Bone Marrow Histopathological Changes in Neoplastic and Non-Neoplastic Diseases

肿瘤和非肿瘤疾病的骨髓组织病理学变化

基本信息

  • 批准号:
    9154156
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
  • 资助国家:
    美国
  • 起止时间:
  • 项目状态:
    未结题

项目摘要

In collaboration with Dr. Wiestner, NHLBI, we studied bone marrow changes in patients with chronic lymphocytic leukemia (CLL) and TP53 aberrations enrolled into single-arm phase 2 study of oral agent ibrutinib. Ibrutinib (PCI-32765) is a covalent inhibitor of Bruton's tyrosine kinase (BTK). Once-daily administration causes sustained inactivation of the kinase, resulting in inhibition of B-cell receptor signaling and tumor-microenvironment interactions. Patients with chronic lymphocytic leukemia with TP53 aberrations respond poorly to first-line chemoimmunotherapy, resulting in early relapse and short survival. Eligible adult patients with active CLL with TP53 aberrations received 28-day cycles of ibrutinib 420 mg orally once daily until disease progression or the occurrence of limiting toxicities. 47 patients had CLL with deletion 17p13.1 and four carried a TP53 mutation in the absence of deletion 17p13.1. All patients had active disease requiring therapy. 35 enrolled patients had previously untreated CLL and 16 had relapsed or refractory disease. Median follow-up was 24 months. 33 previously untreated patients and 15 patients with relapsed or refractory CLL were evaluable for response at 24 weeks. Responses were assessed based on IWCLL 2008 criteria, incorporating the recent updates on partial response with lymphocytosis. Clinical response was assessed at each visit. At 2, 6, and 12 months, radiological assessments were done. Bone marrow evaluation was undertaken in 42 patients at 8 weeks, and in 47 patients at 24 weeks. The bone marrow at 8 weeks was omitted in the first patients and one patient refused bone marrow biopsy at 24 weeks. Bone marrow samples were assessed by immunostaining for CD20, CD79a, PAX-5, CD5 and CD3. FISH for deletion 17p13.1 was repeated on blood samples at 24 weeks. 32 (97%; 95% CI 86-100) of 33 previously untreated patients achieved an objective response, including partial response in 18 patients (55%) and partial response with lymphocytosis in 14 (42%). One patient had progressive disease at 0.4 months. 12 (80%; 95% CI 52-96) of the 15 patients with relapsed or refractory CLL had an objective response: six (40%) achieved a partial response and six (40%) a partial response with lymphocytosis; the remaining three (20%) patients had stable disease. Rapid disease control was achieved in all tissue compartments, reaching at least a 50% mean reduction in tumor burden in both spleen and lymph nodes at 8 weeks, with further improvements on continued therapy. Responses in the bone marrow seemed to be somewhat slower than in the spleen and lymph nodes. At 8 weeks, at least a 50% decrease in tumor burden in the bone marrow, lymph node, and spleen was recorded in 16 (44%) of 36, 31 (70%) of 44, and 30 (79%) of 38 patients with complete data, respectively. At the completion of 24 weeks of treatment, the proportion of patients with at least a 50% reduction in tumor burden in bone marrow, lymph node, and spleen was 34 (83%) of 41, 42 (93%) of 45, and 38 (95%) of 40 patients with complete data, respectively. In three patients, no residual CLL infiltrate was detected in the bone marrow by immunohistochemistry. Treatment with ibrutinib was well tolerated. The activity and safety profile of single-agent ibrutinib in CLL with TP53 aberrations is encouraging and supports its consideration as a novel treatment option for patients with this high-risk disease in both first-line and second-line settings. During the course of this trial, we noticed that single-agent ibrutinib treatment decreased CD20 expression in B-cells. We demonstrated that CD20 expression on ibrutinib was rapidly and persistently down-regulated (median reduction 74%, P<0.001) compared to baseline. Concomitantly, CD20 mRNA was decreased concurrent with reduced NF-kappaB signaling. An NF-kappaB binding site in the promoter of MS4A1 (encoding CD20) and down-regulation of CD20 by NF-kappaB inhibitors support a direct transcriptional effect. In addition, tumor cells from patients on ibrutinib were less susceptible to anti-CD20 mAb-mediated complement-dependent cytotoxicity than pre-treatment cells (median reduction 75%, P<0.001); however, opsonization