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%，其特征是频繁复发和生存期缩短。目前没有可用的治愈性疗法，也没有标准的一线治疗。初始治疗包括强化联合化疗与干细胞移植或较低侵略性的方法与维护利妥昔单抗，这取决于患者的年龄和性能状态。最近，口服布鲁顿酪氨酸激酶抑制剂伊曲替尼在复发性疾病患者中具有显著的活性，并且患者保持该药剂长达2年，毒性有限。该提案的主要目的是在俄亥俄州州立大学（OSU）建立一个专门的研究中心，专注于MCL的新型治疗方法和与伊克替尼的联合治疗，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学员;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，该计划旨在支持和培训OSU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，以了解上级临床研究的复杂性。该专业研究计划的主要目标包括以下所有内容：1。探索与伊曲替尼的新型治疗组合（包括与来那度胺、帕博西尼、KPT-330、利妥昔单抗和苯达莫司汀的组合）作为新诊断或复发MCL患者的治疗，2.评价其他新型药物在伊布替尼耐药MCL患者中B细胞受体信号传导和类似通路（包括BKM 120、LEE 011和MLN 8237）的作用，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50%的努力）将 服务于发展初级教师，研究员和居民的职业生涯在俄勒冈州立大学和在美国致力于通过在俄勒冈州立大学进行的指导计划，通过血液学的美国社会，并通过淋巴瘤研究基金会在淋巴瘤的临床研究。最终，在Blum博士指导下，这些试验使用了伊鲁替尼和其他新型药物，预计这些学员中的一些人将成为NHL治疗领域的独立研究者，不仅有出版记录，而且还有职业发展资金，包括NCI K23和基金会赠款以支持他们的研究。

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