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: 10522937
• 负责人: Elliot Stieglitz
• 金额: $ 71.13万
• 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/10522937
• 关键词: Acute; Acute Myelocytic Leukemia; Algorithms; Azacitidine; Biological Markers; CBL gene; Cells; Child; Childhood; Clinical; Clinical Trials; Collaborations; Combination Drug Therapy; Cytarabine; DNA; DNA Methylation; Data; Development; Diagnosis; Disease; Disease Progression; Disease remission; Disease-Free Survival; Dysmyelopoietic Syndromes; 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; Mus; Mutate; Mutation; 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; Transplant Recipients; Work; base; chemotherapy; clinically actionable; combinatorial; 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; 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.

项目概要/摘要 幼年型粒单核细胞白血病 (JMML) 是一种儿童期造血障碍，与 目前的护理标准涉及造血干细胞移植（HCT），导致预后不良。 然而，尽管 HCT 强度很大，但结果仍然很差。 令人费解的是，很少有患者的三年无事件生存率 (EFS) 仅为 50%。 患者的疾病几乎无需治疗即可自然消退，同时具有强大的生物标志物。 历史上这种疾病缺乏有利和不利的预后，我们已经证明 低甲基化 DNA 特征可识别出最有可能在无需治疗的情况下自然缓解的患者 相比之下，即使在 HCT 后，高甲基化 DNA 特征的存在也预示着结果不佳。 我们早期的工作还表明，存在多个体细胞突变基因。 此后，这两种生物标志物均已在其他研究中得到验证。 在治疗方面，阿扎胞苷和曲美替尼在早期临床试验中均显示出前景。 尽管单一疗法都无法治愈这种疾病，但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。我们的总体假设是 风险分层治疗对于新诊断的 JMML 患者是可行的，并最终导致 我们预计阿扎胞苷和曲美替尼（“Aza-MEK”）的联合治疗将改善结果。 为低风险 JMML 患者提供出色的疾病控制，而 Aza-MEK + 化疗将产生效果 对于高危 JMML 患者，HCT 前进行分子反应，因此术后效果更好 HCT 我们进一步发现 JAK/STAT 和 MAPK 信号传导的双重抑制将产生协同作用，并且， 因此，我们将在临床前模型中测试这些药物，为未来我们将实施的临床试验提供信息。 JMML 中的第一个风险分层试验在目标 1a 中，我们将确定在低风险中避免 HCT 的可行性。 患者（定义为具有低 DNA 甲基化特征且只有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，仅对低风险患者进行。 在目标 1b 中，我们将确定是否在阿糖胞苷中添加 Aza-MEK 和 HCT。 氟达拉滨用于高危患者（具有多种突变或中/高甲基化特征的患者） 将增加 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。我们的数据来自体外和体内测试。 在 Aim 2a 中，我们将利用基因工程小鼠并揭示 JAK2 抑制剂的单药活性。 目标 2b，患者衍生的异种移植模型，以测试鲁索替尼在以下方面具有协同作用的假设： 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 HCT 之外的治疗选择。