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Association between myeloid disorders and adult onset-inflammatory syndromes, successful treatment with JAK-inhibitors: Case series and literature review 髓系疾病与成人发病炎症综合征之间的关联，JAK抑制剂的成功治疗：病例系列和文献综述。
IF 2.1 4区 医学 Q3 HEMATOLOGY
Leukemia research
Pub Date : 2024-09-04 DOI: 10.1016/j.leukres.2024.107584

Approximately one-third of patients with myeloid disorders like myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) exhibit inflammatory and autoimmune disorders (IADs). These IADs often include atypical and incomplete forms of common autoimmune conditions, and exhibit resistance to conventional immunosuppressive therapies. There is growing interest in molecular relationships between IADs and MDS/CMML to find potential targeted therapies. Recently, patients with somatic mutations in the UBA1 gene were identified as having VEXAS syndrome. Herein, we present a concise case-series illustrating concurrent elderly-onset inflammatory manifestations and myeloid disorders (MDS, CMML, and idiopathic cytopenia of undetermined significance). These patients manifested inflammatory or autoimmune symptoms, including erythema nodosum, Raynaud's phenomenon, Sjogren syndrome, and refractory pruritus, having onset after 60-years of age. The inflammatory manifestations were largely refractory to traditional immunosuppressive regimens. Remarkably, treatment with a JAK-1 inhibitor, upadacitinib, in two cases yielded marked resolution of inflammatory symptoms, facilitating the gradual tapering of corticosteroids, improvement of hemoglobin levels, and reduction in serum C-reactive protein levels. Upon loss of response to upadacitinib, JAK-2 inhibitor ruxolitinib provided clinical benefit in one of the cases, facilitating further tapering of glucocorticoids. This arena warrants further exploration through prospective studies of larger cohorts to delineate optimal management strategies.

骨髓增生异常综合征（MDS）和慢性粒细胞白血病（CMML）等髓系疾病患者中，约有三分之一表现为炎症和自身免疫性疾病（IADs）。这些 IADs 通常包括非典型和不完全形式的常见自身免疫疾病，并表现出对常规免疫抑制疗法的抗药性。人们越来越关注 IAD 与 MDS/CMML 之间的分子关系，以寻找潜在的靶向疗法。最近，UBA1 基因发生体细胞突变的患者被确定为 VEXAS 综合征患者。在此，我们展示了一个简明的病例系列，说明了同时出现的老年炎症表现和骨髓性疾病（MDS、CMML 和意义未定的特发性全血细胞减少症）。这些患者表现为炎症或自身免疫症状，包括结节性红斑、雷诺现象、Sjogren 综合征和难治性瘙痒症，发病年龄均在 60 岁以后。这些炎症表现对传统的免疫抑制疗法基本无效。值得注意的是，在两个病例中，使用 JAK-1 抑制剂达帕替尼（upadacitinib）治疗后，炎症症状明显缓解，皮质类固醇的用量也逐渐减少，血红蛋白水平得到改善，血清 C 反应蛋白水平也有所下降。其中一个病例对乌达替尼失去反应后，JAK-2 抑制剂鲁索利替尼带来了临床获益，促进了糖皮质激素的进一步减量。这一领域需要通过更大规模的前瞻性研究来进一步探索，以确定最佳治疗策略。
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引用次数: 0
Germline genetic variants that predispose to myeloproliferative neoplasms and hereditary myeloproliferative phenotypes 易患骨髓增生性肿瘤和遗传性骨髓增生性表型的基因变异
IF 2.1 4区 医学 Q3 HEMATOLOGY
Leukemia research
Pub Date : 2024-08-25 DOI: 10.1016/j.leukres.2024.107566
Epidemiological evidence of familial predispositions to myeloid malignancies and myeloproliferative neoplasms (MPN) has long been recognised, but recent studies have added to knowledge of specific germline variants in multiple genes that contribute to the familial risk. These variants may be common risk alleles in the general population but have low penetrance and cause sporadic MPN, such as the JAK2 46/1 haplotype, the variant most strongly associated with MPN. Association studies are increasingly identifying other MPN susceptibility genes such as TERT, MECOM, and SH2B3, while some common variants in DDX41 and RUNX1 appear to lead to a spectrum of myeloid malignancies. RBBP6 and ATM variants have been identified in familial MPN clusters and very rare germline variants such as chromosome 14q duplication cause hereditary MPN with high penetrance. Rarely, there are hereditary non-malignant diseases with an MPN-like phenotype. Knowledge of those genes and germline genetic changes which lead to MPN or diseases that mimic MPN helps to improve accuracy of diagnosis, aids with counselling regarding familial risk, and may contribute to clinical decision-making. Large scale population exome and genome sequencing studies will improve our knowledge of both common and rare germline genetic contributions to MPN.
髓系恶性肿瘤和骨髓增生性肿瘤（MPN）的家族易感性的流行病学证据早已得到公认，但最近的研究增加了对导致家族风险的多个基因中特定种系变异的了解。这些变体可能是普通人群中常见的风险等位基因，但其渗透率较低，会导致散发性 MPN，如 JAK2 46/1 单倍型，它是与 MPN 关系最密切的变体。越来越多的关联研究发现了其他 MPN 易感基因，如 TERT、MECOM 和 SH2B3，而 DDX41 和 RUNX1 的一些常见变异似乎会导致一系列髓系恶性肿瘤。在家族性骨髓增生性恶性肿瘤群中发现了RBBP6和ATM变体，而非常罕见的种系变体（如染色体14q重复）会导致高渗透性的遗传性骨髓增生性恶性肿瘤。极少数遗传性非恶性疾病具有类似 MPN 的表型。了解导致多发性骨髓瘤或类似多发性骨髓瘤的疾病的基因和种系遗传变化有助于提高诊断的准确性，帮助提供有关家族风险的咨询，并有助于临床决策。大规模的人群外显子组和基因组测序研究将提高我们对常见和罕见种系遗传对多发性骨髓瘤影响的认识。
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引用次数: 0
Impact of spliceosome mutation on outcomes of myelodysplastic syndrome and chronic myelomonocytic leukemia patients undergoing allogeneic hematopoietic cell transplantation 剪接体突变对接受异基因造血细胞移植的骨髓增生异常综合征和慢性粒细胞白血病患者预后的影响
IF 2.1 4区 医学 Q3 HEMATOLOGY
Leukemia research
Pub Date : 2024-08-25 DOI: 10.1016/j.leukres.2024.107565

