Global Perspectives on Cellular Therapy for Children with Sickle Cell Disease

Abstract

Purpose of Review:

Low- and middle-income countries (LMICs), primarily in sub-Saharan Africa (SSA), experience the burden of sickle cell disease (SCD) worldwide. High frequency of acute and chronic complications leads to increased utilization of healthcare, which burdens fragile health systems. Mortality for children with limited healthcare access remains alarmingly high. Cellular-based therapies such as allogeneic hematopoietic stem cell transplant (HSCT) are increasingly used in resource-rich settings as curative therapy for SCD. Broad access to curative therapies for SCD in SSA would dramatically alter the global impact of the disease.

Recent Findings:

Currently, application of cellular-based therapies in LMICs is limited by cost, personnel, and availability of HSCT-specific technologies and supportive care. Despite the challenges, HSCT for SCD is moving forward in LMICs. Highly-anticipated gene modification therapies have recently proven safe and feasible in clinical trials in resource-rich countries, but access remains extremely limited.

Summary:

Translation of curative cellular-based therapies for SCD should be prioritized to LMICs where the disease burden and cost of non-curative treatments is high, and long-term quality of life is poor. Focus on thoughtful modifications of current and future therapies to meet the need in LMICs, especially in SSA, will be especially impactful.

Introduction: The Global Burden of Sickle Cell Disease

Sickle cell disease (SCD) is the most common inherited hemoglobinopathy worldwide. SCD is caused by a point mutation which results in the production of an abnormal hemoglobin. The hallmark of the disease is recurrent polymerization of sickle hemoglobin under conditions of low oxygen tension, causing chronic hemolysis, inflammation, and recurrent vasoocclusion. Low- and middle-income countries (LMICs) bear the highest burden of SCD: an estimated 90% of the 300,000 annual births occur in LMICs and 75% of all births occur in sub-Saharan Africa (SSA) (1).

Significant progress has been made in reducing childhood mortality in resource-rich countries over the last 50 years such that more children now survive into adulthood (2). Early advances such as the widespread adoption of newborn screening, provision of penicillin prophylaxis, administration of childhood immunizations, and general improvements in health care led to increased childhood survival (3). Despite these advances, at present, adults with SCD still develop multiple organ dysfunction and eventual premature death, with organ damage contributing to up to 50% of mortality in adults with SCD (4). Hydroxyurea, the mainstay of therapy for SCD, was approved for use in the US in 1996 (5, 6). More recently, the approval of new disease modifying agents L-glutamine (7), voxelotor (8), and crizanlizumb (9) have offered additional promise to improve quality of life and reduce end organ damage. In LMICs where most people with SCD live, access to care and access to disease modifying agents for SCD are poor.

An estimated 35–80% of children with SCD with access to medical care die before age 5 years in SSA (10, 11). Estimates for mortality among children with limited access to care likely exceed 50% (11). SCD is associated with poor quality of life where survivors endure recurrent pain, hemolytic anemia and resultant fatigue, and progressive organ damage including stroke, kidney dysfunction, pulmonary hypertension, leg ulcers, avascular necrosis and other complications (12–14). The high frequency of both acute and chronic complications leads to increased utilization of medical services, which burdens fragile health systems in LMICs and would certainly overwhelm these systems as childhood survival improves. The need to implement the wider use of hydroxyurea to reduce the complications of SCD is urgent. However, optimisms about the cost effectiveness and actual uptake of this and other disease-modifying therapies must be viewed with caution in LMICs as they are not curative. The burden of lifelong medications which do not cure the disease might affect adherence and enthusiasm for hydroxyurea (10, 11, 13–17).

Cellular-based therapies with a goal of cure should be considered in LMICs where the disease burden is high, cost of non-curative treatments is high, and long-term quality of life is poor. Over the last two decades, advances in stem cell transplantation and gene therapy have improved quality of life and been a source of hope for patients in resource-rich countries. More recently, hematopoietic stem cell transplant (HSCT) has been performed successfully in LMICs and the momentum for expansion is strong (18). Challenges must be critically analyzed in each locale, costs determined, and quality ensured before establishing HSCT centers in any LMICs (19). In this review, we summarize the current status of HSCT globally with a focus on Africa, highlight challenges, herald the successes, and offer projections for the future of SCT for SCD in LMICs.

