Soiffer R J, Mauch P, Fairclough D, Alyea E, Anderson K, Fisher D, Freedman A, Bartlett-Pandite L, Robertson M, Schlossman R, Gollob J, Marcus K, Murray C, Kuhlman C, Freeman A, Nadler L, Ritz J
Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Biol Blood Marrow Transplant. 1997 Apr;3(1):11-7.
The widespread use of allogeneic bone marrow transplantation (BMT) is limited by the availability of suitable donors. Recent attempts to expand the donor pool by employing HLA matched unrelated marrow have been partially successful. However, severe graft-versus-host disease (GVHD) and graft failure remain obstacles and contribute to the substantial morbidity and mortality associated with matched unrelated BMT. The use of genotypically nonidentical related or unrelated donor marrow could have wider application if problems associated with GVHD could be overcome. Based upon the low incidence of GVHD in recipients of HLA-matched related donor marrow depleted of T cells with T12, an anti-CD6 monoclonal antibody, we applied this approach to 27 adult recipients of HLA mismatched related bone marrow. Ten patients received marrow mismatched at 2 HLA loci, 13 received 1 antigen mismatched marrow, and 4 received phenotypically identical marrow from a non-sibling. Immediately prior to admission, patients were treated with total lymphoid irradiation (750-1050 cGy) to suppress host derived. T lymphocytes capable of mediating graft rejection. The ablative regimen consisted of cyclophosphamide (60 mg/kg x 2 days) followed by total body irradiation (1400 cGy in 7 fractions over 4 days). Patients then received marrow depleted of T cells with T12 (CD6) plus complement. No immune suppressive medications were administered to prevent GVHD. Twenty-four of 27 patients displayed stable hematologic engraftment, achieving an absolute neutrophil count of 0.5 x 10(9)/L at a median of 19 days post-BMT. Degree of HLA disparity did not influence engraftment. Among engrafting patients, grades 2-4 acute GVHD occurred in 40% and grade 3-4 GVHD in 8%. Chronic GVHD developed in 5 patients. Patients mismatched at 2 loci were more likely to develop GVHD than those mismatched at 0-1 loci (logrank, p = .04). Disease relapse has occurred in only 3 patients receiving mismatched marrow. Estimated overall survival for mismatched patients is 56% at 2 years and is independent of HLA disparity. Among the patients transplanted for chronic myelogenous in stable phase or acute leukemia in first remission, estimated event free survival is 69% at 2 years compared to 20% for patients with more advanced disease. Our results suggest that transplantation of mismatched related marrow using modalities designed to reduce GVHD without immune suppressive medication (CD6 depletion) is feasible and should prompt wider investigation into the extended families of patients in the search for potential marrow donors. This approach also merits investigation in recipients of matched unrelated marrow as a potential means of reducing transplant-related toxicity.
同种异体骨髓移植（BMT）的广泛应用受到合适供体可用性的限制。最近通过使用人类白细胞抗原（HLA）匹配的无关骨髓来扩大供体库的尝试取得了部分成功。然而，严重的移植物抗宿主病（GVHD）和移植物失败仍然是障碍，并导致与匹配无关BMT相关的高发病率和死亡率。如果与GVHD相关的问题能够得到克服，使用基因上不相同的相关或无关供体骨髓可能会有更广泛的应用。基于用抗CD6单克隆抗体T12去除T细胞的HLA匹配相关供体骨髓受者中GVHD的低发生率，我们将这种方法应用于27名HLA不匹配的成年相关骨髓受者。10名患者接受了2个HLA位点不匹配的骨髓，13名接受了1个抗原不匹配的骨髓，4名接受了来自非同胞的表型相同的骨髓。在入院前即刻，患者接受全身淋巴照射（750 - 1050 cGy）以抑制宿主来源的、能够介导移植物排斥的T淋巴细胞。预处理方案包括环磷酰胺（60 mg/kg×2天），随后进行全身照射（4天内分7次给予1400 cGy）。然后患者接受用T12（CD6）加补体去除T细胞的骨髓。未给予免疫抑制药物来预防GVHD。27名患者中有24名显示出稳定的血液学植入，在BMT后中位数为19天时绝对中性粒细胞计数达到0.5×10⁹/L。HLA不相合程度不影响植入。在植入的患者中，2 - 4级急性GVHD发生率为40%，3 - 4级GVHD发生率为8%。5名患者发生了慢性GVHD。2个位点不匹配的患者比0 - 1个位点不匹配的患者更易发生GVHD（对数秩检验，p = 0.04）。仅3名接受不匹配骨髓的患者发生了疾病复发。不匹配患者2年的估计总生存率为56%，且与HLA不相合无关。在移植处于稳定期的慢性粒细胞性白血病或首次缓解期急性白血病的患者中，2年的估计无事件生存率为69%，而病情更晚期的患者为20%。我们的结果表明，使用旨在减少GVHD而不使用免疫抑制药物（CD6去除）的方式移植不匹配的相关骨髓是可行的，并且应该促使对患者的扩展家族进行更广泛的调查以寻找潜在的骨髓供体。这种方法作为减少移植相关毒性的一种潜在手段，在匹配无关骨髓受者中也值得研究。
