Schwartz M A, Lovett D R, Redner A, Finn R D, Graham M C, Divgi C R, Dantis L, Gee T S, Andreeff M, Old L J
Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
J Clin Oncol. 1993 Feb;11(2):294-303. doi: 10.1200/JCO.1993.11.2.294.
Mouse monoclonal antibody (mAb) M195 (anti-CD33) is reactive with most myeloid leukemia cells, monocytes, and hematopoietic progenitors, but not with other hematopoietic cells or stem cells nor with nonhematopoietic human tissues. A therapeutic dose-escalation study of M195 labeled with iodine 131 was conducted in patients with relapsed or refractory myeloid leukemias.
Twenty-four patients (16 relapsed or refractory acute myeloid leukemias, five blastic myelodysplastic syndromes [MDS], two chemotherapy-related secondary leukemias, and one blastic chronic myelogenous leukemia [CML]), including seven who had failed to respond to prior bone marrow transplantation (BMT), received from 50 mCi/m2 to 210 mCi/m2 of 131I-M195 in divided doses.
In 22 patients, whole-body gamma-imaging demonstrated marked uptake of antibody into all areas of bone marrow. Twenty-three patients (96%) demonstrated decreases in peripheral-blood cell counts, with decreased percentage of bone marrow blasts seen in 83% of cases. Eighty-nine percent of bone marrow biopsies examined quantitatively demonstrated substantial decreases in the number of blasts, with greater than 99% of blasts killed in some patients. The two cases that failed to demonstrate leukemic cytoreduction occurred in the first two dose levels. For 131I doses of 135 mCi/m2 or greater, pancytopenia was profound and lasted for at least 12 days. Eight patients had sufficient marrow cytoreduction to proceed to BMT. Three of these achieved marrow remission, one of 6+, and one of 9 months' duration. Two patients in blastic phase temporarily reverted to their original myelodysplastic states. Thirty-seven percent of assessable patients developed human anti-mouse antibody (HAMA). In two patients with HAMA who were re-treated, plasma 131I-M195 levels could not be maintained and no therapeutic effect resulted. Significant nonhematologic toxicity (hepatic) was seen in one patient and the maximum-tolerated dose (MTD) was not reached.
These data suggest that safe leukemic cytoreduction can be achieved with 131I-M195 even in multiply relapsed or chemotherapy-refractory leukemias. This agent may be useful as part of a preparative regimen for BMT.
小鼠单克隆抗体（mAb）M195（抗CD33）可与大多数髓系白血病细胞、单核细胞及造血祖细胞发生反应，但不与其他造血细胞或干细胞以及非造血人体组织发生反应。对复发或难治性髓系白血病患者开展了一项用碘131标记的M195的治疗性剂量递增研究。
24例患者（16例复发或难治性急性髓系白血病、5例原始细胞增多型骨髓增生异常综合征[MDS]、2例化疗相关继发性白血病以及1例原始细胞增多型慢性粒细胞白血病[CML]），包括7例对既往骨髓移植（BMT）无反应者，接受了分剂量为50mCi/m²至210mCi/m²的131I-M195。
22例患者的全身γ显像显示抗体在骨髓所有区域均有明显摄取。23例患者（96%）外周血细胞计数下降，83%的病例骨髓原始细胞百分比降低。89%经定量检查的骨髓活检显示原始细胞数量大幅减少，部分患者超过99%的原始细胞被杀死。在前两个剂量水平出现了2例未显示白血病细胞减少的情况。对于131I剂量为135mCi/m²或更高的患者全血细胞减少严重且持续至少12天。8例患者骨髓细胞减少程度足以进行BMT。其中3例实现骨髓缓解，1例缓解持续6个月以上，1例缓解持续9个月。2例处于原始细胞期的患者暂时恢复到原来的骨髓增生异常状态。37%可评估患者产生了人抗鼠抗体（HAMA）。2例HAMA患者再次治疗时，血浆131I-M195水平无法维持，未产生治疗效果。1例患者出现显著的非血液学毒性（肝脏毒性），未达到最大耐受剂量（MTD）。
这些数据表明，即使对于多次复发或化疗难治性白血病，131I-M195也可实现安全的白血病细胞减少。该药物作为BMT预处理方案的一部分可能有用。
