Development of a comprehensive research program in mantle cell lymphoma in the ibrutinib era

 描述(申请人提供)：套细胞淋巴瘤(MCL)是非霍奇金淋巴瘤(NHL)的一种不常见的亚型，占所有NHL诊断的不到10%，特点是复发频繁和生存期缩短。目前没有可用的根治疗法，也不存在标准的一线疗法。最初的治疗包括强化联合化疗和干细胞移植，或较小侵袭性的方法和维持性利妥昔单抗，这取决于患者的年龄和表现状况。最近，口服Bruton‘s酪氨酸激酶抑制剂ibrutinib对复发性疾病患者具有显著的活性，患者持续服用该药长达2年，毒性有限。这项建议的主要目的是在俄亥俄州立大学(OSU)建立一个专门的研究中心，专注于MCL中的新疗法和与ibrutinib的组合，并培训该领域的新研究人员。Blum博士在过去五年中指导了多名受训人员；然而，淋巴瘤临床研究的培训机会和资金有限，不足以应对MCL和其他NHL亚型药物开发的临床挑战。该奖项将支持Blum博士开发临床研究培训计划的努力，旨在支持和培训俄亥俄州立大学和全国的初级教员、血液学/肿瘤学研究员、住院医生和医学生，了解高级临床研究的复杂性。本专业研究计划的主要目的包括以下所有内容：1.探索伊布鲁替尼(包括与来那度胺、帕波西利、KPT-330、利妥昔单抗和苯达莫司汀的联合)治疗初诊或复发的MCL的新疗法；2.评估其他新药在B细胞受体信号转导和类似途径(包括BKM120、LEE011和MLN8237)中的作用；3.在B细胞恶性肿瘤的临床研究中建立制度性和全国性的临床研究指导计划。目标1-3(布鲁姆博士50%的努力)将 致力于在俄亥俄州立大学和美国境内致力于淋巴瘤临床研究的初级教员、研究员和住院医生的职业发展，通过在俄亥俄州立大学实施的指导计划，通过美国血液学学会和淋巴瘤研究基金会。最终，在布鲁姆博士对伊布鲁替尼和其他新药进行这些试验的指导下，预计其中几名学员将成为非霍奇金淋巴瘤治疗领域的独立调查人员，他们不仅有发表记录，而且拥有包括NCI K23在内的职业发展资金和基金会赠款来支持他们的研究。

 DESCRIPTION (provided by applicant): Mantle cell lymphoma (MCL) is an uncommon subtype of non-Hodgkin's lymphoma (NHL), comprising less than 10% of all NHL diagnoses, characterized by frequent relapses and shortened survival. There are no currently available curative therapies and no standard front-line therapy exists. Initial treatment includes intensive combination chemotherapy with stem cell transplantation or less aggressive approaches with maintenance rituximab, depending on the age and performance status of the patient. Recently, ibrutinib, an oral bruton's tyrosine kinase inhibitor, has had significant activity in patients wit relapsed disease and patients have remained on the agent up to 2-years with limited toxicities. The primary aim of this proposal is to develop a specialized center for research at the Ohio State University (OSU) focused on novel therapeutics and combinations with ibrutinib in MCL and to train new investigators in the field. Dr. Blum has mentored multiple trainees over the past five years; however, training opportunities and funding for lymphoma clinical research is limited and insufficient to address the clinical challenges of drug development in MCL and other NHL subtypes. This award will support Dr. Blum's efforts to develop a clinical research training program designed to support and train junior faculty, hematology/oncology fellows, residents, and medical students at OSU and nationally in the complexities of superior clinical research. The primary aims of this specialized research program include all of the following: 1. To explore novel therapeutic combinations with ibrutinib (including combinations with lenalidomide, palbociclib, KPT-330, and rituximab and bendamustine) as therapy for patients with newly diagnosed or recurrent MCL, 2. To evaluate other novel agents in the B-cell receptor signaling and similar pathways (including BKM120, LEE011, and MLN8237) in patients with ibrutinib resistant MCL, and 3. To develop an institutional and national clinical research mentoring program in clinical investigation in B-cell malignancies. Aims 1-3 (50% of Dr. Blum's efforts) will serve to develop the careers of junior faculty, fellows, and residents at OSU and within the United States committed to clinical research in lymphoma through mentoring programs conducted at OSU, through the American Society of Hematology, and through the Lymphoma Research Foundation. Ultimately, with Dr. Blum's mentorship in the conduct of these trials with ibrutinib and other novel agents, it is anticipated that several of these trainees will become independent investigators in the field of NHL therapeutics that not only have a track record of publication, but also have career development funding including NCI K23 and foundation grants to support their research.