Clonal hematopoiesis predicts development of therapy-related myeloid neoplasms post–autologous stem cell transplantation

Abstract

Therapy-related myeloid neoplasms (tMN) develop after exposure to cytotoxic and radiation therapy, and due to their adverse prognosis, it is of paramount interest to identify patients at high risk. The presence of clonal hematopoiesis has been shown to increase the risk of developing tMN. The value of analyzing hematopoietic stem cells harvested at leukapheresis before autologous stem cell transplantation (ASCT) with next-generation sequencing and immunophenotyping represents potentially informative parameters that have yet to be discovered. We performed a nested case-control study to elucidate the association between clonal hematopoiesis, mobilization potential, and aberrant immunophenotype in leukapheresis products with the development of tMN after ASCT. A total of 36 patients with nonmyeloid disease who were diagnosed with tMN after treatment with ASCT were included as case subjects. Case subjects were identified from a cohort of 1130 patients treated with ASCT and matched with 36 control subjects who did not develop tMN after ASCT. Case subjects were significantly poorer mobilizers of CD34+ cells at leukapheresis (P = .016), indicating that these patients possess inferior bone marrow function. Both clonal hematopoiesis (odds ratio, 5.9; 95% confidence interval, 1.8-19.1; P = .003) and aberrant expression of CD7 (odds ratio, 6.6; 95% confidence interval, 1.6-26.2; P = .004) at the time of ASCT were associated with an increased risk of developing tMN after ASCT. In conclusion, clonal hematopoiesis, present at low variant allele frequencies, and aberrant CD7 expression on stem cells in leukapheresis products from patients with nonmyeloid hematologic cancer hold potential for the early identification of patients at high risk of developing tMN after ASCT.

Clonal hematopoiesis and its emerging effects on cellular therapies

“…More important, the presence of CH has been suggested to affect process-related results and to influence short-and long-term clinical outcome parameters. To this end, the presence of CH has been associated with inferior mobilization capacity [76,[80][81][82][83] and delayed engraftment [84], however, inferior mobilization is not a consistent finding [79,84].…”

“…The presence of CH in the autologous graft has in a few retrospective studies been linked to an increased risk for therapyrelated myeloid neoplasms (tMN) [78,80,83] and reduced overall survival (OS) [80,81], partly due to an increase in CVD [80]. Assuming that the detection of somatic mutations in the autologous graft simply reflects the presence of CH, the increase in myeloid neoplasms and CVD-associated mortality, when compared to non-CH patients, merely confirms the known risk profile.…”

Genetic and Genomic Landscape of Secondary and Therapy-Related Acute Myeloid Leukemia

“…It is also notable that TP53 and PPM1D mutations are among the more frequently mutated genes in patients with CHIP and both genes that are necessary for proper DNA repair. The detection of mutations in either of these genes in patients scheduled to receive cytotoxic chemotherapy may identify those patients at highest risk for chemo-refractory t-MN [ 111 , 113 , 114 ]. A summary of the acquired mutations implicated in pathogenesis of t-MN is available in Table 5 .…”

“…Immunophenotyping complements genotypic approach in predicting the risk of t-MN. For example, the presence of CH (5.9-fold) or an aberrant expression of CD7 (6.6-fold), predicted an increased risk of t-MN, while all the patients with both CH and aberrant CD7 expression developed t-MN [ 114 ].…”

Flow cytometry reveals the nuances of clonal haematopoiesis

“…At the current time, the significance of CH in the setting of AML in morphologic and molecular remission is controversial; the results of the Loghavi study suggest that CH in this setting is variable and that flow cytometry represents an additional tool to study its nuances and clinical implications. Recently, aberrant blast immunophenotype (CD7 expression) and CH were both found to confer increased risk of therapy‐related myeloid neoplasia in patients undergoing autologous cell transplantation, underscoring the complementary nature of genetics and immunophenotype in evaluating for abnormal haematopoiesis 5 . Further study with longer follow‐up and on broader AML cohorts is needed to determine if immunophenotypically abnormal CH in remission may identify patients at higher risk of long‐term relapse or other complications that can be associated with CH, such as cardiovascular disease.…”