Challenges for cellular therapies

Challenges to providing cellular-based therapies for children with SCD in LMICs may present at the patient level, at the institution level, and at the societal level. In essence, cellular therapies require expensive investments in infrastructure and human resources (20). A review of crucial elements of a transplant program as defined by an expert panel of providers from LMICs in the Eastern Mediterranean countries lends insights into the particular resource limitations that must be overcome (21).

Whereas many patients with SCD have limited access to care or initiate care at a later age, they may present to transplant with evidence of numerous prior blood transfusions. Particular challenges for transplantation include the presence of iron overload and the accumulation of antibodies to red cell antigens. In a recent review of transfusion practices in Senegal, 16% of patients were found to have alloantibodies and 7.8% had elevated ferritin suggestive of iron overload (22). A meta-analysis of studies reviewing alloimmunization in Africa identified prevalence rates ranging from 4–26% (23). High rates of either iron overload or alloimmunization would contribute to worse post-transplant outcomes (24).

To reduce the risk for SCD-related acute events and to reduce inflammatory stress hematopoiesis prohibiting successful engraftment, most transplant protocols include a period of chronic blood transfusions and/or automated RBC exchanges. This is also employed in preparation for autologous stem cell collection. Additionally, higher hemoglobin and platelet thresholds are typically maintained in the early post-HSCT period for neurologic protection due to increased risk for ischemic and hemorrhagic stroke (25). Robust facilities for blood banking and transfusion support are necessary. Of the 60 countries with the lowest rate of blood donation per person, all are LMICs. More than half are in the WHO Afro region, where the incidence of SCD is highest (26).

At the institutional level, robust infection control, including the ability to surveil, prevent, and treat bacterial and fungal infections, is important for the success of transplantation as well as to limit the duration of hospitalization. Further, the facility should have the ability to detect and treat viral reactivations and infections. Environmental services are crucial for reducing the risk of nosocomial infection. Radiology is important to monitor for complications. A successful transplant course often requires subspecialists across multiple disciplines.

At the level of the health care system, tools to prepare for HSCT must be available. Advanced diagnostic laboratory tools and expertise to interpret HLA typing is important. Capacity for cell collection and cell processing are crucial and lacking in many LMICs. There should be human resource capacity to enable local expertise at all levels of healthcare providers, though some programs have demonstrated success with external partners (27). Although the health care workforce is limited in many countries, lower patient-to-provider ratios in specific centers and 24-hour staffing are needed to provide close monitoring necessary for a safe transplant course. Most importantly, the infrastructure to ensure an uninterrupted power supply is a critical safety measure.

In many LMICs, the limited or absent social safety net forces families to pay for the bulk of health care. The costs for HSCT in LMICs is significantly lower compared to the cost in HICs: the average cost of HSCT in Egypt of $17,000 USD is about 10% of the cost in HICs (28). HSCT may be affordable for a minority of families. Many families lack financial resources not only to cover for the procedure but also to cover other necessary costs such as medication and tests needed before and after HSCT. This results in frequent interruptions in care and treatment abandonment. In an analysis of cost of stem cell transplantation in northeast Mexico, the costliest items were drugs and laboratory tests. However, they identified a large contribution to cost from inpatient hospital days, a potential modifiable expense (29). By limiting these hospital days, especially for nonmyeloablative procedures, the costs could be reduced.

How to equitably provide SCT to all patients in need will be a challenge for most LMICs in SSA. By 2050, Piel and colleagues estimate that Nigeria, India, and Democratic Republic of Congo will account for 55% of new births per year of children with SCD worldwide, or an estimated 219,400 infants per year (30). The rates of SCD births in Uganda and Tanzania are not far behind, and the birth rates are expected in increase in both countries. Currently, allogeneic HSCT for SCD requires a donor and most African countries do not have a donor registry. This limits the availability of unrelated donors (28).

