ASH 2020 – virtual
Lecture Board: Paul Barr, MD; Chan Cheah, MBBS; Paolo Ghia, MD, PhD; Preetesh Jain, MD, PhD; Stephen Opat, MD; Kerry Rogers, MD; Alessandra Tedeschi, MD
Medical Writer: Dr. Judith Moser
Preface – ASH 2020
The ASH Annual Meeting and Exposition is the premier event for presentation of novel data on malignant and non-malignant hematologic diseases, attracting up to 30,000 specialists from all over the world. The 62nd ASH Annual Meeting was planned to be held on December 5–8, 2020 in San Diego, California, but due to the COVID-19 pandemic had been transformed to an all-virtual event.
What is new in Waldenström’s macroglobulinemia?
Constitutive activation of the Bruton’s tyrosine kinase (BTK) pathway has been shown to induce malignant cell survival in patients with Waldenström’s macroglobulinemia (WM). The disease is based on the accumulation of IgM-secreting clonal lymphoplasmacytic cells in the bone marrow and extramedullary sites. MYD88L265P mutations (> 90 % of cases) and CXCR4WHIM-like mutations (approximately 27 % of cases) have been established as the pathologic hallmarks of WM.
Management of CLL patients: BTK inhibition and beyond
BTK inhibitors, the Bcl-2 inhibitor venetoclax and anti-CD20 antibodies such as obinutuzumab have dramatically changed the therapeutic landscape of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Ibrutinib, as the first-generation representative of the BTK inhibitor class, is a therapeutic mainstay, although it has notable shortcomings that led to the introduction of second-generation agents.
Insights from early clinical trials on targeted treatment in B-cell malignancies
Richter’s transformation (RT), which describes transformation of CLL/SLL to diffuse large B-cell lymphoma (DLBCL) or Hodgkin lymphoma, is a rare event occurring in approximately 5–7 % of CLL cases [1]. However, defined standards of care are lacking, and outcomes are generally poor once patients are refractory to rituximab plus chemotherapy.
Approaching marginal zone lymphoma from various angles
Approximately 10 % of Non-Hodgkin lymphomas are classified as marginal zone lymphoma (MZL) [1]. This is a heterogeneous malignancy with three main subtypes (i.e., extranodal, nodal, splenic) arising from memory B cells in the marginal zone of secondary lymphoid follicles [2, 3]. Due to its rarity and heterogeneous nature, the optimal therapeutic strategies for patients with MZL have been difficult to define.
Advancing treatment in patients with mantle cell lymphoma
High relapse rates after standard-of-care regimens in the frontline setting are typical of mantle cell lymphoma (MCL), which is an aggressive, rare, B-cell Non-Hodgkin lymphoma. The second-generation, highly selective BTK inhibitor acalabrutinib has been approved in the US for the treatment of patients with MCL after ≥ 1 prior therapy based on the single-arm, open-label, multicenter, phase II ACE-LY-004 study.
Finding the way among a multitude of targets and regimens
I would like to address two factors here. The first one relates to favorable disease biology. Patients who have mutated immunoglobulin genes or lack TP53 mutations or 17p loss are more likely to experience treatment-free remission. The other main factor is treatment capable of inducing deep remission, which is usually combination therapy. Historically, the fludarabine/cyclophosphamide/rituximab regimen was the gold standard with which patients could achieve deep remissions.
PD-1 inhibition and (Non-)Hodgkin lymphoma: promising outcomes in an emerging field
Mediastinal gray zone lymphoma (MGZL) is an extremely rare type of Non-Hodgkin lymphoma with a predominance in young men. This disease exhibits transitional features between nodular sclerosis classical Hodgkin lymphoma (cHL) and primary mediastinal B-cell lymphoma (PMBL). However, compared to PMBL, survival of patients with MGZL is inferior after conventional chemotherapy.
Bone marrow microenvironment: culprit and target
Apart from factors such as genetic events that contribute to the malignant transformation in Waldenström’s macroglobulinemia (WM), the bone marrow microenvironment has been identified as a crucial player in WM disease progression. Similarly, it appears to be essential for the emergence and progression of multiple myeloma (MM) and constitutes a significant reason why MM patients are not amenable to cure but inevitably develop relapses.
序言
ASH年会暨展览会是介绍恶性及非恶性血液病相关新数据的重要活动,吸引了来自全球多达30,000名专家。 第62届ASH年会原定于2020年12月5日至8日在加利福尼亚州圣地亚哥举行,但由于COVID-19疫情,已转为全线上会议。与会者可以获得数千份着重于血液学领域前沿研究的科学文摘。本出版物总结了在B细胞恶性肿瘤领域介绍的著作,重点在于靶向疗法。
华氏巨球蛋白血症领域有何新进展?
