Resistance Mechanism for Zanubrutinib in Marginal Zone Lymphoma.

John Sharp, Arwa Y Shana'ah, Timothy J Voorhees, David A Bond, Yazeed Sawalha, Audrey Sigmund, Walter Hanel, Lalit Sehgal, Lapo Alinari, Robert Baiocchi, Kami Maddocks, Dan Jones, Beth Christian, Narendranath Epperla
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Abstract

Marginal zone lymphoma (MZL) is the third most common B-cell non-Hodgkin lymphoma and tends to follow the relapsing course typical of other indolent lymphomas, meaning that many patients receive multiple lines of therapy. Brüton's tyrosine kinase inhibitors (BTKis) have been a promising addition to the treatment landscape of relapsed MZL; however, development of resistance to these agents remains a significant problem that warrants further characterization. This case report presents a patient with relapsed MZL receiving the BTKi zanubrutinib who experienced large cell transformation of their lymphoma in concert with the development of mutations predictive of resistance to BTKi therapy, specifically BTK C481S and PLCG2 D334H. To our knowledge, this is the first reported case of a patient with MZL acquiring co-mutations in BTK and PLCG2 in concert with the development of disease progression while receiving BTKi therapy. Outcomes for patients with MZL who develop resistance to BTKis have not been fully characterized, but are poor in other B-cell malignancies that have acquired BTKi resistance, such as mantle cell lymphoma and chronic lymphocytic leukemia. Improved understanding of the genetic and molecular drivers of MZL is leading to new treatment strategies. Further studies of novel therapeutic approaches are ongoing to improve outcomes for patients with MZL, including those who acquire resistance to BTKis.

扎鲁替尼治疗边缘区淋巴瘤的耐药机制。
边缘带淋巴瘤(MZL)是第三种最常见的b细胞非霍奇金淋巴瘤,并且往往遵循其他惰性淋巴瘤的典型复发过程,这意味着许多患者接受多种治疗。br顿的酪氨酸激酶抑制剂(BTKis)已经成为复发性MZL治疗前景的一个有希望的补充;然而,对这些药物的耐药性的发展仍然是一个重要的问题,需要进一步的表征。本病例报告介绍了一名接受BTKi zanubrutinib治疗的复发性MZL患者,其淋巴瘤经历了大细胞转化,同时发生了预测BTKi治疗耐药的突变,特别是BTK C481S和PLCG2 D334H。据我们所知,这是首次报道的MZL患者在接受BTKi治疗时,随着疾病进展获得BTK和PLCG2共突变的病例。对BTKi耐药的MZL患者的预后尚未完全确定,但在其他获得BTKi耐药的b细胞恶性肿瘤中,如套细胞淋巴瘤和慢性淋巴细胞白血病的预后较差。对MZL的遗传和分子驱动因素的进一步了解正在导致新的治疗策略。新的治疗方法的进一步研究正在进行中,以改善MZL患者的预后,包括那些对BTKis产生耐药性的患者。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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