Brisco M J, Condon J, Hughes E, Neoh S H, Sykes P J, Seshadri R, Toogood I, Waters K, Tauro G, Ekert H
Flinders Medical Centre, Bedford Park, South Australia.
Lancet. 1994 Jan 22;343(8891):196-200. doi: 10.1016/s0140-6736(94)90988-1.
Methods to detect and quantify minimal residual disease (MRD) after chemotherapy for acute lymphoblastic leukaemia (ALL) could improve treatment by identifying patients who need more or less intensive therapy. We have used a clone-specific polymerase chain reaction to detect rearranged immunoglobulin heavy-chain gene from the leukaemic clone, and quantified the clone by limiting dilution analysis. MRD was successfully quantified, by extracting DNA from marrow slides, from 88 of 181 children with ALL, who had total leucocyte counts below 100 x 10(9)/L at presentation and were enrolled in two clinical trials, in 1980-84 and 1985-89. Leukaemia was detected in the first remission marrow of 38 patients, in amounts between 6.7 x 10(-2) and 9.9 x 10(-7) cells; 26 of these patients relapsed. Of 50 patients with no MRD detected, despite study of 522-496,000 genomes, only 6 relapsed. The association between MRD detection and outcome was significant for patients in each trial. In the first trial, patients relapsed at all levels of detected MRD, whereas in the later trial, in which treatment was more intensive and results were better, the extent of MRD was closely related to the probability of relapse (5 of 5 patients with > 10(-3) MRD, 4 of 10 with 10(-3) to 2 x 10(-5), 0 of 3 with levels below 2 x 10(-5), and 2 of 26 with no MRD detected). Early quantification of leukaemic cells after chemotherapy may be a successful strategy for predicting outcome and hence individualizing treatment in childhood ALL, because the results indicate both in-vivo drug sensitivity of the leukaemia and the number of leukaemic cells that remain to be killed by post-induction therapy.
检测和定量急性淋巴细胞白血病（ALL）化疗后的微小残留病（MRD）的方法，可通过识别需要更强化或较弱治疗的患者来改善治疗。我们使用了克隆特异性聚合酶链反应来检测白血病克隆中重排的免疫球蛋白重链基因，并通过有限稀释分析对克隆进行定量。通过从骨髓涂片提取DNA，成功地对181例ALL患儿中的88例进行了MRD定量，这些患儿在1980 - 1984年和1985 - 1989年参加了两项临床试验，初诊时白细胞总数低于100×10⁹/L。在38例患者的首次缓解期骨髓中检测到白血病，数量在6.7×10⁻²至9.9×10⁻⁷个细胞之间；其中26例患者复发。在50例未检测到MRD的患者中，尽管研究了522 - 496000个基因组，只有6例复发。在每个试验中，MRD检测与预后之间的关联都很显著。在第一个试验中，所有检测到MRD水平的患者都复发了，而在后来治疗更强化且结果更好的试验中，MRD的程度与复发概率密切相关（MRD>10⁻³的5例患者中有5例复发，10⁻³至2×10⁻⁵的10例患者中有4例复发，低于2×10⁻⁵水平的3例患者中无复发，未检测到MRD的26例患者中有2例复发）。化疗后白血病细胞的早期定量可能是预测儿童ALL预后并因此实现个体化治疗的成功策略，因为结果既表明了白血病的体内药物敏感性，也表明了诱导后治疗仍需杀死的白血病细胞数量。
