伊马替尼联合化疗治疗成年人费城染色体阳性急性淋巴细胞白血病效果分析

目的分析伊马替尼联合化疗治疗成年人费城染色体阳性(Ph^+)急性淋巴细胞白血病(ALL)的临床疗效。方法收集2012年6月至2016年1月就诊于中国医科大学附属第一医院的成年Ph^+ALL患者35例,其中联合化疗组21例,单纯化疗组14例。定期监测血常规、骨髓细胞形态学、免疫分析、染色体及融合基因等,评估疗效。联合化疗组4例患者第1次完全缓解(CR1)后行造血干细胞移植治疗。结果联合化疗组诱导治疗后完全缓解(CR)率为76%(16/21),单纯化疗组为36%(5/14),两组比较差异有统计学意义(χ^2=5.734,P=0.033)。联合化疗组(除移植患者)中位总生存(OS)时间为14个月(2~18个月),单纯化疗组5个月(0.33~10个月),两组比较差异有统计学意义(U=12.0,P=0.007)。联合化疗组中位无病生存(DFS)时间为8个月(0~15个月),单纯化疗组为2个月(0~6个月),两组比较差异有统计学意义(U=12.5,P=0.007)。4例移植患者中位OS时间26个月(22~39个月),中位DFS时间22个月(17~36个月)。结论Ph+ALL患者诱导治疗期采用伊马替尼联合化疗可提高CR率,延长DFS及OS时间,为移植赢得时间与机会。CR1后有条件者及时行造血干细胞移植治疗可延长生存时间。     

伊马替尼联合化疗序贯异基因造血干细胞移植治疗费城染色体阳性急性淋巴细胞白血病疗效的Meta分析

目的 系统评价伊马替尼联合化疗序贯异基因造血干细胞移植（allogeneic hematopoietic stem cell transplantation,allo-HSCT）治疗费城染色体阳性的急性淋巴细胞白血病（Philadelphia chromosome+acute lymphoblastic leukemia,Ph+ALL）的疗效。方法 采用Cochrane图书馆、Embase、PubMed、CNKI、CBM、Google 学术搜索等数据库,按纳入标准和排除标准筛选相关文献并提取资料、评估质量,采用RevMan 5.2软件进行Meta 分析。结果 纳入12个研究共620例患者。Meta分析显示,与非移植组比较,移植组治疗提高了患者无瘤生存率（disease free survival,DFS）（HR＝0.48, 95% CI：0.31~0.74,P<0.001）及总生存率（overall survival,OS）（HR=0.49,95% CI：0.35~0.68,P<0.001）,减少了死亡事件（RR＝0.62,95% CI：0.39~0.97,P=0.04）。结论 在伊马替尼联合化疗治疗Ph+ALL患者的基础上,序贯allo-HSCT可能优于无allo-HSCT方案。     

Philadelphia chromosome-positive acute lymphoblastic leukemia: current treatment and future perspectives

The Philadelphia chromosome (Ph) is the most common cytogenetic abnormality associated with adult acute lymphoblastic leukemia (ALL). Before the advent of tyrosine kinase inhibitors (TKIs), Ph-positive ALL carried a dismal prognosis and was characterized by a poor response to most chemotherapy combinations, short remission durations, and poor survival rates. Outcomes for patients with Ph-positive ALL improved substantially with the introduction of TKIs, and the TKI imatinib induced complete remissions in >95% of patients with newly diagnosed Ph-positive ALL when it was combined with chemotherapy. However, imatinib resistance remains a problem in a substantial proportion of patients with Ph-positive ALL, and multiple molecular mechanisms that contribute to imatinib resistance have been identified. Second-generation TKIs (eg, dasatinib and nilotinib) have demonstrated promising efficacy in the treatment of imatinib-resistant, Ph-positive ALL. Future strategies for Ph-positive ALL include novel, molecularly targeted treatment modalities and further evaluations of TKIs in combination with established antileukemic agents. For this article, the authors reviewed past, current, and future treatment approaches for adult and elderly patients with Ph-positive ALL with a focus on TKIs and combined chemotherapeutic regimens.     

