Elemination of the preleukemic clone in children with Down syndrome and transient myeloproliferative disorder (TMD) to prevent AML - Model of Leukemia prevention

综上所述，“消除唐氏综合征和短暂性骨髓增生性疾病（TMD）儿童的白血病前克隆以预防AML -白血病预防模型”的研究招募符合预期。此外，不合格儿童的估计数量被证明是正确的（30%）。因此，如预计的那样，需要再进行2.5年的招募，以达到计划的合格患者数量。与来自荷兰、捷克共和国和斯洛伐克的研究小组合作，最终的可分析患者总数甚至可能更高。在80% - 90%的TL患者中，我们已经证明了前瞻性鉴定GATA1突变的可行性。我们证实了GATA1基因外显子2和3上编码的突变的可变性。我们进一步证明，通过免疫表型和定量PCR对特异性GATA1突变进行MRD监测在大多数患者中是可行的。现在推测主要假设还为时过早，然而，到目前为止，所有因素都表明主要目标是可以实现的。无论临床试验的最终结果如何，我们今天已经可以说，仅仅通过这项研究的启动（提高了全国和国际儿童血液肿瘤学单位和新生儿病房的认识），越来越多的差异化参考诊断的表现以及24小时咨询服务的建立，21三体和TL儿童的预后正在不断改善。几个意想不到的情况大大增加了研究的努力和成本：地方伦理委员会费用相对较高。非常高的行政管理能力（与中心/伦理委员会的沟通）即使在低细胞计数患者中也能检测到GATA1突变的复杂算法4。GATA1基因2/3外显子内的可变突变需要在几乎所有患者中设计特异性探针。

In summary, the study “Elimination of the preleukemic clone in children with Down syndrome and transient myeloproliferative disorder (TMD) to prevent AML - Model of leukemia prevention” recruited as expected. Furthermore, the estimated number of ineligible children proved true (30%). Thus, another 2.5 years of recruitment, as projected, will be necessary to achieve the planned number of eligible patients. In cooperation with the groups from the Netherlands, Czech Republic and Slovakia, the final total number of analyzable patients might even be higher. In 80 to 90% of our cohort with TL, we have already proven the feasibility to identify prospectively a GATA1 mutation. We confirmed the variability of mutations encoded on exon 2 and 3 of the GATA1 gene. We further demonstrated that MRD monitoring by immunophenotyping and quantitative PCR of the specific GATA1 mutation is feasible in most patients. It is much too early to speculate about the primary hypothesis, however, so far, all factors suggest that the main objectives are achievable. Irrespective of the final results of the clinical trial, we can already say today that the prognosis of children with trisomy 21 and TL is improving continuously just by the initiation of this study ( increasing awareness raising in the nationwide and international pediatric hematology-oncology units and newborn wards), the performance of more and more differentiated reference diagnostics and the establishment of a round-the-clock consulting service. Several unexpected circumstances have increased the efforts and costs of the study substantially:1. Relative high fees of the local ethic committees2. Very high administrative efforts (communication with centers/ethic committees)3. Sophisticated algorithm to detect GATA1 mutations even in patients with low blast counts4. Variable mutations within exon 2/3 of the GATA1 gene  need to design specific probes in almost all patients.