老年急性骨髓性白血病患者输注HLA配型不合的外周血干细胞可改善化疗预后
2011-05-06 MedSci原创 MedSci原创
出处：Blood. 2011 Jan 20;117(3):936-41. Epub 2010 Oct 21. 作者：Guo M, Hu KX, Yu CL, Sun QY, Qiao JH, Wang DH, PMID：20966170译者： F1000因子：10 评级：必读 人们对老年急性骨髓性白血患者的疗效仍是不甚满意。既往研究发现输注粒细胞集落刺
出处：Blood. 2011 Jan 20;117(3):936-41. Epub 2010 Oct 21.
作者：Guo M, Hu KX, Yu CL, Sun QY, Qiao JH, Wang DH,
PMID：20966170
译者： F1000因子：10 评级：必读
专家点评
Arati Rao
Oncology, Duke University, USA
I found this article very interesting because it provides an option for elderly acute myeloid leukemia (AML) patients that is not typically thought of and in addition it led to very high remission rates with not as much toxicity.
The basis for the paper was that (1) while reduced intensity conditioning (RIC) stem cell transplant (SCT) is feasible in the elderly, 70% of patients do not have donors; (2) SCT is limited by graft-versus-host disease (GVHD) and infections; (3) granulocyte colony-stimulating factor (GCSF)-mobilized peripheral blood stem cells (PBSCs) can mediate the graft versus leukemia effect and hasten hematologic recovery without amplifying GVHD; (4) this group studied this first in a mouse model in vitro.
Patients (N=58) were all aged >60 years with de novo or secondary AML, lacking a human leukocyte antigen (HLA)-matched sibling, enrolled from May 2004 to Dec 2009. Patients were defined as 'high risk' if they had >=3 cytogenetic abnormalities, had secondary AML or had a white blood cell count (WBC) >=50,000. All patients had related donors who were HLA-mismatched (including HLA-C). Of 30 patient-donor pairs, 21 were mismatched at five of 10 loci and nine were mismatched at four of 10 loci. The median donor age was 35 years: 18 sons, 10 daughters and three brothers were among the donors.
Patients received induction with cytarabine 150mg/m2 for 7 days intravenously (IV) and mitoxantrone 8-10mg/m2 for 3 days IV+/-HLA-mismatched G-PBSCs. Three patients in the SCT arm were aged >80 years and received reduced-dose chemotherapy with cytarabine at 50mg/m2 for 5 days IV and mitoxantrone 3mg/m2 daily for 3 days IV. HLA-mismatched GCSF-stimulated PBSCs (G-PBSCs) were given 36 hours after the last dose of cytarabine. Bone marrow biopsy to assess response was done between days 10-14, and if patients had a complete remission (CR) they received consolidation with two more courses of cytarabine 0.5-1.0mg/m2 IV+/-PBSCs. If patients did not have a CR then the induction regimen was repeated once more and if they then achieved CR, consolidation as above was given, and if no CR, the patient was deemed refractory and taken off the study. PBSCs were mobilized using 5mcg/kg bid of GCSF for 5 days. Cells that were CD34+, CD3+, CD16+, CD56+ were infused. Donor chimerism was measured by standard cytogenetic and semiquantitative PCR-based analysis of short tandem repeats (STRs). Microchimerism in <1% donor cells was monitored in all four female patients with male donors by looking for a sex-determining region of the Y chromosome by RT-PCR.
The chemotherapy only (N=28, control) arm had (not statistically significant) slightly more patients with unfavorable karyotype, secondary AML and patients aged >70 years than patients in the G-PBSC plus chemotherapy arm (N=30). The CR rate in patients that received G-PBSCs plus chemotherapy was 80% vs. only 42.8% in patients who received chemotherapy alone (p=0.006). The CR rate was high even after just a first cycle of chemotherapy: 63.3% in the G-PBSC arm vs. 28.6% in the chemotherapy alone arm, p=0.006. The CR in patients >70 years was phenomenonal: 92.8% in the G-PBSC arm vs. only 12.5% in the chemotherapy alone arm, p=0.0003. No other high risk category showed a difference in CR rates. Lower resistance was also noted: 10% in the G-PBSC arm vs. 39% in the chemotherapy alone arm, p=0.01.
Early death rates were 6.7% and 14.3% (p=0.69) in the G-PBSC group and in the control group, respectively. The median recovery times for neutrophils and platelets were 11 days and 14.5 days, respectively, in the G-PBSC group and 16 days and 20 days, respectively, in the control group after the first cycle of induction chemotherapy (p<=0.02).
Most impressively, no signs of acute or chronic GVHD were observed in any of the patients during treatment. Severe infection rates were lower in the G-PBSC group than in the control group (26.7% vs. 57.1%) after the first cycle of induction chemotherapy (p=0.03). In patients in remission, the probabilities of 2-year disease-free survival (DFS) and overall survival (OS) were 38.9% and 39.3%, respectively, in the G-PBSC group. These probabilities were significantly higher (10.0% and 10.3%, respectively, p=0.01 and p=0.0006) than those in the control group.
These impressive results may be explained by the possibility that G-PBSC therapy can significantly speed hematopoietic recovery after chemotherapy, thereby reducing the induction chemotherapy-related rates of morbidity and mortality. The large number of lymphocytes, CD34+ cells, natural killer (NK) cells, as well as cytokines contained in G-PBSCs may contribute to promoting hematopoietic recovery. Another explanation is the enhanced anti-leukemia effects mediated by the alloreactive G-PBSCs infused, which contained many more NK cells than usual. Also, all patient-donor pairs were HLA-C-mismatched and patients with C2 donors had a significantly higher OS than patients without this (p=0.01). This result suggests that NK cells contributed to the anti-leukemic effects and improved clinical outcome. This study should be done and evaluated in North America and Europe in a prospective clinical trial. For further reading please see refs {1-3}.
