Bonnet Christophe, Dupuis Jehan, Tilly Hervé, Lamy Thierry, Fruchart Christophe, le Gouill Steven, Thieblemont Catherine, Morschhauser Franck, Casasnovas Olivier, Bouabdallah Krimo, Ghesquieres Hervé, Van Den Neste Eric, André Marc, Cartron Guillaume, Salles Gilles
Clinical Hematology Unit, Centre Hospitalier Universitaire de Liège, Liège Université, B35, Campus Universitaire du Sart-Tilman, 4000 Liège, Belgium.
Lymphoid Malignancies Unit, Hôpital Henri Mondor, 51 Avenue du Maréchal de Lattre de Tassigny, CEDEX, 94000 Créteil, France.
Cancers (Basel). 2022 Mar 30;14(7):1761. doi: 10.3390/cancers14071761.
In the post-rituximab era, patients with relapsed/refractory non-Hodgkin B-cell lymphoma (R/R B-NHL) responding to a platinum salt-based salvage regimen can potentially be cured after intensification followed by autologous stem cell transplantation, with the quality of the response to salvage predicting survival. The Bruton tyrosine kinase inhibitor ibrutinib, given as monotherapy or combined with other molecules, has proven effective in numerous B-cell lymphomas. To evaluate the safety of the combination of ibrutinib, rituximab, dexamethasone, and cytarabine with either cisplatin (R-DHAP) or oxaliplatin (R-DHAOx), we conducted a multicenter Phase 1b-II study in transplant-eligible R/R B-NHL patients, with ibrutinib given using a 3-by-3 dose-escalation design. The combination of R-DHAP and ibrutinib (given from Day 1 to Day 21 of each cycle) was associated with dose-limiting hematological, infectious, and renal toxicities, while we were unable to reach a dose to recommend for Phase II. R-DHAOx could only be combined with a daily dosage of 280 mg ibrutinib when administered continuously. R-DHAP combined with intermittent ibrutinib administration (from Day 5 to Day 18) was found to be highly toxic. On the other hand, when this administration schedule was combined with R-DHAOx, ibrutinib dosing could be increased up to 560 mg but with relevant toxicities. Despite a strong rationale for combining ibrutinib and R-DHAP/R-DHAOx, as both target lymphoma B-cells by different mechanisms, this approach was limited by significant toxicities.
在利妥昔单抗时代之后，复发/难治性非霍奇金B细胞淋巴瘤（R/R B-NHL）患者若对基于铂盐的挽救方案有反应，在强化治疗后进行自体干细胞移植有可能治愈，挽救治疗的反应质量可预测生存情况。布鲁顿酪氨酸激酶抑制剂伊布替尼，无论是单药治疗还是与其他分子联合使用，已在众多B细胞淋巴瘤中证明有效。为了评估伊布替尼、利妥昔单抗、地塞米松和阿糖胞苷与顺铂（R-DHAP）或奥沙利铂（R-DHAOx）联合使用的安全性，我们对符合移植条件的R/R B-NHL患者进行了一项多中心1b-II期研究，伊布替尼采用3×3剂量递增设计给药。R-DHAP与伊布替尼联合使用（在每个周期的第1天至第21天给药）与剂量限制性血液学、感染性和肾脏毒性相关，而我们无法确定推荐用于II期试验的剂量。R-DHAOx只有在持续给药时才能与每日280 mg的伊布替尼联合使用。发现R-DHAP与间歇性伊布替尼给药（第5天至第18天）联合使用时毒性很大。另一方面，当这种给药方案与R-DHAOx联合使用时，伊布替尼剂量可增加至560 mg，但会出现相关毒性。尽管有充分的理由将伊布替尼与R-DHAP/R-DHAOx联合使用，因为两者通过不同机制靶向淋巴瘤B细胞，但这种方法受到显著毒性的限制。
