Seeger K, Kreuzer K A, Lass U, Taube T, Buchwald D, Eckert C, Körner G, Schmidt C A, Henze G
Department of Pediatric Oncology/Hematology, Otto-Heubner-Centrum Berlin, Germany.
Cancer Res. 2001 Mar 15;61(6):2517-22.
Although TEL-AML1 positivity [translocation t(12;21)(p13;q22)], detected in 20-25% of initial childhood acute lymphoblastic leukemia (ALL), has been associated with an excellent prognosis, its positive predictive value is insufficient for appropriate treatment stratification considering reported prevalence in relapsed ALL (3-28%). Molecular quantification of response to therapy by PCR-based methods has been shown to improve risk assessment. Here, we report on the sensitive quantification of leukemia-specific TEL-AML1 fusion transcript levels normalized to beta-actin expression (sensitivity threshholds, 10(-5)) by a novel real-time reverse transcription-PCR (RQ-RT-PCR) based on fluorescent TaqMan technique providing early and rapid evidence on the treatment efficacy of children with initial or relapsed TEL-AML1+ ALL enrolled in frontline or relapse trials of the Berlin-Frankfurt-Münster (BFM)-Study Group. In initial ALL, TEL-AML1/beta-actin decrease was > or =10(5)-fold in 50% of patients after induction therapy (day 33) and stayed TEL-AML1-negative throughout therapy, which suggested high sensitivity of leukemic cells to antineoplastic therapy. The remaining patients were still TEL-AML1+ before reintensification (ratios, 0.7 x 10(-2):10(-4)). In relapsed ALL, TEL-AML1/beta-actin decrease was generally less pronounced at corresponding time points, and conversion to TEL-AML1 negativity was observed in 40% of patients. Most notably, subsequent relapses occurred only among molecular poor responders, whereas all early responders remain in their second complete remission. In conclusion, real-time quantification of TEL-AML1/beta-actin kinetics distinguishes distinct molecular response groups, and provides indications capable of directing therapeutic interventions for patients with TEL-AML1+ ALL. Before considering modification of therapy, results should be interpreted cautiously taking into account the long duration of remission associated with TEL-AML1+ ALL.
虽然在20%-25%的儿童初发急性淋巴细胞白血病（ALL）中检测到的TEL-AML1阳性[易位t(12;21)(p13;q22)]与良好的预后相关，但其阳性预测值对于考虑到复发ALL中报道的患病率（3%-28%）进行适当的治疗分层而言并不充分。已证明通过基于PCR的方法对治疗反应进行分子定量可改善风险评估。在此，我们报告了一种基于荧光TaqMan技术的新型实时逆转录PCR（RQ-RT-PCR）对白血病特异性TEL-AML1融合转录本水平相对于β-肌动蛋白表达进行敏感定量（灵敏度阈值为10^(-5)），该技术为参与柏林-法兰克福-明斯特（BFM）研究组一线或复发试验的初发或复发TEL-AML1+ ALL患儿的治疗效果提供了早期且快速的证据。在初发ALL中，50%的患者在诱导治疗后第33天TEL-AML1/β-肌动蛋白降低≥10^5倍，且在整个治疗过程中保持TEL-AML1阴性，这表明白血病细胞对抗肿瘤治疗具有高敏感性。其余患者在强化治疗前仍为TEL-AML1阳性（比率为0.7×10^(-2):10^(-4)）。在复发ALL中，在相应时间点TEL-AML1/β-肌动蛋白的降低通常不那么明显，40%的患者出现了TEL-AML1转阴。最值得注意的是，随后的复发仅发生在分子反应不佳的患者中，而所有早期反应者均保持第二次完全缓解。总之，TEL-AML1/β-肌动蛋白动力学的实时定量区分了不同的分子反应组，并为TEL-AML1+ ALL患者的治疗干预提供了指导依据。在考虑修改治疗方案之前，应谨慎解释结果，同时考虑到TEL-AML1+ ALL相关的缓解期较长。