Introduction

Allogeneic Hematopoietic cell transplantation (allo-HCT) remains the only curative therapy for myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML). The impact of spliceosome mutations on allo-HCT outcome is unclear and further understanding is needed to assess the implications of this class of mutations on risk of relapse, overall survival (OS) and non-relapse mortality (NRM) in order to make decision regarding timing of allo-HCT. We examined the allo-HCT outcomes of MDS/CMML patients based on their spliceosome mutation profile to understand the impact of these mutations on transplant outcomes.

Objective

To compare outcomes of MDS/CMML patients with and without spliceosome mutations undergoing allo-HCT.

Methods

This is a single institution, retrospective study of MDS/CMML patients who underwent allo-HCT with myeloablative or reduced intensity conditioning (RIC) regimen at City of Hope from January 2016 to December 2021. Among them, patients who underwent molecular mutation profiling by NGS (Next Generation Sequencing) for a set of genes known to be mutated in myeloid neoplasms are included in this analysis. We compared OS, relapse free survival, NRM and acute/chronic graft versus host disease (GVHD) incidence between the spliceosome-mutated and unmutated groups.

Results

We identified 258 consecutive MDS/CMML patients who underwent allo-HCT. Of these, 126 (48.8 %) patients had molecular profiling done among whom 57 (45.2 %) patients carried a spliceosome mutation. 84.9 % of patients had MDS and 55.6 % underwent a matched unrelated donor transplant. The median age for the whole cohort was 66 years (range 12–77).78.6 % and 73.7 % received RIC in the spliceosome and non-spliceosome groups, respectively. The 2-year OS for the whole cohort was 66.5 % (95 %CI 0.55–0.75) with a day 100 NRM of 7.1 % and 2-year cumulative incidence of relapse of 20 %. Grade II-IV acute GVHD at day 100 was 36.3 % (95 % CI 0.27–0.44) and any chronic GVHD at 2-years was 48.4 % (95 % CI 0.37–0.58). Patients who carried a spliceosome mutation had a significantly better 2-year survival of 83.8 % vs 55.9 % in the non-spliceosome group (P=0.002) and a better PFS of 73.7 % vs 50.0 % (P=0.007). There was no difference in the cumulative incidence of relapse at 2-years 15.9 % vs 18.5 % (P=0.59) between two groups but the spliceosome group had a significantly lower NRM at 2-years 10.4 % vs 31.5 % (P=0.009). There was no difference in incidence of acute or chronic GVHD between the two groups.

Conclusions

Among patients with MDS or CMML who underwent allo-HCT, our study shows better OS for patients who have spliceosome mutations due to lower NRM compared to those carrying non- spliceosome mutations. This favorable outcome of the spliceosome-mutated patients could have implications for timing of allo-HCT, particularly for patients in the in

