Conducting hematopoietic stem cell transplantation in low and middle income countries

ABSTRACT Background Hematopoietic stem cell transplantation (HSCT) is a well-recognized therapeutic procedure; costs limit its widespread use in low and middle income countries (LMIC). Methods Over a 30-year period, we have conducted HSCT in LMIC, making adaptations to the conventional procedures conducted in high-income countries (HIC). Results These salient observations stem from our practice: (1) Start with autologous transplantations in patients with hematological malignancies, specifically multiple myeloma; cell freezing devices are not necessary. (2) Next, consider auto-HSCT in patients with autoimmune diseases. (3) Introduce allogeneic transplants, initially using reduced intensity conditioning regimens. Conducting the HSCT on an outpatient basis is cheaper and safer. (4) Do not build HEPA-filtered rooms nor laminar flow cabins. (5) Do not graft cord blood cells nor start a cord blood blank. (6) Engage in haploidentical transplantations which are more feasible and cost-effective. (7) Matched unrelated donors are extremely expensive. (8) Use generic drugs and biosimilars. (9) Blood product irradiation devices are not necessary. (10) Do not try to reproduce other HSCT programs from HIC; develop your own methods. Conclusions HSCT can be conducted in LMIC with reduced costs and similar efficacy, thus making this therapeutic option affordable for more persons.

