Detection, prevention and treatment of acute myeloid leukemia (AML) relapse.

急性髓系白血病（AML）复发的检测、预防和治疗。

• 批准号: 9354132
• 负责人: Christopher Hourigan
• 金额: $ 224.57万
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9354132
• 关键词: Academic Medical Centers; Acute Myelocytic Leukemia; Acute leukemia; Adopted; Adult; Adult Acute Myeloblastic Leukemia; Age; Allogenic; American; Area; Autologous; Autologous Transplantation; Biological Assay; Biological Markers; Blood specimen; Bone Marrow; Bone Marrow Examination; Bone Marrow Neoplasms; CD34 gene; CD8B1 gene; CSF3 gene; California; Cancer Center; Cancer Therapy Evaluation Program; Categories; Cells; Chromosome abnormality; Clinic; Clinical; Clinical Trials; Clonality; Comorbidity; Cytogenetics; Cytotoxic Chemotherapy; Data; Data Analyses; Detection; Development; Diagnosis; Disease; Disease remission; Donor Lymphocyte Infusion; Dose; Educational process of instructing; Elderly; Eligibility Determination; Enrollment; Flow Cytometry; Foundations; Future; Gender; Gene Expression; Gene Rearrangement; Genes; Genetic Variation; Genomics; Goals; Hematopoietic Stem Cell Transplantation; Homologous Transplantation; Human; Immune; Immune system; Immunologics; Immunology; Immunotherapy; In complete remission; Individual; Institution; Investigation; Laboratories; Lymphocyte; Malignant Neoplasms; Marrow; Masks; Measurable; Medical; Medical Oncologist; Medical Oncology; Methods; Molecular; Monitor; Multivariate Analysis; Myeloid Leukemia in Remission; Myeloproliferative disease; Newly Diagnosed; Outcome; Patient Recruitments; Patients; Phase II Clinical Trials; Prevention; Prevention program; Race; Randomized; Recurrent disease; Refractory; Refractory Disease; Relapse; Residual Neoplasm; Residual Tumors; Residual state; Risk; Sampling; San Francisco; Site; Somatic Mutation; Stem cell transplant; T-Lymphocyte; TRB@ gene cluster; Testing; Therapeutic; Time; Transplantation; Treatment-related toxicity; United States National Institutes of Health; Universities; WT1 gene; Work; Writing; base; burden of illness; chemotherapy; cohort; common treatment; conventional therapy; digital; graft vs host disease; immunogenic; improved; inhibitor/antagonist; innovation; interest; leukemia; novel; novel marker; patient stratification; peripheral blood; prevent; programs; relapse prediction; relapse risk; response; standard of care; targeted treatment; tumor microenvironment

The fundamental interest of the Myeloid Malignancies Section is the detection, prevention and treatment of acute myeloid leukemia (AML) relapse with particular focus on novel immunotherapy. Foundational to this objective has been the development of high sensitivity biomarkers for residual AML in those patients who have been treated to remission but remain at risk of relapse. Previous work in our laboratory involved the development of a multi-gene RQ-PCR expression panel for AML measurable residual disease (MRD). This panel demonstrated the ability to risk stratify, based on a peripheral blood sample collected prior to transplantation, AML patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT) into groups with high and low leukemic relapse rates (PMID: 25665046). During the past year we also performed a re-analysis of this data to show that there was no significant difference in overall survival between those who underwent allo-HCT with active disease and those in morphologic complete remission but with detectable minimal residual disease, confirming similar data from the Fred Hutchinson cancer center using a different MRD detection method on an independent cohort (PMID: 27185839) We have now extended this work by testing this MRD multigene approach on the autograft of a cohort of 72 adult AML patients who underwent autologous hematopoietic stem cell transplantation (auto-HCT) between 2004 and 2013 at a single academic medical center (University of California San Francisco). This is the largest study to date of MRD in auto-HCT for AML. We showed, contrary to multiple prior smaller studies, that WT1 RQ-PCR testing of the autograft has low sensitivity for AML relapse prediction post auto-HCT. We further demonstrated that cryopreserved autograft material presents unique challenges for AML MRD testing because of the masking effects of previous GCSF exposure on gene expression and flow cytometry signatures. Increased personalization of MRD monitoring by use of a multigene panel, particularly incorporation of assays for detection of somatic mutations or chromosomal abnormalities, however improved