ASH 2025 | The incidence and impact of early-onset high-risk clonal hematopoiesis in sickle cell disease

So we undertook a study, a human genetic study, to really understand what the prevalence and age distribution as well as the gene distribution of clonal hematopoiesis was in sickle cell disease. And this was a study that was motivated by several observations over the last decade or so. One is that individuals with sickle cell disease actually have an increased relative risk of leukemia. Their risk is about three to four-fold higher than individuals without sickle cell disease. And then second, when we treat individuals with sickle cell disease with the curative therapies, so things like allogeneic stem cell transplantation or autologous curative therapies like gene therapy, we see a signal for post-treatment MDS and AML in sickle cell disease patients. And then lastly, an observation that my lab has recently made is that individuals with sickle cell disease tend to get a flavor of MDS and AML that is really high risk. So it’s characterized by things like TP53 mutations or complex cytogenetics. And so this all sort of led us to believe that maybe there was some biological underpinning of sickle cell disease that led to an increased risk of myeloid malignancies. And this has not been sort of borne out in the literature. 

And so we looked at clonal hematopoiesis as maybe being that biological link. And clonal hematopoiesis is now a very well accepted precursor of blood cancers such as MDS and AML. And so we took a multinational collection of samples from 17 different cohorts across four different countries. And we had a little under 4,000 individuals with sickle cell disease, a little under 4,000 individuals without sickle cell disease, so normal hemoglobin and sickle cell trait. And then we had a little under 200 individuals with beta thalassemia. And this allowed us, by sequencing the blood DNA from these populations, it allowed us to really ask, is there a higher risk of having clonal hematopoiesis if you have sickle cell disease versus not? Is there a risk of having clonal hematopoiesis or getting clonal hematopoiesis earlier in sickle cell disease versus individuals without sickle cell disease? And, you know, are there different genes that are associated with the clonal hematopoiesis we see in sickle cell versus individuals without sickle cell? 

So we used a targeted gene platform to do our sequencing in collaboration with the Broad Institute at MIT. And we were able to get down to a limit of detection of about 0.1% variant allele fraction, which is orders of magnitude more sensitive than the clinical tests that we typically use to measure clonal hematopoiesis. And we made a couple of really critical observations. One was that clonal hematopoiesis actually is seen earlier in individuals with sickle cell disease relative to individuals without. So in a population in our cohort that was 0 to 19 years old, for example, about 10% of the sickle cell disease population had clonal hematopoiesis detected versus about 3% of the non-sickle cell disease population. So there was much more clonal hematopoiesis in individuals, and it sort of shifted to the left or shifted towards younger ages. 

We second observed that this increased prevalence, particularly increased prevalence in younger ages, was really driven by DNA damage repair and response pathway genes. So genes such as TP53 or PPM1D, ATM, and CHEK2. So these genes that are involved in sort of helping to respond to DNA damage or repair DNA damage. And so we saw at most of the age groups evaluated in children as well as in adults with sickle cell disease, we observed the higher prevalence of DNA damage response pathway clonal hematopoiesis in sickle cell disease relative to individuals without. 

And then lastly, we were able, because of how we set up our cohort, to make comparisons between sickle cell disease and non-sickle cell disease, but also sickle cell disease and sickle cell trait, as well as sickle cell disease and beta thalassemia. And what we observed was that the rate or the prevalence of clonal hematopoiesis was similar in sickle cell trait as it was in individuals without sickle cell disease. And it was actually a lower rate of clonal hematopoiesis than what we see in sickle cell. And so that’s basically saying that being heterozygous for the sickle allele or having sickle cell trait does not increase your risk of clonal hematopoiesis. 

And then lastly, individuals with beta thalassemia, so another type of beta hemoglobinopathy that also causes hemolysis, that also causes high red cell turnover, was associated with a similar prevalence of clonal hematopoiesis as individuals without sickle cell disease as well, suggesting that this is not a phenomenon that’s generalizable to high erythropoietic output states or beta hemoglobinopathies, that this is really a sickle cell disease-specific phenomenon. 

And so in all of this, we were really able to identify that sickle cell disease is associated with clonal hematopoiesis, that this begins in early childhood, and that this precocious development of clonal hematopoiesis in sickle cell disease is driven by a distinct flavor of CH that we see in this context, but not in the age-related context. So we see mutations in TP53, PPM1D, ATM, CHEK2, and not in the age-related genes like DNMT3A or TET2. And all in all, this really sort of provides a plausible mechanism for how we get to these high-risk myeloid malignancies that we’re seeing in sickle cell disease as people age, but also in the populations following curative therapy.

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