La Rosée Paul, Holm-Eriksen Susanne, Konig Heiko, Härtel Nicolai, Ernst Thomas, Debatin Julia, Mueller Martin C, Erben Philipp, Binckebanck Anja, Wunderle Lydia, Shou Yaping, Dugan Margaret, Hehlmann Ruediger, Ottmann Oliver G, Hochhaus Andreas
III. Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg, Theodor-Kutzer-Ufer 1-3 68167 Mannheim, Germany.
Haematologica. 2008 May;93(5):765-9. doi: 10.3324/haematol.12186. Epub 2008 Mar 26.
Actual BCR-ABL kinase inhibition in vivo as determined by phospho-CRKL (pCRKL) monitoring has been recognized as a prognostic parameter in patients with chronic myelogenous leukemia treated with imatinib. We report a biomarker sub-study of the international phase I clinical trial of nilotinib (AMN107) using the established pCRKL assay in imatinib-resistant chronic myeloid leukemia or Ph+ acute lymphoblastic leukemia. A minimum dose (200 mg) required for effective BCR-ABL inhibition in imatinib resistant/intolerant leukemia was determined. The pre-clinical activity profile of nilotinib against mutant BCR-ABL was largely confirmed. Substantial differences between peripheral blood baseline pCRKL/CRKL ratios were observed when comparing chronic myeloid leukemia with Ph+ acute lymphoblastic leukemia. Finally, rapid BCR-ABL-reactivation shortly after starting nilotinib treatment was seen in acute lymphoblastic leukemia patients with progressive disease carrying the P-loop mutations Y253H, E255K, or mutation T315I. Monitoring the actual BCR-ABL inhibition in nilotinib treated patients using pCRKL as a surrogate is a means to establish effective dosing and to characterize resistance mechanisms against nilotinib.
通过磷酸化CRKL（pCRKL）监测确定的体内实际BCR-ABL激酶抑制作用，已被认为是接受伊马替尼治疗的慢性粒细胞白血病患者的一个预后参数。我们报告了一项使用已确立的pCRKL检测方法，针对伊马替尼耐药的慢性髓性白血病或Ph+急性淋巴细胞白血病患者开展的尼洛替尼（AMN107）国际I期临床试验的生物标志物子研究。确定了伊马替尼耐药/不耐受白血病中有效抑制BCR-ABL所需的最小剂量（200 mg）。尼洛替尼针对突变型BCR-ABL的临床前活性概况在很大程度上得到了证实。比较慢性髓性白血病与Ph+急性淋巴细胞白血病时，观察到外周血基线pCRKL/CRKL比值存在显著差异。最后，在携带P环突变Y253H、E255K或T315I突变且病情进展的急性淋巴细胞白血病患者中，观察到开始尼洛替尼治疗后不久BCR-ABL迅速重新激活。使用pCRKL作为替代指标监测尼洛替尼治疗患者的实际BCR-ABL抑制作用，是确定有效剂量并表征对尼洛替尼耐药机制的一种手段。