the ability to risk stratify patients for post-auto-HCT relapse. In multivariate analysis of clinical variables, including age, gender, race, cytogenetic risk category, and CD34+ cell dose, only autograft multigene MRD as assessed by RQ-PCR was statistically significantly associated with relapse risk (PMID: 27544285). The predominant activity of the section in the past year however has been the establishment and development of a new clinical program for the prevention and treatment of adults with relapsed and refractory AML at the NIH clinical center. In September 2015 we opened a new clinical trial for AML patients with relapsed or refractory disease, PEARL15: Personalized Early Assessment of Response During Salvage Chemotherapy in People With Relapsed or Refractory Acute Myeloid Leukemia (PEARL15, 15-H-0176, NCT02527447). This trial integrates the MRD multigene assay described above, performed in real time by our laboratory such that the results after day 4 of treatment are available by day 8. We have exceeded our patient recruitment goals for this trial, with clinical outcomes that appear equal or better than expected. We have also established a weekly AML clinic, which serves as a teaching clinic for medical oncology clinical fellows, and developed a referral network of medical oncologists in the local area. In addition, we have opened the NIH clinical center as a site and enrolled patients onto a randomized phase 2 clinical trial of Nivolumab (anti PD-1 immune checkpoint inhibitor) to eliminate minimal residual disease and prevent relapse in patients with AML in remission after chemotherapy (REMAIN, 16-H-0015, NCI CIRB 15-0185/CTEP 9706/NCT02275533). We also serve as a central laboratory site for assessing AML MRD on this trial. Given that AML is already known to be an immunogenic malignancy, as demonstrated by the measurable efficacy of allogeneic transplantation and donor lymphocyte infusion, we have also started a program of laboratory investigation of the human immune system present within the bone marrow of both AML patients and healthy adult donors. Examination of bone marrow samples from patients with relapsed or refractory AML on our PEARL15 clinical trial, as compared with healthy donors, revealed that the bone marrow tumor microenvironment appears enriched for PD-1 positive CD8 positive marrow-infiltrating lymphocytes, and high-throughput genomic sequencing of productive TCRB gene rearrangements demonstrated significantly higher average marrow T-cell clonality. Such T-cell oligoclonality was however found in only 25% of bone marrow from an independent cohort of twenty newly diagnosed untreated AML patients. These findings are suggestive that relapsed and refractory AML patients, for whom cytotoxic chemotherapy is often suboptimal, may benefit from immune checkpoint blockade therapies, particularly PD-1 axis inhibition, to enable improved immunologic control of AML by autologous T-lymphocytes already resident in the tumor microenvironment. Based in part on these data, a clinical trial of anti-PD-1 immunotherapy in combination with a hypomethylating agent for the treatment of relapsed and refractory AML patients has been written and we aim to open this study at our institution in the next six months. In summary, the primary interest of the Myeloid Malignancies Section remains the detection, prevention and treatment of AML relapse, with the long-term objective of using immunotherapy without the need for hematopoietic stem cell transplantation. Our laboratory work to develop novel methods to detect and quantify AML disease burden with high sensitivity continues, but already provides a foundation to allow correlative assessment of the efficacy of traditional stem cell transplantation and more innovative immunotherapy approaches as tested in clinical trials. We are also extending our interest in the human immune system within the bone marrow compartment both in healthy individuals and in patients with AML in parallel with clinical trials of immunotherapy for both the prevention and treatment of AML relapse. In the future we anticipate that the laboratory work of the section will continue to focus both on molecular methods (including genomics and digital droplet PCR) for AML MRD detection and investigation of the human immunology resident within the bone marrow microenvironment. The clinical work of the section will focus on biomarker and novel combination immunotherapy in a highly translational program of investigation on the prevention and treatment of AML relapse.

