Late relapse in acute myeloid leukemia (AML): clonal evolution or therapy-related leukemia?

Abstract

Late relapse, defined as relapse arising after at least 5 years of remission, is rare and occurs in 1-3% of patients with acute myeloid leukemia (AML). The underlying mechanisms of late relapse remain poorly understood. We identified patients with AML who achieved remission with standard induction chemotherapy and relapsed after at least five years of remission (n = 15). Whole exome sequencing was performed in available bone marrow samples obtained at diagnosis (n = 10), remission (n = 6), and first relapse (n = 10). A total of 41 driver mutations were identified, of which 11 were primary tumor-specific, 17 relapse-specific, and 13 shared (detected both in primary and relapsed tumor samples). We demonstrated that 12 of 13 shared mutations were in epigenetic modifier and spliceosome genes. Longitudinal genomic characterization revealed that in eight of 10 patients the founder leukemic clone persisted after chemotherapy and established the basis of relapse years later. Understanding the mechanisms of such quiescence in leukemic cells may help designing future strategies aimed at increasing remission duration in patients with AML.

Fig. 1

Patient selection AML acute myeloid leukemia, CR complete remission, BM bone marrow

Fig. 2. Karyotype and driver mutations in 10 primary-relapse tumor pairs.

^¥UPN5 had two TET2 mutations; shared (c.3347delT:p.111 fs) and relapse-specific (c.C4609T:p.R1537X) [not shown in figure]. ^†UPN3 had two primary-specific ZRSR2 mutations; c.865delG:p.G289fs and c.1239delG:p.K413fs

Fig. 3. Karyotype and VAF of driver mutations in primary tumor (n = 10), remission (n = 6) and relapse (n = 10) tumors.

a The mutations detected in the primary and relapse tumor samples from eight patients (UPN1,5,6,7,9,10,12 and 14) with AML: the founding clone in the primary tumor gained relapse-specific mutations or cytogenetic abnormalities and evolved into a relapse clone. b The mutations detected in the primary and relapse tumor samples from two patients (UPN3 and 15) with AML: the founding clone detected at relapse was different from the founding clone at diagnosis (the relationship between mutations in the primary and relapse tumors are shown by lines linking them). Remisison bone marrow samples were available only for six patients VAF: variant allele frequency ^¥UPN5: *p.R1537X, ^†p.I1116fs ^µUPN3: *p.G289fs, ^†p.K413fs