Jiang H

[Dasatinib treatment based on BCR- ABL mutation detection in imatinib- resistant patients with chronic myeloid leukemia].

目的 探讨在BCR-ABL突变检测指导下选用达沙替尼治疗伊马替尼耐药慢性髓性白血病（CML）患者的有效性。 方法 83例伊马替尼耐药和39例伊马替尼与尼洛替尼均耐药的CML患者，持续口服达沙替尼，其中慢性期（CP) 55例，加速期（AP) 21例，急变期（BP) 46例。达沙替尼治疗前，经BCR-ABL突变筛查，除外具有对达沙替尼高度耐药突变类型（T315I/A、F317L/V/C和V299L）的患者。定期监测血液学、细胞遗传学和分子学反应，评估疾病进展和生存情况。当发生达沙替尼治疗失败时检测BCR-ABL突变。 结果 CP患者中，完全血液学反应（CHR）率为92.7%，完全细胞遗传学反应（CCyR）率为53.7%，主要分子学反应（MMR）率为29.6%，MR4.5率为14.8%，4年疾病无进展生存（PFS）率和总生存（OS）率分别为84.4％和89.5%。AP患者中，血液学反应（HR）率和CCyR率分别为81.0％和35.0%，3年PFS率和OS率分别为56.1％和59.3%。BP患者中，HR率和CCyR率分别为63.0%和21.4%，1年PFS率和OS率分别为43.6％和61.8%。达沙替尼作为二线和三线酪氨酸激酶抑制剂时，治疗反应相似。当发生达沙替尼治疗失败时，75例患者中37例（48.7%）检出新突变，T315I最为多见（59.5%）。达沙替尼治疗前存在突变的患者与无突变患者相比，治疗反应、PFS和OS差异均无统计学意义，但当出现达沙替尼耐药时，发生新突变的可能性显著增高（65.7％对34.1%，P=0.006）。 结论 达沙替尼可以有效治疗伊马替尼耐药或伊马替尼与尼洛替尼均耐药的CML各期患者，CP和AP患者疗效持久。达沙替尼治疗前BCR-ABL突变筛查及治疗中突变监测非常重要。OBJECTIVE To evaluate the efficiency of dasatinib as the second- or third-line tyrosine kinase inhibitor (TKI)in imatinib-resistant patients with chronic myeloid leukemia (CML)based on BCR-ABL mutation detection. METHODS 122 CML patients received dasatinib treatment, including 83 with imatinib-resistance and 39 with both imatinib- and nilotinib-resistance, 55 in the chronic-phase (CP), 21 in the accelerated- phase (AP)and 46 in the blast- phase (BP). Those harboring dasatinib highly- resistant mutations (T315I/A, F317L/V/C and V299L)were excluded based on BCR-ABL kinase domain mutation screening by Sanger sequencing at baseline. Hematologic, cytogenetic and molecular responses were evaluated regularly, and rates of progression-free-survival (PFS)and overall survival (OS)were analyzed. BCR- ABL mutation detection was performed once the patients failed on dasatinib. RESULTS In the CP patients, the rates of complete hematological response (CHR), complete cytogenetic response (CCyR), major molecular response (MMR)and molecular response 4.5 (MR4.5)were 92.7%, 53.7%, 29.6% and 14.8%, respectively. 4-year PFS and OS rates were 84.4% and 89.5%, respectively. In the AP patients, HR and CCyR rates were 81.0% and 35.0%; and 3-year PFS and OS rates were 56.1% and 59.3%, respectively. In the BP patients, HR and CCyR rates were 63.0% and 21.4%; and 1-year PFS and OS rates were 43.6% and 61.8%, respectively. Outcomes were similar when dasatinib was used as the second- line TKI or the third-line TKI. Of the 75 patients who were resistant to dasatinib, 37 (48.7%)developed new mutation(s), and T315I (59.5%)was the most common mutation type. The patients who already harbored mutation(s)before dasatinib therapy achieved similar responses and outcomes to those with no mutation at baseline. However, they had higher likelihood of developing additional mutations associated with resistance to dasatinib (65.7%vs 34.1%,P=0.006). CONCLUSIONS Dasatinib was proved to be effective in the treatment of imatinib- or/and nilotinib-resistant CML patients, especially in both CP and AP cohorts. The significance of BCR-ABL mutation screening and monitoring should be highlighted before and during dasatinib therapy.

