Clonal hematopoiesis in sickle cell disease

Abstract

Curative gene therapies for sickle cell disease (SCD) are currently undergoing clinical evaluation. However, the occurrence of myeloid malignancies in these trials has prompted safety concerns. Individuals with SCD are predisposed to myeloid malignancies, but the underlying causes remain undefined. Clonal hematopoiesis (CH) is a pre-malignant condition that also confers significant predisposition to myeloid cancers. While it has been speculated that CH may play a role in SCD-associated cancer predisposition, no data addressing this issue have been reported. Here, we leveraged 74,190 whole genome sequences to robustly study CH in SCD. Somatic mutation calling methods were used to assess CH in all samples and comparisons between individuals with and without SCD were performed. While we had sufficient power to detect increased rates of CH, we found no variation in rate or clone properties between individuals affected by SCD and controls and this is unaltered by hydroxyurea use. We did not observe an increased risk for acquiring CH in SCD, at least as measured by whole genome sequencing. These results should help guide ongoing efforts that seek to better define the risk factors underlying myeloid malignancy predisposition in SCD and help ensure that curative therapies can be more safely applied.

The hematopoietic saga of clonality in sickle cell disease

“…Recent reports describing the risk of CH in SCD have reached different conclusions about its relative incidence. Liggett et al’s ( 19 ) work supports the notion that the prevalence of CH in individuals with SCD may be more similar to that of the general population than was previously thought. If true, the increased risk of AML observed in SCD may come from low-VAF CH clones that were undetectable by the methods used.…”

“…In contrast to the earlier findings referenced above, the authors did not detect an increased risk of CH in SCD, although there was a trend in this direction. Although the rate of CH reported by Liggett et al ( 19 ) in SCD was slightly lower, it appears that difference in risk in each control group drove most of the difference in the results of the two studies. Comparison of the distribution of specific genes and VAFs between the two studies could further inform comparison.…”

“…Liggett et al ( 19 ) used whole-genome sequencing (WGS) data from the NHLBI TOPMed consortium ( 20 ) to characterize CH in 3,090 individuals affected by SCD and 71,100 unaffected individuals. CH calls were made in a set of leukemia-driver mutations using an established software pipeline (GATK Mutect2).…”

“…Liggett et al ( 19 ) also evaluated the relative risk of CH in patients with SCD treated with HU and found that HU-treated SCD patients did not have an increased risk of CH relative to those not treated with HU. Despite unavoidable confounders inherent to this comparison it is very reassuring that HU was not associated with an increased risk of CH.…”

Clonal Hematopoiesis and the Risk of Hematologic Malignancies after Curative Therapies for Sickle Cell Disease

“…Due to an increased risk of leukemia in individuals with SCD (see below), reports are coming forth and studies are ongoing to evaluate the prevalence of CH in SCD. Because of an increased incidence of leukemia in patients with CH with a VAF of at least 10% [ 49 , 50 ], Liggett and colleagues recently evaluated almost 75,000 whole genome sequencing analyses from 3090 individuals with SCD and 71,100 individuals without SCD [ 64 ]. Clonal hematopoiesis was reliably evaluable in clones with a VAF of >10% and in about half of the clones with a VAF of 5–10%.…”