摘要
目的评价基线ABL激酶区点突变对尼洛替尼治疗伊马替尼耐药或不耐受慢性髓系白血病（CML）患者的疗效影响。方法34例伊马替尼耐药或不耐受CML患者口服尼洛替尼400mg，每Et2次，中位随访时间14（1．5-50）个月。于治疗前（基线时）及治疗后每6个月检测ABL激酶区点突变，同时评估血液学、细胞遗传学、分子生物学疗效及疾病进展情况。结果34例患者中慢性期13例、进展期21例（加速期11例及急变期10例）。慢性期与进展期患者获得主要细胞遗传学反应（MCyR）率分别为70％及30％（P=0．027），完全细胞遗传学反应（CCyR）率分别为70％及20％（P=0．005）。慢性期与加速期患者4年疾病无进展生存率分别为（81．8±11．6）％及（20．5±12．9）％（P〈0．01）。17例（50％）患者基线时检出ABL激酶区点突变。基线时有突变患者完全血液学反应（CHR）、MCyR、CCyR及主要分子学反应（MMR）率分别为56％、43％、37％及31％；无突变患者分别为59％、53％、41％和18％（P值均〉0．05）。具有体外对尼洛替尼高度敏感性突变[即半数抑制浓度（IC50）≤150nmol／L]、体外对尼洛替尼敏感性未知的突变及无突变患者的CHR、MCyR、CCyR率相当，而具有体外对尼洛替尼高度不敏感性突变（即IC，0〉150nmol／L；Y253H、F359V／C、T315I）的患者CHR和MCyR率仅为17％，6例患者中无一例获得CCyR，治疗24个月内均疾病进展。结论尼洛替尼对伊马替尼耐药或不耐受CML患者可产生持久性疗效，其疗效在CML慢性期优于进展期患者。尼洛替尼对基线时突变为Y253H、F359V／C、T315I的患者疗效不佳。
Objective To evaluated the impact of baseline ABL kinase domain point mutations on re- sponses to nilotinib in imatinib-resistant or-intolerant patients with chronic myeloid leukemia （CML）. Meth- ods 34 CML patients after imatinib failure or intolerance received oral administration of 400 mg nilotinib twice daily. The median follow-up duration of nilotinib therapy was 14 （1.5 -50）months. ABL kinase domain point mutations were detected from bone marrow of CML patients at baseline and once every 6 months before and after nilotinib therapy. Hematologic, eytogenetic, molecular response and progression were evaluated re- spectively at the same time. Results Among 34 patients, 13 were in chronic phase（ CP）, 11 were in accel- erated phase（AP）, 10 were in blastic crisis（BC）. Major cytogenetic response （MCyR） was achieved in 70% of patients with CP, 30% of patients with AP and BC （ P = O. 027 ）. Complete cytogenetic response （CCyR） was achieved in 70% of patients with CP and 20% of patients with AP and BP, respectively （P = 0. 005 ）. The 4-year progressive free survival of patients with CP and AP was （ 81.8±11.6） % and （20.5±12.9） %, respectively （P 〈 0.01 ）. The cases of ABL kinase domain point mutations at baseline was 17 （50%）. CHR was achieved in 56% , MCyR in 43%, CCyR in 37% , MMR in 31% of patients with baseline mutations versus 59% （P 〉 0.05 ）, 53% （P 〉 O. 05 ）, 41% （ P 〉 O. 05 ）, 18% （ P 〉 O. 05 ）, respectively,of patients without baseline mutations. The CHR, MCyR, CCyR and MMR in patients who harbored mutations with high sensitivity to nilotinib in vitro（IC50≤150nmol/L） or mutations with unknown nilotinib sensitivity in vitro were equivalent to those responses in patients without mutations. Patients with mutations less sensitive to nilotinib in vitro （IC50 〉 150 nmol/L, Y253H, F359V/C, T315I） achieved 17% of CHR and MCyR, none of them（6 cases） achieved CCyR, and 6 cases had disease progression within 24 mouth after treatment. Con- clusions Nilotinib is a more effective option for imatinib-resistant or-intolerant CML patients. Response for patients with CP was better than patients with AP and BC. Mutational status at baseline may influence re- sponse. Less sensitive mutations may be associated with less favorable resDonses to nilotinb.
出处
《中华血液学杂志》
CAS
CSCD
北大核心
2012年第2期123-126,共4页
Chinese Journal of Hematology
基金
ENACT国际多中心研究
重大新药创制（2008ZX09312-026）
研究与发展基金（RDC2009~7）
