Analysis of Molecular Predictors of Response to 5-Azacitine Treatment in AML and MDS Patients Preemptively Treated for Molecular Relapse of Disease

• Published in: Blood 2014-12, Vol.124 (21), p.2384-2384
• Main Authors: Lilly, Meredith, Haack, Beatrice, Otto, Anne, Sockel, Katja, Middeke, Jan Moritz, Mütherig, Anke, Trautmann, Karolin, Bornhäuser, Martin, Ehninger, Gerhard, Platzbecker, Uwe, Thiede, Christian
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V124.21.2384.2384

Background: Relapse of disease remains the major cause of treatment failure in patients with acute myeloid leukemia (AML) or advanced myelodysplastic syndrome (MDS), even after allogeneic hematopoietic stem cell transplantation (HSCT). Treatment of relapsed AML or MDS is difficult, especially after HSCT, and long-term prognosis of patients suffering from relapse is dismal. One approach to overcome this problem is to use sensitive molecular diagnostic strategies to detect recurring disease already at the level of minimal residual disease (MRD), thus avoiding the development of overt hematologic relapse by treatment of patients at the stage of molecular relapse. We have recently implemented preemptive treatment with the demethylating drug 5-Azacitidine (AZA) in patients with molecular evidence of recurrent disease in a prospective Phase II study (RELAZA). In this study, 80% of the patients showed responses, with reduction of MRD and prolonged leukemia free survival, 20% of patients even showed molecular clearance of their leukemia and long-term disease free survival. More recently, results from several groups studying demethylating agents in MDS or AML suggested that patients with mutations in genes involved in epigenetic DNA-modification, such as TET2, DNMT3A or IDH1 or IDH2 might be more responsive to treatment with these drugs. Since we observed varying clinical response in the patients treated preemptively with AZA for molecular evidence of recurrent disease, we correlated the clinical response in these patients with the presence of mutations in epigenetic regulator genes in order to identify potential predictors of response. Patients and Methods: A cohort of 44 patients (23 f/21 m), median age 55.6 years (range 21-75 years), in hematological remission with AML (N=40) or MDS (N=4) were given AZA to treat molecular relapse defined by mutant NPM1 (N=23) or CD34+ chimerism (N=21). Patients were monitored post allogeneic HSCT (N=26) or standard chemotherapy (N=18). The cohort received a median of 5 cycles of AZA (ranging from 1-18 cycles). DNA taken at first diagnosis was analyzed using amplicon based resequencing on a MiSeq next generation sequencing system for the following genes, either analyzing the complete coding region (EZH1, EZH2, DNMT3A, TET1 and TET2) or hot-spot regions (ASXL1, ASXL2, IDH1, IDH2). First diagnosis samples were unavailable for 4 patients. In these, DNA from sorted CD34+ cells taken at the time of molecular relapse was used as a subs