Low variant allele frequency (VAF) clonal hematopoiesis, aberrant CD7 expression on hematopoietic stem cells, and specific gene mutations at the time of autologous hematopoietic cell transplantation (AHCT) were predictive of post-transplant therapy-related myeloid neoplasms (tMN) in patients with nonmyeloid disease, according to a study published in Blood Advances. The authors, led by Johannes Frasez Soerensen, from Aarhus University in Denmark, wrote that these clinical variables may help identify patients who are at high risk for developing post-AHCT tMN at time of pretransplant leukapheresis.
This nested case-control study included 36 patients without myeloid disease who underwent AHCT (median age = 55 years; range = 29-69) at the Aarhus University Hospital between 1989 and 2016. Only patients who had a diagnosis of tMN after AHCT were included in the cases cohort. A control cohort consisting of 36 patients with nonmyeloid primary disease and no evidence of post-AHCT tMN (median age = 56.6 years; range = 35-67) was included as a comparison group. Both groups were matched 1:1 for age, sex, follow-up time, and conditioning regimen.
Prior to AHCT, mononuclear cells were harvested as part of leukapheresis, and flow cytometry was performed. In addition, targeted next-generation sequencing (NGS) was performed with a 30-gene panel to identify the presence of clonal hematopoiesis in cases and controls.
In the cases cohort, the numbers of patients diagnosed with therapy-related acute myeloid leukemia, myelodysplastic syndromes, and unclassifiable myeloproliferative neoplasms were 10, 25, and 1, respectively. Conditioning regimens in each group included either an alkylating agent or topoisomerase II inhibitor or both. There was no difference between cases and controls regarding the proportion of patients treated with post-AHCT cytotoxic maintenance therapy (p=0.393).
The median time of follow-up from AHCT was 3.5 years (range = 0.2-18.1) in the cases cohort, which was significantly shorter than in the control cohort (median = 8.2 years; range = 2.2-16.7; p<0.001).
The authors noted that people who developed tMN were “poorer mobilizers” and had significantly fewer mobilized CD34+ stem cells at leukapheresis compared with controls (median = 3.57×106 cells/kg [range = 0.4-29] vs. 5.32×106 cells/kg [range = 2-18]; p=0.016). According to the authors, this finding indicated that “normal hematopoiesis could be impaired as early as at time of AHCT.”
No difference was observed between cases and controls in terms of the frequency of low VAF mutations in DNMT3A and TET2. Targeted NGS found DNMT3A and TET2 mutations in 50% and 16% of cases, respectively, whereas 33% of controls had DNMT3A mutations and 28% of controls had mutations in TET2. There also was no significant association between the presence of these mutations and the development of tMN (p=0.216).
After DNMT3A and TET2, the most frequently mutated genes in patients with tMN were:
- TP53 (26%)
- ASXL1 (20%)
- ZRSR2 (13%)
The presence of ≥1 mutation at the time of AHCT was observed in approximately 47% of cases, versus 14% of controls. The investigators determined, therefore, that detectable clonal hematopoiesis at AHCT was significantly associated with the development of post-transplant tMN (odds ratio [OR] = 5.9; 95% CI 1.8-19.1; p=0.003). The authors emphasized that close monitoring with early intervention may be a feasible management option for these patients with clonal hematopoiesis at time of transplant.
In addition, aberrant expression of CD7+ stem cells at time of AHCT was associated with an increased risk of tMN after transplant (OR = 6.6; 95% CI 1.6-26.2; p=0.004).
Given that both targeted NGS and aberrant expression of CD7 at the stem cell level appeared to identify patients at high risk of developing tMN, the investigators then assessed the screening capabilities of combining NGS with flow cytometry. While the combined screening method would likely have identified 66% of high-risk cases (n=24) at the time of AHCT, it would have misclassified 22% of controls (n=8) as cases. The model had a sensitivity of 66% and a specificity of 78% (75% positive predictive value and 70% negative predictive value).
“New research into the predictive potential of the individual mutations in the spectrum of clonal hematopoiesis, preferably combined with sequential NGS analyses to map the potential evolution of early leukemic clones over time, will drive future clinical decision-making,” the authors concluded.
A limitation of this study was the relatively small number of cases and controls included, the reliance on data from a single center, and the use of a commercially available NGS panel that did not include PPM1D. The authors suggest this gene has been strongly linked to tMN.
The authors report no relevant conflicts of interest.
- Soerensen JF, Aggerholm A, Kerndrup GB, et al. Clonal hematopoiesis predicts development of therapy-related myeloid neoplasms post-autologous stem cell transplantation. Blood Adv. 2020;4:885-892.