The Ohio State Blood and Marrow Transplant Reseach Consortium

描述（由申请人提供）：我们提议成立一个由经验丰富的移植中心组成的联盟，该联盟通过癌症和白血病组B（CALGB）移植委员会建立了富有成效的合作记录，目的是在血液和骨髓移植临床试验网络（BMT CTN）内提出、开发和开展创新性临床试验。我们联盟提出的临床试验概念侧重于降低自体造血细胞移植（AHCT）后复发性弥漫性大B细胞淋巴瘤（DLCL）患者中观察到的惊人的高复发风险。DLCL仍然是全球AHCT的第二大最常见适应症，因为许多患者在化疗和利妥昔单抗治疗后仍会复发，并可能从大剂量化疗中获益。尽管如此，即使在AHCT后复发的风险也太高，特别是对于那些在完成治疗后一年内复发的患者，因此必须努力降低AHCT后复发的风险。免疫调节剂来那度胺目前正在针对许多不同亚型的非霍奇金淋巴瘤（NHL）进行测试，并且在DLCL中具有显著的单药活性，即使在AHCT后复发的患者中也是如此。另一种新型化合物PCI-32765是布鲁顿酪氨酸激酶（BTK）的一流选择性抑制剂，在1期研究中，该抑制剂导致38%的复发性/难治性DLCL患者出现缓解。两种药物均具有针对DLCL的主要分子亚型（生发中心B细胞样（GCB）和活化B细胞样（ABC））的活性。复发性DLCL患者更有可能患有ABC亚型，因此这些药物靶向此类患者有很好的理由。我们假设，作为AHCT后的维持药物，这些化合物将降低DLCL进展的风险，特别是在ABC亚型患者中。我们将通过以下具体目的来检验这一假设：目的1：我们将在AHCT后复发风险高的DLCL患者中进行一项高剂量化疗和AHCT，随后用来那度胺或PCI-32765维持治疗的随机II期研究，使用2年无进展生存期作为主要终点。目标二：我们将探索通过诊断性DLCL活检的IHC染色确定的DLCL分子亚型（GCB或ABC）与AHCT和来那度胺或PCI-32765维持治疗后患者结局之间的关系。相关性（见说明）：弥漫性大B细胞淋巴瘤（DLCL）是最常见的非霍奇金淋巴瘤类型。许多患者可以用目前的疗法治愈，但仍有太多患者复发。当DLCL复发时，高剂量化疗后自体造血细胞移植（AHCT）是治疗的选择，但许多患者即使在AHCT后复发。我们寻求在DLCL患者中进行AHCT后测试新药物，以确定我们是否可以降低复发风险并改善这些患者的生活。

DESCRIPTION (provided by applicant): We propose a consortium of highly experienced transplant centers with an established track record of productive collaborations through the Cancer and Leukemia Group B (CALGB) Transplant Committee for the purposes of proposing, developing, and conducting innovative clinical trials within the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). The clinical trial concept our consortium proposes focuses on reducing the alarmingly high risk of relapse observed in patients with recurrent diffuse large B-cell lymphoma (DLCL) following autologous hematopoietic cell transplantation (AHCT). DLCL remains the second most common indication for AHCT worldwide because many patients still relapse following chemotherapy and rituximab and may benefit from high dose chemotherapy. Nonetheless, the risk of relapse even after AHCT is too high, particularly for those who relapse within a year of completing therapy, and efforts to mitigate the risk of relapse following AHCT are essential. The immunomodulatory agent lenalidomide is currently being tested against a number of different subtypes of non-Hodgkins lymphoma (NHL) and has significant single agent activity in DLCL, even in those relapsing following AHCT. Another novel compound, PCI-32765 is a first-in-class selective inhibitor of Bruton's Tyrosine Kinase (BTK) which in a phase 1 study led to responses in 38% of patients with relapsed/refractory DLCL. Both agents have activity against the major molecular subtypes of DLCL, the germinal center B-cell like (GCB) and activated B-cell like (ABC). Relapsed DLCL patients are more likely to have the ABC subtype so there is a good rationale for targeting such patients with these agents. We hypothesize that as maintenance agents following AHCT, these compounds will decrease the risk of DLCL progression, particularly in patients with the ABC subtype. We will test this hypothesis with the following specific aims: Aim 1: We will perform a randomized Phase II study of high dose chemotherapy and AHCT followed by maintenance treatment with either lenalidomide or PCI-32765 in patients with DLCL at high risk for relapse following AHCT, using progression free survival at 2 years as the primary endpoint. Aim 2: We will explore the relationship between molecular subtypes of DLCL (GCB or ABC), determined by IHC staining of diagnostic DLCL biopsies, and patient outcomes following AHCT and maintenance treatment with either lenalidomide or PCI-32765. RELEVANCE (See instructions): Diffuse large B-cell lymphoma (DLCL) is the most common type of non-Hodgkin lymphoma. Many patients can be cured with current therapy but still too many patients relapse. When DLCL relapses, high dose chemotherapy followed by autologous hematopoietic cell transplantation (AHCT) is the treatment of choice, but many patients relapse even after AHCT. We seek to test new agents following AHCT in patients with DLCL to determine if we can lower the risk of relapse and improve the lives of these patients.