Hematopoietic stem cell transplantation (HSCT) is a therapeutic procedure that cannot be overlooked in the modern practice of medicine; it is a highly complex, costly procedure for patients with oncologic, hematologic, genetic, and immunologic diseases. Moreover, timely diagnoses, appropriate therapy for primary diseases, and supportive care are not universally available. Up to now, HSCT has also been very expensive and, as a result, the number of HSCTs in low and middle income countries (LMIC) is well below that of high-income countries (HIC) [1]. Demographics and socioeconomic status, as well as donor availability and the type of health care systems, are important factors that influence access to and outcomes following HSCT. Significant trends detected in Latin America include rising numbers of the procedures reported, a faster increase in allogeneic HCT compared with autologous HCT, and a significant increase in family mismatched/haploidentical donors and there is data indicating that, in México, only 5% of persons needing an HSCT finally get one [2]. Several efforts have been done to make HSCT accessible to patients living in LMIC, which can be grouped as reproducing methods already developed in HIC [3] and/or developing HSCT methods adapted to the limitations of the practice of medicine in LMIC. Convinced that the latter is more adequate for developing economies, in the past 30 years the Mexican HSCT group has been dedicated to developing HSCT methods different from those started in HIC, with the main goal of making HSCT more accessible for persons living in LMIC. As a result of the experience gained in these 30 years, the Mexican decalogue recommendations to start an HSCT program in low and middle income countries are: (1) Start with autologous transplantations, specifically in patients with hematological malignancies, in particular for multiple myeloma or lymphoma [4,5]. Autologous HSCT can be done in the outpatient setting using non-frozen hematopoietic stem cells (HSCs) [5]. You can start autografting patients with multiple myeloma, lymphoma, or other hematological malignancies by using preparative regimens that do not require freezing the HSCs. The use of short preparative regimens for autologous HSCT, such as high dose melphalan for patients with multiple myeloma or lymphoma [6], allows for keeping HSCs in a conventional blood bank at 4 degrees for up to seven days [7]. Therefore, it is not necessary to have cell freezing capability to start a BMT program in underprivileged circumstances. The use of conditioning regimens that do not include drugs difficult to obtain is recommended [6]. Cell freezing devices may be necessary to employ other conditioning regimens, to store cells for future procedures, or for other purposes which can be pursued or accomplished later on, but it is clear that buying a cell freezer before starting an HSCT program is not necessary. Conducting auto-transplants on an outpatient basis is cheaper and safer [4][5][6][7]. (2) Proceed to autologous transplantation in patients with autoimmune diseases. Doing autologous transplantation in patients with autoimmune conditions, most of them not previously exposed to chemotherapy is relatively simple and can also be done on an outpatient basis [7]. Current data indicate that of all the autoimmune conditions, the best results are obtained in persons with multiple sclerosis (MS). In the Mexican experience with 1277 MS patients autografted on an outpatient basis, 80% achieve a response after 18 months of receiving the autotransplant with cyclophosphamide 200 mg/kg and rituximab 1000 mg: 40% improved their neurological condition, whereas 40% achieved stabilization [8,9]; in this group, only two fatalities have been recorded, thus highlighting the low morbimortality of the procedure. Other autoimmune diseases such as systemic sclerosis, systemic lupus erythematosus, Sjögreńs syndrome, and autoimmune type 1 diabetes can also benefit from auto-HSCT after immunoablative chemotherapy. This is an important clinical option in the setting of not having access to newer and expensive immunosuppressors. (3) Move into allogeneic stem cell transplants after gaining expertise with autografting is a uniform recommendation in Mexico and Brazil. Conducting allotransplants in an outpatient basis must be carefully evaluated because it may be cheaper and safer in centers already experienced with this strategy, with even fewer clinical complications [10,11]. In allogeneic transplantation, the Mexican group has shown that the long-term overall survival and the prevalence and severity of graft versus host disease (GVHD) are improved in those patients allografted outside the hospital compared with inpatients and that the long-term overall survival of persons grafted as outpatients is better than those grafted in the hospital [10][11][12], despite the use of the fact that peripheral blood HSCs are used. Doing allogeneic HSCTs on an outpatient basis is only feasible if reduced intensity conditioning regimens are used, therefore not appropriate for all patients, especially pediatric patients that have much better outcomes when using myeloablative preparative regimens. In Mexico, allogenic HSCTs done with reduced intensity conditioning and on an outpatient basis have a reduced prevalence and severity of GVHD and a lower prevalence of C. difficile infections [12]. Although it is now clear that reduced intensity conditioning is not the best choice in all settings, it seems to be cost-effective compared with conventional myeloablative conditioning, a point that is critical to programs organized in underprivileged circumstances.
(4) Inpatient rooms with laminar flow rooms and/or high-efficiency particulate air (Hepa) filters are not necessary. In underprivileged circumstances, it is reasonable to start doing the HSCT on an outpatient basis and to spend more wisely the limited resources on critical aspects of the HSCT program, such as laboratory support, apheresis equipment, antibiotics, and antifungals [1]. Hepa filters and laminar flow cabins are not needed in these settings and many programs have safely worked with portable HEPA filters and vigilant hospital room and restroom hygiene for several years. (5) Do not focus on cord blood cell transplantation or start a cord blood bank In LMICs, setting up a bank or importing cord blood cells is extremely expensive [13]. It was once thought that grafting cord blood cells were the solution for those patients who needed allogeneic transplantation and did not have a matched sibling donor. Cord blood allografts initially flourished and cord blood banks were started in many countries. We did several unrelated cord blood transplants in Mexico with a high rate of graft failure [13]. Imported cord blood products with better cell viability were expensive and became substantially more in the past years after the US National Marrow Donor Program took over the distribution of blood cord cells coming from the rest of the world. Moreover, cord blood grafts have delayed engraftment and immune reconstitution, with a high number of viral infections that are usually life threatening in LMICs. (6) Put more efforts in improving haploidentical transplantations, since they are much more realistic in LMICs. Allografting haploidentical HSCs is cheaper and safer than allografting blood cord HSCs, and the long-term outcomes for patients are similar to both approaches. In Mexico, the outcomes of patients who received haploidentical allogeneic transplantation are improved compared with those who received blood cord cells, and the costs are substantially lower for haploidentical HSCT [14,15]. In resource-constrained settings, these differences have made haploidentical HSCT clearly superior to cord blood HSCT in all aspects. Additionally, the use of reduced intensity conditioning regimens and post-transplantation cyclophosphamide allows to do haploidentical HSCT in the outpatient setting [14][15][16]. For patients without an available matched sibling, matched unrelated transplantation diminishes costs compared with blood cord transplantation [14][15][16]. As a result of the development of the haploidentical transplants, cord blood allografts have practically disappeared in LMICs and has been a decline in their use worldwide. Therefore, it seems wiser to devote the resources of an HSCT program to defray other components instead of starting a cord blood bank [1]. (7) Importing matched unrelated donor HSCs is very expensive. The US National Marrow Donor Program has offices in several countries, and they do HLA testing to transplantation recipients for free. However, the cost of importing HLAmatched HSCs from abroad is very high, around US$ 20,000-50,000 per donation. Therefore, the use of haploidentical donors is preferred, as it is substantially more affordable and has similar long-term outcomes for patients [1,15]. (8) Test and employ generic drugs and biosimilars. HSC mobilizing agents are one of the most expensive drugs when conducting an HSCT. In Mexico, a vial of filgrastim is US$ 300, whereas the biosimilar distributed in the country is four times cheaper (US$ 80), with effectiveness equivalence shown [1,16,17]. In the case of plerixafor, half of the recommended dose of the biosimilar is as effective as the full recommended dose of plerixafor to mobilize HSCs [19], and its use results in substantial savings [1,18 (9) Blood product irradiation. After an allogeneic HSCT, blood products given to the recipient are traditionally irradiated to prevent GVHD. Conventional linear accelerators are used in many centers that cannot afford specific devices. The Mexican group has reported doing reduced intensity allogeneic and autologous HSCT for 30 years using unirradiated blood products, only leucocyte depleting filters, achieving a similar GVHD prevalence in patients who received irradiated blood products and those who received leucocyte depleted products [20]; accordingly, it seems that blood irradiation devices are nor strictly necessary. (10) Be creative, systematically collect your data and save your samples for future research. Reproducing in LMIC HSCT programs well stablished in HIC is not always possible, this is the reason why HSCT methods and other healthcare procedures should be adapted to the limitations and realities of each country [21]. Scientists from LMIC training in HIC should consider the mechanisms to adapt their learnings to the conditions of the countries where they eventually will return; those pretending to reproduce methods of other countries may not be successful. Academic relations between scientists in LMIC and HIC are necessary and, if properly conducted, very fruitful for both ends.
Participating actively in multicenter studies and registries is an important strategy to continuously evaluate and improve resultsfor patients worldwide. Critical for the success of an HSCT program in LMIC is strong laboratory support with highresolution HLAs, chimerism studies, flow cytometry, drug levels, etc. It seems that the monies saved following the previous suggestions could be better employed in the development of a strong laboratory to support the HSCT program.

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