Phospho-CRKL monitoring for the assessment of BCR-ABL activity in imatinib-resistant chronic myeloid leukemia or Ph+ acute lymphoblastic leukemia patients treated with nilotinib | Haematologica

Paul La Rosée; Susanne Holm-Eriksen; Heiko Konig; Nicolai H?rtel; Thomas Ernst; Julia Debatin

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Phospho-CRKL monitoring for the assessment of BCR-ABL activity in imatinib-resistant chronic myeloid leukemia or Ph+ acute lymphoblastic leukemia patients treated with nilotinib | Haematologica

机译：磷酸CRKL监测用于评估尼洛替尼治疗的伊马替尼耐药的慢性粒细胞白血病或Ph +急性淋巴细胞白血病患者的BCR-ABL活性|血液学

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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.

机译：通过磷酸-CRKL（pCRKL）监测确定的体内实际BCR-ABL激酶抑制作用已被确认为伊马替尼治疗的慢性粒细胞性白血病患者的预后参数。我们报告尼洛替尼（AMN107）的国际I期临床试验的生物标志物子研究，该研究使用已建立的pCRKL测定法在伊马替尼耐药的慢性粒细胞白血病或Ph +急性淋巴细胞白血病中进行了研究。确定在伊马替尼耐药/不能耐受的白血病中有效抑制BCR-ABL所需的最小剂量（200 mg）。尼洛替尼针对突变BCR-ABL的临床前活性概况得到了充分证实。当比较慢性粒细胞白血病与Ph +急性淋巴细胞白血病时，观察到外周血基线pCRKL / CRKL比率之间存在实质性差异。最后，在开始尼罗替尼治疗后不久，在患有进行性疾病的急性淋巴细胞白血病患者中，其携带P环突变Y253H，E255K或突变T315I的BCR-ABL快速重新活化。使用pCRKL作为替代品监测尼洛替尼治疗患者的实际BCR-ABL抑制是建立有效剂量和表征对尼洛替尼耐药机制的手段。

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《Haematologica》 |2008年第5期|共6页
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Paul La Rosée; Susanne Holm-Eriksen; Heiko Konig; Nicolai H?rtel; Thomas Ernst; Julia Debatin;
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中图分类血液及淋巴系疾病;
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机译：在急性髓性白血病，BCR-ABL阳性急性淋巴细胞性白血病和慢性髓性白血病中，相互易位的亚显微缺失发生率相似。血液学
2. The role of serial BCR-ABL transcript monitoring in predicting the emergence of BCR-ABL kinase mutations in imatinib-treated patients with chronic myeloid leukemia | Haematologica [J] . L Wang, K Knight, C Lucas, Haematologica . 2006,第2期

机译：连续BCR-ABL转录本监测在预测伊马替尼治疗的慢性粒细胞白血病患者中BCR-ABL激酶突变的出现中的作用|血液学
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机译：连续BCR-ABL转录本监测在预测伊马替尼治疗的慢性粒细胞白血病患者中BCR-ABL激酶突变的出现中的作用|血液学
4. Optimizing the Classification of Acute Lymphoblastic Leukemia and Acute Myeloid Leukemia Samples using Artificial Neural Networks [C] . Nuannuan Zong, Malek Adjouadi, Melvin Ayala Annual Rocky Mountain Bioengineering Symposium . 2006

机译：利用人工神经网络优化急性淋巴细胞白血病和急性髓性白血病样品的分类
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6. Clinical Trials and Observations: Epidemiologic study on survival of chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia patients with BCR-ABL T315I mutation [O] . Franck E. Nicolini, Michael J. Mauro, Giovanni Martinelli, -1

机译：临床试验和观察：BCR-ABL T315I突变的慢性粒细胞白血病和Ph +急性淋巴细胞白血病患者生存的流行病学研究
7. Nilotinib (Tasigna) Therapy Post Allogeneic Stem Cell Transplantation (AlloSCT) for Advanced (>CP1) Chronic Myeloid Leukemia (CML) and Ph+ Acute Lymphoblastic Leukemia (ALL) [O] . Nagler A., Volchek Y., Varda-Bloom N., 2012

机译：异基因干细胞移植（AlloSCT）后尼罗替尼（Tasigna）治疗晚期（> CP1）慢性粒细胞白血病（CML）和Ph +急性淋巴细胞白血病（ALL）

Phospho-CRKL monitoring for the assessment of BCR-ABL activity in imatinib-resistant chronic myeloid leukemia or Ph+ acute lymphoblastic leukemia patients treated with nilotinib | Haematologica

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