Implementation of an interventional, risk-adapted clinical trial for children with newly diagnosed juvenile myelomonocytic leukemia.

针对新诊断的幼年粒单核细胞白血病儿童实施一项介入性风险适应临床试验。

• 批准号: 10673917
• 负责人: Elliot Stieglitz
• 金额: $ 65.8万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10673917
• 关键词: Acute; Acute Myelocytic Leukemia; Algorithms; Azacitidine; Biological Markers; CBL gene; Child; Childhood; Clinical; Clinical Trials; Collaborations; Combination Drug Therapy; Cytarabine; DNA; DNA Methylation; Data; Development; Diagnosis; Disease; Disease Progression; Disease remission; Disease-Free Survival; Epigenetic Process; Europe; Future; Genes; Genetic; Genetically Engineered Mouse; Genomics; Genotype; Goals; Grant; Hematologic Neoplasms; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hypermethylation; In Vitro; In complete remission; Inferior; International; Intervention Trial; JAK2 gene; Juvenile Myelomonocytic Leukemia; KRAS2 gene; Lead; MAP Kinase Gene; MEKs; Methylation; Molecular; Mutate; Mutation; Myelodysplastic/Myeloproliferative Disease; Myeloproliferative disease; NF1 gene; Newly Diagnosed; Outcome; PTPN11 gene; Pathway interactions; Patient-Focused Outcomes; Patients; Pediatric Oncology Group; Phase; Pre-Clinical Model; Prognosis; Relapse; Resolution; Risk; Signal Transduction; Stem cell transplant; Survival Analysis; Testing; Therapeutic; Work; biomarker validation; chemotherapy; clinically actionable; combinatorial; demethylation; disorder control; early childhood; early phase clinical trial; efficacy testing; epigenomics; experience; fludarabine; genome-wide; hematopoietic cell transplantation; high risk; implementation intervention; improved; improved outcome; in vivo evaluation; induced pluripotent stem cell; inhibitor; mouse model; outcome prediction; patient derived xenograft model; patient stratification; pre-clinical; preclinical study; primary endpoint; prognostic; response; risk stratification; side effect; standard of care; synergism; targeted treatment; therapeutic target; transplantation therapy

Project Summary/Abstract Juvenile myelomonocytic leukemia (JMML) is a hematopoietic disorder of childhood that is associated with a poor prognosis. The current standard of care involves hematopoietic stem cell transplantation (HCT), resulting in many short and long-terms side effects. However, despite the intensity of HCT, outcomes are still poor with event free survival (EFS) at three years of only 50%. Enigmatically, there are rare patients who are known to experience spontaneous resolution of their disease with little to no treatment. While robust biomarkers of favorable and unfavorable prognosis have historically been lacking in this disease, we have demonstrated that a hypomethylated DNA signature identifies patients most likely to experience spontaneous resolution without HCT. In contrast, the presence of a hypermethylated DNA signature portended a poor outcome even after HCT. Our earlier work also showed that the presence of more than one somatically mutated gene was predictive of exceedingly poor outcomes. Both these biomarkers have since been validated in additional studies. Therapeutically, azacitidine and trametinib have each shown promise in early phase clinical trials in this disease although neither is curative as a monotherapy. Our preclinical data demonstrates that the combination of azacitidine and trametinib is more effective than either agent alone.Our overall hypothesis is that risk stratified therapy will be feasible in patients with newly diagnosed JMML and will ultimately result in improved outcomes. We expect that combinatorial therapy with azacitidine and trametinib (“Aza-MEK”) will provide excellent disease control for those with lower-risk JMML, while Aza-MEK + chemotherapy will yield molecular responses prior to HCT for those with high-risk JMML, therefore leading to better outcomes post- HCT. We further hypothesize that dual inhibition of JAK/STAT and MAPK signaling will confer synergy and, as such, we will test these agents in pre-clinical models to inform future clinical trials. In Aim 1 we will implement the first risk-stratified trial in JMML. In Aim 1a we will determine the feasibility of avoiding HCT in lower-risk patients (defined as those with a low DNA methylation signature and only one mutated gene) by treating with azacitidine in combination with trametinib (Aza-MEK) for up to 12 cycles. Lower-risk patients will only proceed to HCT in the setting of disease progression. In Aim 1b we will determine if adding Aza-MEK to cytarabine and fludarabine for high-risk patients (those with multiple mutations or an intermediate/high methylation signature) will increase the number of patients achieving a molecular remission pre-HCT. Finally, in Aim 2 we will interrogate the JAK/STAT pathway as a therapeutic target in JMML. Our data from in-vitro and in-vivo testing revealed single-agent activity of JAK2 inhibitors. In Aim 2a we will harness genetically engineered mice and in Aim 2b, patient derived xenograft models to test the hypothesis that ruxolitinib will be synergistic in combination with trametinib. Collectively, these studies will improve outcomes for patients with JMML by expanding treatment options beyond just HCT.

