Tracking the Evolution of Therapy-Related Myeloid Neoplasms Using Chemotherapy Signatures

Abstract

Patients treated with cytotoxic therapies, including autologous stem cell transplantation, are at risk for developing therapy-related myeloid neoplasms (tMN). Pre-leukemic clones (i.e., clonal hematopoiesis; CH) are detectable years before the development of these aggressive malignancies, though the genomic events leading to transformation and expansion are not well-defined. Here, leveraging distinctive chemotherapy-associated mutational signatures from whole-genome sequencing data and targeted sequencing of pre-chemotherapy samples, we reconstruct the evolutionary life-history of 39 therapy-related myeloid malignancies. A dichotomy is revealed, in which neoplasms with evidence of chemotherapy-induced mutagenesis from platinum and melphalan are hypermutated and enriched for complex structural variants (i.e., chromothripsis) while neoplasms with non-mutagenic chemotherapy exposures are genomically similar to de novo acute myeloid leukemia. Using chemotherapy-associated mutational signatures as temporal barcodes linked to a discrete clinical exposure in each patient's life, we estimate that several complex events and genomic drivers are acquired after chemotherapy is administered. For patients with prior multiple myeloma who were treated with high-dose melphalan and autologous stem cell transplantation, we demonstrate that tMN can develop from either a reinfused CH clone that escapes melphalan exposure and is selected following reinfusion, or from TP53-mutant CH that survives direct myeloablative conditioning and acquires melphalan-induced DNA-damage. Overall, we reveal a novel mode of tMN progression that is not reliant on direct mutagenesis or even exposure to chemotherapy. Conversely, for tMN that evolve under the influence of chemotherapy-induced mutagenesis, distinct chemotherapies not only select pre-existing CH, but also promote the acquisition of recurrent genomic drivers.

Isatuximab, Carfilzomib, Lenalidomide, and Dexamethasone for the Treatment of High-Risk Newly Diagnosed Multiple Myeloma

“…30 As we and others have shown that high rates of MRD negativity and sustained MRD negativity are achieved with extensive quadruplet treatment approaches, it is time to re-evaluate the role of high-dose melphalan, especially considering recent findings of significantly increased mutational burden and detrimental long-term effects of genomic damage. [32][33][34][35] In the near future, consequent implementation of T-cell engaging strategies in frontline treatment with CAR-T cell application replacing high-dose melphalan or use of bispecific antibodies in maintenance strategies will allow further treatment optimization and are expected to achieve unprecedented high MRD negativity and sustained MRD negativity rates. standard-of-care arm was ethically not justifiable.…”

Pathophysiology of Acute Myeloid Leukemia

“…Overall, t-MN has an increased rate of mutations compared to de novo AML due to chemotherapy-induced mutagenesis [92]. There is an increase in CN and structural variants, likely associated with chemotherapy-induced chromothripsis [92]. Antecedent CH, as has been seen in pre-therapy samples, may contribute to t-MN [92].…”

“…There is an increase in CN and structural variants, likely associated with chemotherapy-induced chromothripsis [92]. Antecedent CH, as has been seen in pre-therapy samples, may contribute to t-MN [92]. This has been demonstrated for patients undergoing treatment for lymphoma [93] or other non-myeloid disease using autologous stem cell transplant [94] and multiple myeloma [95].…”

Myeloid neoplasms post cytotoxic therapy: epidemiology, pathogenesis outcomes, prognostic factors, and treatment options

“…Benjamin et al. [ 17 ] revealed a novel mode of t-MN progression that is not reliant on direct mutagenesis or even exposure to chemotherapy. Conversely, for t-MN that evolve under the influence of chemotherapy-induced mutagenesis, distinct chemotherapies not only select preexisting CH but also promote the acquisition of recurrent genomic drivers.…”

“…With the development of sequencing technology, significant progress has been made in the pathogenesis, diagnoses and treatment of MN-pCT, early detection of DNA lesions is vital in occurrence of disease, so some authors recommend that primary malignancy may be treated with targeted therapy [ 17 ]. In the future, it is urgent to take further studies aiming at the relationship between tumor susceptibility gene mutations and the occurrence of MN-pCT after primary tumor treatment, the risk of developing MN-pCT.…”