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

Abstract

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.

Azathioprine/hydroxyurea preconditioning prior to nonmyeloablative matched sibling donor hematopoietic stem cell transplantation in adults with sickle cell disease: A prospective observational cohort study

“…28 Recent reports about a higher incidence of clonal hematopoiesis in SCD and secondary hematological malignancies after graft failure or in case of poor donor chimerism in transplanted SCD patients have raised concerns about the safety of nonmyeloablative conditioning regimens aiming for stable mixed chimerism. 13,29,30 In one study, three of 19 patients developed leukemia after rejection out of a total cohort of 76 transplanted patients with SCD. 12 Two patients had TP53 mutation at diagnosis of leukemia, which turned out to be already present before the transplant.…”

“…13 Additionally, it is postulated that the proliferative stress of regenerative hematopoiesis after graft rejection, or autologous repopulation after gene therapy following exposure to toxic chemo-or radiotherapy may drive clonal expansion of pre-existing mutations. 13 Next to graft failure, mixed chimerism has also been reported as a risk factor for secondary hematological malignancies in transplant recipients with SCD. 29 In the series described by Lawal et al, 29 donor myeloid chimerism in transplant recipients developing myeloid malignancies was <40% in all cases.…”

“…Using whole exome sequencing, a large study showed a higher incidence of clonal hematopoiesis in SCD patients 31 . Proliferative and genotoxic stress, as well as clonal selection due to the inflammatory environment present in SCD are assumed to be responsible 13 . Additionally, it is postulated that the proliferative stress of regenerative hematopoiesis after graft rejection, or autologous repopulation after gene therapy following exposure to toxic chemo‐ or radiotherapy may drive clonal expansion of pre‐existing mutations 13 .…”

“…Another 20%–30% were unable to stop sirolimus due to too low donor T‐cell chimerism (<50%). Moreover, graft failure in patients with SCD was recently associated with the development of hematological malignancies 12–14 . Thus, despite mostly favorable outcomes after matched sibling donor transplantations with the alemtuzumab/TBI conditioning, there remains a need for further improvements.…”

Sickle cell disease and acute leukemia: one case report and an extensive review

“…Despite limitations coming from the retrospective nature of our study involving missing data and biases related to cases reported over an extended period, our review of the literature tend to suggest that chronic hemolysis, increased iron levels, and increased bone marrow turnover, which form the pathophysiologic mechanisms of the clinical manifestations of SCD are mainly responsible for a situation in which cells are undergoing constant hematopoietic hyperplasia, leading to the increased risk of acute leukemia by inducing genomic damage and somatic mutations [ 77 ]. The effects of SCD on progenitor cells have not been fully determined [ 78 ].…”