项目摘要/摘要 幼年性粒单核细胞白血病(JMML)是一种儿童造血系统疾病，与 预后不良。目前的护理标准涉及造血干细胞移植(HCT)，结果 有许多短期和长期的副作用。然而，尽管HCT的强度很大，但结果仍然很差 无事件生存率(EFS)在三年内仅为50%。令人费解的是，有一些罕见的患者 经历他们的疾病在很少或根本不治疗的情况下自发解决。虽然强健的生物标记物 这种疾病历来缺乏良好和不良的预后，我们已经证明 低甲基化的DNA签名确定了最有可能经历自发缓解的患者 HCT。相比之下，高甲基化DNA签名的存在预示着即使在 HCT。我们早期的工作也表明，不止一个体细胞突变基因的存在 预示着极其糟糕的结果。自那以后，这两个生物标志物都在其他 学习。在治疗方面，阿扎替丁和曲美替尼在#年的早期临床试验中都显示出了希望。 虽然这两种疾病都不是单一疗法可以治愈的。我们的临床前数据表明 阿扎替丁和曲美替尼联合使用比单独使用任何一种药物都更有效。 这种风险分层治疗在新诊断的JMML患者中是可行的，并最终将导致 改善了结果。我们预计阿扎替丁和曲美替尼(“aza-mek”)的联合治疗将 为风险较低的JMML患者提供出色的疾病控制，而Aza-MEK+化疗将产生 对于患有高危JMML的患者，HCT前的分子反应，因此导致了更好的预后 HCT。我们进一步假设，JAK/STAT和MAPK信号的双重抑制将产生协同作用，并且，AS 因此，我们将在临床前模型中测试这些药物，以便为未来的临床试验提供信息。在目标1中，我们将实施 JMML中的第一个风险分层试验。在目标1a中，我们将确定在风险较低的情况下避免红细胞压积的可行性。 患者(定义为DNA甲基化特征较低且只有一个突变基因的患者) 阿扎替丁联合曲美替尼(aza-MEK)，最多12个周期。风险较低的患者只会继续 在疾病进展的背景下与红细胞压积有关。在目标1b中，我们将确定在阿糖胞苷中加入氮杂甲酸甲酯和 氟达拉滨适用于高危患者(具有多个突变或中/高度甲基化特征的患者) 将增加接受HCT前实现分子缓解的患者数量。 最后，在 目标2我们将 询问JAK/STAT通路作为JMML的治疗靶点。我们来自体外和体内测试的数据 揭示了JAK2抑制剂的单剂活性。在目标2a中，我们将利用转基因小鼠，并在 目的2b，患者来源的异种移植模型，以验证鲁索利替尼将在 与曲美替尼联合应用。总的来说，这些研究将通过以下方式改善JMML患者的预后 扩大治疗选择，而不仅仅是HCT。