Current status of cellular therapies in LMICs in sub-Saharan Africa

The formation of several regional academic and clinical and research networks have led to advocacy, knowledge sharing, and advances in care for SCD in SSA. Networks such as the African Research and Innovative Initiative for Sickle Cell Education (ARISE) (31), the International Hemoglobinopathy Research Network (INHERENT) (32), the Réseau d’Etudé de la Drépanocytose en Afrique Centrale (REDAC) (33), the Sickle Pan-African Research Consortium (SPARCO) (34), and others have brought together leading clinicians and scientists on the continent to critically appraise and address the challenges of SCD care. Furthermore, increased recognition of the contribution of non-communicable diseases to mortality in LMICs through the Millenium Development Goals has added to the demand for improvements in care for SCD (35). Despite the challenges outlined above, some countries in Africa have managed to establish local programs for cellular therapies. The first meeting of the African Blood and Marrow Transplant Society (AfBMT) was held in 2018 (36).

Various groups in LMICs in South-East Asia, Middle East/North Africa, India, and South America have reported success with allogeneic HSCT for hemoglobinopathies, primarily matched related donors for transfusion-dependent thalassemia (24, 27, 37–39). The earliest HSCT programs on the African continent were established in lower-middle and middle-income countries in North Africa and Southern Africa, but centers in SSA are emerging. Cellular therapies were first available in South Africa and Egypt, both of which have lower burdens of SCD compared to neighboring countries in SSA. Egypt is a prototype of a LMIC that successfully established a cellular therapy center in 2008 and has managed to scale up services (28). By 2020 Egypt had 15 transplant centers with a transplant rate of 8.4/million. This is a remarkable increase from the 2008 transplant rate of 2.8/million and is approaching 36–40/million seen in resource-rich countries. Other North African countries with HSCT services, such as Tunisia and Morocco, are also participants in a regional network, the Eastern Mediterranean Blood and Marrow Transplantation Group (21).

Nigeria was an early leader in SSA to pilot HSCT for SCD, performing a matched related donor transplant in 2014 (18). Since then, dedicated HSCT centers have now opened in Ghana in 2019 (40) and in Nigeria in 2022 (41). Tanzanian experts collaborated with partners from India to perform the first autologous HSCT (not for SCD) in five patients at the Muhimbili National Hospital in 2021 (42, 43). Notably, the cost of HSCT for one patient done within the country was one third of the cost of referring a patient abroad for HSCT (42).

An increasing number of patients living in SSA pursue cellular therapies outside of their home countries and often, outside of the continent. A burgeoning medical tourism industry for HSCT for SCD threatens to create significant burden on health systems and providers upon their return to their home country. Untrained providers and limited access to medications and monitoring increase the risk of complications during post-transplant care (44). Establishing HSCT centers and HSCT knowledge locally is critical for long-term success.

The future of HSCT for SCD in LMICs

Success of matched related donor transplant for SCD has been well established. HICs report 90–95% disease-free survival in young people (45–50). Efforts to expand access to potentially curative allogenic HSCT using unrelated and haploidentical donors, and with reduced toxicity and nonmyeloablative conditioning regimens are promising (51–55). However, these therapies remain limited to availability through clinical trials and are recommended only for those with a severe, high-risk phenotype. Long-term efficacy of gene modification therapies for SCD is now under investigation primarily in Europe and the US. The success of first-in-human feasibility, safety, and efficacy trials have naturally prompted consideration of global applicability (56, 57).

