esent standard risk leukemia, whereas early and mature T ALL confers high risk. Other than that, nonresponse to induction and consolidation regimens or increase of the MRD load during the course of disease can GDC-0879 Raf inhibitor be indications to allogeneic transplantation. 5.Monitoring of theMinimal Residual Disease Load After patients achieve complete remission following either chemotherapy or HSCT, the MRD load should be serially assessed. It is thus desirable to identify a sufficiently specific leukemia specific marker before therapy, such as the BCR ABL1 fusion. The preferred MRD technique depends on the desired level of sensitivity or the depth of remission. Cytogenetics has a sensitivity of 10? cells. Interphase fluorescence in situ hybridization allows to evaluate 100 200 cells.
Immunophenotyping Brivanib alaninate FGFR inhibitor using multi parameter flow cytometry achieves sensitivity levels of 10? to 10?. Real time PCR is particularly useful, as it can achieve a sensitivity of 10? to 10?. Additionally, molecular techniques can be used to access MRD in ALL even in the absence of fusion genes, by assessing the levels of clonespecific rearrangements of the immunoglobulin or T cell receptor and have been introduced into treatment stratification already. In a study from the German Multicenter Study Group for Adult Acute Lymphoblastic Leukemia, a total of 196 patients with standard risk ALL were investigated at repeated time points in the first year by quantitative PCR monitoring of clonal immunoglobulin or TCR rearrangements. Three risk groups could be defined.
Patients with a rapid decline of the MRD load to 10? or below detection limit in the early treatment period were classified as low risk and had a threeyear relapse rate of 0%. Patients with an MRD of 10? until week 16 formed the high risk group with a 3 year relapse rate of 94%. The remaining patients had an intermediate risk. In another study from the GMALL, postconsolidation samples of 105 patients with standard risk ALL were investigated by real time quantitative PCR for clonal immune gene rearrangements. All patients were beyond the first year of chemotherapy, in hematological remission, and were MRD negative before study entry. The relapse rate was 61% in patients converting to MRD positivity thereafter, whereas only 6% of continuously MRD negative patients relapsed.
Expert panels have already suggested recommendations on the minimal technical requirements before implementation of MRD diagnostics into clinical trials and have standardized criteria for complete MRD response, MRD persistence, and MRD reappearance. These steps facilitate the comparison of MRD results between different treatment protocols. The determination of B cell specific donor chimerism may facilitate monitoring and therapeutic decisions in patients with B lineage ALL in the posttransplant period. 6. Conclusion In recent years, molecular diagnostics in the acute lymphoblastic leukemia have progressed rapidly. PCR based analyses in combination with other approaches have allowed us to define various distinct ALL subtypes, part of which already defines separate entities within the WHO classification of 2008, for example, the t/BCR ABL1 or the t/ETV6 RUNX1. Deeper insights into the networks of molecular markers have facilitated the understanding of the heterogeneity of the clinical courses within distinct genetic subgroups and improved therapeutic deci