Outcomes of adult patients with de novo acute myeloid leukemia received idarubicin plus cytarabine regimen as induction chemotherapy

Objective: To explore outcomes in adult with de novo acute myeloid leukemia (AML) received IA10 (10 mg/m(2) d1-3 idarubicin plus cytarabine 100 mg/m(2) d1-7) regimen as induction chemotherapy. Methods: From January 2008 to February 2016, data of consecutive newly-diagnosed AML (non-M(3)) adults treated with IA10 who achieved morphologic leukemia-free state (MLFS) but not accepted allogeneic hematopoietic stem cell transplantation (allo-HSCT) were assessed retrospectively. Results: A total of 198 patients were included in this study with 96 (48.5%) male and a median age of 42 years old (range, 18-62 years old). Using the SWOG cytogenetic classification, 45 (22.7%), 104 (52.5%), 24 (12.1%) and 25 (12.6%) patients belonged to favorable, intermediate, unfavorable and unknown categories, respectively. 6 (3.0%) patients had monosomal karyotype, and 28 (14.1%) positive FLT3-ITD mutation. A complete remission (CR, defined as MLFS with ANC ≥ 1×10(9)/L and PLT ≥ 100×10(9)/L) achieved in 168 (84.8%) patients, a CRp (defined as MLFS with incomplete PLT recovery) in 16 (8.1%) and a CRi (defined as MLFS with incomplete ANC and PLT recovery) in 14 (7.1%). With a median follow-up period of 15 months (range, 1 to 70 months) in survivors, the probabilities of cumulative incident of relapse (CIR), disease free survival (DFS) and overall survival (OS) rates at 2-year were 45.2%, 46.9% and 62.9%, respectively; the median durations of relapse, DFS and OS were 34, 20 and 37 months respectively. At the time of achieving first MLFS, multivariate analyses showed that positive FLT3-ITD mutation and CRi were common adverse factors affecting CIR, DFS and OS; unfavorable-risk of SWOG criteria was an adverse factor affecting CIR and DFS; monosomal karyotype was associated with shorter OS. After first consolidation therapy, FLT3-ITD mutation positive and unfavorable-risk of SWOG criteria had negatively impact on CIR, DFS and OS; peripheral blasts ≥ 0.50 and positive MRD (defined as RQ-PCR WT1 mRNA ≥ 0.6% or any level of abnormal blast population detected by flow cytometry) after first consolidation therapy were common adverse factors affecting CIR and DFS; CRi was an adverse factor affecting DFS and OS. Conclusions: In adult with de novo AML received IA10 regimen as induction regimen, unfavorable molecular markers or cytogenetics at diagnosis and CRi independently predicted poor outcome. In addition, a higher percentage of peripheral blasts, monosomal karyotype and positive MRD after first consolidation therapy had negatively impact on outcomes.目的 探讨接受IA10[去甲氧柔红霉素（IDA）10 mg·m−2·d−1×3 d联合阿糖胞苷（Ara-C）100 mg·m−2·d−1×7 d]作为诱导方案且未接受异基因造血干细胞移植（allo-HSCT）的成人急性髓系白血病（AML）患者的预后影响因素。 方法 回顾2008年1月至2016年2月收治的接受IA10作为诱导化疗方案、获得形态学无白血病状态（MLFS）后未接受allo-HSCT的198例AML（不包括急性早幼粒细胞白血病）连续病例，分析诊断时特征、首次获得MLFS时血细胞恢复程度、首次获得MLFS时和巩固1个疗程后微小残留病（MRD）水平对预后的影响。 结果 198例患者中，男96例（48.5%），中位年龄42（18~62）岁。SWOG分组：低危45例（22.7%），中危104例（52.5%），高危24例（12.1%），危险度未知25例（12.6%）。FLT3-ITD突变阳性28例（14.1%）。完全缓解（CR，MLFS伴ANC≥1×109/L和PLT≥100×109/L）168例（84.8%），CRp（MLFS伴PLT未恢复）16例（8.1%），CRi（MLFS伴ANC和PLT均未恢复）14例（7.1%）。131例（66.2%）存活患者中位随访时间15（1~70）个月，2年累积复发率（CIR）、无病生存（DFS）、总生存（OS）率分别为45.2%、46.9%、62.9%,中位复发、DFS、OS时间分别为34、20、37个月。在所有获得MLFS的患者中进行多因素分析，FLT3-ITD突变阳性和CRi是影响患者CIR、DFS、OS的共同不利因素；SWOG危险度为高危是影响患者CIR和DFS的共同不利因素；单体核型是影响患者OS的独立危险因素。分析接受巩固治疗≥1个疗程的患者，FLT3-ITD突变阳性和SWOG危险度为高危是影响患者CIR、DFS、OS的共同不利因素；外周血原始细胞≥0.50和巩固治疗1个疗程后MRD阳性[FCM和（或）WT1 mRNA阳性]是影响患者CIR和DFS的共同不利因素；CRi是影响患者DFS和OS的共同不利因素。 结论 对于接受IA10作为诱导方案且获得MLFS后未接受allo-HSCT的初治成人AML患者，初诊时不良的遗传学特征和CRi是影响患者总体预后的不利因素。此外，外周血原始细胞比例高、单体核型和巩固治疗1个疗程后MRD阳性也与预后不良相关。