Mustjoki S, Ekblom M, Arstila T P, Dybedal I, Epling-Burnette P K, Guilhot F, Hjorth-Hansen H, Höglund M, Kovanen P, Laurinolli T, Liesveld J, Paquette R, Pinilla-Ibarz J, Rauhala A, Shah N, Simonsson B, Sinisalo M, Steegmann J L, Stenke L, Porkka K
Hematology Research Unit, Biomedicum Helsinki, Helsinki University Central Hospital, Helsinki, Finland.
Leukemia. 2009 Aug;23(8):1398-405. doi: 10.1038/leu.2009.46. Epub 2009 Mar 19.
Dasatinib, a broad-spectrum tyrosine kinase inhibitor (TKI), predominantly targets BCR-ABL and SRC oncoproteins and also inhibits off-target kinases, which may result in unexpected drug responses. We identified 22 patients with marked lymphoproliferation in blood while on dasatinib therapy. Clonality and immunophenotype were analyzed and related clinical information was collected. An abrupt lymphocytosis (peak count range 4-20 x 10(9)/l) with large granular lymphocyte (LGL) morphology was observed after a median of 3 months from the start of therapy and it persisted throughout the therapy. Fifteen patients had a cytotoxic T-cell and seven patients had an NK-cell phenotype. All T-cell expansions were clonal. Adverse effects, such as colitis and pleuritis, were common (18 of 22 patients) and were preceded by LGL lymphocytosis. Accumulation of identical cytotoxic T cells was also detected in pleural effusion and colon biopsy samples. Responses to dasatinib were good and included complete, unexpectedly long-lasting remissions in patients with advanced leukemia. In a phase II clinical study on 46 Philadelphia chromosome-positive acute lymphoblastic leukemia, patients with lymphocytosis had superior survival compared with patients without lymphocytosis. By inhibiting immunoregulatory kinases, dasatinib may induce a reversible state of aberrant immune reactivity associated with good clinical responses and a distinct adverse effect profile.
达沙替尼是一种广谱酪氨酸激酶抑制剂（TKI），主要作用于BCR-ABL和SRC癌蛋白，同时也抑制非靶向激酶，这可能导致意外的药物反应。我们在接受达沙替尼治疗的患者中识别出22例血液中出现明显淋巴细胞增殖的患者。分析了克隆性和免疫表型，并收集了相关临床信息。从治疗开始起，中位3个月后观察到突然出现淋巴细胞增多（峰值计数范围为4 - 20×10⁹/L），伴有大颗粒淋巴细胞（LGL）形态，且在整个治疗过程中持续存在。15例患者具有细胞毒性T细胞表型，7例患者具有自然杀伤细胞（NK）表型。所有T细胞扩增均为克隆性。不良反应，如结肠炎和胸膜炎很常见（22例患者中有18例），且在LGL淋巴细胞增多之前出现。在胸腔积液和结肠活检样本中也检测到相同细胞毒性T细胞的聚集。对达沙替尼的反应良好，包括晚期白血病患者出现完全缓解，且缓解期意外地持久。在一项针对46例费城染色体阳性急性淋巴细胞白血病的II期临床研究中，淋巴细胞增多的患者与无淋巴细胞增多的患者相比，生存期更长。通过抑制免疫调节激酶，达沙替尼可能诱导一种与良好临床反应和独特不良反应谱相关的可逆性异常免疫反应状态。
