Blood Neoplasia最新文献

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Lenalidomide, ixazomib, or daratumumab maintenance therapy in multiple myeloma 多发性骨髓瘤的来那度胺、伊沙佐米或达拉曲单抗维持疗法

Blood Neoplasia

Pub Date : 2024-09-16 DOI: 10.1016/j.bneo.2024.100042

Abstract

Lenalidomide, ixazomib, and daratumumab have been proposed as maintenance therapies for patients with newly diagnosed multiple myeloma (MM; NDMM). There are, however, no randomized controlled trials (RCTs) comparing them. We conducted a network meta-analysis (NMA) of RCTs comparing these agents against placebo in NDMM. A Bayesian NMA model was used to assess the relative effects of competing treatments on progression-free survival (PFS) and overall survival (OS) in 9 studies including 4115 patients with transplant-eligible MM (TEMM) and 1689 patients with non–transplant-eligible MM (NTEMM). Lenalidomide and daratumumab but not ixazomib were associated with improved PFS compared with placebo in patients with TEMM (lenalidomide [hazard ratio (HR), 0.46; 95% credible interval (CrI), 0.36-0.56]; daratumumab [HR, 0.49; 95% Crl, 0.32-0.76]; and ixazomib [HR, 0.72; 95% CrI, 0.46-1.12]) and those with NTEMM (lenalidomide [HR, 0.46; 95% CrI, 0.29-0.75] and ixazomib [HR, 0.69; 95% CrI, 0.43-1.18]). The PFS benefit for daratumumab was present regardless of whether daratumumab-based induction therapy was received. None of the agents showed an OS benefit, and PFS benefits were not seen in patients with high-risk cytogenetics. Lenalidomide was associated with second malignancies, ixazomib with thrombocytopenia, and daratumumab with pneumonia. We propose that lenalidomide remains the maintenance therapy of choice for NDMM.

摘要来那度胺、伊沙佐米和达拉曲单抗已被提议作为新诊断多发性骨髓瘤（MM；NDMM）患者的维持疗法。然而，目前还没有随机对照试验（RCT）对它们进行比较。我们对在 NDMM 中比较这些药物与安慰剂的 RCT 进行了网络荟萃分析（NMA）。我们使用贝叶斯NMA模型评估了9项研究中竞争治疗对无进展生存期（PFS）和总生存期（OS）的相对影响，这些研究包括4115名符合移植条件的MM（TEMM）患者和1689名不符合移植条件的MM（NTEMM）患者。与安慰剂相比，来那度胺和达拉曲单抗改善了TEMM患者的PFS（来那度胺[危险比（HR），0.46；95%可信区间（CrI），0.36-0.56]；daratumumab[HR，0.49；95% Crl，0.32-0.76]；ixazomib[HR，0.72；95% CrI，0.46-1.12]]）和NTEMM患者（来那度胺[HR，0.46；95% CrI，0.29-0.75]和ixazomib[HR，0.69；95% CrI，0.43-1.18]）。无论是否接受了基于达拉土单抗的诱导治疗，达拉土单抗的PFS获益都是存在的。没有一种药物显示出OS获益，高危细胞遗传学患者也没有PFS获益。来那度胺与二次恶性肿瘤有关，伊沙佐米与血小板减少有关，达拉土单抗与肺炎有关。我们建议来那度胺仍是NDMM的首选维持疗法。

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引用次数: 0

BIRC5 upregulation enhances DNMT3A-mutant T-ALL cell survival and pathogenesis BIRC5 上调可提高 DNMT3A 突变 T-ALL 细胞的存活率和发病率

Blood Neoplasia

Pub Date : 2024-09-05 DOI: 10.1016/j.bneo.2024.100040

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic neoplasm. Although the prognosis of pediatric T-ALL has improved with intensified chemotherapy regimens, this benefit has largely not translated to the adult T-ALL population. Development of new treatments requires understanding the mechanisms driven by specific mutations. DNMT3A mutations are identified in ∼10% to 18% of adult patients with T-ALL and are associated with poor clinical outcomes. Here, using primary human specimens, we show that cells from patients with T-ALL with DNMT3A mutations are resistant to apoptosis and certain chemotherapies. Elevated JAK/STAT signaling drove prosurvival programs in patients with mutant DNMT3A, and JAK/STAT inhibition restored sensitivity to chemotherapy. The prosurvival gene BIRC5 was upregulated in patients with DNMT3A-mutant T-ALL, and these cells were specifically sensitive to the Baculoviral IAP Repeat Containing 5 (BIRC5) inhibitor YM155. Genetic inhibition of BIRC5 in vivo lead to rapid depletion of DNMT3A-mutant T-ALL cells in patient-derived xenografts, positioning BIRC5 as a precision medicine target for these patients.

