The Changing Landscape of Opportunity for Cure of Severe Hemoglobinopathies in Middle-Income Regions

Abstract

Thalassemia and sickle cell disease remain the most common life-threatening non-communicable diseases in children worldwide and an increasing burden on affected families and health services. Significant progress has been made in terms of technologies to improve access to a cure by both allogeneic and autologous gene-modified hematopoietic stem cell transplantation (HSCT). However, the high cost of cutting-edge treatments often places them beyond the reach of individual families or even national healthcare systems. Advances in frugal innovation and simplified HSCT procedures for low-risk transplants have significantly reduced the costs and complexities associated with HSCT without compromising on quality and outcomes. Because of the geographical distribution of hemoglobinopathies, i.e., largely in low- and middle-income countries (LMICs), HSCT cost optimization has the potential to impact a huge number of patients, increasing hope for a cure and health-related quality of life normalization, which in turn may affect supportive care compliance. Furthermore, because of the high burden of disease, LMIC transplant centers are rapidly increasing in number and developing unique expertise for the cure of thalassemia and sickle cell disease, particularly in India, where the Sankalp India Foundation with the support of DKMS and Cure2Children has implemented several cost-conscious transplant services. In fact, the very high success rate, increasing cost-effectiveness of transplantation, as well as the chronic nature of these conditions make them ideal initial candidates for start-up transplant centers, so it is likely that the global capacity for a cure for severe hemoglobinopathies will substantially increase in the years to come.

1. Introduction

Cutting-edge clinical research improving the outcomes, safety, and tolerability of treatments should ideally progress in parallel with innovations, increasing their affordability and accessibility. Patients with severe hemoglobinopathies are benefiting from both.

Curative therapies such as hematopoietic stem cell transplantation (HSCT) and, more recently, gene-modifying therapies have shifted the paradigm for treating hemoglobinopathies. HSCT has long been a beacon of hope, offering the possibility of a cure for patients with compatible donors [1,2,3,4,5,6]. Advances in reduced-toxicity conditioning regimens and haploidentical transplantation have made this option more feasible for a broader population [7,8,9,10,11,12].

Gene therapy, however, marks a true revolution. Techniques like gene addition using lentiviral vectors [13] and genome editing via CRISPR/Cas9 [14] have shown promise in clinical trials, with patients achieving transfusion independence and relief from severe symptoms. These therapies are transformative, but they come with steep costs and complex implementation challenges, especially in low- and middle-income countries (LMICs).

Conventional allogeneic stem cell transplantation has also substantially improved over the years, to the point where severe graft versus host disease, the main reason for which gene therapy could be preferable, has become a rare event as has transplant-related mortality, at least for the 30–40% of cases who have a fully matched related donor in middle-income regions. In fact, the latter group is generally not considered eligible for gene therapy since the results are very good with conventional transplantation.

2. Middle-Income Regions: Bridging the Gap

Thalassemia and sickle cell disease are the most common life-threatening non-communicable diseases of childhood globally [15,16]. These conditions place a disproportionate burden on middle-income regions, where resources are often insufficient to manage their lifelong medical and social implications. However, the landscape of treatment and cure is undergoing a remarkable transformation, driven by advancements in medical technology and an evolving focus on global health equity.

HSCT has been performed for the cure of severe hemoglobinopathies disease for over four decades [1,17]; during this time, the cumulative experience of thousands of transplants has allowed us to gradually shave off layers of complexity associated with the original procedures, which were driven by common sense rather than evidence, which not always withstood the test of time.

Frugal innovation approaches capitalize on cumulative knowledge to simplify procedures without compromising on quality or outcomes [18]. A field in which this is true is HSCT, where there are several examples of this, from laminar airflow rooms to gut decontamination, which have been abandoned almost universally. These experience-driven simplifications have gradually reduced the cost of HSCT, to the point that a matched-related transplant can currently be performed, for example, in India, for a cost in the range of USD 10,000 to 15,000, with outcomes on par with the international standards [19,20]. These figures, however, may not be generalized to other regions not benefiting from local drug production or competition among laboratories with high-quality standards.

HSCT in LMICs is increasingly justified medically, ethically, and financially given the substantial reduced life expectancy of children with hemoglobinopathies in these regions [21,22] and the high cost of supportive care [23,24].

Buccal swab-based HLA-typing technology has greatly facilitated centralized compatibility testing so that patients can easily be typed worldwide and referred to HSCT centers.

The realistic prospect of a definitive cure also improved compliance with supportive care and engages families in cascade screening and prevention programs, e.g., most mothers of thalassemic children are likely to accept the offer of free prenatal diagnosis for subsequent pregnancies (personal observation).