导言异基因造血细胞移植（allo-HCT）仍然是骨髓增生异常综合征（MDS）和慢性粒细胞白血病（CMML）的唯一治愈疗法。目前还不清楚剪接体突变对异体HCT结果的影响，需要进一步了解这类突变对复发风险、总生存期（OS）和非复发死亡率（NRM）的影响，以便决定异体HCT的时机。我们根据剪接体突变情况研究了MDS/CMML患者的allo-HCT结果，以了解这些突变对移植结果的影响。目的比较有和没有剪接体突变的MDS/CMML患者接受allo-HCT的结果。方法这是一项单机构回顾性研究，研究对象是2016年1月至2021年12月期间在希望之城接受析出性或降低强度调理（RIC）方案allo-HCT的MDS/CMML患者。其中，通过 NGS（下一代测序）对一组已知在髓样瘤中发生突变的基因进行分子突变分析的患者也包括在本分析中。我们比较了剪接体突变组和未突变组的OS、无复发生存率、NRM和急性/慢性移植物抗宿主疾病（GVHD）发生率。其中，126 例（48.8%）患者进行了分子图谱分析，57 例（45.2%）患者携带剪接体突变。84.9%的患者患有 MDS，55.6%的患者接受了匹配的非亲属供体移植。在剪接体组和非剪接体组中，分别有78.6%和73.7%的患者接受了RIC治疗。全组 2 年的 OS 为 66.5%（95%CI 0.55-0.75），第 100 天的 NRM 为 7.1%，2 年累计复发率为 20%。第100天发生II-IV度急性GVHD的比例为36.3%（95 % CI 0.27-0.44），2年发生任何慢性GVHD的比例为48.4%（95 % CI 0.37-0.58）。携带剪接体突变的患者2年生存率为83.8%，非剪接体组为55.9%（P=0.002），PFS为73.7%，非剪接体组为50.0%（P=0.007）。两组患者两年后的累积复发率没有差异，分别为 15.9% vs 18.5% (P=0.59)，但剪接体组患者两年后的 NRM 显著较低，分别为 10.4% vs 31.5% (P=0.009)。结论在接受allo-HCT的MDS或CMML患者中，我们的研究显示，与携带非剪接体突变的患者相比，剪接体突变的患者由于较低的NRM而获得更好的OS。剪接体突变患者的这一良好结局可能会对allo-HCT的时机产生影响，尤其是对MDS预后风险中等组的患者。
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引用次数: 0
Evolution of transcriptomic profiles in relapsed inv(16) acute myeloid leukemia 复发 inv(16) 急性髓性白血病转录组特征的演变。
IF 2.1 4区 医学 Q3 HEMATOLOGY
Leukemia research
Pub Date : 2024-08-22 DOI: 10.1016/j.leukres.2024.107568

Acute myeloid leukemia (AML) with inv(16) is typically associated with a favourable prognosis. However, up to 40 % of patients will eventually experience disease relapse. Herein, we dissected the genomic and transcriptomic profile of inv(16) AML to identify potential prognostic markers and therapeutic vulnerabilities. Sequencing data from 222 diagnostic samples, including 44 relapse/refractory patients, revealed a median of 1 concomitant additional mutation, cooperating with inv(16) in leukemogenesis. Notably, the mutational landscape at diagnosis did not differ significantly between patients experiencing primary induction failure or relapse when compared to the rest of the cohort, except for an increase in the mutational burden in the relapse/refractory group. RNA-Seq of unpaired diagnostic(n=7) and relapse(n=6) samples allowed the identification of oxidative phosphorylation (OXPHOS) as one of the most significantly downregulated pathways at relapse. Considering that OXPHOS could be targeted by Venetoclax/Azacitidine combination, we explored its biological effects on an inv(16) cell-line ME-1, but there was no additional advantage in terms of cell death over Azacitidine alone. To enhance Venetoclax efficacy, we tested in vitro effects of Metformin as a potential drug able to enhance chemosensitivity of AML cells by inhibiting the mitochondrial transfer. By challenging ME-1 with this combination, we observed a significant synergistic interaction at least similar to that of Venetoclax/Azacitidine. In conclusions, we identified a downregulated expression of oxidative phosphorylation (OXPHOS) at relapse in AML with inv(16), and explored the in vitro effects of metformin as a potential drug to enhance chemosensitivity in this setting.