by the complement protein C3d, which targets cells for phagocytosis, was relatively maintained. Expression of decay accelerating factor (CD55) decreased on ibrutinib, providing a likely mechanism for the preserved C3d opsonization. Additionally, ibrutinib significantly inhibited trogocytosis, a major contributor to antigen loss and tumor escape during mAb therapy. The data indicate that ibrutinib promotes both positive and negative interactions with anti-CD20 mAbs, suggesting that successfully harnessing maximal anti-tumor effects of such combinations requires further investigation. In collaboration with Dr. Landgren, we studied bone marrow changes in patients with plasma cell neoplasms treated with carfilzomib-lenalidomide-dexamethasone therapy in newly diagnosed multiple myeloma (NDMM) and high-risk smoldering multiple myeloma (SMM). 45 patients with NDMM and 12 patients with SMM were treated with median follow-up of 17.3 months (NDMM) and 15.9 months (SMM). All patients with SMM achieved at least a very good partial response during the study period. Among the 28 patients with NDMM and the 12 with SMM achieving at least a near-complete response, MRD negativity was found in 28 of 28 (100% 95% CI, 88%-100%), 11 of 12 (92% 95% CI, 62%-100%) (multiparametric flow cytometry), 14 of 21 (67% 95% CI, 43%-85%), and 9 of 12 (75% 95% CI, 43%-94%) (next-generation sequencing), respectively. No patients had neuropathy of grade 3 or greater. The study revealed that carfilzomib-lenalidomide-dexamethasone therapy is tolerable and demonstrates high rates of MRD negativity in NDMM, translating into longer progression-free survival in these patients. In a separate study, treatment responses to pan-KIR2D blockade with IPH2101 humanized monoclonal antibody were assessed. Total of 9 SMM patients were enrolled onto the first stage of the study. After completion of the first stage, the study was terminated due to lack of patients meeting the defined primary objective (50% decline in M-protein). Clinical response rates during the first 6 cycles of IPH2101 yielded 1 of 9 (11%) patients with minimal response (MR), 6 of 9 (66%) patients with stable disease (SD), 1 of 9 (11%) with biochemical progression (BP), and 1 of 9 (11%) patients with clinical progression to symptomatic MM. During the follow-up period (median follow up 32 months, range 837), 2 additional patients progressed to symptomatic MM. IPH2101 infusions were well tolerated with no grade 3 or 4 toxicities reported. Although this study showed no clinical response to single agent IPH2101, KIR blockade given in combination with other agents (e.g. lenalidomide) to bolster NK-cell cytotoxicity or in the setting of adoptive transfer of allogeneic or ex vivo expanded autologous NK cells may generate clinically significant responses in future trials.
我们与Dr. Wiestner, NHLBI合作,研究了慢性淋巴细胞白血病(CLL)和TP53畸变患者的骨髓变化,这些患者参加了口服伊鲁替尼单臂2期研究。Ibrutinib (PCI-32765)是布鲁顿酪氨酸激酶(BTK)的共价抑制剂。每日一次给药导致激酶持续失活,从而抑制b细胞受体信号传导和肿瘤-微环境相互作用。TP53异常的慢性淋巴细胞白血病患者对一线化疗免疫治疗反应差,导致早期复发和短生存期。符合条件的TP53异常的活动性CLL成年患者接受ibrutinib治疗,每28天一次,每次420 mg,直至疾病进展或出现限制性毒性。47例患者患有缺失17p13.1的CLL, 4例患者在没有缺失17p13.1的情况下携带TP53突变。所有患者均为活动性疾病,需要治疗。35例入组患者以前未接受治疗的CLL, 16例复发或难治性疾病。中位随访时间为24个月。33名先前未接受治疗的患者和15名复发或难治性CLL患者在24周时可评估反应。根据IWCLL 2008标准对反应进行评估,并结合最近对淋巴细胞增多症部分反应的更新。在每次访问时评估临床反应。在2、6和12个月时,进行放射学评估。42例患者在8周时进行骨髓评估,47例患者在24周时进行骨髓评估。第1例患者8周时省略骨髓,1例患者24周时拒绝骨髓活检。骨髓标本采用免疫染色法检测CD20、CD79a、PAX-5、CD5和CD3。在24周时对血液样本重复FISH检测17p13.1缺失。33名先前未接受治疗的患者中有32名(97%;95% CI 86-100)获得了客观缓解,包括18名患者(55%)的部分缓解和14名患者(42%)的部分缓解伴淋巴细胞增多。1例患者在0.4个月时病情进展。15例复发或难治性CLL患者中有12例(80%;95% CI 52-96)有客观缓解:6例(40%)达到部分缓解,6例(40%)部分缓解伴有淋巴细胞增多;其余3例(20%)患者病情稳定。在所有组织区室中都实现了快速疾病控制,在8周时脾脏和淋巴结的肿瘤负荷平均减少至少50%,并在继续治疗时进一步改善。骨髓的反应似乎比脾和淋巴结的反应稍慢。8周时,36例患者中有16例(44%),44例中有31例(70%),38例数据完整的患者中有30例(79%)分别记录到骨髓、淋巴结和脾脏肿瘤负荷减少至少50%。在24周治疗结束时,骨髓、淋巴结和脾脏肿瘤负担减少至少50%的患者比例分别为41例患者中34例(83%)、45例患者中42例(93%)和40例数据完整的患者中38例(95%)。在3例患者中,免疫组化未检测到骨髓中残留CLL浸润。依鲁替尼治疗耐受性良好。单药依鲁替尼治疗TP53异常的CLL的活性和安全性令人鼓舞,并支持将其作为一线和二线高风险疾病患者的新治疗选择。在本试验过程中,我们注意到单药伊鲁替尼治疗降低了b细胞中CD20的表达。我们证明,与基线相比,ibrutinib上的CD20表达快速且持续下调(中位数降低74%,P<0.001)。同时,CD20 mRNA表达减少,NF-kappaB信号传导减少。MS4A1启动子中的NF-kappaB结合位点(编码CD20)和NF-kappaB抑制剂对CD20的下调支持直接转录作用。此外,接受依鲁替尼治疗的患者的肿瘤细胞对抗cd20单克隆抗体介导的补体依赖性细胞毒性的敏感性低于治疗前的细胞(中位数降低75%,P<0.001);然而,靶向细胞吞噬的补体蛋白C3d的调理作用相对维持。衰变加速因子(CD55)的表达在伊鲁替尼上下降,为保存C3d的机制提供了可能的机制。此外,伊鲁替尼显著抑制细胞增生,这是单克隆抗体治疗期间抗原丢失和肿瘤逃逸的主要因素。数据表明,ibrutinib促进与抗cd20单抗的正相互作用和负相互作用,这表明成功利用这种组合的最大抗肿瘤作用需要进一步的研究。