References:
{1} Slavin et al. Blood 1998, 91:756-63 [PMID:9446633].
{2} Estey et al. Blood 2007, 109:1395-400 [PMID:17038533].
{3} Spitzer TR, Hematology Am Soc Hematol Educ Program 2005, 390-5 [PMID:16304409].
专家评价：
这篇文章非常有意义，因为它为老年急性髓性白血病（AML）患者提供了一个治疗选择，而且此疗法通常不易想到。此外，此疗法缓解率非常高且毒性不大。
本文的偏倚：（1）尽管低强度预处理（RIC）干细胞移植（SCT）治疗对于老年患者具有可行性，但70％的患者没有供者；（2）SCT受移植物抗宿主病（GVHD）和感染所限；（3）粒细胞集落刺激因子（GCSF）动员的外周血干细胞（PBSCs）可以调节移植物抗白血病效应以及加快造血功能恢复但不会增强移植物抗宿主病；（4）研究小组最先在体外小鼠模型进行研究。
2004年5月至2009年12月入选的58例患者，年龄均大于60岁，为初发或继发性AML，缺少人类白细胞抗原（HLA）匹配的兄弟姐妹。如果患者的细胞遗传学异常> = 3项，有继发性AML，或白细胞计数（WBC）>=50,000，则被确认为“高风险”。所有患者都有相应的HLA不相合的（包括HLA-C抗原）的供者。30对患者-供者中，其中有21对10个基因位点中5个不相合，9对4个基因位点不相合。供者年龄中位数为35岁，供者中有18个儿子，10个女儿和3个兄弟。
患者接受静脉注射（IV）阿糖胞苷150mg/m 2诱导治疗7天，以及静脉注射米托蒽醌8-10mg/m2治疗3天+ / -HLA不相合的G –PBSCs。SCT组3例患者年龄大于80岁，接受静脉注射小剂量阿糖胞苷50mg/m2化疗5天及米托蒽醌每日3mg/m2治疗3天。最后一次阿糖胞苷给药后36小时，给予HLA不相合的G –PBSCs。10-14天进行骨髓活检以评估疗效，如果患者完全缓解（CR），那么患者继续接受两个以上疗程的静脉注射阿糖胞苷 0.5-1.0mg/m2+ / - PBSCs治疗。如果没有完全缓解，再重复一次诱导治疗，如果达到完全缓解，按前者巩固治疗。如果仍没有完全缓解，则视为难治性患者，并从研究中剔除。使用GCSF 5mcg/kg次/日，连续5天进行PBSCs动员。输注的细胞为CD34+，CD3 +，CD16+，CD56+细胞。采用基于细胞遗传学和半定量PCR技术的短串联重复序列（STRs）分析法测定供体（细胞）嵌合率。经RT - PCR检测性别决定基因发现所有的4例供者为男性的女性患者供体细胞微嵌合小于1％。
化疗组（28例，对照组）的核型不佳，继发性AML以及年龄大于70岁的患者比G-PBSC加化疗组（30例）稍（无显著统计学意义）。 G-PBSC加化疗组患者完全缓解率为80%，与之相比，仅接受化疗组患者为42.8％（p= 0.006）。甚至第一个化疗疗程后，G-PBSC组完全缓解率很高为63.3％，而仅接受化疗组为28.6％，p= 0.006。70岁以上患者的完全缓解率相差更大：G-PBSC组为92.8％，而仅接受化疗组为12.5％，p= 0.0003。其他高风险因素完全缓解率无差异。G-PBSC组耐药性较低为10％，仅接受化疗组为39％，p= 0.01。
G-PBSC组和对照组早期死亡率分别为6.7％和14.3％（p= 0.69）。首次诱导化疗后G-PBSC组中性粒细胞和血小板恢复时间中位数分别为11天、14.5天，对照组分别为16天、20天（P <= 0.02）。
令人印象最深的是，治疗期间所有患者未观察到急性或慢性移植物抗宿主病。首次诱导化疗后G-PBSC组的严重感染率明显低于对照组（26.7％ VS 57.1％）（p= 0.03）。G-PBSC组缓解患者的2年无病生存率（DFS）和总生存率（OS）分别为38.9％和39.3％。这些数据明显高于对照组（10.0％和 10.3％，P= 0.01和P = 0.0006）。
这些令人印象深刻的结果可能解释为G-PBSC治疗可以显著加快化疗后造血恢复，从而减少诱导化疗有关的发病率和死亡率。G-PBSCs中含有大量的淋巴细胞，CD34 +细胞，自然杀伤（NK）细胞，以及细胞因子可能有助于促进造血恢复。另一种解释是输注同种异体G-PBSCs介导抗白血病作用增强，同种异体G- PBSCs比平常的含有更多的NK细胞。而且，所有患者-供者为HLA - C型不相合，C2供者的患者的总生存率比那些非C2供者的患者明显的高（p= 0.01）。这一结果表明，NK细胞有助于抗白血病作用，并改善临床预后。这项研究应在北美和欧洲的前瞻性临床试验中进行并评估。
点评专家
Arati Rao
Oncology, Duke University, USA
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#急性骨髓性白血病#
32
#HLA#
36
#髓性#
30
#外周血#
40