Slavin S, Naparstek E, Nagler A, Ackerstein A, Kapelushnik J, Or R
Department of Bone Marrow Transplantation, Hadassah University Hospital, Jerusalem, Israel.
Exp Hematol. 1995 Dec;23(14):1553-62.
Allogeneic bone marrow transplantation (BMT) is the treatment of choice for hematologic malignancies resistant to conventional chemotherapy and for patients who are at high risk for relapse. Until recently, no cure could be offered to patients relapsing following allogeneic BMT. We present our long-term observations of the first patient with remission reinduced by allogeneic cell therapy (allo-CT) using donor peripheral blood lymphocytes (PBL). In addition, we review the cumulative international experience with allo-CT used to treat 163 patients, 105 with CML and 58 with other hematologic diseases, who relapsed following allogeneic BMT. The first patient treated by allo-CT was diagnosed with acute resistant pre-B lymphoblastic leukemia (ALL) in extensive third hematologic and extramedullary relapse shortly after BMT. He was given infusions of donor (sister) PBL in multiple increments. Subsequently, he developed mild, reversible graft-vs-host disease (GVHD) in parallel with regression of all hematologic and cytogenetic disease manifestations. More than 8 years after allo-CT, he is disease-free with Karnofsky score 100% and no evidence of residual male cells by PCR. International data show that relapse after BMT was successfully reversed by donor PBL treatment in 97 of 158 evaluable patients; 72/100 (72%) with chronic myeloid leukemia (CML) and 25/58 (44.8%) with other malignant hematologic diseases including acute leukemia, lymphoma, and myelodysplastic syndrome. T cell depletion (TCD) for prevention of GVHD was performed for 60/105 (57%) patients with CML and 31/58 (53.4%) patients with other hematologic malignancies. Complete response after allo-CT was obtained in recipients of both TCD-BMT and unmodified BMT. GVHD due to allo-CT developed in 86/158 (54.4%) of the patients, 63/100 (63.0%) with CML and 23/58 (39.6%) with other hematologic diseases. alpha-interferon (IFN-alpha) was given to 67.9% of patients with CML and 28.1% of patients with other diseases. The cumulative experience shows that allo-CT can successfully reverse chemoradiotherapy-resistant relapse of acute leukemia and even more effectively of chronic leukemia independently of alpha-interferon therapy. Although GVHD was frequent among responders, accompanied occasionally by transient or irreversible marrow aplasia, remissions were also obtained in patients with no GVHD. Allo-CT should therefore be considered as treatment of choice for overt relapse or de novo minimal residual disease post-BMT. Administration of donor peripheral blood lymphocytes in graded increments at an early stage of relapse may be the best approach for combining optimal timing at the stage of minimal disease while controlling and minimizing the risk of GVHD on an individual basis.
异基因骨髓移植（BMT）是治疗对传统化疗耐药的血液系统恶性肿瘤以及复发风险高的患者的首选方法。直到最近，对于异基因BMT后复发的患者仍无法治愈。我们报告了首例使用供体外周血淋巴细胞（PBL）进行异基因细胞治疗（allo-CT）诱导缓解的患者的长期观察结果。此外，我们回顾了国际上使用allo-CT治疗163例异基因BMT后复发患者的累积经验，其中105例为慢性粒细胞白血病（CML），58例为其他血液系统疾病。首例接受allo-CT治疗的患者在BMT后不久被诊断为急性耐药前B淋巴细胞白血病（ALL），处于广泛的第三次血液学和髓外复发期。他多次接受供体（姐姐）PBL输注。随后，他出现了轻度、可逆的移植物抗宿主病（GVHD），同时所有血液学和细胞遗传学疾病表现均消退。allo-CT治疗8年多后，他无病生存，卡诺夫斯基评分100%，PCR检测无残留男性细胞证据。国际数据显示，158例可评估患者中有97例通过供体PBL治疗成功逆转了BMT后的复发；100例慢性粒细胞白血病（CML）患者中有72例（72%），58例其他恶性血液系统疾病（包括急性白血病、淋巴瘤和骨髓增生异常综合征）患者中有25例（44.8%）。60/105（57%）的CML患者和31/58（53.4%）的其他血液系统恶性肿瘤患者进行了T细胞清除（TCD）以预防GVHD。TCD-BMT和未改良BMT的受者均在allo-CT后获得了完全缓解。86/158（54.4%）的患者发生了allo-CT相关的GVHD，100例CML患者中有63例（63.0%），58例其他血液系统疾病患者中有23例（39.6%）。67.9%的CML患者和28.1%的其他疾病患者接受了α干扰素（IFN-α）治疗。累积经验表明，allo-CT可成功逆转急性白血病对放化疗耐药的复发，对慢性白血病甚至更有效，且与α干扰素治疗无关。尽管GVHD在缓解者中很常见，偶尔伴有短暂或不可逆的骨髓再生障碍，但无GVHD的患者也获得了缓解。因此，allo-CT应被视为BMT后明显复发或初发微小残留病的首选治疗方法。在复发早期按分级增量给予供体外周血淋巴细胞可能是在疾病微小阶段结合最佳时机，同时根据个体情况控制和最小化GVHD风险的最佳方法。
