Identifying Inherited and Acquired Genetic Factors Involved in Poor Stem Cell Mobilization and Donor-Derived Malignancy

Abstract

Analysis of the clinical characteristics of hematopoietic stem cell transplant (HSCT) donors has proven beneficial for identifying cases of heritable hematopoietic disorders. This study examines poor peripheral blood hematopoietic stem cell mobilization after granulocyte colony–stimulating factor administration among 328 donors as a potential marker for suspected familial predisposition to myeloid malignancies. Here, we present data comparing the clinical characteristics of poor-mobilizing versus nonpoor-mobilizing donors and the results of panel-based sequencing of hematopoietic genes in poor-mobilizing donors. From this analysis, we identified a novel case of a donor-derived myelodysplastic syndrome in an HSCT recipient that is consistent with clonal evolution of TET2-mutated clonal hematopoiesis of indeterminate potential (CHIP) within the donor. This study demonstrates the potential risk of using hematopoietic stem cells from a donor with CHIP and raises the question of whether there should be increased screening measures to identify such donors.

Germline Genetic Predisposition to Hematologic Malignancy

“…A personal or family history of excessive toxicities with chemotherapy or radiation, including protracted or nonrecovering cytopenias, or a history of poor stem cell yield during mobilization may also hint at an underlying disorder. 11 A family history of first-or seconddegree relatives with malignancy-particularly cancers presenting at a young age-cytopenias, unexplained macrocytosis, congenital anomalies, or characteristic features associated with inherited cancer syndromes should also raise suspicion. Please refer to Table 2 for a list of major genetic syndromes associated with hematologic malignancies together with references for additional information.…”

Familial myelodysplastic syndrome/acute myeloid leukemia

“…Lastly, evaluation of allogeneic stem cell donors is also an important encounter for the detection of a hereditary MDS/AML syndrome. Specifically, unexplained cytopenias or failure to mobilize stem cells well in related donors of patients with MDS/AML require further evaluation [18, 19]. …”

How I diagnose and manage individuals at risk for inherited myeloid malignancies

“…Inadvertent use of HSCs from donors carrying an HMMS germ line mutation may result in poor engraftment and/or donor-derived MDS/AL. [26][27][28][29][30][31] Therefore, it is vital that all related and unrelated donors are screened for HMMSs. 41 Further evaluation of the potential donor and/or recipient is warranted if a donor notes a personal or family history suggestive of an HMMS, has unexplained cytopenias, or mobilizes peripheral blood HSCs poorly.…”

“…41 Further evaluation of the potential donor and/or recipient is warranted if a donor notes a personal or family history suggestive of an HMMS, has unexplained cytopenias, or mobilizes peripheral blood HSCs poorly. 31 Patients with an HMMS gene mutation identified in their leukemia cells. Molecular diagnostic testing is increasingly being used to analyze malignancies for mutations in genes, such as CEBPA, FLT3, and NPM1 in AML, to determine prognosis, guide clinical decision making, and inform therapeutic options.…”

“…Second, a genetic diagnosis can help avoid the use of hematopoietic stem cells (HSCs) from an asymptomatic HMMS mutation carrier. [26][27][28][29][30][31] Finally, routine clinical care now requires knowledge of HMMSs. For example, the National Comprehensive Cancer Network (NCCN) recommends surveillance for HMMSs in patients at high risk for Li-Fraumeni syndrome, 32 and clinicians ordering genetic testing of malignant cells (eg, CEBPA for AML prognosis) will encounter reports suggesting that an identified mutation may be germ line.…”