NEJM evidence · 2026
Clonal Selection and Evolution after Treatment of Severe Aplastic Anemia.
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Gutierrez-Rodrigues Fernanda, Groarke Emma M, Miao Rui, Shalhoub Ruba, Alemu Lemlem, Mizumaki Hiroki, Rios Olga, Glass Joshua, Durrani Jibran, Bazzo Catto Luiz Fernando, Arcuri Luca, Kajigaya Sachiko, Gao Shouguo, Paul Subrata, Lack Justin, Yoshida Masanori, Quinones Raffo Diego, Lotter Jennifer, Wu Colin O, Dunbar Cynthia E, Wlodarski Marcin, Young Neal S, Patel Bhavisha A
Аннотация
BACKGROUND: Clonal hematopoiesis (CH) is a feature of severe aplastic anemia (SAA), but its clinical significance is debated.
METHODS: We integrated longitudinal clinical and CH data from patients with SAA treated with immunosuppression plus eltrombopag (IST-EPAG) in a phase 2 trial to characterize clonal dynamics during recovery and progression to myeloid cancer or paroxysmal nocturnal hemoglobinuria (PNH); CH was defined as the presence of somatic mutations at a variant allele frequency of 0.1% or greater.
RESULTS: In total, 204 SAA patients treated with IST-EPAG were evaluated from disease onset to median follow-up of 5.5 years. CH was observed in 128 of 204 (63%) patients before treatment and in 131 of 180 (73%) after therapy who were evaluated at the 6-month timepoint and were not off-study. Patients mostly had CH in PIGA (N=53, 26%), DNMT3A (N=42, 21%), BCOR (N=35, 17%), and ASXL1 (N=25, 12%). There appeared to be two distinct patterns of malignant clonal evolution. Early evolutions, within 1 year from treatment, were primarily chromosome 7 aberrations and occurred in 11 (5%) patients. In another eight (4%) patients, late evolutions, 4-5 years after therapy, were initiated by early selection of ASXL1-mutated or U2AF1-mutated clones. Evolution to PNH, observed in 10 of 204 patients (5%), was associated with expansion of PIGA clones usually present before treatment.
CONCLUSIONS: Among patients with SAA treated with IST-EPAG, early and late patterns of clonal evolution to myeloid cancer were observed: Chromosome 7 abnormalities occurred within 1 year, whereas later events (4-5 years) involved stepwise mutation acquisition in preexisting ASXL1- or U2AF1-mutated clones.
METHODS: We integrated longitudinal clinical and CH data from patients with SAA treated with immunosuppression plus eltrombopag (IST-EPAG) in a phase 2 trial to characterize clonal dynamics during recovery and progression to myeloid cancer or paroxysmal nocturnal hemoglobinuria (PNH); CH was defined as the presence of somatic mutations at a variant allele frequency of 0.1% or greater.
RESULTS: In total, 204 SAA patients treated with IST-EPAG were evaluated from disease onset to median follow-up of 5.5 years. CH was observed in 128 of 204 (63%) patients before treatment and in 131 of 180 (73%) after therapy who were evaluated at the 6-month timepoint and were not off-study. Patients mostly had CH in PIGA (N=53, 26%), DNMT3A (N=42, 21%), BCOR (N=35, 17%), and ASXL1 (N=25, 12%). There appeared to be two distinct patterns of malignant clonal evolution. Early evolutions, within 1 year from treatment, were primarily chromosome 7 aberrations and occurred in 11 (5%) patients. In another eight (4%) patients, late evolutions, 4-5 years after therapy, were initiated by early selection of ASXL1-mutated or U2AF1-mutated clones. Evolution to PNH, observed in 10 of 204 patients (5%), was associated with expansion of PIGA clones usually present before treatment.
CONCLUSIONS: Among patients with SAA treated with IST-EPAG, early and late patterns of clonal evolution to myeloid cancer were observed: Chromosome 7 abnormalities occurred within 1 year, whereas later events (4-5 years) involved stepwise mutation acquisition in preexisting ASXL1- or U2AF1-mutated clones.