研究表明,布鲁顿酪氨酸激酶(BTK)途径的组成性激活可诱导华氏巨球蛋白血症(WM)患者的恶性细胞存活。该疾病是基于分泌IgM的克隆性淋巴浆细胞在骨髓和髓外部位的积累。MYD88L265P突变(> 90 %的病例)和CXCR4WHIM样突变(大约27 %的病例)已被确定为WM的病理学标志。 依鲁替尼对BTK的抑制作用已大大改变了WM的治疗前景。
CLL患者管理:BTK抑制及其他
BTK抑制剂、Bcl-2抑制剂维奈托克(venetoclax)和诸如阿托珠单抗(obinutuzumab)等抗CD20抗体已大大改变了慢性淋巴细胞性白血病(CLL)/小淋巴细胞性淋巴瘤(SLL)的治疗前景。依鲁替尼,作为BTK抑制剂类的第一代代表,是主要治疗手段,但其明显的缺点导致引入了第二代药物。 阿卡替尼(acalabrutinib)已在美国和欧洲获得批准用于治疗CLL患者,而泽布替尼则在2020年在中国被批准用于该适应症。
来自B细胞恶性肿瘤靶向治疗早期临床试验的见解
Richter转化(RT)描述了CLL/SLL向弥漫性大B细胞淋巴瘤(DLBCL)或霍奇金淋巴瘤的转化,是一种发生在大约5-7 %的CLL病例中的罕见事件[1]。 但是,缺乏明确的护理标准,一旦用利妥昔单抗加化疗难以治疗,患者的结果通常很差。一种新的策略是合成致死方法,该方法描述了同时抑制导致细胞死亡的多种途径。主要异常途径和补偿途径均被抑制。
从多种角度尝试治疗边缘区淋巴瘤
约10 %的非霍奇金淋巴瘤被分类为边缘区淋巴瘤(MZL)。这是一种异质性恶性肿瘤,由次级淋巴滤泡边缘区域的记忆B细胞引起,具有三种主要的亚型(即结外、结内、脾脏)。 由于其稀有性和异质性,难以确定MZL患者的最佳治疗策略。晚期疾病在很大程度上被认为是无法治愈的,具有持续的复发和缓解模式。但是,在2020年ASH大会上介绍的II期数据表明,新的治疗选择,例如BTK抑制剂泽布替尼和PI3Kδ抑制剂parsaclisib,有可能改变相当一部分患者的病程。
套细胞淋巴瘤患者中的先进疗法
套细胞淋巴瘤(MCL)的典型特征在于一线标准护理方案后的高复发率,它是一种侵袭性、罕见的B细胞非霍奇金淋巴瘤。基于单组、开放标签、多中心、II期ACE-LY-004研究,第二代高选择性BTK抑制剂阿卡替尼已在美国被批准用于治疗经过≥1种先前疗法的MCL患者[5] 。 在ASH 2020上,Wang等人报告了在经过额外一年的随访后,该试验更新的疗效和安全性结果[6]。总计招募了124名r/r MCL患者。在38.1个月的中位随访时,仍有55(44 %)名患者接受研究,其中24(19 %)名患者仍接受阿卡替尼治疗。
在众多靶标和方案中寻找出路
在这里我想强调两个因素。第一个因素涉及有利的疾病生物学。免疫球蛋白基因突变或者缺乏TP53突变或17p缺失的患者更有可能获得无治疗的缓解。 另一个主要因素是能够引起深度缓解的治疗,通常是联合疗法。从历史上看,氟达拉滨/环磷酰胺/利妥昔单抗方案是金标准,可以使患者获得深度缓解。但是,我们有几个固定持续时间的选项。CLL14研究调查了维奈托克加阿托珠单抗,而CAPTIVATE评估了依鲁替尼加维奈托克。此外,还测试了阿卡替尼、维奈托克和阿托珠单抗的组合。
PD-1抑制和(非)霍奇金淋巴瘤:在新兴领域的结果可期
纵隔灰区淋巴瘤(MGZL)是一种非常罕见的非霍奇金淋巴瘤,主要出现在年轻男性中。该病表现出在结节性硬化经典霍奇金淋巴瘤(cHL)与原发性纵隔B细胞淋巴瘤(PMBL)之间的过渡特征。 但是,与PMBL相比,MGZL患者的常规化疗后生存率较差[4]。II期Checkmate 436试验已经在成年r/r PMBL患者中确定了抗PD-L1抗体纳武单抗联合抗体-药物缀合物 维布妥昔单抗(brentuximab vedotin,BV)的高缓解率。
骨髓微环境:元凶和靶标
除了诸如引起华氏巨球蛋白血症(WM)恶性转化的遗传事件等因素外,骨髓微环境还被认为是WM疾病进展的关键因素。同样,它对于多发性骨髓瘤(MM)的出现和进展似乎必不可少,并且是MM患者难以治愈且不可避免会复发的重要原因。大约在15年前,在骨髓微环境的背景下对恶性细胞生长的描述就已成为研究的重点,因为这可能实现针对MM和WM设计更有效的治疗策略。
EXPERT VIDEOS
All video interviews from ASH 2020
Alessandra Tedeschi summarizes the results from the MAGNOLIA and iNNOVATE trials, relates to recent advances in the management of marginal zone lymphoma and discusses the effect of the introduction of BTK inhibition on the prognosis of patients with Waldenström’s macroglobulinemia.