The transplant debate: defining innovation for sickle cell

In this issue of Blood Advances, Jones et al¹ apply a historical lens to comprehensively review the advancements and current state of curative therapies for sickle cell disease (SCD) since the groundbreaking achievement of the first successful cure using matched-related allogeneic hematopoietic stem cell transplantation (alloHSCT) in 1984. They juxtapose this established approach against evolving reduced intensity conditioning (RIC) regimens for alloHSCT and the technologies leveraged in gene therapy approaches, offering a comparative analysis of their risks, benefits, and long-term potential.

At the heart of their review lies a pivotal question: does alloHSCT still have a place in the burgeoning age of gene therapy? This query is not just academic; it shapes the future trajectory of SCD treatment strategies. AlloHSCT, particularly with matched sibling donors, has a proven track record. Since its inception, more than 1000 individuals with SCD have undergone this treatment, boasting event-free and overall survival rates >90%.² However, its application is severely limited by donor scarcity where fewer than 10% of patients have a suitable matched sibling donor. Moreover, the toxicity of early myeloablative regimens (eg, transplant-related organ toxicity and infertility) confined this option to pediatric patients until RIC emerged in the 2000s, mitigating these risks.¹ 

The advent of RIC regimens revolutionized alloHSCT by lowering treatment-related toxicity, particularly for young adults. Jones et al delve into how incremental adjustments, such as modestly increasing total body irradiation doses (200-400 cGy), addition of thiotepa, preconditioning with hydroxyurea, and implementing post-transplant cyclophosphamide protocols, have dramatically improved outcomes.^1,3 In addition, the authors emphasize the potential for fertility preservation and the tolerability of conditioning regimens in adult patients with preexisting end-organ damage resulting from SCD. While not the emphasis of this article, matched unrelated donor transplants present another avenue for children without sibling donors. Although initial trials were fraught with complications, recent studies using rigorous graft-vs-host disease prophylaxis have revealed encouraging outcomes.^4,5 

Gene therapy, defined as an autologous transplant of a person’s genetically modified stem cells, offers a tantalizing alternative; punctuated by the US Food and Drug Administration’s approval of 2 therapies, lovotibeglogene autotemcel (lovo-cel) and exagamglogene autotemcel (exa-cel). Early clinical trial results are promising, with most recipients achieving improved to normal hemoglobin levels and remaining free of vaso-occlusive crises. Yet, significant challenges remain, including the need for myeloablative conditioning and the unknown risks related to unintentional genetic modification. The authors also do not shy away from discussing the financial implications and note that gene therapies far outstrip alloHSCT in cost. The staggering costs (up to $3.3 million per treatment) raise questions about accessibility and deployment equity.⁶ Furthermore, the paucity of comprehensive care models for SCD leaves these therapies out of reach for many patients. Publicly funded programs such as Medicaid and Medicare are particularly ill-equipped to shoulder such expenses, necessitating broader policy discussions.^6-8 To begin to address this challenge, the Centers for Medicare & Medicaid Services has created a Cell and Gene Therapy Access model and entered outcomes-based agreements with the manufacturers for lovo-cel and exa-cel. The success of this model relies on voluntary participation from individual states.⁹ 

This brings us back to the primary question raised by the authors: the space occupied by innovative conditioning regimens and alternative donor transplant in the era of rapid technological advancements and gene therapy. In the last 15 years, RIC has been found to have the potential to revolutionize alloHSCT for SCD and expand the donor pool to haploidentical and matched unrelated donors. This approach also benefits from the 40 years of experience in alloHCT for SCD including well-established long-term benefits, notably, extended life span, increased productivity, and improved patient-reported quality of life.¹⁰ Nevertheless, gene therapy for SCD represents the success of cutting-edge technology yet paradoxically relies on “crude” myeloablative conditioning chemotherapy. Myeloablation, exorbitant costs, and lack of long-term data limit the role of gene therapy for SCD today. Its enduring impact remains to be found and will necessitate ongoing clinical trials, late-effect studies, and the ability to break down significant barriers to care.

The authors also stress the importance of personalized treatment decisions. Although preventive and supportive care allows many children with SCD to thrive, factors such as age, family preferences, insurance coverage, and the patient’s ability to tolerate myeloablative conditioning should guide the pursuit of curative options. Emerging disease-modifying therapies could further influence these conversations.

Jones et al deliver a thoughtfully crafted summary of the state of curative therapies for SCD. By discussing advances in alloHSCT and the emerging potential of gene therapy, they outline a path forward while recognizing the challenges that still need to be addressed. As researchers, clinicians, policymakers, and the SCD community grapple with these challenges, the ultimate goal remains clear: to improve the quality of life and extend the life span of individuals with SCD. Whether innovative breakthroughs arise from conditioning or genetic technologies, the quest for safe and effective cures marches on.

Conflict-of-interest disclosure: The authors declare no competing financial interests.