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.

项目摘要/摘要 青少年脊髓细胞性白血病（JMML）是一种童年的造血疾病，与 预后不良。当前的护理标准涉及造血干细胞移植（HCT），导致 在许多短期和长期副作用中。但是，hct的强度，结果仍然很差 三年的无事件生存（EFS）为50％。神秘地，有罕见的患者 经历了对疾病的赞助，几乎没有治疗。而强大的生物标志物 从历史上看，这种疾病缺乏有利和不利的预后，我们证明 低甲基化的DNA签名确定最有可能经历赞助的患者而没有 HCT。相比之下，即使在 HCT。我们较早的工作还表明，存在多个体外突变基因的存在是 预测结果非常差。此后，这两种生物标志物已在其他 研究。在治疗上，偶氮替丁和曲米替尼在早期临床试验中均表现出希望 这种疾病尽管两者都没有治愈为单一疗法。我们的临床前数据表明 偶氮替丁和曲米尼的组合比单独的任何一种药物更有效。我们的总体假设是 这种风险分层疗法对于新诊断的JMML患者是可行的，最终将导致 改善的结果。我们期望与azacitidine和trametinib（“ Aza-Mek”）的组合疗法将 为患有低风险JMML的人提供极好的疾病控制，而AZA-MEK +化学疗法将产生 HCT之前的分子响应对于具有高风险JMML的人，因此导致更好的结果 HCT。我们进一步假设，对JAK/Stat和MAPK信号的双重抑制作用将与协同作用，并将其作为 这样，我们将在临床前模型中测试这些代理，以告知未来的临床试验。在AIM 1中，我们将实施 JMML中的第一次风险分层试验。在AIM 1A中，我们将确定避免在低风险中避免HCT的可行性 患者（被定义为具有低DNA甲基化特征的患者 偶氮替丁与Trametinib（Aza-Mek）结合使用12个周期。低风险患者只会进行 在疾病进展的情况下进行HCT。在AIM 1B中，我们将确定是否将Aza-Mek添加到Cytarabine和 高风险患者的氟达拉滨（具有多重突变或中间/高甲基化特征的患者） 将增加获得HCT分子缓解的患者数量。 最后，在 目标2我们将 将JAK/STAT途径作为JMML中的治疗靶标询问。我们的数据来自体外和体内测试 揭示了JAK2抑制剂的单药活性。在AIM 2A中，我们将利用一般设计的小鼠，在 AIM 2B，患者衍生的异种移植模型，以测试鲁u属尼在 与曲米替尼结合。总的来说，这些研究将改善JMML患者的预后 扩大治疗方案不仅仅是HCT。