r and major clones during the early phases of chemotherapy. This might result in a higher reliability to predict the relapse risk and might contribute to identify those patients who might benefit from an early allogeneic HSCT. 4. T Lineage Acute Lymphoblastic Leukemia Clonal cytogenetic anomalies are detectable in 50 70% of all cases of T cell ALL. Reciprocal translocations ZM-447439 Aurora Kinase inhibitor usually involve the T cell receptor genetic loci, TCRA and TCRD, TCRB, or TCRG. The partner genetic loci reported are usually transcription factors particularly HOX11, HOX11L2, others include the MYC or TAL1 genes. Other fusion genes are, for example, CALM AF10 or NUP214 ABL1. For molecular MRD measurement, suitable fusion transcripts are available for only 10 20% of T ALL patients.
If appropriate targets are available, quantitative real time PCR can achieve sensitivity of 10�? to 10�?. In the alternative, clone specific TCR rearrangements of the leukemic T cells could equally serve for MRD monitoring in remission with comparable sensitivity. However, amplification of clonespecific TCR rearrangements is highly laborious as patienttailored assays are required. Furthermore, BMS-582664 FGFR inhibitor molecular clonal evolution can lead to false negative results. 4.1. Therapeutic Strategies in T Lineage ALL. Although current treatment protocols result in complete remission in 80 90% of adults with newly diagnosed T cell acute lymphoblastic leukemia or lymphoblastic lymphoma, approximately half of these patients relapse within the first two years. The prodrug nelarabine is demethylated by adenosine deaminase to a deoxyguanosine derivative.
DeAngelo et al. administered nelarabine to 26 patients with T ALL and 13 with T LBL who were refractory to at least one multiagent regimen or had relapsed. Cycles were repeated every three weeks. The complete remission rate was 31%, and the 1 year overall survival was 28%. The overall tolerability was acceptable. Due to the clear antitumor activity in relapsed/refractory T ALL/T LBL, the compound has been approved by the FDA for patients who failed at least in two prior regimens. In comparison to B lineage ALL, it is more difficult to clarify the prognostic meaning of karyotypes in T lineage ALL due to the lower incidence. Normal karyotypes and the t/HOX11 TCR were shown to be associated with good outcomes in pediatric T ALL. 4.2. Indication for Allogeneic HSCT in T Lineage ALL.
The use of conventional ALL chemotherapy for T cell ALL has been associated with inferior outcomes compared to B cell ALL, and thus most T cell ALL were considered high risk. However, there have been suggestions of improved outcomes with more aggressive use of antimetabolite therapy in T ALL subgroups, largely because these lymphoblasts accumulate methotrexate polyglutamates less avidly than blasts of other subtypes. In the pediatric setting, Schrappe et al. had indeed shown clinically that high dose methotrexate is associated with improved outcomes in T cell ALL. Advances in Hematology 5 Similarly, Pui et al. used increased doses of methotrexate in the 76 pediatric patients diagnosed with T ALL and also achieved improved outcomes, with estimated 10 year survival rate of 90%. The indication for allogeneic stem cell transplantation in the first remission of T lineage ALL is based on the individual risk profiles defined, for example, by the immunophenotype. Thymic T ALL is considered to repr