患有inv(16)的急性髓性白血病（AML）通常预后良好。然而，高达 40% 的患者最终会复发。在此，我们剖析了inv(16) AML的基因组和转录组特征，以确定潜在的预后标志物和治疗弱点。来自 222 份诊断样本（包括 44 例复发/难治性患者）的测序数据显示，中位数存在 1 个与 inv(16) 共同参与白血病发生的额外突变。值得注意的是，除了复发/难治组的突变负荷增加外，初治诱导失败或复发患者在诊断时的突变情况与队列中的其他患者相比没有显著差异。通过对未配对的诊断样本（7 例）和复发样本（6 例）进行 RNA-Seq 分析，发现氧化磷酸化（OXPHOS）是复发时最显著下调的通路之一。考虑到Venetoclax/阿扎胞苷联合疗法可靶向OXPHOS，我们探讨了其对inv（16）细胞系ME-1的生物效应，但与单独使用阿扎胞苷相比，在细胞死亡方面并无额外优势。为了增强 Venetoclax 的疗效，我们测试了二甲双胍的体外效应，它是一种潜在的药物，能够通过抑制线粒体转移来增强 AML 细胞的化疗敏感性。通过用这种组合挑战 ME-1，我们观察到了显著的协同作用，至少与 Venetoclax/Azacitidine 的作用类似。总之，我们发现了inv(16)型急性髓细胞性白血病复发时氧化磷酸化（OXPHOS）表达下调，并探索了二甲双胍作为一种潜在药物在体外的作用，以增强这种情况下的化疗敏感性。
{"title":"Evolution of transcriptomic profiles in relapsed inv(16) acute myeloid leukemia","authors":"","doi":"10.1016/j.leukres.2024.107568","DOIUrl":"10.1016/j.leukres.2024.107568","url":null,"abstract":"<div><p>Acute myeloid leukemia (AML) with inv(16) is typically associated with a favourable prognosis. However, up to 40 % of patients will eventually experience disease relapse. Herein, we dissected the genomic and transcriptomic profile of inv(16) AML to identify potential prognostic markers and therapeutic vulnerabilities. Sequencing data from 222 diagnostic samples, including 44 relapse/refractory patients, revealed a median of 1 concomitant additional mutation, cooperating with inv(16) in leukemogenesis. Notably, the mutational landscape at diagnosis did not differ significantly between patients experiencing primary induction failure or relapse when compared to the rest of the cohort, except for an increase in the mutational burden in the relapse/refractory group. RNA-Seq of unpaired diagnostic(n=7) and relapse(n=6) samples allowed the identification of oxidative phosphorylation (OXPHOS) as one of the most significantly downregulated pathways at relapse. Considering that OXPHOS could be targeted by Venetoclax/Azacitidine combination, we explored its biological effects on an inv(16) cell-line ME-1, but there was no additional advantage in terms of cell death over Azacitidine alone. To enhance Venetoclax efficacy, we tested <em>in vitro</em> effects of Metformin as a potential drug able to enhance chemosensitivity of AML cells by inhibiting the mitochondrial transfer. By challenging ME-1 with this combination, we observed a significant synergistic interaction at least similar to that of Venetoclax/Azacitidine. In conclusions, we identified a downregulated expression of oxidative phosphorylation (OXPHOS) at relapse in AML with inv(16), and explored the in vitro effects of metformin as a potential drug to enhance chemosensitivity in this setting.</p></div>","PeriodicalId":18051,"journal":{"name":"Leukemia research","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142055994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Cost-effectiveness of blinatumomab for the treatment of B‑precursor acute lymphoblastic leukemia pediatric patients with high‑risk first‑relapse in Mexico 在墨西哥，用 blinatumomab 治疗 B 前体急性淋巴细胞白血病儿科高危首次复发患者的成本效益
IF 2.1 4区 医学 Q3 HEMATOLOGY
Leukemia research
Pub Date : 2024-08-22 DOI: 10.1016/j.leukres.2024.107560

Background

Blinatumomab is a CD3/CD19-directed bispecific T-cell engager molecule that engages T cells to lyse CD19-expressing B cells. Based on a multicenter, open-label, phase 3, randomized clinical trial (Clinical Trials ID: NCT02393859), we aimed to evaluate the cost-effectiveness (CE) of blinatumomab compared to standard consolidation chemotherapy (SC) for the treatment of pediatric patients with high-risk first-relapsed Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia (B-ALL) from a Mexico healthcare payer perspective.

Methods

A decision-analytic model, a partitioned survival model, was used to estimate the life-years (LYs) and costs over a lifetime horizon. We assumed that patients who remained alive beyond a 5-year period were cured. To account for the lingering impacts of cancer treatment, an excess mortality rate was incorporated into the model. Event-free survival (EFS) and overall survival (OS) were estimated by fitting mixture-cure and standard parametric survival distributions to the time-to-event data from the phase 3 trial. The model accounted for treatment costs, adverse event costs, follow-up costs, subsequent allogeneic hematopoietic stem cell transplantation (alloHSCT) costs, and subsequent treatment costs.

Results

Blinatumomab was associated with a lifetime gained of 5.11 years at an incremental cost of $621,111 MXN, relative to SC. The ICER for blinatumomab vs Standard of care was estimated to be $121,526 MXN/LY gained in the base case. Cost-effectiveness was sensitive to varying the time horizon. Blinatumomab had a probability of 99 % of being cost-effective, relative to SC, at the willingness to pay threshold defined in Mexico.

Limitations

Health-related quality of life values were not included in the analysis and therefore we did not estimate the quality-adjusted life-years gained.

Conclusions

Blinatumomab was associated with greater benefit in terms of OS and EFS relative to SC. Probabilistic, deterministic, and scenario analyses indicate that blinatumomab represents the best value for money. Therefore, blinatumomab administered as part of consolidation therapy in B-ALL pediatric patients with high-risk first relapse is a cost-effective option.

背景blinatumomab是一种CD3/CD19定向双特异性T细胞吞噬分子，能吸引T细胞裂解表达CD19的B细胞。基于一项多中心、开放标签、3期随机临床试验（临床试验编号：NCT02393859），我们旨在从墨西哥医疗支付方的角度评估blinatumomab与标准巩固化疗（SC）相比治疗高风险初治复发费城染色体阴性B细胞前体急性淋巴细胞白血病（B-ALL）儿科患者的成本效益（CE）。方法 采用决策分析模型--分区生存模型来估算患者一生中的生命年数（LY）和成本。我们假设存活超过 5 年的患者均已治愈。为了考虑癌症治疗的残留影响，我们在模型中加入了超额死亡率。无事件生存期（EFS）和总生存期（OS）是通过将混合治愈和标准参数生存分布拟合到 3 期试验的事件时间数据来估算的。该模型考虑了治疗成本、不良事件成本、随访成本、后续异基因造血干细胞移植（alloHSCT）成本和后续治疗成本。结果相对于SC，Blinatumomab的终生获益期为5.11年，增量成本为621,111美元。在基础病例中，blinatumomab与标准治疗相比的ICER估计为121,526美元。成本效益对时间跨度的变化很敏感。在墨西哥确定的支付意愿阈值下，相对于SC，Blinatumomab的成本效益概率为99%。结论相对于SC，Blinatumomab在OS和EFS方面具有更大的获益。概率、确定性和情景分析表明，blinatumomab 具有最佳性价比。因此，在高危首次复发的B-ALL儿童患者中，作为巩固治疗的一部分使用blinatumomab是一种经济有效的选择。
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引用次数: 0
Distinctive features associated with differentiation syndrome in acute promyelocytic leukemia in patients treated by all-trans retinoic acid and arsenic trioxide 接受全反式维甲酸和三氧化二砷治疗的急性早幼粒细胞白血病患者与分化综合征相关的显著特征
IF 2.1 4区 医学 Q3 HEMATOLOGY
Leukemia research
Pub Date : 2024-08-22 DOI: 10.1016/j.leukres.2024.107567

