Mutational analysis of disease relapse in patients allografted for acute myeloid leukemia

Abstract

Key Points• We identify genes prognostic of disease relapse in patients allografted for AML.• Mutational profiles often change at relapse postallograft, which may have implications for the design of posttransplant interventions.Disease relapse is the major cause of treatment failure after allogeneic stem cell transplantation (allo-SCT) in acute myeloid leukemia (AML). To identify AML-associated genes prognostic of AML relapse post-allo-SCT, we resequenced 35 genes in 113 adults at diagnosis, 49 of whom relapsed. Two hundred sixty-two mutations were detected in 102/113 (90%) patients.An increased risk of relapse was observed in patients with mutations in WT1 (P 5 .018), DNMT3A (P 5 .045), FLT3 ITD (P 5 .071), and TP53 (P 5 .06), whereas mutations in IDH1were associated with a reduced risk of disease relapse (P 5 .018). In 29 patients, we additionally compared mutational profiles in bone marrow at diagnosis and relapse to study changes in clonal structure at relapse. In 13/29 patients, mutational profiles altered at relapse. In 9 patients, mutations present at relapse were not detected at diagnosis. In 15 patients, additional available pre-allo-SCT samples demonstrated that mutations identified posttransplant but not at diagnosis were detectable immediately prior to transplant in 2 of 15 patients. Taken together, these observations, if confirmed in larger studies, have the potential to inform the design of novel strategies to reduce posttransplant relapse highlighting the potential importance of post-allo-SCT interventions with a broad antitumor specificity in contrast to targeted therapies based on mutational profile at diagnosis.

Outcome of Azacitidine Therapy in Acute Myeloid Leukemia Is not Improved by Concurrent Vorinostat Therapy but Is Predicted by a Diagnostic Molecular Signature

“…Sequencing was performed on an Illumina MiSeq with 300 bp paired-end reads, yielding an average read depth of 912 reads per amplicon. Fluorescent capillary electrophoresis was performed in addition to NGS for the detection of FLT3 internal tandem duplications (ITD), because the rate of detection of ITDs is $60% using NGS alone (18). Details of NGS methodology is provided within Supplementary Information (Supplementary Tables S1-S3).…”

Immune Escape after Hematopoietic Stem Cell Transplantation (HSCT): From Mechanisms to Novel Therapies

“…Most mutations involve genes whose products have a tumor suppressive (e.g., PTEN) or a proliferative (e.g., KRAS) function. Thanks to this proliferative advantage leukemic cells may outnumber the anti-tumor activity of T cells, thereby promoting immune escape by these newly mutated clones [71,72].…”

Selected biological issues affecting relapse after stem cell transplantation: role of T-cell impairment, NK cells and intrinsic tumor resistance

“…With the development of next-generation sequencing, investigators have reported that AML relapse occurring after chemotherapy often gains and loses subclones containing unique somatic variants, including putative driver mutations [87][88][89][90][91]. Recent studies investigating clonal evolution after HSCT relapses have focused on mutations in recurrently mutated AML genes, and while the presence of certain mutations can predict higher risk for relapse, the mechanisms by which these mutations may promote relapse remain unclear [92][93][94].…”