Allogeneic Stem Cell Transplantation in Developing Countries

1. Introduction

Currently, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy available for high-risk acute leukemias in developing countries. This therapy is technically complex and costly, posing a clinical and social challenge to balance the limited resources of national public health systems while achieving clinical outcomes similar to those reported by transplant units in developed countries.

The cumulative incidence rate of hematopoietic neoplasms requiring allogeneic transplantation in emerging economies is comparable to that of developed countries. Despite the increasing number of bone marrow transplants in recent years, coverage and access remains significantly lower compared to developed regions. Most hospitals with allogeneic transplant units in developing countries are private and centralized, with very few public hospitals capable of performing allogeneic transplants, further limiting access for the entire population. Similarly, access to cytogenetic and molecular monitoring is not universal, making morphology and flow cytometry our primary diagnostic and follow-up tools, while NGS, qPCR, and chimerism analysis are almost exclusively available to patients in private health systems.

Here, we present our allogeneic transplant protocol in a cost-effective manner for public and private health regimes in emerging economies. After many years of work and analysis, we have achieved procedure-related mortality rates (TRM <15%) and 12-month disease-free survival rates (DFS of 52% in ALL and 65% in AML), slightly lower than those reported by units accredited under the Joint Accreditation Committee ISCT-Europe & EBMT (JACIE).

2. Epidemiology of bone marrow transplant in developing countries

The history of bone marrow transplantation in Latin America began in 1980 at the Federal University Hospital in Curitiba, Brazil [1]. Since then, there has been an increase in the number of programs and certified hospitals for these procedures. According to the Latin America Bone Marrow Transplant group (LABMT), in 2018, 5445 transplants were performed (2196 – 40% allogeneic and 3249–60% autologous), reported by 127 transplant units in 14 Latin American countries [2].

Despite this, the transplant rate (number of transplants per 10 million inhabitants per year) in Colombia and Latin America is 8 to 10 times lower than those reported in the United States and Europe. This is evidenced in the latest publication of the Worldwide Network for Blood and Marrow Transplantation (WBMT), which reports 2016 transplant rates of 560.8 for North America, 438.5 in Europe, 76.7 in Latin America, 53.6 in Southeast Asia/Pacific West, and 27.8 in Africa/Mediterranean East [3]. Regarding transplant indications, they vary according to the type of transplant. For allogeneic transplants, the primary indication is acute leukemia, while for autologous transplants, the main indications are multiple myeloma and relapsed high-grade lymphomas [4].

In recent decades, there has been a shift in the proportion of haploidentical transplants worldwide. Particularly in emerging economies, there is an increase in the relative frequency of haploidentical transplants. The Southeast Asia/Pacific West region accounts for 32%, and 26% of haploidentical transplants correspond to Latin America [5]. In contrast, in Europe and the United States, there is an increase in the number of unrelated identical allogeneic transplants compared to emerging economies, explained by the need to import unrelated hematopoietic cells, which is economically unfeasible, limiting this type of transplant for the minority of patients [6]. In Colombia, the bone marrow transplant rate has shown a progressive increase, rising from 75 transplants per 10 million inhabitants in 2017 to 108 in the following year, as reported by the LABMT [5].

3. Advancements in bone marrow transplantation in developing countries

In developing countries, significant improvements have been made in survival rates and hematologic outcomes for patients undergoing related allo-HSCT. Key advancements include better donor selection, enhanced monitoring and stratification of hematologic diseases, improved prophylactic tools for infections and graft-versus-host disease (GVHD), and the formation of dedicated multidisciplinary teams for bone marrow transplantation. These advancements follow the guidelines and management protocols of JACIE-accredited bone marrow units [7] (see Table 1).

Currently, the transplant-related mortality (TRM), relapse rate (R), and disease-free survival (DFS) for related allogeneic transplants in developing countries are comparable to those in non-emerging countries (TRM + R = 1-DFS).

4. Exploration of donor-related variables in developing countries

GVHD is undoubtedly the most significant complication currently associated with allo-HSCT in our region. The best strategy to mitigate GVHD remains the careful selection of the donor prior to transplantation. However, to date, it is necessary to employ multiple additional strategies to attenuate the allo-reactivity of the donor’s T lymphocyte populations, thereby ensuring that GVHD does not become severe [8].

In developing countries, various pharmacological options are available for both prophylaxis and treatment of GVHD, though their effectiveness can vary depending on the stage of the disease, sometimes proving minimally effective. Occasionally, it becomes necessary to use costly medications over extended periods, which poses a financial challenge for our healthcare system.

Reported outcomes for severe acute GVHD in haploidentical transplantation and for histocompatible transplants in benign conditions such as bone marrow aplasia are significantly better when direct marrow collection from the donor is employed compared to peripheral blood stem cell apheresis. This cell collection method is currently used more frequently in children than in adults in developing countries, especially for benign transplant indications [9]. In adult haploidentical transplants and non-neoplastic conditions, direct marrow collection also presents a viable alternative in our region for controlling acute GVHD, and it offers a lower long-term cost for allogeneic bone marrow transplantation (see Table 2).

Hierarchy for donor selection:

1. HLA (9/10–10/10) identical donor, <55 years of age.

2. Haploidentical HLA (5/10–8/10), <55 years of age

   1. Youngest male relative

   2. Females generally not eligible (discussed in medical boards for selected cases)

3. Antibodies anti-HLA absent in haploidentical transplants

4. ABO compatibility

5. CMV serological status

6. KIR ligand compatibility

Nowadays, in emergent countries, allogenic transplants from unrelated donors are almost nonexistent.