摘要T细胞急性淋巴细胞白血病（T-ALL）是一种侵袭性造血肿瘤。虽然小儿 T-ALL 的预后随着化疗方案的加强而有所改善，但这种益处在很大程度上并没有转化到成人 T-ALL 群体中。开发新的治疗方法需要了解特定突变的驱动机制。在10%到18%的成人T-ALL患者中发现了DNMT3A突变，而且与不良的临床预后有关。在这里，我们利用原代人类标本表明，来自T-ALL患者的细胞如果存在DNMT3A突变，就会对细胞凋亡和某些化疗产生耐药性。JAK/STAT信号的升高推动了DNMT3A突变患者的促生存程序，抑制JAK/STAT可恢复对化疗的敏感性。在DNMT3A突变的T-ALL患者中，前生存基因BIRC5上调，这些细胞对含有IAP重复序列5的杆状病毒（Baculoviral IAP Repeat Containing 5，BIRC5）抑制剂YM155特别敏感。在体内对BIRC5进行基因抑制可迅速清除患者异种移植中的DNMT3A突变T-ALL细胞，从而将BIRC5定位为这些患者的精准医疗靶点。

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引用次数: 0

Ibrutinib and venetoclax in combination for chronic lymphocytic leukemia: synergy in practice 伊布替尼和 venetoclax 联合治疗慢性淋巴细胞白血病：实践中的协同作用

Blood Neoplasia

Pub Date : 2024-09-01 DOI: 10.1016/j.bneo.2024.100034

Abstract

The combination of ibrutinib and venetoclax has emerged as a promising therapeutic strategy for patients with chronic lymphocytic leukemia (CLL). Preclinical investigations demonstrated a synergistic antitumor effect through multiple mechanisms, providing a robust foundation for translating this regimen into clinical trials. Beyond the dual inhibition by 2 small molecules, another innovative concept being tested with this combination is the use of measurable residual disease (MRD)–driven treatment vs fixed-duration treatment to meet the escalating demand for oral, convenient, cost-effective, and time-limited therapeutic approaches. The clinical translation of this combination has yielded remarkable outcomes with significant improvements in the progression-free survival and overall survival rates for both treatment-naïve patients and those with relapsed/refractory CLL. Notably, a substantial proportion of patients achieved undetectable MRD. Clinical trial updates following the initial published results have shown consistency and durability of responses over time. In this review, the initial investigator-initiated trial results for ibrutinib and venetoclax are discussed, several multicenter clinical trial designs and outcomes are examined, variables such as chromosome 17p deletion that influence treatment responses are addressed, and the safety of the regimen is discussed. In addition, we reviewed the usage of this combination in other B-cell malignancies and discussed how current knowledge can be used for shaping the future CLL treatment regimens.

摘要 ibrutinib和venetoclax联合治疗慢性淋巴细胞白血病（CLL）已成为一种很有前景的治疗策略。临床前研究表明，这两种药物通过多种机制产生协同抗肿瘤作用，为将这一治疗方案转化为临床试验奠定了坚实的基础。除了两种小分子的双重抑制作用外，这种组合疗法的另一个创新理念是使用可测量残留疾病（MRD）驱动的治疗与固定疗程的治疗，以满足对口服、方便、经济、有时限的治疗方法不断升级的需求。这种组合疗法的临床应用取得了显著成果，治疗无效患者和复发/难治性 CLL 患者的无进展生存率和总生存率都得到了明显改善。值得注意的是，相当一部分患者的MRD检测不到。在首次公布结果后，临床试验更新显示，随着时间的推移，反应具有一致性和持久性。在这篇综述中，我们讨论了研究者发起的伊布替尼和 venetoclax 最初的试验结果，研究了几项多中心临床试验的设计和结果，探讨了影响治疗反应的染色体 17p 缺失等变量，并讨论了治疗方案的安全性。此外，我们还回顾了这一联合疗法在其他 B 细胞恶性肿瘤中的应用，并讨论了如何利用现有知识制定未来的 CLL 治疗方案。

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引用次数: 0

Augmented use of L-asparaginase markedly improves AYA ALL outcomes: FBMTG prospective MRD2014 study 加强使用 L-天冬酰胺酶可显著改善 AYA ALL 的预后：FBMTG前瞻性MRD2014研究