Imatinib combined chemotherapy for Philadelphia chromosome-positive acute lymphoblastic leukemia: major challenges in current practice

The prognosis of Philadelphia chromosome-positive (Ph+) and/or BCR-ABL-positive acute lymphoblastic leukemia (ALL) is extremely poor, and for decades allogeneic hematopoietic stem cell transplantation (HSCT) has been considered the only option for a cure. However, the treatment for Ph+ ALL has been rapidly changing since imatinib, a selective inhibitor of the ABL tyrosine kinase, was introduced. Earlier clinical trials in which a moderate anti-leukemic effect of imatinib monotherapy was demonstrated have prompted investigators to explore the combination of imatinib and chemotherapy. The results of multiple studies indicate that chemotherapy combined with imatinib is well tolerated, induces complete hematological remission in almost every patient with newly diagnosed Ph+ ALL, and molecular remission in more than half of the cases. Future clinical studies need to focus on how imatinib can be incorporated into chemotherapy more effectively by determining the optimal dosage of imatinib, the optimal combinational schedule, and the role of allogeneic HSCT.     

Management of adult patients with acute lymphoblastic leukemia in first complete remission

BACKGROUND:

The optimal postremission therapy in adults with acute lymphoblastic leukemia (ALL) is still a matter of debate. The objective of this study was to compare the various potential therapeutic options for patients who achieved first complete remission.

METHODS:

The authors conducted a systematic review and meta‐analysis of randomized trials, including patients with standard‐risk (SR) All and high‐risk (HR) ALL who received first postremission therapy. Outcomes assessed were all‐cause mortality (ACM), disease recurrence (relapse), and nonrelapse mortality (NRM). Relative risks (RRs) with 95% confidence intervals (CIs) were estimated and pooled.

RESULTS:

Overall, there was a significant reduction in ACM in the allogenic stem cell transplantation (alloSCT) arm (RR, 0.88; 95% CI, 0.8‐0.97) compared with autologous stem cell transplantation (ASCT) or chemotherapy. Subgroup analyses revealed a similar pattern among SR patients (RR, 0.8; 95% CI, 0.68‐0.94) but a nonsignificant advantage for alloSCT among HR patients (RR, 0.88; 95% CI, 0.76‐1.01). There was an increase in NRM (RR, 2.99; 95% CI, 1.37‐6.53) and a decrease in the relapse rate in the alloSCT arm (RR, 0.52; 95% CI, 0.33‐0.83). There was no difference in ACM or the relapse rate between the ASCT and chemotherapy arms.

CONCLUSIONS:

Overall, alloSCT was superior to ASCT or chemotherapy for patients with ALL in first complete remission. The survival advantage was of greater statistical significance for patients with SR ALL than for patients with HR ALL. Cancer 2010. © 2010 American Cancer Society.     

异基因造血干细胞移植治疗成人Ph染色体阳性急性淋巴细胞白血病的临床疗效

目的:回顾性分析异基因造血干细胞移植（allo-HSCT）治疗成人Ph染色体阳性的急性淋巴细胞白血病（Ph+ALL）的疗效。方法:收集本院自2011年9月至2018年12月行allo-HSCT的Ph+ALL成人患者29例。移植前处于CR1 23例;CR2 3例;CR3 1例;未缓解（UR）2例。无关供者相合1例,同胞全相合5例,亲缘单倍体23例。骨髓+外周血造血干细胞移植14例,外周血造血干细胞移植15例。预处理方案:白消安/环磷酰胺（Bu/Cy）者1例,TBI/Cy者13例,TBI/Flu者7例,FBA者5例,CBA者3例。21例患者移植后使用TKI维持治疗至MRD阴性后1年。结果:26例获得完全造血重建,另3例患者获得ANC重建,未获得PLT重建。中位随访时间为 13（3~54）个月,死亡10例（34.5%）,死于疾病复发者6例,死于治疗相关并发症者4例（感染2例,严重肝脏GVHD 1例,TA-TMA 1例）。复发患者中均有相关高危因素（移植前未缓解及MRD阳性）。总生存率为65.5%。预期2年DFS 60%,预期2年OS 66%。移植后使用TKI维持组及不维持组预期2年DFS分别为78% vs 46%。结论:allo-HSCT是治疗急性淋巴细胞白血病患者的有效方法,移植后使用TKI维持治疗可提高移植疗效。     