In acute promyelocytic leukemia (APL), the combination treatment of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) appears to have a synergistic effect. Due to this synergism, differentiation syndrome (DS) in APL assumes a distinct identity separate from the formerly known ATRA syndrome, with distinct temporal patterns, diagnostic parameters, and clinical behavior. We retrospectively evaluated single-center data of years 2013–2022. Patients with newly diagnosed APL were categorized into three groups (16 patients in ATRA/ATO standard-risk group, 3 patients in ATRA/chemotherapy standard-risk group, and 5 patients in ATRA/chemotherapy high-risk group). Our aim was to analyze leukocytosis, signs of DS, and hepatic impairment within the first 25 days of treatment. The incidence of DS in the ATRA/ATO SR group was 43.8 %, with a median of 4 days and 2 days from ATRA and ATO initiation, respectively. This group also exhibited higher peak levels of leukocytosis 34.5 (6.0–113.4) x109/L (p = 0.0809). ALT elevation was more prevalent in the ATRA/ATO SR group (93.75 %), with 68.75 % grade 3–4 elevations (p = 0.0094). Importantly, all patients in this group had ALT levels that returned to normal during the subsequent consolidations. These findings suggest hepatopathy as a potential manifestation of ATRA/ATO induced leukocyte differentiation and/or DS. Diverse differentiation patterns were identified within the ATRA/ATO group, classifying patients into three distinct subgroups based on the concurrent dynamics of leukocytes and ALT levels, illustrating simultaneous, sequential, and divergent elevation patterns. These emphasize the different distribution of differentiation (organs vs. peripheral blood). We introduced real-world data and advocated for reevaluation of the current DS definition and associated diagnostic thresholds. Our study, conducted in a small country with a limited number of APL patients, acknowledges the inherent constraints in sample size. Further investigations with larger patient cohorts are warranted to validate and reinforce the outcomes observed in our study.

在急性早幼粒细胞白血病（APL）中，全反式维甲酸（ATRA）和三氧化二砷（ATO）的联合治疗似乎具有协同作用。由于这种协同作用，APL 的分化综合征（DS）与以前已知的 ATRA 综合征截然不同，具有不同的时间模式、诊断参数和临床表现。我们对 2013-2022 年的单中心数据进行了回顾性评估。新确诊的 APL 患者被分为三组（ATRA/ATO 标准风险组 16 例、ATRA/化疗标准风险组 3 例、ATRA/化疗高风险组 5 例）。我们的目的是分析治疗最初 25 天内的白细胞增多、DS 征兆和肝功能损害情况。ATRA/ATO SR组的DS发生率为43.8%，中位数分别为ATRA和ATO开始治疗后的4天和2天。该组的白细胞增多峰值也较高，为 34.5 (6.0-113.4) x109/L（p = 0.0809）。ALT 升高在 ATRA/ATO SR 组更常见（93.75%），3-4 级升高占 68.75%（p = 0.0094）。重要的是，该组所有患者的 ALT 水平在随后的巩固治疗中均恢复正常。这些发现表明，肝病是 ATRA/ATO 诱导的白细胞分化和/或 DS 的一种潜在表现形式。在 ATRA/ATO 组中发现了不同的分化模式，根据白细胞和 ALT 水平的同时动态变化，将患者分为三个不同的亚组，说明了同时、连续和不同的升高模式。这些都强调了分化的不同分布（器官与外周血）。我们引入了真实世界的数据，并主张重新评估当前的 DS 定义和相关诊断阈值。我们的研究是在一个APL患者人数有限的小国进行的，承认样本量存在固有的局限性。有必要对更大的患者群体进行进一步调查，以验证和巩固我们研究中观察到的结果。
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引用次数: 0
Triplet therapy with gilteritinib, venetoclax, and azacitidine for relapsed/refractory FLT3mut acute myeloid leukemia 吉特替尼、venetoclax和阿扎胞苷三联疗法治疗复发/难治性FLT3突变急性髓性白血病。
IF 2.1 4区 医学 Q3 HEMATOLOGY
Leukemia research
Pub Date : 2024-08-22 DOI: 10.1016/j.leukres.2024.107564

