Long-Term Health Effects of Curative Therapies on Heart, Lungs, and Kidneys for Individuals with Sickle Cell Disease Compared to Those with Hematologic Malignancies

The goal of curing children and adults with sickle cell disease (SCD) is to maximize benefits and minimize intermediate and long-term adverse outcomes so that individuals can live an average life span with a high quality of life. While greater than 2000 individuals with SCD have been treated with curative therapy, systematic studies have not been performed to evaluate the long-term health effects of hematopoietic stem cell transplant (HSCT) in this population. Individuals with SCD suffer progressive heart, lung, and kidney disease prior to curative therapy. In adults, these sequalae are associated with earlier death. In comparison, individuals who undergo HSCT for cancer are heavily pretreated with chemotherapy, resulting in potential acute and chronic heart, lung, and kidney disease. The long-term health effects on the heart, lung, and kidney for children and adults undergoing HSCT for cancer have been extensively investigated. These studies provide the best available data to extrapolate the possible late health effects after curative therapy for SCD. Future research is needed to evaluate whether HSCT abates, stabilizes, or exacerbates heart, lung, kidney, and other diseases in children and adults with SCD receiving myeloablative and non-myeloablative conditioning regimens for curative therapy

Allogeneic Transplant and Gene Therapy: Evolving Toward a Cure.

Curative therapies for sickle cell disease (SCD) include allogeneic human leukocyte antigen (HLA)- matched sibling and haploidentical hematopoietic cell transplant (HCT), gene therapy, and gene editing. However, comparative trial data that might facilitate selecting one curative therapy over another are unavailable. New strategies to decrease graft rejection and graft-versus-host disease (GVHD) risks are needed to expand haploidentical HCT. Myeloablative gene therapy and gene editing also has limitations. Herein, we review recent studies on curative therapies for SCD in the past 5 years

The case for HLA-identical sibling hematopoietic stem cell transplantation in children with symptomatic sickle cell anemia.

This article has a companion Counterpoint by DeBaun and Clayton

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

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

Hematopoietic stem cell transplantation for patients with sickle cell disease. Progress and future directions

Considerable progress has been achieved in allogeneic hematopoietic stem cell transplantation (HSCT) for patients with sickle cell disease. Many studies have solidified matched sibling marrow, cord blood, or mobilized peripheral blood as the best source, with low graft rejection and graft versus host disease (GvHD), and high disease-free survival rates. For transplant eligible patients without HLA-matched sibling donors, fully allelic matched unrelated donor appears to be the next best option, though ongoing studies in sickle cell disease will provide data that are currently lacking. In general, unrelated cord transplant studies reported relatively high GvHD rates and low engraftment rates. Haploidentical transplants have emerged in the last decade to have less GvHD, but improvements are needed to increase the low engraftment rate. As there is no clear preferred choice, the decision to use unrelated cord blood units or haploidentical donors depends on the institutional expertise, and performed in the context of clinical trials. Data regarding 7/8 or lower matched unrelated donors are discouraging. Before routine use of these less matched donor sources, work is needed to improve patient selection, conditioning regimen, and/or GvHD prophylaxis