异基因造血干细胞移植治疗成人费城染色体阳性急性淋巴细胞性白血病的疗效分析

Allogeneic hematopoietic stem cell transplantation for treatment of adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia

目的:探讨异基因造血干细胞移植(allo-HSCT)治疗成人费城染色体阳性(Ph+)的急性淋巴细胞白血病(ALL)的疗效。方法:回顾性分析经VDP(长春新碱、蒽环类、糖皮质激素)±C(环磷酰胺或异环磷酰胺)±L(左旋门冬酰胺酶或培门冬酶)方案诱导化学治疗(化疗)的12例Ph+ALL患者。初始诱导缓解患者在等待移植期间进行巩固化疗,并加用伊马替尼(400～800 mg/d),与化疗同步或交替应用。初始诱导失败患者及巩固治疗期间复发患者应用Hyper-CVAD/LALA(大剂量环磷酰胺、长春新碱、多柔比星、地塞米松或米托蒽醌、阿糖胞苷)方案联合伊马替尼或达沙替尼进行再次诱导。所有患者缓解后经白消安联合环磷酰胺(Bu-Cy)或改良Bu-Cy方案预处理后进行allo-HSCT。部分患者干细胞回输后2～3个月始继续服用酪氨酸激酶抑制剂。结果:12例患者移植前均获得血液学缓解、7例获得分子学缓解。其中完全缓解(CR)1期9例、CR 2期2例、初发难治性1例。移植前11例患者应用伊马替尼;移植后5例患者应用酪氨酸激酶抑制剂,其中4例应用伊马替尼、1例应用达沙替尼。中位随访时间12.7(3～54)个月,7例患者生存,3例患者死于疾病复发,2例患者死于治疗相关并发症。所有患者均植入,移植后2年总生存率66.7%±13.6%;2年累计复发率40.6%±16.0%;2年累计非复发病死率16.7%±10.8%。首次缓解(CR1)后移植治疗的2年总生存率70.0%±14.5%;2年累计复发率40.0%±18.2%;2年累计非复发病死率20.0%±12.6%。结论:酪氨酸激酶抑制剂可能会使更多患者获得缓解,从而有机会进行allo-HSCT。CR1的生存获益更大。allo-HSCT联合酪氨酸激酶抑制剂为Ph+ALL患者有前景的治疗方案。

Objective To study the efficacy of allogeneic hematopoietic stem cell transplantation （allo-HSCT） for treatment of adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia （Ph＋ALL）. Methods The treatment outcomes of 12 patients with Ph＋ ALL who had received allo-HSCT were analyzed respectively. All 12 patients received VDP （vincristine, anthracycline and glucocorticoid） ±C （cyclophosphamide or ifosfamide） ±L （L-asparaginase or pegaspargase） as induction therapy. Those who achieved complete remission （CR） after induction then underwent consolidation chemotherapy in combination with imatinib either concurrently or alternately. Patients who did not achieve CR and those who relapsed during consolidation therapy received hyper-CVAD（cyclophosphamide, vincristine, doxorubicin and dexamethasone）or LALA（mitoxantrone and cytarabine） chemotherapy in combination with imatinib or dasatinib. Allo- HSCT was conducted in all patients with standard or modified busulfancyclophosphamide（Bu-Cy） pre-treatment regimen. Some of them received tyrosine kinase inhibitor （TKI） maintenance therapy after allo-HSCT. Results All 12 patients achieved hematology remission, and 7 patients achieved molecular remission. Of the 12 patients, 9 cases were in CR 1, 2 in CR2 and 1 with primary refractory disease. Imatinib was given to 11 patients before transplantation at a dose of 400- 800 mg/d, and 5 patients received TKI treatment started at 2-3 months after transpiantation,among whom 4 with imatinib （300-400 mg/d） and 1 with dasatinib （50-100 mg/d）. All patients obtained successful engraftment. With a median follow- up of 12.7 （3-54） months, 7 patients were alive, 2 died from treatment related co-morbidity, and 3 died of disease relapse. The estimated overall survival （OS）, cumulative relapse incidence （RI） and non-relapse mortality （NRM） at 2 years were 66.7%±13.6%, 40.6%±16.0% and 16.7%±10.8%, respectively. For patients undergoing allo-HSCT in CR1, OS, RI and NRM were 70.0%±14.5%, 40%±18.2% and 20.0%±12.6%, respectively. Conclusions With the addition of TKI to induction chemotherapy, a higher proportion of patients with Ph＋ALL could achieve CR and thus proceeded to allo-HSCT. Better outeome could be expected when allo-HSCT was perfoimed for patients in CR1. Allo-HSCT in combination with TKI was a promising strategy for treatment of adult patients with Ph＋ALL.