Emerging developments in stem cell biology, conditioning approaches, and stem cell manufacturing development promise to increase access to therapy around the world. Scientific interest in hematopoietic progenitor and stem cell biology in hemoglobinopathies highlights the universal need for high quality and adequate quantity of cells for both allogenic HSCT and for autologous gene modification therapies (58, 59). Three potential sources of cells, unmanipulated bone marrow, stimulated peripheral blood stem cells, and preserved umbilical cord blood cells, present differing challenges to quality of product and feasibility of use. Unmanipulated bone marrow is the most feasible stem cell source for use in LMICs due to limited availability of cell processing facilities. However, the utility of unmanipulated marrow is limited by large collection volumes yielding low stem cell concentration. Collection of stimulated peripheral blood stem cells is feasible and safe from genotype AS and AA donors, and is the current preferred stem cell source for gene therapies (58–62). Collection of peripheral blood stem cells is less feasible in LMICs as it remains resource intensive, requiring a pheresis program and sometimes CD34+ selection and cryopreservation facilities. Preserved cord blood is a useful stem cell source in matched related donor transplant and may be globally applicable for allogeneic HSCT or gene modification therapies (47, 63, 64). Feasibility of cord blood processing also requires collection expertise and cryopreservation facilities. Other strategies to overcome technical limits in stem cell collection which are in pre-clinical conception include ex vivo induced pluripotent stem cell-derived HPSC expansion or in vivo targeting of HPSCs for gene editing (65, 66). While both would eliminate the need for extensive cell collection, even if developed, ex vivo manufacturing of cellular products will likely require specialized lab equipment, personnel, and expertise, and in some cases, proprietorship.

Myeloablative conditioning approaches with busulfan are preferentially used in allogeneic HSCT and gene modification therapies to achieve optimal engraftment (45–48). However, stable partial donor engraftment after allogeneic HSCT is sufficient to achieve disease amelioration (67–69). Therefore, reduced toxicity and nonmyeloablative conditioning regimens for allogeneic HSCT are of high research interest and, if successful, could have broad global applicability (50–53, 70–71). Current regimens require optimization before use should become widespread. With nonmyeloablative conditioning, the higher risk of graft rejection due to low donor engraftment must be mitigated. Low donor engraftment has also been associated with higher risk for myeloid malignancies after both allogeneic HSCT and lentivirus vector beta globin gene insertion therapy (72, 73).

Other conditioning regimens for use in LMICs are under investigation. For gene modification therapies, single dose melphalan may be less toxic and more broadly applicable as it could be administered in the outpatient setting. More information is required regarding optimal dosing strategies to achieve sustained and effective engraftment after melphalan conditioning (74). Non-chemotherapy preparative approaches using selective antibody and antibody-drug-conjugates targeting hematopoietic stem cells may be ideal especially in resource-limited settings as these preserve blood counts and immunity (75). The feasibility of these single agents is currently limited by host immune competence and interference from extensive marrow inflammation and stress hematopoiesis in SCD (76). Combining these agents with low dose irradiation and/or chemotherapeutic agents may increase potency and improve durable engraftment, but radiation therapy is a particularly limited resource in LMICs.

Conclusion

The need for cellular-based therapies with curative intent for SCD is high worldwide and especially in LMICs in SSA. Currently, broad access is limited by cost, personnel, and availability of HSCT-specific technologies and supportive care. Although gene modification therapies hold great promise by side-stepping some challenges of HSCT, these therapies are in development and currently limited in resource-rich countries by research status, proprietorship, and high cost. Despite many challenges outlined, HSCT for SCD is moving forward in LMICs in SSA. Heightened awareness of the need has spurred efforts to overcome these limitations and explore future global application. While there are many successes to celebrate with cellular therapies for SCD, focus on thoughtful modifications of current and future therapies to meet the need in LMICs, especially in SSA, will be most impactful and should be a priority.

Key Points.

• Expanding cellular therapies for sickle cell disease in low- and middle-income countries will require investments in infrastructure, health systems, and human resources.

• Several countries in Africa with high burden of sickle cell disease have recently opened transplant programs for sickle disease, thereby reducing cost for patients and improving post-transplant care over out-of-country procedures.

• High costs, proprietorship, and infrastructural challenges are among the challenges that will need to be addressed before promising gene modification therapies are feasible in low- and middle-income countries.

• Conditioning approaches and stem cell collection and manufacturing techniques for hematopoietic stem cell transplantation will need adjustment to accommodate low-resource countries.