费城染色体阳性成年急性淋巴细胞白血病患者治疗效果及预后因素分析

目的 分析费城染色体阳性(Ph+)的成年急性淋巴细胞白血病(ALL)患者治疗效果及预后影响因素.方法 回顾性分析49例Ph+ALL患者的临床资料,探讨治疗效果及不同因素对预后的影响.结果49例患者中,男性24例,女性25例;中位年龄38岁(15~77岁),酪氨酸激酶抑制剂(TKI)治疗组血液学完全缓解(CR)率、主要分子生物学反应(MMR)率及完全分子生物学缓解(CMR)率均高于单纯化疗组(96.8 %比72.2 %,64.5 %比16.7 %,25.8 %比11.1 %),差异均有统计学意义(χ2=4.308,P=0.038;χ2=10.468,P=0.001;χ2=4.250,P=0.039).生存分析提示中位总生存(OS)时间为24个月(3~70个月),3年OS率及无复发生存(RFS)率分别为32.7 %、21.4 %;TKI治疗组3年OS率及1年RFS率高于单纯化疗组(40.3 %比11.1 %,67.8 %比11.1 %),差异有统计学意义(χ2=12.725, P<0.001;χ2=17.401,P<0.001);异基因造血干细胞移植(allo-HSCT)组3年OS率及RFS率高于非移植组(62.5 %比25.7 %、41.7 %比15.0 %),差异有统计学意义(χ2=6.196,P=0.013;χ2=8.032,P=0.005);经2个疗程治疗后达MMR组3年OS率及RFS率分别为45.1 %和28.9 %,高于未达MMR组(17.6 %和11.7 %),差异有统计学意义(χ2=5.446,P=0.020;χ2=6.484,P=0.011);Cox多因素分析结果显示,联合TKI治疗(HR=0.227,95 % CI 0.094~0.550,P=0.001)是OS的独立预后因素;联合TKI治疗(HR=0.225,95 % CI 0.082~0.618,P=0.004)及移植(HR=0.275,95 % CI 0.077~0.983,P=0.047)是RFS的独立预后因素.结论 联合TKI治疗能提高患者CR、MMR及CMR率,提高长期生存,为患者接受移植提供更多机会;在TKI时代,移植仍是治疗Ph+ALL的重要方法,尤其那些经化疗联合TKI治疗但早期未达MMR者预后差,应尽早行造血干细胞移植.     

酪氨酸激酶抑制剂在费城染色体阳性急性淋巴细胞白血病诱导治疗中的作用

目的 探讨低剂量化疗联合酪氨酸激酶抑制剂(TKI)作为初诊费城染色体阳性急性淋巴细胞白血病(Ph+ ALL)一线诱导治疗方案的可行性.方法 回顾性分析61例初诊Ph+ ALL患者接受不同诱导治疗方案的疗效与不良反应.结果 全部患者初次诱导治疗的完全缓解(CR)率为73.8％(45/61),再次诱导CR率为86.7％(13/15),两程诱导治疗总的CR率为95.1％(58/61),治疗相关死亡1例(1.6％).无论是否联用TKI,常规剂量组与低剂量组有效率差异无统计学意义[未联用组:65.5 ％(19/29)比60.0％(3/5),P=0.812;联用组:90.5％(19/21)比100.0％(6/6),P=0.432];低剂量化疗联合TKI的有效率与单用常规剂量化疗比较,差异亦无统计学意义(P=0.089).无论化疗强度如何,联合TKI均能提高初次诱导治疗有效率(常规剂量组:P=0.041;低剂量组:P=0.087);联用TKI方案总有效率显著高于未联用TKI方案[92.6％(25/27)比64.7％(22/34),P=0.010].对于未获CR患者,初次诱导时未联用TKI者再次诱导治疗联用TKI的有效率明显高于初次诱导曾联用TKI者[100.0％(8/8)比33.3％(1/3),P=0.011].不同遗传学亚组间初次诱导治疗的有效率差异无统计学意义(均P＞0.05),联用TKI可在一定程度上提高有效率,但差异均无统计学意义(均P＞0.05).全部患者初次诱导治疗的感染率为50.8％(31/61),出血发生率为4.9％(3/61).常规剂量组总感染率[56.0％(28/50)]高于低剂量组[27.3％(3/11)],但差异无统计学意义(P=0.084),两组总出血发生率差异亦无统计学意义[6.0％(3/50)比0(0/11),P=0.405].低剂量化疗联合TKI组的感染率低于常规剂量化疗联合TKI组[0(0/6)比71.4％(15/21),P=0.002],也低于单用常规剂量化疗组[0(0/6)比44.8％(13/29),P=0.039],组间出血发生率差异均无统计学意义(均P＞ 0.05).结论 低剂量化疗联合TKI作为Ph+ ALL一线诱导治疗方案值得进一步探索.     

