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

伊布替尼时代套细胞淋巴瘤综合研究计划的制定

• 批准号: 9751793
• 负责人: KRISTIE A BLUM
• 金额: $ 17.47万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-23 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751793
• 关键词: 1-Phosphatidylinositol 3-Kinase; Address; Agammaglobulinaemia tyrosine kinase; Age; American Society of Hematology; Appointment; Autologous Stem Cell Transplantation; Award; B lymphoid malignancy; B-Cell NonHodgkins Lymphoma; Binding Sites; Bortezomib; CDK4 gene; Centers of Research Excellence; Clinical; Clinical Investigator; Clinical Research; Clinical Trials; Combination Drug Therapy; Combined Modality Therapy; Cyclin D1; Cysteine; Data; Development; Diagnosis; Disease; Evaluation; Faculty; Fellowship; Foundations; Funding; Grant; Hematology; In complete remission; Institutes; Journals; Lymphoma; Maintenance; Maintenance Therapy; Mantle Cell Lymphoma; Medical Students; Medicine; Mentors; Mentorship; Methotrexate; Mutation; New England; Newly Diagnosed; Non-Hodgkin' s Lymphoma; Nuclear Protein; Ohio; Oral; Paper; Pathway interactions; Patient Agents; Patients; Performance Status; Phase; Phase I Clinical Trials; Progression-Free Survivals; Protein Export Pathway; Publications; Publishing; Randomized; Receptor Signaling; Receptors, Antigen, B-Cell; Recurrence; Recurrent disease; Refractory; Regimen; Relapse; Research; Research Personnel; Research Training; Resistance; Resources; SECTM1 gene; Specialized Center; Stem cell transplant; Testing; Therapeutic; Toxic effect; Training; Training Programs; Tyrosine Kinase Inhibitor; United States; Universities; Utah; Wit; aurora kinase; career; career development; chemotherapy; clinical investigation; curative treatments; design; drug development; inhibitor/antagonist; lenalidomide; male; next generation; novel; novel therapeutics; oncology; overexpression; patient oriented research; patient subsets; phase 1 study; phase 2 study; phase II trial; programs; public health relevance; recruit; relapse patients; resistance mechanism; response; rituximab; training opportunity

 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.

 描述（由申请人提供）：套细胞淋巴瘤 (MCL) 是非霍奇金淋巴瘤 (NHL) 的一种罕见亚型，占所有 NHL 诊断的不到 10%，其特点是频繁复发和生存期缩短。目前没有可用的治疗方法，也没有标准的一线治疗方法。初始治疗包括强化联合化疗与干细胞移植或不太激进的利妥昔单抗维持治疗，具体取决于患者的年龄和体能状态。最近，伊布替尼（一种口服布鲁顿氏酪氨酸激酶抑制剂）对疾病复发的患者具有显着的活性，患者可以继续使用该药物长达 2 年，且毒性有限。该提案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 的新型疗法和与依鲁替尼的组合，并培训该领域的新研究人员。布鲁姆博士在过去五年中指导了多名学员；然而，淋巴瘤临床研究的培训机会和资金有限，不足以解决 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，旨在支持和培训俄勒冈州立大学和全国的初级教师、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。该专门研究项目的主要目标包括以下所有内容： 1. 探索伊布替尼的新型治疗组合（包括与来那度胺、哌柏西利、KPT-330、利妥昔单抗和苯达莫司汀的组合）作为新诊断或复发性 MCL 患者的治疗方法， 2. 评估 B 细胞受体信号传导和类似途径中的其他新型药物（包括 BKM120、LEE011 和 MLN8237）用于治疗依鲁替尼耐药的 MCL 患者，以及 3. 制定 B 细胞恶性肿瘤临床研究的机构和国家临床研究指导计划。目标 1-3（Blum 博士努力的 50%）将 通过在俄勒冈州立大学、美国血液学会和淋巴瘤研究基金会开展的指导项目，致力于发展俄勒冈州立大学和美国境内致力于淋巴瘤临床研究的初级教员、研究员和住院医师的职业生涯。最终，在 Blum 博士对 ibrutinib 和其他新型药物进行这些试验的指导下，预计其中几名学员将成为 NHL 治疗领域的独立研究人员，他们不仅拥有发表的记录，而且还拥有包括 NCI K23 在内的职业发展资金和基金会拨款来支持他们的研究。

项目成果

Phase IIa study of the CD19 antibody MOR208 in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma.

• DOI: 10.1093/annonc/mdy056
• 发表时间: 2018-05-01
• 期刊: Annals of oncology : official journal of the European Society for Medical Oncology
• 作者: Jurczak W;Zinzani PL;Gaidano G;Goy A;Provencio M;Nagy Z;Robak T;Maddocks K;Buske C;Ambarkhane S;Winderlich M;Dirnberger-Hertweck M;Korolkiewicz R;Blum KA
• 通讯作者: Blum KA

B-cell receptor pathway modulators in NHL.

• DOI: 10.1182/asheducation-2015.1.82
• 发表时间: 2015
• 期刊: Hematology. American Society of Hematology. Education Program
• 作者: Blum KA

Incidence and outcomes of lymphoid malignancies in adolescent and young adult patients in the United States.

• DOI: 10.1111/bjh.15532
• 发表时间: 2018-11
• 期刊: British journal of haematology
• 影响因子: 6.5
• 作者: Blum KA;Keller FG;Castellino S;Phan A;Flowers CR
• 通讯作者: Flowers CR

De novo CD5+ diffuse large B-cell lymphoma: Adverse outcomes with and without stem cell transplantation in a large, multicenter, rituximab treated cohort.

• DOI: 10.1002/ajh.24299
• 发表时间: 2016-06
• 期刊: American journal of hematology
• 影响因子: 12.8
• 作者: Alinari L;Gru A;Quinion C;Huang Y;Lozanski A;Lozanski G;Poston J;Venkataraman G;Oak E;Kreisel F;Park SI;Matthews S;Abramson JS;Iris Lim H;Martin P;Cohen JB;Evens A;Al-Mansour Z;Singavi A;Fenske TS;Blum KA
• 通讯作者: Blum KA