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

• Applicant: Professor Dr. Dirk Reinhardt
• Subject Area: Pediatric and Adolescent Medicine
• Term: from 2007 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 34181068

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.

• DFG Programme: Clinical Trials