Clonal hematopoiesis in sickle cell disease

Pincez, Thomas; Lee, Simon S K; Ilboudo, Yann; Preuss, Michael; D'Orengiani, Anne-Laure Pham Hung D'Alexandry; Bartolucci, Pablo; Galactéros, Frédéric; Joly, Philippe; Bauer, Daniel E.; Loos, Ruth J.F.; Lindsley, R. Coleman; Lettre, Guillaume

doi:10.1182/blood.2021011121

Cited by 34 publications

(20 citation statements)

References 29 publications

(32 reference statements)

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“…CH is an important factor predisposing to myeloid malignancies and it has been speculated that individuals with SCD may have elevated rates of CH (20). A preliminary study even reported an observed, albeit slight, increase in CH in people with SCD within a pilot cohort in comparison to external controls (21).…”

Section: Discussionmentioning

confidence: 93%

Clonal hematopoiesis in sickle cell disease

Liggett¹,

Cato²,

Weinstock³

et al. 2022

Journal of Clinical Investigation

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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.

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Section: Discussionmentioning

confidence: 93%

Clonal hematopoiesis in sickle cell disease

Liggett¹,

Cato²,

Weinstock³

et al. 2022

Journal of Clinical Investigation

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“…While whole genome sequencing did not show an increased prevalence in CH [ 64 ], deeper whole exome sequencing revealed a higher prevalence of CH in patients with SCD compared to healthy controls [ 2 ]. Though the relative risk of leukemia is higher in individuals with SCD, the absolute risk is low.…”

Section: Discussionmentioning

confidence: 99%

“…To assess CH at a deeper level, Pincez et al assessed whole exome sequencing data from 1459 patients with SCD and 6848 African-American controls; 517 had sickle cell trait [ 2 ]. Variant allele frequency ranged from 2.5 to 26%, with a median of 7%.…”

Section: Clonal Hematopoiesismentioning

confidence: 99%

“…The risk of leukemia development increases in individuals with SCD, particularly in specific curative therapy settings. Early data suggest that clonal hematopoiesis may be more prevalent in patients with SCD [ 2 ] and that clonal hematopoiesis may expand prior to leukemia development [ 3 ]. This review discusses risk factors for clonal hematopoiesis, leukemia development after various curative therapy strategies, and why patients may be at increased risk for leukemia after curative therapy for SCD.…”

Section: Introductionmentioning

confidence: 99%

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

Gondek

Sheehan

Fitzhugh

2022

JCM

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Sickle cell disease (SCD) is associated with severe morbidity and early mortality. Two large population studies found an increased risk for leukemia in individuals with SCD. Notably, while the relative risk of leukemia development is high, the absolute risk is low in individuals with SCD who do not receive cell-based therapies. However, the risk of leukemia in SCD is high after graft rejection and with gene therapy. Clonal hematopoiesis (CH) is a well-recognized premalignant condition in the general population and in patients after high-dose myelotoxic therapies. Recent studies suggest that CH may be more common in SCD than in the general population, outside the cell-based therapy setting. Here, we review risk factors for CH and progression to leukemia in SCD. We surmise why patients with SCD are at an increased risk for CH and why leukemia incidence is unexpectedly high after graft rejection and gene therapy for SCD. Currently, we are unable to reliably assess genetic risk factors for leukemia development after curative therapies for SCD. Given our current knowledge, we recommend counseling patients about leukemia risk and discussing the importance of an individualized benefit/risk assessment that incorporates leukemia risk in patients undergoing curative therapies for SCD.

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“…One study ( 18 ) analyzed CH in whole-exome sequencing data from 1,459 patients with SCD using an adjacent set of 6,848 African Americans as a comparator. In this study, subjects were considered to have CH if they had an alteration in any of 46 handpicked genes with VAF greater than or equal to 2% and less than 40%.…”

Section: Incidence Of Ch In Scdmentioning

confidence: 99%

The hematopoietic saga of clonality in sickle cell disease

Stonestrom¹,

Levine²

2022

Journal of Clinical Investigation

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Sickle cell disease (SCD) is associated with an increased risk of vascular-occlusive events and of leukemia. Clonal hematopoiesis (CH) may increase both risks. In turn, physiologic abnormalities in SCD may modify the incidence and/or distribution of genetic alterations in CH. In a recent issue of the JCI , Liggett et al. found no difference in CH rate between individuals with versus without SCD. Here we contextualize this report and discuss the complex interplay between CH and SCD with particular attention to consequences for emerging gene therapies. We further consider the limitations in our current understanding of these topics that must be addressed in order to optimize therapeutic strategies for SCD.

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Clonal hematopoiesis in sickle cell disease

Cited by 34 publications

References 29 publications

Clonal hematopoiesis in sickle cell disease

Clonal hematopoiesis in sickle cell disease

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

The hematopoietic saga of clonality in sickle cell disease

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