Blood Neoplasia

Pub Date : 2024-09-01 DOI: 10.1016/j.bneo.2024.100033

Abstract

The enhanced utilization of native L-asparaginase (L-Asp) aims to improve treatment outcomes for adult patients with non-Philadelphia chromosome (Ph) acute lymphoblastic leukemia (ALL). In this measurable residual disease 2014 (MRD2014) study, we modified our protocol to include an augmented dose of native L-Asp. Compared with former MRD2008, the total dose of L-Asp was raised from 36 000 U/m² to 232 000 U/m² in patients aged 16 to 35 and from 36 000 U/m² to 132 000 U/m² in patients aged 36 to 65 years. Adult patients with ALL were enrolled between January 2014 and December 2019 based on the following eligibility criteria: non-L3 ALL, age 16 to 65 years, Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate liver and kidney functions (serum bilirubin ≤ 2.0 mg/dL; serum creatinine ≤ 2.0 mg/dL). The median follow-up time was 1128 days (range, 35-2400). A total of 81 patients with non-Ph ALL (40 males and 41 females; median age, 39 years [range, 16-64]) in whom MRD status was assessed were included. Complete remission was achieved in 72 patients (89%). The probability of 3-year event-free survival (EFS) and overall survival (OS) in these patients were 55% and 72%, respectively. The outcomes for patients aged 16 to 35 years demonstrated remarkable improvement. The 3-year EFS of MRD2008 at 45% significantly increased to 71% for MRD2014. Our study unequivocally demonstrated the beneficial effects of augmented use of L-Asp in this adolescent and young adult population. This trial was registered at UMIN Clinical Trials Registry as #UMIN000012382.

摘要提高原生L-天冬酰胺酶（L-Asp）的使用率旨在改善非费城染色体（Ph）急性淋巴细胞白血病（ALL）成人患者的治疗效果。在这项可测量残留疾病2014（MRD2014）研究中，我们修改了治疗方案，增加了原生L-Asp的剂量。与之前的MRD2008相比，16至35岁患者的L-Asp总剂量从36000 U/m2提高到232000 U/m2，36至65岁患者的L-Asp总剂量从36000 U/m2提高到132000 U/m2。2014年1月至2019年12月期间，成人ALL患者根据以下资格标准入组：非L3 ALL、年龄16至65岁、东部合作肿瘤学组表现状态为0至2、肝肾功能正常（血清胆红素≤2.0 mg/dL；血清肌酐≤2.0 mg/dL）。中位随访时间为 1128 天（35-2400 天不等）。共纳入了81例评估了MRD状态的非Ph ALL患者（男性40例，女性41例；中位年龄39岁[16-64岁]）。72名患者（89%）获得了完全缓解。这些患者的 3 年无事件生存率（EFS）和总生存率（OS）分别为 55% 和 72%。16 至 35 岁患者的疗效显著改善。MRD2008的3年无事件生存率为45%，而MRD2014的3年无事件生存率则大幅提高到71%。我们的研究明确显示，在青少年和年轻成年人群体中增加使用 L-Asp 有益。该试验已在 UMIN 临床试验注册中心注册，注册号为 #UMIN000012382。

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引用次数: 0

T-cell lymphoblastic lymphoma compared with T-cell acute lymphoblastic leukemia: similar subtypes and different fusions T 细胞淋巴细胞淋巴瘤与 T 细胞急性淋巴细胞白血病的比较：相似的亚型和不同的融合

Blood Neoplasia

Pub Date : 2024-09-01 DOI: 10.1016/j.bneo.2024.100029

引用次数: 0

Targeting SLFN11-regulated pathways restores chemotherapy sensitivity in AML 靶向 SLFN11 调控通路可恢复急性髓细胞白血病化疗敏感性

Blood Neoplasia

Pub Date : 2024-08-28 DOI: 10.1016/j.bneo.2024.100037

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。

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引用次数: 0

Clinical and pathological features of pediatric peripheral T-cell lymphoma after solid organ transplantation 实体器官移植后小儿外周T细胞淋巴瘤的临床和病理特征

Blood Neoplasia

Pub Date : 2024-08-28 DOI: 10.1016/j.bneo.2024.100039

引用次数: 0

Intensive chemotherapy after hypomethylating agent and venetoclax in adult acute myeloid leukemia 成人急性髓性白血病患者使用低甲基化药物和 Venetoclax 后的强化化疗

Blood Neoplasia

Pub Date : 2024-08-28 DOI: 10.1016/j.bneo.2024.100038

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。

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引用次数: 0

A phase 1 study adding pitavastatin to venetoclax therapy in AML and CLL/SLL: a mechanism-based drug repurposing strategy 在AML和CLL/SLL治疗中加入匹伐他汀的1期研究：基于机制的药物再利用策略

Blood Neoplasia

Pub Date : 2024-08-28 DOI: 10.1016/j.bneo.2024.100036

引用次数: 0

COVID-19 vaccination in patients with classic and variant hairy cell leukemia 为典型和变异毛细胞白血病患者接种 COVID-19 疫苗

Blood Neoplasia

Pub Date : 2024-08-28 DOI: 10.1016/j.bneo.2024.100035

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）。

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