Early detection and evolution of preleukemic clones in therapy-related myeloid neoplasms following autologous SCT

Abstract

Therapy-related myeloid neoplasms (tMNs) are severe adverse events that can occur after treatment with autologous hematopoietic stem cell transplantation (ASCT). This study aimed to investigate the development of tMNs following ASCT at the molecular level by whole-exome sequencing (WES) and targeted deep sequencing (TDS) in sequential (pre-) tMN samples. WES identified a significantly higher number of mutations in tMNs as compared with de novo myelodysplastic syndrome (MDS) (median 27 vs 12 mutations; = .001). The mutations found in tMNs did not carry a clear aging-signature, unlike the mutations found in de novo MDS, indicating a different mutational mechanism. In some patients, tMN mutations were identified in both myeloid and T cells, suggesting that tMNs may originate from early hematopoietic stem cells (HSCs). However, the mutational spectra of tMNs and the preceding malignancies did not overlap, excluding common ancestry for these malignancies. By use of TDS, tMN mutations were identified at low variant allele frequencies (VAFs) in transplant material in 70% of the patients with tMNs. Reconstruction of clonal patterns based on VAFs revealed that premalignant clones can be present more than 7 years preceding a tMN diagnosis, a finding that was confirmed by immunohistochemistry on bone marrow biopsies. Our results indicate that tMN development after ASCT originates in HSCs bearing (pre-)tMN mutations that are present years before disease onset and that post-ASCT treatment can influence the selection of these clones. Early detection of premalignant clones and monitoring of their evolutionary trajectory may help to predict the development of tMNs and guide early intervention in the future.

Clonal hematopoiesis and preleukemia—Genetics, biology, and clinical implications

“…Conversely, in another report, CH mutations were found in the stem cell product in 7 of 10 patients who later developed t-MN. 80 Similar to the findings in CCUS described previously, autoSCT recipients with two or more mutations at the time of transplantation were at particularly high risk of developing t-MN. 79 Patients with CH also had a 1.5-fold increased risk of death from any cause, mostly due to t-MN and cardiovascular disorders.…”

PPM1D Mutations Drive Clonal Hematopoiesis in Response to Cytotoxic Chemotherapy

“…Indeed, deep sequencing before and after chemotherapy has shown that TP53 mutant cells can pre-exist at low frequencies in the bone marrow prior to chemotherapy and then rise in proportional contribution afterward, likely due to a selective advantage ( Wong et al., 2015 ). Yet, not all CH mutations detected in the blood prior to therapy subsequently evolve into a malignant clone ( Berger et al., 2018 , Gillis et al., 2017 , Takahashi et al., 2017 ). In fact, CH can be detected in 95% of healthy adults ( Young et al., 2016 ), yet most expanded clones do not evolve into leukemia (reviewed in Bowman et al., 2018 ).…”

Functional Dominance of CHIP-Mutated Hematopoietic Stem Cells in Patients Undergoing Autologous Transplantation

“…Reports investigated the presence of CHIP in the collected grafts of patients with lymphoid diseases undergoing ASCT (Gibson et al, 2017;Chitre et al, 2018) and showed reduced overall survival and a higher incidence of therapy-related myeloid neoplasms (t-MN) in patients carrying CHIP mutations in their pretransplant sample (Gibson et al, 2017). An analysis of the development of mutated clones by sequencing matched graft and post-transplantation samples was done either only in lymphoma patients who progressed into a t-MN (Gibson et al, 2017;Berger et al, 2018) or, in a single study, in 40 lymphoma patients in short-term follow-up of several months (Wong et al, 2018). In the latter study, most mutated clones remained stable in size after ASCT, and highly depending on the affected gene, only a small proportion increased in size (Wong et al, 2018).…”