Outcomes and long-term effects of hematopoietic stem cell transplant in sickle cell disease

ABSTRACT

Introduction

Hematopoietic stem cell transplant (HSCT) is the only readily available curative option for sickle cell disease (SCD). Cure rates following human leukocyte antigen (HLA)-matched related donor HSCT with myeloablative or non-myeloablative conditioning are >90%. Alternative donor sources, including haploidentical donor and autologous with gene therapy, expand donor options but are limited by inferior outcomes, limited data, and/or shorter follow-up and therefore remain experimental.

Areas Covered

Outcomes are improving with time, with donor type and conditioning regimens having the greatest impact on long-term complications. Patients with stable donor engraftment do not experience SCD-related symptoms and have stabilization or improvement of end-organ pathology; however, the long-term effects of curative strategies remain to be fully established and have significant implications in a patient’s decision to seek therapy. This review covers currently published literature on HSCT outcomes, including organ-specific outcomes implicated in SCD, as well as long-term effects.

Expert Opinion

HSCT, both allogeneic and autologous gene therapy, in the SCD population reverses the sickle phenotype, prevents further organ damage, can resolve prior organ dysfunction in both pediatric and adult patients. Data support greater success with HSCT at a younger age, thus, curative therapies should be discussed early in the patient’s life.

KEYWORDS:

• Allogeneic transplantation
• alternative donor transplants
• autologous transplantation
• gene therapy
• hematopoietic stem cell transplant
• long-term effects
• organ function
• sickle cell disease

Article highlights

• SCD is a growing health disorder with minimal disease modifying options to reduce disease burden. Allogeneic HSCT and autologous gene therapy HSCT are potentially curative strategies to reduce disease burden.

• SCD mortality increases after adolescence/young adulthood; TRM also increases with age, thus, the latter supports early HSCT before severe SCD-associated morbidities occur.

• HLA-MRD is associated with the best outcomes compared to alternative donor transplants in SCD with OS and DFS > 90%; Alternative donor transplants remain restricted to patients with severe SCD and are largely limited to clinical trials. Nonetheless, several advancements to decrease GVHD and graft failure are being studied to enhance safety of these transplants and subsequently expand them to patients without a MRD.

• Donor type, HSC source, conditioning regimens, graft manipulation techniques, and patient age all impact the long-term outcomes following allogeneic HSCT. Outcomes after autologous gene therapy appear to be most dependent on HSC source and transduction or editing efficiencies and therefore expression of the therapeutic gene of interest.

• Successful HSCT can halt the progression and/or lead to improvement in various organ systems affected by SCD.

• Infertility and the risk of secondary malignancy are significant limitations as a result of HSCT. Fertility preservation should be offered to all patients seeking a curative option. To minimize the risk of secondary AML, strategies to improve myeloid chimerism or ensure therapeutic transgene expression in the setting of gene therapy are underway.

• Autologous gene therapy, its targets, and its application are a growing field in SCD with promising results.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Supplementary Material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/17474086.2023.2268271

Additional information

Funding

This paper was not funded.