The spectrum of HSCT indications and procedures differ between the West and East [25]: in North America and Europe, hematological malignancies are the most frequent indication, and unrelated donors are often employed because of the small average family size. In the Middle East and Asia, non-malignant disorders, e.g., hemoglobinopathies and aplastic anemia, tend to be the most common indications, and matched related donors are more frequently available [26,27,28]. Moreover, in addition to financial and logistic issues, the limited use of unrelated volunteer donors in the East is also due to the fact that non-malignant disorders require stringent HLA matching, and non-Caucasian ethnicities are generally underrepresented in donor registries [29]. Lastly, results using partially matched family doors for so-called haploidentical transplantation, typically the mother or father, are increasingly encouraging [11] and have the potential to extend donor availability to virtually all patients.

There is no evidence that, at least for low-risk matched-related HSCTs, the outcomes are substantially different in high-income countries compared to LMICs. Gliebel et al. assessed the impact of the Human Development Index (HDI) on HSCT results in adults with acute leukemia and found that transplantations performed in countries with an upper HDI were associated with improved leukemia-free survival; this, however, was not due to higher transplant-related mortality but rather to higher relapse rates in LMICs, suggesting that the survival differences were probably related to patient selection and residual disease assessment rather than the HSCT procedure itself [30], and thus may not apply to non-malignant disorders.

However, middle-income regions face unique challenges in leveraging these advancements. Despite having greater resources than low-income countries, they often lack the infrastructure needed for advanced therapies, consistent supply chains, and well-trained healthcare professionals.

3. Innovative Financing and Collaboration

Addressing the financial barriers to curative therapies requires innovative solutions. Public–private partnerships, and support from international organizations, can play critical roles. Global health initiatives such as the DKMS Access To Transplantation program and collaborations with other NGOs like the Cure2Children Foundation or governmental bodies like the Coal India Thalassemia Bal Sewa Yojana program [31] have been quite successful in reducing costs and expanding opportunities for cure directly in settings with limited resources [12,32,33].

Information and communication technologies are already having a major impact on improving quality and reducing cost, so online collaboration tools are allowing access to condition-specific expertise which would otherwise be unavailable or unaffordable [34,35].

Because of large patient loads, there is great potential for building unique capacity on specific diseases curable by HSCT, for example, the Indian subcontinent has at least 100 times the incidence of thalassemia compared to the West, and many cases have a compatible sibling donor due to, on average, larger family sizes. As a result, many more transplants for young thalassemic children with a compatible donor are currently carried out in LMICs compared to Europe or North America [36]. However, to take advantage of this opportunity, increasing efforts are needed to focus on quality assurance platforms [34] and outcome-reporting programs, such as the FACT/JACIE international accreditation system [37], as a means for reassuring national and international patients, patient advocates, insurances, and other sponsoring bodies. It seems reasonable to assume that if quality standards are assured, expertise is higher, and costs are much lower, there might be the potential for patient attraction.

4. The Cure of Severe Hemoglobinopathies as a Capacity-Building Opportunity

Counterintuitive as it may initially appear, HSCT may actually be the best option for many patients with thalassemia in developing countries: it is a one-time procedure not depending on long-term access to appropriate medical care and at the same time greatly improves quality of life for both patients and families by decreasing medical, psychological, and financial burdens [38,39].

HSCT for thalassemia offers several advantages for start-up centers in LMICs: (a) it is the least expensive and simplest form of allogeneic HSCT with relatively basic technology requirements; (b) dealing with a chronic disease provides us with enough time to adequately prepare patients in order to maximize initial success rates; (c) the affected families have high commitment and compliance rates; (d) children generally enjoy high cure rates and excellent HRQoL; (e) there is high cost-effectiveness; and (f) there is the potential for leading expertise and patient attraction.

The opportunity to cure hemoglobinopathies is no longer a distant dream but rather a tangible reality. For middle-income regions, the challenge lies in transforming this potential into equitable and sustainable access. Governments, global health organizations, and pharmaceutical companies must collaborate to develop policies that balance affordability, scalability, and innovation.

As prevention programs and access to curative therapies improve, the burden of severe hemoglobinopathies in LMICs can be alleviated. These advances not only offer hope to millions of patients but also underscore the transformative power of science and global cooperation in addressing complex health disparities.

By embracing this moment of opportunity, middle-income countries can pave the way for a healthier and more equitable future, turning the tide against hemoglobinopathies and setting an example for addressing other genetic disorders worldwide.

5. Conclusions and Future Directions

HSCT for severe hemoglobinopathies should no longer be perceived as highly risky, unrealistic, or unaffordable. This paradigm shift is justified by substantial cumulative experience in middle-income regions where the bulk of disease burden lies. Costs and transplant unit complexities providing children with fully matched related donors have drastically reduced in parallel with improved long-term outcomes. HSCT can save the lives of many children while being a great opportunity to strengthen healthcare. In fact, the very high success rate, increasing cost-effectiveness of transplantation, as well as the chronic nature of these conditions make them ideal initial candidates for start-up transplant centers, so it is likely that the global capacity for a cure for severe hemoglobinopathies will substantially increase in the years to come. In the future, artificial intelligence may assist in HSCT decision algorithms as well as in simplifying and improving access to gene therapy.