项目成果

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Irina Maric其他文献

Irina Maric的其他文献

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{{ truncateString('Irina Maric', 18)}}的其他基金

Laboratory Assessment of Patients with Hypereosinophilic Syndrome
嗜酸性粒细胞增多综合征患者的实验室评估
  • 批准号:
    8565378
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Bone Marrow Histopathological Changes in Neoplastic and Non-Neoplastic Diseases
肿瘤和非肿瘤疾病的骨髓组织病理学变化
  • 批准号:
    8565402
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Laboratory Assessment of Patients with Hypereosinophilic Syndrome
嗜酸性粒细胞增多综合征患者的实验室评估
  • 批准号:
    9555574
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Laboratory Assessment of Patients with Hypereosinophilic Syndrome
嗜酸性粒细胞增多综合征患者的实验室评估
  • 批准号:
    10684570
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Laboratory Assessment of Patients with Systemic Mastocytosis
系统性肥大细胞增多症患者的实验室评估
  • 批准号:
    10019275
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Bone Marrow Histopathological Changes in Neoplastic and Non-Neoplastic Diseases
肿瘤和非肿瘤疾病的骨髓组织病理学变化
  • 批准号:
    10255219
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Laboratory Assessment of Patients with Systemic Mastocytosis
系统性肥大细胞增多症患者的实验室评估
  • 批准号:
    9354088
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Laboratory Assessment of Patients with Systemic Mastocytosis
系统性肥大细胞增多症患者的实验室评估
  • 批准号:
    8952884
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Laboratory Assessment of Patients with Hypereosinophilic Syndrome
嗜酸性粒细胞增多综合征患者的实验室评估
  • 批准号:
    8952883
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Laboratory Assessment of Patients with Chronic Myeloproliferative Diseases
慢性骨髓增生性疾病患者的实验室评估
  • 批准号:
    7593142
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:

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ATTAC 时间:针对 gp100 细胞的 T 细胞过继转移来治疗 LAM
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自体叶酸受体-α重定向CAR T细胞过继转移治疗卵巢癌的I期临床试验
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Determining mechanisms of enhanced antitumor efficacy of four-day expanded Th17 cells for adoptive transfer
确定用于过继转移的四天扩增 Th17 细胞增强抗肿瘤功效的机制
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调节性 T 细胞 (Treg) 和低剂量白细胞介素 2 (IL-2) 过继转移治疗慢性移植物抗宿主病 (GVHD) 的 I 期临床研究:基因标记为合理的联合治疗提供信息
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确定用于过继转移的四天扩增 Th17 细胞增强抗肿瘤功效的机制
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