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

消除唐氏综合症和短暂性骨髓增生性疾病 (TMD) 儿童的白血病前期克隆以预防 AML - 白血病预防模型

• 批准号: 34181068
• 负责人: Professor Dr. Dirk Reinhardt
• 金额: --
• 依托单位: Klinik für Kinderheilkunde III
• 依托单位国家: 德国
• 项目类别: Clinical Trials
• 财政年份: 2007
• 资助国家: 德国
• 起止时间: 2006-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/34181068?language=en
• 关键词: Elemination; preleukemic; clone; children; Down

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.

总之，研究“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”招募符合预期。此外，不合格儿童的估计数字被证明是正确的（30%）。因此，按照预测，还需要再招募2.5年才能达到计划的合格患者数量。与荷兰、捷克共和国和斯洛伐克的研究小组合作，最终可分析的患者总数甚至可能更高。在我们80%至90%的TL队列中，我们已经证明了前瞻性识别GATA 1突变的可行性。我们证实了GATA 1基因外显子2和3上编码的突变的变异性。我们进一步证明，MRD监测免疫表型和定量PCR的特定GATA 1突变是可行的，在大多数患者。现在推测主要假设还为时过早，但到目前为止，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，21三体综合征和TL儿童的预后正在不断改善，仅仅是因为这项研究的启动（在全国和国际儿科血液肿瘤科和新生儿病房提高认识），越来越多的差异化参考诊断的表现以及全天候咨询服务的建立。几个意想不到的情况大大增加了研究的努力和成本：1。地方伦理委员会收费相对较高。非常高的行政工作（与中心/伦理委员会的沟通）3。复杂的算法检测GATA 1突变，即使在低原始细胞计数的患者4。GATA 1基因第2/3外显子的可变突变几乎在所有患者中都需要设计特异性探针。

项目成果

A 15q24 microdeletion in transient myeloproliferative disease (TMD) and acute megakaryoblastic leukaemia (AMKL) implicates PML and SUMO3 in the leukaemogenesis of TMD/AMKL

• DOI: 10.1111/j.1365-2141.2012.09028.x
• 发表时间: 2012-04
• 期刊: British Journal of Haematology
• 影响因子: 6.5
• 作者: Susanne Haemmerling;W. Behnisch;T. Doerks;J. Korbel;P. Bork;U. Moog;S. Hentze;U. Grasshoff;M. Bonin;O. Riess;J. W. Janssen;A. Jauch;C. Bartram;D. Reinhardt;Karin Koch;O. Bandapalli;A. Kulozik

Acute leukemias in children with Down syndrome.

唐氏综合症儿童急性白血病

• DOI: 10.1016/j.pcl.2007.11.001
• 发表时间: 2008
• 期刊: Pediatric clinics of North America
• 影响因子: 2.6
• 作者: Zwaan MC;Reinhardt D;Hitzler J;Vyas P
• 通讯作者: Vyas P

Normal karyotype is a poor prognostic factor in myeloid leukemia of Down syndrome: a retrospective, international study

• DOI: 10.3324/haematol.2013.089425
• 发表时间: 2014-02-01
• 期刊: HAEMATOLOGICA
• 影响因子: 10.1
• 作者: Blink, Marjolein;Zimmermann, Martin;Zwaan, C. Michel
• 通讯作者: Zwaan, C. Michel