The FMS-related tyrosine kinase 3 (FLT3) inhibitor gilteritinib is standard therapy for relapsed/refractory (R/R) FLT3-mutated (FLT3mut) acute myeloid leukemia (AML) but the overall survival (OS) is only approximately 20 % and few patients achieve deep and/ or durable response. We retrospectively analyzed 29 R/R FLT3mut AML patients treated on triplet regimens (gilteritinib+ venetoclax［VEN] +azacitidine［AZA]). Nineteen patients (65.5 %) had received prior FLT3 inhibitor therapy. The modified composite complete remission (mCRc) rate was 62.1 % (n = 18; CR, 4/29,13.8 %; CRi, 6/29, 20.7 %; MLFS, 8/29, 27.6 %). Among 18 patients achieved mCRc, FLT3-PCR negativity was 94.4 % (n=17), and flow-cytometry negativity was 77.7 % (n=14). The mCRc rate was 70 % (n=7) in 10 patients without prior FLT3 TKI exposure and 57.8 % (n=11) in 19 patients with prior FLT3 TKI exposure (P=0.52). At the end of the first cycle, the median time to ANC > 0.5× 109/L was 38 days and platelet > 50× 109/L was 31 days among responders, but 60-day mortality was 0 %. The estimated 2-year OS was 60.9 % for all R/R FLT3mut patients. The 1-year OS was 80 % and 58.8 % in patients without and with prior FLT3 TKI exposure, respectively (P=0.79). The estimated 2-year OS was 62 % in 19 (65.5 %) patients who received allo-HSCT after triplet therapy and 37 % in 10 patients who did not receive allo-HSCT (P=0.03). In conclusion, triplet therapy with gilteritinib, VEN, and AZA is effective and safe and an excellent frontline option for R/R FLT3mut AML.

FMS相关酪氨酸激酶3（FLT3）抑制剂吉特替尼是治疗复发/难治性（R/R）FLT3突变（FLT3mut）急性髓性白血病（AML）的标准疗法，但其总生存率（OS）仅为约20%，且很少有患者获得深度和/或持久应答。我们回顾性分析了29例接受三联方案（吉瑞替尼+ Venetoclax［VEN］+阿扎胞苷［AZA］）治疗的R/R FLT3mut AML患者。19名患者（65.5%）曾接受过FLT3抑制剂治疗。改良复合完全缓解（mCRc）率为62.1%（n = 18；CR，4/29，13.8%；CRi，6/29，20.7%；MLFS，8/29，27.6%）。在18名获得mCRc的患者中，FLT3-PCR阴性率为94.4%（n=17），流式细胞术阴性率为77.7%（n=14）。10名既往未使用过FLT3 TKI的患者的mCRc率为70%（n=7），19名既往使用过FLT3 TKI的患者的mCRc率为57.8%（n=11）（P=0.52）。第一个周期结束时，应答者ANC>0.5×109/L的中位时间为38天，血小板>50×109/L的中位时间为31天，但60天死亡率为0%。所有R/R FLT3mut患者的2年OS估计为60.9%。既往未接触过FLT3 TKI的患者和接触过FLT3 TKI的患者的1年OS分别为80%和58.8%（P=0.79）。在三联疗法后接受allo-HSCT的19例（65.5%）患者中，估计2年OS为62%；在未接受allo-HSCT的10例患者中，估计2年OS为37%（P=0.03）。总之，吉特替尼、VEN和AZA三联疗法既有效又安全，是治疗R/R FLT3mut AML的绝佳一线选择。
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引用次数: 0
Decitabine consolidation after CD19/CD22 CAR-T therapy as a novel maintenance treatment significantly improves survival outcomes in relapsed/refractory B-ALL patients CD19/CD22 CAR-T 疗法作为一种新型维持疗法，可显著改善复发/难治性 B-ALL 患者的生存预后
IF 2.1 4区 医学 Q3 HEMATOLOGY
Leukemia research
Pub Date : 2024-08-22 DOI: 10.1016/j.leukres.2024.107569

Objective

We aimed to evaluate the efficacy of decitabine consolidation after treatment with CD19/CD22 chimeric antigen receptor T-cell (CAR-T) for patients with relapsed/refractory B-cell acute lymphoblastic leukaemia (r/r B-ALL).

Methods

We retrospectively analysed 48 patients with r/r B-ALL who received CD19/CD22 CAR-T therapy between September 2017 and May 2021. Sixteen patients received decitabine consolidation (20 mg/m2/day for 5 days at 3-month intervals) after CAR-T therapy (DAC group), while 32 patients did not receive decitabine consolidation (CON group). Overall survival (OS), leukaemia-free survival (LFS), and cumulative incidence of relapse (CIR) were evaluated in both groups. Time-to-event analysis was performed using the Kaplan-Meier method.

Results

The median follow-up periods in the DAC and CON groups were 41.2 months and 28.6 months, respectively. The 4-year OS and 4-year LFS rates in both groups were 93.3 % and 64.3 % (P=0.029) and 87.5 % and 55.9 % (P=0.059), respectively. The 1-year CIR was 6.25 % and 28.6 %, respectively. Univariate and multivariate Cox regression analyses showed that decitabine consolidation after CAR-T therapy was significantly associated with superior OS (hazard ratio [HR]: 0.121, 95 % confidence interval [CI]: 0.015–0.947, P=0.044), and bridging to haematopoietic stem cell transplantation after CAR-T therapy was significantly associated with superior LFS (HR: 0.279, 95 %CI: 0.093–0.840, P=0.023).

