Cortes Jorge, Rousselot Philippe, Kim Dong-Wook, Ritchie Ellen, Hamerschlak Nelson, Coutre Steven, Hochhaus Andreas, Guilhot Francois, Saglio Giuseppe, Apperley Jane, Ottmann Oliver, Shah Neil, Erben Philipp, Branford Susan, Agarwal Prasheen, Gollerkeri Ashwin, Baccarani Michele
M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Blood. 2007 Apr 15;109(8):3207-13. doi: 10.1182/blood-2006-09-046888. Epub 2006 Dec 21.
The prognosis for patients with chronic myeloid leukemia (CML) in myeloid blast crisis (MBC) or lymphoid blast crisis (LBC) remains poor. Although imatinib can induce responses in a subset of these patients, resistance to the drug develops rapidly. Dasatinib is a novel, oral, multitargeted kinase inhibitor of BCR-ABL and SRC family kinases. After promising phase 1 results, we report the results of phase 2 clinical trials of dasatinib in patients with imatinib-resistant or -intolerant blast crisis CML (MBC, n = 74; LBC, n = 42). At the 8-month follow-up, dasatinib induced major hematologic responses (MaHRs) in 34% and 31% of MBC- and LBC-CML patients and major cytogenetic responses (MCyRs) in 31% and 50% of these patients, respectively. Most (86%) of these MCyRs were complete cytogenetic responses (CCyRs). Responses were rapid and durable: 88% and 46%, respectively, of MBC- and LBC-CML patients achieving MaHR had not experienced disease progression at the 8-month follow-up. Response rates were similar in patients with and without BCR-ABL mutations known to confer resistance to imatinib. Dasatinib was well tolerated. Nonhematologic adverse events were mild to moderate. Cytopenias were common and could be managed by dose modification. Dasatinib is highly active and produces hematologic and cytogenetic responses in a significant number of patients with imatinib-resistant or -intolerant MBC- and LBC-CML. These trials were registered at www.clinicaltrials.gov as #CA180006 and #CA180015.
慢性髓性白血病（CML）处于髓系原始细胞危象（MBC）或淋巴系原始细胞危象（LBC）的患者预后仍然很差。尽管伊马替尼可使部分此类患者产生反应，但对该药的耐药性迅速出现。达沙替尼是一种新型的口服多靶点激酶抑制剂，可抑制BCR-ABL和SRC家族激酶。在1期试验取得令人鼓舞的结果后，我们报告了达沙替尼针对伊马替尼耐药或不耐受的原始细胞危象CML患者（MBC，n = 74；LBC，n = 42）进行的2期临床试验结果。在8个月的随访中，达沙替尼在34%的MBC-CML患者和31%的LBC-CML患者中诱导产生了主要血液学反应（MaHR），在这些患者中分别有31%和50%产生了主要细胞遗传学反应（MCyR）。这些MCyR中的大多数（86%）为完全细胞遗传学反应（CCyR）。反应迅速且持久：在8个月的随访中，达到MaHR的MBC-CML和LBC-CML患者分别有88%和46%未出现疾病进展。在已知对伊马替尼耐药的有或无BCR-ABL突变的患者中，反应率相似。达沙替尼耐受性良好。非血液学不良事件为轻至中度。血细胞减少常见，可通过调整剂量进行处理。达沙替尼具有高活性，可使大量伊马替尼耐药或不耐受的MBC-和LBC-CML患者产生血液学和细胞遗传学反应。这些试验已在www.clinicaltrials.gov注册，注册号为#CA180006和#CA180015。
