Clonal haemopoiesis following cytotoxic therapy for lymphoma

Patients successfully treated for lymphoma by conventional cytotoxic therapy are at increased risk of developing treatment-related myelodysplasia and acute myeloid leukaemia. In this study we have investigated a group of haematologically normal females in remission from lymphoma for evidence of clonal haemopoiesis as a possible marker for the development of clonal haemopoietic disorders. Unilateral X-inactivation, and hence clonality, can be determined in females heterozygous for X-linked restriction fragment length polymorphisms by differences in methylation between active and inactive X-chromosomes. We have studied methylation patterns at the DXS255 locus and the phosphoglycerate kinase (PGK) gene in 25 females in remission from lymphoma and compared them to 35 normal females. Unilateral X-inactivation was detected in 4/15 patients in remission from lymphoma versus 2/27 normals at the DXS255 locus and in 4/13 treated lymphoma patients versus 0/11 normals at the PGK locus. Six individuals were analysed by both techniques with complete concordance. Unilateral X-inactivation was more common following cytotoxic therapy for lymphoma (7/25) than in normals (2/35) (p < 0.025) and in the lymphoma cohort was associated with increasing time from the end of therapy (p = 0.03). Patients in remission from lymphoma have an increased incidence of clonal haemopoiesis compared to normal individuals. This may be due to either the clonal expansion of an abnormal genetically damaged stem cell or a variation of normal haemopoiesis. Prospective studies will establish whether this finding is associated with an increased risk of developing treatment-related myelodysplasia and acute myeloid leukaemia.