Idiopathic and clonal cytopenias of undetermined significance in long-term allogeneic hematopoietic cell transplantation survivors
Background: Clonal hematopoiesis (CH) and idiopathic cytopenia of undetermined significance (ICUS) are age-related indicators of early hematopoietic dysfunction that increase the risk of developing myeloid malignancies. When these conditions coincide as clonal cytopenia of undetermined significance (CCUS), the risk of malignant progression is markedly higher—up to tenfold compared with CH alone. Long-term survivors of allogeneic hematopoietic cell transplantation (allo-HCT) are particularly prone to CH, but the prevalence of ICUS and CCUS in this population remains largely unknown.
Aims: To determine the prevalence and clinical implications of CH, ICUS and CCUS in long-term allo-HCT survivors and to identify transplant-related risk factors associated with these conditions.
We evaluated 299 allo-HCT survivors (transplanted at pediatric/AYA age) enrolled in the Long-Term HIT study, a clinical cohort investigating hematopoietic integrity ≥5 years post-transplant. CH was assessed by targeted, error-corrected sequencing of 38 known leukemia driver genes in whole blood at a variant allele frequency (VAF) cutoff of ≥1%. CCUS was defined as CH with concurrent unexplained cytopenia (cutoffs defined by WHO), and ICUS as unexplained cytopenia without CH. Hematopoietic stem cell age was defined as donor age at transplantation plus years since transplantation. Group comparisons were performed using Wilcoxon rank-sum and Chi-squared tests.
CH was detected in 20.9% of survivors (n=62) at a median recipient age of 30.1 years. Both recipient age (30.1 vs. 21.7 years, p<0.001) and HSC age (48.7 vs. 30.3 years, p<0.001) were significantly higher in individuals with CH compared with those without. The most frequently mutated genes were DNMT3A (n=64; 79.0% of mutations) and TET2 (n=9; 11.1%), with less frequent mutations in ASXL1, PPM1D, RUNX1, STAG2, TP53, and BCOR. 70.4% of survivors had normal blood counts (at a median follow-up time of 11.9 years (range: 7.4-18.6) post HCT), whereas 13.7% (n=40) displayed cytopenia in ≥1 lineage. Anemia was the most prevalent cytopenia (n=17; 5.8%), closely followed by thrombocytopenia (n=15; 5.1%) and neutropenia (n=11; 4.8%). The prevalence of cytopenias did not differ significantly between individuals with and without CH. ICUS was present in 9 survivors. CCUS was identified in 9 survivors (14.5% of survivors with CH; 3.0% of total cohort) at a median age of 34.6 years. Clone size did not differ significantly between survivors with CCUS compared with those with CH (median VAF 3.1 vs. 2.1 vs. y; p=0.42).
CH and cytopenias are common among long-term allo-HCT survivors. While CH was not associated with an increased prevalence of cytopenias, their coexistence as CCUS emerged at a younger age than typically observed in the general population and may be clinically relevant. Ongoing analyses aim to elucidate clinical consequences and transplant-related risk factors for CH, ICUS, and CCUS in this unique survivor population.