达沙替尼一线治疗费城染色体阳性急性淋巴细胞白血病四例并文献复习

目的 探讨二代酪氨酸激酶抑制剂（TKI）达沙替尼一线治疗费城染色体阳性急性淋巴细胞白血病（Ph^＋ALL）的临床疗效.方法 应用达沙替尼一线治疗4例Ph^＋ ALL患者并进行文献复习.结果 4例患者用达沙替尼一线治疗4～6周后均获完全血液学反应（CHR）,其中1例患者已达完全细胞遗传学反应（CCyR）;治疗10～12周后均获完全分子生物学反应（CMR）.1例化疗3个周期未缓解的难治性Ph^＋ALL患者用单药达沙替尼治疗6周后达CHR及部分细胞遗传学反应（PCyR）.4例患者的无进展生存期（PFS）分别为10.5、24.0、8.5、10.0个月.结论 达沙替尼治疗Ph^＋ALL临床疗效显著,可获得深度分子生物学反应,同时耐受性良好,可考虑作为Ph^＋ALL的一线治疗.     

Tyrosine kinase inhibitors for the treatment of Philadelphia chromosome-positive adult acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is a heterogeneous disorder, with the greatest prevalence in children, but it also affects adults, and has an increasing incidence with age. Chromosomal abnormalities in ALL have been frequently described, the most common is the Philadelphia chromosome (Ph). The resulting fusion gene, BCR-ABL1, encodes for a chimerical oncoprotein (BCR-ABL) with constitutive tyrosine kinase activity, which leads to uncontrolled cell proliferation, reduced apoptosis, and impaired cell adhesion. Treating Philadelphia chromosome-positive (Ph+) ALL patients with conventional chemotherapy has not substantially improved their long-term outcomes. Recently, however, BCR-ABL-targeted strategies have been successfully adopted. Imatinib is an oral competitive inhibitor of ABL with demonstrated phase 2 efficacy in patients with treatment-naive and pretreated ALL. Despite its efficacy, imatinib may induce specific resistance in a large proportion of patients, mainly because of the occurrence of ABL1 mutations. Therefore, novel inhibitors have been developed. Dasatinib is a multitargeted kinase inhibitor of BCR-ABL, SRC, C-KIT, PDGFRs, and ephrin A receptor kinases. Unlike imatinib, it binds both the active and inactive BCR-ABL as well as the majority of ABL mutants. Dasatinib is approved for treatment of imatinib-pretreated Ph+ ALL, and chronic myeloid leukemia (CML) on the basis of phase 2 trials that demonstrated impressive efficacy and favorable tolerability profiles. Nilotinib is another BCR-ABL targeted agent that is similar in structure to imatinib but has significantly greater binding affinity. It also has demonstrated promising efficacy in Ph+ ALL but is still being evaluated in phase 2 trials. In this article, the authors reviewed current knowledge on novel tyrosine-kinase inhibitors in adult Ph+ ALL patients.     

成人急性淋巴细胞白血病的诊疗进展

急性淋巴细胞白血病(acute lymphoblastic leukemia,ALL) 是一种常见的恶性血液疾病。虽然成人ALL患者在诱导缓解治疗后完全缓解率可达80%以上,但大多数患者最终出现复发,长期生存率低。本研究对近年来成人ALL诊疗的进展进行综述,为成人ALL患者的诊疗提供参考和依据,以进一步改善该类患者的生存质量。     

Haploidentical hematopoietic stem cell transplantation in adults with Philadelphia‐negative acute lymphoblastic leukemia: No difference in the high‐ and low‐risk groups

