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[1,2]。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[3]。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[4-6]。

iNNOVATE: 依鲁替尼(ibrutinib) 加利妥昔单抗(rituximab

依鲁替尼对BTK的抑制作用已大大改变了WM的治疗前景。III期iNNOVATE研究在初治或经先前治疗的WM患者中比较了依鲁替尼加利妥昔单抗与安慰剂加利妥昔单抗;使用后者的患者必须对利妥昔单抗敏感(即,上一次基于利妥昔单抗的疗法有效,并且在首次研究剂量之前的12个月内未使用利妥昔单抗治疗)。每个组包括75个人。中位随访26.5个月后,iNNOVATE的初步分析表明,组合优于利妥昔单抗单药治疗[7]。这些数据构成了在美国和欧洲批准依鲁替尼加利妥昔单抗的基础。

在ASH 2020上,Buske等人报告了研究在63个月的总体随访后的最终分析结果[8]。方案允许对照组在疾病进展后交叉使用单药依鲁替尼。实际上,这些患者中有35名(47 %)进行了交叉。在研究结束后,有68名(45 %)患者仍采用依鲁替尼,因为32名参加了治疗扩展计划,另外36名继续在商业环境中接受依鲁替尼。

甚至在试验开始后5年,实验组仍未达到中位无进展生存期(PFS)。相比之下,用安慰剂加利妥昔单抗观察到的中位PFS为20.3个月,这意味着风险降低了75 %(HR,0.25;p <0.0001; 图)。在54个月时,无进展生存率分别为68 %与25 %。在两个组中,PFS益处均不取决于基因型(即, MYD88L265P或MYD88野生型与 CXCR4WHIMCXCR4野生型的任何组合)。此外,无论先前的治疗状态如何,依鲁替尼加利妥昔单抗均可改善PFS。在经先前治疗的患者和未经先前治疗的患者中,接受该联合治疗的所有预先指定的亚组中的PFS最优。

Graph

: 采用依鲁替尼加利妥昔单抗与安慰剂加利妥昔单抗的无进展生存率获益 

快速且持续改善

实验组较早出现缓解,主要缓解的中位时间为3个月,相比之下,对照组为6个月。总体而言,两个组的主要缓解率分别为76 %和31 %。依鲁替尼加利妥昔单抗治疗后,经历良好部分缓解的患者的比例随时间增加。同样,缓解基本上与基因型和先前的治疗状态无关。

在治疗的第一年中,IgM水平迅速下降。最大变化对于联合用药为在56个月时的-33.5 g/L,对于利妥昔单抗单药治疗为在57个月时的为-26.9 g/L。同样,在实验组接受治疗的患者中,有较大一部分患者的血红蛋白持续改善,这种改善定义为增加≥20 g/L(如果基线水平≤110 g/L,则增加≥5 g/L)持续≥8 数周而无需输血或生长因子。总体组(77%与43%;p <0.0001)和基线血红蛋白水平低的组(95 %与56 %;p <0.0001)均是这种情况。所有治疗组均未达到中位总生存期(OS)。54个月的OS率分别为86 %与84 %。

经过63个月的随访,该组合保持了可控的安全特性,并且没有出现新的安全信号。随着时间推移,包括腹泻、关节痛和高血压在内的主要不良事件(AE)的发生率均下降。在第4-5年,与AE相关的依鲁替尼剂量减少和治疗中止的发生率分别为5 %。88 %的导致依鲁替尼剂量减少的AE随后得到解决。作者在其结论中指出,在华氏巨球蛋白血症患者的不同临床结果中,依鲁替尼加利妥昔单抗显示出持续的优势。

Table

泽布替尼(zanubrutinib)的II期数据

不可逆的新一代选择性BTK抑制剂泽布替尼已被设计用于最大化BTK的占有率,并最小化其他激酶的脱靶抑制作用[9-11]。一项关键性、单组、开放标签、多中心II期试验在44名复发且难治性WM中国患者中评估了160 mg每日两次的泽布替尼,直至进展[12]。这些患者已经接受了≥1种标准的含化学疗法的治疗,并且未达到至少轻微缓解,或者在对最近方案产生缓解后又进展。主要缓解率(MMR)被定义为主要终点;这包括完全缓解,部分缓解和非常好的部分缓解,由独立评审委员会评估。根据WM预后评分,75 %的患者处于中度或高度风险状态。曾接受中位2条先前全身治疗方案。该研究还招募了MYD88野生型患者,他们占总群体的15.9 %。其中75 %在基线时出现贫血(血红蛋白≤110 g/L)。

在中位随访18.6个月后,泽布替尼表现出明显且持久的疗效。近70 %的患者出现MMR,其中32.6 %的患者经历非常好的部分缓解(表)。很快便实现缓解;至总体缓解的中位时间为2.76个月。中位PFS和主要缓解的中位持续时间尚未达到。在12个月时,有78.3 %的患者无进展,并且88.1 %的患者显示持续的主要缓解。泽布替尼的MMR获益在各亚组中基本一致。治疗相关AE主要包括嗜中性粒细胞减少、血小板减少、感染和腹泻。泽布替尼的安全特性和耐受特性与先前在WM患者中报告的相符。11.4 %的患者需要停用研究药物。

