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.

项目总结/摘要 青少年粒单核细胞白血病（JMML）是一种儿童期造血系统疾病， 预后不良。目前的护理标准涉及造血干细胞移植（HCT）， 在许多短期和长期的副作用。然而，尽管HCT的强度，结果仍然很差， 3年无事件生存率（EFS）仅为50%。令人费解的是，有一些罕见的病人 他们的疾病在很少或没有治疗的情况下自发消退。虽然生物标志物 有利和不利的预后历来缺乏这种疾病，我们已经证明， 低甲基化DNA特征识别出最有可能经历自发消退而不 HCT。相比之下，高甲基化DNA标记的存在预示着即使在 HCT。我们早期的工作也表明，存在一个以上的体细胞突变基因， 预测极差的结果。此后，这两种生物标志物都在其他研究中得到了验证。 问题研究在治疗上，阿扎胞苷和曲美替尼在早期临床试验中均显示出前景， 这种疾病，虽然两者都不是治愈作为单一疗法。我们的临床前数据表明， 阿扎胞苷和曲美替尼的组合比单独使用任何一种药物更有效。 风险分层治疗在新诊断的JMML患者中是可行的，并最终导致 改善成果。我们预期使用阿扎胞苷和曲美替尼（“Aza-MEK”）的组合疗法将 为低风险JMML患者提供良好的疾病控制，而Aza-MEK +化疗将产生 对于高危JMML患者，HCT前的分子反应，因此导致HCT后更好的结局。 HCT。我们进一步假设JAK/STAT和MAPK信号传导的双重抑制将赋予协同作用， 因此，我们将在临床前模型中测试这些药物，为未来的临床试验提供信息。目标1：实现 JMML的第一个风险分层试验。在目标1a中，我们将确定在低风险患者中避免HCT的可行性。 患者（定义为具有低DNA甲基化特征和仅一个突变基因的患者）， 阿扎胞苷与曲美替尼（Aza-MEK）联合治疗最多12个周期。低风险的病人只会继续 在疾病进展的情况下进行HCT。在目标1b中，我们将确定是否将Aza-MEK添加到阿糖胞苷中， 氟达拉滨用于高风险患者（具有多个突变或中等/高甲基化特征的患者） 将增加HCT前达到分子缓解的患者数量。 最后在 目标2我们将 将JAK/STAT通路作为JMML的治疗靶点。我们的体外和体内测试数据 揭示了JAK 2抑制剂的单一药剂活性。在目标2a中，我们将利用基因工程小鼠， 目的2b，患者来源的异种移植物模型，以测试鲁索利替尼在以下假设中将是协同的： 曲美替尼Trametinib总的来说，这些研究将通过以下方式改善JMML患者的结局： 扩大了HCT以外的治疗选择。