Conclusions

Our study recommends decitabine consolidation after CD19/CD22 CAR-T therapy as a novel maintenance strategy to improve the survival outcomes of patients with r/r B-ALL.

目的我们旨在评估CD19/CD22嵌合抗原受体T细胞（CAR-T）治疗复发/难治性B细胞急性淋巴细胞白血病（r/r B-ALL）患者后地西他滨巩固治疗的疗效。方法我们回顾性分析了2017年9月至2021年5月期间接受CD19/CD22 CAR-T治疗的48例r/r B-ALL患者。16例患者在CAR-T治疗后接受了地西他滨巩固治疗（20 mg/m2/天，5天，间隔3个月）（DAC组），32例患者未接受地西他滨巩固治疗（CON组）。对两组患者的总生存期（OS）、无白血病生存期（LFS）和累积复发率（CIR）进行了评估。结果 DAC组和CON组的中位随访时间分别为41.2个月和28.6个月。两组的4年OS率和4年LFS率分别为93.3%和64.3%（P=0.029）以及87.5%和55.9%（P=0.059）。1年CIR分别为6.25%和28.6%。单变量和多变量考克斯回归分析显示，CAR-T疗法后地西他滨巩固治疗与较好的OS显著相关（危险比[HR]：0.121，95%置信区间，P=0.059）：0.121, 95 %置信区间 [CI]：结论我们的研究推荐在CD19/CD22 CAR-T治疗后使用地西他滨巩固治疗，作为一种新型的维持治疗策略，以改善r/r B-ALL患者的生存预后。
{"title":"Decitabine consolidation after CD19/CD22 CAR-T therapy as a novel maintenance treatment significantly improves survival outcomes in relapsed/refractory B-ALL patients","authors":"","doi":"10.1016/j.leukres.2024.107569","DOIUrl":"10.1016/j.leukres.2024.107569","url":null,"abstract":"<div><h3>Objective</h3><p>We aimed to evaluate the efficacy of decitabine consolidation after treatment with CD19/CD22 chimeric antigen receptor T-cell (CAR-T) for patients with relapsed/refractory B-cell acute lymphoblastic leukaemia (r/r B-ALL).</p></div><div><h3>Methods</h3><p>We retrospectively analysed 48 patients with r/r B-ALL who received CD19/CD22 CAR-T therapy between September 2017 and May 2021. Sixteen patients received decitabine consolidation (20 mg/m<sup>2</sup>/day for 5 days at 3-month intervals) after CAR-T therapy (DAC group), while 32 patients did not receive decitabine consolidation (CON group). Overall survival (OS), leukaemia-free survival (LFS), and cumulative incidence of relapse (CIR) were evaluated in both groups. Time-to-event analysis was performed using the Kaplan-Meier method.</p></div><div><h3>Results</h3><p>The median follow-up periods in the DAC and CON groups were 41.2 months and 28.6 months, respectively. The 4-year OS and 4-year LFS rates in both groups were 93.3 % and 64.3 % (P=0.029) and 87.5 % and 55.9 % (P=0.059), respectively. The 1-year CIR was 6.25 % and 28.6 %, respectively. Univariate and multivariate Cox regression analyses showed that decitabine consolidation after CAR-T therapy was significantly associated with superior OS (hazard ratio [HR]: 0.121, 95 % confidence interval [CI]: 0.015–0.947, P=0.044), and bridging to haematopoietic stem cell transplantation after CAR-T therapy was significantly associated with superior LFS (HR: 0.279, 95 %CI: 0.093–0.840, P=0.023).</p></div><div><h3>Conclusions</h3><p>Our study recommends decitabine consolidation after CD19/CD22 CAR-T therapy as a novel maintenance strategy to improve the survival outcomes of patients with r/r B-ALL.</p></div>","PeriodicalId":18051,"journal":{"name":"Leukemia research","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142088144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Characteristics and outcomes of children, adolescent, and young adult patients with myelodysplastic neoplasms: A single-center retrospective analysis 骨髓增生异常肿瘤儿童、青少年和年轻成人患者的特征和预后：单中心回顾性分析
IF 2.1 4区 医学 Q3 HEMATOLOGY
Leukemia research
Pub Date : 2024-08-20 DOI: 10.1016/j.leukres.2024.107563

Myelodysplastic syndrome, or myelodysplastic neoplasms, are a rare finding in pediatric, adolescent, and young adult (AYA) patients. More literature is needed to highlight trends of survival or treatment resistance in subpopulations to improve treatment. Here we report a single center retrospective analysis of pediatric and AYA patients from 2000 to 2022 including molecular and cytogenetic data. Using the IPSS-R and IPSS-M, which have been reported exclusively in adults, and excluding patients with bone marrow failure syndromes, we analyzed 119 pediatric and AYA patients with myelodysplastic neoplasms. Therapy-related myelodysplastic neoplasms were present in 36 % of patients, and 31 % of patients developed acute myeloid leukemia. The 5-year overall survival (OS) rate for the entire cohort was 45 %. Contrary to young adults and older adults, mutations were not common in pediatrics. Those who underwent stem cell transplant (SCT)(at any time) had significantly longer median OS. Although SCT at any time improved OS in the de novo myelodysplastic neoplasm group, the choice of the initial treatment with intensive chemotherapy, hypomethylating agents, or SCT did not significantly alter OS. Median OS was shorter in the pediatric group (<18 years old) and longer for those with isolated deletion of 5q or TET2 mutation, but these were not significant findings. Median OS was significantly shorter in those with monosomy 7 or 7q deletion and those with therapy-related myelodysplastic neoplasms. These findings build on previously reported findings and encourage the use of SCT along with molecular and cytogenetic analysis.

