摘要目的：研究免疫治疗用于治疗及预防骨髓移植(bone marrow transplantation, BMT)后的白血病复发。方法：A组为异基因骨髓移植(Allo-BMT)后白血病复发患者10例，接受供者白细胞治疗。B组为自身外周血干细胞移植(autogenous peripheral blood stem cells transplantation, APBSCT)或BMT后共10例患者输注免疫杀伤细胞(cytokine-induced killer， CIK)细胞治疗。结果：A组患者中血液学复发的6例，1例Ph¹染色体100%转阴，无病存活至今已超过18个月，4例达暂时缓解；1例未缓解；微小残留及中枢神经系统复发共4例，均完全缓解，其中Ph¹染色体全部转阴。B组10例中1例患者带有的白血病融合基因转阴。结论：(1)供者白细胞的输注能使某些BMT后慢性粒细胞性白血病遗传学及血液学复发患者完全缓解。(2)CIK细胞输注是安全的，对某些白血病复发患者的治疗是有效的。

中国图书资料分类法分类号R733.7

Immunotherapy after bone marrow transplantation

JIANG Hao, LU Dao-Pei, GUO Nai-Lan, LU Xi-Jing, TONG Chun-Rong， GENG Yan-Biao

(Institute of Hematology， People's Hospital, Beijing Medical University, Beijing100044)

MeSHBone marrow transplantImmunotherapyNeoplasm recurrence, local/prevLeukemia/ther

ABSTRACTObjective: To study immunotherapy for leukemia relapse and prophylaxis after bone marrow transplantation(BMT).Methods: In group A, 10 cases of leukemia relapse after Allo-BMT were treated with concentrated mononuclear cells from the marrow donor. In group B, 10 cases of leukemia after APBSCT (autogenous peripheral blood stem cells transplantation) or BMT were treated with CIK (cytokine induced killer) cells.Results: Among 6 patients with hematological relapse in group A, one patient has being living well for 18 months with disappearance of the Ph¹ chromosome. 4 patients showed temporary remission and then relapsed again. One patient showed no response. The other 4 patients (2 with CNS relapse and 2 patients with relapse of minimal residual disease) showed remission, and remained Ph¹ chromosome negative. In group B, a patient treated with CIK cells with a special leukemia infused gene (AML/ETO) turned negative after one treatment of CIK cells.Conclusion: (1) Donor derived leukocyte infusion can induce CML post-BMT to cytogenetic and hematological CR. It has also therapeutic effects on acute leukemia relapse but is less sustained. (2) CIK cells can be safely infused into patients and is effective in the therapy of leukemia relapse at least in some patients.

(J Beijing Med Univ, 1999,31:395-399)

骨髓移植(bone marrow transplantation, BMT)给白血病患者带来根治疾病、长期存活的机会,但无论是异基因还是自体骨髓移植，都存在一定的复发率。自体骨髓由于移植缺乏异基因骨髓移植(Allo-BMT)所具有的移植物抗白血病(GVL)作用，所以Auto-BMT后白血病复发更是影响患者长期存活的主要原因。复发提示BMT后患者体内仍存在着少量的肿瘤细胞。由于BMT前患者所处的疾病状态，对移植相关毒副作用的耐受力及对化疗药物的耐药情况不同，复发后患者很难再次缓解。近年来，BMT后免疫治疗给这部分患者带来希望，Allo-BMT后给白血病复发患者输注供者白细胞进行过继免疫治疗，国外已有诸多报道^［1～4］，其中部分患者达到缓解并长期存活。在我们所的临床研究中，也得到同样疗效。免疫杀伤细胞(cytokine induced killer, CIK)是多种因子激活的杀伤细胞，在体外具有明显的增殖及高杀伤活性。美国斯坦福大学介绍了CIK细胞的培养程序,在动物体内应用发现这种细胞的体内抗肿瘤效果远高于LAK细胞^［5］。我们在现有实验室条件下培养出一定量的CIK细胞，主要用于临床自体BMT后复发的预防或治疗。本文观察了BMT后患者输注供者白细胞或各种细胞因子和抗CD3单抗共同激活的CIK细胞的反应。

1材料与方法

1.1病例选择

本文观察两组患者为1991～1997年间在我院接受骨髓移植后复发就诊于本所的患者。A组：Allo-BMT后白血病复发患者10例，接受供者白细胞治疗;平均年龄31.4岁(18～45)；男6例，女4例；诊断为CML-CP 5例、AML-CR₁ 3例、AML-CR₂ 1例、ALL-CR₁ 1例。供者均为患者同胞，HLA配型和MLC（混合淋巴培养）均与患者相合。10例患者于Allo-BMT后+60至+1 277天白血病复发，复发状态为2例遗传学复发，2例脑膜白血病复发，5例血液学复发，1例表现为髓外复发，全身广泛皮下结节。其中2例脑膜白血病复发患者予鞘内注射(阿糖胞苷30 mg/次或甲氨喋呤10 mg/次)后完全缓解。7例患者予以联合化疗，1例未化疗。化疗结果：3例达完全缓解，1例部分缓解，3例患者未缓解。详见表1、2。B组：观察1995～1997年造血干细胞移植后接受CIK细胞治疗的患者10例，平均年龄为33岁（14～44）；男6例，女4例；诊断为AML-CR₁ 3例、AML-CR₂ 2例、ALL-CR₁ 5例；分别为接受自体PBSCT 8例、同基因BMT 1例和异基因BMT者1例。

表1A组血液学复发患者输注供者白细胞前后情况及结果

Table 1Donor derived leukocyte (DDL) for gross hematological relapse in group A

UPN Relapse Chemotherapy Infusion of DDL Outcome t(post

-BMT）

／d Status Yes

(No) Result t(post-

relapse)

/d No. of

treatments t(interval)

/d MNC

(×10⁸／kg) GVHD t(alive and

well)

/months t(relapse

from

therapy)/

months t(post-

relapse)

/d Grade 47 80 AML Yes CR 12 4 13－28 14.76 － 10 89 62 APL Yes PR 56 3 10－15 2.72 49 Ⅳ Disappearance of subcutaneous node; died of IP. (subcutaneous node) 85 1030 APL Yes CR 20 2 15 4.0 90 Ⅱ，S 7 228 89 CML/Ph¹+ Yes NR 38 2 14 3.52 3 Ⅱ 3 247 165 CML/Ph¹+ Yes NR 3 2 27 2.43 － NR 104 1277 CML/Ph¹+ Yes CR 10 6 7－15 5.23 30 Ⅱ ＞18 UPN, unique patient number; MNC， mononuclear cells； GVHD， graft versus host disease； IP， interstitial pneumonia； S, system; CR, complete remission; PR, partly remission; NR, no response; APL, acute promyelocytic leukemia.

表2A组遗传学及中枢神经系统白血病复发患者输注供者白细胞治疗情况

Table 2Donor derived leukocyte (DDL) for cytogenetic or CNS relapse in group A UPN Relapse Chemotherapy Infusion of DDL Outcome t(post

-BMT）

／d Status Yes

(No) Result t(post-

relapse)

/d No. of

treatments t(interval)

/d