Ryan Christine E, Sahaf Bita, Logan Aaron C, O'Brien Susan, Byrd John C, Hillmen Peter, Brown Jennifer R, Dyer Martin J S, Mato Anthony R, Keating Michael J, Jaglowski Samantha, Clow Fong, Rezvani Andrew R, Styles Lori, Coutre Steven E, Miklos David B
Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA.
Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA.
Blood. 2016 Dec 22;128(25):2899-2908. doi: 10.1182/blood-2016-06-715284. Epub 2016 Nov 1.
Ibrutinib, a potent and irreversible small-molecule inhibitor of both Bruton's tyrosine kinase and interleukin-2 inducible kinase (ITK), has been used to treat relapsed/refractory chronic lymphocytic leukemia (CLL) with prolongation of progression-free and overall survival. Here, we present 27 patients with relapsed CLL following allogeneic hematopoietic cell transplant (HCT) who subsequently received ibrutinib salvage therapy. Sixteen of these patients were part of multi-institutional clinical trials and achieved an overall response rate of 87.5%. An additional 11 patients were treated at Stanford University following US Food and Drug Administration approval of ibrutinib; 7 (64%) achieved a complete response, and 3 (27%) achieved a partial response. Of the 9 patients treated at Stanford who had mixed chimerism-associated CLL relapse, 4 (44%) converted to full donor chimerism following ibrutinib initiation, in association with disease response. Four of 11 (36%) patients evaluated by ClonoSeq achieved minimal residual disease negativity with CLL <1/10 000 white blood cells, which persisted even after ibrutinib was discontinued, in 1 case even after 26 months. None of the 27 patients developed graft-versus-host-disease (GVHD) following ibrutinib initiation. We postulate that ibrutinib augments the graft-versus-leukemia (GVL) benefit through a T-cell-mediated effect, most likely due to ITK inhibition. To investigate the immune modulatory effects of ibrutinib, we completed comprehensive immune phenotype characterization of peripheral B and T cells from treated patients. Our results show that ibrutinib selectively targets pre-germinal B cells and depletes Th2 helper cells. Furthermore, these effects persisted after drug discontinuation. In total, our results provide evidence that ibrutinib effectively augments GVL without causing GVHD.
依鲁替尼是一种强效且不可逆的小分子抑制剂，可抑制布鲁顿酪氨酸激酶和白细胞介素-2诱导激酶（ITK），已被用于治疗复发/难治性慢性淋巴细胞白血病（CLL），可延长无进展生存期和总生存期。在此，我们报告了27例异基因造血细胞移植（HCT）后复发的CLL患者，这些患者随后接受了依鲁替尼挽救治疗。其中16例患者参与了多机构临床试验，总缓解率为87.5%。在美国食品药品监督管理局批准依鲁替尼后，另外11例患者在斯坦福大学接受治疗；7例（64%）达到完全缓解，3例（27%）达到部分缓解。在斯坦福大学接受治疗的9例混合嵌合体相关CLL复发患者中，4例（44%）在开始使用依鲁替尼后转变为完全供体嵌合体，并伴有疾病缓解。通过ClonoSeq评估的11例患者中有4例（36%）实现了微小残留病阴性，CLL低于1/10 000白细胞，即使在停用依鲁替尼后仍持续存在，1例患者甚至在26个月后仍保持阴性。27例患者在开始使用依鲁替尼后均未发生移植物抗宿主病（GVHD）。我们推测依鲁替尼通过T细胞介导的效应增强移植物抗白血病（GVL）作用，最可能是由于抑制了ITK。为了研究依鲁替尼的免疫调节作用，我们完成了对接受治疗患者外周B细胞和T细胞的全面免疫表型特征分析。我们的结果表明，依鲁替尼选择性靶向生发前B细胞并消耗Th2辅助细胞。此外，这些效应在停药后仍然持续。总体而言，我们的结果提供了证据，表明依鲁替尼可有效增强GVL而不引起GVHD。