骨髓增生异常综合征或骨髓增生异常肿瘤在儿童、青少年和年轻成人（AYA）患者中较为罕见。需要更多的文献来突出亚人群的生存趋势或耐药性，以改善治疗。在此，我们报告了一项对2000年至2022年期间儿科和青少年患者的单中心回顾性分析，包括分子和细胞遗传学数据。我们使用仅在成人中报道过的 IPSS-R 和 IPSS-M，并排除了骨髓衰竭综合征患者，对 119 名儿童和青壮年骨髓增生异常肿瘤患者进行了分析。36%的患者出现了与治疗相关的骨髓增生异常肿瘤，31%的患者发展为急性髓性白血病。整个组群的5年总生存率（OS）为45%。与年轻人和老年人相反，突变在儿科并不常见。在任何时间接受干细胞移植（SCT）的患者，中位生存期明显更长。虽然任何时候进行干细胞移植都能改善新生骨髓增生异常肿瘤组的OS，但选择强化化疗、低甲基化药物或干细胞移植进行初始治疗并不会显著改变OS。儿童组（18 岁）的中位生存期较短，而5q缺失或TET2突变者的中位生存期较长，但这些结果并不显著。7单体或7q缺失患者以及与治疗相关的骨髓增生异常肿瘤患者的中位生存期明显较短。这些研究结果建立在之前报道的基础上，鼓励在使用 SCT 的同时进行分子和细胞遗传学分析。
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引用次数: 0
Allogeneic stem cell transplant with TBI-based myeloablative conditioning in adolescents and young adults with Philadelphia chromosome-negative ALL treated with pediatric protocols 费城染色体阴性 ALL 青少年和年轻成人异体干细胞移植与基于 TBI 的髓脱落调理的儿科治疗方案
IF 2.1 4区 医学 Q3 HEMATOLOGY
Leukemia research
Pub Date : 2024-08-20 DOI: 10.1016/j.leukres.2024.107562

To investigate the safety of total body irradiation-based myeloablative conditioning (TBI-MAC) in adolescent and young adult (AYA) Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) patients treated with pediatric protocols, treatment outcomes of 106 AYA patients aged 16–39 years old undergoing allogeneic stem cell transplant (allo-SCT) with TBI-MAC in the first remission were compared according to chemotherapy types before transplant. Pediatric and adult protocols were used in 56 and 50 of the patients, respectively. The cumulative incidence (CI) of non-relapse mortality (NRM) and the overall survival (OS) rates were not significantly different between the pediatric-protocol and adult-protocol group (NRM: 4 % vs. 14 % at five years post-transplant, respectively, p = 0.26; OS: 81 % vs. 66 %, respectively, p = 0.14). Multivariate analysis for NRM revealed that a performance status >0 (hazard ratio [HR] = 4.8) and transplant due to chemotherapy toxicities (HR = 3.5) were independent risk factors, but a pediatric protocol was not (HR = 0.48). The CI of NRM and the OS rates were also similar among patients aged over 24 years old. These findings suggested that conventional allo-SCT with TBI-MAC can be performed without increasing NRM in AYA patients with Ph-negative ALL even after pediatric protocols.

为了研究基于全身辐照的髓鞘剥脱调理（TBI-MAC）在接受儿科方案治疗的青少年费城染色体（Ph）阴性急性淋巴细胞白血病（ALL）患者中的安全性，我们根据移植前化疗类型，比较了106名接受异基因干细胞移植（allo-SCT）并在首次缓解期接受TBI-MAC治疗的16-39岁青少年费城染色体（Ph）阴性急性淋巴细胞白血病（ALL）患者的治疗结果。分别有56名和50名患者采用了儿童和成人方案。儿科方案组和成人方案组的非复发死亡率（NRM）累积发生率（CI）和总生存率（OS）没有显著差异（NRM：移植后五年分别为4%和14%，P = 0.26；OS：移植后五年分别为81%和66%，P = 0.26）：分别为 81% 对 66%，p = 0.14）。NRM的多变量分析显示，表现状态为0（危险比[HR] = 4.8）和因化疗毒性而移植（HR = 3.5）是独立的危险因素，但儿科方案不是（HR = 0.48）。24岁以上患者的NRM CI和OS率也相似。这些研究结果表明，对于Ph阴性ALL的青壮年患者，即使采用儿科方案，也可以使用TBI-MAC进行常规allo-SCT，而不会增加NRM。
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