5. Receptor, disease, and indications for transplantation in developing countries

Evaluation for potential bone marrow transplant recipients in developing countries includes beyond HLA compatibility studies, assessing the viability of allo-HSCT using internationally validated risk scores. These scores help identify patients who may have a higher risk of transplant-related mortality [11].

Initially, we use the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) published by Sorror et al. [12], which attempts to objectively measure comorbidities and their severity. The comorbidities evaluated by the score include pulmonary function and pathological history (mild, moderate, or severe); cardiac; hepatic (mild, moderate, or severe); renal; infectious; psychiatric conditions; obesity; and a history of previous solid malignant tumors.

Additionally, we use the European Group for Blood and Marrow Transplantation (EBMT) risk score, which provides a score from 0 to 7 to evaluate outcomes and transplant-related mortality. Five factors are assessed: the patient’s age; disease stage; time from diagnosis; donor type; and the correlation between donor and recipient gender. This risk score can be used regardless of the type of transplant, the type of conditioning, and the technology applied to the transplant [13].

Using these risk scores and many other variables related to unfavorable transplant outcomes helps us determine transplant viability and identify high-risk patients who require strict monitoring.

6. Conditioning strategies before allo-HSCT in developing countries

The EBMT and EWALL recommends MAC TBI-based regimens for ALL and selected AML patients, a stance also supported by the American Society for Transplantation and Cellular Therapy [14, 15]. These recommendations are based on large retrospective studies showing that TBI-based regimens significantly improve PFS and OS compared to chemotherapy-only conditioning [16, 17, 18, 19, 20, 21, 22].

We conducted a retrospective study at a single center that analyzed 100 adult patients with ALL who underwent allo-HSCT, using two different TBI-based MAC regimens. No significant differences were found in OS (p = 0.305), DFS (p = 0.23), nor cumulative incidence of relapse (p = 0.32) between the SD-TBI and LD-TBI groups. The risk of aGVHD was lower in patients with SD-TBI, specifically in patients with HLA-Identical donors (RR 0.26 95% CI 0.08–0.82). This suggests that SD-TBI MAC regimens have comparable outcomes to LD-TBI and are associated with a lower incidence of aGVHD.

The EBMT reported significantly reduced NRM at 2 years and improved leukemia-free survival (LFS) with TBI-based conditioning in the setting of haploidentical HSCT with post-transplant cyclophosphamide, although the overall survival benefit was not significant [23]. Other studies have found that fludarabine-TBI reduced NRM compared to thiotepa, busulfan, and fludarabine (TBF), but increased relapse risk without affecting OS or GVHD. This suggest that fludarabine could be a reasonable alternative to cyclophosphamide and/or etoposide in TBI-based MAC [24, 25]. However, some controversy exists regarding the survival advantage of TBI-based conditioning regimens [26]. A randomized study of ALL patients in CR1 receiving either Bu-Cy or TBI-Cy found Bu-Cy to be noninferior, with similar rates of relapse at 2 years and NRM. There were no significant differences in toxicity, GVHD, or late effects between the groups [27]. Thus, multiple conditioning schemes are used today in clinical practice and the ideal regimen prior to allo-HCST in ALL remains controversial. Our results show that high dose Flu-TBI 12 Gy does not significantly differ in outcomes and relapse incidence compared to lower intensity TBI (4 Gy) with Bu-Flu myeloablative chemotherapy regimens.

Globally, the number of allogeneic transplants is increasing, particularly in treating conditions like ALL, where they offer a curative possibility. However, the cost of these procedures, especially in countries with emerging economies, poses a significant challenge for public health systems [28]. MAC has also been reported as one of the major determinants of overall costs for allo-HSCT [29]. Mainly due to its higher complexity, prolonged hospital stay and related complications [30]. Thus, there is critical need for conditioning regimens that are effective, safe, cost-efficient, and feasible to implement in LMICs. TBI-based protocols can be significantly more cost-effective compared to chemotherapy-containing regimens, provided the center is well-equipped with radiotherapy facilities. Additionally, the scarcity of crucial chemotherapy drugs such as busulfan, thiotepa, and treosulfan enhances the appeal of TBI-based regimens for HSCT in LMICs [31]. At our institution, costs are individualized by drug and radiation therapy. Based on unpublished intrainstitutional data, we have observed that costs are reduced when conditioning TBI >12 Gy is used. As high-cost treatments become accessible to more patients, it is crucial not only to evaluate clinical outcomes but also to manage financial costs effectively. Therefore, in LMIC, future cost-effectiveness studies are essential to determine if certain conditioning regimens offer financial advantages over others (Figures 1 and 2).

7. Conclusions

Globally, the number of allo-HSCT procedures is increasing, and although it is considered the only curative therapy for high-risk acute leukemias, its price and technical complexity poses significant challenges for developing countries. Here, we present our allogeneic transplant protocol in a cost-effective manner for public and private health regimes in emerging economies, with outcomes comparable to those reported by units accredited under the Joint Accreditation Committee ISCT-Europe & EBMT (JACIE). There is a critical need for development and future research for cost-effective strategies in these regions.

Author contribution

All authors declare to have contributed to the conception and design of the work, the acquisition, analysis, and interpretation of data for the work; participation in drafting and revising the work; approval of the manuscript version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.