。最后，我们报告了抗自相残杀的 CD38-CAR NK 细胞，它们的代谢能力和对 CD38+ 血液恶性肿瘤的细胞毒性都得到了增强，与 ATRA 的联合治疗进一步提高了这种能力。
{"title":"CD38-CAR human NK cells in combination with ATRA enhance cytotoxicity against CD38-expressing hematologic malignancies","authors":"Ella Troy , Joseph Caporale , Yasemin Sezgin , Marcelo S. F. Pereira , Gregory Behbehani , Justin Lyberger , Dean A. Lee ∗ , Meisam Naeimi Kararoudi ∗","doi":"10.1016/j.bneo.2024.100032","DOIUrl":"10.1016/j.bneo.2024.100032","url":null,"abstract":"<div><h3>Abstract</h3><div>CD38 is a metabolically active enzyme broadly expressed on the surface of normal and malignant hematologic cells. It has been targeted clinically with anti-CD38 monoclonal antibodies (mAbs), for which efficacy may be limited by natural killer (NK)–cell fratricide. Isatuximab is an anti-CD38 mAb that uniquely inhibits CD38 metabolic activity. Here, we used CRISPR/adeno-associated virus (AAV) to generate fratricide–resistant and metabolically–enhanced CD38<sup>KO</sup>/CD38-chimeric antigen receptor (CAR) NK cells using 2 isatuximab-based CD38 single-chain variable fragments (scFvs; reversing heavy and light chain orientation) on the same CD8α/4-1BB/CD3ζ base, and we demonstrate their activity against a range of CD38<sup>+</sup> hematologic malignancies (acute myeloid leukemia, multiple myeloma, Burkitt lymphoma, and T-cell leukemia/lymphoma). The cytotoxicity of the CAR NK cells was enhanced by upregulating CD38 expression on the malignant targets with all-trans retinoic acid (ATRA). By generating CD38<sup>KO</sup>/CD38-CAR T cells using the same engineering approach, we show that the CAR NK cells had higher cytotoxicity than CAR T cells against all hematologic tumor targets. Additionally, AAVS1<sup>KO</sup>/CD38-CAR NK cells were capable of targeting CD38 without experiencing fratricide and have a similar enhanced metabolic activity via the inhibitory activity of the cis-acting isatuximab-based scFv. Finally, we report fratricide-resistant CD38-CAR NK cells with enhanced metabolism and cytotoxicity toward CD38<sup>+</sup> hematologic malignancies, further increased by combination treatment with ATRA.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"1 4","pages":"Article 100032"},"PeriodicalIF":0.0,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142319604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-17DOI: 10.1016/j.bneo.2024.100030
Linde Dekker , Coco C. H. de Koning , A. Laura Nijstad , Kim C. M. van der Elst , Rick Admiraal , A. Birgitta Versluijs , Jaap Jan Boelens , Alwin D. R. Huitema , Caroline A. Lindemans ∗ , Stefan Nierkens ∗
{"title":"Effect of clofarabine and fludarabine exposure on outcome after pediatric allogeneic hematopoietic cell transplantation","authors":"Linde Dekker , Coco C. H. de Koning , A. Laura Nijstad , Kim C. M. van der Elst , Rick Admiraal , A. Birgitta Versluijs , Jaap Jan Boelens , Alwin D. R. Huitema , Caroline A. Lindemans ∗ , Stefan Nierkens ∗","doi":"10.1016/j.bneo.2024.100030","DOIUrl":"10.1016/j.bneo.2024.100030","url":null,"abstract":"","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"1 3","pages":"Article 100030"},"PeriodicalIF":0.0,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S295032802400030X/pdfft?md5=a83ce01ede357dd3a3742161f0bb3508&pid=1-s2.0-S295032802400030X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141841000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号