Rajala Hanna L M, Missiry Mohamed El, Ruusila Anniina, Koskenvesa Perttu, Brümmendorf Tim H, Gjertsen Bjorn T, Janssen Jeroen, Lotfi Kourosh, Markevärn Berit, Olsson-Strömberg Ulla, Stenke Leif, Stentoft Jesper, Richter Johan, Hjorth-Hansen Henrik, Kreutzman Anna, Mustjoki Satu
Hematology Research Unit Helsinki, Department of Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Haartmaninkatu 8, 00290, Helsinki, Finland.
Internal Medicine IV (Oncology, Hematology and Stem Cell Transplantation), University Hospital Aachen (RWTH), Aachen, Germany.
J Cancer Res Clin Oncol. 2017 Aug;143(8):1543-1554. doi: 10.1007/s00432-017-2378-6. Epub 2017 Mar 23.
Tyrosine kinase inhibitors (TKIs) have well-characterized immunomodulatory effects on T and NK cells, but the effects on the humoral immunity are less well known. In this project, we studied TKI-induced changes in B cell-mediated immunity.
We collected peripheral blood (PB) and bone marrow (BM) samples from chronic myeloid leukemia (CML) patients before and during first-line imatinib (n = 20), dasatinib (n = 16), nilotinib (n = 8), and bosutinib (n = 12) treatment. Plasma immunoglobulin levels were measured, and different B cell populations in PB and BM were analyzed with flow cytometry.
Imatinib treatment decreased plasma IgA and IgG levels, while dasatinib reduced IgM levels. At diagnosis, the proportion of patients with IgA, IgG, and IgM levels below the lower limit of normal (LLN) was 0, 11, and 6% of all CML patients, respectively, whereas at 12 months timepoint the proportions were 6% (p = 0.13), 31% (p = 0.042) and 28% (p = 0.0078). Lower initial Ig levels predisposed to the development of hypogammaglobulinemia during TKI therapy. Decreased Ig levels in imatinib-treated patients were associated with higher percentages of immature BM B cells. The patients, who had low Ig levels during the TKI therapy, had significantly more frequent minor infections during the follow-up compared with the patients with normal Ig values (33% vs. 3%, p = 0.0016). No severe infections were reported, except recurrent upper respiratory tract infections in one imatinib-treated patient, who developed severe hypogammaglobulinemia.
TKI treatment decreases plasma Ig levels, which should be measured in patients with recurrent infections.
酪氨酸激酶抑制剂（TKIs）对T细胞和NK细胞具有明确的免疫调节作用，但对体液免疫的影响尚鲜为人知。在本项目中，我们研究了TKI诱导的B细胞介导免疫的变化。
我们收集了慢性髓性白血病（CML）患者在一线使用伊马替尼（n = 20）、达沙替尼（n = 16）、尼洛替尼（n = 8）和博舒替尼（n = 12）治疗前及治疗期间的外周血（PB）和骨髓（BM）样本。检测血浆免疫球蛋白水平，并通过流式细胞术分析PB和BM中不同的B细胞群体。
伊马替尼治疗降低了血浆IgA和IgG水平，而达沙替尼降低了IgM水平。在诊断时，IgA、IgG和IgM水平低于正常下限（LLN）的患者比例分别占所有CML患者的0%、11%和6%，而在12个月时间点，这些比例分别为6%（p = 0.13）、31%（p = 0.042）和28%（p = 0.0078）。较低的初始Ig水平易导致TKI治疗期间发生低丙种球蛋白血症。伊马替尼治疗患者的Ig水平降低与未成熟BM B细胞百分比升高有关。与Ig值正常的患者相比，TKI治疗期间Ig水平低的患者在随访期间轻微感染的频率明显更高（33%对3%，p = 0.0016）。除了一名发生严重低丙种球蛋白血症的伊马替尼治疗患者出现复发性上呼吸道感染外，未报告严重感染。
TKI治疗可降低血浆Ig水平，对于反复感染的患者应检测该指标。
