The Ohio State Blood and Marrow Transplant Reseach Consortium

描述(由申请人提供)：我们建议一个由经验丰富的移植中心组成的联盟，通过癌症和白血病B组(CALGB)移植委员会(CALGB)建立一个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)内提议、开发和进行创新的临床试验。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)后复发的弥漫性大B细胞淋巴瘤(DLCL)患者的高复发风险。DLCL仍然是全球AHCT的第二个最常见的适应症，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受益。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一年内复发的人，努力减少AHCT后复发的风险是至关重要的。免疫调节剂来那度胺目前正在对一些不同亚型的非霍奇金淋巴瘤(NHL)进行测试，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。另一种新化合物，pCI-32765是一种一流的布鲁顿酪氨酸激酶(BTK)选择性抑制剂，在一项1期研究中，该药在38%的复发/难治性DLCL患者中产生了反应。这两种药物对DLCL的主要分子亚型，生发中心B细胞样(GCB)和激活的B细胞样(ABC)都有活性。复发的DLCL患者更有可能患有ABC亚型，因此有很好的理由使用这些药物来针对这类患者。我们推测，作为AHCT后的维持剂，这些化合物将降低DLCL进展的风险，特别是在ABC亚型的患者中。我们将通过以下具体目标来验证这一假说：目标1：我们将以2年无进展生存期为主要终点，对有高复发风险的DLCL患者进行大剂量化疗和AHCT，然后用来那度胺或pCI-32765维持治疗的II期随机研究。目的：我们将探讨诊断DLCL的免疫组化染色确定的DLCL分子亚型(GCB或ABC)与来那度胺或来那度胺或卡介苗-32765维持治疗后患者预后的关系。

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.