Department of Haematology, Alfred Hospital and Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia.
Department of Haematology, Monash Health and Monash University, Clayton, VIC, Australia.
Blood Adv. 2024 Apr 9;8(7):1639-1650. doi: 10.1182/bloodadvances.2023010906.
The phase 3 ASPEN trial (NCT03053440) compared Bruton tyrosine kinase inhibitors (BTKis), zanubrutinib and ibrutinib, in patients with Waldenström macroglobulinemia (WM). Post-hoc biomarker analysis was performed using next-generation sequencing on pretreatment bone marrow samples from 98 patients treated with zanubrutinib and 92 patients treated with ibrutinib with mutated (MUT) MYD88 and 20 patients with wild-type (WT) MYD88 treated with zanubrutinib. Of 329 mutations in 52 genes, mutations in CXCR4 (25.7%), TP53 (24.8%), ARID1A (15.7%), and TERT (9.0%) were most common. TP53MUT, ARID1AMUT, and TERTMUT were associated with higher rates of CXCR4MUT (P < .05). Patients with CXCR4MUT (frameshift or nonsense [NS] mutations) had lower very good partial response (VGPR) and complete response rates (CR; 17.0% vs 37.2%, P = .020) and longer time to response (11.1 vs 8.4 months) than patients with CXCR4WT treated with BTKis. CXCR4NS was associated with inferior progression-free survival (PFS; hazard ratio [HR], 3.39; P = .017) in patients treated with ibrutinib but not in those treated with zanubrutinib (HR, 0.67; P = .598), but VGPR + CR rates were similar between treatment groups (14.3% vs 15.4%). Compared with ibrutinib, patients with CXCR4NS treated with zanubrutinib had a favorable major response rate (MRR; 85.7% vs 53.8%; P = .09) and PFS (HR, 0.30; P = .093). In patients with TP53MUT, significantly lower MRRs were observed for patients treated with ibrutinib (63.6% vs 85.7%; P = .04) but not for those treated with zanubrutinib (80.8% vs 81.9%; P = .978). In TP53MUT, compared with ibrutinib, patients treated with zanubrutinib had higher VGPR and CR (34.6% vs 13.6%; P < .05), numerically improved MRR (80.8% vs 63.6%; P = .11), and longer PFS (not reached vs 44.2 months; HR, 0.66; P = .37). Collectively, patients with WM with CXCR4MUT or TP53MUT had worse prognosis compared with patients with WT alleles, and zanubrutinib led to better clinical outcomes.
ASPEN 三期试验（NCT03053440）比较了 Bruton 酪氨酸激酶抑制剂（BTKi），泽布替尼和伊布替尼，在华氏巨球蛋白血症（WM）患者中的疗效。对 98 例接受泽布替尼治疗和 92 例接受伊布替尼治疗的患者的预处理骨髓样本进行了下一代测序的基于基因的生物标志物分析，这些患者存在突变型（MUT）MYD88 和 20 例野生型（WT）MYD88 接受泽布替尼治疗。在 52 个基因的 329 个突变中，CXCR4（25.7%），TP53（24.8%），ARID1A（15.7%）和 TERT（9.0%）的突变最常见。TP53MUT，ARID1AMUT 和 TERTMUT 与更高的 CXCR4MUT 发生率相关（P<.05）。与 CXCR4WT 患者相比，具有 CXCR4MUT（移码或无意义[NS]突变）的患者具有更低的非常好的部分缓解（VGPR）和完全缓解率（CR；17.0% vs 37.2%，P=.020）和更长的缓解时间（11.1 与 8.4 个月）。与伊布替尼治疗的患者相比，接受泽布替尼治疗的患者的 CXCR4NS 与无进展生存期（PFS；危险比[HR]，3.39；P=.017）相关，但与伊布替尼治疗的患者相比，接受泽布替尼治疗的患者的无进展生存期（HR，0.67；P=.598）并无差异，但是两组之间的 VGPR+CR 率相似（14.3% vs 15.4%）。与伊布替尼相比，接受泽布替尼治疗的 CXCR4NS 患者具有良好的主要缓解率（MRR；85.7% vs 53.8%；P=.09）和 PFS（HR，0.30；P=.093）。在 TP53MUT 患者中，接受伊布替尼治疗的患者的 MRR 明显降低（63.6% vs 85.7%；P=.04），但接受泽布替尼治疗的患者则无差异（80.8% vs 81.9%；P=.978）。在 TP53MUT 中，与伊布替尼相比，接受泽布替尼治疗的患者具有更高的 VGPR 和 CR（34.6% vs 13.6%；P<.05），MRR 也有所改善（80.8% vs 63.6%；P=.11），且 PFS 更长（未达到 vs 44.2 个月；HR，0.66；P=.37）。总体而言，与 WT 等位基因相比，具有 CXCR4MUT 或 TP53MUT 的 WM 患者具有更差的预后，而泽布替尼可带来更好的临床结局。
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