Clonal hematopoiesis in AML long-term survivors: Risk factors and clinical consequences

Abstract

Clonal hematopoiesis (CH) is common in the general population and associated with various health risks, but its prevalence and clinical implications in acute myeloid leukemia (AML) long-term survivors (LTS; ≥5-year survival) are unknown. We analyzed CH in 373 AML-LTS with a median 11.6-year follow-up from diagnosis using a sensitive targeted sequencing assay based on single-molecule molecular inversion probes. CH variants were detected in 61.9% of survivors, with 26% having small-clone CH (SC-CH, variant allele frequency (VAF) < 2%) and 35.9% CH of indeterminate potential (≥2% VAF). CH was more prevalent in survivors treated with chemotherapy only (75.7%) compared to those who received allogeneic stem cell transplantation (alloSCT, 54.0%) and to age group-matched healthy controls. In chemotherapy-treated survivors, CH prevalence increased with age, whereas in alloSCT recipients, it most closely associated with hematopoietic age (i.e., the sum of donor age and time since transplantation). The variant spectrum also differed by treatment, with TP53 and PPM1D variants being more common in the chemotherapy group. CH variants ≥10% VAF associated with increased risks of diabetes in alloSCT recipients and secondary neoplasms in chemotherapy-treated survivors. This study provides insights into the high prevalence and potential clinical relevance of CH in AML-LTS.

Figure 1

Comparison of clonal hematopoiesis (CH) prevalence, variant allele frequency (VAF), and variant count between treatment groups. (A) Stacked bar plot comparing prevalence of CH of indeterminate potential (CHIP) and small‐clone CH (SC‐CH) in chemo and allogeneic stem cell transplantation (alloSCT) groups. (B) Violin‐boxplot comparing VAF between chemo and alloSCT groups. (C) Histogram comparing variant count per survivor between chemo and alloSCT groups.

Figure 2

Overview of time factors associated with clonal hematopoiesis (CH) prevalence. (A, B) Stacked barplots displaying CH prevalence in chemo survivors in dependence of either age group or years since first chemotherapy. (C, D) Stacked barplots displaying CH prevalence in survivors treated with allogeneic stem cell transplantation (alloSCT) in dependence of either age group or years since last allogeneic transplantation. (E, F) Stacked barplots displaying CH prevalence in a subset of alloSCT survivors with known donor age, either in dependence of donor age at transplantation or hematopoietic age, that is, the sum of donor age and time since transplantation. (G) Univariable ordinal logistic regression analysis of the same factors as in (A)–(F). Age was treated as a continuous variable, and odds ratio (OR) is shown per year. CHIP, clonal hematopoiesis of indeterminate potential; SC‐CH, small‐clone clonal hematopoiesis.

Figure 3

Distribution of clonal hematopoiesis (CH)‐associated genetic variants stratified by treatment modality. (A) Proportion of survivors of their respective treatment group carrying CH variants in specific genes. (B) Oncoplot depicting variants across all 231 affected survivors, stratified by treatment modality. Each column represents one survivor, while each row represents a specific gene, with coloring indicating the variant type. Percentages on the right axis denote the frequency of gene variants within the group of survivors affected by CH. alloSCT, allogeneic stem cell transplantation; CHIP, clonal hematopoiesis of indeterminate potential; SC‐CH, small‐clone clonal hematopoiesis.

Figure 4

Lollipop plot displaying distribution and classification of TP53 and PPM1D variants. Protein domains are indicated by colored regions. Amino acid changes are shown based on the canonical reference transcript. Variants are colored and classified by type and stratified by treatment modality. Variant size (i.e., clonal hematopoiesis [CH] status) is indicated by lollipop size and stem length. Multiple variants at the same position are displayed as stacked lollipops. (A) TP53 (reference transcript: NM_000546; domains: InterPro P04637). One splice site mutation (c.375+2T>G) is not shown due to missing amino acid annotation, and one frameshift deletion (NM_001276696:exon10:c.897delA:p.E300Kfs*11) is not shown due to missing annotation to the canonical reference transcript. (B) PPM1D (reference transcript: NM_003620; domains: InterPro O15297). alloSCT, allogeneic stem cell transplantation; CHIP, clonal hematopoiesis of indeterminate potential; SC‐CH, small‐clone clonal hematopoiesis.

Figure 5

Association between clonal hematopoiesis (CH) and somatic comorbidities presented as forest plot. Odds ratio (OR), CI, and P‐values were calculated via univariable logistic regression. No/yes columns display the number of survivors affected by each comorbidity.

Figure 6

Association of clonal hematopoiesis (CH) with diabetes and secondary neoplasms stratified by treatment modality. (A) Forest plot displaying the association of diabetes with CH status stratified by treatment modality. Odds ratio (OR), CI, and P‐values were calculated via multivariable logistic regression adjusting for survivor age. (B) Cumulative event curves depicting the cumulative incidence of secondary neoplasms in survivors stratified by CH status and treatment modality over 20 years following the first chemotherapy (chemo group) or the last allogeneic transplantation (alloSCT group). Tick marks represent censored observations. (C) Results of multivariable Cox proportional hazards analysis for the risk of developing secondary neoplasms based on CH status and adjusted for age, stratified by treatment modality.