Treatment-related myeloid neoplasms (t-MN), including t-myelodysplastic syndromes (t-MDS) and t-acute myeloid leukemia (t-AML), are a rare but feared complication in patients who previously received chemotherapy and/or radiation for the treatment of a primary cancer; the risk varies by primary disease as well as the therapies used.1 Multiple myeloma is a chronic hematologic malignancy for which patients, throughout their lifetime, can receive multiple treatments along with high-dose therapy and autologous hematopoietic stem cell transplantation (aHSCT). As such, MDS-associated cytogenetic abnormalities as well as clinical presentations of t-MDS and t-AML have relatively high rates reported in patients with myeloma.2 As these secondary malignancies are most often associated with an unfavorable prognosis, it is valuable to identify risk factors and predispositions that can lead to their development. Information about clonal hematopoiesis of indeterminate potential (CHIP; defined by the presence of somatic mutations in the blood in the absence of cytopenia or overt hematologic malignancy3 ), which may already present at the time of primary therapy, informs our thoughts about future risk in these patients.4 Additionally, it is important to note where the cell populations that may harbor the CHIP mutations may fall in the hematopoietic lineage, as subclones, or in stem or progenitor cells.5
In the current study, Dr. Ashwin Sridharan and colleagues sought to identity whether stem and progenitor cells were the reservoirs of the myeloid mutations that were ultimately seen in the t-MN developed by myeloma patients. Six myeloma patients who developed t-MN after aHSCT from a single institution had stem cells, identified by CD34 positivity, available from pretransplant harvest. The mean time to t-MN in this small group was five years (range, 3 months to >10 years). The group used established and rigorous cell sorting methodology to separate phenotypically normal and abnormal stem cells. Sorted cell populations were used for DNA isolation for targeted sequencing of known genes in t-MN. All six patients had the identical driver mutation (TP53 or RUNX1) observed in the t-MN samples. These mutations were detected in stem or progenitor cells collected at the time of myeloma treatment. The resultant data suggest that aberrant phenotypic leukemia stems can be detected years before the clinical onset of t-MN. Unsurprisingly, the stem and progenitor cells likely act as reservoirs of these mutant subclones, harboring the CHIP that ultimately may become the later t-MN. Additionally, the authors observed phenotypic aberrant stem cells with expression of leukemia stem cell markers including CD123 positivity. Previous reports have also demonstrated that CD123+ populations are associated with higher risk of MDS and AML.6
In Brief
Currently in the field of hematology/oncology, there is an explosion of data based on our ability to do sophisticated sorting of cell populations as well as next-generation sequencing/molecular testing of peripheral blood or bone marrow, as elegantly demonstrated in this article. These tests have the ability to detect mutations in individuals without morphologic or cytogenetic evidence of MN. Certainly, t-MN represent a unique clinical scenario in which chemotherapy or radiation may select for a mutant hematopoietic stem cell clone, increasing the risk that this clone will acquire additional mutations and progress to malignancy.7 As shown here in myeloma, similar reports have also shown that individuals with CHIP who are treated for solid tumors have an elevated risk of t-MN and increased overall mortality,8,9 and that mutations in TP53 gain a selective advantage in response to radiation or chemotherapy.7 The novelty of this report is the localization of the mutant population to those cells with the leukemia stem cell phenotype.
Some could make the rational argument that this additional genetic information just “incites panic” in patients and providers alike, without the currently available tools to change therapy for the present disease or a future potential diagnosis. However, much of what we do in hematology/oncology (and medicine globally) is about managing expectations. Increasingly, we are going to have the capacity to sort cells and monitor certain populations to ensure we can make t-MN diagnoses earlier to enable selective therapies. Future studies, based on the biology described here, may also test aberrant CD123 expression on stem cells and whether this presence could be a potential biomarker for future development of t-MN. Therapeutic avenues that target this population may ultimately be feasible.
In summary, the capacity for understanding the biology of t-MN is ever increasing. Our patients will benefit from monitoring and management algorithms10 for longitudinal follow up after initial therapies and further studies will refine these, based on scientific advances. Thereafter, we can look forward to additional therapeutics for our patients.
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Competing Interests
Dr. DeZern indicated no relevant conflicts of interest.