Allogeneic hematopoietic stem cell transplantation (HSCT) is the most effective post‐consolidation therapy and curative option for adult patients with Philadelphia chromosome‐negative (Ph‐negative) acute lymphoblastic leukemia (ALL) in first complete remission (CR1). A human leukocyte antigen (HLA)‐haploidentical related donor (haplo‐RD) is one of the most important alternative sources for those without HLA‐identical sibling donor (ISD). The present study aimed to evaluate the outcomes of haploidentical hematopoietic stem cell transplantation (haplo‐HSCT) in adult Ph‐negative ALL CR1 patients (n = 183). We produced an unmanipulated haplo‐HSCT protocol including granulocyte colony stimulating factor (G‐CSF) for all donors, intensive immune suppression, anti‐thymocyte globulin, and combination of G‐CSF‐primed bone marrow harvest and G‐CSF‐mobilized peripheral blood stem cells harvest as the source of stem cell grafts. The median age for high‐risk versus low‐risk groups were 29 versus 23 years. Three‐year incidences of relapse mortality and nonrelapse mortality for high‐risk versus low‐risk groups were 7.1% versus 11.1% (p = 0.498) and 18.0% versus 16.2% (p = 0.717), respectively. Three‐year probabilities of disease‐free survival and overall survival for high‐risk versus low‐risk groups were 67.6% versus 68.2% (p = 0.896) and 74.9% versus 72.7% (p = 0.981), respectively. Multivariate analysis showed that limited cGVHD and a lower pre‐HSCT comorbidity burden were associated with better outcomes. In summary, comparable outcomes were observed among high‐ and low‐risk Ph‐negative ALL CR1 patients after haplo‐HSCT. Haplo‐RD could be considered for adults with Ph‐negative ALL in CR1 as an important alternative source of donors in cases when no ISD is available.     

异基因造血干细胞移植治疗急性T 淋巴细胞白血病和淋巴瘤：附50例临床报告

目的 探讨异基因造血干细胞移植（allogeneic hematopoietic stem cell transplantation,allo-HSCT）治疗急性T淋巴细胞白血病（T cell acute lymphoblastic leukemia,T-ALL）和急性T淋巴母细胞淋巴瘤（T cell acute lymphoblastic lymphoma, T-LBL）的疗效及预后。方法 回顾性分析2014—2019年于航天中心医院接受allo-HSCT的50例T-ALL/LBL患者的临床资料,分析其临床疗效、并发症及预后。结果 50例患者中男性41例,女性9例,中位年龄20.5岁（范围：9.0~63.0岁）;单倍体移植44例,脐血移植 2例,同胞全合移植 4例;T-ALL 40例,T-LBL 10例;移植前处于完全缓解（CR）状态16例,处于未完全缓解（非CR）状态34例。移植后,中位随访20个月（范围：1~84个月）,存活23例,死亡27例;移植后24个月的总生存率和无复发生存率分别为50.0%和44.0%,36个月的总生存率和无复发生存率分别为45.5%和40.0%。随访期间,共有20例患者复发,复发率为40.0%（20/50）。移植前获CR、无髓外病变、无中枢神经系统受累的患者预后较好,而移植前有无基因突变、不同预处理方案、有无急性/慢性GVHD患者的总生存期及无复发生存期组间比较差异无统计学意义（均P>0.05）。结论 在这项小样本、无对照的临床研究中,T-ALL/LBL患者在缓解期行allo-HSCT可能较挽救性移植的生存预后有所改善,其中复发为移植失败的主要原因。     

微移植联合化疗治疗老年急性髓系白血病临床观察

目的:观察微移植联合化疗治疗老年急性髓系白血病患者的临床疗效及安全性.方法:回顾性分析我院35例老年急性髓系白血病患者经单纯诱导化疗(n=16)或联合微移植(n=19)的治疗过程及转归情况.结果:微移植联合化疗组14例(73.7%)完全缓解(CR),单纯诱导化疗组6例(37.5%)CR;微移植组中性粒细胞、血小板中位恢复时间分别为11.5 d、16 d,而单纯诱导化疗组则分别为15 d、22 d(P<0.05);微移植组无重症感染及相关死亡发生,单纯化疗组因重症感染死亡3例.结论:微移植联合化疗治疗老年急性髓系白血病提高了疾病缓解率,降低了化疗相关死亡率.