Clonal hematopoiesis in patients with stem cell mobilization failure: a nested case-control study

Abstract

Inadequate mobilization of peripheral blood progenitor cells (PBPCs) is a limiting factor to proceeding with autologous hematopoietic cell transplantation (auto-HCT). To assess the impact of clonal hematopoiesis (CH) on mobilization failure of PBPC for auto-HCT, we investigated the characteristics of poor mobilizers (with a total PBPC collection <2 × 106 CD34+ cells per kg) in a consecutive single-center cohort of 776 patients. Targeted error-corrected next-generation sequencing of 28 genes was performed in a nested case-control cohort of 90 poor mobilizers and 89 matched controls. CH was detected in 48 out of 179 patients (27%), with most patients carrying a single mutation. The presence of CH (detected at variant allele frequency [VAF] ≥ 1%) did not associate with poor mobilization potential (31% vs 22% in controls, odds ratio, 1.55; 95% confidence interval, 0.76-3.23; P = .238). PPM1D mutations were detected more often in poor mobilizers (P = .005). In addition, TP53 mutations in this cohort were detected exclusively in patients with poor mobilization potential (P = .06). The incidence of therapy-related myeloid neoplasms (t-MN) was higher among patients with mobilization failure (P = .014). Although poor mobilizers experienced worse overall survival (P = .019), this was not affected by the presence of CH. We conclude that CH at low VAF (1%-10%) is common at the time of stem cell mobilization. TP53 mutations and PPM1D mutations are associated with poor mobilization potential and their role in subsequent development of t-MN in these individuals should be established.

Graphical abstract

Figure 1.

Flowchartdepicting the nestedcase-control study cohort and availability of samples.

Figure 2.

Spectrum of CH detected in poor mobilizers and controls. (A) Prevalence of CH in 90 poor mobilizers and 89 matched controls. (B) Distribution in the highest VAF for poor mobilizers (red) and matched controls (blue) carrying CH. Boxplots indicate median, first, and third quartiles, with whiskers extending to 1.5× IQR. (C) Violin plot displaying the distribution in number of detected mutations in poor mobilizers (red) and controls (blue) carrying CH. (D) Prevalence of CH according to age (n = 179). Red, poor mobilizers (n = 90); blue, matched controls (n = 89). (E) Proportion of poor mobilizers and matched controls carrying specific gene mutations. The absolute number of individuals with the respective gene mutation is given. (F) Prevalence of CH in failure subgroups 1 (n = 17), 2 (n = 13) and 3 (n = 60), as compared with their respective matched controls.

Figure 3.

Landscape of concurrent gene mutations in poor mobilizers and controls. Each row indicates a specific gene mutation, with columns representing individual patients. The darker shade indicates multiple mutations within the same gene. Subgroups of poor mobilizers are indicated. Individuals developing t-MNs are indicated by an asterisk.

Figure 4.

Outcomes for poor mobilizers and controls. (A) Cumulative incidence of t-MNs among poor mobilizers (n = 106) and successful mobilizers (n = 670). (B) OS for poor mobilizers and controls. HRs for OS are shown for poor mobilization potential in the entire cohort (n = 776) in the upper graph. Within the case-control cohort with NGS data, HRs are shown for the presence of CH among cases (n = 90) and controls (n = 89) in the lower part of the graph. Forest plots display HR and 95% CI from Cox proportional hazard regression, corrected for age, sex, and major histological subtype.