这些结果已提交至中国国家药品监督管理局以批准将泽布替尼用于WM患者。基于III期ASPEN临床试验而对该适应症的欧洲批准预计将在2021年夏季[13, 14]。

在中国的实际观察结果

在中国进行的一项大型、多中心、回顾性研究评估了22个省的35家三级医院中在2003年1月至2019年12月期间确诊的WM患者的临床表现、一线治疗、结果和预后[15]。总体上,纳入了1,141名患者,中位年龄为63岁。40 %的患者年龄超过65岁。男女比例为2.7:1。根据修订的国际预后评分系统(rIPSS),大多数患者具有低风险(n=342)和中度风险(n=325)。

734名患者有记录的治疗信息可用。由于临床表现的差异性和疾病的稀有性,一线治疗的选择显示出相当大的多样性。苯丁酸氮芥(chlorambucil)、依鲁替尼和利妥昔单抗等单药治疗占总数的10.2 %。化学免疫疗法(例如,利妥昔单抗/地塞米松(dexamethasone)/环磷酰胺(cyclophosphamide)、利妥昔单抗/泼尼松(prednisone)/环磷酰胺、R-COP、R-CHOP、利妥昔单抗/氟达拉滨(fludarabine)/环磷酰胺)占36.0 %。在53.8 %的群体中,使用了其他组合,首先是基于硼替佐米的方案,其次是氟达拉滨/环磷酰胺、CHOP和免疫调节剂加地塞米松。

在中位随访32个月后,估计的3年OS率为83 %。根据rIPSS,大多数确定的预后因素表明该群体的预后较差。这些因素包括LDH水平≥250 IU/L, 白蛋白水平<3.5 g/dL,β-2微球蛋白≥4 mg/L,以及年龄> 65岁。≤65岁的患者尚未达到中位OS,而66-75岁和>75岁的患者的中位OS分别为132个月和61个月。而且,血小板计数≤100 x 109/L也构成预后因素。

参考文献

  1. Rickert RC, New insights into pre-BCR and BCR signalling with relevance to B cell malignancies. Nat Rev Immunol 2013; 13(8): 578-591
  2. Argyropoulos KV et al., Clonal B cells in Waldenström’s macroglobulinemia exhibit functional features of chronic active B-cell receptor signaling. Leukemia 2016; 30(5): 1116-1125
  3. Janz S, Waldenström macroglobulinemia: clinical and immunological aspects, natural history, cell of origin, and emerging mouse models. ISRN Hematol 2013; 2013: 815325
  4. Treon SP et al., MYD88 L265P somatic mutation in Waldenstrom’s macroglobulinemia. N Engl J Med 2012; 367: 826-833
  5. Hunter ZR et al., The genomic landscape of Waldenstrom macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis. Blood 2014; 123: 1637-1646
  6. Roccaro AM et al., C1013G/CXCR4 acts as a driver mutation of tumor progression and modulator of drug resistance in lymphoplasmacytic lymphoma. Blood 2014; 123: 4120-4131
  7. Dimopoulos MA et al., Phase 3 trial of ibrutinib plus rituximab in Waldenström’s macroglobulinemia. N Engl J Med 2018; 378(25): 2399-2410
  8. Buske C et al., Five-year follow-up of ibrutinib plus rituximab vs placebo plus rituximab for Waldenström’s macroglobulinemia: final analysis from the randomized phase 3 iNNOVATETM study. ASH 2020, abstract 336 
  9. Guo Y et al., Discovery of zanubrutinib (BGB-3111), a novel, potent, and selective covalent inhibitor of bruton’s tyrosine kinase. J Med Chem 2019; 62(17): 7923-7940
  10. Tam CS et al., Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. Blood 2019; 134(11): 851-859
  11. Mu S et al., Effect of rifampin and itraconazole on the pharmacokinetics of zanubrutinib (a Bruton’s tyrosine kinase inhibitor) in Asian and non-Asian healthy subjects. Cancer Chemother Pharmacol 2020; 85: 391-399
  12. An G et al., Safety and efficacy of the Bruton tyrosine kinase inhibitor zanubrutinib (BGB-3111) in patients with Waldenström macroglobulinemia from a phase 2 trial. ASH 2020, abstract 2940
  13. Dimopoulos M et al., ASPEN: Results of phase 3 randomized trial of zanubrutinib versus ibrutinib for patients with Waldenström macroglobulinemia. EHA 2020, abstract S225
  14. Dimopoulos M et al., Updated results of the ASPEN trial from a cohort of patients with MYD88 wild-type Waldenström macroglobulinemia. EHA 2020, abstract EP1180
  15. Cao XX et al., Treatment and outcome patterns of patients with Waldenström’s macroglobulinemia: a large, multicenter retrospective review in China. ASH 2020, abstract 2053

© 2020 Springer-Verlag GmbH, Impressum

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