髓样恶性肿瘤部分的基本兴趣是急性髓样白血病（AML）复发的检测，预防和治疗，特别关注新型免疫疗法。 该目标的基础是那些接受缓解但仍有复发风险的患者中残留AML的高灵敏度生物标志物的发展。 我们实验室的先前工作涉及开发用于AML可测量残留疾病（MRD）的多基因RQ-PCR表达面板。 该小组表明，基于移植前收集的外周血样本，接受同种异体造血干细胞移植（Allo-HCT）成组成具有高和低白血病复发率的基团的AML患者（PMID：25665046）。 在过去的一年中，我们还对这些数据进行了重新分析，以表明那些接受Allo-HCT患有活性疾病的人与形态学完全缓解的人之间的总体生存没有显着差异，但可检测到的最小残留疾病，可以使用弗雷德·霍奇森癌症中心的类似数据，使用不同的MRD检测方法（PMID：PMID：PMID：27185918991891891891891891）。 现在，我们通过在2004年至2013年间在一个学术医疗中心（加利福尼亚大学旧金山大学）之间在一个自体造血干细胞移植（AUTO-HCT）（AUTO-HCT）（AUTO-HCT）（AUTO-HCT）（AUTO-HCT）（AUTO-HCT）（AUTO-HCT）（AUTO-HCT）（AUTO-HCT），对72名成年AML患者的自体进行了测试，从而扩展了这项工作。 这是AML自动HCT中MRD迄今为止最大的研究。 我们表明，与先前的较小研究相反，自体移植的WT1 RQ-PCR测试对自动HCT后AML复发预测的灵敏度较低。 我们进一步证明，冷冻保存的自体移植物材料对AML MRD测试提出了独特的挑战，因为先前的GCSF暴露对基因表达和流式细胞仪特征的掩盖作用。通过使用多基因面板，增加了MRD监测的个性化，尤其是掺入用于检测体细胞突变或染色体异常的测定法，但是提高了风险将患者分层后自动hct后HCT复发的能力。在对临床变量的多元分析中，包括年龄，性别，种族，细胞遗传风险类别和CD34+细胞剂量，仅由RQ-PCR评估的自体移植多基因MRD在统计上与复发风险显着相关（PMID：27544285）。 然而，过去一年中该部分的主要活动是在NIH临床中心建立和开发一项新的临床计划，以预防和治疗成人复发和难治性AML。 2015年9月，我们针对患有复发或难治性疾病的AML患者开设了一项新的临床试验，PEARL15：在救助化疗期间对复发或难治性急性骨髓性白血病患者进行救助化疗期间的反应的个性化评估（Pearl15，15-H-0176，NCT02527447）。 该试验整合了上述MRD多基因测定法，该试验是由我们的实验室实时执行的，以便在第8天之前获得治疗后的第4天的结果。我们已经超过了该试验的患者招聘目标，其临床结果似乎相等或更好。 我们还建立了每周一次的AML诊所，该诊所是医学肿瘤学临床研究员的教学诊所，并在当地建立了医学肿瘤学家的推荐网络。 In addition, we have opened the NIH clinical center as a site and enrolled patients onto a randomized phase 2 clinical trial of Nivolumab (anti PD-1 immune checkpoint inhibitor) to eliminate minimal residual disease and prevent relapse in patients with AML in remission after chemotherapy (REMAIN, 16-H-0015, NCI CIRB 15-0185/CTEP 9706/NCT02275533). 我们还作为该试验中AML MRD评估的中央实验室地点。 鉴于已知AML已知是一种免疫原性恶性肿瘤，如同种异体移植和供体淋巴细胞输注的可测量疗效所证明的那样，我们还启动了对AML患者骨髓内的人类免疫系统的实验室研究计划。 与健康的供体相比，在我们的Pearl15临床试验中对骨髓样品的检查表明，骨髓肿瘤微环境似乎在PD-1阳性CD8阳性阳性型骨髓浸入式淋巴细胞和高含量均具有较高的平均形成型TCRB的PD8阳性阳性含量均具有富含PD-1的阳性cd8阳性型TCRB gene gene gene gene gene gene gene gene gene gene gene gene gene gene gene gene gene gene gene gene gene gene gene gene gene gene gene gene gene gene gene，克隆性。 然而，仅在25％的骨髓中发现了这种T细胞的寡克隆性，该骨髓的独立队列由20个新诊断的未经治疗的AML患者组成。 这些发现暗示了复发和难治性的AML患者（通常是优化的细胞毒性化学疗法）可能会受益于免疫检查点阻断疗法，尤其是PD-1轴抑制，以改善自体T-乳细胞的免疫学控制AML的免疫学控制。一部分基于这些数据，已经写了抗PD-1免疫疗法的临床试验，并结合甲基化剂治疗复发和难治性AML患者的临床试验，我们的目标是在接下来的六个月内在我们的机构中​​开设这项研究。 总之，髓样恶性肿瘤部分的主要利益仍然是AML复发的检测，预防和治疗，其长期目标是使用免疫疗法而无需造血干细胞移植。 我们的实验室工作旨在开发新的方法来检测和量化高灵敏度的AML疾病负担，但已经为允许对传统干细胞移植的疗效以及在临床试验中测试的传统干细胞移植和更具创新性免疫疗法方法的疗效相关性评估。 我们还在健康个体和AML的患者中与与免疫疗法的临床试验同时进行预防和治疗AML复发的临床试验，在骨髓舱内和AML的患者中，我们还在扩大了对人类免疫系统的兴趣。将来，我们预计本节的实验室工作将继续关注分子方法（包括基因组学和数字液滴PCR），用于AML MRD检测和研究居住在骨髓微环境中的人类免疫学。 本节的临床工作将重点放在有关AML复发的预防和治疗的高度转化调查计划中。